MBF17015415

Textbook of
Hepato-gastroenterology
Textbook of
Hepato-gastroenterology
Editors
Mahmud Hasan Sheikh Mohammad Fazle Akbar

Chairman Principal Investigator
Bangladesh Medical Research Council Department of Medical Sciences
Former Vice Chancellor Toshiba General Hospital, Tokyo, Japan
Bangabandhu Sheikh Mujib Medical University Adjunct Professor
Former Chairman Faculty of Medical Sciences
Department of Gastroenterology State University of Bangladesh
Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh
Dhaka, Bangladesh
Mamun-Al-Mahtab
Associate Professor
Department of Hepatology
Bangabandhu Sheikh Mujib Medical University
Dhaka, Bangladesh
Foreword
Parveen J Kumar
The Health Sciences Publishers

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Textbook of Hepato-gastroenterology
First Edition: 2015
ISBN: 978-93-5152-378-9
Printed at
Dedicated to
Bangabandhu Sheikh Mujibur Rahman

Father of the Nation of the Peoples Republic of Bangladesh
None of us and nothing would have been here, had HE not been there!
CONTRIBUTORS
A Kadir Dokmeci Anil Arora

Professor Chairman
Department of Gastroenterology Department of Gastroenterology and Hepatology
Ankara University School of Medicine Ganga Ram Institute for Postgraduate
Ankara, Turkey Medical Education and Research
Sir Ganga Ram Hospital
New Delhi, India
Abhijit Chowdhury Arun J Sanyal

Professor and Head Professor and Chairman
Department of Hepatology Division of Gastroenterology
School of Digestive and Liver Diseases Hepatology and Nutrition
Institute of Post Graduate Virginia Commonwealth
Medical Education and Research University Medical Center - MCV Campus
Kolkata, West Bengal, India West Hospital, Richmond, USA
Ajay Duseja Ashish Kumar

Assistant Professor Associate Professor and Consultant Hepatologist
Department of Hepatology Department of Gastroenterology and
Post Graduate Institute of Medical Hepatology
Education and Research Ganga Ram Institute for Postgraduate
Chandigarh, India Medical Education and Research
Sir Ganga Ram Hospital, New Delhi, India
Ajesh Goyal AS Soin

Consultant Gastroenterology and Hepatology Chairman and Chief
Tagore Hospital Liver Transplant and Hepatobiliary Surgeon
Jalandhar, Punjab, India Medanta Institute of Liver Diseases and
Transplantation
Medanta- The Medicity
Gurgaon, Haryana, India
Amna Subhan Butt Axel Hsu

Assistant Professor Resident Specialist
Consultant Gastroenterologist Division of Gastroenterology and Hepatology
Department of Medicine Department of Medicine
Aga Khan University Hospital Queen Mary Hospital
Karachi, Pakistan Hong Kong
Andrew Vaillant Cassiano Ribeiro Pires

Vice President, Operations and Chief Scientific Gastroenterologist
Officer, REPLICor Inc. Member of the Medical Staff in Endoscopy Unit
Montreal, Canada of Azevedo, Lima State Hospital
Rio de Janeiro, Brazil
viii Textbook of Hepato-gastroenterology
Christopher A Wadsworth Gourdas Choudhuri

Senior Research Fellow Director and Head
St Marys Hospital Campus Department of Gastroenterology and Hepato-
Imperial College of London biliary Sciences
London, UK Fortis Medical Research Institute
Cihan Yurdaydin Govind K Makharia

Chief, Hepatology Institute Additional Professor
Professor of Gastroenterology Department of Gastroenterology and Human
Department of Gastroenterology Nutrition
University of Ankara Medical School All India institute of Medical Sciences
Ankara, Turkey New Delhi, India
Cristiane Alves Villela-Nogueira Hamama-tul-Bushra Khaar

Associate Professor Professor
Department of the Internal Medicine Department of Medicine
Hepatology Division Rawalpindi Medical College
School of Medicine Gastroenterologist and Hepatologist
Federal University of Rio de Janeiro Holy Family Hospital
Rio de Janeiro, Brazil Rawalpindi, Pakistan
Debashis Misra Hamizah Razlan

Resident Medical Officer cum Clinical Tutor Associate Professor
Division of Gastroenterology Consultant Gastroenterologist
School of Digestive and Liver Diseases Head of Gastroenterology Unit
Institute of Postgraduate Medical Education and Medical Department
Research, Kolkata, West Bengal, India Faculty of Medicine
University Kebangsaan Malaysia
Kuala Lumpur, Malaysia
Fazal Karim Izazul Haque

Associate and Head Assistant Professor and Head
Department of Hepatology Department of Hepatology
Sir Salimullah Medical College Mitford Hospital Comilla Medical College
Dhaka, Bangladesh Comilla, Bangladesh
Furqan Ahmed Javed Yakoob

Consultant Gastroenterologist and Hepatologist Assistant Professor
South City Hospital Department of Medicine
Karachi, Pakistan Aga Khan University
Karachi, Pakistan
GK Dhali Julio Cesar Aguilar

Professor and Head Head of Clinical Trials
School of Digestive and Liver Diseases Vaccine Division
Institute of Postgraduate Medical Department of Biomedical Research
Education and Research Center for Genetic Engineering and
Kolkata, West Bengal, India Biotechnology
Havana, Cuba
Contributors ix
Kaushal Kishor Prasad Mandish K Dhanjal

Additional Professor and Chief Consultant Obstetrician and Gynecologist
Division of GE Histopathology Honorary Senior Lecturer
In-Charge, Division of GE Enzymology Queen Charlottes and Chelsea Hospital
Department of Superspeciality of Imperial College Healthcare NHS Trust
Gastroenterology London, UK
Postgraduate Institute of Medical Education and
Research
Chandigarh, India
Khin Maung Win Mazhar Haque

Head Senior Lecturer, Department of Medicine
Department of Hepatology University of Queensland
Yangon GI and Liver Center Staff specialist Gastroenterologist
Yangon, Myanmar Mater Adult Hospital
Brisbane, Australia
Kshaunish Das Md Delwar Hossain

Associate Professor Head
Division of Gastroenterology Department of Gastroenterology
School of Digestive and Liver Diseases Combined Military Hospital
Institute of Postgraduate Medical Education Dhaka, Bangladesh
and Research
Kolkata, West Bengal, India
Mahesh Gupta Md Rabiul Hossain

Consultant Gastroenterologist Consultant Physician General
Kailash Group of Hospitals Bangladesh Armed Forces
New Delhi, India Dhaka, Bangladesh
Mamun-Al-Mahtab Mian Mashhud Ahmad

Associate Professor Professor and Senior Consultant
Department of Hepatology Department of Gastroenterology
Bangabandhu Sheikh Mujib Medical University LabAid Specialized Hospital
Dhaka, Bangladesh Dhaka, Bangladesh.
Man-Fung Yuen Moiss Copelman

Chairman, Gastroenterology and Hepatology Assistant Professor
and Li Shu Fan Medical Foundation in Medicine Department of Gastroenterology
Assistant Dean, Faculty of Medicine Postgraduate Course in the Medical and
The University of Hong Kong Rehabilitation Brazilian Institute (IBMR)
Chief, Division of Gastroenterology and Member of the Medical Staff
Hepatology Gastroenterology and Endoscopy Unit
Deputy Chief, Service and Honorary Consultant State University of Rio de Janeiro (Uerj)
Department of Medicine, Queen Mary Hospital Residency Supervisor
Hong Kong Digestive Endoscopy Program
Bonsucesso Federal Hospital
Rio de Janeiro, Brazil
x Textbook of Hepato-gastroenterology
Monjur Ahmed Om Parkash

Clinical Associate Professor of Medicine Senior Instructor
Division of Gastroenterology and Hepatology Consultant Gastroenterologist
Thomas Jefferson University Department of Medicine
Philadelphia, USA The Aga Khan University and Hospital
Karachi, Pakistan
Muhammad Umar Paisarn Vejchapipat

Principal Associate Professor and Head
Rawalpindi Medical College Pediatric Surgery Unit
Chief, Allied Hospitals, Rawalpindi Department of Surgery
Chief Gastroenterology and Chulalongkorn Hospital
Hepatology Division Bangkok, Thailand
Holy Family Hospital
Rawalpindi, Pakistan
Murat Saru Parimal Lawate

Professor Consultant Gastroenterologist
Department of Gastroenterology Department of Gastroenterology and
Acibadem University School of Medicine Endoscopy
Istanbul, Turkey Jehangir Hospital
Pune, Maharashtra, India
Mustafa Yakut P Karayiannis

Professor Professor
Department of Gastroenterology Department of Microbiology
Ankara University School of Medicine and Molecular Virology
Ankara, Turkey St Georges University of London
Medical School at University of Nicosia
Nicosia, Cypsus
Narendra Choudhary Premashis Kar

Consultant Hepatologist Director and Professor of Medicine
Medanta institute of Liver Transplantation and and Gastroenterologist
Regenerative Medicine Department of Medicine
Medanta- The Medicity Maulana Azad Medical College
Gurgaon, Haryana, India University of Delhi
New Delhi, India
Natalia Balbi Flores Punit Singla

Gastroenterologist Associate Consultant
Member of the Medical Staff in Endoscopy Unit Liver Transplant and Gastrointestinal Surgeon
of Getulio Vargas State Hospital Medanta Institute of Liver Diseases and
Rio de Janeiro, Brazil Transplantation
Nurdan Tzn Rakesh Kochhar

Prefessor Professor
Department of Gastroenterology Department of Superspeciality of
Acibadem University Gastroenterology
Acibadem Kozyatagi Hospital Postgraduate Institute of Medical Education and
Istanbul, Turkey Research, Chandigarh, India
Contributors xi
Ramazan Idilman Sachin Gupta

Professor in Medicine Assistant Professor
Department of Gastroenterology Department of Gastroenterology
Ankara University Faculty of Medicine Laxmi Narayan Medical College and Hospital
Ankara, Turkey Bhopal, Madhya Pradesh, India
Ravi Mohanka Saeed Hamid

Senior Consultant The Ibn-e-Sina Chair and Professor
Hepatobiliary and Multiorgan Transplant Consultant Gastroenterologist
Surgeon Department of Medicine
Medanta Institute of Liver Diseases and The Aga Khan University and Hospital
Transplantation Karachi, Pakistan
Roger W Chapman Salimur Rahman

Consultant Hepatologist Professor
John Radcliffe Hospital Department of Hepatology
Oxford University Hospitals Bangabandhu Sheikh Mujib Medical University
Oxford, UK Dhaka, Bangladesh
Rosmawati Mohamed Sanjay Govil

Consultant Hepatologist Senior Consultant
Department of Medicine HPB Surgery and Liver Transplantation
Faculty of Medicine Global Health City
University Malaya Chennai, Tamil Nadu, India
Kuala Lumpur, Malaysia
SM Wasim Jafri Saroj Kant Sinha

Ali Charan Professor of Medicine Additional Professor
(Gastroenterology) Department of Superspeciality of
Associate Dean Gastroenterology
Chairman, Department of Continuing Postgraduate Institute of Medical
Professional Education Education and Research
Aga Khan University Chandigarh, India
Karachi, Pakistan
Sabyasachi Ray Shahab Abid

Consultant Gastroenterologist Professor and Head
Peerless Hospital Section of Gastroenterology
Kolkata, West Bengal, India Department of Medicine
Aga Khan University
Karachi, Pakistan
xii Textbook of Hepato-gastroenterology
Shahid A Khan Taranjeet S Jolly

Senior Lecturer in Hepatology and Resident
Consultant Physician St Joseph Mercy Health System
St Marys Hospital Campus Livonia, USA
Imperial College of London
London, UK
Sheikh Mohammad Fazle Akbar Uday C Ghoshal

Principal Investigator Professor
Department of Medical Sciences Department of Gastroenterology
Toshiba General Hospital, Tokyo, Japan Sanjay Gandhi Postgraduate Institute
Adjunct Professor Lucknow, Uttar Pradesh, India
Faculty of Medical Sciences
State University of Bangladesh
Dhaka, Bangladesh
Shelley Haynes Vikas Singla

Consultant Obstetrician and Gynecologist Senior Resident
Southampon General Hospital All India Institute of Medical Sciences
Southampton, UK New Delhi, India
Shivaram Prasad Singh Voranush Chongsrisawat

Head Associate Professor
Department of Gastroenterology Department of Pediatrics
SCB Medical College Faculty of Medicine, Chulalongkorn University
Cuttack, Odisha, India Bangkok, Thailand
Simon D Taylor-Robinson YK Chawla
Professor of Translational Medicine Director
Clinical Dean, Faculty of Medicine Postgraduate Institute of Medial Education and
Department of Medicine Research
St Marys Hospital Campus Chandigarh, India
Imperial College London
London, UK
Sittisak Honsawek Yong Poovorawan

Professor Professor
Department of Biochemistry Center of Excellence in Clinical Virology
Faculty of Medicine Faculty of Medicine, Chulalongkorn University
Chulalongkorn Hospital Bangkok, Thailand
Bangkok, Thailand
Sony Sebastian Thazhath Zaigham Abbas

PhD Research Fellow Head
Discipline of Medicine Department of Hepatogastroenterology
University of Adelaide Sindh Institute of Urology and Transplantation
Adelaide, Australia Karachi, Pakistan
Sujay Ray Ziauddin Ahmed

Associate Professor Professor of Medicine
Division of Gastroenterology Drexel University College of Medicine
School of Digestive and Liver Disease Philadelphia, USA
Institute of Postgraduate Medical Education and
Research and SSKM Hospital
Kolkata, West Bengal, India
F or e w or d
It gives me great pleasure to write this Foreword. It takes great courage to embark on producing
a new textbook and tremendous hard work to fulfill this aim. It is a daunting task, and there
is absolutely no doubt that editing and authoring a new textbook is not for the faint-hearted
person. The idea has to be converted into practice. The design and format, listing appropriate
topics, searching for suitable authors, and producing guidelines and instructions for these
authors, and finally, when the chapters are written, there is the horrendous and daunting
task of editing! So why do it? Well, there are several reasons for wanting to take on this task,
but one of the most compelling ones is whether there is a need for such a textbook. The
editors have succeeded in this, as this new textbook has definitely filled a necessary gap.
Gastroenterology and hepatology are, relatively, new specialties despite the fact that the
diseases of these fields are highly prevalent in all populations throughout the world. There is a need for experts to tackle
the morbidity and mortality from these diseases. Alongside this, the changes in the practice of medicine are moving
rapidly with new therapies and novel surgical procedures. This requires all of us in the field to keep up-to-date with the
latest changes.
The book is divided into 46 chapters. The first half of the book deals with the diseases of esophagus, stomach, and
small and large intestines. The anatomy, pathophysiology, clinical presentation, and management are all covered in a
detailed and fairly consistent fashion. The second half of the book is devoted to liver disease. This starts with a chapter
on immunology giving the readers the facts that can be utilized for understanding disorders described later in the
book. There are useful chapters on viral hepatitis but also one covering coinfection with more than one virus. I was also
delighted to see a chapter on hepatitis virus control in developing countries, which is extremely practical and useful.
Some of the chapters cover highly specialized areas, such as liver disease in pregnancy, an often neglected topic. All
chapters describe the latest therapies and are also well referenced.
The book emanates from a team based in Bangladesh and Japan. The three editors are all distinguished and
experienced physicians. The contributors are mainly Asians, based also in Asia, and have practical knowledge of the
diseases in the local setting. Some of the contributors come from the west and Far-East giving the book an international
flavor. However, with the current rapidity of travel and transmission of diseases across a fast-dwindling distance, diseases
are much the same across the world, although they may differ in the numbers encountered in different countries.
The editors should be congratulated for having produced a new textbook on gastroenterological and liver disorders. It
would be a very useful textbook for trainees as well as for the practicing experienced gastroenterologists and hepatologists
to keep updated. I enjoyed reading it!
Parveen J Kumar cbe

Professor of Medicine and Education
Honorary Consultant Physician and Gastroenterologist
Barts and the London School of Medicine and Dentistry
Queen Mary, University of London UK
PREFACE
Diseases of the digestive system are common all over the world, more so in the developing countries, because of the
extra burden of infection with diverse organisms in all parts of the system. They present a challenge to the clinicians
specializing in this field and make the specialty more interesting. Since the early seventies of the last century, advances in
technology have enabled physicians to look into the hollow organs, initially via fiberoptic and later by videoendoscopy.
This has not only improved the accuracy of diagnosis of diseases but also has enabled clinicians to perform therapeutic
procedures previously undertaken at surgery. Advances in modalities of imaging by radiology, ultrasound and magnetic
resonance have extended the reach further.
Advances in technology continue in a manner that defies prediction. Specialists have a difficult task keeping
themselves up-to-date with the progress. It has become even more time-consuming to acquire the newer skills. In fact,
things have come to such a point that one can only acquire the necessary skills and experiences in a particular area.
Specialization in therapeutic endoscopy, endosonography, etc. has become inevitable. This trend is likely to continue.
The field has already been divided into various sectors depending on organ, such as liver, pancreas, colorectum.
Despite this state of affairs, training in the basics of digestive diseases remains mandatory for all aspiring specialists.
Furthermore, only a fraction of all patients are seen by the specialists, the vast majority being dealt with by general
physicians or general surgeons. These categories of doctors need to be aware of newer methods of diagnosis or treatment
available, even if they are not involved in its delivery.
Bearing all this in mind, the task of preparing a textbook on diseases of the liver and digestive system, which can cater
to the needs of all categories of doctors involved in the care of patients with diseases of these systems, has indeed become
difficult. The burden has been shared by many contributors, themselves reputable on their own right. Some degree of
duplication has been unavoidable despite the care taken to avoid this. We express our gratitude to all the contributors.
Among us, Mamun-Al-Mahtab has been the guiding spirit in all this, encouraging the contributors and urging them to
come up with their part of the book. He deserves all the appreciation for the success of this endeavor.
Many would argue that the need for another textbook on this subject is not clear. Yet, the fact remains that almost all
textbooks originate in the developed countries. The practice of this specialty in developing countries varies for a number
of reasons.
Firstly, the spectrum of diseases are different. Diseases of infection are still quite prevalent in many parts of the developing
world. Moreover, a number of diseases occur in developing countries which are only rarely, if ever, seen in the Western
world. One can cite the examples of tropical calcific pancreatitis and veno-occlusive disease of liver, among others.
Secondly, the paucity of diagnostic and therapeutic modalities makes the clinical approach to a patient somewhat
different in developing countries.
Thirdly, access to Western textbooks is limited in many areas of the developing world. The contributors have kept
these things in mind while preparing their part of the book.
The book is intended to the specialists and the general physicians to update their knowledge in this field and also to
the trainees to learn the stock of the trade. Our effort will be worthwhile if they find what they are looking for in this book.
It is, however, advisable to supplement the information from current journals, as the time frame of preparation of any
textbook of this kind does not allow for inclusion for the most recent advances.
The publishers have been very kind and supportive in their endeavors as they have to bear a great part of the burden
of collecting, coordinating and finalizing the manuscripts. No amount of thanks will do them justice.
Mahmud Hasan
Sheikh Mohammad Fazle Akbar
Mamun-Al-Mahtab
ac k no w l e d g m e nts
We extend our heartfelt thanks to our families, who sacrificed their share of our time allowing us to divert our attention
for this book.
We acknowledge all our contributors, who are global leaders in their respective fields and despite being so busy,
devoted their valuable time to contribute chapters to this book.
We also acknowledge Mr. Helal Uddin, who helped us with invaluable, but voluntary, secretarial support.
We thank our publisher Jaypee Brothers Medical Publishers (P) Ltd The Health Sciences Publishers for believing
in us.
Finally, we thank all the readers of this book for encouraging us by accepting our book.
CONTENTS
Chapter 1: Gastroesophageal Reflux Disease 1

Sujay Ray, Kshaunish Das, GK Dhali
Denition1; Epidemiology1; Pathogenesis4; Diagnosis5; Management8
Chapter 2: Carcinoma of Esophagus 17

Md Rabiul Hossain, Md Delwar Hossain
Epidemiology 17; Risk Factors 17; Biology and Genetics 18;
Clinical Presentation18; Complications19; Prognostic Factors19;
Investigations20; Treatment21; Prognosis23
Chapter 3: Peptic Ulcer Disease 25

Javed Yakoob, SM Wasim Jafri
Clinical Features25; Etiology26; Risk Factors27; Differential Diagnosis28;
Diagnosis29; Treatment29
Chapter 4: Peptic Ulcer Disease in AsiaPacific 31

Sony Sebastian Thazhath, Mazhar Haque
Prevalence31; Risk Factors31; Helicobacter pylori and Peptic Ulcer Disease in
Asia32; Nsaids and Peptic Ulcer Disease in the East 32; Racial and Regional
Differences in Peptic Ulcer Disease 32; Management of Peptic Ulcer Disease 32;
Management of Peptic Ulcer Bleed 33
Chapter 5: Functional Dyspepsia 35

Shahab Abid, SM Wasim Jafri
Rome Criteria for Functional Dyspepsia 35; Epidemiology 36;
Physiological Dysfunctions in Functional Dyspepsia 36;Symptoms and
Pathophysiological Mechanism-based Categorization of Functional Dyspepsia 37;
Etiologic Factors Associated with Functional Dyspepsia 38; Management 38;
Functional Dyspepsia and Quality of Life 41
Chapter 6: Gastric Cancer 43

Mian Mashhud Ahmad, Mamun-Al-Mahtab
Etiology 43; Pathology and Molecular Pathogenesis of Gastric Cancer 45;
Histologic Appearance 46; Clinical Features, Diagnosis, and
Staging of Gastric Cancer 47; Diagnosis 48; Treatment 51;
Further Research 57; Early Gastric Cancer 57
xx Textbook of Hepato-gastroenterology
Chapter 7: Malabsorption Disorders 61

Axel Hsu, Man-Fung Yuen
Epidemiology61; Pathophysiology61; Clinical Features62;
Differential Diagnoses 63; Diagnostic Workup 63; Management Plan 66
Chapter 8: Abdominal Tuberculosis 68

Zaigham Abbas
Risk Factors 68;Sites of Involvement 68; Pathogenesis 68;
Clinical Features71; Investigations71; Differential Diagnosis75;
Management75
Chapter 9: Inflammatory Bowel Disease 77

Vikas Singla, Govind K Makharia
Epidemiology77; Pathogenesis77; Extraintestinal Manifestations 81;
Diagnostic Criteria 81; Evaluation of Patients 82; Investigations for the
Diagnosis and Extent of the Disease 82; Assessment of the Activity of the
Disease 84; Assessment for the Extent of the Disease 85; Differential Diagnosis 85;
Natural History 86; Management 86; Fertility and Pregnancy 91;
Breastfeeding 92; Nutrition in Inflammatory Bowel Disease 92
Chapter 10: Irritable Bowel Syndrome 94

Monjur Ahmed
Pathophysiology94; Clinical Manifestations95; Physical Examination96;
Diagnostic Testing96; Differential Diagnosis97; Management97
Chapter 11: Colorectal Carcinoma 101

Kaushal Kishor Prasad, Saroj Kant Sinha, Rakesh Kochhar
Epidemiological Trends in Asia 101; Incidence of Colorectal Carcinoma in Asia 101;
Distribution According to Age and Sex 102; Right Shift in the Position of Colorectal
Cancer Lesions 103; Mortality Rate for Colorectal Cancer in Asia 103; Colorectal
Polypoid and Nonpolypoid Adenoma 103; Pathophysiology of Colorectal
Carcinoma 104; Molecular Biology: is it Different in Asians? 105; Inherited
Susceptibility to Colorectal Carcinoma 106; Molecular Genetics of Sporadic
Colorectal Carcinoma 108; Risk Factors 109; Clinical Features and
Diagnosis112; Management113; Treatment115
Chapter 12: Gastrointestinal Lymphomas 121

Moiss Copelman, Natalia Balbi Flores, Cassiano Ribeiro Pires
Gastric Lymphomas 121;Small Intestinal Lymphomas 125; Others Sites 128
Chapter 13: Gastrointestinal Stromal Tumor 132

Histogenesis132; Epidemiology132; Clinical Features132; Imaging133;

Histology133; Immunohistochemistry133; Cytogenetics133; Kit-Negative
Contents xxi
Gists and Their Associations 134; Prognostic Value of Genetic Aberrations 134;
Risk Stratification 135; Treatment of Gastrointestinal Stromal Tumors 135
Chapter 14: Acute Diarrheal Diseases 138

Sabyasachi Ray
Definition138; Epidemiology138; Etiology138; Mechanisms139;
Bacteria140; Virus141; Parasites141; Prevention142; Management142
Chapter 15: Liver Immunology 145

Julio Csar Aguilar
Main Liver Cellular Types Related to the Immune Response 145; Biology of the
Liver Immune Response 147; Liver T-Cell Response and Potentialities for
Immunomodulating Vaccines 148; Toll-like Receptors and Innate Immunity
Activation within the Liver 149; Immunoprivileged Status of the Liver,
Toll-Like Receptors, and Immunomanipulations 150
Chapter 16: Inborn Errors of Bilirubin Metabolism 153

Cristiane Alves Villela-Nogueira
Clinical Approach to A Patient with Hyperbilirubinemia 153
Chapter 17: Hepatitis A and E Viruses 157

P Karayiannis
Hepatitis A Virus 157; Hepatitis E Virus 160
Chapter 18: Hepatitis B Virus 164

Narendra Choudhary, Ajay Duseja
Molecular Biology of the Hepatitis B Virus 164; Various Antigens and Antibodies of
Hepatitis B Virus 165; Genotypes of Hepatitis B Virus 165; Modes of Hepatitis B
Virus Transmission 165; Disease Manifestations of Hepatitis B Virus 165;
Pregnancy and Hepatitis B 172; Hepatitis B Virus and Hepatocellular Carcinoma 172;
Extrahepatic Manifestations of Hepatitis B Virus 173; Hepatitis B Vaccination 173;
Postexposure Prophylaxis 173; Coinfection with Hepatitis C Virus, Hepatitis D
Virus, and Human Immunodeficiency Virus 173
Chapter 19: Viral Factors and Host Immune

Response to Hepatitis B Virus 176
Andrew Vaillant
Acute Infection 176; Chronic Infection 179; Effect of Hepatitis B Viral
Components on Immune Function 179; Implications for Current and Future
Hepatitis B Virus Treatments 181
Chapter 20: Hepatitis C 184

Amna Subhan Butt, SM Wasim Jafri
Discovery of Novel Hepatitis C Virus 184; Global Burden of Hepatitis C 184;
Incidence 186; Risk Factors for Hcv Transmission 187; Population at Higher
xxii Textbook of Hepato-gastroenterology
Risk 188; Genotypes: Distribution Across the World 188; Pathogenesis and
Viral Characteristics 188; Clinical Characteristics and Natural History of the
Disease 189; Who should be Screened for Hepatitis C? 189; Diagnostic Workup 190;
Economic Burden of Hepatitis C 191; Treatment 191;Strategies to Prevent and
Control Hepatitis C 195; Challenges 195
Chapter 21:
Emerging and Re-Emerging Factors about Hepatitis Virus
Control in Developing Countries 199
Sheikh Mohammad Fazle Akbar, Mamun-Al-Mahtab
Hepatitis A Virus 200; Hepatitis E Virus 200; Hepatitis B Virus 201;
Hepatitis C Virus 202
Chapter 22: Nonalcoholic Fatty Liver Disease 204

Taranjeet S Jolly, Arun J Sanyal
Epidemiology 204; Pathogenesis of Fatty Liver and Nonalcoholic Steatohepatitis 205;
Natural History of Disease 206; Clinical Features 206; Risk Factors for Advanced
Disease207; Diagnosis207; Management210
Chapter 23: Alcoholic Liver Disease 214

Hamizah Razlan, Rosmawati Mohamed
Disease Spectrum and Risk Factors 214; Pathogenesis 215; Diagnosis 215;
Prognosis 216; Therapy for Alcoholic Liver Disease 217
Chapter 24: Primary Sclerosing Cholangitis 220

Roger W Chapman
Epidemiology 220; Prevalence of Primary Sclerosing Cholangitis in Inflammatory
Bowel Disease 221; Etiology and Pathogenesis 221; Clinical Features 222;
Diagnosis 222; Management of Complications 223; Medical Treatment 225;
Prognosis 225; Hepatic Transplantation 225;Secondary Sclerosing Cholangitis 225
Chapter 25: Primary Biliary Cirrhosis 229

Nurdan Tzn, Murat Saru
Epidemiology 229; Etiology and Pathophysiology 230; Clinical Manifestations 231;
Diseases Associated with Primary Biliary Cirrhosis 232;Special Cases 232;
Diagnosis233; Patient Management and Treatment 234
Chapter 26: Autoimmune Hepatitis 239

Khin Maung Win
Epidemiology239; Classification239; Immunopathogenesis240;
Clinical Features242; Differential Diagnosis243; Diagnosis243; Treatment243
Chapter 27: Amebic Liver Abscess 248

Premashis Kar
Pathology248; Clinical Presentation248; Diagnosis249; Medical Therapy249;
Aspiration or Drainage of Abscess 250;Surgical Intervention 250; Long-term
Follow-up250; Prognostic Marker250
Contents xxiii
Chapter 28: Pyogenic Liver Abscess 251

Furqan Ahmed
Epidemiology251; Pathogenesis251; Clinical Manifestations252;
Microbiology252; Diagnosis253; Differential Diagnosis 253; Treatment253;
Complications255; Mortality255
Chapter 29: Hydatid Cyst of Liver 257

Fazal Karim, Salimur Rahman
Epidemiology257; Transmission258; Clinical Features258;
Complications 258; Diagnosis258; Treatment259; Prevention261
Chapter 30: Leptospirosis 262

Izazul Haque, Fazal Karim
Epidemiology262; Risk Factors262; Microbiology262; Pathogenesis263;
Clinical Manifestations 263; Differential Diagnosis 264; Laboratory Diagnosis 264;
Treatment265; Prognosis265; Prevention265
Chapter 31: Cirrhosis of Liver 267

Anil Arora, Ashish Kumar
Pathogenesis of Cirrhosis 268; Clinical Presentation 269; Diagnosis 269;
Treatment of Cirrhosis 272; Complications of Cirrhosis and its Management 273
Chapter 32: Ascites 280

Gourdas Choudhuri, Ajesh Goyal
Etiology280; Pathogenesis280; Evaluation and Diagnosis282; Physical
Examination 282; Definitions of some Commonly used Terms 285;
Complications285; Treatment of Ascites288; Refractory Ascites293; Prognosis295
Chapter 33: Hepatic Encephalopathy 297

Cihan Yurdaydin, Ramazan Idilman
Clinical Signs and Clinical Importance of Hepatic Encephalopathy 297; Diagnosis 298;
Minimal Hepatic Encephalopathy298; Pathogenesis299; Treatment300
Chapter 34: Hepatocellular Carcinoma 302

Sachin Gupta, YK Chawla
Epidemiology 302; Demographic Factors 302; Environmental Risk Factors 302;
Host Factors 304; Natural History of Hepatocellular Carcinoma 304;
Surveillance 305; Clinical Manifestations 305; Diagnosis and Staging 306;
Treatment307; Prevention310
Chapter 35: Portal Hypertension: Pathophysiology and Management 313

Debashis Misra, Abhijit Chowdhury
Portal Vein and Portal Hypertension 313;Etiology314;Pathophysiology of
Portal Hypertension in Cirrhosis 316; Clinical Sequelae of Portal Hypertension 317;
xxiv Textbook of Hepato-gastroenterology
Evaluation and Diagnosis 320; Treatment 321; Clinical Scenerios and the use of
Modalities 323; Failure of Initial Therapy and Salvage 325; Prophylactic
Therapies 326;Shunts and Surgery in Variceal Bleeding: Transjugular Intrahepatic
Portosystemic Stent 327
Chapter 36: Hepatorenal Syndrome 330

Ziauddin Ahmed
Definition 330; Pathogenesis 330; Estimation of Renal Function 330;
Clinical Presentation330; Incidence331; Precipitants331; Diagnosis331;
Differential Diagnosis331; Treatment332;Surgical Procedures332;
Prevention333; Prognosis333
Chapter 37: Drug-induced Liver Injury 335

Saeed Hamid, Om Parkash
Definition 335; Epidemiology 335; Types of Drug-induced Liver Injury 336;
Pathogenesis 337; Risk Factors for Idiosyncratic Variety of Drug-induced Liver
Injury 338; Clinical and Laboratory Features 339; Diagnosis 340;
Determinants of Prognosis in Drug-induced Liver Injury 342; Management and
Treatment343; Prevention344
Chapter 38: Acute Liver Failure 346

Shivaram Prasad Singh, Parimal Lawate
Definition 346;Subclassification of Acute Liver Failure 346; Etiology 347;
Pathophysiology 351; Clinical Features and Evaluation 351; Diagnostic
Evalulation in Acute Liver Failure 352; Management 352; Assessment of
Prognosis and Guidance for Liver Transplant Listing 356; Liver
Transplantation for Acute Liver Failure 358
Chapter 39: Biliary Atresia 359

Voranush Chongsrisawat, Sittisak Honsawek, Paisarn Vejchapipat, Yong Poovorawan
Pathogenesis 360; Diagnosis 361;Screening for Biliary Atresia 361;
Clinical Manifestations361; Investigations361; Management364
Chapter 40: Liver Diseases in Pregnancy 369

Shelley Haynes, Mandish K Dhanjal
Physiological Changes in Pregnancy 369; Hepatic Disorders Specific to
Pregnancy 369; Disorders not Specific to Pregnancy 376
Chapter 41: Liver Transplantation 379

Ravi Mohanka, Punit Singla, AS Soin
History and Evaluation 379; Indications for Liver Transplantation 380;
Indications for Liver Transplantation, Selection, and Prioritization for Organ
Allocation 381; Contraindications for Liver Transplantation 383; Recipient
Contents xxv
Evaluation and Preparation 383; Donor Evaluation and Preparation 385;

Surgical Technique 386; Innovative Strategies in Liver Transplantation 391;
Postoperative Management, Complications, and Outcomes 392
Chapter 42: Gallstone Disease 404

A Kadir Dokmeci, Mustafa Yakut
Risk Factors in Gallstone Formation 404; Genetic Factors in Gallstone Formation 405;
Bile Lipids and Cholesterol Gallstone Pathogenesis 406; Pigment Stones 407;
Diagnosis and Follow-up in Gallstone-related Diseases 408; Gallstone Diseases 409
Chapter 43: Cholangiocarcinoma 412

Christopher A Wadsworth, Simon D Taylor-Robinson, Shahid A Khan
Epidemiology and Prognosis 412; Risk Factors 412; Pathogenesis 413;
Histopathological Classification 413; Pathological Diagnosis 414;
Clinical Features 414; Laboratory Tests and Imaging 415;Screening for
Cholangiocarcinoma 419;Staging of Cholangiocarcinoma 419;
Treatment420; Published Guidelines423
Chapter 44: Acute Pancreatitis 426

Mahesh Gupta, Uday C Ghoshal
Definitions426; Etiology426; Pathophysiology430; Factors Determining the
Severity of Pancreatitis 431;Severity Assessment 432; Complications of
Acute Pancreatitis434; Management436; Diagnosis436; Treatment438
Chapter 45: Chronic Pancreatitis 442

Muhammad Umar, Hamama-tul-Bushra Khaar
Pathogenesis 442; Classification of Pancreatitis 445;Symptoms and Signs 448;
Complications of Chronic Pancreatitis 449; Diagnosis 450; Treatment 455
Chapter 46: Carcinoma Pancreas 466

Sanjay Govil
Pathogenesis466; Tumor Markers468; Imaging/Staging468; Treatment469
Index 473
1
cHAPTER
Gastroesophageal
Reflux Disease
Sujay Ray, Kshaunish Das, GK Dhali
DeFInition at least 3 times per week was 15.4%.9 Studies from china has
revealed a wide range of variation in prevalence of GERD. Hu
Gastroesophageal reflux disease (GERD) is a disorder in et al.10 demonstrated that only 4.8% of Chinese population had
which gastric contents reux recurrently into esophagus, GERD. On the other hand, Wong et al.11 in a study by telephone
causing troublesome symptoms and/or complications This contact,reported a prevalence of 29.8%.Thus Geographic
statement is similar to the Montreal denition. 1 The term differences in GERD prevalence are difficult to interpret, due to
troublesomeconnotes impairment of quality of life . different patient selectionand questionnaires used.12 In a study
in southern Iran, the prevalence of GERD was signifcantly
higher in rural and illiterate persons. 9 The relationship
EpidemIology between lower educational status and the prevalence of GERD
probably reflects the interaction of certain unhealthy lifestyle
Gastroesophageal reflux disease is a major clinical problem in habits or poor ability to modify such habits. Meucci et al.13
Western countries. found that patients with reflux-like and ulcer-like dyspepsia,
Several recent studies have suggested that the overall the prevalence of migraine headache did not differ from that
prevalence of reflux esophagitis (RE) in Western countries in controls, whereas a higher prevalence of migraine was noted
was around 1020%. 2 In contrast, GERD has traditionally in patients with dysmotility-like dyspepsia and in patients
been considered to be less common in Asian countries.3 But with nausea and vomiting alone. In the study by Aamodt
more recent studies suggest that the prevalence of GERD et al.14 higher prevalence of headache was found in individuals
in Asia is increasing in Japan, and the overall prevalence of with reflux, diarrhea, constipation, and nausea. They
RE among the adult population is around 16%. 4 While in suggested that headache sufferers commonly are predisposed
Taiwan, the prevalence of RE in patients evaluated for upper to gastrointestinal complaints. In a recent multicentric
gastrointestinal tract sympoms is 15%.5 study from India study showed that 8% of Indians reported
These results are similar to the findinngs reported in the symptoms of GER frequent or severe enough to be diagnosed
West. RE has been considered quite rare among Koreans. as GERD. The low prevalence could be attributed to genetic
However, recent studies have revealed that the incidence factors as Asians have a smaller parietal cell mass and a lower
is increasing in the Korean population. RE prevalence in acid output compared with Caucasians.The lower prevalence
subjects undergoing a routine check-up was reported to 2.36% of hiatus hernia and smaller body mass index in the Asian
in 19933 and 3.4% in 1997.6 In 1999, the prevalence of RE was population might also have accounted for the lower prevalence
found to be 5.3% in subjects with gastrointestinal symptoms. of GERD similar to that reported from the rest of south Asian
However in a recent study from Korea in 2009 the prevalence countries. H. pylori infection, common in Indian population,
of RE in male was 14.6% and the in female was only 4.7%.7 might also reduce the frequency of GERD by causing gastritis
According to univariate analysis, male sex, smoking history, and reduced acid secretion. Subjects with GERD were older,
total cholesterol >250 mg/dL, LDL cholesterol 160 mg/dL, more often female, frequently consulted doctors, and often
triglyceride 150 mg/dL, high BP, and fasting glucose 110 mg/ had overlapping functional lower GI symptoms. Frequency of
dL, were significant risk factors of RE.7 The prevalence rate of intake meat, fried food, fruit and spices was higher amongst
GERD in Qashgai migrating Nomads in sourthern Iran, defined subjects with GERD; also, meat, fried food, spice, aerated drink,
as reflux occurring at least one time per week in the preceding tea, coffee, and smoking were often associated with induction
year, was 33%.8 In a study from urban and rural population of of symptoms among subjects with GERD. On multivariate
southern Iran, the prevalence of refux symptoms occurring analysis, induction of symptoms of GERD following smoking
2 Textbook of Hepato-gastroenterology
and nonvegetarian foods was independently associated with words in the local language what heartburn means, i.e. a
GERD. Frequency of GERD was comparable in northern and burning discomfort arising from the epigastrium and rising
southern Indian population. (ISG Task Force Report -In Press). retrosternallyto clarify the term. Asian patients more easily
Assessment of health-related quality of life (HRQL) through understand acid regurgitation, meaning the experience of sour
the use of validated patient-completed questionnaires is or acidic uid in the mouth.
likely to provide a good indication of how troublesome Other symptomatic presentations are chest pain, belching,
gastroesophageal reux symptoms are. There are few nausea, dysphagia, early satiety, and epigastric pain, with or
studies assessing the relationship between HRQL and without typical reux symptoms. There was much discussion
symptoms of GERD in the general population using validated that Asian patients may not complain of the cardinal symptoms
questionnaires. 15 A population-based study in Malm, of heartburn and acid regurgitation, but instead complain of
Sweden showed that even mild reux symptoms on a weekly other upper gastrointestinal symptoms which may be more
basis were associated with a clinically meaningful reduction prominent. Noncardiac chest pain, is a common condition
in well-being,16 while another large survey of the Swedish among Asian patients.23,24 and may be a presenting feature
population (the Kalixanda study) found that daily or weekly of GERD. GERD symptoms among Asian patients are more
symptoms of heartburn and/or regurgitation substantially protean, and atypical symptoms may occur in the absence of
disrupted subjects everyday lives. 17 Similar results were heartburn and acid regurgitation (Table 1).
obtained in two recent studies in the USA.18,19 These studies
showed that the impact of GERD increased with symptom
frequency and severity in the general population. There are Spectrum
few data on the impact of GERD on HRQL in Asia generally. Symptomatic GERD is endoscopically manifested in three
One epidemiological study of GERD in Sanghai, East China, spectrumnonerosive reflux disease (NERD), consisting of
evaluated HRQL impairment in GERD subjects using a Chinese majority of around 60%, erosive esophagitis of around 35%,
version of the SF-3620 (Figs 1 and 2). and complicated GERD of 5%.Compliations of GERD are peptic
stricture, bleeding ulcer, Barretts esophagus, and esophageal
adenocarcinoma. NERD is dened as troublesome reux
Symptoms symptoms in the absence of esophageal mucosal damage on
Typical symptoms of reux are heartburn (retrosternal burning endoscopy. Barretts esophagus is the presence of columnar
sensation) and acid regurgitation. Heartburn, although lined epithelium suspected at endoscopy and proven by
an english term that has no equivalent in any of the Asian histology which requires the presence of intestinal metaplasia.
languages, is now thought to be increasingly understood The term Barretts esophagus has been loosely used, giving
by Asian patients.21,22 Doctors may still have to describe in rise to undue alarm and concern among doctors and patients.
Fig. 1: Health-related quality of life in subjects with and without GERD. Subjects with GERD,
(black bars); subjects without GERD, (white bars). GERD, gastroesophageal reux disease;
QOLRAD, Quality of Life in Reux and Dyspepsia. *P < 0.001;P = 0.003. P-values were
calculated by t-test. R. Wang et al. Digestive and Liver Disease. 2009;41:110-5
Gastroesophageal Reflux Disease 3
Fig. 2: Health status and well-being in subjects with and without GERD. Subjects with GERD, (black bars); subjects without GERD,
(white bars). BP, bodily pain; GERD, gastroesophageal reux disease; GH, general health; MH, mental health; PF, physical functioning;
RE, role-emotional;RP, role-physical; SF, social functioning; SF-36, 36-item short-form health survey; VT, vitality. *P < 0.001; P =
0.019. P-values were calculated by t-test. R. Wang et al. Digestive and Liver Disease. 2009;41:110-5
Table 1: Symptoms of gastroesophageal reflux disease Histological conrmation of columnar lined epithelium with
intestinal metaplasia in the denition of Barretts esophagus,
Typical symptoms Alarm symptoms
in addition to endoscopic diagnosis is important (Fig. 3).
Heartburn (pyrosis) Dysphagia Community-based studies identied older age and male
Acid regurgitation Gastrointestinal hemorrhage sex as risk factors for GERD symptoms.25,26 Endoscopy-based
Iron deficiency anemia studies have also revealed age and male sex as risk factors
Nausea and/or vomiting for ERD.27,28 Alcohol , smoking , BMI more than 25 and hiatus
Weight loss
hernia are important risk factors.29 Three reports from South-
east Asia identied Indian race as being a risk factor for
Family history of cancer
GERD.28,30
Fig 3: Spectrum of gastroesophageal disease

The prevalence and incidence of GERD is increasing in comes into contact of lower esophageal mucosa during reflux
asian countries as revealed in many studies.31,32 Time trend episodes.The pathophysiological mechanisms of GERD in
studies have shown both an increase in symptoms of GERD33 Asian patients are similar to those in Western populations.
in the community, as well as an increase in the prevalence of Among the various motor dysfunction abnormalities of
esophagitis.34-40 esophagus, transient lower esophageal sphincter relaxation
The prevalence of Barretts esophagus and adenocarcinoma (TLESR) with excessive acid reflux is the single most important
of the esophagus, although lower than in the Western mechanism. 42 In patients with more severe GERD, hiatus
populations, is also increasing in Asia. The prevalence of hernia, impaired esophageal peristalsis and weak lower
Barretts esophagus is generally low in Asian patients and esophageal sphincter (LES) pressure play a more important
ranges from 0.9 to 2%.13,35 role in the pathogenesis.4244 However, it is intriguing to note
An isolated study, however, showed prevalence rates of up that rates of TLESR tend to be lower in both Asian GERD
to 6% of patients endoscoped, which was different from other patients and healthy volunteers compared to their Western
studies from the same region. A study based at the Singapore counterparts.42 Furthermore, the reported prevalence of hiatus
Cancer Registry has shown a signicant decrease in squamous hernia in Asian populations is substantially lower than those
cell carcinoma of the esophagus over 34 years and a numerical, reported in Western populations.45 Chang et al. reported that
but not statistically signicant, increase in adenocarcinoma of the prevalence of hiatus hernia was only 2.2% in the Taiwanese
the esophagus.41 general population. 21 In another study of patients with
dyspepsia, the prevalence of hiatus hernia was 49% in English
patients, but only 4% in Singaporeans, most of whom were
Pathogenesis Chinese, respectively. After adjusting for age and body mass
index (BMI), race remains an independent risk factor for hiatus
hernia.46 Furthermore, the prevalence of hiatus hernia has been
Pathophysiology reported as being lower in Asian GERD patients, ranging from
7 to 20% in NERD, and 20 to 30% in esophagitis.47,48 Further
Esophageal dysmotility and hiatus hernia studies are required to elucidate whether there are clear ethnic
The GERD results from imbalance between aggressive and differences in TLESR dysfunction and hiatus hernia, but the
protective factors which interact at lower esophageal mucosa apparent lower prevalence of these conditions could contribute
(Fig. 4). The protectve factors being lower esophageal sphincter to the lower prevalence of GERD and its complications in Asia.
which is supported by diaphragmatic crus, the esophageal
clearance, and esophageal tissue resistance. The aggressive
factors are the acid peptic secretion of stomach and bile which
Esophageal acid hypersensitivity
Esophageal acid hypersensitivity has been implicated in the
pathogenesis of heartburn symptoms, especially in NERD
patients.49 Psychological stress increases perception to low-
intensity stimuli in the esophagus and is perceived as heartburn
in NERD patients.50 It has been reported that NERD patients
have higher positive rates of the acid perfusion test compared
to those with erosive esophagitis, but results are conflicting.51,52
Obesity
The strong association between GERD and abdominal obesity
has been extensively reported in Western populations.53 Recent
studies also support a similar dose-response association
between GERD and BMI in Asians. Patients with reflux
esophagitis tend to have a higher BMI compared to NERD
patients and non-reflux controls.54,55 Recent studies have also
reported a positive association between metabolic syndrome
and GERD. Thus, hyperglycemia, hyperlipidemia, and high
blood pressure have all been shown to be independent risk
factors of esophagitis. 56 The underlying mechanism(s) of
Fig. 4: Pathogenesis of gastroesophageal disease
obesity-related GERD is/are unclear. It has been reported that Diagnosis

the prevalence of hiatus hernia increases with BMI, suggesting
that hiatus hernia may play a role in the development of GERD- Heartburn and regurgitation (or both) that occurs after meals
associated obesity.57 It has also been reported that BMI and are symptoms highly suggestive for GERD. Although the
waist circumference are significantly correlated with TLESR Montreal Consensus reported a high level of agreement on
and gastroesophageal pressure gradient in both asymptomatic this issue, but the denition of heartburn and the specicity
and GERD patients. This finding indicates that postprandial of the term for GERD had been studied mostly in Caucasian
LES dysfunction plays an important role in the pathogenesis populations, whereas the term heartburn carries different
of obesity related GERD.58 The rising problem of obesity may meanings to different parts in Asia.1
be one of the major contributing factors for the increasing There is lack of published data on the specicity and
prevalence of GERD in Asia. sensitivity of heartburn as a predictor of GERD in the Asia-
Pacic region so the term heartburn must be clealy described
and tested in different regions.
Role of H. pylori GERD symptoms do not predict the severity of esophagitis.
The role of H. pylori in GERD has been a controversial subject However, there is some correlation between the severity of
and a major area of substantial discrepancies between Asian symptoms and the presence and grade of esophagitis. 21,75
and Western studies. Most case-control and population-based Longer duration of symptoms, with increased frequency and
presence of symptoms at night, as well as in the daytime, are
studies tend to suggest a negative association between H.
features that are more likely to be associated with erosive
pylori infection and GERD in Asia. The prevalence of H. pylori
esophagitis (figs 5 and 6). This correlation has been established
infection in GERD patients ranges from 25 to 35%, which
in Caucasian GERD patients; about 3040% of patients are
is 2540% lower than that of the non-reflux population in
found to have ERD, with the remainder having NERD. In Asian
Asia.59,60 The negative association is more prominent in the
populations, the ratio of ERD to NERD is much lower and the
elderly,61 however, is only confined to patients with severe correlation of symptoms with erosive disease in this population
GERD in Western countries, especially for those infected has not been tested sufciently.
by more virulent cytotoxin-associated gene A (CagA+) Endoscopy should be done in patients with alarm
strains. 62-64 The prevalence of H. pylori is also inversely symptoms. But the sensitivity and specicity of alarm
related to the severity of GERD. The prevalence of H. pylori symptoms (like dysphagia, weight loss, and anemia)
in patients ranges from 20 to 33% for esophagitis 65, 66 and 0 varies on the denitions, duration of symptoms, and the
to 37% for Barretts esophagus.67 Furthermore, patients with population studied. Clinical diagnosis made by a physician
reflux esophagitis have lower rates of virulence for H. pylori on the basis of alarm symptoms is very specic (range,
infection compared to non-reflux controls.67, 68 Compared to 9798%), but it lacks sensitivity. 76 Urgent endoscopy in
cross-sectional prevalence studies, however, the results are patients with alarm symptoms results in a signicant yield
less consistent in H. pylori eradication studies for peptic ulcer of cancer (approximately 4% in one series) and of serious
patients.69, 70 These conflicting observations may be attributed benign disease, such as peptic ulcer, stricture, and severe
to different dominant patterns of H. pylori gastritis and acid esophagitis (13%).77 There are no published regional data
secretion between peptic ulcer patients and nonulcer patients on the correlation between alarm symptoms and peptic
in the general population. Changes in patients with duodenal stricture and esophagitis mainly because of the rarity of
ulcer and nonulcer dyspepsia are characterized by antrum- these in the Asia-Pacic region. In this region, patients
with alarm features more likely to have gastric rather than
predominant gastritis, hypergastrinemia, and relatively-
esophageal pathology due to the higher prevalence of peptic
preserved acid-secreting corpus mucosa. As a result, gastric
ulcer disease and gastric cancer in the region. Nevertheless,
acid hypersecretion is a common feature. 71,72 However,
alarm features suggest advanced malignancy. 78 In clinical
patients with gastric ulcer and gastric cancer are characterized
practice, expectation and anxiety of the patient is a major
by corpus-predominant gastritis or pangastritis, which is driver because any delay in the diagnosis of any pathologic
associated with profound destruction or even atrophy of acid- condition will lead to patient dissatisfaction.
secreting mucosa. These patients are characterized by gastric Patients with GERD symptoms for 5 years but no alarm
acid hyposecretion, while eradication of H. pylori is followed features should also undergo endoscopy to exclude Barretts
by rebound gastric acid hypersecretion. It has been reported esophagus. But the statement is irrelevant to Asia as there is a
that recovery of gastric acid secretion and the emergence of very low prevalence of Barretts esophagus and adenocarcinoma
reflux esophagitis occurs after H. pylori eradication in patients of the esophagus at present in this region. Due to the overlap of
with corpus gastritis and atrophic gastritis.73,74 upper gastrointestinal symptoms and the greater prevalence
A B
Figs 5A and B: (A) One (or more) mucosal break, no longer than 5 mm (Grade A); (B) One (or more) mucosal break, more than 5 mm that
does not extend between the tops of mucosal folds (Grade B).
Source: Lundell et al. 1999, published with permission from professor G Tytgat and professor J Dent
A B
Figs 6A and B: (A) One (or more) mucosal break that is continuous. Between the tops of two or more mucosal folds, but which involves less than
75% of the circumference. (Grade C); (B) One (or more) mucosal break that involves at least 75% of the esophageal circumference (Grade D).
Source: Lundell et al. 1999, published with permission from professor G Tytga and professor J Dent
of peptic ulcer and gastric cancer in the region, the indication

for endoscopy is more often to exclude gastric pathology.
Every patient with GERD symptoms should undergo
endoscopy once in a lifetime.
The major reason to investigate a patient suffering from
symptoms of GERD is to detect Barretts esophagus. The highest
risk factor for development of Barretts esophagus is in white
men with chronic symptoms of GERD.79 However, the criteria to
select patients for screening of Barretts are not yet well dened
and it is recognized that persons with Barretts esophagus may A B C
be asymptomatc. Even within the Western population, this a Fig. 7: Endoscopic biopsy: (A) Normal mucosa; (B) Reflux esophagitis;
strategy of screening for Barretts esophagus is not uniformly (C) Eosinophilic esophagitis
accepted.80 Such a strategy is irrelevant to Asia at this time
because of its low prevalence.31,32 A recent direct comparative of basal cell layer to more than 15% of the thickness of the
study also found a lower prevalence of esophagitis (6% vs 27%) epithelium, (ii)an increase in height of the papilla to greater
and columnar-lined esophagus (1% vs 4%) in Asians compared than two third of thickness, (iii) presence of blood lakes at the
to Western patients. 81 In this region, the major reason for top of papilla, (iv) presence balloon cells, or (v) presence of
endoscopy is to diagnose or exclude gastric cancer or peptic inflammatory cells in epithelium or lamina propia (fig. 7).
ulcer. There is considerable debate regarding performance A negative ambulatory pH study off therapy helps exclude
of endoscopy at least once in patients with chronic upper GERD, if a PPI test fails.
gut symptoms, recognizing the difficulty of clinical diagnosis The test is considered positive if the total time for which
between GERD and peptic ulcer and the ability of endoscopy pH is <4 is >4.5% (fig. 8). However ambulatory pH testing
to provide or exclude a diagnosis and aid in tailoring therapy. is not widely available in Asia and is rarely done outside of
In one study, 18% of patients suffering from H. pylori-related major centers. Furthermore, there are few data on the test
peptic ulcers were misdiagnosed as GERD based on symptoms characteristics in Asian populations. For diagnostic purposes,
alone.82 As fear of gastric cancer is a major concern, endoscopy the need to have patients off PPIs when performing pH studies
should be performed early rather than later. Empiric use of was stressed. The likelihood of a positive test while on PPIs is
proton pump inhibitors (PPIs) is common prior to endoscopy low; the main role of the test with the patient on PPIs is for the
resulted increased risk of a false-negative H. pylori biopsy test, assessment of the adequacy of acid suppression in patients
so there is requirement to cease PPI prior to testing. Widespread with GERD who are not responding to therapy.
availability of endoscopy in many parts of the region favored Other diagnostic modalities are barium swallow and
endoscopic approaches over a noninvasive test. fluoroscopy and radionuclide scintigraphy, which are not
Symptomatic response to a trial of PPI is sufcient for commonly used tests. In a recent study from Delhi, when all
a presumptive diagnosis of GERD in a patient with typical the individual tests were compared against the gold standard
symptoms, in the absence of alarm symptoms. Although a of three or more positive tests, then as a single test, 24-hour
symptomatic response to a trial of PPI therapy has been used to pH monitoring had the best combination of sensitivity and
support a diagnosis of GERD in patients with typical symptoms, specificity.84
a meta-analysis revealed that the combined sensitivity and There is currently no established role for the use of narrow
specicity of this is only modest.83 As there is overlap of GERD band imaging (NBI), capsule endoscopy, and wireless pH
with the symptoms of peptic ulcer and the response of ulcer monitoring in the routine management of GERD in the Asia-
symptoms to PPI therapy, and the higher prevalence of ulcer Pacic region. However, these newer diagnostic modalities
in the region, such a strategy needs to be validated locally. require validation as research tools and for clinical practice. It
However, there is support for an empirical trial of PPI in those is recognized that they are not appropriate for routine clinical
with typical symptoms, particularly in the primary care setting. use in the region at present as the impact on diagnosis and
Histopathology also plays an important role in diagnosis of management and the cost effectiveness of these new tests
GERD and its complication. Barretts esophagus is defined as are yet to be determined. Nevertheless, NBI is considered a
presence of specialized intestinal metaplasia on histological potentially valuable tool in diagnosing GERD, in particular in
examination of biopsies taken from suspected areas (if patients with Barretts esophagus. Wireless pH monitoring has
present) above gastroesophageal junction. Biopsies are taken been shown to increase the diagnostic yield of GERD by 20%,85
from all four quadrants of distal 5 cm of the esophagus for in Caucasian population.
histopathologic diagnosis of GERD which require presence Diagnostic strategies in the Asia-Pacic region must take
of any of the following findings: (i) an increase in thickness consideration regarding the coexistence of GERD with other
Fig. 8: Common pattern of24 hours esophageal pH monitoring. Upper panel showing physiologic
pattern of gastroesophageal reflux (GER) seen in healthy subject. Reflux is noted after meals (M) but
not while asleep(S). A reflux episode is defined when pH drops below 4.middle panel showing upright
reflux pattern with extensive GER during the day but not at night.Lower panel showing combined
pattern with GER during the day and night
common conditions like gastric cancer and peptic ulcer. Gastric infected with H. pylori. It is accepted to offer eradication therapy
cancer still accounts for nearly one million deaths worldwide prior to long-term PPI therapy in this setting.88 The decision to
annually, with much of this occurring in the region. There is test for and treat H. pylori infection in the context of reux must
immense difficulty in designing the management strategies be individualized based on patient factors including comorbidity,
in a large diverse region, where the prevalence and spectrum age, gastric histology, family history, and informed choice.
of GERD, peptic ulcer, and gastric cancer vary considerably.
The strategy for management of upper gut symptoms must
recognize that symptoms of GERD, peptic ulcer disease, and Management
functional dyspepsia frequently overlap, causing difficulty in
differentiating these conditions clinically. Goals of Therapy
H. pylori testing should be considered in patients presenting
with GERD symptoms in regions with a high prevalence of gastric Resolution of symptoms (symptoms no longer bothersome)
cancer or peptic ulcer disease. Symptoms were an imprecise way Healing of esophagitis or ulcer, if present. Prevent long-term,
of distinguishing between upper gastrointestinal conditions in etc. complications (ulcer, bleeding, Barretts esophagus,
Asia and that GERD may coexist. Peptic ulcer and gastric cancer stricture, etc.). Weight loss and elevation of head of bed could
have greater impact than GERD on morbidity and mortality. improve symptoms in GERD patient. There is insufficient data
There is evidence that benefits are gained by testing and treating to support other lifestyle modification recommendations.
H. pylori infection in the context of reducing symptoms, curing Lifestyle modifications are commonly used as first line of
ulcer disease, and reducing the risk of gastric cancer.86 H. pylori therapy in patients presenting with GERD-related symptoms.
does not cause or prevent reux disease and that eradication of They include weight loss, smoking cessation, avoidance of
this organism does not appreciably increase the risk of GERD postprandial recumbency for a period of at least 3 hours,
occurring.87 Long-term PPI therapy for GERD increases the risk of elevation of the head of the bed, avoidance of tight-tting
progression of gastric atrophy and intestinal metaplasia in those garments, and avoidance of large heavy meals as well as food
and drink that exacerbate GERD symptoms (e.g. spicy foods,

fatty meals, peppermint, chocolate, onions, citrus juices, and
carbonated beverages).89 However, for many patients lifestyle
modications are difficult to follow, very restrictive, and may
adversely affect the quality of life. In a recent systematic review
that evaluated the value of the different lifestyle modications
in GERD, the authors demonstrated that only weight loss and
elevation of the head of the bed are effective in improving
symptoms of GERD.90 Elevation of the head of the bed and left
lateral decubitus positioning improved the overall time pH
<4.0, and weight loss improved pH proles and GERD-related
symptoms. There was no evidence that lifestyle interventions,
such as dietary measures and tobacco or alcohol cessation were
effective in reducing esophageal acid exposure or ameliorating
GERD symptoms.90, 91 Fig. 9: Healing rates following up to 4 weeks of treatment with
PPIs are the most effective medical intervention for GERD. esomeprazole 40 mg (n = 1562) or pantoprazole 40 mg (n = 1589) by
Studies have shown repeatedly and consistently that PPIs are baseline Los Angeles (LA) grade of erosive esophagitis severity. Aliment
superior to histamine 2 receptor antagonists (H2RAs) in healing Pharmacol Ther. 2005;21:739-46
the esophageal mucosa and relieving GERD-related symptoms
of patients with ERD.9294
In a meta-analysis, the investigators demonstrated that with ERD, as compared to those with NERD. In one meta-
after 12 weeks of treatment, healing rates were 83.6% with analysis, response rates at 4 weeks were signicantly higher
PPIs, 51.9% with H2RAs, 39.2% with sucralfate, and 28.2% with for patients with ERD as compared to those with NERD (56%
placebo.95 In addition, treatment with PPIs resulted in healing vs 37%, P < 0.0001).98
rates of esophageal inammation and relief of GERD symptoms All PPIs are equally efficacious. In GERD/NERD/esophagitis
that were twofold higher than what was observed in patients 6 good quality systematic reviewsno clinically important
receiving H2RAs. Similarly, PPIs demonstrate superiority in differences in standard doses PPIs. Comparisons showing some
relieving heartburn symptoms in patients with NERD when degree of difference involved non-equivalent comparisons (e.g.
compared to H2RAs.96-98 high dose vs. standard dose). However with higher grades of
The superiority of PPIs over H2RAs in ERD is not esophagitis esomeprazole is more effective (Fig. 9).
limited to acute therapy but has also been demonstrated in High or double-dose PPI, as initial therapy, is no better than
maintenance studies over as long as 11 years.99 The symptoms standard daily dose therapy in the management of erosive
response rate to once daily PPI in randomized controlled esophagitis (fig. 10). Double-dose PPIs: step-up therapy for
trials has been shown to be signicantly higher in patients nonresponders to standard dose PPI can be used.
Fig. 10: Result of studies showing comparison between Standard vs double dose PPIno
difference in healing of esophagitis or symptom relief
H2RAs and antacids are useful in treating episodic in NERD patients have lasted only 4 weeks. The studies were
heartburn. H2RAs and antacids are commonly used for designed with the assumption that 4 weeks are sufcient to
episodic heartburn, primarily for postprandial heartburn. assess symptom improvement as opposed to esophageal
The perception of heartburn serves as a trigger for medication mucosal healing, which requires more than 4 weeks of PPI
use, and the expectation is an immediate symptom relief that therapy. This arbitrary time frame is unlikely to provide
PPIs are unlikely to provide. The onset of action of antacids the full symptomatic response rate of patients with NERD
on esophageal acid concentration is 30 min after dosing and undergoing PPI treatment. A systematic review of the
inhibition persists for 1 hour. 100 However, studies reported literature, revealed a trend in increased therapeutic gain
that effective heartburn relief can be achieved 19 min after for NERD patients throughout the 4 weeks, suggesting that
consumption. 101 In contrast, H2RAs have been shown to a 4-week follow-up evaluation alone may be insufficient to
provide symptom relief within 30 min of dosing that can last show the full therapeutic gain in this patient population.98
up to 12 hours.102 ERD patients will require a minimum of 48 weeks of initial
When consumed 30 min prior to a meal, H2RAs are effective continuous therapy with a PPI. Therapeutic studies in
in completely or partially preventing postprandial heartburn.103 patients with ERD have almost always lasted 8 weeks. Healing
There is some evidence to suggest that simultaneous rates in those receiving PPI once daily for 8 weeks ranged
consumption of both an H2RA and an antacid provides better from 8596%, regardless of the PPI that was used and the
control of heartburn symptoms, when compared to the clinical underlying severity or ERD.108-111
effect of each one of these products alone. 100 On-demand However, patients with severe grades of ERD demonstrated
treatment with H2RAs has been shown to be safe and effective higher PPI failure rates as compared to those with mild-to-
in GERD patients. In one study, ranitidine 75 mg daily was moderate disease after 8 weeks of treatment.107
consumed on demand (up to three times daily) as compared In one study, patients were randomized to either
to placebo in patients with uninvestigated GERD.104 The study omeprazole 20 mg once daily versus esomeprazole 40 mg
revealed that 3841% of those receiving H2RAs reported relief once daily.112 The failure rate in those with Los Angeles grade
of at least 75% of heartburn episodes during the study period A was 9.6% and 6.6%; grade B, 28.7% and 10.6%; grade C,
as compared to 28% on placebo. 29.6% and 12.8%; and grade D 26.2% and 20%, respectively.
The use of prokinetic agents either as monotherapy or Patients with lower grades of ERD are likely to heal earlier,
adjunctive therapy to PPIs may have a role in the treatment of and thus 4 weeks of treatment could be sufcient. This is
GERD in Asia. Several recent studies have demonstrated the particularly important in the Asian context where generally
value of prokinetic agents in GERD management. Itopride, a patients are less likely to develop severe ERD, specically
dopamine D2 antagonist with antiacetylcholinesterase effect, Los Angeles grades C and D, as compared to their Western
has been recently evaluated in patients with an abnormal counterparts.32 The rate of symptom resolution in patients
pH test and mild ERD. After 30 days of treatment in an open with ERD is commonly 515% lower when compared
label study design, itopride signicantly reduced the extent to esophageal mucosal healing rate after 8 weeks of
of esophageal acid exposure and improved GERD-related treatment.108-112 This clearly suggests that a small portion of
symptoms as compared to baseline values.105 Mosapride, a the patients with ERD will continue to report GERD-related
newly developed 5-HT4 agonist, has been shown to increase symptoms despite complete esophageal mucosal healing. In
the rate of complete esophageal bolus transit and enhances a meta-analysis of 43 therapeutic trials in ERD, the authors
esophageal bolus transit in normal controls.106 In one study reported an overall 65% healing rate of esophageal mucosa
from India, 68 patients suffering from heartburn twice a week after 4 weeks, 80% after 8 weeks, and 84% after 12 weeks of
were randomized to either pantoprazole 40 mg twice daily or treatment with PPI once daily.
pantoprazole 40 mg twice daily plus mosapride 5 mg thrice PPIs provided a healing rate of 11.7% per week and complete
daily for a period of 8 weeks.107 The investigators found that heartburn relief at a rate of 11.5% per week. The meta-analysis
the PPI + mosapride regimen provided signicantly better demonstrated that 12 weeks of treatment with PPI once a
symptom control in patients with ERD as compared to the day provided only a modest increase in the healing rate as
PPI alone. However, there was no difference between the two compared to 8 weeks of treatment in patients with ERD.
therapeutic arms in ERD healing rates or symptomatic response O n - d e ma n d t h e rapy i s a n ap p ro p r i at e o n g o i n g
of subjects with NERD. Further studies using the new prokinetic management strategy in NERD patients. Several alternative
agents are needed, but those that are currently available therapeutic strategies have been proposed for patients
demonstrate little efcacy as sole therapy or in combination with NERD. The one that has been studied the most is
with a PPI in subsets of patients with GERD. on-demand therapy dened as PPI consumption (up to
NERD patients will require a minimum of 4 weeks of initial once daily) when needed and for the duration desired.
continuous therapy with a PPI. Almost all therapeutic trials This patient-driven therapeutic strategy has been shown
to be clinically efcacious and cost effective. On-demand antireux surgery is highly predictive of clinical success.132 In
therapy is attractive to patients because it provides their addition, several cost-effectiveness analyses have revealed
input into their own management, addresses concerns that medical therapy is significantly less costly than antireux
about chronic ingestion of PPIs, and offers personal cost surgery.134
savings. Studies have also demonstrated that patients are Thus, only in GERD patients who wish to discontinue
commonly consuming PPIs in an on-demand fashion despite maintenance of medical treatment, surgery by a fully trained
instructions to take their medications on a daily basis.113 Many and highly experienced surgeon is recommended. Endoscopic
studies have assessed the value of on-demand PPI therapy treatment of GERD should not be offered outside well-designed
as a maintenance strategy in patients with NERD.114-120 These clinical trials
studies commonly followed a similar design. Patients who
responded to an acute treatment (4 weeks) with a daily PPI
were then randomized to either placebo or PPI for a period
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2
cHAPTER
Carcinoma of
Esophagus
Md Rabiul Hossain, Md Delwar Hossain
INTRODUCTION RISK FACTORS

Worldwide, esophageal cancer is the sixth leading cause of Many factors are responsible for the development of
death from cancer. There were 7,966 people diagnosed with esophageal cancer (Table 1). It varies with the types of
esophageal cancer in the UK in 2007, with twice as many cases carcinoma. Cigarette smoking and alcohol consumption are
occurring in men as in women. Squamous cell carcinoma the most important predisposing factors for esophageal cancer
(SCC) is the most common esophageal carcinoma worldwide. in developed countries, particularly for SCC. The carcinogenic
Adenocarcinoma is less common (<15%) esophageal cancer. effects are more pronounced for SCC. The mechanism of
Small cell carcinoma of esophagus is very rare. Approximately carcinogenesis is obscure. It is postulated that many tobacco-
15% of esophageal cancers arise in the upper one-third, derived chemicals, such as nitrosamines may initiate the
50% in the middle-third and 35% in the lower-third, and
gastroesophageal junction. Table 1: Risk factors for esophageal carcinoma
Squamous cell carcinoma

Chronic tobacco use
EPIDEMIOLOGY Heavy alcohol consumption
The incidence of carcinoma differs significantly by geographic History of radiation therapy
regions, race, sex, and also types. The rates can vary between Chronic esophagitis (most common in Asia and Africa)
regions in a given country due to environmental and possibly Chronic stricture
nutritional factors. The disease predominantly affects older age
Tylosis
groups with the peak incidence between 60 and 70 years of age. In
Plummer-Vinson syndrome
low-risk countries, male-to-female ratio of cases is usually 3:4.1,
but it is nearly equal in high-risk countries. For SCC worldwide, Achalasia
the highest risk populations (incidence rate >100 cases per Dietary deficiency of carotene, vitamins C, E and riboflavin, selenium and
100,000 inhabitants/year) are found in north central China, zinc
northeastern Iran and the intervening central Asian countries Low intake of fruits and vegetables
sometimes collectively called the Central Asian esophageal High intake of red meat and nitrate-containing foods
cancer belt. Intermediate-risk populations with incidence rates Consumption of hot beverages
approximately 2050 cases per 100,000 inhabitants per year are
Adenocarcinoma
found in eastern and southern Africa, southern Brazil, Uruguay,
Barretts esophagus and gastroesophageal reflux disease
northern Argentina, and northwest France. Most of the world
is considered low risk with the incidence rates less than 10 Obesity
cases per 100,000 inhabitants per year. By far, SCC is the most Cigarette smoking
common esophageal cancer worldwide and adenocarcinoma Alcohol consumption
accounts for less than 15% of all esophageal cancers. Over the Scleroderma
last two decades, the incidence of adenocarcinoma has risen
History of colon cancer
sharply particularly among white males, although SCC remains
Medications: theophylline and -agonists (long-term use >5 years)
the predominant cell type among African Americans.
favorable indicator of risk for digestive tract neoplasms in this

population.
BIOLOGY AND GENETICS

The progression from basal cell hyperplasia and dysplasia to
the development of invasive SCC is variable and may be of long
duration. The premalignant stages may persist for 20 years or
more. Alterations of oncogenes, tumor suppressor gene and
deoxyribonucleic acid (DNA) mismatch repair genes play a
role in the genesis of SCC of esophagus like in other cancers
of the digestive tract. Cyclin D1 is overexpressed in many
cancers and in up to 50% of esophageal SCC. Overexpression
is associated with a poor prognosis.
The p53 gene is mutated in up to 70% of esophageal cancers.
Inherited germline mutations of the E-cadherin gene lead to
loss of E-cadherin expression that causes increased activation
of other genes, such as cyclooxygenase-2 (COX-2) and c-myc
Fig. 1: Barretts esophagusrisk for esophageal carcinoma
that may induce proliferation.
Abnormal variants of interleukin-1 gene are associated with
esophageal carcinoma or act as promotional agents. Barretts an increased risk of development of cancer of gastric cardia.
esophagus is the most important risk factor for esophageal So, these genes may make possible screening of individuals
adenocarcinoma (Fig. 1). It is a premalignant lesion that with intestinal metaplasia of the esophagus. Furthermore,
results from gastroesophageal reflux disease (GERD) in which anti-inflammatory drugs, such as cyclooxygenase inhibitors
the squamous epithelium of the distal esophagus is replaced may provide a means of medical intervention.
by intestinal type columnar epithelium. The lifetime risk of
esophageal carcinoma in Barretts esophagus is estimated to
be 5%. In addition to this, GERD is an independent risk factor CLINICAL PRESENTATION (TABLE 2)
for esophageal adenocarcinoma.
Dysphagia
Decreased Risk for Esophageal Progressive dysphagia (90%) is the most common
presentation of esophageal cancer leading to its diagnosis. A
Carcinoma patient may not manifest dysphagia until the lumen is more
The risk appears to be less in patients using aspirin or related than 5060% obstructed by the tumor mass by stretching the
drugs (NSAIDs). The role of Helicobacter pylori in progression smooth muscle due to lack of serosal layer. Initially, there is
to esophageal adenocarcinoma is still uncertain, but on the dysphagia to solid and later on for both solid and liquid.
basis of population data, it may carry a protective effect. It
is postulated that H. pylori induces chronic gastritis, which Table 2: Signs and symptoms of esophageal carcinoma
is a risk factor for reflux, which in turn is a risk factor for Dysphagia (most common)solids then liquids
esophageal adenocarcinoma. Odynophagia
According to the National Cancer Institute, diets high
Back pain and chest pain
in cruciferous (cabbage, broccoli/broccolini, cauliflower,
brussel sprouts), and green and yellow vegetables and fruits Anorexia
are associated with a decreased risk of esophageal cancer. Weight loss
Moderate coffee consumption is associated with a Regurgitation
decreased risk. Hoarseness/voice change
According to one Italian study of diet surveys completed by Aspiration/cough/recurrent pneumonia
5,500 Italiansa study which has raised debates questioning
Anemia
its claims among cancer researchers cited in news reports
about it, eating pizza more than once a week appears to be a Hematemesis
Carcinoma of Esophagus 19
Odynophagia Clinical Stage

Odynophagia (50%) is the second most common presenting The new system recognizes five major prognostic stages from
symptom of esophageal cancer. It may be due to an ulcerated stage 0 to stage IV of tumor extent and tumor stage based on
area in the tumor or mediastinal involvement. But constant local invasion, nodal involvement and presence of metastases
pain in the mid back or mid chest is the typical presentation (Table 3). The 5-year survival rates associated with the tumor
of mediastinal invasion. invasion (T1 to T4) are approximately 80%, 45%, 25% and less
than 20%, respectively.
Anorexia and Weight Loss

Table 3: American Joint Committee on Cancer (AJCC) TNM staging
Up to 75% of patients have experienced anorexia and weight system for esophageal cancers (1997 revision)
loss when they seek medical attention.
Primary tumor infiltration (T)
Gastrointestinal Bleeding and Anemia TX Primary tumor cannot be assessed
T0 No evidence of primary tumor

Overt gastrointestinal bleeding as manifested by hematemesis
or melena rarely occur. But anemia is more common due to Tis Carcinoma in situ
subclinical bleeding. Hoarseness of voice, severe cough and T1 Tumor limited to mucosa/submucosa
recurrent pneumonia may present. T2 Tumor involving muscularis propria
T3 Involvement of adventitia, no extraesophageal involvement
COMPLICATIONS Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed

Pulmonary complications: Dyspnea, chronic cough,
N0 No nodal involvement
aspiration and postobstructive pneumonia, lung abscess,
esophagoairway fistula, pleural effusion, and halitosis N1 Regional nodes involved
Cardiovascular complications: Hemorrhage from the Distant metastasis (M)
aorta, arrhythmias, conduction abnormalities, and
MX Distant metastases cannot be assessed
pericardial effusion
M0 No distant metastases
M1 Distant metastases for tumors of the lower thoracic esophagus

PROGNOSTIC FACTORS

M1a Metastases in celiac nodes
M1b Other distant metastases
Tumors of the mid-thoracic esophagus
Radiographic Endoscopic M1a Not applicable
M1b Nonregional lymph nodes and/or other distant metastasis
Tumors measuring less than 5 cm are often confined to the Tumors of the upper thoracic esophagus
esophageal wall, whereas only 10% of those measuring greater M1a Metastases in cervical nodes
than 5 cm are localized. The presence of metastases is a poor M1b Other distant metastases
prognostic sign and is a contraindication to surgery. The AJCC stage groupings
presence of transmural invasion into adjacent organs, such Stage 0 Tis N0 M0
as pericardium or trachea is associated with poor prognosis.
Stage I T1 N0 M0
Evidence of lymph node involvement is also associated with a
poor overall 5-year survival (5%). Stage IIA T23 N0 M0
Stage IIB T12 N1 M0
Pathologic Stage III T3 N1 M0
The prognosis of any malignancy depends on the histologic T4 Any N M0

type and grade, and clinical stage. The vast majority of Stage IV Any T Any N M1
esophageal cancer are either SCC or adenocarcinoma. The Stage IVA Any T Any N M1a
overall prognosis of a poorly differentiated tumor is worse
Stage IVB Any T Any N M1b
than that of a well-differentiated tumor.
INVESTIGATIONS
Radiography
Chest X-ray
Posteroanterior (PA) and lateral chest radiography is indicated
in patients with chronic cough and in case of abnormal
chest findings on auscultation to demonstrate pulmonary
metastases, pneumonia or esophagorespiratory fistula.
Barium Swallow Radiography

It is indicated in selected patients and details high-grade
stenosis, obstruction, and fistulas (Fig. 2).
Fig. 3: CT with contrast axial image revealing esophageal carcinoma
Computed Tomography
Computed tomography scanning of the chest and upper
abdomen is indicated to assess the lymph nodes, and
pulmonary and hepatic metastases. The primary tumor
is seen as low density mass. The length and extent can be
assessed as well. Magnetic resonance imaging can assess but
has no advantages over CT scan (Fig. 3).
Endoscopy
Upper gastrointestinal endoscopy allows direct visualization
of the esophagus as well as tissue sampling to confirm the
diagnosis (Fig. 4). It allows accurate characterization of
tumors configuration, length and localization. At least six
biopsy samples should be taken from a non-necrotic area to
yield an accuracy approaching 100%. Brush cytology may be
used as a complementary technique.
Fig. 4: Endoscopic view of esophageal carcinoma
Investigations for Staging

Computed tomography and MRI are highly effective in
identifying solid organ metastases when these lesions are
larger than 510 mm (Fig. 3). For metastases detection by CT
scan, the accuracy is 6090% with overall sensitivity from 41
to 62% and specificity from 63 to 83%.
Positron Emission Tomography

Positron emission tomography (PET) is a noninvasive
procedure to detect distant metastases with a sensitivity of
88%, specificity of 93%, and accuracy of 91%. In one study
Fig. 2: Barium swallow of the esophagus showing irregular filling that compared PET with CT and endoscopic ultrasonography
defects suggestive of esophageal carcinoma (EUS) for local lymph node (LN) disease, the sensitivity of PET
A B
Figs 5A and B: (A) Endoscopy and (B) radial ultrasound revealing submucosal esophageal tumor
was lower than that of EUS (33% vs 81%), but the specificity Primary Therapy
may have been higher (87% vs 67%).
Surgery
Endoscopic Ultrasonography General considerations: Patients in the subgroup with
limited local spread (T1T2) and no regional lymph node
It is the most accurate in identifying T3 or T4 stage. Overall
involvement are potentially curable by surgery. Resectable
EUS nodal staging is less accurate. Endoscope ultrasound-
tumors are characterized by the absence of extension into
guided fine-needle aspiration has significantly improved the mediastinal structures and the absence of nodal or organ
diagnosis of malignant adenopathy (Figs 5A and B). metastases. Prior to surgery, the patient should have sufficient
cardiopulmonary reserve. Forced expiratory volume (FEV1)
should be 2 L or more. Resting ejection fraction of less than
TREATMENT 40% is an ominous finding.
Surgical approach: The surgical options available for
Esophageal carcinoma is a treatable disease, but it is rarely
esophageal tumor resection include:
curable. Whether the patient is a candidate for major curative
Transhiatal: It is currently the preferred surgical approach.
surgery is to be determined first before going to start treatment.
Combined right thoracic and abdominal (Ivor Lewis)
Unfortunately, over 60% patients with esophageal carcinoma Left thoracoabdominal
are not candidates for surgery at the time of presentation due En bloc, either two field- or three field-resection remains
to advanced stage of the disease or significant comorbidity. the definitive surgical cure for esophageal cancer (field
Primary treatment modalities include: oneceliac and splenic nodes, field twoinfracarinal
Surgery alone posterior mediastinal nodes, field threeupper
Chemotherapy with radiation therapy mediastinal and cervical nodes).
Combined modality therapy (chemotherapy + surgery,
chemotherapy and radiation therapy + surgery) is under
clinical evaluation Combination Therapy
Endoscopic mucosal resection (EMR) and or photodynamic It is alternative to surgery. Definitive radiation therapy in
therapy in selected patients with superficial carcinoma is combination with chemotherapy (fluorouracil and mytomycin)
also under evaluation. is used for treatment.
Treatment of Superficial Esophageal Cancer Chemical sclerosant injection: Absolute alcohol is the
most widely used sclerosant chemical agent
Endoscopically Photodynamic therapy (PDT): It has been successful in
EMR reducing tumor bulk and in opening the lumen in patients
Laser therapy with complete obstruction. It also acts as a salvage therapy
Argon plasma coagulation (APC) in patient with stents failure due to tumor ingrowth
Photodynamic therapy. or overgrowth. It is done by intravenous injection of a
photosensitive chemical, porfimer sodium (Photofrin),
at a dose of 2 mg/kg body weight followed by exposure of
Palliation Therapy red light at a wave length of 630 nm to tumor resulting in
Palliative therapy remains the mainstay of treatment options necrosis of the tumor
for incurable esophageal carcinoma with what the majority of Monopolar and bipolar electrocautery: It is rarely used
patients present. The following palliative therapy options are now a days
available. Argon plasma coagulation: It uses ionized argon gas to
convey electrical energy to achieve thermal desiccation
of the tumor tissue. But it is less effective in relieving
Radiation Therapy dysphagia in advanced esophageal cancer
Neodymium:yttrium-aluminium-garnet (Nd:YAG):
External beam radiation therapy alone provides reasonable
Nd:YAG laser relieves dysphagia by coagulating and
palliation for esophageal cancer. Radiotherapy achieves
vaporizing the malignant tissue under endoscopic control.
palliation of dysphagia in 7090% of patients. Combination of
Multiple laser sessions are required to improve dysphagia.
external beam radiation with intraluminal irradiation using
The requirement for the laser therapy are as follows:
cobalt-60, cesium-137 or iridium-192 is possible to increase
Growth should be exophytic or polypoid
the dose of radiation to the tumor, and it is promising both in
Preferably, it will be located in the straight segment of
median and 5-year survival.
esophagus
Contraindication to radiotherapy: Mass shorter than 5 cm.
Tracheal or bronchial involvement
Endoscopic mucosal resection: EMR or mucosectomy is used
Cervical esophageal location of the tumor
to treat superficial flat and polypoid neoplasm of the mucosa
Stenosis.
of gastrointestinal tract. Long-term studies show that EMR
outcomes are similar to those of surgery to the treatment,
Chemotherapy particularly in early gastrointestinal cancers. Different EMR
techniques are as follows:
Single agents: The clinical response rates (510%) and Injection and snare cautery
duration response (24 months) of any single agent of any Injection with precut
class of chemotherapy are poor. EMR with cap
Combination chemotherapy: It is superior to single agent EMR with band ligation.
chemotherapy in the management of esophageal cancer. It is indicated:
In general, the cisplatin-based combination chemotherapy When the lesion is superficial lesion
(commonly used) has yielded a response rate of 2535%. No evidence of lymph node metastasis
To date, there is no role of single agent or combination Bleeding, perforation and necrosis are the major
chemotherapy as an adjuvant to surgery. complications.
The commonly employed modalities of EMR include strip
biopsy, double-snare polypectomy, resection with combined
Endoscopic Therapy use of highly concentrated saline and epinephrine, and
Dilation: Esophageal dilation is commonly done by resection using a cap.
expandable balloons through-the-scope or wire-guided Esophageal prostheses: The prostheses (stents) are inserted
polyvinyl bougies under fluoroscopy. endoscopically under fluoroscopic guidance and provide
Ablation: The available options for tumor ablation are as relief of dysphagia effectively. At present, self-expanding
follows: metallic stents (SEMS) covered/uncovered are widely used
chemotherapy and as an adjunct to other palliative measures.

Enteral access is achieved surgically (gastrojejunostomy),
endoscopically [percutaneous endoscopic gastrostomy
(PEG), direct percutaneous jejunostomy or PEG with a jejunal
feeding tube extension] or radiologically.
PROGNOSIS
Despite the widespread use of different modalities of
treatment, the reported overall 5-year survival rates are at
best 1015%. Delayed presentation, rapid intramural invasion
and distant metastases are responsible for poor prognosis.
The patients with early stage of disease carry better prognosis.
The 5-year survival rate is greater than 40% in a patient with
T1 or T2 disease without nodal involvement, but it is less than
25% for patients with T3 or T4 lesion.
Stage 0, I, and III tumors are resectable for cure and 5-year
survival is greater than 85%, 50% and 40%, respectively. On
the other hand, stage IV tumors are considered incurable and
nonresectable. Nodal involvement has prognostic impact and
Fig. 6: Self-expanding metallic stents used for the palliation of
esophageal carcinoma it is independent of the T classification. The 5-year survival is
over 70% for N0 disease, but for N1 disease it is near to 40%.
(Fig. 6). Covering the stent with a polymer sheet effectively

reduces tumor ingrowth and provides for treatment of
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metallic (plastic) stent recently introduced. It is approved 4. EII C, May A, Gossner L, et al. Endoscopic mucosal resection of
by the Food and Drug Administration (FDA) for palliation of early cancer and high-grade dysplasia in Barretts oesophagus.
malignant dysphagia. Gastroenterogy. 2000;118:670-7.
Major complications of SEMS placement include tumor 5. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med.
ingrowth or tumor overgrowth (520%), which can be treated 2003;349:2241-52.
effectively with laser or thermal contact therapy, stent 6. Heath EI, Limburg PJ, Hawk ET, et al. Adenocarcinoma of the
migration (10%) and chest pain. Other complications are food esophagus: risk factors and prevention. Oncology (Williston
impaction, bleeding, and reflux esophagitis. Park). 2000;14(4):507-14.
7. Koshy M, Esiashvilli N, Landry JC, et al. Multiple management
modalities in esophageal cancer: epidemiology, presentation
Enteral Nutrition and progression, work-up and surgical approaches. Oncologist.
2004;9(2):137-46.
Enteral nutrition support may be indicated in an attempt to 8. Ku GY, Ilson DH. Preoperative therapy for esophageal cancer.
improve functional status before and after surgery, during Gastroenterol Clin North Am. 2009;38(1):135-52.
9. Lagergren J, Bergstrm R, Lindgren A, et al. Symptomatic [online]. Available from http://guidance.nice.org.uk/IPG206

gastroesophageal reflux as a risk factor for esophageal [Accessed January, 2013].
adenocarcinoma. N Engl J Med. 1999;340(11):825-31. 13. Pisani P, Parkin DM, Bray F, et al. Estimates of the worldwide
10. Lepage C, Rachet B, Jooste V, et al. Continuing rapid increase mortality from 25 cancers in 1990. Int J Cancer. 1999;83:
in esophageal adenocarcinoma in England and Wales. Am J 18-29.
Gastroenterol. 2008;103(11):2694-9.
14. Radu A, Wagnires G, van den Bergh H, et al. Phtodynamic
11. Narahara H, Lishi H, Tatsuta M, et al. Effectiveness of endoscopic
therapy of early squamous cell cancers of the esophagus.
mucosal resection with submucosal saline injection technique
for superficial squamous carcinomas of the esophagus. Gastrointest Endosc Clin N Am. 2000;10(3):439-60.
Gastrointest Endosc. 2000;52:730-4. 15. Systemic review of the staging performance of 18F-fluorod
12. NICE Interventional Procedural Guideline. (2007). Palliative eoxyglucose position emission tomography in esophageal
photodynamic therapy for advanced oesophageal cancer. cancer. J Clin Oncol. 2004;22:3805-12.
3
cHAPTER
Peptic Ulcer Disease
Javed Yakoob, SM Wasim Jafri
INTRODUCTION drugs suggest the role of acid in this process. GU is associated

with severe abdominal pain associated with meals that is
Peptic ulcers (PUs) are mucosal breaks in the gastric or infrequently relieved by food or antacids.
small intestinal mucosa that extend through the muscularis Epigastric discomfort described as a vague or cramping
mucosa. In contrast to erosions, which are small and is experienced in two-thirds of the patients that may localize
superficial mucosal lesions, PU varies in size from 5 mm to in the upper quadrants or the hypochondrium. It may also
several centimeters. The term PU is used to group together be associated with burning pain that may radiate to the
chronic duodenal ulcer (DU) and chronic benign gastric ulcer back. Symptomatic periods lasting weeks are associated
(GU). A precise diagnosis of either DU or GU is required to with similar to longer duration symptom-free periods is
manage them clinically as separate though related diseases. characteristic of DUs. The reliance on symptoms alone may
PU is an important cause of morbidity and increased result in overdiagnosis of nonulcer dyspepsia (NUD) and will
healthcare costs. They can progress to complete resolution miss PUs in patients.
without treatment or complications, such as bleeding and The classic symptoms of acid dyspepsia relieved with food
perforation with considerable morbidity and mortality. occur in only about 50% of patients with DU. An increase in
Those experiencing ulcer complications are at risk of further appetite or weight gain, indigestion associated with particular
complications. Those with history of delayed ulcer healing dietary food resulting in anorexia, weight loss and fatty food
are likely to experience early recurrence. These recurrences intolerance is reported in approximately 20%. In 2060%,
are usually associated with active Helicobacter pylori (H. DU pain may be described as heartburn or irritable bowel
pylori) infection, intake of nonsteroidal anti-inflammatory syndrome like crampy abdominal pain associated with
drugs (NSAIDs), etc. Eradication of H. pylori infection alters altered bowel habit. Silent asymptomatic PU was detected on
the incidence of ulcer relapse. A meta-analysis of 14 studies screening endoscopy in 11% of 6,457 subjects.1
demonstrated recurrence of DUs followed in less than 10% Also, 2050% of complicated asymptomatic ulcers are
who had documented H. pylori eradication compared to 65 presented in elderly patients and individuals on NSAIDs.
90% in those who did not have H. pylori eradicated. Mechanism of PU symptoms is unclear. Some patients with
DU are known to develop symptoms when the ulcer crater is
exposed to acid. The secretory rates and concentration of acid
CLINICAL FEATURES in DU patients are similar to that of asymptomatic patients
and in controls. Often there is no correlation between the
Symptoms presence of an active ulcer and symptoms. Symptoms may
persist in 40% of patients with endoscopically healed ulcers,
The symptoms vary from nausea, vomiting, epigastric pain, while 1544% with an ulcer crater may be symptom-free.
postprandial belching, bloating, anorexia and early satiety. Absence of symptoms does not guarantee ulcer healing is
Clinical assessment has poor predictive value for the specific complete, nor does the persistence of symptoms predict the
diagnosis found upon endoscopy. The classic symptoms presence of an ulcer crater. In some cases, this sensitization
of DU occur when acid is in excess. Symptoms also occur to acid is related to an ulcer crater or secretion of an excess
late at night when the circadian acid secretion is maximal. acid, but it may also occur in grossly normal mucosa with
Symptoms relieved by food, antacids, and acid-reducing physiologic levels of acid secretion.
Clinical Signs Nonsteroidal Anti-inflammatory Drugs

The physical examination is often normal and unreliable. Nonsteroidal anti-inflammatory drugs act by inhibiting
Some patients may exhibit epigastric tenderness to deep prostaglandin synthesis that affect the amount of gastric
palpation. Hematemesis or occult blood may be detected in acid generated, integrity of the mucosal barrier, amount of
the setting of bleeding ulcers. Tachycardia and orthostatic bicarbonate and glutathione generated and rate of mucosal
hypotension may be found in patients with significant blood flow.
bleeding or dehydration, while rigid abdomen with diffuse
tenderness may reflect ulcer perforation with peritonitis.
Rarely, a distended abdomen or a succession splash can be Gastric Acid Hypersecretion
noted in patients with an ulcer-associated outlet obstruction. Although only a small proportion of DU patients have acid
The majority of DUs develop in the bulb or pyloric channel. hypersecretion, high normal or modestly elevated values
Patients with DUs tend to have a younger age of onset, often appear to be associated with DU. Among H. pylori-positive
between 30 years and 55 years. In the stomach, most benign subjects with DU, the drive for acid secretion that includes
ulcers are found in the antrum and lesser curvature of the H. pylori-dependent hypergastrinemia reverses following
stomach at the junction of the body and antrum. GUs often cure of the infection.3 Relative hypergastrinemia is seen
occur among patients between the ages of 55 years and 70 in H. pylori-infected subjects are due to suppression of
years with a peak incidence in the sixth decade. somatostatin. The abnormality in acid secretion seen in
DU subjects is linked to the host predisposition rather than
H. pylori infection. The defective regulation of acid secretion
ETIOLOGY in DU is related to impaired control of inhibitory mechanisms
and can be seen in people without DU. The abnormalities in
Multiple factors are involved in the pathophysiology of most gastrin, somatostatin and acid secretion normalizes within
PUs. Primary malfunction of gastric secretory, defense or 1 year of H. pylori eradication.
repair mechanisms are uncommon causes of ulcer. Most A higher basal and pentagastrin-stimulated acid secretion
ulcers are associated with H. pylori infection and NSAIDs was described in patients with recurrent ulcers following
intake. successful H. pylori eradication compared to patients without
recurrent ulcers. Among H. pylori-negative subjects, a subset
has acid hypersecretion without hypergastrinemia. Another
Helicobacter pylori study with non-H. pylori, non-NSAID DU found increased
H. pylori affects gastric acid secretion, gastric metaplasia, gastrin response to a meal and increased peak gastric acid
immune responses and mucosal defense mechanisms. secretion. Some subjects with non-H. pylori, non-NSAID
Two virulence markers of H. pylori strains that include the hypersecretion may have a component of muscarinic-
cytotoxin-associated gene A (cagA) and the vacuolating dependent, vagal hyperactivity. In the absence of H. pylori or
cytotoxin (vacA) have been found to be associated with distinct gastrinoma, fasting hypergastrinemia is only rarely found in
gastroduodenal disorders. Various studies demonstrated an hypersecretory DU patients, sometimes linked to antral G-cell
association between the presences of cagA antibodies and hyperfunction. Increased acid secretion is an important factor
PU and gastric carcinoma. The gene encoding vacA is present in some patients with ulcer recurrences following successful
in all H. pylori strains; however, the activity of this cytotoxin H. pylori eradication and in some patients with non-H. pylori,
is dependent on its allelic type is positive in only 4060% of non-NSAID DU.
patients with PU disease and in only 30% of H. pylori strains
isolated from patients with chronic gastritis. In a recent study,
cagA was found associated with GU in 20 (63%) (p = 0.04), Duodenum
DU in 23 (72%) (p = 0.003) and GC in 29 (73%) (p = 0.001) The majority of DU patients have impaired duodenal
compared to NUD in 51 (42%). The vacA allele s1am1 was bicarbonate secretion, which is H. pylori-dependent, since
associated with GU in 23 (72%) (p = 0.001), DU in 17 (53%) cure of the infection reverses the defect. The increased gastric
(p < 0.001) and GC in 23 (58%) (p = 0.003) compared to NUD acid secretion with reduced duodenal bicarbonate lowers
in 38 (32%), while vacA s1bm1 was associated with GU in 9 duodenal pH and promotes development of gastric metaplasia
(28%) (p = 0.001), DU in 12 (37%) (p < 0.001) and GC 11 (28%) in the duodenum. Areas of gastric metaplasia infected by
(p < 0.001) compared to NUD in 13 (11%), respectively.2 H. pylori results in duodenitis and enhances the susceptibility
Peptic Ulcer Disease 27
to acid injury and DU. In patients with endoscopy-negative, Twin studies provide evidence for genetic predisposition
NUD has described duodenal colonization by H. pylori as a to PU independent of predisposition to H. pylori infection.
highly significant predictor of the subsequent development There is a high concordance of a self-reported ulcer history
of DU. In gastrinoma patients, there is an excess gastric in monozygotic compared to dizygotic twins. Another twin
acid secretion, which is associated with prominent gastric study also concluded that genetic factors were linked to DU,
metaplasia in the duodenum. independent of environmental variables. A study described a
family in which PU was linked to elevated serum pepsinogen
group A in the absence of H. pylori infection. Blood groups
Gastric Ulcer O and A, the Lewis phenotype Le (a + b-), and nonsecretors
A GU occurring in the stomach proximal to the distal antrum of ABH, in particular, have an increased risk of DU. However,
and prepyloric region is usually associated with low-normal other studies did not show any association of blood group O
acid secretion associated with a low-normal parietal cell with H. pylori infection or with PU.
mass. These findings correspond to the encroachment of
oxyntic mucosa by advancing inflammation and oxyntic
gland atrophy.4 In contrast to GU involving the gastric body,
Factors that Influence the Course of
patients with ulcers in the distal antrum or GU associated Peptic Ulcer
with concurrent DU have normal or even increased levels of
A number of risk factors potentially impact the rate of ulcer
acid secretion.
healing, complications, and the tendency for recurrence.
RISK FACTORS Smoking

Studies found that smoking facilitated development of PU
Familial Aggregation disease.11 PUs in smokers are difficult to treat and have a
Studies have recognized a polygenic inheritance pattern higher rate of recurrence. In a prospective study, the ulcer
in families with history of PU disease (PUD). First-degree risk progressively increased with number and years of
relatives of patients with GU have a threefold increase in the cigarette smoking. The evidence supports an association
prevalence of GU but not DU, while patients with DU have a between smoking and PUD in H. pylori-infected subject.
threefold increase in the prevalence of DU but not GU. However, smoking does not appear to be a risk factor for ulcer
relapse once H. pylori have been eradicated. Smoking also
did not influence recurrence of the H. pylori infection, which
Genetic Factors was observed in 4.8 and 4.4% of smokers and nonsmokers,
respectively. As an example, smoking and chronic nicotine
Host factors appear to be important in predisposing to H.
treatment stimulated basal acid output to a greater extent in
pylori infection and to disease outcomes, such as DU and
smokers with DU history compared to smokers without a DU
gastric cancer. Genetic polymorphism related to synergy
history.12
between host [tumor necrosis factor (TNF)- promoter]
and bacterial (induced by contact with epithelium, or the
iceA1 gene) factors have been related to DU in children.5 Nonsteroidal Anti-inflammatory Drugs
Host polymorphisms involving the cytokine interleukin
(IL)-1- are linked to DU probably related to effects of H. Nonsteroidal anti-inflammatory drugs are responsible for the
pylori-associated inflammation and acid secretion.6,7 Host majority of PUs not caused by H. pylori. These are associated
polymorphisms in TNF- were associated with increased with an increased risk of complications. NSAIDs cause de
risk for GU and gastric cancer, but not DU in Japanese novo PUs and exacerbate underlying PUD due to H. pylori.
population.8 Other studies have been negative for both factors In a study, NSAID histories of 494 patients with PUD were
in DU.9 One study involving 200 patients with DU and GU compared with 972 matched controls. The odds ratio for the
and 342 healthy controls found that the TGFB1+869(*) C/C development of GU and DU was 5.9 and 4.9, respectively for
genotype was associated with reduced risk of developing NSAID users compared to controls. The odds ratio for the
DU.10 Genetic polymorphism relating to cyclooxygenase-1 development of hemorrhage complicating a PU was 5.2, as
(COX-1) and prostaglandin production demonstrated was the risk of perforation. NSAIDs are also responsible for
T1676C COX-1 polymorphism associated with GU in non- a significant number of PUs that is refractory to conventional
NSAID users and with both GU and DU in NSAID users. therapy.
Alcohol Functional Dyspepsia

Alcohol also stimulates acid secretion. In high concentrations Dyspepsia commonly encountered in primary care and
it damages the gastric mucosal barrier and induces acute gastroenterology practice is also known as functional
gastric mucosal lesions that are characterized by mucosal (idiopathic) or NUD. It is described as chronic recurrent
hemorrhages. Alcohol abuse interferes with patient abdominal pain or discomfort centered in the upper abdomen;
compliance and ulcer healing. a duration of greater than or equal to 4 weeks with symptoms
25% of the time (i.e. on 7 days or more) in the absence of clinical,
biochemical, endoscopic or ultrasonographic evidence of
Diet any known organic disease to explain the symptoms (i.e.
Fried fat rich foods, drinks and spices cause dyspepsia; acid-peptic, neoplastic disease of the stomach, esophagus or
however, there are no convincing data that these specific foods duodenum, pancreas or hepatobiliary system), and no history
can cause or reactivate PUs. DU is much more common in the of major gastric or intestinal surgery.
rice-eating southern regions of India compared to the wheat-
eating northern regions.13 A study described low consumption
of chili peppers by DU patients compared to controls,
Gastric Carcinoma
protected against mucosal damage. High consumption of Gastric malignancy may be associated with chronic dyspepsia,
fruits and vegetables, dietary fiber and vitamin A reduced particularly in patients over 4555 years of age and in those
risk of ulcer disease. Coffee-stimulated acid secretion and with alarm symptoms, e.g. unintended weight loss, bleeding,
produced dyspepsia, which often resulted from enhanced anemia, dysphagia, odynophagia, hematemesis, a palpable
esophageal reflux. However, coffee consumption is not a risk abdominal mass or lymphadenopathy, persistent vomiting,
factor for ulcer disease, although increased consumption unexplained iron deficiency anemia, family history of
may be associated with H. pylori infection. Food intolerances upper gastrointestinal cancer, previous gastric surgery and
common in patients with PU disease may reflect sensitivities jaundice. Early gastric cancer is usually asymptomatic or
to substances in foods. Milk because of its calcium and has few associated symptoms. It can present with dyspepsia
protein content stimulates more acid secretion than it indistinguishable from PU. A new onset of symptoms or a
buffers and is not an effective antacid. Human milk contains recent change in pattern should raise concern over possible
protective factors including growth factors, surface active neoplasia. In a recent review of presenting symptoms epigastric
phospholipids and prostaglandin E2. Thus, it is possible that pain or dyspepsia similar to PU was present in 6590%, nausea
milk has antiulcer actions that override the stimulation of and/or vomiting in 640% and anorexia in 1240%. Alarm
acid secretion. signs or symptoms suggestive of invasive disease, such as
anemia or weight loss, occurred less frequently (515% and
440%, respectively). Other neoplastic processes can mimic
Psychologic Factors PUs, presenting with dyspepsia or ulcers, such as gastric
Poorly tolerated stress or depressive symptoms increased lymphoma, leiomyosarcomas, primary gastric and metastatic
the risk of ulcer development over the next 915 years. Work- malignant melanoma and metastatic renal cell carcinoma.
related stress, social problems and post-traumatic stress
disorder are predictive of subsequent ulcer disease. PU
complications become much more prevalent during periods
Drug-induced Dyspepsia
of natural disaster. Stress, anxiety and depression are known Many drugs are known to cause dyspepsia, epigastric distress,
to impair healing and to promote relapse of ulcers. nausea or vomiting. These include NSAIDs, with or without
ulceration, theophylline and digitalis. Caffeine, coffee,
alcohol and smoking can also contribute to symptoms.
DIFFERENTIAL DIAGNOSIS
Disorders that cause symptoms in the upper abdomen and Infiltrative or Granulomatous Diseases
ulcerative lesions of the stomach and duodenum include the Infiltrative or granulomatous diseases can present with
following: dyspepsia and occasionally ulceration. Involvement of
Peptic Ulcer Disease 29
the stomach is the most common site of sarcoidosis in the Biopsy specimen sent for histologic examination is stained
gastrointestinal tract, almost always occurring in association with hematoxylin and eosin, modified Giemsa, Warthin-
with pulmonary disease. Ulceration resembling PUD Starry or Genta staining for H. pylori infection. The presence
can occur with or without enlargement of mucosal folds. of polymorphonuclear leukocytes in inflamed gastric tissue
Eosinophilic granuloma and Wegeners granulomatosis can is suggestive of H. pylori gastritis. Culture of H. pylori from
have similar presentation. Hypertrophic gastritis (including biopsy samples has a specificity of 100% if results are positive,
Mntriers disease) may present with dyspeptic symptoms. but it is not routinely performed. Culture is difficult and is
Crohns disease of the stomach or duodenum may produce usually performed to determine antibiotic susceptibilities
symptoms and a radiographic appearance that mimics PU. for patients who fail to respond to second-line eradication
Isolated gastroduodenal Crohns may produce radiographic therapy. Urea breath test (UBT) based on detecting H. pylori-
abnormalities that are usually present in distal portions of the derived urease activity in the stomach and stool antigen test
duodenum and the small intestine. using polyclonal anti-H. pylori capture antibody adsorbed
to microwells are also used for the diagnosis of H. pylori
infection. It is generally recommended to wait for 4 weeks
Infections after completing eradication therapy to confirm successful
Gastric and duodenal tuberculosis can present with mucosal cure. Proton pump inhibitors (PPIs) should be withheld for
ulceration. It is difficult to diagnose in the absence of a 24 weeks and antibiotics and bismuth compounds for 4
negative acid-fast stain and caseating granulomas, which are weeks prior to testing for H. pylori infection.
often submucosal, are not demonstrated in the superficial For patients on PPIs, the diagnostic yield of RUT and
gastric biopsies obtained at endoscopy. Other infections also histology was reduced from both the gastric antrum and
associated with chronic ulcer and abdominal pain includes body. In these patients, polymerase chain reaction for H.
Mycobacterium avium intracellulare, strongyloidiasis pylori is more sensitive than RUT and histology.15
and giardiasis. Giardiasis may produce upper abdominal
discomfort, nausea, diarrhea and sometimes anorexia and
malabsorption.14 Dyspeptic symptoms may persist over TREATMENT
months associated with periods of diarrhea lasting a few days.
There are more effective medications for the suppression of
stomach acid. They relieve symptoms and allow ulcers to heal.
Duodenal Tumors If an ulcer is associated with aspirin or other NSAID, avoiding
Duodenal carcinoma or localized lymphoma may present them prevent ulcer recurrence. There are several antibiotic
with gastrointestinal bleeding or as benign ulcer. They are regimes available to treat H. pylori infection and cure ulcers.
uncommon and most cases present as a mass lesion rather Younger patients with symptoms suggestive of
an ulcer. functional dyspepsia without alarm symptoms are
often treated with antacids or H2 antagonists before
esophagogastroduodenoscopys undertaken. Patients on
NSAIDs may also be prescribed a prostaglandin analog
DIAGNOSIS (misoprostol) to prevent PUs. When H. pylori infection is
Definitive diagnosis of PUs can be made with upper present, combinations of two antibiotics (e.g. clarithromycin
endoscopy. Endoscopy has a much higher diagnostic and amoxicillin or metronidazole) and one PPI are
yield than barium contrast radiology and enables biopsy commonly used. In triple therapy failures, three antibiotics
specimens to be obtained for evaluation of H. pylori infection (e.g. amoxicillin + clarithromycin + metronidazole) are used
and underlying malignancy. Up to 5% GUs are malignant; together with a PPI and sometimes with bismuth compound.
biopsy is recommended from the ulcer margin. A follow- First-line therapy for uncomplicated cases consists of
up endoscopy is scheduled 12 weeks after starting acid amoxicillin + clarithromycin + PPI. In a recent study of
suppressive medications to document complete healing. GUs triple therapy with esomeprazole 20 mg, amoxicillin 1g and
greater than 3 cm in size and those associated with a mass clarithromycin 500 mg twice a day for 10 days were prescribed
are more likely to be malignant. Actively bleeding or ulcers to 111 patients with a mean age of 46 16 years and 14C UBT
at risk of rebleeding can be treated during endoscopy with repeated 4 weeks after treatment. The mean age of treatment
hemostasis therapy. In patients undergoing endoscopy, an failure was 39 14 years compared to 48 16 years with
antral biopsy can be obtained for rapid urease test (RUT), eradication (P = 0.002). Treatment failure was associated
which has sensitivity of 89100% and specificity of 92100%. with a younger mean age; collagen-like region-related point
mutations in the 23S rRNA gene of H. pylori and vacA s1a and 4. Malaty HM, Graham DY, Isaksson I, et al. Are genetic influences
m1 alleles associated with cagA negativity.16 on peptic ulcer dependent or independent of genetic influ
In another study, H. pylori isolates resistance rate noted to ences for Helicobacter pylori infection? Arch Intern Med. 2000;
clarithromycin was 33%, metronidazole 48% and amoxicillin 160(1):105-9.
2%. Clarithromycin resistance was seen in 30 H. pylori 5. Wilschanski M, Schlesinger Y, Faber J, et al. Combination of
Helicobacter pylori strain and tumor necrosis factor-alpha
isolates, 20 (67%) from patients with NUD, six (20%) with GU
polymorphism of the host increases the risk of peptic ulcer disease
and four (13%) with DU. Triple therapy failure was associated
in children. J Pediatr Gastroenterol Nutr. 2007;45(2):199-203.
with clarithromycin resistance in 28 (93%) (P < 0.001). It was 6. Furuta T, El-Omar EM, Xiao F, et al. Interleukin 1beta
associated with A2142G mutation in 20 (67%; P < 0.001), polymorphisms increase risk of hypochlorhydria and atrophic
A2143G mutation in 12 (40%; P < 0.001) and A2142C mutation gastritis and reduce risk of duodenal ulcer recurrence in Japan.
in five (17%; P = 0.003).17 Gastroenterology. 2002;123(1):92-105.
In the absence of H. pylori infection, PPIs are often used 7. Garcia-Gonzalez MA, Lanas A, Savelkoul PH, et al. Association of
in high doses for long-term. Treatment of H. pylori relieves interleukin 1 gene family polymorphisms with duodenal ulcer
symptoms and leads to eventual healing of DUs. Eradication disease. Clin Exp Immunol. 2003;134(3):525-31.
of H. pylori infection must be documented when a decision 8. Sugimoto M, Furuta T, Shirai N, et al. Different effects of
has been made to treat it. Recurrence of infection requires polymorphisms of tumor necrosis factor-alpha and interleukin-1
beta on development of peptic ulcer and gastric cancer. J
retreatment if necessary with other antibiotics. For this H.
Gastroenterol Hepatol. 2007;22(1):51-9.
pylori sensitivities to commonly used antibiotics must be
9. Garcia-Gonzalez MA, Strunk M, Piazuelo E, et al. TGFB1 gene
known. Since the widespread use of PPIs, surgical procedures polymorphisms: their relevance in the susceptibility to
like highly selective vagotomy for uncomplicated PUs Helicobacter pylori-related diseases. Genes Immun. 2006;7(8):
became obsolete. Perforated PUs requires surgical repair. 640-6.
Most bleeding ulcers are treated with either cautery, injection 10. Arisawa T, Tahara T, Shibata T, et al. Association between promoter
or clipping. PUs generally heal within 13 months. Smoking polymorphisms of nuclear factor-erythroid 2-related factor 2
and use of alcohol or NSAIDs are known to inflame the gene and peptic ulcer diseases. Int J Mol Med. 2007;20(6):849-53.
stomach and duodenal mucosa leading to failure of the ulcer 11. Rosenstock S, Jrgensen T, Bonnevie O, et al. Risk factors
to heal. Use of nonprescription medications that include for peptic ulcer disease: a population based prospective
some NSAIDs including aspirin, ibuprofen and naproxen is cohort study comprising 2416 Danish adults. Gut. 2003;52(2):
186-93.
an important cause. In other cases, some H. pylori bacteria
12. Maity P, Biswas K, Roy S, et al. Smoking and the pathogenesis
are resistant to prescribed antibiotics. In rare cases, refractory
of gastroduodenal ulcerrecent mechanistic update. Mol Cell
ulcers (fail to heal) may be the result of Crohns disease or Biochem. 2003;253(1-2):329-38.
cancer or gastrinomas leading to extreme overproduction of 13. Tovey FI, Hobsley M, Kaushik SP, et al. Duodenal gastric metaplasia
gastric acid. and Helicobacter pylori infection in high and low duodenal ulcer
prevalent areas in India. J Gastroenterol Hepatol. 2004;19(5):497-
505.
REFERENCES 14. Yakoob J, Jafri W, Abid S, et al. Giardiasis in patients with
dyspeptic symptoms. World J Gastroenterol. 2005;11(14):
1. Lu CL, Chang SS, Wang SS, et al. Silent peptic ulcer disease: 6667-70.
frequency, factors leading to silence, and implications regarding 15. Yakoob J, Jafri W, Abbas Z, et al. The diagnostic yield of various
the pathogenesis of visceral symptoms. Gastrointest Endosc. tests for Helicobacter pylori infection in patients on acid-reducing
2004;60(1):34-8. drugs. Dig Dis Sci. 2008;53(1):95-100.
2. Yakoob J, Abid S, Abbas Z, et al. Distribution of Helicobacter pylori 16. Yakoob J, Jafri W, Abbas Z, et al. Risk factors associated with
virulence markers in patients with gastroduodenal diseases in Helicobacter pylori infection treatment failure in a high prevalence
Pakistan. BMC Gastroenterol. 2009;9:87. area. Epidemiol Infect. 2010;7:1-10.
3. Hirschowitz BI, Lanas A. Atypical and aggressive upper 17. Yakoob J, Abid S, Abbas Z, et al. Antibiotic susceptibility patterns
gastrointestinal ulceration associated with aspirin abuse. J Clin of Helicobacter pylori and triple therapy in a high-prevalence
Gastroenterol. 2002;34(5):523-8. area. Br J Biomed Sci. 2010;67(4):197-201.
4
cHAPTER
Peptic Ulcer Disease in

AsiaPacific
Sony S Thazhath, Mazhar Haque
INTRODUCTION AND PREVALENCE the GU group and five deaths in the DU group. However, a 10-
year experience on children and adolescents from Hong Kong
Peptic ulcer can be described as a breach in the mucous from 1996 to 2006 had contrasting findings with 75% of UGIB
membrane, which lines parts of the alimentary tract exposed cases attributed to DUs, with H. pylori infection implicated in
to digestive juices, such as esophagus, stomach, duodenum, majority of them. There was a male predominance at a ratio of
jejunum, and parts of ileum. Peptic ulcer disease (PUD) tends 2.6:1.
to have a chronic remitting course with poor correlation
between symptoms and severity of the disease, which
limits the ability to accurately document its incidence and RISK FACTORS
prevalence. A rural Chinese random endoscopic survey on
2,423 subjects showed a prevalence of 9.3%, of which 5.7% Nonsteroidal anti-inflammatory drugs and H. pylori infection
were duodenal ulcers (DUs), 3.4% were nonmalignant gastric account for the majority of peptic ulcer bleeds. Both these
ulcers (GUs), and 0.2% were concurrent GUs and DUs. In are more prevalent in the elderly population who are least
comparison, a Western study from Sweden showed PUD able to tolerate ulcer complications. Other causes of peptic
prevalence of only 4.1% with a 1:1 ratio between GU and DU. ulcer include gastric malignancies, lymphomas, eosinophilic
A downward trend in the prevalence of DUs in South Korea gastroduodenitis, systemic mastocytosis, radiation damage,
has been noted from 1994 to 1995 and from 2004 to 2005, burns (Curlings ulcer) and severe systemic disease (stress
whereas GUs showed a rising trend. The investigators attribute ulcer). Anastomotic ulcer after subtotal gastric resection is
the reduction of DU prevalence to the widespread efforts well known as is the Cameron ulcer where a hiatus hernia
at Helicobacter pylori eradication; and the increase in GU passes through the diaphragmatic hiatus.
prevalence to the increasing use of aspirin and nonsteroidal Helicobacter pylori infection itself can account for a
anti-inflammatory drugs (NSAIDs). Another similar study 1.8-fold increase in the risk of DU development. The risk
involving retrospective analysis of the endoscopic records of ulcer formation is increased substantially when NSAID
from a busy South Indian tertiary referral center between the users are infected with H. pylori. Though cyclooxygenase-2
years 1989 and 2004 showed a decreasing trend of endoscopic (COX-2) inhibitors are known to carry lower risk of PUD
diagnosis of GUs as well as DUs, which were attributed to and its complications as compared to nonselective NSAIDs,
improving sanitation and hygiene along with widespread use concurrent use of nonselective NSAIDs or COX-2 inhibitors
of proton pump inhibitors (PPIs) and treatment of H. pylori with aspirin increase the incidence of PUD (more commonly
infection. GUs) as compared with using aspirin alone. Another widely
Although chronic ulcers can be asymptomatic, upper used medication implicated in the causation of peptic ulcer
gastrointestinal bleeding (UGIB) is the most frequent and is glucocorticoids. However, if used alone, it does not seem
severe complication of PUD. In Korea, the incidence of peptic to increase the risk of ulcer formation. Other reported risk
ulcer bleed was 22.1 per 100,000 during 20062007, and the factors for the development of PUD include use of antiplatelet
age-specific incidence rate and 30-day mortality showed a agents, Helicobacter heilmannii, cytomegalovirus infections,
rising trend with advancing age. In a recent observation in Behcets disease, Zollinger Ellison syndrome, Crohns disease
Australia, over a period of about 4 years from 2004 to 2008 and cirrhosis with portal hypertension.
on 265 bleeding peptic ulcer cases, the mean age of patients Idiopathic PUD is also well described and multiple DUs are
was 71 years (SD = 15). Gastric ulcers (n = 146) outnumbered more frequently seen in this group. With increasing rates of H.
DUs (n = 119) and melena was the most common presenting pylori treatment, a disproportionate rise in the incidence of
complaint. The overall mortality was 3.4% with four deaths in idiopathic bleeding peptic ulcer has been noted in Hong Kong
and South Korea. In Australia, non-H. pylori, non-NSAID RACIAL AND REGIONAL DIFFERENCES
related PUD (idiopathic) was found to be prevalent in younger
age groups as compared to NSAID-induced counterparts. IN PEPTIC ULCER DISEASE
In India, this group consisted more of patients with GUs
Chinese population has less parietal cell mass as compared to
than DUs.
the Caucasians, which may account for the increased efficacy
of PPIs. Genetic variations can also moderately influence the
liability to acquire PUD and H. pylori infection independent
HELICOBACTER PYLORI AND PEPTIC of each other. Regional variations in the dietary habits could
ULCER DISEASE IN ASIA be yet another factor. This is based on the observations of
increased DU prevalence in the rice-eating areas of India
Prevalence rate of H. pylori is higher in Asian countries as and China as compared to the non-rice eating or less rice-
compared to the West, which could be at least partly attributed eating areas. The physiological basis for such a difference is
to the lower socioeconomic status of majority of the Asian unknown.
population and probably to some cultural practices. In recent
years, improvement in hygienic practices has resulted in a
decline in the rate of infection. The overall prevalence of H. MANAGEMENT OF PEPTIC ULCER
pylori was 80% in one of the South Indian hospital study of
500 patients. In this study, clean water index (CWI) was the DISEASE
most significant contributor. In rural China, mother-to-child
In Asians requiring long-term use of NSAIDs, prior
transmission of H. pylori may be facilitated by some cultural
eradication of H. pylori helps to prevent the occurrence
practices, such as sharing the same bed, eating from the same
of PUD and UGIB. Those already on NSAIDs and with
bowl, using the same chopsticks and feeding infants by pre-
past history of PUD will benefit from switching to a COX-
chewing their food. An Australian population-based study
2 selective NSAID (if they were on a nonselective NSAID)
reported a low prevalence rate of 18%, which is significantly
and will additionally require PPIs. In aspirin users with
less even compared to Western observations, highlighting the
high gastrointestinal bleeding risk, cotherapy with a PPI
association of socioeconomic status and H. pylori prevalence.
is recommended instead of switching to clopidogrel.
However, despite relatively poor socioeconomic condi-
Prophylactic PPI is also recommended in patients receiving
tions, Indonesia has a low prevalence rate for H. pylori. In
dual antiplatelet therapy with aspirin and clopidogrel.
Malaysia, prevalence rates as low as 11.929.2% were noted in
However, in vitro studies show that some PPIs reduce the
Malays and as high as 49.452.3% in Indians; those with Chi-
antiplatelet activity of clopidogrel by inhibiting CYP2C19,
nese ethnicity had an intermediate prevalence rate of 26.7
a hepatic cytochrome P450 enzyme. In slow metabolizers
57.5%. This racial difference cannot be explained by environ-
of clopidogrel due to genetic polymorphisms of CYP2C19,
mental effects or by the differences in socioeconomic status.
this effect could potentially be clinically significant,
It appears reasonable to speculate the possibilities of yet un-
although not conclusively proven. CYP2C19*2 and *3
known host mechanisms of resistance against H. pylori. Re-
variants are the most common loss-of-function alleles of
gional variations in the interplay between host factors, such
CYP2C19. In Caucasians, CYP2C19*3 allele is very rare,
as interleukin-1 gene cluster polymorphisms and the viru-
but it is very common in East Asians, especially in Chinese
lence factors of H. pylori are being increasingly recognized.
populations (710%). CYP2C19*2 allele frequencies in
different populations are reported as follows: Mexican
Americans (9.7%), Caucasians (12.7%), African Americans
NSAIDs AND PEPTIC ULCER DISEASE IN (18.2%), and Chinese (29%). This would mean that there
THE EAST could be a considerable variation in the drug effects based
on genetic polymorphism of the enzyme, which could
The prevalence of GUs in patients on NSAIDs was found to adversely affect the Asians compared to the Western
be similar in Japanese population when compared to the population. So far, prospective data are not available in
Western studies. But meta-analyses of randomized, placebo- this regard and conclusive evidence is lacking to ascertain
controlled trials of low-dose aspirin suggest the possibility if pharmacogenomic assessment of individual patients will
that the risk of major GI bleeding from the use of low-dose help to tailor therapy. Current approach is to assess both the
aspirin may possibly be higher in Japanese populations as gastrointestinal and cardiovascular risks to decide about
compared to their Western counterparts; the reason for such the need for combination therapy, including clopidogrel
a difference is unclear. and PPI.
Peptic Ulcer Disease in AsiaPacific 33
To diagnose H. pylori infection, 13C or 14C urea breath tests angiographic embolization may be attempted to achieve
and monoclonal stool antigen tests are preferred over the hemostasis, although the efficacy of this method is yet not
less accurate serology as noninvasive diagnostic methods; conclusively proven.
although in cases of UGIB, histology is preferred. First-
line treatment for H. pylori eradication in Asian population
includes PPI, amoxicillin and clarithromycin for 7 days. SUMMARY
Alternatively, sequential therapy with 5-day dual therapy (20
mg of rabeprazole and 1 g of amoxicillin twice daily) followed Peptic ulcer disease and its complications continue to be a
by a 5-day triple therapy (20 mg of rabeprazole, 500 mg of significant burden to the health systems around the world
clarithromycin and 500 mg of metronidazole twice daily) has despite increasing awareness about the etiologies and
also shown good results. However, rising trend of antibiotic declining prevalence of H. pylori. Management strategies
resistance especially to clarithromycin and metronidazole as need to be tailored to suit the economic limitations and
seen in many Asian populations could be an impediment to drug resistance patterns as well as the racial, cultural and
eradication of H. pylori. In such situations, bismuth-based dietary diversity of different parts of the Asia-Pacific. More
quadruple therapy (for 10 days) or triple therapy with at robust studies are needed to identify the best approach in
least one antibiotic different from the previously tried one or the resource-limited healthcare facilities of the developing
with addition of levofloxacin (for 10 days) or rifabutin (for 10 world.
days) can be tried as salvage therapy. If the salvage therapy
is ineffective due to suspected inefficacy of PPIs (possibly
from activating polymorphisms of CYP2C19, which is less BIBLIOGRAPHY
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5
cHAPTER
Functional Dyspepsia
Shahab Abid, SM Wasim Jafri
INTRODUCTION three categories of dyspepsia: (i) dyspepsia with an

identified cause that, if treated, led to improvement, such as
Dyspepsia is a very common clinical condition, which is chronic peptic ulcer disease, reflux esophagitis, malignancy
frequently encountered in daily practice of gastroenterologists or hepatobiliary disease; (ii) dyspepsia with identified
as well as general physicians. The term dyspepsia is abnormalities of uncertain significance like H. pylori infection
derived from Greek language, which means upset stomach and gastroparesis, and (iii) dyspepsia with no explanation
or indigestion. In the early 18th century, dyspepsia was identified. The term FD was used for dyspepsia with
classified into dietary, moral, or nervous dyspepsia. An identified underlying mechanisms of uncertain significance
increase awareness and rapid surge in research was observed or dyspepsia for which no explanation was available.
following the rediscovery of Helicobacter pylori (H. pylori) by The definition of FD was further elaborated by splitting
Barry Marshall and Robin Warren as a cause of peptic ulcer it into three subgroups: (i) ulcer-like dyspepsia with
disease in the early 1980s. predominant pain symptoms localized to the upper abdomen,
Functional dyspepsia (FD) is a heterogeneous disorder relieved by taking food, antacid, H2 receptor antagonist
whose etiology is largely unknown. Several etiopathogenetic (H2RA) or proton pump inhibitors (PPIs), (ii) dysmotility-like
mechanisms have been investigated, but FD remains a dyspepsia where three or more of the following symptoms
diagnosis of exclusion. Likewise its treatment is not yet early satiety, nausea, recurrent retching or vomiting, bloating
established, and it has an unpredictable course, which overlaps without visible distension or abdominal discomfort are often
with irritable bowel syndrome (IBS) or reflux disease at time. aggravated by food. The latter subgroup excludes abdominal
pain as the predominant symptom, and (iii) unspecified FD.
It was also defined that the symptoms should be present for at
ROME CRITERIA FOR least 3 months.
FUNCTIONAL DYSPEPSIA
In parallel to the classification of psychological disorder Rome II Criteria
(Diagnostic and Statistical Manual of Mental Disorders), In 1999, the Rome committee partially changed the criteria
the Rome process is an international effort to organize for dyspepsia, although the definition of dyspepsia was not
gastrointestinal (GI) symptoms of unknown etiology and to altered. The main focus of Rome II was to align one specific
group them into various groups collectively called functional predominant symptom with underlying Rome I based
gastrointestinal disorders (FGID). This latter includes IBS, subgroups of FD. Main purpose of this change was to target the
FD and several other functional disorders of the GI tract. The predominant symptom. In additions Rome II also modified
Rome criteria are issued after passing through a consensus the duration of symptoms by stating that the symptoms had
process using the Delphi technique. to be present for at least 12 weeks over a 12-month period,
which need not to be consecutive.
Rome I Criteria Both Rome I and II criteria for FD received disagreement.
It was argued that FD patients were frequently unable to
In 1991, the Rome committee defined dyspepsia as persistent distinguish abdominal pain from discomfort. Moreover, it was
or recurrent abdominal pain or abdominal discomfort noted the word predominant symptom (in Rome II) was
centered in the upper abdomen. Rome I criteria identified unclear. Furthermore, subgrouping of patients on the basis
of symptoms could not be correlated well with underlying EPIDEMIOLOGY

pathophysiological mechanisms. The duration and time
course specification for dyspepsia also thought to be clumsy. There is a wide variation in the prevalence estimates for FD.
It ranges from 7 to 63% in one study; while in another study,
it was 2.541%. This wide range of prevalence is probably due
Rome III Criteria to variability in the definition of dyspepsia used in various
Several changes were made in FD definition and subgroups papers.
by Rome III committee in 2006. An elaborative localization of A recently published population-based study showed that
the pain in the epigastric area has been described. The term FD was present in 11% of the Italian general population. The
abdominal discomfort was abandoned and the key concept same study also documented the existence of two distinct
was replaced by the terms postprandial fullness and early subgroups of FD (as defined in Rome III) in the general
satiety. Predominant symptom-based subgroups of FD were population.
replaced by placing symptoms into new categories. The term Natural history of FD is largely unknown because of
functional dyspepsia was abandoned for research purposes heterogeneity of its symptoms fluctuation in predominant
in favor of a more detailed classification of functional symptoms over a period of time and conservable overlap
gastroduodenal disorders. Rome III-based criteria for FD is with other FGIDs. Studies have demonstrated both short-
given in Table 1. term and long-term fluxes of dyspeptic symptoms with
gastroesophageal reflux disease and IBS. A Swedish study
noted some symptom fluctuation in the shorter-term, but
Table 1: Rome III criteria for functional dyspepsia
troublesome GI complaints remained stable in approximately
Symptoms 90% of subjects over a period of 16 months.
At least 3 months with onset at least 6 months previously A 40% prevalence of FGID was observed in a Japanese
One or more of the following: study with overlapping functional bowel disorders. In
Bothersome postprandial fullness Malaysia, dyspepsia has been reported in up to 15% of rural
Early satiation and 25% of urban population.
Epigastric pain
Epigastric burning
No evidence of structural disease (including upper endoscopy that is
likely to explain the symptoms)
PHYSIOLOGICAL DYSFUNCTIONS IN
1.Epigastric pain syndrome: FUNCTIONAL DYSPEPSIA
Pain or burning localized to the epigastrium of at least moderate
severity and at least once per week There is no uniform pattern of pathophysiological
Pain is intermittent abnormalities found in all FD patients. Various mechanisms
Pain is not generalized or localized to other abdominal or chest have been described (Table 2). Functional abnormalities
regions
have been identified at gastroduodenal region while there
Pain is not relieved by defecation or passage of flatus
Pain does not fulfill criteria for gallbladder or sphincter of Oddi is growing evidence of deranged biochemical abnormalities
disorders and cortical dysfunction in a subset of FD patients.
Supportive criteria:
Pain may be of a burning quality but without a retrosternal
component
Pain is commonly induced or relieved by ingestion of a meal, but
may occur while fasting
Pain may coexist with postprandial distress syndrome. Table 2: Pathophysiologic mechanisms of functional dyspepsia
2.Postprandial distress syndrome:
Visceral hypersensitivity (Fat, H+, wall distension, etc.)
Bothersome postprandial fullness, occurring after ordinary sized
meals, at least several times per week Decreased fundic accommodation
Early satiation that prevents finishing a regular meal at least several Delayed gastric emptying/antral hypomotility
times per week.
Supportive criteria Inflammation [bacteria (H. pylori), virus, etc.]
Upper abdominal bloating, postprandial nausea or excessive Vagal neuropathy
belching can be present
Duodenal hypersensitivity
May coexist with epigastric pain syndrome.
Small bowel dysmotility
Source: Adapted from Rome III criteria
Functional Dyspepsia 37
Impaired Gastric Emptying Other Evolving Pathogenetic

Relationship between impaired gastric emptying and FD Mechanisms for Functional Dyspepsia
symptoms groups remains controversial. While several
Bacterial gastroenteritis leading to persistent symptoms
studies have demonstrated delayed gastric emptying in
after the treatment of infection
2050% of patients with FD, a meta-analysis of 17 studies
Untreated celiac disease is associated with intestinal
evaluating a total of 868 patients with dyspepsia and 397
inflammation proximal gut motility dysfunction.
controls, a delayed gastric emptying was observed in 40
Interestingly it was found that a gluten-free diet in these
patients with FD. In a subset of patients with FD, rapid gastric
patients normalized gastric emptying rate
emptying has also been observed.
Food intolerance has been debated for a long time as
a factor causing FD. In patients with food intolerance,
Increased Visceral Hypersensitivity ingestion of a meal is associated with a rise in dyspeptic
symptoms, which is significant within 15 minutes after the
Increased perception of visceral stimuli has been considered start of the meal, and which persists for at least 4 hours
as one of the major pathophysiological mechanisms in FGID. postprandially. The underlying mechanism is unclear but
Studies have demonstrated that a subset of patients with sensorimotor dysfunction is a likely possibility
FD have enhanced sensitivity to isobaric gastric distension. Autonomic dysfunction notably impaired vagal activity
The exact site of hypersensitivity generated in these patients has also been implicated in the pathogenesis of FD
is however unknown. Two possible sites for generating Recently, the role of eosinophils and mast cells in the
hypersensitivity in these patients are the central nervous intestinal functional disease has been a subject of
system (CNS) and enteric nervous system (ENS) especially considerable debate. Eosinophils and mast cells are an
visceral afferents. important link between innate and adaptive immunity,
Several receptors have been identified as potential targets and are important in allergic T-helper type 2 inflammation.
for future drug development which are potentially responsible Eosinophils may give rise to symptoms due to release
to bring visceral hypersensitivity. These include transient of preformed cytokine proteins, which trigger neural
potential receptor vanilloid type I, voltage-gated sodium excitation, muscle spasm, and pain.
channels, adenosine triphosphate (ATP), acid-sensing ion
channels, protease-activated receptor-2, cannabinoid,
prostaglandin, tachykinin and 5-hydroxytryptamine (5-HT) SYMPTOMS AND
receptors.
PATHOPHYSIOLOGICAL MECHANISM-
BASED CATEGORIZATION OF
Impaired Gastric Accommodation
FUNCTIONAL DYSPEPSIA
Gastric accommodation is a receptive relaxation of primarily
gastric fundus after taking a meal, a vagus nerve-mediated In order to facilitate treatment in patients with FD, attempts
reflex. This reflex relation of stomach increases the gastric were made to classify symptoms into groups based upon
volume, which facilitates accumulations of a meal and underlying pathophysiological mechanism. Unfortunately,
enables the stomach to handle intragastric volumes in clinical practice, this classification showed great overlap
without a proportional increase of intragastric pressure. It is between subclasses. Moreover, a detailed analysis has
speculated that impaired accommodation of the proximal revealed that the predominant symptom does not reliably
stomach during and after the ingestion of a meal may be identify pathophysiological subsets.
accompanied by increase in intragastric pressure, which In a slightly different approach, pathophysiology-based
activates mechanoreceptors in the gastric wall, thus, inducing subgroups of FD were formed, and an attempt was made to fit
dyspeptic symptoms. Using a barostat, impaired gastric various symptoms into such groups. A study has demonstrated
accommodation was demonstrated in 40% of patients with FD association between delayed gastric emptying and symptoms
who presented with symptoms of early satiety and weight loss. of fullness, nausea, and vomiting. Likewise an association
Other tests, which can measure the gastric volume include was also found between impaired fundic accommodation
single photon emission computed tomography, three- and early satiety and weight loss. A recent study on a large
dimensional ultrasound and magnetic resonance imaging. group of patients with FD in a tertiary care setting performed
All these evolving techniques are promising alternatives to factor analysis of symptom patterns. This study showed that
Barostat, as these are noninvasive techniques for measuring the presence of weight loss was strongly associated with early
gastric accommodation. satiety and also with nausea and vomiting.
An alternate to GI symptom-based Rome criteria for the MANAGEMENT

diagnosis of FD has been suggested recently. This alternative
for Rome III was based upon a cluster analysis approach. In Functional dyspepsia is a diagnosis of exclusion; therefore,
this study, it has been documented that anxiety, depression, it is essential to exclude serious potentially treatable causes.
and somatization are the most important variables along with A list of organic causes is given in Table 3 that indicates that
gastroduodenal symptom-based clusters of FD to define the the causes of dyspeptic symptoms are not only associated
subgroups of patients with FD. with upper GI diseases but also include liver and gallbladder
pathologies. There is a long list of medicines, which also
cause dyspeptic symptoms. A practical approach to a patient
ETIOLOGIC FACTORS ASSOCIATED with dyspeptic symptoms is given in Figure 1. Several
physiological tests are now available to evaluate the proximal
WITH FUNCTIONAL DYSPEPSIA gut dysfunction. These tests can assess the gastric emptying
Genes
Certain genetic polymorphism was found to be associated
Table 3: Differential diagnosis of dyspepsia
with increased susceptibility to FGIDs. Homozygous GNB3
825C carrier status was identified to be associated with 1. Functional (nonulcer) dyspepsia 16. Systemic disorders
unexplained predominantly upper abdominal symptoms. 2. Peptic ulcer disease Diabetes mellitus
Recently, Japanese study found an association of IL-17F and 3. Reflux esophagitis Thyroid and parathyroid
MIF gene polymorphisms with the development of FD in H. disorders
pylori-infected patients. 4. Gastric or esophageal cancer Connective tissue disease
5. Abdominal cancer, especially
Psychosocial Disorders pancreatic cancer
6. Biliary tract disease 17. Drugs:
Patients with FD have demonstrated a high score on
7. Carbohydrate malabsorption: Acarbose
psychomotor scale compared to normal individuals.
Lactose Alcohol
Psychosocial stress, mood symptoms, and coping style
Sorbitol Antibiotics, oral (e.g.
diversity are the major predictors of FD. A recent population- Fructose erythromycin)
based study found that anxiety was linked to uninvestigated Mannitol Bisphosphonates
dyspepsia and FD. The same study, however, did not find Corticosteroids
depression as an associated factor in patients with FD. Iron
8. Gastroparesis Metformin (glucophage)
9. Hepatoma Miglitol (glyset)
Helicobacter pylori and Functional
10. Infiltrative diseases of the stomach Nonsteroidal anti-
Dyspepsia inflammatory drugs, including
cyclooxygenase-2 inhibitors
The relationship between H. pylori infection and symptoms of
Crohns disease Opiates
FD is not yet established. Studies have not shown consistency
Sarcoidosis
between the frequency and severity of symptoms in FD
11. Intestinal parasites: Orlistat (xenical)
patients with the H. pylori status. Additionally, the effects of
eradication of H. pylori on epigastric symptoms of dyspepsia Giardia species Potassium chloride
Strongyloides species Theophylline
are arguable. A Cochrane meta-analysis suggested a small
but significant beneficial effect of eradicating H. pylori on 12. Ischemic bowel disease
symptoms associated with FD. The influence of H. pylori on 13. Medication effects
the pathogenesis and symptom generation in patients with 14. Metabolic disturbances:
FD remains unclear. Therefore, it is debatable whether H. Hypercalcemia
pylori-associated FD is different disease as compared to FD Hyperkalemia
without H. pylori infection. 15. Pancreatitis
Table 4: Pathophysiological tests for the assessment of functional

dyspepsia
Test Indication
13C octanoic acid Gastric emptying
Scintigraphy Gastric emptying
SPECT Gastric accommodation
Barostat Gastric accommodation and sensations
Ultrasound Gastric accommodation and emptying
MRI Gastric accommodation and emptying
Electrogastrography Gastric myoelectric activities
Antroduodenal motility Motility study of stomach and small intestine
SmartPill Gastric emptying and transit time
Satiety drinking test Gastric sensations and accommodation
Abbreviations: SPECT, single photon emission computed tomography; MRI,
magnetic resonance imaging
Table 5: Functional dyspepsia treatment options and their benefits
Significant clinical benefits

Helicobacter pylori eradications
Protonpump inhibitors
H2 blockers
Prokinetics (metoclopramide)
Probable clinical benefits:
Tegaserod (5-HT4 partial agonist)
Alternative therapies:
Hypnosis
Psychological therapies
Iberogast (herbal extract STW 5)
Chinese herbal medicine
Japanese herbal medicine
Fig. 1: Approach to a patient with dyspeptic symptoms No benefits:

Mucosal protecting agents
Itopride (D2 antagonist, acetylcholinesterase inhibitor)
rate, gastric accommodation, and sensation. Additional tools, information is available about the role of dietary modification,
such as antroduodenal manometry and electrogastrography such as ingestion of low fat diet and small frequent meals and
can be applied to understand the myoelectrical disturbances its actual benefit in FD patients symptoms improvement.
in the proximal gut. However, the practical usefulness of these Various treatment options and their clinical usefulness are
tests is limited beyond the scope of experimental studies and summarized in Table 5.
evaluation of disease process. A list of such tests is given in
Table 4.
Acid Suppression and Neutralization
Treatment Options for Patients with Empiric acid suppression with H2RAs or PPIs is likely superior
to placebo in the treatment of FD. Most recent meta-analysis
Functional Dyspepsia of 10 randomized controlled trails (RCTs) evaluating 3,347
A strong physicianpatient relationship is of utmost participants demonstrated an average 34% response to PPI
importance in treating individual patient with FD so that as compared to 25% response to placebo. Overall, there was
reassurance and education may be provided. Very little a statistically significant benefit of PPI over placebo with
number needed to treat was 10. Likewise 12 RCTs compared Erythromycin which is a motilin agonist stimulates gastric
H2RAs (ranitidine or famotidine) with placebo assessing 2,183 and duodenal motility by acting on smooth muscles and
participants. Overall 54% symptoms improvement was noted enteric nerves. Erythromycin may promote gastric emptying
as compared to 40% placebo response and number needed but does not improve dyspeptic symptoms, and there are
to treat was 7. issues of tachyphylaxis.
Symptom intensity can be reduced significantly by
antacids as well. In a randomized placebo controlled study
using a combination of simethicone, activated charcoal and Antidepressants
magnesium oxide showed significantly more effectiveness It is plausible that selective serotonin reuptake inhibitors
as compared to placebo in relieving dyspeptic symptoms. (SSRI) might be useful in patients with FD. SSRI increase the
Similarly, bismuth compounds have demonstrated same amount of serotonin within the synapse by inhibiting the
beneficial effects on symptoms in patients with FD. serotonin reuptake transporter in both the CNS and ENS. This
However, mucosal protective agents (such as sucralfate and increased availability of serotonin to the enteric nerves may
misoprostol) did not show any significant improvement in lead to alteration in sensorimotor functions of the gut. Almost
dyspepsia symptoms. no data regarding the efficacy of SSRIs in the treatment of
patients with FD exist. Studies are underway to assess the
effects of SSRIs on visceral sensation and clinical symptoms
Helicobacter pylori Eradication in in patients with FD.
Functional Dyspepsia Tricyclic antidepressants (TCA) block serotonin and
norepinephrine reuptake pumps. Hence, TCA have the
A Cochrane meta-analysis has shown a small but significant
potential to stimulate serotonin and noradrenergic neurons,
benefit from eradication of H. pylori in patients with FD
and thus affect sensorimotor functions of the gut as well
that will reduce the risk of symptoms by 10% and number
as analgesic pathways. Very few studies with TCAs in the
needed to improve the condition of one patient is 14. A test
treatment of FD have been completed. Amitriptyline, a TCA
and treatment policy for eradication of H.pylori is, therefore,
has shown decreased perception of symptoms as compared
recommended for patients with uninvestigated dyspepsia
to placebo in patients with FD but it was not associated with
when there are no alarming features, especially in areas,
decreased perception to gastric distension.
where H. pylori prevalence is 20% or higher.
Prokinetics in Functional Dyspepsia Other Agents for Treatment of

Usefulness of prokinetics in treatment of FD symptoms is
Functional Dyspepsia
doubtful and the experience is very limited. Domperidone This includes opioid, neurokinin and vanilloid receptors
and metoclopramide are two commonly used drugs from and drugs that target receptors involved in pain perception.
prokinetics; former is a D2 antagonist which acts peripherally All these agents are modifiers of visceral hypersensitivity
to increase antral motility, while latter acts centrally. One trial a key mechanism in patients with FD. These are under
comparing metoclopramide and domperidone demonstrated development and yet no conclusive data is available to
no significant difference in side effects. support their use at present. Recently, the analgesic effects
Some emerging prokinetic agents include itopride, which of the gamma-aminobutyric acid type-B (GABAB) receptor
is D2-receptor antagonist with acetylcholinesterase inhibitory agonist, baclofen, has shown pain attenuation in a rodent
and low central activities. However, the clinical usefulness of model of FD, which provide the basis for clinical trials of this
itopride in FD patients is debated. drug in FD patients.
Tegaserod is a 5-HT4 partial agonist found to accelerate
gastric emptying and improvement in symptoms. This drug
has been withdrawn from the market because of increase Alternate Medicines
cardiovascular ischemic side effects. Transcutaneous electroacupuncture has shown marked
Triptans (notably sumatriptan) which relaxes the gastric improvement in dyspepsia symptoms with possible
fundus is a 5-HT1 B/D receptor agonist and was found to mechanism that may be associated with increase in high
increase perception threshold in healthy volunteers and frequency of heart rate variability and the modulation of
decrease sensitivity to gastric distension. neuropeptide.
Likewise hypnotherapy and psychotherapy in randomized 8. Bolling-Sternevald E, Aro P, Ronkainen J, et al. Do gastrointestinal
trials showed some improvement in dyspepsia symptoms. symptoms fluctuate in the short-term perspective? The
Cochrane review evaluating the impact of psychological Kalixanda study. Dig Dis. 2008;26(3):256-63.
therapies concluded that there was insufficient evidence to 9. Bouin M, Lupien F, Riberdy M, et al. Intolerance to visceral
confirm the efficacy of psychological intervention despite distension in functional dyspepsia or irritable bowel syndrome:
an organ specific defect or pan intestinal dysregulation?
good results in individual studies.
Neurogastroenterol Motil. 2004;16(3):311-4.
Herbal medicines, such as rikkunshito and Chinese herbal
10. Brook RA, Kleinman NL, Choung RS, et al. Functional dyspepsia
medicine, xiaoyao showed effects on gastric sensorimotor impacts absenteeism and direct and indirect costs. Clin
function and dyspeptic symptoms. Similarly, Iberogast, a Gastroenterol Hepatol. 2010;8(6):498-503.
herbal extract, showed its efficacy in FD in a placebo-controlled 11. Chey WD, Wong BC, Practice Parameters Committee of the
study. However, lack of standardization and identification of American College of Gastroenterology. American College
the active ingredients are its major limitations. of Gastroenterology guideline on the management of
Helicobacter pylori infection. Am J Gastroenterol. 2007;102(8):
1808-25.
FUNCTIONAL DYSPEPSIA AND 12. Coffin B, Bortolloti C, Bourgeois O, et al. Efficacy of a simethicone,
activated charcoal and magnesium oxide combination
QUALITY OF LIFE (Carbosymag) in functional dyspepsia: results of a general
practice-based randomized trial. Clin Res Hepatol Gastroenterol.
Functional dyspepsia has a significant impact over quality 2011;35(6-7):494-9.
of life and burden on healthcare facilities of the society. A 13. De la Roca-Chiapas JM, Sols-Ortiz S, Fajardo-Araujo M, et al.
Swedish population-based study has shown its significant Stress profile, coping style, anxiety, depression, and gastric
impacts on all main domains describing physical, mental emptying as predictors of functional dyspepsia: a case-control
and social aspects of health-related quality of life in general study. J Psychosom Res. 2010;68(1):73-81.
population. A retrospective analysis of payroll data has shown 14. Delgado-Aros S, Camilleri M, Cremonini F, et al. Contributions
significantly greater costs (both direct and indirect) and lower of gastric volumes and gastric emptying to meal size and
productivity than employees without FD. postmeal symptoms in functional dyspepsia. Gastroenterology.
2004;127(6):1685-94.
15. El-Serag HB, Talley NJ. Systemic review: the prevalence and
clinical course of functional dyspepsia. Aliment Pharmacol Ther.
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6
cHAPTER
Gastric Cancer
Mian Mashhud Ahmad, Mamun-Al-Mahtab
introduction Helicobacter pylori

Gastric cancer (cancer of the stomach) is a disease in which Helicobacter pylori is a gram-negative bacterium, which has
malignant cells arise in the tissues of the stomach. Since most been etiologically linked with gastric cancer in numerous
malignant tumors of the stomach are epithelial in origin, ecologic, cohort, and case-control studies over the last
the overwhelming majority of cancers of the stomach are 2 decades. The strongest evidence to support the role of
adenocarcinoma and most of the routine statistics about H. pylori in gastric cancer development comes from
gastric cancer refer to this histological entity. Worldwide, prospective cohort studies. A pooled analysis of data from 12
there are currently over 900,000 new diagnoses of gastric prospective cohort studies demonstrated a sixfold elevation
cancer each year making this the third and fifth most common in risk occurring after 10 years of follow-up. More recent
form of cancer in males and females, respectively. evidence indicates that the use of more sensitive methods
Incidence rate in males is approximately double than those to detect H. pylori infection results in substantially higher
in females. The consistency of this difference has never been risk estimates for gastric cancer. Although there are a variety
adequately explained, although theories have been advanced of proposed mechanisms whereby H. pylori infection may
in which female sex-specific hormones may play a protective increase the risk of gastric cancer, it is thought that the
role. The incidence rate of gastric cancer increases with age, primary mode of action is through the induction of long-term
and the cancer is relatively rare in males or females under 45 chronic inflammation. Relatively few studies have examined
years. Most patients are between 60 years and 80 years old at the joint effects of both H. pylori infection and diet as causes
diagnosis. There is a tenfold variation in incidence between of gastric cancer suggesting that H. pylori infection may act as
the highest risk populations and lowest risk populations and an effect modifier for dietary risk factors. The role of H. pylori
rates are notably high in East Asia, South Asia, South America, in the etiopathogenesis of gastric cancer is discussed further
and Eastern Europe. Incidence rate in most populations have in the chapter.
been declining substantially over several decades. However,
proximal cardia cancers have been found to be increasing
Dietary Factors
in incidence in some populations compared with noncardia
cancer. Many studies, including a recent meta-analysis of studies
investigating the interactions between dietary factors and
the development of gastric cancer concluded that a diet high
ETIOLOGY in fruit and vegetables reduces the risk of developing gastric
cancer. There are many potential mechanisms through
which a diet high in fruit and vegetables may be protective
Common Identified Risk Factors against cancer, what the active component is in the case of
The main identified environmental risk factors for gastric stomach cancer is not clear yet. One possibility is related
cancer are Helicobacter pylori infection and various dietary to the antioxidant capacity of fruit and vegetables, which is
exposures associated with at least sixfold risk of cancer. related to the content of beta-carotene, alpha-tocopherol,
Evidence relating to the etiology of gastric cancer to and vitamin C content. Infection with H. pylori is known to
Helicobacter pylori infection, dietary factors, smoking, substantially reduce the bioavailability of vitamin C leading
occupation, physical activity, and anthropometry is discussed to reduced plasma vitamin C concentrations. This lower
here. vitamin C may be in itself a potential causative factor in the
development of gastric cancer. A randomized controlled However, the use of nonsteroidal anti-inflammatory drugs
trial in which the treatment of patients at high risk of gastric has been suggested to reduce the risk of stomach cancer.
cancer with a combination of vitamin C, beta-carotene and
H. pylori eradication had successfully promoted the regression
of premalignant lesions. There has been a considerable Occupation
epidemiological research focus on the effects of vegetables Occupational factors have been regarded as playing a
from the Allium family (onions, garlic, leeks). A recent meta- smaller part in the etiology of gastric cancer than dietary
analysis on the effects of garlic intake found a risk estimate and other environmental exposures. Excess risks have been
of 0.53 (95% CI: 0.31, 0.92) associated with high levels of found for several occupational groups, including miners
consumption, indicating a protective effect. and quarryman, farmers, fishermen, masonry and concrete
A possible increase in risk of gastric cancer associated with worker, machine operators, nurses, food industry workers,
alcohol intake has been suggested from a meta-analysis of cooks, launderers and dry cleaners.
number of cohort and case-control studies of gastric cancer
and reported a pooled relative risk of 1.3 for a high intake
of alcohol (100 g/day) but on the basis of the significant Anthropometry
heterogeneity observed between studies, the authors Whilst measures of obesity are generally positively related
concluded that it was not possible to infer causality from these to the risk of cancer, for stomach cancer there is a lack of
data. What is clear that in direct contrast to the cardiovascular epidemiological literature. However, some recent prospective
system, there is less evidence that moderate consumption studies suggested that risk of cancer occurring in the cardia or
of alcoholic beverages has beneficial health effects on the proximal region of the stomach somewhat elevated in obese
stomach. individuals.
Evidence that salt intake is inversely associated with the risk
of stomach cancer has accumulated over many decades. The
mechanism of action of salt on gastric cancer risk is thought Physical Activity
to be via irritation of the stomach lining and ultimately the
Relatively few studies have examined the relationship
development of atrophic gastritis, and this is also thought to
between the physical activity and stomach cancer. A
occur with H. pylori infections, the effects of salt intake may
prospective cohort study of Japanese residents of Hawai
be readily confounded by the lack of adjustment for infection.
found an elevated risk of stomach cancer associated with
Adverse effects of cured or salted meat and fish are thought
highest levels of both recreational and occupational physical
to be linked to the N-nitroso model of gastric carcinogenesis,
activity when compared with mostly sedentary activity levels.
a process inhibited by vitamin C in gastric juice. In the
One recent population-based case-control study found no
stomach nitrites are mainly derived from food and water
significant association for cancer of the gastric cardia with
sources. Despite continuing concern that the formation of
occupational activity.
nitrosamines from dietary precursors may be casually related
to gastrointestinal cancer, the epidemiological literature has
failed to support this link with any degree of conviction. Practice Points
Despite a worldwide decline in incidence of gastric
Smoking cancer, it remains as a major malignant disease in many
populations
Both cohort and case-control studies have found a causal role Helicobacter pylori is an established cause of gastric cancer
of tobacco smoking in the development of gastric cancer. The High intake of fruit and vegetables has been associated
worldwide estimated attributable risk of smoking was 11% with reduced risk of gastric cancer although recent data
derived from a meta-analysis of smoking and stomach cancer. have failed to confirm this relationship. Adherence to
recommendations to consume at least five portions of
fruits and vegetables daily remains, strongly advisable
Medical Conditions There is no evidence that antioxidant vitamin supplements
Pernicious anemia and prior experience of gastric surgery are useful in the prevention of gastric cancer
have been suggested to increase the risk of stomach cancer. Smoking contributes to the risk of gastric cancer.
Gastric Cancer 45
PATHOLOGY AND MOLECULAR event in DGCA is loss of expression of E-cadherin, a key cell
surface protein for establishing intercellular connections
PATHOGENESIS OF GASTRIC CANCER and maintaining the organization of epithelial tissues.
Biallelic inactivation of the gene encoding E-cadherin, CDH1,
Several classifications of gastric cancer (GCA) have been
can occur through germline or somatic mutation, allelic
proposed in the past decades by WHO, Ming, Mulligan and
imbalance events (e.g. loss of heterozygosity) or epigenetic
Lauren. The most successful and currently widely used
silencing of gene transcription through aberrant methylation
classification was presented by Lauren in 1965 depending on
the microscopic morphology alone. There are two main cancer of the CDH1 promoter. In contrast, the pathogenesis of IGCA
pathogenesis appeared as clearly dissimilar in clinical and is less well-defined. However, it appears to follow a multistep
epidemiological entities. These are gastric adenocarcinomas progression that is usually initiated by H. pylori infection.
of diffuse (DGCA) and intestinal (IGCA) subtypes. However, Some tumors display areas of both intestinal and diffuse
in clinical practice, particularly as far as survival is concerned, phenotypes. In such cases, CDHI mutations and loss
all classification of gastric cancer is of limited significance of expression of E-cadherin are seen only in the diffuse
so far. The clinical stage of GCA, irrespective of cancer type component of the tumor, suggesting that E-cadherin loss is
is the most important single and independent factor that the likely basis for the divergence of a diffuse type clone from
determines survival. an intestinal type gastric cancer.
Gastric adenocarcinoma is one of the few malignant Intestinal type caners is most common in high-risk
neoplasms for which infectious agent have been recognized populations, more likely to be sporadic than inherited and
as having an important etiologic role. related to environmental factors, such as diet, cigarette
In 1994, based mostly upon epidemiologic evidence, the smoking and alcohol use. It is also the type that has
International Association for Research on Cancer, a World decreased most markedly over the past several decades. In
Health Organization (WHO) organ, recognized infection low-risk populations, the frequency of IGCA more closely
by H. Pylori as a primary cause of gastric adenocarcinoma. approximates the incidence of DGCA.
However H. pylori-associated preneoplastic lesions are a Intestinal type of gastric cancer are causally related to
feature of IGCA and the DGCA type. The DGCA is more likely H. pylori while the infection usually starts in infancy or
to have a primary genetic etiology and the involvement of H. early childhood, there is a long latency period, a prolonged
pylori is probably limited to a subset of sporadic cases. precancerous process takes place, represented by a cascade
Outcomes of H. pylori infection vary individually and only of events with the following well-characterized, sequential
a small minority of infected subjects develops gastric cancer histopathological stages: chronic active nonatrophic gastritis,
(estimated at approximately three cases per year for every multifocal atrophic gastritis, intestinal metaplasia, dysplasia
10,000 infected persons). It is thought that modulation of the and invasive cancer, while there is a steady progression from
effects of H. pylori by gastric susceptibility, environmental infection to invasive cancer, there may be temporary episodes
factors, and possibly bacterial strain differences influence its of regression to a less advanced stage. The manner in which
evolution into a neoplastic or nonneoplastic process. environmental risk factors contribute to or influence the
progression of H. pylori-induced gastric carcinogenesis is
unclear.
Intestinal versus Diffuse Types Nonatrophic gastritis is the first stage, predominates in the
As noted above, there are two distinct types of gastric gastric antrum, and is characterized by an interstitial infiltrate
adenocarcinoma, intestinal (well-differentiated), and of lymphocytes, macrophages, and plasma cells. The term
diffuse (undifferentiated), which have distinct morphologic activity has been coined to specify the presence of focal acute
appearance pathogenesis and genetic patterns. The inflammation-infiltration of polymorphonuclear neutrophils
morphological differences are attributable to intercellular in the stroma and epithelial layer in a background of chronic
adhesion molecules, which are well-preserved in intestinal gastritis.
type tumors and defective in diffuse carcinomas. In IGCA, Atrophic gastritis is characterized by multifocal loss of
the tumor cells adhere to each other and tend to arrange the original gastric glands. Nonatrophic antral gastritis is the
themselves in tubular or glandular formations. In contrast, predominant finding in H. pylori-associated duodenal peptic
a lack of adhesion molecules in DGCA allows the individual ulcer, not associated with cancer risk.
tumor cells to grow and invade neighboring structures Intestinal metaplasia is the appearance of glands having an
without the formation of tubules or glands. A molecular basis intestinal phenotype. The larger the atrophic and metaplastic
for this difference is now apparent. The main carcinogenic area, the greater the cancer risk.
As atrophic and metaplastic glands replace original proximal stomach and gastroesophageal junction have
glands, the normal gastric secretions decrease leading to actually increased in frequency
hypochlorhydria and low levels of perinogen-I and gastrin 17. Cardia cancers are also biologically more aggressive, with
These markers can be used as an indicator of gastric atrophy a worse prognosis than distal cancers. Cardia cancers have
and cancer risk. a greater tendency toward deeper wall penetration, lymph
Dysplasia is the next step in the progression of the node metastases and lymphatic vessel invasion
precancerous process. Neoplastic phenotype is characterized It has been suggested that the genetic alterations seen in
by the large, hyperchromatic and disorganized nuclei, cardia cancers more closely resemble those of esophageal
confined to the glandular structures and do not penetrate rather than distal gastric adenocarcinomas
basement membrane. Dysplasia is classified as low grade or The relationship of proximal gastric cancers with H. pylori
high grade. Rates of progression to invasive carcinoma from infection and their association with preneoplastic atrophic
low-grade dysplasia are 023%, while the corresponding rates gastritis/intestinal metaplasia has been questioned.
for high-grade dysplasia are 6085%. These observations support the view that at least a subset
Majority of clinician recommend surgical or endoscopic of proximal cancers represents different subtype from distal
resection for patients with high grade dysplasia, because gastric cancers.
areas of microinvasion can be found in some high-grade
resection samples.
Grossly most IGCA are ulcerated masses, located in the HISTOLOGIC APPEARANCE
region of the incisura angularis and its neighboring antral and
corpus mucosa. Some have their epicenter in the antrum or The WHO classification assigns the terms tubular, papillary
the corpus. and mucinous to the histologic varieties of intestinal type
cancers. Regardless of the specific variant the depth of
invasion in to the stomach wall determines the primary
Diffuse Type Gastric Cancer tumor (T) stage.
Like intestinal type cancers, DGCA can be induced by H.
pylori infection; there are also prominent differences between
these two variants, H. pylori-associated invasive IGCA are
Association between H. pylori and
characterized by a defined series of preneoplastic stages Gastric Cancers
which are not seen with DGCA. Epidemiological studies and several meta-analyses
Diffuse types of gastric cancer are highly metastatic demonstrate a strong correlation between H. pylori
and characterized by rapid disease progression and a poor seropositivity and gastric cancer incidence. H. pylori can
prognosis. DGCA also have a greater tendency to invade be identified histologically in the uninvolved mucosa from
gastric wall, sometimes extending to the lower esophagus or stomachs harboring cancers or precancerous changes.
to the duodenum. Occasionally, a broad region of the gastric Regression of premalignant lesion has been demonstrated
wall or even the entire stomach is extensively infiltrated, with eradication of H. pylori, although whether progression to
resulting in a rigid thickened stomach, termed linitis plastica. invasive gastric cancer can be halted is still unclear. Only one
Histologically, individual tumor cells are seen to invade randomized trial was sufficiently powered to demonstrate that
the surrounding tissues, there is no gland formation. When invasive cancer can be prevented if anti-H. pylori treatment is
intracellular mucin is abundant, it pushes aside the nucleus undertaken before the development of gastric precancerous
of the individual cells, resulting in the so-called signet ring lesions, such as atrophy or intestinal metaplasia.
carcinoma. Signet ring histology is an independent predictor Several hypotheses have been proposed to explain the
of poor prognosis in gastric adenocarcinoma. role of H. pylori in gastric cancer initiation, although the
exact mechanism is incompletely understood. Initiation of
carcinogenesis process has been linked to oxidative stress
Proximal versus Distal Carcinomas brought about by inducible nitric oxide synthase (iNOS)
Proximal cancers that are located in the cardia differ in a that is produced by inflammatory cells responding to H.
number of ways from distal cancers: pylori infection. Nitric oxides are mutagenic and may induce
From an epidemiologic standpoint, although the incidence abnormalities in the DNA of epithelial cells. Furthermore,
of gastric cancer has decreased over the past decades, this support for the role of oxidative and nitrosative stress in
accounted for almost exclusively by distal; cancers of the gastric carcinogenesis is provided by the finding that H. pylori
Gastric Cancer 47
isolates from high cancer risk populations have the ability to infection with cag-A producing H. pylori strain, but not with
induce excessive expression of iNOS and spermine oxidase, the noncarcinogenic clinical isolate.
enzymes linked to DNA damage.
The subsequent molecular events, which promote
progression through the precancerous cascade and culminate Hereditary Diffuse Gastric Cancer
in the development of an invasive gastric cancer are largely Hereditary diffuse gastric cancer (HDGC) has an autosomal
unknown. It is proposed that well-defined histopathologic dominant pattern of inheritance, with early onset gastric
stages of gastric carcinogenesis are accompanied by a stepwise cancers in the majority of affected individuals. The lifetime
accumulation of genetic and/or epigenetic alterations. A cumulative risk for gastric cancer (penetrance) is 4067% in
comprehensive compilation of all the events in the molecular men and 6083% in women. These early gastric cancers are
pathogenesis of gastric cancer is beyond the scope of this multifocal and located beneath an intact mucosal surface.
chapter. The proposed abnormalities are observed in K-ras Because of the difficulty in early detection and the poor
oncogene mutations, p53 tumor suppressor gene alteration, prognosis of these tumors when locoregionally advanced
mutations in the adenomatous polyposis coli gene, loss are candidates for prophylactic gastrectomy. H. pylori seems
of trefoil factor family (TFF) proteins (protect mucous not to play any role in HDGC. Germline CDHI mutations are
epithelium), cyclin E overexpression (cell-cycle regulator) identified in families with an inherited propensity to diffuse
and aberrant gene promoter methylation as an epigenetic gastric cancer (HDGC).
event and all these are associated with H. pylori infection
and have high risk for gastric cancer. The orderly sequential
accumulation of genetic abnormalities as an explanation for CLINICAL FEATURES, DIAGNOSIS, AND
cancer development is being challenged.
It is increasingly recognized that tumor progression STAGING OF GASTRIC CANCER
for colorectal and other cancers is characterized by a
temporary loss of cellular differentiation at the leading edge Clinical Features
of invading tumor cells. Once established, the invading Most patients with gastric cancer are symptomatic and already
cells then redifferentiates from mesenchymal to epithelial have advanced incurable disease at the time of presentation.
phenotypes. This dynamic process of dedifferentiation, At diagnosis approximately 50% have disease that extends
invasion and redifferentiation cannot be explained solely beyond locoregional confines and only half of those who
by the accumulation of genetic alternations; it is regulated appear to have locoregional tumor involvement can undergo
by the tumor microenvironment. Beta-catenin is a critical a potentially curative resection. Surgically curable early
component that regulates morphogenesis during embryonic gastric cancers are usually asymptomatic and infrequently
development. In normal mucosa and well-differentiated detected outside the realm of a screening program.
tumor cells beta-catenin is normally bound to protein The common presenting symptoms are weight loss and
complexes in the cell membrane that are involved in normal persistent abdominal pain. Weight loss usually results from
intercellular adhesions. insufficient caloric intake rather than increased catabolism
Beta-catenin mutation is a frequent cause of activation and may be attributable to anorexia, nausea, abdominal
of gastric carcinogenesis. It has been proposed that gastric pain, early satiety and/or dysphagia. Abdominal pain tends
carcinogenesis involves an initial stage of dedifferentiation to be epigastric, vague and mild early in the disease but more
(gastric atrophy), followed by abnormal redifferentiation severe and constant as the disease progresses.
(intestinal metaplasia), and that this process is mediated by Dysphagia is a common presenting symptom in patients
the effect of H. pylori infection particularly cag-A containing with cancers arising in the proximal stomach or at the
strains on beta-catenin. H. pylori strains carrying virulence esophagogastric junction.
factors cag-A and vac-A s1 and m1 are associated with severe Patients may also present with nausea or early satiety from
gastritis, precancerous lesions, and gastric cancer. Cag-A the tumor mass or in cases of an aggressive form of diffuse type
expression disrupt E-cadherin dependent cell-to-cell contact gastric cancer called linitis plastica, from poor distensibility
and impairs the complex formation between E-cadherin and of the stomach. They may also present with gastric outlet
beta-catenin, causing cytoplasmic and nuclear accumulation obstruction from an advanced distal tumor.
of beta-catenin and constitutive activation of transcription Occult gastrointestinal bleeding with or without iron-
markers of intestinal differentiation. Nuclear localization of deficiency anemia is not uncommon, while overt bleeding
beta-catenin was observed in a human gastric cell line after (i.e. melena or hematemesis) is seen in less than 20% of
cases. The presence of palpable abdominal mass is the most DIAGNOSIS

common physical finding and generally indicates long-
standing, advanced disease. Even though a delay in diagnosis has not been associated with
A pseudoachalasia syndrome may occur as the result of a poorer prognosis, a prompt diagnostic evaluation should be
involvement of Auerbachs plexus due to local extension or commenced when gastric cancer is suspected.
due to malignant obstruction near the gastroesophageal
junction.
Approximately 25% of patients have a history of gastric Endoscopy
ulcer. All gastric ulcers should be followed to complete Tissue diagnosis and anatomic localization of the primary
healing and those that do not heal should undergo resection. tumor are best obtained by upper gastrointestinal (upper
GI) endoscopy. This procedure is more specific and sensitive
for diagnostic modalities (such as barium studies). Since
Signs of Tumor Extension or Spread up to 5% of malignant ulcers appear benign grossly, it is
Propensity of gastric cancer spread by direct extension imperative that all such lesions be evaluated by biopsy and
through gastric wall, as an example, are feculent emesis or histologic assessment. A single biopsy has 70% sensitivity
passage of recently ingested material in the stool can be seen while performing multiple biopsies (up to seven) from the
with malignant gastrocolic fistula. Patients may present with ulcer margin and base increases the sensitivity to greater than
signs or symptoms of distant metastatic disease. The most 98% for diagnosing any suspicious appearing gastric ulcer
common metastatic distribution is to the liver, peritoneal harboring gastric cancer. It may be even more important to
surfaces and distant lymph nodes. Less commonly metastasis take numerous biopsies from smaller, benign-appearing
may be seen in ovaries, central nervous system, bone and gastric ulcers, since the diagnosis of early gastric cancer offers
lungs. the greatest opportunity for surgical cure and long-term
Physical examination may reveal a left supraclavicular survival. Combination of strip and bite biopsy techniques
adenopathy (a Virchows node) due to spread via lymphatics, should be used in cases of linitis plastica type cancer because
is the most common physical finding of metastatic disease. involvement is usually in the submucosa and muscularis
Periumbilical nodule (Sister Mary Josephs node) and left propria. Poor distensibility of the stomach at endoscopy
axillary node (Irish node) are the less common examination may suggest the presence of this type of lesion. If bleeding
findings. Patients may present with an enlarged ovarian mass with biopsy is of concern to the endoscopist, it is reasonable
(Krukenbergs tumor) or mass in the cul-de-sac on rectal to brush the ulcer base, since the risk of bleeding from this
examination (Blumers shelf ) can result from peritoneal technique is negligible.
spread. Follow-up endoscopy for gastric ulcers: In view of the
Presence of ascites, an indication of peritoneal metastasis sensitivity of multiple biopsy technique, the issue of follow-
and a palpable liver mass can indicate metastases. Jaundice up endoscopy for documented gastric ulcers is controversial.
or clinical evidence of liver failure is seen in the terminal Most of the literature supporting the need for endoscopic
stages of metastatic disease. follow-up of gastric ulcers to document healing is based upon
older surgical and radiologic, rather than endoscopic data.
More recent studies have called in question the common
Paraneoplastic Manifestations practice of repeat endoscopy to verify post-treatment gastric
The phenomena are rarely seen at initial presentation. ulcer healing. Studies have shown that in more than 98%
Dermatological findings may include the appearance of cases malignant lesions can be identified by their appearance
diffuse seborrheic keratoses or acanthosis nigricans, which and/or by histology on initial endoscopy. However, a large
is characterized by velvety and darkly pigmented patches on study found that early gastric cancer were likely to be missed
skin folds. Neither finding is specific for gastric cancer. Other by relying upon appearance and histology alone, and
paraneoplastic abnormalities that can occurr in gastric cancer that follow-up endoscopy with repeat biopsy of unhealed
include microangiopathic hemolytic anemia, membranous ulcers was essential for diagnosing early lesions. The issue
nephropathy and hypercoagulable states (Trousseaus of whether it is cost-effective to routinely perform repeat
syndrome). endoscopy for all gastric ulcers needs to be determined.
Gastric Cancer 49
Until such time, the American Society of Gastrointestinal Staging and Preoperative Evaluation
Endoscopy recommends follow-up endoscopy 812 weeks
after initial endoscopy and initiation of therapy to verify There are two major classification systems currently in use for
healing with repeat biopsies performed on any remaining gastric cancer. The most elaborate, the Japanese classification
ulcers. is based upon refined anatomic location, particularly of the
Barium studies can identify both malignant gastric ulcers lymph node stations. The other and more widely used staging
and some early gastric cancers; however, false-negative barium system, developed jointly by the American Joint Committee on
studies can occur in as many as 50% of cases. Thus, in most Cancer (AJCC) and the Union for International Cancer Control
settings, upper endoscopy is the preferred initial diagnostic (UICC), is the classification most often used in the Western
test for patients in whom gastric cancer is suspected. hemisphere and now commonly in Asian countries as well.
The barium study may be superior to upper endoscopy in Tumor, node, and metastasis (TNM) staging criteria, the
patients with linitis plastica. The characteristic stiff, leather- staging, schema of the AJCC/UICC is based upon tumor (T),
flask appearing stomach is more obvious on the radiography node (N) and metastasis (M) classifications and is outlined in
and the endoscopic appearance may be relatively normal. Table 1.
Table 1: TNM staging for gastric cancer
Primary tumor (T)

TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ: Intraepithelial tumor without invasion of the lamina propria
T1 Tumor invades lamina propria, muscularis mucosae or submucosa
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures.
Tumor invades serosa (visceral peritoneum) or adjacent structures.
T4 Tumor invades serosa (visceral peritoneum)
T4a Tumor invades adjacent structures.
T4b
Regional lymph nodes (N)
NX Regional lymph node(s) cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 12 regional lymph nodes
N2 Metastasis in 36 regional lymph nodes
N3 Metastasis in seven or more regional lymph nodes
N3a Metastasis in 715 regional lymph nodes
N3b Metastasis in 16 or more regional lymph nodes
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Anatomic stage/prognostic groups
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T2 N0 M0
T1 N1 M0
Stage IIA T3 N0 M0
T2 N1 M0
T1 N2 M0
Stage IIB T4a N0 M0
T3 N1 M0
T2 N2 M0
T1 N3 M0
Contd...
Contd...
Stage IIIA T4a N1 M0

T3 N2 M0
T2 N3 M0
Stage IIIB T4b N0 M0
T4b N1 M0
T4a N2 M0
T3 N3 M0
Stage IIIC T4b N2 M0
T4b N3 M0
T4a N3 M0
Stage IV Any T Any N M1
Note: cTNM is the clinical classification, pTNM is the on their symptoms and functional status. The purpose of
pathologic classification. A tumor may penetrate the preoperative evaluation is to stratify patients into two clinical
muscularis propria with extension into the gastrocolic groups: those with locoregional (stage I to III) disease and
or gastrohepatic ligaments, or into the greater or lesser those with systemic (stage IV) involvement.
omentum, without perforation of the visceral peritoneum
covering these structures. In this case, the tumor is classified
T3. If there is perforation of the visceral peritoneum covering
Abdominal Computed Tomography Scan
the gastric ligaments or the omentum, the tumor should be It is best suited to evaluating widely metastatic disease,
classified T4. especially hepatic, adnexal metastases, ascites, or distant
The adjacent structures of the stomach include the spleen, nodal spread. CT defined visceral metastases need biopsy
transverse colon, liver, diaphragm, pancreas, abdominal wall, confirmation to avoid false-positive findings. Peritoneal
adrenal gland, kidney, small intestine, and retroperitoneum. metastases and hematogenous metastases smaller than
Intramural extension to the duodenum or esophagus is 5 mm are frequently missed by CT. Accuracy of CT in the T
classified by the depth of the greatest invasion in any of these stage assessment is about 5070% of cases. Sensitivity and
sites, including the stomach. specificity rates for detection of regional nodal metastases
A designation of pNO should be used if all examined range from 6597%. Furthermore, false-positive findings may
lymph nodes are negative, regardless of the total number
be attributed to inflammatory lymphadenopathy.
removed and examined. Used with the permission of the
AJCC, Chicago, Illinois. The original source for this material
is the AJCC Cancer Staging Manual, Seventh Edition (2010) Endoscopic Ultrasonography
published by springer, New York, Inc.
Endoscopic ultrasonography (EUS) is one of the reliable
T stage is dependent on the depth of tumor invasion and
methods available for evaluating the depth of invasion of
not size. Nodal stage is based upon the number of positive
primary gastric cancers, particularly for early (T1) lesions. The
nodes rather than proximity of the nodes to the primary
accuracy of EUS for differentiation of individual tumor stages
tumor.
(T1 to T4) ranges from 77 to 93%, with the experience of the
Regional nodes include those located along the greater
curvature (greater omental, gastroduodenal, gastroepiploic, operator markedly influencing these rates. In comparative
prepyloric and pancreaticoduodenal) lesser curvature (lesser studies, EUS generally provides a more accurate prediction
omental, left gastric, cardioesophageal, common hepatic, of T-stage than does CT, although three-dimensional
celiac and hepatoduodenal) and pancreatic and splenic multidetector row CT and MRI may achieve similar results in
area. Involvement of other intra-abdominal nodal groups term of diagnostic accuracy in T-staging. Accuracy for nodal
(i.e. hepatoduodenal, retropancreatic, portal, mesenteric staging is between 65% and 90%.
and para-aortic) is classified as distant metastases. Clinical Endoscopic ultrasonography-guided fine needle aspiration
staging/preoperative evaluation (Table 2, AJC stage group) of suspicious nodes and regional areas adds to the accuracy of
although staging is most accurately determined through nodal staging. However, overstaging can occur that is attributed
surgical pathology, clinical staging directs the initial approach to inflammation around the tumor or in lymph nodes. Risk of
to therapy. Patients who have locoregional disease after serious complications is negligible, most of which occurs in the
evaluation are potentially curable. Patients with systemic setting of obstructing esophageal tumors. Due to limited field
disease are usually referred for palliative therapy depending of vision with echoendoscope, the utility of EUS as a screen for
Gastric Cancer 51
metastatic disease is questionable. EUS findings alone rarely in serum pepsionogen II or decreases in the pepsinogen I to
affect decisions regarding the need for laparotomy, except when II ratio has been used in population screening programs to
considering patients for a neoadjuvant therapy. Clinical trials identify patients at increased risk for gastric cancer. However,
in individuals with T1 disease are generally excluded from such these markers are not sufficiently sensitive or specific for
studies. However, even patients with locoregionally advanced establishing a diagnosis in an individual patient.
tumors may still be candidates for surgery, particularly
if a palliative resection would be considered. EUS is not
recommended for pretreatment evaluation of gastric cancer in Staging Laparoscopy
guidelines from the National Comprehensive Cancer Network Laparoscopy, though more invasive than CT or EUS has the
(NCCN). EUS staging is of greatest utility for patients with early advantage of directly visualizing liver surface, the peritoneum
gastric cancer to assess accurate submucosal invasion and and local lymph nodes. Between 20% and 30% of patients
essential before considering the option of endoscopic mucosal laparoscopy detects peritoneal metastases despite having
resection (EMR). a negative CT scan. On the other hand, sensitivity of PET
scans is nearly 50% in the detection of peritoneal metastases.
Opportunity to perform peritoneal cytology without visible
Positron Emission Tomography Scan evidence of peritoneal spread is another important advantage
The role of positron emission tomography (PET) scan using of laparoscopy. Positive cytology is a poor prognostic sign,
8-fluorodeoxyglucose in the preoperative staging of gastric even in the absence of overt peritoneal dissemination and
adenocarcinoma is evolving. The integrated PET/CT imaging predicts for early peritoneal relapse. Patients found to have
is especially useful to confirm malignant involvement of CT- peritoneal disease on laparoscopy will never require a
detected lymphadenopathy. Furthermore, large tumors with laparotomy or resection. Positive peritoneal cytology in the
low metabolic activity and most DGCA maybe PET negative. absence of other evidence of intra-abdominal disease is an
The main benefit of PET is that it is more sensitive than CT for indication for neoadjuvant therapy. Therefore, it is routinely
the detection of distant metastases. advised to obtain peritoneal washings during laparoscopy in
The PET scan is not an adequate replacement for staging the absence of visible peritoneal disease.
laparoscopy due to its poor sensitivity in the detection of National Comprehensive Cancer Network guidelines
peritoneal metastasis. NCCN guidelines suggest integrated suggest that laparoscopy should be considered for patients
PET/CT for preoperative evaluation of gastric cancer. who appear to have locoregional disease after conventional
radiographic and EUS staging, especially the patients who
appears to have more than T1 lesion on EUS.
Chest Imaging
Sensitivity of chest X-ray for metastasis is limited. However,
chest CT scan is preferred particularly for patients with a Treatment
proximal gastric cancer in the detection of intrathoracic
disease, which would help the treatment plan. Surgery
Surgery in patients with advanced gastric cancer: Despite
the best efforts of clinicians, gastric cancer in most countries
Serologic Markers is usually diagnosed at a fairly advanced stage. Once the
Low rates of sensitivity and specificity prevent the use of disease has become invasive and spread into the submucosa,
serologic markers as diagnostic tests for gastric cancer. In the risk of dissemination to the lymphatic system increases
a minority of patients, an elevated level of CEA and/or CA- rapidly. Curative treatment for disease, which has entered the
125 may correlate with response to preoperative therapy submucosa is therefore generally centered around surgical
but clinical decisions are never made based upon tumor extirpation. Still surgery remains the mainstay of treatment
marker changes alone. Recommendations for preoperative with curative intent for established gastric cancer. Patient
evaluation of gastric cancer from the NCCN do not include selection is critical to achieving satisfactory outcomes and
assay of any tumor marker. involves careful assessment of both patient fitness and
Hepatoid adenocarcinoma of the stomach a subset of disease stage. Current best practice involves a combination
gastric cancer is associated with elevated level of alpha- of spiral CT scan, endoscopic ultrasound, PET scanning, and
fetoprotein (AFP) has histologic appearance similar to that laparoscopy. Only a minority of patients progress to potentially
of hepatocellular carcinoma. AFP producing gastric cancers curative surgery after staging and fitness assessment in
are aggressive and associated with poor prognosis. Increases Western centers. Prognosis has improved only marginally
over the last 2 decades despite the declining incidence and options: a distal subtotal gastrectomy or a total gastrectomy.
significant advances in surgical therapy and postoperative These have multiplied in recent years, due to improvement in
care. The overall 5 years survival rate for all stages combined staging, multiplied in surgical technique, pathophysiological
was 27% between 1999 and 2005, compared to 16% between understanding of the disease and minimally invasive
1975 and 1977. The high mortality rate reflects the presentation instrumentation.
and relatively aggressive biology. Early lesions are usually
asymptomatic and infrequently detected outside the realm
of screening program. An additional contributing factor to Extent of Gastric Resection
persistently high mortality is the change in the distribution of Tumors in the pyloric canal, antrum or on the lesser curve
cancers from the body and antrum to the proximal stomach in the body of the stomach can be treated by subtotal
during the past 20 years. gastrectomy. This normally encompasses a four-fifths gastric
Surgery for gastric cancer is often challenging because resection, but this is not strictly necessary providing that an
of the extent of the operation and the frailty of the patient. adequate margin can be provided from the edge of gastric
The extent of the resection required has been the subject of tumor. A 5 cm margin in the operative specimen is generally
considerable debate. The mode of spread of gastric cancer adequate. Traditional teaching has been that a wider margin
differs substantially from that of colorectal cancer. Whilst is required for diffuse cancers than for well-differentiated
liver metastasis without evidence of other metastatic disease intestinal tumors and some have advanced the idea of total
is relatively common in colorectal disease, it is very rare in gastrectomy for these tumors, but the results of a large well-
gastric cancer, which conversely has a tendency to remain designed randomized trial comparing total versus subtotal
confined to the stomach and locoregional nodes until a very gastrectomy indicate that in practice this is not necessary.
late stage. This observation has been used by some as an An exception is generally made for linitis plastica, whose
argument for more radical surgical therapy. propensity for widespread infiltration mandates a total
Surgical procedures: The selection of the appropriate surgical gastrectomy even in cases where one portion of the stomach
techniques requires integration of the information from appears unaffected. There is considerable evidence of
staging and fitness assessment. The first decision for the additional mortality risk and a poorer nutritional result with
surgeon is whether the aim of the operation is complete a total gastrectomy and this should sway the surgeon toward
removal of all malignant tissue with a view to surgical cure preservation of a portion of the stomach where this can be
or palliation of symptoms. If aim is the former, then a further carried out safely. For relatively early tumors in the distal
decision needs to be made about the extent of surgical stomach, techniques have been described preserving the
resection required to remove all locoregional disease whilst vagus nerves and pylorus to improve gastric emptying and
minimizing the risks to the patient. There is considerable function.
evidence available about the outcomes of the various surgical For diseases in the proximal half of the stomach, the time-
options, but the selection of the correct procedure for the honored treatment is total gastrectomy. In most Western
individual patient remains a matter where experience and countries there has been a rapid rise in the incidence of
judgments are important. In particular, the attitude of the tumors at or close to be gastroesophageal junction (GEJ) over
patient is crucial in weighing up the balance of risks versus the last 2030 years. Where these are detected at an early stage,
benefits. the surgeon is often placed in the rather paradoxical position
A limited surgery for cure: where disease is confined to of resecting the entire stomach for a lesion that is only just
the mucosa or in the submucosa EMR may be a satisfactory within the stomach itself and may be extremely small. Another
treatment option. This has been fully dealt with in the early option for the surgeon is that a 2 cm difference in the location
gastric cancer section of the chapter. of the primary tumor, from just below the GEJ to just above
Decisions on the extent of surgery the surgeon is required it, changes the classically recommended procedure from a
to make four choices in designing the appropriate operation total gastrectomy to a total esophagectomy with resection of
for an individual. First, the proximal and distal extent of the cardia. There are two main reasons for this odd situation.
the resection of the stomach (with or without esophagus or First, neither esophagectomy nor total gastrectomy was
duodenum); second, the extent and site of the lymph node designed for the type of tumor that are currently seeing
dissection required to give the best chance of removing in large numbers in the West. Second, long experience
any locoregional disease; third, the least invasive option had taught surgeons that a limited resection of the upper
combining adequate resection of both the GI tube and the stomach and lower esophagus with esophagogastrostomy
lymph nodes; finally, what reconstruction technique should is a disastrous operation, inducing appalling bile reflux
be used. Traditional surgical teaching provided just two symptoms in majority of the patients, with consequently poor
Gastric Cancer 53
quality of life. Currently, the extent of gastric and esophageal Postmortem studies and observations from case series
resection for junctional tumors is dependent mainly on the pointed out that gastric cancer remained a macroscopically
surgeons preference and the normal practice of the treating locoregional disease at the time of death in a high percentage
unit. However, option for relatively small or early tumors is of cases, differing markedly in this respect from colorectal
a proximal gastrectomy with jejunal interposition. This was cancer and other tumors, such as breast cancer. Large
originally described by Merendino as a possible antireflux prospective Japanese studies also confirmed that the
procedure, but good outcome has been observed when it is progression of gastric cancer to local lymph nodes proceeded
used for early proximal cancer. in a highly predictable stepwise fashion. These factors led
surgeons from the US and Japan to propose radical enbloc
resection of the lymphatic tissue along the branches of the
Total versus Subtotal Gastrectomy celiac axis in association with gastrectomy in an attempt to
Gastrectomy is the most widely used approach for therapy remove all locoregional disease. The American experiments
of invasive gastric cancer, although superficial cancers can were attended by a high mortality and quickly abandoned but
sometimes be treated endoscopically. Total gastrectomy is the Japanese series produced impressive results and a much
usually performed for lesions in the proximal (upper-third) of better safety record. Therefore, it becomes one of the most
the stomach, while distal subtotal gastrectomy with resection controversial areas in the surgical management of gastric
of adjacent lymph nodes appears to be sufficient for lesions cancer regarding the optimal extent of lymph node dissection.
in the distal (lower two-thirds) of the stomach. However, The term extended lymphadenectomy variably refers to
patients with large mid gastric lesions or infiltrative disease either a D2 or a D3 lymph node dissection. The draining
(e.g. linitis plastica) may require total gastrectomy. In most lymph node basins for the stomach can be divided into 16
series, quality of life after subtotal gastrectomy is superior to stations: stations 16 are perigastric and the remaining 10 are
that after a total gastrectomy at least at short term. located adjacent to major vessels, behind the pancreas and
along the aorta.
A D1 lymphadenectomy refers to a limited dissection of
Linitis Plastica only the perigastric lymph nodes
In about 5% of primary gastric cancers, a broad region of A D2 lymphadenectomy is an extended lymph node
the gastric wall or even the entire stomach is extensively dissection, entailing removal of nodes along the hepatic,
infiltrated by malignancy, resulting in a rigid thickened left gastric, celiac and splenic arteries as well as those in
stomach, termed linitis plastica. The prevalence may be the splenic hilum (stations 111)
higher in younger individuals. Although most commonly A D3 dissection is a super extended lymphadenectomy.
due to poorly differentiated (diffuse type) infiltrating gastric The term has been used by some to describe a D2
cancers, this pattern can, in rare circumstances, represent lymphadenectomy plus the removal of nodes within the
metastatic spread from lobular cancer of the breast. Linitis porta hepatis and periaortic regions (stations 116), while
plastica has an extremely poor prognosis. other use the term to denote a D2 lymphadenectomy plus
It has been reported that one-half of all patients had periaortic nodal dissection alone. Most Western surgeons
metastatic disease (mainly within peritoneal cavities) at classify disease in these regions as distant metastases and
diagnosis: Nodal involvement frequent. Many surgeons do not routinely remove nodes in these areas during a
consider the presence of linitis plastica to be a contraindication potentially curative gastrectomy.
to potentially curative resection. The arguments in favor of extended lymphadenectomy
(i.e. D2 or D3 versus D1) are that removing a larger number
of nodes more accurately stages the disease extent and that
Nodal Dissection failure to remove these nodes leaves behind the disease in as
The appropriate extent of lymph node dissection in gastric many as one-third of patients, which would adversely affect
cancer surgery has been a major topic of surgical controversy survival. The influence of total lymph node count on stage-
for several decades. The survival results of limited surgery, specific survival was studied in a large series of patients
as reported in the Western literature prior to 1970, were undergoing gastrectomy for T1-3 No-1 stages. For every
extremely poor, whilst a number of features of gastric cancer stage subgroup (T1/2 No, T1N1, T2 N0, T3 N1), survival was
suggested that radical enbloc lymph node dissection might significantly better as more nodes were examined. However,
improve survival rates. Detailed lymphatic mapping studies there are two main arguments against the routine use of an
showed that there appeared to be centrifugal flow of lymph extended lymphadenectomy: the higher associated morbidity
from the stomach to a series of concentric rings of nodes in and mortality and the lack of survival benefit for extended
a stepwise fashion, which could be relatively well-predicted. lymphadenectomy in most large randomized trials.
Although retrospective reports suggest that extended may be possible laparoscopically in first elderly patients
lymphadenectomy improves survival, multiple prospective who would not be candidates for a laparotomy. As ye,t there
randomized trials both in Asian and Western populations are insufficient data to allow definite conclusions about the
have failed to show a survival benefit with D2 versus D1 or place of laparoscopic gastrectomy, but it seems likely that it
with D3 compared D2 lymphadenectomy. Any statement will become an option in most specialist centers in the near
about lymph node dissection in gastric cancer surgery is liable future, probably for small bulk disease and in poorer risk
to prove controversial, but a reasonable summary based on patients.
the evidence would be as follows:
Gastric cancer frequently spreads to local and regional
lymph nodes once the submucosa is invaded and Palliative Surgery
consideration should therefore be given to resection of Palliative surgery for cancer should by definition concentrate
lymph nodes which are liable to be involved with cancer on relieving symptoms. The role of surgery in palliating
The extent of nodal invasion can be predicted with symptoms of gastric cancer has declined in recent years,
reasonable accuracy from the characteristics of the because of the improving results of nonsurgical options.
primary tumor. Modern staging investigations provide The principal symptoms, which need treatment in patients
further information with advanced gastric cancer are pain, vomiting, bleeding
The main argument against radical lymph node dissection and anorexia. Gastrectomy has no role to play in correcting
in gastrectomy is its association with increased morbidity anorexia but can effectively deal with the other three
and mortality. This type of surgery should therefore only symptoms in particular circumstances. Intractable pain from
be carried out in units, which can demonstrate satisfactory gastric cancer is relatively rare and is often associated with
results in a properly conducted audit very widespread disease. Operation for pain should therefore
In patients where there is clear evidence of locoregional only be undertaken when there is good evidence from CT or
node involvement curative surgery must of necessity other modalities that a resection is feasible and nonsurgical
involve the resection of these nodes. There will therefore measures have failed to relieve the pain. Chronic hemorrhage
be a subset of patients for whom the surgical choices are from gastric cancer commonly leads to anemia but this
palliative resection and radical lymph node dissection can very often be dealt with by repeated transfusions on a
Both the randomized trials and case series, indicate very fortnightly basis.
clearly that splenectomy and distal pancreatectomy Occasional patients present with large life-threatening
are strongly associated with increased morbidity and hemorrhages, surgery is usually effective in arresting this
mortality. They should not therefore be carried out unless type of hemorrhage although resection of the tumor is often
this is strictly necessary to ensure clearance of all tumor not possible. Ligation of the left gastric artery together with
tissue gastrostomy and oversewing of particular bleeding points is
Finally, very extensive (D3) resection should not be often adequate palliation and less likely to put the patient life
regarded as a suitable treatment option in centers without at immediate risk than an attempted emergency palliative
extensive experience of this and other radical cancer resection. If the patient can be successfully resuscitated, it
operations. may be preferable to attempt embolization of the left gastric
In patients with poor level of fitness, a commonly selected artery or other vessel feeding the tumor, thereby, avoiding
option is the D1 + 7 operation, involving removal of the surgery altogether.
stomach and perigastric nodes together with the whole left Intractable vomiting from gastric cancer commonly
gastric artery and associated lymph nodes. arises either from pyloric obstruction, complete paralysis of
the gastric tube due to widespread infiltration or multiple
peritoneal and retroperitoneal metastases causing effective
Minimally Invasive Surgery paralysis of the entire GI tract. Clearly the infiltrative lesion
Laparoscopic distal gastrectomy was first performed in 1992 has no surgical solution, however, patients with linitis
and total gastrectomy in 1996. Technical advances together plastica can occasionally be benefited from a palliative total
with increasing experience laparoscopic resection appear gastrectomy and experience an improved quality of life for a
safe associated with a lower mortality rate in comparison to limited period of time. Pyloric obstruction on the other hand is
open operation in the same type of patient. now being dealt with successfully by duodenal stenting in the
Randomized comparisons have shown that average majority of cases and this should undoubtedly be preferred to
hospital stay and return to normal activities were shorter surgical bypass if it is technically possible. Although there is
than for open operation. Nevertheless, safe gastrectomy as yet no randomized trial evidence, the symptoms relief and
Gastric Cancer 55
survival rates from stenting are impressive, as is the relatively attributed to suture line and dissected lymphatic trunks
minor disruption to the patients quality of life. This should leakage.
be contrasted with higher mortality from gastrojejunostomy
in the debilitated patient with advanced cancer, which
approaches 30% in many series. Where stenting cannot be Clinical Practice Points
achieved, gastrojejunostomy may still have a role to play and Patient selection for gastric cancer surgery should involve
should be carried out laparoscopically to minimize the effects careful assessment of both fitness and disease stage, as
of surgery on the patient. well as the attitude of the patient
Staging should include a high quality CT scan, together
with the laparoscopy, PET scan and endoscopic ultrasound
Efficacy and Side Effects of Surgery as clinical indications and local resources dictate
The main outcome measure for the efficacy of surgery for There is a case for radical node dissection in selected cases
established gastric cancer is long-term patient survival. but only in units which can demonstrably perform this
Figures for this vary greatly depending on the stage of the without additional morbidity and mortality
tumor at the time of operation. The majority of cancer Splenectomy, distal pancreatectomy and total gastrectomy
recurrence in gastrectomy occurs during the first 2 years after should be avoided unless oncologically necessary
the operation. The most common areas of recurrence are the Gastric function may be preserved by constructing
peritoneal cavity, followed by locoregional disease originating substitute reservoirs, avoiding resection of the pylorus or
from regional lymph nodes or the resection margin. Overall 5 vagi or proximal gastrectomy with jejunal interposition
years survival figures of 3040% are now frequently reported Minimally invasive gastrectomy is feasible but requires
for apparently curative resection from major Western centers. further study.
Stage-specific survival has been confounded by the problem
of stage migration, because the removal of more lymph nodes
lead to the discovery of more positive lymph nodes. These
Role of Chemotherapy in Patients with
patients are therefore classified as having more advanced Established Gastric Cancer
stage. Chemotherapy significantly improves survival in comparison
to best supportive care (BSC) in patients with metastasized
Mortality gastric cancer.
Chemotherapy for metastasized gastric cancer (TNM
Gastrectomy is traditionally seen as a major procedure with T1-4, NXM1, AJCC stage IV) the use of chemotherapy is
a high mortality risk. Publications from high volume expert internationally accepted as standard of care. However, the use
centers in countries with well-developed health systems of single agent or combination chemotherapy and the best
currently report mortality rates between 3% and 5%. Total combination chemotherapy regimens are matters of ongoing
gastrectomy is consistently at least twice as dangerous as debate. A recently published Cochrane review addressed the
distal gastrectomy, although there are some exceptions to following comparisons:
this rule. There is a reasonable amount of evidence about
Adjuvant therapy: Gastric cancer frequently manifests
the factors which are associated with high and low mortality
with local and systemic recurrence after curative surgical
from gastrectomy. Apart from selection of procedure
resection. Hence, postoperative therapy with chemoradiation
the factor with the strongest association with increased
was explored. Chemoradiation has shown some encouraging
mortality is comorbid pathology and strong correlations
results but has not translated into an overall survival (OS)
between decreasing fitness and operative risk are found in
benefit in some of small studies. The benefit of postoperative
a number of studies. Age is certainly a risk factor although adjuvant combined modality therapy using contemporary
not an independent one in the effect of fitness. Sex is a factor radiotherapy techniques and leucovorin-modulated
in some series, female patients doing better than males. 5-fluorouracil was undertaken by United States Intergroup
In common with other forms of major cancers surgery, Study (INT-0116), showed a significantly better 3 years OS
gastrectomy morbidity is associated with uncorrected and disease-free survival receiving chemoradiotherapy (52%
preoperative malnutrition. versus 41% and 49% versus 32%, respectively).
Causes of mortality: The principal causes of death after However, interpretation of the benefit of chemoradiotherapy
gastrectomy are respiratory infections and failure, cardiac is complicated by the inadequacy of surgical treatment.
failure and liver failure in cirrhotic patient and anastomotic Nevertheless, patients undergoing potentially curative
leaks and their consequences. Intra-abdominal abscesses resection of gastric cancer should be offered postoperative
combined modality therapy. Postoperative chemoradiation MAGIC and French trials have led to the adoption of the
with 5 FU/LV remains the standard care in the United perioperative chemotherapy approach to treatment of gastric
States. Updated analysis demonstrated that adjuvant cancer in much of Europe and other parts of the World.
chemoradiation for gastric cancer was not associated with Preoperative chemoradiation: Preoperative therapy has
late toxic events. However, the most predominant reported certain potential advantages over postoperative therapy.
hematologic and gastrointestinal toxicities are leucopenia Preoperative therapy may downstage the tumor and
and nausea, emesis and diarrhea, respectively. Mortality was potentially increases the rate of respectability. Preoperative
uncommon. The results of adjuvant chemotherapy in gastric therapy may sterilize the operative field and thereby reduce
cancer have been disappointing. A number of randomized the risk of tumor seeding. Furthermore early administration
studies conducted over the last 3 decades have failed to of systemic chemotherapy in the preoperative setting may
show a consistent survival benefit. Recently, meta-analysis eliminate micrometastasis without delay. Preoperative
of adjuvant gastric cancer trials has shown marginal benefit chemoradiation also allows better radiation field design.
of adjuvant chemotherapy with some showing a relative risk Clinically, preoperative chemoradiation is better tolerated.
reduction of 2028%. Most recently, the GASTRIC (Global Number of prospective studies have assessed the efficacy
Advance/Adjuvant Stomach Tumour Research International of preoperative chemoradiation in gastric cancer. The
Collaboration) Group-I published a large scale of meta- pathologic complete response rates (RR) were between 16%
analysis that included recently published studies using newer and 27% of patients and R0 resection rate was up to 77%.
agents, such as epirubicin. The studies showed that adjuvant The 3 years OS rate was higher in the chemoradiation
chemotherapy is associated with a statistically significant group (47%) compared with the chemomonotherapy group
benefit OS (hazard ratio 0.82, 95% CI 0.750.9, P < 0.001). (28%) in a recent randomized trial from Germany. The results
Neoadjuvant chemotherapy and chemoradiotherapy: The of these prospective studies of preoperative chemoradiation
goals of preoperative therapy are to increase the respectability appeared promising. However, randomized trials are needed
rate, reduce the rate of local and distant recurrences and to validate the benefit of preoperative chemoradiation.
ultimately improve survival.
Therapy for Metastatic Disease

Preoperative/Perioperative Chemotherapy Both single-agent and combination chemotherapy have
The benefit of perioperative chemotherapy has been been used in advanced gastric cancer. Active agents include
demonstrated in metastatic colon cancer and squamous cell 5-FU, cisplatin, mitomycin C, doxorubicin, epirubicin, and
carcinoma of the esophagus. The most compelling evidence etoposide with RRs varying from 10 to 20%. Meta-analysis
for perioperative is the phase III UK Magic trial. The largest from randomized trials showed that chemotherapy is better
and most influential trial is the United Kingdom Medical than BSC, combination chemotherapy with doublet is
Research Council MAGIC Trial, in which patients with superior than single agent and the best survival is achieved
potentially resectable gastric, distal esophageal or GE junction with three agents at the cost of more toxicities.
adenocarcinomas were randomly assigned to surgery alone Commonly used single, doublet and triplet agents are
or surgery plus perioperative chemotherapy [epirubicin, 5-FU, 5-FU plus adriamycin, 5-FU plus cisplatin and S-1
cisplatin, and 5 fluorouracil (ECF)]. A higher proportion of plus cisplatin; etoposide, cisplatin and 5-FU (ECF) and
the perioperative chemotherapy ECF treated patients had a docetaxel-cisplatin 5-FU (DCF), etc., respectively. Three-
potentially curative procedure and had a significantly better drug combinations have almost similar RRs but associated
OS, 5 years survival rate and progression free survival. The with increasing hematological toxicities. Therefore, palliative
trial was criticized for its nonstandardized surgery, resulting chemotherapy in patients with metastatic gastric cancer
in a relatively poor outcome in the surgery alone group. should be individualized. For those with good performance
Clearly, the MAGIC trial demonstrated survival advantage of status, DCF and ECF are reasonable first-line therapies.
perioperative chemotherapy, similar benefit for preoperative Integration of targeted agents has been extensively
chemotherapy was noted in a French multicenter trial. investigated over past couple of years. Agents have been
Patients undergoing neoadjuvant chemotherapy were evaluated included bevacizumab, cetuximab and trastuzumab.
significantly more likely to undergo curative resection (R0). Randomized trial in patients with Her 2/Neu positive metastatic
With median 5.7 years follow-up, neoadjuvant chemotherapy gastric cancer who receives either chemotherapy plus
was associated with a significant (35%) reduction in the risk trastuzumab/bevacizumab or chemotherapy alone. Overall
of disease recurrence and a significant (31%) lower risk of RR was up to 47%, the medium OS was up to 13.5 months with
death. addition of targeted agent with chemotherapy.
Gastric Cancer 57
Intraperitoneal Chemotherapy FURTHER RESEARCH

The observation that resected gastric cancer tends to recur The balance between relief of tumor-associated symptoms
within the peritoneum has provided the rationale for the and treatment-associated toxicity needs to be evaluated from
evaluation of adjuvant intraperitoneal (IP) chemotherapy. the patients perspective to determine the palliative value of
Meta-analysis of a number of trials has shown a significant any novel therapy for metastasized disease.
survival benefit for hyperthermic IP chemotherapy, but these
investigators were unable to detect a significant survival
benefit from normothermic intraoperative IP chemotherapy.
However, there is insufficient evidence from randomized
SUMMARY
trials to recommend intraperitoneal chemotherapy. The poor long-term survival rates after surgery alone in patients
with gastric cancer have led to the exploration of a variety of
Postoperative Cancer Surveillance adjuvant and neoadjuvant treatment strategies incorporating
chemotherapy and radiation therapy. In patients with
There are no randomized trials to guide the postoperative metastasized gastric cancer, chemotherapy significantly
surveillance strategy. Consensus-based guidelines from the improves survival in comparison to BSC. Best survival results
NCCN suggest the following: are achieved with regimens containing 5-FU, an anthracycline
History and physical examination every 36 months for 13 and cisplatin, such as ECF or epirubicin, oxaliplatin, and
years, then every 6 months for years 4 and 5, then annually. capecitabine. Adjuvant 5-FU-based chemoradiation is
Complete blood count and chemistry profile, as clinically accepted as a therapeutic standard in the United States,
indicated but not in Europe because of considerable toxicity and the
Radiologic imaging or endoscopy, as clinically indicated type of surgery with minimal lymphadenectomy used in the
Monitor for vitamin B12 deficiency in surgically treated relevant trial. According to the results from the UK MAGIC
patients and treat as indicated. trial, perioperative treatment with ECF (3 cycles prior to and
post-surgery) results in a significantly reduced risk of death
for patients with resectable gastric cancer as compared to
Practice Points surgery alone. Neoadjuvant chemotherapy has the ability to
In patients with metastatic disease and without relevant down size gastric tumors and appears to improve curative
comorbidities, chemotherapy with ECF (as continuous (R0) resection rates. Since its potential to improve OS is still
infusion) should be regarded as standard of care. However, questionable, it should be performed within clinical trials.
results for ECF have been challenged by EOX (epirubicin,
oxaliplatin and capecitabine) in the recently presented
REAL-2 trial EARLY GASTRIC CANCER
For patients with metastasized disease, in whom a three
drug regimen is not considered as the treatment of Gastric cancer is one of the most common causes of cancer
choice, either combinations of 5-FU/cisplatin or 5-FU and mortality worldwide. Although there has been a decline in
anthracycline or single-agent chemotherapy with 5-FU gastric cancer incidence in developed countries over the last
should be administered several decades, gastric cancer still accounts for over 10% of
5-Fluorouracil should be given as a continuous infusion annual cancer deaths, second only to lung cancer.
when used in combination of chemotherapy Because of the high incidence of gastric cancer in regions,
Docetaxel+cisplatin-5-FU and IFF [irinotecan, 5-FU such as Eastern Asia and Western South America, nationwide
(folinic acid)] are new, alternative treatment options for screening programs to detect gastric cancer have been
patients with metastasized disease implemented in countries such as Japan, Chile and Venezuela
Perioperative therapy with ECF should be considered in and have led to some improvements in mortality associated
patients with stages II and III gastric cancer with gastric cancer. In the United States where the incidence
Adjuvant chemoradiation is not accepted as international is much lower, screening does not appear warranted and is
standard of care not recommended.
Some patients with locally advanced disease may benefit One of the benefits of large-scale screening programs
from preoperative chemotherapy but no optimal regimen in high-risk areas has been the identification of early
has been defined. gastric cancer (EGC). As proposed by Japanese Society of
Gastroenterological Endoscopy in 1962, early gastric cancer for progression between these stages. Estimated median
is defined as adenocarcinoma that is limited to the gastric duration of EGC before becoming advanced was 37 months,
mucosa or submucosa regardless of whether regional lymph reported in a Japanese follow-up without surgery. EGC has
nodes are involved or not. EGC represents a subset of gastric been reported to have a higher frequency of synchronous
cancers that has a favorable prognosis compared to invasive cancers and longer symptom duration compared to advanced
gastric cancers that extend beyond the submucosa. disease. These observations suggest that EGC undergoes
Survival rates of 85 to over 90% 5 years after surgical a period of slow growth before becoming advanced. From
resection of EGCs have been reported in Japan and the different series it has been observed that antisecretory therapy
West. In one series from Europe reported a similar survival could mask the symptoms associated with gastric cancer,
for EGC and benign gastric ulcer and no EGC patient died perhaps due in part to the ability of antisecretory therapy to
of disseminated disease. On the other hand, 5-year survival mask the disease by permitting mucosal healing.
without surgery was only 65% in a series from Japan due This is an important cause why most patients with gastric
to progression to invasive disease. These survival rates are cancer tend to present with advanced disease despite the
still better than the 1544% 5 year survival that is reported availability of endoscopy.
after surgery for more advanced (T3/4 or node positive) but The average size of EGC ranges from 1.7 to 3.0 cm.
nonmetastatic invasive gastric cancers, indicating that EGC However, with improved techniques for detection, there is a
may be an earlier stage of disease with a long latent period. trend toward increased reporting of small diameter lesions.
Since EGC usually progresses to invasive disease, the The depth of invasion generally parallels the macroscopic
pathogenesis of the two disorders (at least for the most appearance of the tumor, as ulcerated lesions tend to have
common intestinal type variety) is thought to be similar, deeper penetration than flat lesions; lymph-node invasion is
following a sequence of superficial gastritis, atrophic gastritis, present in 1020% of cases and is more common in tumors
intestinal metaplasia, dysplasia, cancer. that invaded submucosa. Distant metastases in EGC are
infrequent.
Epidemiology
The reported incidence of EGC is higher in Japan, being present
Classification
in 40% of surgically resected specimens. On the other hand, According to Lauren classification the tumors are subdivided
reports from Western centers indicate that EGC is detected into intestinal and diffuse types:
in 1020% of all resections for gastric carcinoma. There do The intestinal type (expanding) is characterized by the
not appear to be significant differences in the epidemiologic presence of distinct glands that are comprised of well-
features of EGC between Japan and the West. The sex and age differentiated columnar epithelial cells with a well-developed
distribution of EGC are similar in Japan, Europe and America. brush border. The morphologic appearance is similar to that
The average age at diagnosis is approximately 60 years and of intestinal carcinomas; hence, the term intestinal type. The
men are more commonly affected. intestinal type is seen in 5070% of patients with EGC.
The diffuse (infiltrative) type is characterized by the
Histological Interpretation absence of intercellular adhesions poorly organized clusters
or solitary mucin-rich (signet ring) cells that lack distinct
Regional histological interpretation explains variation in glandular formations and a diffusely infiltrating growth
the EGC incidence between parts of the World. The main pattern.
differences in interpretation were due to the requirement
of the Western pathologists for invasion into the lamina
propria before diagnosing a cancer, while nuclear features Endoscopic Appearances
and glandular structures were more important for Japanese Type I lesions found in the human as a polypoid lesion
pathologists. with a short, broadband stalk, occasionally multiple but
remain localized
Early Gastric Cancer versus Invasive Disease Type II lesions are superficial, flat, either slightly elevated
or without distinct elevations or depressions. Some of the
Patients with EGC tend to be younger than those with type II lesions have localized area of depression of less than
advanced disease, presumably reflecting the time required 1.5 cm in area without penetration of muscularis mucosa.
Gastric Cancer 59
Clinical Features Endoscopic Ultrasonography

Because mass screening is designed to detect asymptomatic Endoscopic ultrasonography has become a useful method for
lesions, there is little recent information on the symptoms staging EGC, can identify the degree of gastric wall invasion
of EGC in Japan. In reports from the West, symptoms were and regional lymph nodes. In addition, EUS permits fine
present from 6 to 12 months prior to the diagnosis of EGC needle biopsies and aspiration cytology.
and occurred in 9095% of patients. Ulcerated lesions have a
longer prodrome of symptoms than protuberant lesions. Most
of the symptoms, however, are fairly vague and nonspecific, Treatment
such as mild epigastric pain or dyspeptic symptoms and Worldwide, gastrectomy remains the most widely used
some patients are asymptomatic. Incidence of symptoms in approach for the treatment of EGC, but endoscopic therapy is
European patients with EGC: gaining popularity in countries with a high incidence of EGC.
Epigastric pain and/or dyspepsia, similar to peptic ulcer Either subtotal or total gastrectomy is used, depending upon
disease 6590% the tumor location. A total gastrectomy is usually performed
Nausea and/or vomiting 640% for lesions in the upper third of the stomach, and subtotal
Anorexia 1240%. gastrectomy for lesions in the lower two-thirds.
Warning or alarm signs or symptoms suggestive of invasive The role of adjuvant therapy, either with systemic
disease, such as anemia or weight loss, occur less frequently chemotherapy, or RT, is not clearly established for EGC
(515% and 440% respectively). In comparison weight loss especially for patients with node-negative disease.
occurs in more than 60% of those with invasive gastric cancer.
However, consensus recommendations are that endoscopy
be performed for dyspepsia in patients over age 45 or with Endoscopic Mucosal Resection/Endoscopic
alarm symptoms suggestive of invasive disease. Submucosal Dissection
On endoscopy, EGC may appear as a subtle polypoid
protrusion, superficial plaque, mucosal discoloration, Endoscopic mucosal resection is an alternative to surgery,
depression or ulcer. Detection of small lesions can be difficult generally involves intramucosal injection of saline to raise
and may be missed even by experienced endoscopists. The the lesion and electrocautery for resection. EMR has been
optional number of biopsies to obtain an accurate diagnosis increasingly used for selected cases, such as, elevated lesions
is uncertain. The finding of intestinal metaplasia or dysplasia less than 2 cm in size, depressed lesions less than 1 cm in size
in the region of subtle mucosal abnormality should further without ulceration and absence of lymph node metastasis.
heighten vigilance, since these changes are precursors to Recent series confirmed the excellent long-term prognosis
adenocarcinoma and may be seen in the vicinity of a cancer. following EMR for small EGCs.
Improved detection of abnormal lesions may be possible with
chromoendoscopy and magnification endoscopy. A novel Endoscopic Submucosal Dissection
endoscopic technology that is rapidly gaining widespread
acceptance is narrow band imaging (NBI). NBI uses green, Endoscopic submucosal dissection (ESD) has been
red and blue filters with narrow wavelength ranges to introduced to resect large tumors and obtain more reliable
visualize the superficial microvascular network with excellent pathologic specimens. Various types of endoscopic
resolution. The potential benefit of NBI is the targeting of electrosurgical knives are used to incise and remove large
endoscopic biopsies to areas of alterations the superficial neoplastic lesions enbloc.
mucosal patterns for the detection of dysplasia and neoplasia. A needle knife is used to incise mucosa surrounding the
The role of follow-up endoscopy for gastric ulcer is uncertain. tumor. The mucosa is subsequently dissected away from the
In one series, follow-up endoscopy with repeat biopsy of underlying submucosa and the entire tumor is removed in
unhealed ulcers detected a small number of additional early one piece.
cancers. The issue of whether it is cost-effective to routinely Although this technique permits larger EGCs to be
perform repeat endoscopy for all gastric ulcers needs to be removed endoscopically than can be excised with EMR,
determined. Therefore, it is still recommended that follow-up lesions with lymphovascular or deep submucosal infiltration
endoscopy of gastric ulcers 812 weeks after initial endoscopy should still not be considered for ESD because of low chance
and initiation of therapy to verify healing, with repeat biopsies of cure, as these findings indicate a significant risk of lymph
performed on remaining ulcers. node metastasis.
Other endoscopic modalities are photodynamic therapy, ulcers within the EGC develop secondary to the EGC and
Nd: YAG laser treatment and argon plasma coagulation. These favor cancer extension and metastasis.
therapies are considered tissue destroying therapies whereas
EMR and ESD are tissue retrieving therapies. Tissue retrieving
therapies allow tissue to be acquired en bloc for a detailed Post-treatment Surveillance
pathological examination of the tumor and assessment of the There is no randomized trial to guide surveillance strategy
tumors depth of penetration, in contrast to tissue destroying following remission. NCCN suggests the following:
which do not. History and physical examination on the following
schedule: up to 3 years: every 36 months
Years 4 and 5: then every 6 months
Anti-Helicobacter pylori Therapy Thereafter: annually
A meta-analysis found that there is a strong association of H. Complete blood count (CBC) and blood chemistries
pylori infection with EGC, when compared both to controls (electrolytes, renal and liver function studies glucose)
and to patients with advanced gastric cancer. Furthermore, Radiologic imaging or endoscopy
eradication of H. pylori following endoscopic resection of EGC Vitamin B12 levels in surgically treated patients
reduced metachronous recurrence rates in a randomized Recurrence rates after gastrectomy were 44, 67 and 86%
controlled trial. Because of association of H. pylori with within 2, 3 and 5 years respectively. Computed tomography
metachronous gastric cancer, eradication is appropriate for (CT) detected 81% of recurrences. It has been suggested that
patients with EGC and H. pylori. patients be followed by CT scan for at least 5 years following
Late recurrences or metachronous lesions occur in the surgical gastrectomy.
gastric remnant in approximately 28% of cases of EGC. Local recurrence rates for either EMR or ESD range from 2
Two major risk factors for recurrence are multifocal areas of to 39%. Close endoscopic surveillance is warranted to monitor
malignancy and lymph node involvement. Late recurrences recurrence who have undergone endoscopic management
are frequently found around the stoma and suture line. for EGC. Most authorities perform surveillance endoscopy on
a quarterly basis during the first year and once to twice yearly
thereafter.
Molecular Markers
Improved understanding of the genetic alterations associated
with gastric cancer has revealed a number of markers that are BIBLIOGRAPHY
associated with disease progression and recurrence. Genetic
pathways differ between intestinal types and diffuse type 1. Farman D, Burley VJ. Gastric cancer: global pattern of the disease
tumors, markers are: and an overview of environmental risk factors. Best Pract Res Clin
Gastroenterol. 2006;20(4):633-49.
Individual with atrophic gastritis who had baseline
2. Correa P. Pathology and molecular pathogenesis of gastric
mutations in K-ras were three times more likely than those
cancer. Official reprint from up-to-date (www.uptodate.com)
without mutations to progress to more advanced lesions 2011.
The expression of P53 (a tumor suppressor gene) and DNA 3. Mansfield PF. Clinical features, diagnosis and staging of gastric
ploidy were associated with tumor invasiveness cancer. Official reprint from up-to-date (www.uptodate.com)
Microsatellite instability and/or loss of heterozygosity 2011.
predicted the development of cancer of the gastric cardia 4. McCulloch P. The role of surgery in patients with advanced gastric
in patients younger than age 40 cancer. Best Pract Res Clin Gastroenterol. 2006;20(4):767-87.
Reduced expression of alpha catenin and overexpression 5. Wagner AD, Schneider PM, Fleig WE. The role of chemotherapy
of P53 predicted lymph node metastasis. in patients with established gastric cancer. Best Pract Res Clin
Gastroenterol. 2006;20(4):789-99.
6. Earle C, Mamon H. Adjuvant and neo-adjuvant treatment of
Coexisting Peptic Ulcer Disease gastric cancer (www.uptodate.com) 2011.
7. Bendell J. Local palliation for advanced gastric cancer (www.
The presence of coexisting peptic ulcer disease may influence uptodate.com) 2011.
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of EGC are associated with the intestinal type of EGC whereas com) 2011.
7
cHAPTER
Malabsorption Disorders
Axel Hsu, Man-Fung Yuen
INTRODUCTION expression causes a primary lactase deficiency resulting in

failed lactose absorption that persists to adulthood. Besides
Malabsorption is defined as the inability to adequately pediatric conditions that include inborn errors of metabolism
absorb nutrients, vitamins, or minerals. It is a common or congenital enzyme defects, many if not most malabsorptive
problem frequently encountered by physicians and conditions occur in the adult population. The rest of this
gastroenterologists. Malabsorption is an important problem chapter focuses primarily on adult causes of malabsorption.
with significant morbidity. It ranges from malabsorption of
a particular type of nutrient to total intestinal failure from
severe small bowel pathologies. As malabsorptive syndrome PATHOPHYSIOLOGY
encompasses a broad scope of gastrointestinal diseases,
this chapter focuses on various types of malabsorption that Malabsorption is a clinical entity related to the inability for
we frequently encounter and the clinical consequences. A the absorption of macronutrients delivered to the small
rational diagnostic approach with comprehensive blood tests, intestines. There are three main stages of absorption. The
imaging, and dedicated tests related to malabsorption have first phase is digestion, commonly known as the luminal
been presented. Finally, a brief management plan related to phase. It is during this phase that the ingested foodstuff
malabsorption in general with a focus on some of the more becomes chemically broken down and hydrolyzed by
common malabsorption syndromes or diseases have been enzymatic activity secreted by the upper gastrointestinal
elaborated. The reader is advised to refer to other chapters tract and pancreas. Polysaccharides are broken down to
of this textbook for a more thorough discussion on the larger monosaccharides. Triglycerides are broken down to fatty
malabsorption-related topics. acids. Proteins are broken down to amino acids. The inability
to digest enzymatically these macronutrients will lead to
specific nutrient deficiencies. Therefore, maldigestion of any
EPIDEMIOLOGY macronutrient will lead to malabsorption. The second phase
is absorption itself. This phase is often known as the mucosal
Malabsorption is a global worldwide problem and occurs phase where chemically broken down proteins, carbohydrates
across all ethnic groups and social economic backgrounds. It is and fats are absorbed through the intact mucosa. Mucosal
important to remember that in patients with failure to absorb absorption can occur by active or passive transport or by
an adequate oral intake is assumed; therefore, malabsorption diffusion. The transport phase is the last postabsorptive
should not be confused with malnourishment, which remains phase where the absorbed nutrients are delivered to the
to be a significant problem in many developing countries. liver via portal system for further processing. This last phase
In more severe malabsorptive disorders, the end result is also relies on an intact vascular and lymphatic circulation,
failure to thrive in pediatric populations, and weight loss and and disease processes here can hinder systemic delivery
anemia in adults resulting in overt malnutrition. A common of absorbed nutrients. A problem at any one of the three
cause of malabsorption worldwide is celiac disease, which phases of absorption results in malabsorption. The problem
is a gluten sensitive enteropathy affecting mainly the young could be a failure of chemical breakdown due to digestive
adult population. Other common causes that affect many problems or a failed enzymatic pathway. Any breach of the
populations, in particular the Asians, are lactose intolerance absorptive ability of the intestinal mucosa and brush border
and lactose malabsorption. During postweaning period, a could also hinder on absorption. Although the three phases
genetically programmed downregulation of intestinal lactase of absorption are simple to understand from a physiological
framework, clinical malabsorption is often more complex CLINICAL FEATURES

and may be interrelated through various phases that affect
each other in causing malabsorption. Besides the intestinal Clinical features of malabsorption most often include
tract, the completion of absorption also relies on the exocrine diarrhea that persists beyond the 4th week when acute
function of the pancreas in aiding digestion of primarily fats infectious etiologies are less likely. In fact, a clinician should
and proteins. Furthermore, solubilization is required for the be alerted to possible malabsorption, if unexplained diarrhea
absorption of nutrients, such as fat or calcium. It cannot be or steatorrhea persists. On the other hand, some patients
overemphasized that the liver, biliary tract, and stomach have more constitutional symptoms that are more vague or
also play a crucial role in digestion and absorption, and insidious in onset. Subtle manifestations, in particular those
significant pathologies in these organs will lead to a certain with extraintestinal manifestations, such as anemia in celiac
degree of malabsorption. In systemic disorders that affect disease, may be more difficult to detect and should not be
gastrointestinal motilitydiabetic autonomic neuropathy, overlooked. For the more common presentation, classical
systemic sclerosis, or hyperthyroidism to name just a few, too symptoms often include malodorous bulky diarrhea, in
quick or too slow intestinal transit can alter the gut flora or particular steatorrhea, significant unintended weight loss and
impair absorption. associated symptoms, which may be related to the underlying
Although the three phases of absorption is a simple etiology. Steatorrhea is often described as foul smelling, oily
concept, in practice, the clinical presentation is often related and bulky stool that floats and is difficult to flush away. Besides
to the malabsorbed substrate. Fat digestion requires adequate steatorrhea, nonspecific abdominal pain, and distension often
mixing of fat with intestinal secretions, adequate bile acid accompanied by bloated sensation is a common coexisting
and micelle formation, and exocrine pancreatic lipase and symptom. Initially, a combination of these symptoms may
colipase secretion. Therefore, diseases with predominant suggest a functional disorder like irritable bowel syndrome.
fat malabsorption include celiac disease, pancreatic Appetite is often preserved, although patients tend to eat less
insufficiency, gut resection and biliary pathologies. Protein or avoid foods that particularly worsen their symptoms. A
malabsorption arises when there are intraluminal defects typical history in a lactose intolerant patient is gastrointestinal
in proteolysis, such as gastric resection, and can also occur symptoms of diarrhea, abdominal pain and bloating that often
in patients with congenital defects of amino acid transport occur within 90 minutes of ingestion of lactose-containing
within the enterocyte. Hartnups disease is a typical congenital foods. Isolated deficiencies may occur and represent the only
disorder in which several neutral amino acids, including presenting feature, and iron deficiency in celiac disease is a
tryptophan are not being absorbed, which ultimately leads typical example. Anemia is often encountered in clinically
to neuropsychiatric features of niacinamide deficiency in significant malabsorption and symptoms of fatigue, malaise,
susceptible pediatric patients. Carbohydrate is an important exertional chest pain, or dyspnea should not be overlooked.
substrate and failure to hydrolyze complex carbohydrates A patient with established chronic liver disease with features
can be due to severe pancreatic insufficiency, extensive small of cholestasis may complain of diarrhea, which reflects bile
bowel disorders with defective mucosa, such as Crohns acid malabsorption. It is important to distinguish whether
disease, and is also commonly seen in postenteritis states. the predominant symptom is diarrhea or steatorrhea as the
Lactose intolerance is common and invariably leads to bile acid malabsorption may be compensated (diarrhea)
diarrhea when lactose-containing foods are taken. Vitamin or decompensated (steatorrhea), and the treatment is
malabsorption, particularly the fat-soluble vitamin K, can different for each. Another symptom is easy bruising and
lead to clinically significant coagulopathy. Vitamin B12 ecchymosis on examination point to acquired vitamin K
(cobalamin) is an important water-soluble vitamin and deficiency as a result of malabsorption. As malabsorption
its deficiency can arise from diseases in the stomach and is a syndrome with many causes, it is important to elicit a
terminal ileum. A search for the cause (see section on vitamin detailed and comprehensive history with an emphasis on
B12 malabsorption) is important as untreated vitamin B12 past health, history of gastrointestinal surgical operations
deficiency can lead to irreversible neurological damage. (with operation records if available), dietary and drinking
Folate deficiency is commonly related to poor oral intake habits, and family history. Fat and protein malabsorption is
and is also often seen in chronic alcoholics. Malabsorption of common in postgastrectomy patients. Concomitant iron or
specific minerals and trace elements can result from extensive vitamin B12 deficiency should be sought. Roux-en-Y bypass
mucosal disease and reduced absorptive mucosal surfaces. In surgery in bariatric patients may lead to clinically significant
short gut syndrome, for example, multiple mineral and trace fat malabsorption and other metabolic disturbances, such
elements are deficient and require exogenous replacement by as hyperoxaluria. Although travel history is more relevant in
dietary supplementation. the context of acute diarrheal illnesses, a recent travel to the
Malabsorption Disorders 63
tropical countries (30 north and south of the equator) and Table 1: Diseases where malabsorption is commonly seen in clinical
subsequent chronic diarrhea should prompt one to think practice
about tropical sprue. Tropical sprue is an infection-triggered
Gastric diseases
autoimmune disease that has clinical and endoscopic features
Atrophic gastritis
somewhat similar to celiac disease. Finally, drugs that can
Pernicious anemia
cause malabsorption include acarbose, olestra, and laxatives Gastric resection or bypass surgery
to name a few. It cannot be overemphasized that a detailed
Intestinal diseases
and comprehensive history is paramount in narrowing down
Amyloidosis
many possible causes of malabsorption.
Celiac disease
Graft-versus-host disease
Immunodeficiencies (selective IgA deficiency)
DIFFERENTIAL DIAGNOSES Infections (HIV and AIDS, cryptosporidiosis, giardiasis, Mycobacterium
avium-complex, tuberculosis, helminth and viral infections, Whipples
disease)
Differential diagnoses related to the classical malabsorption
Intestinal ischemia
syndrome are myriad and extensive. Table 1 illustrates Intestinal resection or bypass
some of the more commonly encountered conditions where Intestinal lymphoma
malabsorption is an important or predominant feature. For Radiation enteritis
clarity and simplification, rare conditions are omitted and the Sarcoidosis
Small bowel intestinal overgrowth
reader is reminded that this list is by no means exhaustive.
Sprue (tropical, collagenous)
Hepatobiliary diseases
DIAGNOSTIC WORKUP Biliary tract obstruction

Biliary tract tumors
Cirrhosis and portal hypertensive states
Approach Inborn errors of bile acid metabolism or transport
Sclerosing or recurrent cholangitis
The diagnostic workup of malabsorption includes tests that Pancreatic diseases
confirm the diagnosis and those that address the related
Congenital pancreatic enzyme deficiency
complications or sequalae as a result of malabsorption. It is Chronic pancreatitis
important to remember that many of the diagnostic tests are Cystic fibrosis
laborious if not tedious and are often only available at tertiary Pancreatic tumors
centers with the necessary equipment and expertise available. Lymphatic diseases
Not all patients will require a stringent workup or battery of Primary intestinal lymphangiectasia
tests. To illustrate, in a patient with suspected small bowel Secondary intestinal lymphangiectasia (lymphoma, tumors, thoracic
intestinal overgrowth, we commonly prescribe an empirical duct pathology)
course of antibiotic therapy. A dramatic improvement in Systemic and metabolic diseases
symptoms often correlates with the suspected diagnosis and Abetalipoproteinemia
is both rewarding for the physician and the patient alike. It is Diabetes
Hyperthyroidism
important to remember that diagnostic workup and choice of
Systemic sclerosis
tests depend on the underlying clinical suspicion, physician Systemic lupus erythematosus
and patient preference and the availability of specialized tests.
Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired
immunodeficiency syndrome
Blood Tests
As the clinical features of malabsorption syndrome may C-reactive protein, electrolytes including calcium and
overlap with functional disorders, a good initial approach is phosphate levels, and liver function tests. Thyroid function
to perform simple screening blood tests to look for common should also be checked as symptoms of thyrotoxicosis may
features of malabsorption, such as iron deficiency anemia, often include persistent diarrhea and significant weight loss.
hepatitis, hypoalbuminemia, and vitamin deficiencies. In the presence of microcytic anemia, an iron profile should
A simple blood panel for malabsorption would include be ordered to look for iron deficiency. Macrocytic anemia
complete blood picture, erythrocyte sedimentation rate, is often related to vitamin B12 or folate deficiency. Anemia
of chronic illness pattern may superimpose on etiologies produced by the pancreas) are also tested in suspected
where inflammation is long-standing. A raised erythrocyte pancreatic insufficiency. Furthermore, stool testing can often
sedimentation rate or C-reactive protein or hypoalbuminemia culture Giardia or other ova, cysts and parasites, which are
also suggest organic pathology. A prolonged prothrombin the common intestinal infections related to malabsorption.
time may be due to vitamin K deficiency, a clue to fat-soluble
vitamin malabsorption. Although laboratory investigation
abnormalities are not usually pathognomonic, such results Tests for Carbohydrate Malabsorption
often point to a possible underlying disease process. For Tests for carbohydrate malabsorption rely upon fermentation
example, a patient with extensive ileal resection (of more of undigested carbohydrates by intestinal bacteria, or
than 60 cm resected) who has confirmed vitamin B12 by direct measurement of the absorbed nutrient after
deficiency is most certainly related to surgical operation. administration of a test dose. The hydrogen breath test is a
Therefore, it is important to correlate the laboratory findings simple but important tool in carbohydrate malabsorption.
to the appropriate clinical setting. Patients suspected to have It can be used to diagnose lactose, fructose or sucrose
celiac disease should have blood serology for antiendomysial malabsorption. Normally, the colonic bacteria ferment
antibodies. The more recently accepted test for celiac disease the nonabsorbed carbohydrate substrate, and hydrogen is
is antitransglutaminase antibody, which has a 98% sensitivity released and exhaled. When lactose or fructose intolerance
and specificity. Once an underlying pathological disease is suspected, an ingestion of a small amount of the substrate
process is suspected, further specific tests for malabsorption (e.g. 2050 grams of lactose) will lead to an excessive amount
should be requested based on the malabsorbed substrate. of hydrogen, which is then detected by the breath test. The
acceptable cutoff often is expressed as greater than 20 ppm
compared with baseline. Furthermore, the hydrogen breath
Tests for Fat Malabsorption test is also useful in documenting patients with suspected
Since the workup of malabsorption entails many different small intestinal bacterial overgrowth. Patients with history of
and often sophisticated tests, it is prudent to confirm the gastric bypass surgery (with blind loops), altered small bowel
presence of steatorrhea if the history is in doubt to avoid transit (systemic sclerosis, diabetes, etc.) and diverticulosis
further unnecessary tests. On the other hand, screening stool are at risk of small bowel bacterial overgrowth. It is important
tests may be unnecessary if the history and macroscopic stool to remember when administrating the hydrogen breath test
appearance are typical and obvious. There are several tests that concurrent or recent antibiotic treatment often alters
performed for fat malabsorption. A good screening test is to the results. In subjects who are nonhydrogen producers (up
collect a stool specimen and to apply acetic acid and Sudan to 18% nonhydrogen producers in the general population),
III stain to look for fat globules under microscopy. Normally, a false negative result may also occur. In these subjects, the
up to 100 globules less than 4 mm diameter per high-power lactose tolerance test could be used instead in which glucose
field is considered normal. Once fat globules are detected, levels are measured at 30 minutes after a test dose of lactose.
a quantitative 72-hour stool collection while taking a 100 Normally, in postlactose ingestion, the serum glucose level
grams fat/day diet is often a good (but not always needed) increases more than 20 mg/dL (or 1.11 mmol/L). In lactose
confirmatory test. An individual normally absorbs about 93% intolerance, the increase is less than 20 mg/dL. These breath
of ingested fat. Therefore, a 72-hour fecal fat excretion greater tests are often limited by the lack of high sensitivity but are
than 7 grams per day is clinically significant steatorrhea commonly performed as they are readily available and
and this finding requires further workup. Up to 14 grams of relatively cheap.
stool output is allowed in patients with diarrhea to account D-xylose breath test is another similar test to determine
for the volume effect of the diarrhea. It is also important to whether malabsorption is due to intestinal cause or
remember that olestra consumption, a fat substitute added pancreatic cause. Normally, xylose is absorbed via intact
to food products, can increase fecal fat excretion leading to proximal intestines by both active transport and passive
a falsely higher excretion value. Besides these limitations, diffusion, and is metabolically excreted unchanged in 50% by
the 3-day fecal fat collection is not always reliable, requires the urine. After an overnight fast, a 25 gram dose of D-xylose is
hospitalization and is cumbersome to perform. Other less ingested and urine collected for next 5 hours. A venous blood
often used tests include the acid steatocrit (a gravimetric assay sample of xylose is also collected at 1 hour. Normal excretion
in which stool mixed with HClO4 is centrifuged and the fatty of D-xylose is 6.0 +/- 1.5 gram in urine and greater than 20 mg/
and solid layers are calculated as a percentage) and the near dL in serum (at 1 hour). In intestinal causes, the level of urine
infrared reflectance analysis but these tests are not widely excretion is reduced and the serum level is low, whereas in
available. Fecal elastase and chymotrypsin (two proteases pancreatic malabsorption, the urine and serum levels remain
normal. It is important to remember that false-negative test acute infectious gastroenteritis was found to have triggered
results occur in impaired renal function and false positive test chronic diarrhea with confirmed bile acid malabsorption. In
results may occur in those with impaired gastric emptying. patients in whom response to Crohns therapy or empirical
As mentioned previously, small bowel bacterial overgrowth bile acid binding therapy, e.g. cholestyramine is suboptimal,
is an important cause of malabsorption, and therapeutic trial objective testing is performed by the selenium homocholic
with antibiotic therapy is often attempted without the tedious acid taurine (75SeHCAT) test. In this test, selenium-75-
testing. With the wide availability of the breath tests, traditional labeled synthetic bile acid (sele-homotaurocholic acid) is
quantitative method of endoscopic intubation to collect small orally ingested followed by measurement of the bile acid by
intestinal aspirate and bacterial counts is becoming obsolete. whole body gamma-scintigraphic scanning on the 7th day
This procedure is both technically demanding and requires to detect the amount of bile acid retention. The test result is
meticulous attention to avoid contamination from nasal and abnormal when the body has less than 5% uptake at day 7.
oral sources. It has been found that in about one-third of irritable bowel
syndrome subjects where diarrhea was the predominant
symptom, the 75SeHCAT test was abnormal and a majority
Vitamin B12 Malabsorption responded well to bile acid chelator therapy.
Vitamin B12 (cobalamin) malabsorption has previously
been mentioned and results in megaloblastic anemia with
possible neurological complications. The Schilling test is
Exocrine Pancreatic Insufficiency
performed to determine whether the malabsorption is at Pancreatic insufficiency can arise from sequalae of chronic
the gastric or at the ileal level. Normally, food cobalamin is pancreatitis and pancreatic tumors with obstruction or cystic
bound to intrinsic factor produced by gastric parietal cells fibrosis. Exocrine function of the pancreas is compromised
and absorbed in the terminal ileum. In the Schilling test, an only when at least 90% of the acinar tissue is destroyed.
oral dose of radiolabeled (57cobalt or 58cobalt) vitamin B12 Simple tests to look for pancreatic insufficiency include fecal
is ingested and intramuscular dose of non-radiolabeled elastase and chymotrypsin, both of which are pancreatic
vitamin B12 is soon given afterwards. The intramuscular dose enzymes. Low levels suggest pancreatic insufficiency.
of vitamin B12 temporarily saturates vitamin B12 carriers Studies have shown that elastase in particular is the preferred
in the liver, hence the excess B12, if absorbed properly, will enzyme of choice and is better at discriminating diarrhea
be excreted in the urine. If less than 710% of administered due to pancreatic from nonpancreatic causes. In suspected
dose is detected in the urine over a 24-hour period, vitamin cases where fecal enzyme assays are inconclusive or
B12 malabsorption is confirmed. In a subsequent part of the equivocal, invasive tests such as pancreatic function tests are
test, oral intrinsic factor is given and if normalization of test available. Although not widely performed, these tests require
result occurs, the cause of malabsorption is gastric in origin duodenal intubation and collection of duodenal aspirates
with pernicious anemia being the likely cause. If oral intrinsic for pancreatic juice volume, bicarbonate and enzyme levels.
factor fails to correct the test result, then ileal pathology is the Venous injection of secretin and cholecystokinin to stimulate
cause of vitamin B12 malabsorption. Although confirmatory, pancreatic enzyme secretion allows for documentation of
the traditional Schilling test is no longer widely performed pancreatic insufficiency. These invasive and uncomfortable
due to (i) lack of production of the cobalt-labeled isotopes, tests with technical limitations are no longer commonplace
(ii) simple and cheap administration of vitamin B12 injection, in standard gastroenterological practice.
which is given regardless of the cause, and (iii) availability
of anti-intrinsic factor and antigastric parietal cell antibody
assays in diagnosing pernicious anemia. Tests for Protein Malabsorption
Protein malabsorption is not routinely investigated
in the clinical setting. It is seldom to see patients with
Bile Acid Malabsorption isolated protein (without concomitant carbohydrate or fat
It is important to consider tests that differentiate bile acid malabsorption) malabsorption. Rather, intestinal protein loss
malabsorption from fat malabsorption as their treatment is more often encountered and is investigated by the stool
differs. The common causes of bile acid malabsorption include alpha-1-antitrypsin clearance. Once protein loss is confirmed
diseases of the terminal ileum, such as Crohns disease with by a raised alpha-1-antitrypsin clearance, further tests are
small bowel involvement or ileal resection greater than 100 performed to target the cause of the hypoalbuminemia.
cm. Human immunodeficiency virus infection and primary 99m-Technetium-labeled albumin injection can localize
bile acid disorders are other causes to consider. Recently, post- the suspected small bowel pathology. This test and other
nuclear scintigraphy tests are often only available at tertiary Crohns disease and lymphangiectasia. Random and targeted
referral centers. Another test not commonly performed is biopsies (aim to have at least 46 well-labeled specimens) are
plasma citrulline and arginine concentrations. The level of recommended during endoscopic examination. Although
these two alpha-amino acids is highly correlated to small rare, it is important to remember that Whipples disease is
bowel length. Therefore, in patients suffering from short gut only diagnostically supported by duodenal biopsy specimens
syndrome, postabsorptive plasma citrulline levels correlate that stain positive for the organism Tropheryma whipplei.
with an estimated functional absorptive bowel length and Endoscopic examination of the stomach and duodenum
help determine the likelihood of intestinal failure. is also necessary for assessment and diagnosis of atrophic
and autoimmune gastritis. Crohns disease with stomach
or duodenal involvement can be detected by biopsies and
Radiological Tests histological assessment. Deep duodenal aspirates can be
A commonly used test is radiographic examination of the examined microscopically in cases of bacterial overgrowth,
small bowel using barium contrast. The meal and follow- and bacterial organisms are quantified and studied. However,
through contrast examination allows a gross depiction of this technically demanding procedure is now infrequently
the intestinal mucosal surface and for structural assessment done as simpler breath tests yield similar information.
especially when extensive ulceration, stricture formation or Colonoscopy with terminal ileum examination is often
fistulous communication is suspected. The transit time of the required when ileal pathology is present or suspected. This is
contrast can also reveal abnormalities pointing toward local the diagnostic standard for Crohns disease with large or small
pathology or a more global motility problem. Small bowel bowel involvement. Other potentially significant findings
enteroclysis via a nasojejunal catheter can improve mucosal during endoscopic examination include strictures and
fold detail by better luminal distension. Often this procedure ulcerations for which biopsies are important for histological
is less well tolerated than the traditional small bowel meal diagnosis. Recently, the wireless capsule endoscopy has
and follow-through. Although not diagnostic and nonspecific, revolutionized the study of small bowel. Although ideal
barium small bowel studies can complement further detailed for detecting small bowel bleeding source and organic
imaging, such as computed tomography (CT) abdominal pathologies, its use in malabsorption syndromes remains
imaging, magnetic resonance enteroscopy or direct relatively new and most studies are on Crohns disease or
examination using (single or double) balloon enteroscopy. celiac disease. It is important to remember that in suspected
Computed tomography imaging of the pancreas can often small bowel obstruction, e.g. Crohns stricture, capsule
delineate the long-standing features of chronic pancreatitis or endoscopy may result in capsule retention. In these cases,
other pancreatic pathology. The reader is advised to refer to barium contrast and CT studies may be the preferred imaging
other parts of this textbook for radiological features of specific of choice. As previously mentioned, investigations dedicated
disease entities. to the pancreas have changed from laborious pancreatic
function tests to more simple tests, such as fecal elastase and
endoscopic retrograde cholangiopancreatography, which
Endoscopic Assessment remain the gold standard for diagnosing chronic pancreatitis.
Endoscopic examination of the whole gastrointestinal tract Endoscopic ultrasound examination of the pancreas in
is now possible with the recent advances in small bowel tertiary centers allows for endoscopic assessment with its
enteroscopy and capsule endoscopy. An upper endoscopy favorable advantage of contrast and radiation-free exposure.
with deep duodenal intubation (beyond the ampulla of
Vater) is often required if celiac disease is suspected, and
the characteristic reduced duodenal folds and scalloping of MANAGEMENT PLAN
mucosa may sometimes be seen which correlate with villous
atrophy on histological studies. While a diagnosis of celiac The general management plan in patients with
disease can often be supported by compatible endoscopic or malabsorption should focus on (i) symptom control, (ii)
histological findings, serological tests are now frequently used replacement of the malabsorbed nutrient, and (iii) monitor
including the antiendomysial and tissue transglutaminase for complications as a result of the malabsorptive disorder.
antibodies that serve as screening and confirmatory Equally important is the treatment of the underlying
purposes. The details on the diagnostic workup for celiac cause of malabsorption. Dietary restriction or avoidance,
disease are discussed elsewhere. One caveat to remember and subsequent adherence are of crucial importance.
during endoscopic small bowel examination is to note that Patients who have bloating and diarrhea from malabsorbed
some intestinal conditions are more focal and patchy, such as carbohydrates should avoid poorly absorbable sugars
such as fructose, sorbitol or fermentable dietary fibers. CONCLUSION

Replacement by supplementation of deficient electrolytes,
minerals and vitamins is often simple and effective. Malabsorption is an important problem commonly
Adequate calcium intake or supplementation is important encountered in medical and surgical practice. It is important
in preventing metabolic bone disease. Iron, vitamin B12 to recognize that presenting symptoms may be insidious
or folate supplementation can improve anemia with in onset and symptoms may seem to suggest functional
normalization of hemoglobin levels. In order to tackle the bowel disorders. The diagnostic workup includes a battery
more specific diseases related to the underlying disorder, of investigations that include blood tests, stool analysis,
a gastroenterologist with experience in the particular area endoscopy, imaging and dedicated tests for malabsorbed
is recommended. Empirical courses of antibiotics are substrates. Celiac disease remains an important disease
important in small intestinal bacterial overgrowth and have and serves as a good model for studying malabsorption.
both diagnostic and therapeutic roles. Frequently, a dietitian The approach and management to malabsorptive disorders
referral is necessary as nutritional counseling and dietary requires a good knowledge of the basic underlying
adjustments are required in patients with celiac disease pathophysiologic mechanisms and to utilize the approach
or carbohydrate intolerance. Medium chain triglyceride tests in arriving at the diagnosis. The workup and investigations
(MCT) diets are beneficial in patients with troublesome are often specialized and challenging. It is important that
steatorrhea since MCT absorption does not require micelle physicians and gastroenterologists alike be familiar with the
formation (for fat solubilization and absorption), which workup of malabsorption. Management principles target
is often required in dietary fat intake. Strict adherence to underlying disorder and symptomatic treatment aims at
an MCT diet can benefit patients with primary intestinal improving quality of life. The reader is encouraged to refer to
lymphangiectasia, short gut syndrome and pancreatic other parts of this textbook for more detailed information on
insufficiency. Furthermore, the MCT diet is recommended specific disease entities related to malabsorption.
for patients with intestinal lymphangiectasia due to the
portal route of absorption rather than the lymphatic route.
Pancreatic protease and lipase preparations are available BIBLIOGRAPHY
commercially and are often effective in clinically significant
pancreatic insufficiency, i.e. steatorrhea with greater than 1. Duerksen DR, Fallows G, Bernstein CN. Vitamin B12 malabsorption
15 g/day fat excreted. Commercially available pancreatic in patients with limited ileal resection. Nutrition. 2006;22:1210-3.
2. Fernandez-Banares F, Rosinach M, Esteve M, et al. Sugar
lipase preparations should start at 40,00050,000 United
malabsorption in functional abdominal bloating: a pilot study on
States Pharmacopeia (USP) units of lipase per meal given
the long-term effect of dietary treatment. Clin Nutr. 2006;25:824-31.
with meal thrice daily. This dose can be titrated until there 3. Masoero G, Zaffino C, Laudi C, et al. Fecal pancreatic elastase 1
is normalization of stool consistency and appearance. If in the work up of patients with chronic diarrhea. Int J Pancreatol.
higher doses do not show marked improvement, empirical 2000;28:175-9.
addition of a proton-pump inhibitor to lower the intestinal 4. Menon S, Jones BJ. Postinfective bile acid malabsorption: is this a
pH can improve drug bioavailability to the proximal long-term condition? Eur J Gastroenterol Hepatol. 2011;23:308-10.
intestine. In patients with malabsorptive disorders, proper 5. Walker MM, Murray JA, Ronkainen J, et al. Detection of celiac
treatment coupled with good patient dietary and drug disease and lymphocytic enteropathy by parallel serology and
compliance will often ensure a good clinical outcome. For histopathology in a population-based study. Gastroenterology.
those with chronic medical problems such as inflammatory 2010;139:112-9.
6. Wedlake L, AHern R, Russell D, et al. Systematic review: the
bowel disease or celiac disease, life-long therapy with
prevalence of idiopathic bile acid malabsorption as diagnosed by
medications and dietary discretion is required. Often those
SeHCAT scanning in patients with diarrhea-predominant irritable
with more complex conditions such as short gut syndrome bowel syndrome. Aliment Pharmacol Ther. 2009;30:707-17.
are jointly managed by gastroenterologists, surgeons and 7. Yadav P, Das P, Mirdha BR, et al. Current spectrum of malabsorption
dietitians with a multidisciplinary approach. syndrome in adults in India. Indian J Gastroenterol. 2011;30:22-8.
8
cHAPTER
Abdominal Tuberculosis
Zaigham Abbas
INTRODUCTION PATHOGENESIS
Tuberculosis (TB) is still common in the developing countries.
Gastrointestinal Tract
The disease has now made a comeback even in the Western
countries with the epidemic of acquired immunodeficiency Tuberculosis is a chronic granulomatous inflammatory
syndrome (AIDS). It is still a killer disease affecting more the disease. The bacteria reach the gastrointestinal tract via
lower socioeconomic classes in the developing countries. hematogenous spread from a primary lung focus and
Abdominal TB denotes involvement of the gastrointestinal infection occurs following reactivation of latent tuberculous
tract, peritoneum, lymph nodes, and solid viscera, e.g. liver, foci in the peritoneum. Gastrointestinal tract may also be
spleen, and pancreas. Tuberculosis of the gastrointestinal involved by ingestion of infected sputum, or direct spread
tract is the sixth most frequent form of extrapulmonary site from infected contiguous lymph nodes and fallopian tubes.
after lymphatic, genitourinary, bone and joint, miliary, and The intestinal lesions may be ulcerative (60%), hypertrophic
meningeal TB. Mycobacterium tuberculosis is the pathogen in (10%), and ulcerohypertrophic (30%). Hypertrophic form is
most cases. Mycobacterium bovis causes disease in some parts characterized by scarring, fibrosis, and pseudotumor lesions.
of the world where pasteurization of milk is not practiced. Ulcerohypertrophic form is more common in the ileocecal
region.
The affinity of M. tuberculosis for ileocecal region may
RISK FACTORS be due to its relative stasis and abundant lymphoid tissue.
The organism penetrates the mucosa and localizes in the
Tuberculosis flourishes wherever there is poverty and submucosal lymphoid tissue and Peyers patches, where
crowding. Vulnerability increases when body defenses are it initiates an inflammatory reaction with tuberculous
weakened, such as chronic debilitating diseases, diabetes granuloma formation, lymphangitis, endarteritis, caseation
mellitus, Hodgkins disease, chronic lung disease, particularly necrosis, mucosal ulceration, and scarring. Then the
silicosis, malnutrition, underlying malignancy, cirrhosis, inflammatory process in the submucosa reaches to the serosa
alcoholism, and immunosuppression, especially AIDS, via lymphatics. The lymphatic obstruction of mesentery
corticosteroid therapy and following treatment with anti- and bowel causes a thick fixed mass. Spread may occur
tumor necrosis factor (TNF) agents, patients undergoing to the glands in the mesenteric root to the para-aortic
continuous ambulatory peritoneal dialysis and in elderly. The glands and on to the cisterna chyli and then to the thoracic
emergence of multidrug resistant bacilli and AIDS has posed duct resulting in miliary dissemination. Caseous glands
newer threats. may invade the peritoneum or form a localized abscess.
Sometimes, intestinal obstruction may result from pressure
of glands or kinking through adhesions and their healing by
SITES OF INVOLVEMENT fibrosis or calcification leading to napkin ring strictures.
Hypertrophic cecal TB may also lead to obstruction.
Tuberculosis can involve any part of the gastrointestinal tract Perforation may occur proximal to a stricture. Malabsorbtion
from mouth to anus (49%), the peritoneum (42%), mesenteric occurs secondary to bacterial overgrowth in stagnant loops,
lymph nodes (4%), and the solid viscera, including liver and bile salt deconjugation, diminished absorptive surface due to
pancreatobiliary system (5%). The most common site of ulceration, and involvement of lymphatics, and lymph nodes.
involvement in intestinal TB is the ileocecal region followed Granulomas associated with TB tend to be large and
by the colon and jejunum. confluent often with caseation necrosis in contrast to those
Abdominal Tuberculosis 69
loops and lymph nodes felt as typical doughy abdomen, or

(iii) encysted (loculated) type with a localized abdominal
swelling, or (iv) a combination of above. Tuberculous
peritonitis has a female predominance. The peritoneum
is studded with multiple yellow-white tubercles (Fig. 3).
It is thick and hyperemic with a loss of its shiny luster.
The peritoneal tubercles are large and loops of intestine
are inflamed and swollen. Ascites develops secondary to
exudation of proteinaceous fluid from the tubercles, similar
to the mechanism leading to ascites in patients with peritoneal
carcinomatosis. Widespread adhesions and fibrosis may lead
to adhesive intestinal obstruction.
Fig. 1: Colonic tuberculosis: inflammation, ulceration, and granuloma

formation in the submucosa (HE x100)
in Crohns disease. Granulomas are often seen just beneath

the ulcer bed, mainly in the submucosal layer (Fig. 1).
Tubercular ulcers are relatively superficial and usually do
not penetrate beyond the muscularis. They may be single or
multiple, and the intervening mucosa is usually uninvolved.
These ulcers are usually transversely oriented in contrast
to Crohns disease where the ulcers are longitudinal or
serpiginous. Cicatricial healing of the circumferential girdle Fig. 2: Thickening of cecal wall in hypertrophic form of ileocecal
ulcers results in strictures. Occlusive arterial changes may tuberculosis
produce ischemia and contribute to the development of
strictures. Patients with strictures have occlusion of the vasa
recta, while ulcerated lesions have hypervascularity. Small
bowel lesions are usually ulcers or strictures while colonic
and ileocecal lesions are ulcerohypertrophic (Fig. 2). The
disease may involve both sides of the ileocecal valve leading
to incompetence of the valve, another point of distinction
from Crohns disease. Isolated involvement of colon without
ileocecal region has also been reported with skip lesions and
multifocal involvement in some cases. In such cases, Crohns
disease is again an important differential.
Peritoneum
Peritoneal involvement may occur by hematogenous
spread or by direct extension from caseating and breaking,
down lymph nodes. It may either be (i) ascitic type with
abdominal distension, or (ii) adhesive (plastic) type resulting Fig. 3: Laparoscopic findings of peritoneal involvement of tuberculosis:
in mesenteric and omental thickening, with matted bowel tubercles and adhesions
Abdominal Lymph Nodes

Lymphadenopathy may present without any other evidence
of abdominal involvement. Mesenteric lymph nodes may
get enlarged and matted, and may caseate. Characteristic
granulomas may be seen in these lymph nodes. There is relative
lack of retroperitoneal lymphadenopathy in patients with TB,
in spite of extensive mesenteric and peritoneal abnormalities.
This can be explained by the fact that mesenteric lymph nodes
drain directly into the thoracic duct (via the cisterna chyli).
This observation can help differentiate abdominal TB from
other systemic diseases, such as lymphomas.
Pancreas
Pancreas is biologically protected from being infected by M. Fig. 4: Well formed hepatic granuloma in a patient with abdominal
tuberculosis, probably because of the presence of pancreatic tuberculosis (HE x400)
enzymes that interfere with the seeding of M. tuberculosis.
Tuberculosis of pancreas is rare and may pose a diagnostic
challenge, specially differentiating it from carcinoma of the
pancreas. Its indolent course and vague symptomatology along
with nonspecific laboratory and radiological findings call for
greater vigilance. Infection is said to involve the pancreas by
direct extension, lymphatic or hematogenous dissemination
or following reactivation of previous abdominal TB.
Liver
Tuberculosis of the liver in isolation is rare. Liver is involved in
association with foci of infection in lungs or intra-abdominal
organs, such as the peritoneum, mesentery, mesenteric
lymph glands, biliary tract, and the gallbladder. The disease
commonly involves the hepatic parenchyma and sometimes
the biliary tree. The most common type of presentation is
diffuse miliary liver involvement via hepatic artery associated
with pulmonary TB. The second form is diffuse hepatic
infiltration without evidence of TB elsewhere. The third form Fig. 5: Hepatic granuloma with Langhans giant cells (HE x400)
presents as a focal or nodular lesion in liver as tuberculoma or
abscess and the portal of entry is the portal vein. The patients
with liver involvement may or may not have jaundice. may coalesce to form a large tumor like tuberculoma. A
Jaundice is usually cholestatic but sometimes obstructive tuberculoma, which has undergone extensive caseation and
either due to porta hepatis nodes causing biliary compression liquefaction necrosis, forms a tubercular abscess.
or pericholangitis or rupture of a tuberculous granuloma into
the bile ducts.
Tuberculosis is an important cause of granulomatous liver
Gallbladder
disease (Figs 4 and 5). Hepatic epitheloid cell granulomas Gallbladder may get involved by hematogenous or lymphatic
may occur in other diseases as well. Only 25% of patients spread from the primary site or secondary to hepatic TB from
with tuberculous granulomas show characteristic caseation excreted bacteria into the biliary tree or by direct spread
in the biopsy specimen. The granulomas are most frequently from liver or periportal lymph nodes. Patients may present
found in the periportal areas (zone 1 of Rappaport) but may with cholecystitis, obstructive jaundice or rarely only with
occasionally occur in zone 3. In focal TB, various granulomas gallbladder wall thickening on sonography.
CLINICAL FEATURES
Abdominal TB is predominantly a disease of young adults.
Majority of the patients are in their twenties and thirties
at the time of presentation, and the sex incidence is equal.
Patients with abdominal TB present with fever, abdominal
pain aggravated by meals, vomiting, weight loss, night sweats,
diarrhea alone or alternating with constipation, abdominal
distension, mass in the right lower abdomen and occasionally
hematochezia. Pain can either be colicky due to luminal
compromise, or dull and continuous when the mesenteric
lymph nodes are involved. Symptoms are usually of moderate
intensity and usually present for more than 3 months when
the patient seeks the medical advice. Presence of coexistent Fig. 6: Esophageal biopsy showing mucosal ulceration and large well
pulmonary TB significantly increases the frequency of fever formed epitheloid granuloma in mucosa (HE x100)
and night sweats, weight loss and pulmonary symptoms.
On examination, pallor, ascites or doughy abdomen and
generalized abdominal tenderness, especially in the right
iliac fossa may be present. Patient may have hepatomegaly.
Abdominal masses due to enlarged lymph nodes, adherent
bowel loops or a cold abscess may be noted.
Patients of ileocecal and small bowel TB present with
colicky abdominal pain, borborygmi, and may have a
palpable lump in the right lower quadrant. These patients
may present with one of the complications like intestinal
obstruction, perforation, or malabsorption, especially in the
presence of stricture. Tuberculosis may also present as an
enterocutaneous fistula after bowel surgery, an umbilical
abscess, a discharging sinus or as nonhealing surgical wound.
Rare clinical presentations of gastrointestinal TB include
dysphagia, odynophagia, and a midesophageal ulcer due to
esophageal TB (Fig. 6); dyspepsia, hematemesis, melena, or
gastric outlet obstruction due to gastroduodenal TB (Fig. 7);
Fig. 7: Well formed epitheloid granuloma with Langhans giant cell in
lower abdominal pain and hematochezia due to colonic TB; gastric antral mucosa. Gastric tuberculosis (HE x200)
and annular rectal stricture and multiple perianal fistulae due
to rectal and anal involvement.
The clinical presentation of hepatic TB is usually insidious mass or hypodense lymph nodes in the peripancreatic region,
and often nonspecific. The patient may present with a particularly if the patient presents with fever and is young, not
protracted illness frequently associated with fever, malaise, jaundiced, lives in an area of endemicity, or was exposed to
weight loss, jaundice, abdominal pain and hepatomegaly. TB in the past.
The liver is usually not tender on percussion or palpation.
Splenomegaly may be present in some cases. These patients
are usually anemic. Mild jaundice may be present. Obstructive INVESTIGATIONS
jaundice may develop if enlarged hilar glands of the liver
compress common hepatic ducts. Diagnosis is based on history, physical examination, and
Pancreatic TB is more common in females. The patients investigations. Laboratory investigations may show anemia,
present with epigastric pain, fever and weight loss; jaundice leukopenia, leukocytosis with left shift, thrombocytopenia,
may or may not be present. Other clinical presentations thrombocytosis, elevated ESR, hyponatremia, elevated
include acute or chronic pancreatitis and gastrointestinal alkaline phosphatase and gamma-glutamyl transferase
bleeding secondary to splenic or portal vein thrombosis. It (GGT), mild elevation of transaminases, hyperbilirubinemia,
should be suspected in young patients having a pancreatic hypoxemia, and sterile pyuria. Anemia, which may be
present in about 60% of patients, is usually a normochromic diagnosing pancreatic TB is approximately 5060%. Culture
normocytic anemia of chronic infection. Leukocytosis is results are positive in only 7075% of all pancreatic TB
more common than leukopenia. Cholestatic jaundice is also cases. Finding of liver granulomas histologically, even in the
well documented in miliary TB. Amylase and lipase levels absence of caseation necrosis or AFB is accepted as evidence
would become elevated in cases of pancreatitis associated of tubercular etiology in most instances unless proven
with miliary TB. otherwise (Figs 4 and 5).
The diagnosis of abdominal TB is confirmed by
demonstration of bacilli from tissues by smear, culture
or polymerase chain reaction (PCR) and demonstrating Tuberculin Skin Test
caseating granulomata at histopathology. Unfortunately, in Tuberculin testing with purified protein derivative (PPD) is
most of our patients such confirmation is not possible. The positive in approximately 70% of patients; however, a negative
treatment for abdominal TB is often instituted on the basis result is of no help in excluding the disease. Intradermal
of a high index of clinical suspicion and ancillary supportive injection of 0.1 mL of PPD should produce a 610 mm wheal
evidences without actually recovering the bacilli. when read at 4872 hours. If first test is negative, retesting
may be done in 13 weeks. Patients with a weakened immune
response may be anergic at the time of PPD reading.
Microbiology
Mycobacteria are aerobic, acid-fast bacilli (AFB). They are
poorly stained with Gram staining, and M. tuberculosis
Interferon-gamma Release Assays
grows slowly with a doubling time of 18 hours compared to They measure T cell release of interferon-gamma (IFN-
most other bacteria having doubling time of less than 1 hour. gamma) following stimulation by antigens unique to M.
Due to this, slow growth cultures of clinical specimens must tuberculosis and have the specificity greater than 90% for
be held for 68 weeks before recording the result. Broth- the diagnosis of latent TB. These tests would take the place
based culture systems to improve the speed and sensitivity of tuberculin skin tests. They are not affected by Bacille
of detection have been developed. The BACTEC system can Calmette-Gurin (BCG) vaccination status. However, they
detect M. tuberculosis in approximately 2 weeks and is more cannot distinguish between latent infection and active TB
sensitive in recovery of mycobacteria than the conventional disease. The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay
LowensteinJensen medium and smear microscopy. is an enzyme-linked immunosorbent assay (ELISA) based
Examination of an acid fast stained smear of ascitic fluid test, while T-SPOT is an enzyme-linked immunosorbent spot
has a disappointingly low yield of 06% and the frequency assay (ELISPOT). The reported sensitivity and specificity of
of a positive ascites culture is less than 20%. Demonstration ELISPOT in the diagnosis of extrapulmonary TB is 94% and
of AFB is more common in tubercular abscess verses solid 88% respectively. The assay may be performed on peripheral
tuberculomas because AFB are abundant in liquefied blood or ascitic fluid.
caseous material. Endoscopic biopsies are culture positive in
40% cases. Polymerase chain reaction assays, which amplify
mycobacterial 16S ribosomal RNA, show promise of rapid Plain X-ray
detection of mycobacteria and are highly sensitive. X-ray of the chest is done to rule out any concomitant
pulmonary TB or any evidence of past infection. Active
pulmonary disease is present in less than one-fifth of patients.
Histopathology A normal chest radiograph does not rule out the diagnosis of
Endoscopic biopsies have low yield for granulomas as the abdominal TB. Plain X-ray of the abdomen may show features
disease is mainly submucosal (Figs 1, 6 and 7). Granulomas of obstruction, perforation or intussusception and evidence
may be seen in 848% of the cases and with caseation in about of ascites. In addition, there may be calcified lymph nodes,
one-third of positive cases. Percutaneous image-guided fine calcified granulomas and hepatosplenomegaly.
needle aspiration (FNA) of suspicious peritoneal, omental
or nodal lesions might suggest the diagnosis of TB, thereby
obviating the need for a diagnostic laparoscopy or explorative
Barium Studies
laparotomy. In case of pancreatic lesion, FNA may be obtained Barium studies are not diagnostic as similar lesions may
by computed tomography (CT) or ultrasound guidance be found in other diseases especially inflammatory bowel
or during endosonography. The success rate of image- disease. Small bowel studies may show features like
guided percutaneous fine needle aspiration for cytology in accelerated intestinal transit, hypersegmentation of the
is seen in healing lesions. Both caseation and calcification

are highly suggestive of a tubercular etiology. Ascites may
be detected. Interloop ascites appears as localized fluid
between radially oriented bowel loops due to local exudation
from the inflamed bowel (the club-sandwich or sliced-bread
sign). The intestinal loops may be dilated or matted. Bowel
wall thickening is best appreciated in the ileocecal region
and is uniform and concentric as opposed to the eccentric
thickening at the mesenteric border found in Crohns disease
and the variegated appearance of malignancy.
A tuberculoma in the liver may be seen as a hypoechoic
lesion without a distinct wall resulting from the conglomeration
of numerous small tubercles or as a low density lesion with
a hyperechoic rim relating to a tuberculous abscess. In both
cases, calcification may be observed.
Fig. 8: Conical cecum, shrunken in size and pulled out of the iliac Computed Tomography
fossa Scan of Abdomen
Computed tomography (CT) scan and CT enteroclysis are
barium column, precipitation, flocculation and dilution of important investigational tools for abdominal TB. Bowel
barium, stiffened and thickened folds, luminal stenosis with wall thickening, adherent loops, mesenteric thickening and
smooth but stiff contours (hour-glass stenosis). Multiple lymphadenopathy are picked up by the scan (Figs 9 and 10).
strictures with segmental dilatation of bowel loops may also Caseating lymph nodes are seen as having hypodense centers
be found as well as fixity and matting of bowel loops. and peripheral rim enhancement. This is in contrast to non-

Early involvement of the ileocecal region on barium Hodgkin lymphoma where homogeneously enhanced lymph
enema manifests as spasm and edema of the ileocecal valve. nodes are seen in the body and root of small bowel mesentery.
There may be thickening of the lips of the ileocecal valve Mesenteric involvement of TB is seen on CT scan as a patchy
or wide gaping of the valve with narrowing of the terminal or diffuse increase in density, strands within the mesentery
ileum. Terminal ileal TB may present with thickening of folds, and a stellate appearance. CT scan can also pick up ulceration
contour irregularity and focal or diffuse aphthous ulcers, or nodularity within the terminal ileum or circumferential
which tend to be linear or stellate, following the orientation wall thickening, narrowing of the lumen and ulceration.
of lymphoid follicles (longitudinal in the terminal ileum). Complications of the disease like perforation, abscess, and
Cecal involvement may end up in conical cecum, shrunken obstruction may also be seen.
in size and pulled out of the iliac fossa due to contraction
and fibrosis of the mesocolon (Fig. 8). Terminal ileum may
become dilated in such cases. When acute inflammation
is superimposed on a chronically involved segment, there
is lack of barium retention in the inflamed segments of the
ileum, cecum and a variable length of the ascending colon.
Persistent narrowing of terminal ileum indicates stenosis.
Crohns disease is an important differential in the setting of
above findings.
Sonography
Findings in patients with abdominal TB include an echogenic
thickened mesentery (15 mm) or omentum. Mesenteric
lymphadenopathy may be discrete or matted with mixed
echotexture. Small discrete anechoic areas representing Fig. 9: Marked thickening of small bowel wall in patient with
zones of caseation may be seen within the nodes. Calcification tuberculosis (D/D lymphoma)
while colonoscopy is an excellent tool to diagnose colonic

and terminal ileal involvement. Colonoscopic findings of
ileocecal TB include ulcers, strictures, nodules, pseudopolyps,
fibrous bands, fistulae and deformed ileocecal valves (Figs
11 and 12). Tuberculous ulcers in colon are circumferential
or transversely located and are usually surrounded by
inflamed mucosa or nodules; while in Crohns disease, there
are aphthous ulcers with normal surrounding mucosa or
longitudinal or serpiginous ulcers and cobblestoning. The
ileocecal valve may be patulous with surrounding heaped
Fig. 10: Extensive omental caking and thickening adjacent to anterior

abdominal wall (D/D malignancy)
Computed tomography findings of hepatic TB may

reveal hypodense mass with or without a hyperdense rim
after enhancement study or a multiseptate liver abscess.
Sometimes, a lesion may have heterogenous density with
central necrosis or central calcification. In cases of pancreatic
involvement, contrast enhanced CT scans may demonstrate a
focal hypodense mass or diffuse enlargement of the pancreas.
Ring enhancement or low-density areas within enlarged
peripancreatic lymph nodes should make one suspect
tuberculous lymph nodes.
Fig. 11: Involvement of ileocecal valve in a patient with tuberculosis
Laparoscopy
Blind peritoneal biopsies have a low success rate in cases of
tuberculous peritonitis. The biopsies from peritoneum, liver
and lymph glands taken under direct vision by laparoscopy
or minilaparotomy have a high diagnostic yield. Laparoscopic
findings consist of multiple yellowish white 45 mm
peritoneal tubercles or scattered erythematous patches (Fig.
3). Thickening of peritoneum with thick adhesions may be
seen in fibroadhesive variety. Histology of peritoneal biopsy
specimens shows granulomas with caseation in majority of
patients, with or without presence of AFB.
Endoscopy
Upper gastrointestinal endoscopy is used to detect
esophageal, stomach, and duodenal TB. Capsule endoscopy Fig. 12: Colonoscopy showing circumferential cecal involvement in
and enteroscopy are used to visualize the small intestine, tuberculosis
up folds or destroyed with fish-mouth opening. Looking into rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA)
terminal ileum, there may be thickening of folds, contour given for 2 months followed by INH and RIF. Ethambutol is
irregularity and focal or diffuse ulcers, which tend to be linear continued in cases of recurrent disease, drug resistance or
or stellate. Endoscopic biopsy is often diagnostic. Multiple serious illness. The utility of corticosteroid for the first 23
biopsies should be taken from the edge of the ulcers. Deep months to decrease fibrosis associated with healing lesions
endoscopic biopsies should be taken from the ulcer margins has not been proven, and evidence-based guidelines do not
and bed since TB granulomas are often submucosal in recommend it. Nearly 80% of patients respond very well to
comparison to the mucosal location of Crohns disease chemotherapy. Supportive measures like good nutrition
granulomas. The material should be sent for histology and and multivitamins help correct deficiencies, which are often
culture and PCR for Mycobacterium. present. Concomitant administration of pyridoxine (vitamin
B6) reduces the chances of INH neurotoxicity.
Isoniazid, RIF, and PZA can cause hepatitis. In general,
Ascitic Fluid Analysis treatment of TB should be discontinued, if a patients
Ascitic fluid in TB is straw colored with protein greater than transaminase level exceeds three times the upper limit of
3 g/dL in more than 90% cases, serum ascites albumin normal when associated with symptoms, or five times the
gradient less than 1.1 g/dL and a total cell count of 1504,000/ upper limit of normal, if the patient is asymptomatic. The risk
L, consisting predominantly of lymphocytes (>70%). Serum is more in patients with pre-existing liver disease. However,
adenosine deaminase (ADA) level above 54 U/L, ascitic fluid because of the effectiveness of these drugs, these should
ADA level above 36 U/L and a ascitic fluid to serum ADA ratio be used if at all possible, even in such patients. If serum
greater than 0.985 may be suggestive of TB. However, the transaminases are elevated more than three times the upper
sensitivity is substantially lower in patients with cirrhosis. limit of normal before the initiation of treatment and the
abnormalities are not thought to be caused by TB, one option
is to treat with RIF, EMB and PZA for 9 months, avoiding
DIFFERENTIAL DIAGNOSIS INH. A second option is to treat with INH, RIF and EMB for 2
months followed by INH and RIF avoiding PZA. For patients
The differential diagnosis of TB includes Crohns disease, with severe liver disease, a regimen with only one hepatotoxic
non-Hodgkin lymphoma, ulcerative colitis, amebic colitis, agent, generally RIF plus EMB could be given for 12 months,
disseminated carcinoma, chronic liver disease, sarcoidoisis, preferably with another agent, such as a streptomycin or
peritoneal mesothelioma and appendicitis. Isolated fluoroquinolone (levofloxacin, moxifloxacin) for the first 2
lymphadenopathy may be easily confused with lymphomas months.
involving abdominal lymph nodes. The differential diagnosis The recommended surgical procedures today are
of ileocecal TB includes Crohns disease, colon cancer, and conservative, and a period of preoperative drug therapy is
less commonly, infection due to Yersinia enterocolitica controversial. Conservative therapy is advocated initially for
and Y. pseudotuberculosis, mucoceles, typhlitis, amebiasis, patients presenting with intestinal obstruction. Obstruction
actinomycosis, carcinoid, appendicular mass and lesions due may become exacerbated during antituberculous therapy
to nonsteroidal anti-inflammatory drugs. Hepatic epitheloid due to healing by cicatrization. Surgical procedures include
cell granuloma alone can occur in primary biliary cirrhosis, resection, anastomosis, adhesiolysis, omentectomy and
sarcoidosis, Crohns disease, chronic active hepatitis, drug stricturoplasty, primary repair of perforation, ileostomy
hypersensitivity, and extrahepatic biliary obstruction. and exteriorization of gut. Right quarter colectomy and
anastomosis (limited ileocecal resection) is the most
common surgical procedure done. Diseased segments of
MANAGEMENT bowel with adequate free margins are removed, avoiding
extensive resection. Extensive adhesiolysis should be avoided
If the clinical, radiographic, and endoscopic data are in patients with advanced plastered intestine as it may end
consistent with the diagnosis of abdominal TB and are up with fistulae formation. If ascites is present, it is evacuated
adequate to rule out other common diseases, e.g. cancer, and the abdomen is closed without leaving drains. In all
nonspecific inflammatory bowel disease, and other cases, histopathological examination of resected specimen
specific infections, it is considered appropriate to give or mesenteric lymph nodes should be performed. Recurrent
a trial of antitubercular chemotherapy. Management is fistula in ano and abscesses are common in tropical countries
with conventional antitubercular therapy for 69 months. and respond to antitubercular treatment. Colonoscopic
Antitubercular therapy regimen includes isoniazid (INH), balloon dilation can be used to manage readily accessible,
short and fibrous tuberculous ileal strictures causing subacute 2. Malik AM, Shah M, Pathan R, et al. Pattern of acute intestinal
obstructive symptoms and may obviate the need for surgery. obstruction: is there a change in the underlying etiology? Saudi
J Gastroenterol. 2010;16(4):272-4.
3. Chong VH, Lim KS. Hepatobiliary tuberculosis. Singapore Med J.
2010;51(9):744-51.
SUMMARY 4. Desai CS, Josh AG, Abraham P, et al. Hepatic tuberculosis in
absence of disseminated abdominal tuberculosis. Ann Hepatol.
Abdominal TB can involve any part of the gastrointestinal
2006;5(1):41-3
tract, the peritoneum, mesenteric lymph nodes, and the 5. Dong P, Wang B, Sun QY, Cui H. Tuberculosis versus non-
solid viscera including liver and pancreatobiliary system. The Hodgkins lymphomas involving small bowel mesentery:
affinity of M. tuberculosis for ileocecal region may be due to evaluation with contrast-enhanced computed tomography.
its relative stasis and abundant lymphoid tissue. Tuberculous World J Gastroenterol. 2008;14(24):3914-8.
granulomas tend to be large and confluent often with 6. Jakubowski A, Elwood RK, Enarson DA. Clinical features of
caseation necrosis. The intestinal lesions may be ulcerative, abdominal tuberculosis. J Infect Dis. 1988;158(4):687-92.
hypertrophic and ulcerohypertrophic. Peritoneal involvement 7. Khan IA, Khattak IU, Asif S, et al. Abdominal tuberculosis an
may be ascitic type, adhesive (plastic) type or encysted experience at Ayub Teaching Hospital Abbottabad. J Ayub Med
(loculated) type. Mesenteric lymph nodes in TB get enlarged Coll Abbottabad. 2008;20(4):115-8.
8. Lai CC, Lee TC, Hsiao CH, et al. Differential diagnosis of
and matted, and may caseate. Liver may get involved in miliary
Crohns disease and intestinal tuberculous by enzyme-linked
TB or there may be isolated granulomatous liver disease.
immunospot assay for interferon-gamma. Am J Gastroenterol.
Focal tuberculomas or abscesses in liver may also occur. 2009;104(8):2121-2.
Patients with abdominal TB present with fever, abdominal 9. Makharia GK, Srivastava S, Das P, et al. Clinical, endoscopic,
pain, vomiting, weight loss, night sweats, and diarrhea alone and histological differentiations between Crohns disease and
or alternating with constipation, abdominal distension intestinal tuberculosis. Am J Gastroenterol. 2010;105(3):642-51.
and mass in the right lower abdomen. These patients may Epub 2010 Jan 19.
also present with one of the complications like intestinal 10. Manohar A, Simjee AE, Haffejee AA, et al. Symptoms and
investigative findings in 145 patients with tuberculous peritonitis
obstruction, perforation or malabsorption especially in the
diagnosed by peritoneoscopy and biopsy over a five year period.
presence of strictures. Diagnosis of abdominal TB is based
Gut. 1990;31(10):1130-2.
on history, physical examination and investigations, which 11. Muneef MA, Memish Z, Mahmoud SA, et al. Tuberculosis in the
include routine tests, endoscopies, barium studies, CT scan belly: a review of forty-six cases involving the gastrointestinal
and biopsy results. Interferon-gamma release assays would tract and peritoneum. Scand J Gastroenterol. 2001;36(5):528-32.
take the place of tuberculin skin tests to rule out exposure 12. Purl AS, Nayyar AK, Vij JC. Hepatic tuberculosis. Ind J Tub.
to TB. The treatment for abdominal TB is often instituted on 1994;41:131-4.
the basis of a high index of clinical suspicion and ancillary 13. Safarpor F, Aghajanzade M, Kohsari MR, et al. Role of laparoscopy
supportive evidences without actually recovering the bacilli. in the diagnosis of abdominal tuberculosis. Saudi J Gastroenterol.
Management is with conventional antitubercular therapy for 2007;13(3):133-5.
69 months. There is no role for steroids. 14. Sharma MP, Bhatia V. Abdominal tuberculosis. Indian J Med Res.
2004 Oct;120(4):305-15.
15. Centers for Disease Control and Prevention. (2010). Updated
guidelines for using interferon gamma release assays to detect
BIBLIOGRAPHY Mycobacterium tuberculosis infectionUnited States, 2010.
1. Afzal S, Qayum I, Ahmad I, et al. Clinical diagnostic criteria for Morbidity and Mortality Weekly Report. [online]. Available from
suspected ileocaecal tuberculosis. J Ayub Med Coll Abbottabad. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm
2006;18(4):42-6. [Accessed January, 2013].
9
cHAPTER
Inflammatory Bowel Disease
Vikas Singla, Govind K Makharia
INTRODUCTION countries suggest that the incidence and prevalence rates

of IBD in AsiaPacific region are low compared with Europe
Inflammatory bowel disease (IBD) is a group of idiopathic, and North America. They are however, increasing rapidly.
chronic, inflammatory diseases of intestine, and they occur In the AsiaPacific region, where the prevalence of IBD is
because of interaction between genetic, environmental, and generally low; the incidence and prevalence of UC is more
immunological factors. IBD consists of two main categories common than CD in most Asian countries. The prevalence
of the diseases, namely ulcerative colitis (UC) and Crohns rates of UC in Asian countries range from 630 per 1,00,000
disease (CD). In UC, the disease is limited to the colon, and the population, which is lower compared to 37.5229 and 21.4
involvement is generally limited to mucosa and submucosa. 243 per 1,00,000 population in North America, and Europe,
Whereas any part of the gastrointestinal (GI) tract from respectively. Similarly, the incidence of UC in Asian countries
mouth to anus can be involved in CD and the inflammation ranges from 0.42.1 per 1,00,000 population, which is lower
in the intestine may be transmural. While the involvement than that in incidence rates of 615.6 and 1020.3 per 1,00,000
of the colon is symmetrical and continuous in patients with in North America and Europe, respectively.
UC, skip lesions and discontinuous lesions are characteristic While IBD in the west is characteristically associated
of CD (Table 1). About 10% of patients while have features of with a bimodal age distribution pattern with a peak at the
IBD; they however, cannot be categorized either into UC or ages of 2039 and a second smaller peak at the age of 6079
CD. They are called IBD unclassified. In their natural course years; such bimodal distribution of age has however not
of evolution, IBD unclassified may ultimately evolve into been consistently observed in Asian studies. The onset of
either UC or CD. the disease may be delayed, and some patient might present
at age more than 60 years also. In the European and North
American studies, the distribution of UC is equal in both
EPIDEMIOLOGY men and women at all ages or in some studies there tends
to be a slight male preponderance while studies of CD have
Inflammatory bowel disease is a disorder of modern society,
consistently revealed a greater incidence in women than in
and its frequency in developed countries has been increasing
men. A male predominance has been reported in patients
since the mid-20th century. In countries where the overall
with UC from a few Asian studies.
IBD prevalence is low, UC appears to be more common than
CD. In countries where the prevalence of IBD is high, CD
tends to be the dominant subtype. Generally, it is thought
that in high-prevalence areas, the incidence of both diseases PATHOGENESIS
may have stabilized but in low-prevalence areas, an initial
increase in UC incidence is followed by an increase in CD Inflammatory bowel disease is a result of complex interplay
incidence years later. of genetic, environment, and immune factors. IBD represents
The AsiaPacific region has been marked as an area with a a state of excessive immune response, which may be targeted
low incidence of IBD, although confusion exists as to whether against an innocuous or pathogenic microorganism. Studies
this low incidence is a result of low diagnostic awareness, a on animal models of IBD suggest that in genetically susceptible
high incidence of infective diarrhea and its diagnostic overlap host, commensal bacteria can induce an inappropriate state
or a true low incidence. As epidemiological studies from Asian of inflammation akin to IBD.
Table 1: Differences between ulcerative colitis and Crohns disease
Features Ulcerative colitis Crohns disease

Clinical
Bloody diarrhea Almost always 50%
Abdominal pain Less severe Very common, more severe
Intestinal obstruction Very uncommon Common
Perianal disease None 2030%
Fever Occasional More common
Growth retardation in children Less marked More marked
Nutritional deficiency Less common More common
Site of the disease
Colon Always In two-thirds
Terminal Ileum 510% In two-thirds
Small intestine Never In two-thirds
Upper gastrointestinal tract Never Occasional
Rectum involvement Almost always In 50% patients
Endoscopic/radiological features
Involvement Diffuse, continuous Skip lesions, discontinuous
Type of ulcer Superficial Deep
Longitudinal ulcer Never Characteristic, present in 30%
Aphthous ulcers
Cobblestoning lesions Never Characteristic, present in 30%
Stricture None Yes
Fistula Never Yes
Pathological features
Type of involvement Mucosa and submucosa Transmural
Granuloma None/rare Noncaseating granuloma
Fibrosis None Yes
Mesenteric thickening None Yes
Fibrofatty proliferation None Yes
Genetic Factors inheritance patterns are not seen in them, and IBD cannot be
credited to a single gene locus. Furthermore, the genetic risk
Variability of prevalence of IBD amongst various ethnic ratio is higher for CD compared to that with UC. Twin studies
groups, and the increased risk amongst the family members are important way to determine a genetic contribution
of patients with IBD suggest an important role of genetic for a disease. If a disease is entirely due to genetics, the
factor in the pathogenesis of IBD. While IBD is more common concordance rates in monozygotic/identical twins will be
in Jewish population and whites; Africans and Asians have higher (and should be approaching 100%) than dizygotic/
low prevalence of IBD. The prevalence of IBD is higher in nonidentical twins (which should be approaching 50%). If
family members of IBD. The risk of IBD increases 213-folds the disease is dependent only on environmental or acquired
in offspring of patients with IBD as compared with the general factors, the concordance rates will be similar among both
population. This predisposition in the offsprings can be types of twins. The concordance rate of CD in monozygotic
attributed to either the shared environment or genetic factors. twins is 2050% and less than 10% in dizygotic twins,
Numerous studies have demonstrated that genetics plays a emphasizing a definite genetic component. The concordance
role in the manifestation of IBD. However, classic Mendelian rates for UC in monozygotic twins is 16% and for dizygotic
Inflammatory Bowel Disease 79
twins is 4%. Recently, genome-wide association studies have Environmental Factors

provided information regarding various genetic loci and
the overall disease pathogenesis. Analyses of these genes Clinical and experimental observations suggest involvement
and genetic loci suggest important role for several pathways of intestinal bacterial microbiota in the pathogenesis of
which are crucial for intestinal homeostasis, including IBD. CD and UC preferentially involve the areas of intestine
barrier function, epithelial restitution, microbial defense, that contains the highest concentration of the bacteria, i.e.
innate immune regulation, reactive oxygen species (ROS) terminal ileum and colon. Diverting fecal stream in CD have
generation, autophagy, regulation of adaptive immunity, been found to help in healing of lesions of CD. In the animal
endoplasmic reticulum (ER) stress and metabolic pathways models for IBD, germ free mice do not develop inflammation,
associated with cellular homeostasis. Approximately 30% of but after bacterial introduction, intestinal inflammation
genetic loci are shared between UC and CD, indicating that rapidly develops. All these evidences, highlight the role of
these diseases may involve common pathways. Till date more bacterial flora in the development of IBD and the dynamic
than 90 nonoverlapping genetic risk loci, including 28 that are balance between microbes, particularly commensal flora,
shared between CD and UC. and host defensive responses at the mucosal frontier has a
Thus far, three pathways in pathogenesis of CD have been pivotal role in the initiation and maintenance of inflammation
highlighted by the genetic studies. The first susceptibility in chronic IBD.
locus for CD was identified in 2001 as (nucleotide-binding The defect in innate immunity or hyper-responsive
oligomerization domain 2 (NOD2) gene, also known as immune response against nonpathogenic bacteria may be
caspase recruitment domain 15 (CARD15). Missense responsible for the chronic low-grade inflammation. On
mutation and frame-shift mutation of NOD2/CARD15 gene the other hand, there may be alteration in gut flora in IBD,
are found to be associated with CD. Both heterozygosity and the loss of protective bacteria may lead to overgrowth
and homozygosity for this mutation are associated with the of pathogenic bacteria. The exact pathogenesis is still to be
increased risk for CDs. In patients with CD with associated defined, but more than one mechanism(s) may be acting in
mutated NOD2, there is decreased activation of NF-B in an individual patient.
mononuclear cells, and expression of NF-B is increased in Smoking is other environmental factor, which may be
inflamed tissues. Moreover, the production of defensin by contributing to the etiology of IBD. UC is more common
the paneth cells is defective in these patients. About 2030% among nonsmokers. After cessation of smoking, within first
of Caucasian patients with CD harbor abnormal variants of two years, risk of developing UC is higher. On the other hand,
NOD2/CARD15. Surprisingly, NOD2/CARD15 gene mutation CD is more common in current smokers. CD is more common
is not seen in CD in the Japanese, Korean, Chinese and Indian in higher socioeconomic group. Past appendectomy is
population. protective against UC.
Genome-wide association studies have suggested the role
of autophagy-related genes in pathogenesis of CD. Minor
Role of Mucosal Barrier and
allele of autophagy-related 16-like 1 (ATG16L1) is found to be
protective against CD. Rare variant of interleukin-23 (IL-23) Immune System
gene is strongly protective against CD, while more common The intestinal mucosa exists in a functional equilibrium with
variant are associated with increased risk for CD. Some the complex luminal bacterial flora. Loss of this functional
variants of IL-12B have also been found to be associated with equilibrium contributes to the pathophysiology of many GI
increased risk of CD. disorders, including IBD. In addition to nutrient absorption,
Similarly, certain genetic variations are found to be intestinal epithelial cells perform both barrier and signal-
associated with risk and protection against UC. Linkage transduction functions, with the capacity to sense luminal
studies have suggested the susceptibility genes on contents through surface receptors and, in return, secrete
chromosomes 1, 2, 3, 5, 6, 7, 10, 12, and 17. IBD2 locus on regulatory products that can coordinate an appropriate
chromosome 12 appears to have strong linkage with UC. response in the underlying lamina propria. Abnormal
Similarly, certain polymorphism of multidrug resistance gene intestinal permeability has been observed in IBD patients
1 (MDR1) gene, which codes for P-glycoprotein, a protein that and in some of their first-degree relatives.
serves an important barrier function, is associated with UC. Normal epithelium, with its highly evolved tight junctions
Similarly, certain alleles of IL-23R, IL-12 are associated with and products of goblet-cell populations, most notably trefoil
risk of UC. peptides and mucin glycoproteins, provides an effective
barrier against luminal agents. The integrity of the barrier Table 2: Extent of the disease (ulcerative colitis) according to the
may be compromised by genetic variations in key molecular Montreal classification
determinants, a diminished reparative response to injury, or
E1 Proctitis
exogenous agents, such as nonsteroidal anti-inflammatory
E2 Left-sided extending up to splenic flexure
drugs (NSAIDs). Chronic, recurrent intestinal inflammation
appears to result from stimulation of the mucosal immune E3 More extensive disease
system by products of commensal bacteria in the lumen.
Antigens from dietary sources may also contribute.
in the setting of UC is due to several mechanisms, including
Stimulation may occur as a result of the penetration of
rectal irritability, failure to absorption of salt and water,
bacterial products through the mucosal barrier, leading
increase in mucosal permeability, and increased colonic
to their direct interaction with immune cells, especially
motility. A few patients, especially those with proctitis, may
dendritic cells and lymphocyte populations, to promote a
complain of constipation.
classic adaptive immune response. Alternatively, bacterial
Abdominal pain in patients with UC occurs generally
products may stimulate the surface epithelium, possibly
during the active phase of the disease. Abdominal pain in
through receptors that are components of the innate immune
them is usually localized to infraumbilical region and left
response. The epithelium can, in turn, produce cytokines
iliac fossa. Persistent pain and worsening in the severity of
and chemokines that recruit and activate mucosal immune
pain in a patient with active UC should suggest an impending
cells. Activation of classic antigen-presenting cells, such
complication, such as toxic megacolon or perforation.
as dendritic cells, or direct stimulation through pattern-
Anemia and pedal edema are seen in patients with severe and
recognition receptors promotes the differentiation of type 1
continuous disease and are due to blood and albumin loss
helper T cells (Th1) in patients with CD type 2 helper T cells in
through the inflamed colon. Patient with UC may lose weight
patients with UC. The stereotypical products of Th1 promote
because of a catabolic state during active phase of the disease
a self-sustaining cycle of activation with macrophages. In
and poor nutritional intake.
addition to producing the key cytokines that stimulate Th1
Physical signs depend upon the severity of the disease.
(IL-12, IL-18, and macrophage migration inhibitor factor),
macrophages produce a mix of inflammatory cytokines, Patients with severe disease can have tachycardia, fever,
including IL-1, IL-6, and most notably tumor necrosis factor anemia, signs of weight loss and malnutrition. Abdomen may
(TNF), which target a broad variety of other types of cells. The be tender in these patients, and the bowel sounds are usually
latter includes endothelial cells, which then facilitates the normal or increased. Patients with severe disease should be
recruitment of leukocytes to the mucosa from the vascular observed for peritoneal signs, which may suggest onset of
space, as well as fibroblasts and epithelium, modulating their perforation and toxic megacolon. Patients with mild clinical
functional properties. As discussed above, these functions disease, may appear normal, exhibiting few clinical signs.
may be altered either by genetically determined variants, such
as NOD2, the product of the IBD1 locus, or by environmental
factors.
Crohns Disease
Symptoms of CD are more heterogeneous, and depend upon
the location and the behavior of the disease. Characteristically,
CLINICAL MANIFESTATIONS (TABLE 1) any part of GI tract can be involved in patients with CD and
there may be multifocal involvement of the intestine. The
Ulcerative Colitis location of the disease is classified as terminal ileal disease,
The extent of the disease is classified according to Montreal isolated colonic disease, ileocolonic disease and upper
classification (Table 2). The cardinal symptoms of UC are GI tract disease. The behavior of the CD is of three types:
bloody diarrhea, urgency, tenesmus, passage of mucus, inflammatory, stricturing and penetrating (fistulizing).
and lower abdominal pain. Almost 95% of patients present (Table 3) The symptoms secondary to inflammatory nature
with episodes of bloody diarrhea. Most patients at the time of the disease include diarrhea and bleeding. The stricturing
of presentation recall presence of these symptoms in the disease will present predominantly with intestinal colic and
past; though few patients can present with acute onset of intestinal obstructive features (bloating, heaviness, gurgling,
severe bloody diarrhea. Urgency and tenesmus (feeling of feeling of movement of ball of wind and/or obstipation).
incomplete evacuation) are due to rectal inflammation and Penetrating disease will present with fistula formation such
loss of rectal capacitance, which leads to desire for defecation, as internal fistula (jejunoileal, jejunocolonic, colocolic) or
even with the small amount of stool in the rectum. Diarrhea perianal fistula. Any or a combination of the three kinds of
Table 3: Phenotype of Crohns disease according to the Montreal loops of the intestine through inflamed serosa. Uncontrolled
classification inflammation in such situation can lead to microperforation
and fistula formation between two adjacent intestinal loops.
Age of onset Location Behavior
Depending upon location of such severe inflammation,
L1: <16 years L1: Terminal ileal disease B1: Non-tricturing, the intestinal loops may communicate with the skin
nonpenetrating
(enterocutaneous fistula), the urinary bladder (enterovesical
L2: 1740 years L2: Colonic B2: Stricturing fistula), and genitalia (rectovaginal fistula) or to an abscess
L3: >40 years L3: Ileocolonic B3: Penetrating cavity in the mesentery. Enterocutaneous fistulas follow
L4: Isolated upper
tissue planes of least resistance, usually draining through
gastrointestinal involvement abdominal surgical scars. Enterovesical fistulas typically
present as dysuria or recurrent bladder infections or less
Note: Disease modifiers: perianal disease, p if perianal disease
commonly as pneumaturia or fecaluria. Enterovaginal fistulas
are rare and present as dyspareunia or as a feculent or foul-
smelling, often painful vaginal discharge.
symptoms can be present in a given patient with CD. Systemic Approximately 20% of all patients with CD develop
symptoms, such as malaise, anorexia, weight loss, and fever symptoms during childhood, and 5% are diagnosed before
are more common in patients with CD. 10 years of age. Typical complications of CD in the pediatric
The ileocolonic disease and terminal ileal disease are the population include delayed puberty, linear growth failure and
most common types of disease in CD. These patients present osteopenia. Active or relapsing disease may slow or even arrest
with recurrent episodes of right lower quadrant pain and the progression of puberty once it has begun. Unlike with
diarrhea. Sometimes the initial presentation mimics acute healthy children, delayed or shortened puberty in children
appendicitis with pronounced right lower quadrant pain, a with CD may result in permanent growth impairment. Thus,
palpable mass, fever, and leukocytosis. Intestinal obstruction inducing disease remission before the onset of puberty
may take several forms. In the early stages of disease, bowel and maintenance of remission during the pubertal years
wall edema and spasm produce intermittent obstructive is crucial. This is required to prevent or even minimize the
manifestations and increasing symptoms of postprandial pain. consequences of a missed pubertal growth spurt, abnormal
Over several months and years, persistent and progressive bone mineralization, and the maintenance of prepubertal
inflammation gradually produces fibro-stenotic narrowing levels of sex hormones. Osteopenia is another important
in the intestine. Acute episodes of intestinal obstruction can potential complication of pediatric IBD because more than
occur as well, precipitated by bowel inflammation and spasm 90% of peak bone mass is attained during childhood and
or sometimes by impaction of undigested food or medication. adolescence. A failure to attain peak bone mass during this
Extensive inflammatory disease involving small intestine stage in development increases future fracture potential.
can lead to loss of surface area for absorption and thus leads to
malabsorption. There could be loss of protein (both albumin
and globulin) from the ulcerated area, a condition called EXTRAINTESTINAL MANIFESTATIONS
protein losing enteropathy. Nutritional deficiencies can also
result from poor intake and enteric losses of protein and other About 1550% of patients with IBD can have extraintestinal
nutrients. Intestinal malabsorption along with protein losing manifestations. Some of these symptoms can be quiet
enteropathy can lead to malnutrition, hypoalbuminemia, distressing. The extraintestinal manifestations of IBD are
hypocalcemia, and hyperoxaluria with nephrolithiasis. described in Table 4.
Vertebral fractures are caused by a combination of vitamin D
deficiency, hypocalcemia, and prolonged glucocorticoid use.
Diarrhea in patients with CD is multifactorial, including DIAGNOSTIC CRITERIA
colonic inflammation, malabsorption, bacterial overgrowth
in obstructive segment, internal fistulization (jejunoileal, There is no single gold standard test for the diagnosis of
jejunocolonic, colocolic) bile-acid malabsorption due to either UC or CD. The diagnosis of both UC and CD is based
diseased or resected terminal ileum. on a combination of clinical, endoscopic, histological, and
Severe and transmural nature of inflammation in a few radiological features. An infectious cause of the colonic
patients with CD can lead to adhesions between adjacent inflammation should be ruled out.
Table 4: Extraintestinal manifestation of inflammatory bowel disease should prompt a thought toward a possibility of associated
primary sclerosing cholangitis and osteomalacia.
Joints Peripheral arthritis
Fecal calprotectin may be used to differentiate IBD from
Ankylosing spondylitis functional diarrhea. Microbiological testing for Clostridium
Sacroiliitis difficile toxin should be done during acute exacerbation.
Skin, mucous membrane Erythema nodosum Reactivation of cytomegalovirus (CMV) is common in patients
Pyoderma gangrenosum with IBD on immunosuppression, therefore a possibility of
Aphthous ulcers
CMV infection should be considered and excluded specially
in those patients with IBD who respond poorly to steroid.
Hepatobiliary Fatty liver
Antineutrophil cytoplasmic antibody (ANCA) and
Pericholangitis anti-Saccharomyces cerevisiae antibody (ASCA) are useful
Primary sclerosing cholangitis adjunctive tests to distinguish between UC and CD in
Gallstones patients with known IBD. ANCA is associated with UC and
Autoimmune hepatitis ASCA is associated with CD. There is insufficient information
Cholangiocarcinoma
at present to recommend the use of these serologic tests to
screen patients with undiagnosed GI symptoms for IBD in
Ocular Conjunctivitis
general population. Patients with undifferentiated colitis who
Episcleritis is ANCA-negative and ASCA-positive is likely to progress to
Uveitis CD, whereas those with ANCA-positive and ASCA-negative
Hematological Agranulocytosis are likely to develop UC.
Hemolytic anemia
Renal Oxalate stone
Amyloidosis INVESTIGATIONS FOR THE DIAGNOSIS
AND EXTENT OF THE DISEASE
The best investigation for diagnosis and evaluation of the
extent of UC is colonoscopy. Through colonoscope, one
EVALUATION OF PATIENTS can examine the nature of the lesion, activity of the lesion
and extent of the disease. Colonoscopy should be avoided
A detailed history should be taken from each patient, including or carefully performed by experienced endoscopist, during
duration of symptoms, severity of symptoms, remissions and episode of acute severe disease, because of high risk of
relapses, and medication history (including antibiotics and perforation. Changes of UC are typically seen in the rectum,
NSAIDs). Particular attention should be paid to factors, which and progress proximally in a symmetrical and circumferential
can have bearing on IBD, such as established risk factors pattern to the variable extent. Endoscopic findings of UC
including smoking, family history, previous appendicectomy vary from edema, loss of vascularity, granularity, friability
and recent episodes of infectious gastroenteritis. A complete of the mucosa, spontaneous bleeding and ulcerations.
physical examination, including perineal and perianal Depending upon the mucosal appearance, the severity of UC
examination should be done. can be classified as mild (loss of vascular pattern, erythema,
Laboratory investigations should include full blood count, granularity, mild friability), moderate (erosions and moderate
liver function tests and erythrocyte sedimentation rate or and friability) and severe (ulcerations and spontaneous bleeding)
C-reactive protein. Patients with active disease, particularly (Figs 1A to F). For the diagnosis of UC, even a sigmoidoscopic
pancolitis, usually have anemia, which is microcytic and examination is sufficient; however, every patient with IBD
hypochromic. Anemia can also be due to bone marrow should have a complete evaluation of the whole colon in
suppression secondary to anemia of chronic disease or order to know the extent of the disease and for differentiation
medications including antimetabolites. Leukocytosis and from CD.
thrombocytosis suggest presence of active disease. Active Colonoscopy helps to differentiate UC from CD, which
disease is also associated with raised levels of markers of is typically characterized by rectal sparing, aphthous
inflammation, such as C-reactive protein, and erythrocyte ulcers, skip lesions (areas of inflammation alternating with
sedimentation rate. These markers do not have diagnostic normal mucosa), a cobblestone pattern, and longitudinal,
value, but can be useful for the assessing the activity of the irregular ulcers (Figs 1A to F). In patients with repeated
disease. A persistently raised serum alkaline phosphatase cycles of inflammation and healing and in those with
lesions are generally superficial in UC and deep in CD (Table

1). Transmural nature of CD leads to intestinal fibrostenotic
lesions, while fibrostenotic lesions do not occur in those with
UC. The histological characteristic, especially the density
of inflammatory cells, differ during the active phase of the
disease and during the phase of remission. Typical histological
A B C
features of UC include basal plasmacytosis (presence of plasma
cells around or beneath the level of the crypts), a diffuse and
transmucosal increase in chronic inflammatory infiltrates
in the lamina propria and crypt architectural abnormalities
(branching, irregularity in crypt size, shape, orientation and
spacing, and decreased crypt density). Neutrophils are not
D E F normally present in normal colonic mucosa. The presence
Figs 1A to F: (A) Colonoscopy pictures showing a normal colonic and infiltration of neutrophils into the lamina propria, crypt
mucosa with normal vascular pattern in a normal individual. In epithelium (cryptitis) and crypt lumen (crypt abscesses) are
patients with ulcerative colitis, (B) there is a loss of vascular pattern the signs of the active disease. Features of acute colitis (such
and erythema, and (C) superficial ulcers. (D) In Crohns disease, as cryptitis or crypt abscesses also present in infectious colitis
patients can have discrete ulcers. (E) Longitudinal and deep ulcers and other colitides and is not pathognomonic of UC (Figs 2A
and (F) cobblestoning of mucosa although seen in one third of to D). The severity of inflammation on histologic examination
patients with Crohns disease, but they are characteristic lesions of and the severity of disease on endoscopic examination may
Crohns disease not always coincide; for instance, histologic findings may
indicate severe disease even in a patient having mild disease
and vice versa. The biopsies should be evaluated for epithelial
chronic, unremitting inflammation, colonoscopy may reveal dysplasia and colonic mitosis especially if the duration of UC
pseudopolyps or mucosal bridging (Table 1). is longer.
Radiology has the limited role in the management of
patients with UC; however, it is quiet useful in knowing the
extent of the involvement in patients with CD (discussed
below). Abdominal plain X-ray should be done in patients
with acute severe colitis to rule out toxic megacolon or
intestinal perforation. The use of barium enema in the
diagnosis of IBD has generally declined; it however has a role
in certain situations. In patients with colonic narrowing due
to stricture or malignancy, where proximal examination may
be difficult, barium enema may provide essential information
regarding the length, location and diameter of the stricture. A B
Moreover, involvement of mucosa proximal to the stricture
can also be evaluated. Earliest sign of UC on barium enema
is fine mucosal granularity. With increasing severity, mucosal
lining become thickened and irregular and superficial and
deep ulcers can appear. The colonic haustral folds may be lost
in long standing disease, but may be normal or thickened in
C D
patients with shorter duration of the disease.
Figs 2A to D: (A) Photomicrographs of histology of the colon from
a patient with ulcerative colitis showing crypt disarray and an
Histologic Evaluation inflammatory infiltrate predominately restricted above muscularis
mucosae (H&E X100) and (B) loss of crypts and crypt branching
Adequate biopsies from different regions of the colon
(arrow) are seen, along with dense mixed inflammatory infiltrate at
(including rectum) and distal ileum should be obtained
lamina propria (H&E X100). (C) Biopsies from patient with ulcerative
for a reliable diagnosis of IBD. In UC, the inflammation is colitis show crypt abscess (arrow) with dense mixed inflammatory
characteristically restricted to the mucosa and submucosa infiltrate in lamina propria (H&E X100). (D) A biopsy from a case of
of the colon; while in CD, the inflammation may involve all Crohns disease shows pericryptal non-necrotizing microgranuloma
the four layers (transmural) of the intestine. Therefore, the (arrow) (H&E X40)
The earliest microscopic lesions in patients with CD are value and body weight. A CDAI score of 150 or less indicates
aphthoid ulcerations and focal crypt abscesses with loose remission, a score of greater than 150 and up to 220 indicates
aggregations of macrophages, which later form noncaseating mild disease activity, a score of greater than 220 and less
granulomas. Granulomas can be seen in lymph nodes, than 450 indicates moderate disease activity, and a score of
mesentery, peritoneum, liver and pancreas. Although CD 450 or greater indicates severe disease activity. The Harvey-
is a granulomatous disease, granulomas are seen in 2040% Bradshaw Index is a simplified version of a clinical disease
of endoscopic mucosal biopsies (Figs 2A to D). Therefore, it activity index often used in long-term open-label studies.
may consider a possibility of CD even if granulomas are not Endoscopic severity could be assessed using CD endoscopic
seen in the endoscopic mucosal biopsies. Surgical resections
reveal granulomas in about half of the patients with CD. Other
histologic features of CD include submucosal or subserosal Table 6: Ulcerative Colitis Disease Activity Index (UCDAI)
lymphoid aggregates, particularly away from areas of
ulcerations, gross and microscopic skip areas, and transmural Variables Frequency Scores
inflammation that is accompanied by fissures that penetrate No. of stools Normal 0
deeply into the bowel wall and sometimes form fistulous >12 than normal 1
tracts or local abscesses. >34 than normal 2
>4 than normal 3
Rectal bleeding No bleeding 0
ASSESSMENT OF THE ACTIVITY OF
Mild 1
THE DISEASE Moderate 2
The natural history of IBD is that of remission and relapses Severe 3

of the disease. The severity of IBD is generally assessed Mucosal friability No friability 0
using clinical parameters, systemic manifestations, mucosal Mild friability 1
appearance and global impact of the disease on the Moderate friability 2
individuals quality of life. The most commonly used clinical
Exudation and spontaneous bleeding 3
disease activity assessment criteria for UC are Truelove and
Physician global Normal 0
Witts criteria and Ulcerative Colitis Disease Activity Index
assessment
(Tables 5 and 6). For CD, although there are many indices Mild 1
for assessment of severity, such as Harvey-Bradshaw index, Moderate 2
van Hees or Dutch Index, St Marks Index; CD Activity Index Severe 3
(CDAI) has been used mostly especially in the clinical trial
Note: UCDAI score: Normal, <2; Mild, >2<4; Moderate, >4<8; Severe, >8
(Table 7). In the CDAI, eight independent variables, including
number of liquid stools, severity of abdominal pain, general
well-being, need for antidiarrheal drugs, presence of
Table 7: Crohns disease activity index (CDAI)
abdominal mass, extraintestinal manifestations, hematocrit
Item (day) Weight
No. liquid or very soft stools (each day for 7 days) 2
Table 5: Truelove and Witts criteria for of severity of ulcerative colitis Abdominal pain, sum of 7 days rating 5
(0 = none, 1 = mild, 2 = moderate, 3 = severe)
Variables Mild Severe Fulminant
General well-being (14) 7
Stools (Number/day) <4 >6 >10
Extraintestinal manifestations (1 per finding) 20
Blood in the stool Intermittent Frequent Continuous arthritis/arthralgia, mucocutaneous lesion, iritis/uveitis
Temperature (oC) Normal >37.5 >37.5 anal disease (fissure, fistula), external fistula
Pulse (per minute) Normal 90100 >100 Fever >36.8
Hemoglobin Normal <75% of normal Transfusion Antidiarrheal use 30

requirement Abdominal mass (none = 0, equivocal =2, definite = 5) 10
ESR (mm/hour) <30 >30 >30 Hematocrit (males, 47) (Females, 42) 6
Serum albumin (g/dL) Normal <3.0 <3.0 Body weight (1body weight/standard weight) 100 1
Note: Moderate disease includes features of both mild and severe disease Total CDAI score
index of severity (CDEIS), which includes lesions, such as basal lymphoid aggregates should point toward a possibility
pseudopolyps, healed ulcerations, erythema, mucosal edema, of UC. Yersinia infections can lead to small intestinal and
aphthoid ulcerations, superficial and deep ulcerations and colonic involvement and the clinical presentation may mimic
stenoses. The index is refined by incorporating the percentage with that of IBD. Stool culture and antibody titer should be
of involvement of all the endoscopic segments (ileum, done for differentiation. Pseudomembranous enterocolitis
ascending colon, transverse colon, descending and sigmoid should be suspected in patients, who had received antibiotics
colon, rectum). in recent time. Moreover, this infection can cause relapse
in the patients, who had otherwise silent UC. Sexually
transmitted disease, such as gonorrhea, Chlamydia and
ASSESSMENT FOR THE EXTENT OF lymphogranuloma venereum may cause proctitis, which may
resemble IBD. History of high-risk behavior, and copious pus
THE DISEASE discharge should raise the suspicion, and the appropriate
tests should be ordered.
The extent of the UC is limited to only rectum (proctitis) in
Intestinal tuberculosis is an important disease in Asian
1020%, rectum, left sided colitis in 3040%, and 3040% of
countries. The clinical, morphological and histological
patients have pancolitis or extensive colitis. In patients with
features of intestinal tuberculosis and CD are so similar that it
CD, about two-thirds of patients have involvement of both
becomes difficult to differentiate between these two entities.
small intestine and large intestine, and one-third each have
In geographical regions like Asia where both CD and intestinal
isolated either small or large intestinal involvement. About
tuberculosis are prevalent, differential diagnosis between
2030% of patients have perianal disease (hemorrhoids,
the two may be challenging. In Asia, intestinal tuberculosis
anal fissure, perianal abscess or perianal fistula). About
is common, but CD is also being increasingly reported from
510% patients have involvement of the upper GI tract all over Asia. Natural history of CD is quite different from
concomitantly. Unlike UC, which almost always involves the that of intestinal tuberculosis. While intestinal tuberculosis
rectum, the rectum is not involved in half of patients with CD. gets cured by appropriate antitubercular treatment, CD has
All patients should undergo evaluation for the extent of a remitting/relapsing or persistent course and usually stays
the disease. Large intestinal involvement can be assessed lifelong. Because of similarity in the clinical presentation and
using colonoscopy and retrograde ileoscopy. Small intestinal morphology of these two entities, at times such patients are
evaluation can be done using CT/MR enteroclysis, or capsule treated empirically with antituberculous drugs. The clinical,
endoscopy/double balloon enteroscopy depending upon endoscopic and histological features which can differentiate
individual centers expertise. Upper GI endoscopy, especially these two diseases are summarized in Table 8. From the Table
in pediatric patients, should also be done to complete the 8, it is obvious that almost all the features are seen in these two
evaluation. All patients with UC should have evaluation of the conditions and, in isolation, they are not diagnostic. However,
colon only; while patients with CD require evaluation of both with a use of combination of these features, one is able to
small and large intestine. make a diagnosis of either tuberculosis or CD in almost half
of patients. Wherever differentiation is not possible, one can
try a course of antituberculous treatment in such situation.
DIFFERENTIAL DIAGNOSIS One should re-evaluate patient not only for resolution of
symptoms but also for healing of the mucosal lesions using
Infections are important differential diagnosis in the ileocolonoscopy and/or enteroscopy. There are instances
first episode of IBD. Moreover, infections can complicate where patients are treated with antituberculous drugs time
underlying IBD, so infections should be ruled out in every and again for non-resolution of symptoms or reappearance
flare of IBD. The most common organisms causing infectious of symptoms, such a strategy is not good. One should revise
colitis, such as Entamoeba histolytica, Salmonella, Shigella the diagnosis and consider CD in such situations. It will be
and Escherichia coli present with short history of fever, pain appropriate to refer such patients at a higher center or to a
abdomen and bloody diarrhea. Initially most such patients gastroenterologist for complete evaluation.
are treated with IV antibiotics, nonresponse to the adequate Noninfectious disease mimicking IBD include diseases
antibiotics course should raise the clinical suspicion of UC, like colonic malignancies, colonic diverticulitis, radiation
and sigmoidoscopy should be done. Sigmoidoscopy picture colitis, diversion colitis, and ischemic colitis, microscopic
may be similar in two conditions; however, biopsy may resolve and drug induced colitis. Colonic malignancies especially
the issue. The presence of chronic inflammatory infiltrate, rectal malignancies may mimic the IBD, and a colonoscopic
architectural disturbance like crypt atrophy, crypt disarray, examination should sort out the issue.
Table 8: Clinical, endoscopic and histological differentiation between year, one can predict that the disease may remain in the stage
intestinal tuberculosis and Crohns disease of remission in the coming year. There may be extension of
the involvement with time in some patients with UC. Overall,
Variables Intestinal Crohns disease
tuberculosis (%) (%) patients with UC have a normal life expectancy.
Symptoms
Chronic diarrhea 2040 6080 Crohns Disease
Blood in the stools 1020 5070
About 1320% of patients with CD have a chronic active
Abdominal pain 90 6080 course of disease activity, 6773% have a chronic intermittent
Constipation 50 1030 course and only 1013% remain in remission for several years.
Partial intestinal obstruction 5060 2030 After 20 years, most patients with CD will require surgery.
Perianal disease 5 3080 Although the anatomical location of CD remains fairly stable,
behavior of the disease varies substantially during its course.
Fever 4070 30
Almost 5060% of patients with CD develop stricture and or
Loss of appetite 4080 4060
fistula over 20 years follow-up. The life expectancy of patients
Weight loss 6090 5060 with CD is slightly reduced.
Extraintestinal manifestations 10 2050
Involvement of the intestine
Anal canal <5 1550 MANAGEMENT
Rectum 1020 4060
Sigmoid colon 510 1050 Drugs Used in
Descending colon 510 1050 Inflammatory Bowel Disease
Ascending colon 4060 5070
Ileocecal area 7090 60
5-Aminosalicylates
Ileum 1020 2040 Sulfasalazine and the newer 5-aminosalicylates (5-ASA)
Endoscopic features are first-line therapy for the treatment of UC. Sulfasalazine
contains a 5-ASA moiety that is linked to sulfapyridine by an
Aphthous ulcers 510 3050
azo bond and is delivered intact to the colon. On entering
Linear ulcers 5 2030
the colon, the azo bond is cleaved by bacterial enzyme
Deep ulcers 5070 3040 azo-reductase, and releases sulfapyridine and 5-ASA. The
Nodularity 50 20 sulfapyridine is absorbed systematically and accounts for
Cobblestoning of the mucosa None 1520 most of the drugs toxicity and intolerance. The 5-ASA is
Histological features the active anti-inflammatory compound and ultimately is
excreted in the feces. As 5-ASA is the active compound, but
Granuloma 3060 30
when administered by mouth, it is rapidly absorbed into
Necrosis in the granuloma 1030 None
the jejunum and consequently does not get into the colon.
Therefore, various delivery systems have been used to obtain
high concentrations of the drug in the colonic lumen. The
NATURAL HISTORY first method is to coat 5-ASA with a resin or a semipermeable
membrane that is pH-sensitive and the second is to link
Ulcerative Colitis 5-ASA with another molecule by an azo bond. Mesalamines
(Mesacol, Tidocol) are coated with Eudragit S, which
Half the patients with UC remain in the state of clinical dissolve at pH 7.0 or higher, whereas salofalk or claversal
remission at any given time, and half have some degree of are coated with Eudragit L. Pentasa is mesalamines within a
activity of the disease. In the first 37 years after diagnosis, 25% semipermeable membrane that releases the drug at luminal
of patients are in remission, 18% has activity every year, and pH values of more than 6.0 in time release manner.
57% has intermittent relapses. The most important predictor Sulfasalazine and 5-ASA are anti-inflammatory agents
of relapse or remission is the disease activity in the preceding that interfere with the production of arachidonic acid by
year. If the disease remained in the remission phase in the last affecting the thromboxane and lipoxygenase synthesis
pathways. Although the precise mechanism of action of due to suppression of T-cell function and natural killer cell
the medications in the treatment of IBD is not known, activity. The usual doses are 2.02.5 mg/kg/day for AZA and
sulfasalazine and the 5-ASA also may have an immune- 1.01.5 mg/kg/day for 6-MP. Idiosyncratic or allergic type
modulatory effect. reactions to AZA include pancreatitis, fever, rash, arthralgia,
Sulfasalazine and the newer 5-ASA preparations are diarrhea and nausea. Non-allergic type reactions include
effective treatment for mild-to-moderate UC. Sulfasalazine bone marrow suppression, infection and hepatitis. AZA or
controls disease activity and induces remission in 6-MP induced pancreatitis usually occurs within the first
approximately 70% of patients. There is a dose response for few weeks of treatment and resolves on discontinuation of
sulfasalazine, and although the maximal recommended the drug. Profound leukopenia can develop suddenly and
dose is 4 g/day, there are data showing increased efficacy unpredictably. It is recommended that each patient on AZA
at 6 g/day. The newer 5-ASA agents have similar efficacy should be monitored. Full blood count and liver function
to sulfasalazine and improve disease in 5075% of treated tests should be done every 24 weeks initially for 2 months
patients. Sulfasalazine and the 5-ASA formulations are and then every 48 weeks.
effective for maintenance of remission of UC. When the active
disease is controlled, the dose required to maintain remission
is the same as that used to induce remission. Generally, 24 Cyclosporine
g/day of sulfasalazine and 2.44.8 g/day of the newer 5-ASA Cyclosporine is a lipophilic peptide that inhibits the
agents are necessary to maintain remission. proliferation and activation of T helper cells by interfering
with IL-2 production. It also decreases recruitment of
Corticosteroids cytotoxic T cells and inhibits production of IL-3, IL-4, TNF-,
and interferon-. In contrast to 6-MP and AZA, intravenous
Corticosteroids were the first medications to be evaluated cyclosporine has an onset of action within days. Compiled
systematically in patients with IBD. In addition to their results from 20 uncontrolled trials showed a benefit of
nonspecific effects on cellular and humoral immune cyclosporine for patients with severe UC failing to respond to
functions, corticosteroids inhibit the production of IV steroids. Of the 185 patients treated with cyclosporine, 68%
cytokines and inflammatory mediators, enhance sodium
initially avoided colectomy, but only 42% had a sustained
and water re-absorption and improve the sense of well-
response after discontinuing therapy. In a randomized,
being. Systemic corticosteroids are effective treatment
placebo-controlled trial, 20 patients with severe UC failing
for moderate-to-severe UC and for controlling acute
intravenous steroids were randomized to either intravenous
exacerbations. Topical corticosteroids are delivered
cyclosporine (4 mg/kg/day) or placebo. Nine of the 11 (82%)
rectally and are effective treatment for distal colitis. Several
modifications of the glucocorticoid backbone have been patients treated with cyclosporine achieved a response by
developed to maximize the mucosal delivery and enteric day 7 compared with none of the patients in the placebo
anti-inflammatory effects while minimizing systemic side group. At the 6 month follow-up, only 59% maintained
effects. Budesonide, a corticosteroid with extensive first- a response on oral cyclosporine and approximately 30%
pass hepatic metabolism and targeted delivery to the required colectomy.
ileum and right colon via a formulation that is pH and The oral microemulsion form of cyclosporine (Neoral)
time dependent, markedly reduces side effects of systemic has similar bioavailability compared with intravenous
corticosteroids. cyclosporine and is more effective than the standard low-
dose oral formulations. Monitoring cyclosporine blood levels
is required to reduce the chance of toxicity. Potential toxicity
Immunosuppressants: Azathioprine and limits the use of cyclosporine and common side effects include
6-Mercaptopurine paresthesias, hypertrichosis, tremor hypertension, nausea,
gingival hyperplasia, vomiting, headaches, nephrotoxicity,
Azathioprine (AZA) and 6-mercaptopurine (6-MP) are
immunomodulators that are effective for the treatment and seizures.
of steroid dependent UC. After absorption, AZA is non-
enzymatically converted to 6-MP, which then is metabolized
to the active end product, 6-thioguanine nucleotide. The
Biological Agents
6-thioguanine nucleotides inhibit ribonucleotide synthesis As understanding of the initiating and amplifying components
and exhibit antiproliferative effects on activated lymphocytes. of the immuno-inflammatory response contributing to
These agents have a direct anti-inflammatory effect that is the syndromes of UC or CD is developing further, novel
therapeutic approaches are also evolving. We now have the Management of Ulcerative Colitis
ability to interrupt both proximal (e.g. lymphocyte or cytokine
mediated) and distal (e.g. arachidonic acid derivatives The goals of management of UC are to induce remission,
leukotrienes, platelet activating factor, oxygen free radicals, maintain remission, prevent complications and improve
nitric oxide) mediators. As is anticipated from the experience quality of life. The treatment of UC depends upon the activity
with steroids and cyclosporine, the more proximal the of the disease (active phase, remission phase), extent of
inhibition, more potential for systemic immune compromise. the disease (proctitis, left sided colitis and pancolitis), and
dependency on steroid, and needs to be individualized for
Thus the present therapy which is evolving is more target
each patient.
specific neutralization of an inflammatory cytokines (anti-
TNF-), and inhibition of specific lymphocytic population.
TNF is a key inflammatory cytokine and mediator of Induction of Remission
intestinal inflammation. Three antiTNF agents are used
in the treatment of IBD. Infliximab is a murinehuman Mild-to-moderate proctitis and left-sided colitis: Delivery of
chimeric monoclonal antibody, adalimumab is a humanized the anti-inflammatory drugs directly to the inflamed segment
monoclonal antibody, and certolizumab pegol is a PEGylated is UC is the best option. The topical route of administration
monoclonal antigen binding fragment (Fab) to TNF|. Other while it delivers a higher dose of the drug directly to the
antiTNF biological agents currently in clinical trial include involved mucosa, the systemic drug absorption is minimized
golimumab, and this may offer an additional therapeutic and has less systemic adverse effects. Therefore, a disease
option. distal to the splenic flexure is treated best by delivering
the drug topically with suppositories, enemas, foams and
The alternative Th17 pathway involves IL23, liberating
gel. The choice of preparation depends on the extent of the
IL17A, IL17F, IL22, and TNF. Cell adhesion molecules
colitis (for example, suppositories are suitable for proctitis
are cell surface proteins involved in cellular binding of
and enemas can reach up to the splenic flexure). Patient
homing leukocytes to each other, to endothelial cells or to
preference regarding route of drug delivery should also be
tissue. Selective adhesion molecules of intestinal endothelial
considered. 5-ASA enemas and suppositories are effective
cells are therefore therapeutic targets for blocking leukocyte first-line therapies for patients with left sided colitis and
trafficking and activation in IBD, particularly because they do ulcerative proctitis. If topical therapy is used, suppositories
not induce systemic immune suppression. Natalizumab is a are most appropriate for proctitis, whereas more extensive
humanized monoclonal antibody directed against the cellular disease affecting the sigmoid colon or greater parts of the left
adhesion molecule 4integrin. This agent blocks leukocyte colon need the addition of enemas or foams. Patients with left
adhesion to the endothelium in the intestinal tract, but also sided colitis can also be treated by oral 5-ASA, but they are
to the brain. The latter property led to its use in patients with less effective than topical 5-ASA compounds.
multiple sclerosis. However, the development of progressive
Mild-to-moderately active extensive colitis: Mild-to-
multifocal leukoencephalopathy (PML), a devastating and moderately active extensive colitis is initially managed with
often fatal cerebral infection caused by the John Cunningham oral 5-ASA compounds in the doses up to 3.24.8 g/day. Once-
virus (JCV), has limited its use in IBD. daily dose of 5-ASA or newer, controlled-release formulations,
such as multi-matrix 5-ASA (1.2 g tablets) are reported to be
Probiotics in Ulcerative Colitis as effective and to promote adherence to treatment. For those
patients who do not respond to only oral 5-ASA, a combined
Intestinal microflora may play an important role in the oral and topical 5-ASA is superior to oral mesalamine alone.
pathogenesis of UC. Several studies have reported an Clinical (and endoscopic) remission can occur in up to 64
unusually high number of pathogenic E. coli strains in patients 70% within 2 weeks.
with UC. Probiotics have been used in induction of remission Severely active ulcerative colitis: Patients with mild-to-
of active disease and maintenance of remission; however, moderately active UC that is refractory to topical therapy
evidences are not sufficient to recommend probiotics for or oral therapy and those with moderate to severe disease
routine use. Probiotic VSL#3 (3,600 billion colony-forming should be treated with oral glucocorticoids. Patients who
units per day for 8 weeks) in conjunction with 5-ASA can have failed to respond to maximal oral treatment with a
help induce remission in mild-to-moderate UC. Probiotics combination of 5-ASA and/or steroids those who present
especially VSL#3 has been found to be very effective in both with severe/fulminant disease should be admitted for
inducing remission in active pouchitis and maintenance of intensive intravenous corticosteroids (hydrocortisone 400
remission in pouchitis. mg/day or methylprednisolone 60 mg/day) therapy. The
patient should be monitored for number and consistency for maintenance of remission of UC are 1,6002,400 mg of
of stool, amount of blood in the stool, vital signs and mesalazine, and 2,000 mg of sulfasalazine.
abdominal signs (fullness, abdominal tenderness, rebound Patients who relapse while on oral 5-ASA, those who are
tenderness, and bowel sound). Therefore a constant vigil on steroid-dependent, and those with severe UC who need
the overall condition of the patient is mandatory. Hemogram, induction therapy with cyclosporine or tacrolimus are
erythrocyte sedimentation rate (ESR), C-reactive protein, candidates for immunosuppressive therapy, such as AZA, or
serum electrolytes and serum protein should be repeated 6-MP. AZA is dosed at 23 mg/kg/day and 6-MP at 1.01.5 mg/
at every 23 days. If on an initial abdominal radiography, kg/day. Infliximab is effective for maintenance of remission
the diameter of transverse colon is found to be dilated (>5.5 and is steroid-sparing in patients who are unable to maintain
cm), then abdominal skiagram should be repeated every remission while on AZA or 6-MP. Most patients will require
day. Anticholinergic, antidiarrheal agents and opioid drugs maintenance treatment for lifelong.
are best avoided, as they can precipitate colonic dilatation.
NSAID can worsen disease activity. Most patients are
generally on mesalamines; mesalamines may be continued Surgery for Ulcerative Colitis
once oral intake resumes. Patients requiring surgery for IBD are best managed under
Patients who do not improve significantly after 57 days the joint care of a surgeon and a gastroenterologist. Surgery
of maximal medical management are unlikely to benefit remains an important component in the treatment algorithm
from prolongation of this form of management and should of UC and early surgical consultation is recommended
either be referred for surgery or offered treatment with an especially for acute severe UC that requires hospitalization.
intravenous cyclosporine or anti-TNF therapy. Although About 520% of patients with UC require colectomy. The
cyclosporine can be effective, it generally delays rather than decision to operate is best taken by the gastroenterologist
prevents subsequent colectomy. Furthermore, infliximab is
and colorectal surgeon in conjunction with the patient.
increasingly used as an alternative treatment for patients with
The type of surgery is dependent on the acuteness of the
refractory disease, given its effectiveness and better short-
indication and the patients condition. The indications may
term safety profile as compared with other therapies.
be classified as emergency (exsanguinating hemorrhage,
Immediate surgical referral is necessary if there is evidence
intestinal perforation and severe colitis unresponsive to
of toxic megacolon (transverse colon diameter >5.5 cm, or
intensive medical treatment) and elective (steroid dependent
cecum >9 cm). The urgency with which surgery is undertaken
after recognition of colonic dilatation depends on the disease, steroid refractory disease, intolerable side effects of
condition of the patient: the greater the dilatation and the drugs and unaffordability of medical treatment or strongly
greater the degree of systemic toxicity, the sooner surgery suspected/confirmed carcinoma). When indicated, the gold
should be undertaken, but signs may be masked by steroid standard elective surgery for UC is proctocolectomy with ileal
therapy. In select patients with mild colonic dilatation, an pouch anal anastomosis (IPAA) and this should be performed
expectant conservative management can be continued, and in a specialized center. Acute complications of IPAA include
clinical, laboratory, or radiological deterioration mandates anastomotic leak, sepsis, and injury to local structures,
immediate colectomy. Those with toxic megacolon, colonic including pelvic nerves.
decompression can be augmented by frequent change in Pouchitis, the most common and the most clinically
posture to knee elbow position. important long-term complication of IPAA, is a nonspecific
inflammation probably caused by an immune response to the
newly established microbiota in the ileal pouch (dysbiosis).
Maintenance of Remission The incidence of pouchitis can be as high as 40%; in 1020%
After remission has been achieved, the goal is to maintain of cases, pouchitis becomes chronic. Symptoms of pouchitis
the symptom-free status, which can be accomplished with include increased stool frequency, urgency, incontinence,
various medications, with the exception of glucocorticoids, seepage, abdominal and perianal discomfort. Treatment of
which have no place in maintenance therapy, given the pouchitis consists primarily of antibiotics (metronidazole,
marked side effects associated with their long-term use. First- ciprofloxacin, or rifaximin). Pouch failure, a condition
line therapy for the maintenance of remission is oral or topical requiring pouch excision or permanent diversion, occurs
mesalamines. Both oral and rectal 5-ASA have greater efficacy in 810% of patients. Probiotics especially VSL#3 has been
than placebo for maintenance of remission in patients with found to be very effective in both inducing remission in active
distal disease. The appropriate dose of 5-ASA compounds pouchitis and maintenance of remission in pouchitis.
Management of Crohns Disease Box 1: Treatment guidelines for Crohns disease
Crohns disease is a dynamic and progressive disease. Since Sulfasalazine can be used for mild CD limited to the colon. There
is no evidence of efficacy of mesalamines in them. Moderately
there is no definite cure for most patients with CD, the
severe or severe colonic disease should be treated with conventional
main objectives of treatment therefore include induction corticosteroids
of remission and maintenance of remission, minimization
Mild-to-moderately active CD involving terminal ileum or localized
of complications of the disease, such as strictures, fistulae, ileocecal disease should be treated with budesonide. Conventional
osteoporosis, short- and long-term toxicities of the drugs, steroids should be used if budesonide is unavailable or fails to respond.
improvement in quality of life, decrease in number of For severe disease, conventional corticosteroid is the initial treatment of
hospitalizations and surgeries, and maintenance of linear choice. Surgical resection and anti-TNF are alternatives
growth in pediatric patients. For extensive small intestinal disease, patients should be treated with
At present, control of symptoms is considered to be an conventional corticosteroids. Alternatives for extensive small intestinal
disease include anti-TNF agent and surgery
end point; however, over the past years, mucosal healing
has emerged as a major therapeutic goal in clinical trials Patients with ileocolonic disease should be treated with conventional
corticosteroids. Alternative include anti-TNF agent and surgery
in patients with CD and UC. Available evidences indicate
that mucosal healing may change the natural course of the Patients with moderate-to-severe disease despite treatment with
sulfasalazine, mesalamine, budesonide, and conventional corticosteroids
disease by decreasing the need for surgery and reducing
can be treated with infliximab. Infliximab is given at a dose of 5 mg/kg at
hospitalization rates in both CD and UC. Mucosal healing 0, 2, and 6 weeks. An alternative to infliximab is a fully human anti-TNF
may also prevent the development of long-term disease antibody, adalimumab, given subcutaneously with a loading dose of 160
complications, such as strictures and fistulae. mg at week 0 and 80 mg at week 2. In the near future, a PEGylated anti-
The treatment of CD depends upon the activity (active TNF antibody FAb fragment certolizumab pegol will become available
that is given subcutaneously at a dose of 400 mg at weeks 0, 2, and 4
phase, remission phase), location, extent and behavior
(inflammatory, stricturing, fistulizing) of the disease. The Active Crohns disease with a concomitant abdominal abscess should
be treated with antibiotics, percutaneous or surgical drainage followed
treatment needs to be tailored for each patient. The predictors
by delayed resection if necessary, in addition to specific medical
of poor outcome in patients with CD include young age of management of CD
onset, presence of extensive disease, stricturing disease and
positive smoking history.
Induction of Remission (Box 1) remission, relapse rates among patients receiving placebo
range from 30 to 60% at one year, and from 40 to 70% at two
Mesalamine has not consistently proved efficacious in years. Patients in remission for at least one year have a risk
patients with CD. Two trials of mesalamine at doses of 3,200 of relapse lower than those with a flare during the previous
4,000 mg/day showed efficacy whereas two other trials with year. About 7080% of patients with active disease during
4,000 mg/day of mesalazine that were never fully reported one year of follow up had active disease in the following
failed to show efficacy. A meta-analysis, which included year; conversely, 80% of patients in remission had no flare
the three largest trials, did not show a clinically important in the following year. The majority of patients treated with
treatment effect. Sulfasalazine at doses of 3,0004,500 mg/day steroids will not be in remission after 1 year and will therefore
is effective for induction of remission in mild-to-moderately require maintenance therapy. All patients should be advised
active disease limited to the colon. Moderately severe or to quit smoking, which is an important factor in maintaining
severe colonic disease should be treated with conventional remission and reducing the risk of relapse in CD. The choice
corticosteroids. of medication for maintenance of remission depends upon
An alternative explanation for symptoms other than active the course of the disease (initial presentation, frequency,
disease should be considered (such as infection, abscess and severity of flares); the extent of disease (localized or
formation, bacterial overgrowth, bile salt malabsorption, extensive) and the effectiveness and tolerance of treatments
dysmotility, gallstones) and disease activity confirmed before previously used for induction of remission or maintenance.
initiating new therapies. Other factors, such as financial resources and tolerance to
drugs should be considered in making treatment choices.
Sulphasalazine, 5-ASA compounds, prednisolone and
Maintenance of Remission budesonide are not effective in long-term maintenance
The natural course of CD is marked by remissions and of in patients with CD. The first line of treatment of
relapses. In clinical trials designed for the maintenance of maintenance of remission in patients with CD is thiopurines
or methotrexate. The dose of AZA should be optimized. Other than clinical examination and endoscopic activity
For those who relapse once immunosuppressants are of the disease, additional diagnostic tests to delineate fistula
stopped, current evidence suggests that AZA/6-MP can be anatomy, extent, and relationship of the tracks to the sphincter
safely restarted. In patients with active CD, the likelihood muscles include pelvic magnetic resonance imaging,
of response to AZA or 6-MP is increased after 17 weeks and anorectal endoscopic ultrasonography, and examination
the clinical response to methotrexate does not occur for 68 under an anesthesia.
weeks, indicating that because of the slow onset of action, While asymptomatic simple perianal fistula may be
these drugs should mainly be considered as maintenance observed, symptomatic fistula requires treatment. Bacterial
rather than induction drugs. AZA is dosed at 23 mg/kg/day infection is thought to play a role in the appearance and
and mercaptopurine at 1.01.5 mg/kg/day. Methotrexate is persistence of perianal fistulous disease. Thus, antibiotics are
given parenterally at doses of 25 mg/week for maintenance used as first-line therapy for fistula healing in simple perianal
therapy. fistula. Overall, antibiotics remain a mainstay of treatment for
Infliximab is effective for maintenance of remission, steroid- simple perianal fistula in patients with CD despite the lack of
sparing, and mucosal healing in patients who are unable to controlled trial evidence. Either metronidazole (7501,500
maintain remission or who remain steroid dependent despite mg/day) or ciprofloxacin (5001000 mg/day) can be used.
treatment with AZA, 6-MP, or methotrexate. For maintenance The antibiotic is generally required to be continued for 34
therapy, infliximab is given at a dose of 5 mg/kg every 8 weeks. months. The adverse events, such as neuropathy especially
Episodic dosing is associated with immunogenicity (loss of with metronidazole can appear with prolonged use.
efficacy and infusion reactions). Alternatives to infliximab are All patients should receive treatment for active intestinal
adalimumab given subcutaneously for maintenance therapy disease. Optimization of medical therapy for control of
as 40 mg subcutaneously every other week. Certolizumab disease elsewhere and in the colon and rectum is important
pegol will be available in the near future, which is given and may help in healing of fistula. Those who have active
subcutaneously for maintenance therapy as 400 mg every 4 perianal abscess, use of corticosteroids should be avoided in
weeks. them.
Azathioprine and 6-MP are effective in healing of fistula
due to CD. Anti-TNF drugs are quiet effective in healing of
Perianal Crohns Disease perianal fistula. Infliximab is given as 5 mg/kg at 0, 2, and 6
The transmural inflammatory nature of CD predisposes weeks for induction and then every 8 weeks for maintenance.
these patients to develop fistula and abscesses. Because An alternative to infliximab is adalimumab, which is given
of local pain and perianal discharge, perianal disease has subcutaneously as 160 mg at week 0 and 80 mg at week 2, and
a very negative impact on the quality of life of the affected then 40 mg every other week beginning at week 4. Surgery
patients. The perianal fistula occurs more often when there is should be used in conjunction with best medical therapy.
involvement of the colon and the rectum. Seton drainage can be a useful technique to provide symptom
The treatment of perianal fistula depends upon the control and can be used as a prelude to medical treatment.
location of fistula, nature of fistula, such as simple or Other surgical approaches, such as advancement flaps, and
complex, presence of abscess and severity of intestinal fistula plugs may be appropriate for persistent or complex
disease. A good examination of perianal area is of immense fistulae in combination with medical treatment.
importance and helps in classification of fistula type. Fistulas
can be classified as either simple or complex. A simple
fistula is low (superficial or low intersphincteric or low trans- FERTILITY AND PREGNANCY
sphincteric origin of the fistula tract), has single external
opening, has no pain or fluctuation to suggest perianal Although fertility in inactive IBD is unaffected, active
abscess, has no evidence of a rectovaginal fistula, and has no disease diminishes the fertility. The reasons for decrease
evidence of anorectal stricture. A complex fistula is high (high fertility in IBD include inflammatory changes in the female
intersphincteric or high trans-sphincteric or extrasphincteric reproductive system during active phase of the disease, local
or suprasphincteric origin of the fistula tract), may have sepsis, pelvic surgery, prior surgery and reversible decrease
multiple external openings, may be associated with the in sperm motility by sulphasalazine. The frequency of
presence of pain or fluctuation to suggest a perianal abscess, abortions, preterm deliveries, cesarean sections, congenital
may be associated with the presence of a rectovaginal abnormalities, and birth weight is no different in patients with
fistula, may be associated with the presence of an anorectal IBD compared with non-IBD controls, as seen in a prospective
stricture, and may be associated with the presence of active study including 332 pregnant women with IBD (145 with CD
rectal disease at endoscopy. and 187 with UC) from 12 European countries. Women who
have IBD are more likely to have a cesarean section, especially B12 deficiency occur. Drug-induced anemia secondary
those with CD. to AZA, 6-MP or sulfasalazine also occurs. Patients with
If pregnancy is planned, patient should be counseled IBD should have at least annual hemoglobin check. The
to conceive during remission and advised to continue their nutritional status of these patients should be assessed and
maintenance medication. Prior to conception patients should optimum nutritional therapy should be provided to them.
be well nourished and should take folate supplements. Osteoporosis is quiet common in patients with IBD.
Maintaining adequate disease control during pregnancy is Systemic inflammation secondary to active colitis and
essential for both maternal and fetal health. Pregnant women recurrent or chronic use of high dose corticosteroids are
with IBD should be managed jointly by a gastroenterologist risk factors for osteoporosis. Optimal nutrition, calcium
and obstetrician. Patients with acute severe disease or other and vitamin D intake, weight-bearing exercise, cessation
life-threatening complications of disease should be managed of smoking, moderation of alcohol consumption, and
minimization of the use of corticosteroids are recommended.
as for the nonpregnant patient. Optimal management of
Because glucocorticoids are mainstay of treatment of
maternal IBD is the key to the best fetal outcome. The mode of
patients with CD, it is important to recognize the effects
delivery should be carefully considered. The mode of delivery
they have on bone remodeling. Corticosteroids have been
is best guided by the obstetric indications rather that of the
shown to impair osteoblast function, induce osteoblast
IBD. Patients with perianal CD or ileoanal pouch formation
apoptosis, reduce intestinal calcium absorption, and increase
may best have a cesarean section to avoid the risk of damage renal excretion of calcium. Patients on glucocorticoids are
to the anal sphincter. Absolute indications for surgery are at increased risk for fracture, with the greatest bone loss
unaltered by pregnancy and surgery should only be delayed occurring in the initial months of treatment. Patients at risk
where aggressive medical therapy may allow critical fetal for or with osteoporosis should receive calcium and vitamin
maturation. D supplementation. The recommendation for younger men
Active flares during pregnancy need to be treated and premenopausal women is daily intake of elemental
aggressively using drugs established to be safe in pregnancy. calcium of 1,000 mg, either from diet or supplementation.
Corticosteroids tend to be safe in pregnancy as placental Men and women over 50 years of age require 1,500 mg of
11-hydroxygenase converts steroids to less active metabolites. calcium. Vitamin D intake of 400800 IU/day should be
Drugs that absolutely need to be avoided during pregnancy adequate for relatively healthy individuals, but patients with
are methotrexate and thalidomide. intestinal malabsorption or housebound patients may need
an increased amount.
BREASTFEEDING
BIBLIOGRAPHY
5-aminosalicylates and corticosteroids are safe during
breastfeeding. Breastfeeding should be avoided for 4 hours 1. Baumgart DC, Carding SR. Inflammatory bowel disease: cause
following oral drug administration to reduce neonatal and immunobiology. Lancet. 2007;369:1627-40.
exposure to drugs. AZA metabolites have not been found in 2. Baumgart DC, Sandborn WJ. Inflammatory bowel disease:
clinical aspects and established and evolving therapies. Lancet.
babies exclusively breastfed by mother receiving thiopurines.
2007;369:1641-57.
Therefore, most clinicians believe that women should not 3. Beaulieu DB, Kane S. Inflammatory bowel disease in pregnancy.
stop thiopurines during breastfeeding. Gastroenterol Clin North Am. 2011;40:399-413.
4. Chowers Y, Sturm A, Sans M, et al. Report of the ECCO workshop
on anti-TNF therapy failures in inflammatory bowel diseases:
NUTRITION IN INFLAMMATORY BOWEL biological roles and effects of TNF and TNF antagonists. J Crohns
Colitis. 2010;4:367-76.
DISEASE 5. Dignass A, Van Assche G, Lindsay JO, et al. The second European
evidence-based Consensus on the diagnosis and management
Nutritional care is an important consideration in the long-
of Crohns disease: Current management. J Crohns Colitis.
term management of IBD. Up to 85% of patients hospitalized
2010;4:28-62.
with exacerbations of IBD have proteincalorie malnutrition. 6. Lichtenstein GR, Abreu MT, Cohen R, et al. American
These patients have malnutrition of both macro- and Gastroenterological Association Institute technical review
micronutrients. Anemia is a common complication of IBD. on corticosteroids, immunomodulators, and infliximab in
Iron deficiency and anemia of chronic disease are the most inflammatory bowel disease. Gastroenterology. 2006;130:
common causes of anemia in IBD, though folate and vitamin 940-87.
7. Makharia GK, Srivastava S, Das P, et al. Clinical, endoscopic, 13. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated
and histological differentiations between Crohns disease and clinical, molecular and serological classification of inflammatory
intestinal tuberculosis. Am J Gastroenterol. 2010;105:642-51. bowel disease: Report of a Working Party of the2005 Montreal
8. Mowat C, Cole A, Windsor A, et al. Guidelines for the management World Congress of Gastroenterology. Can J Gastroenterol.
of inflammatory bowel disease in adults. Gut. 2011;60:571-607. 2005;19(Suppl A):5-36.
9. Ooi CJ, Fock KM, Makharia GK, et al. The Asia-Pacific consensus 14. Stange EF, Travis SP, Vermeire S, et al. European evidence-based
on ulcerative colitis. J Gastroenterol Hepatol. 2010;25:453-68. Consensus on the diagnosis and management of ulcerative
10. Peyrin-Biroulet L, Ferrante M, Magro F, et al. Results from the 2nd
colitis: Definitions and diagnosis. J Crohns Colitis. 2008;
Scientific Workshop of the ECCO. I: Impact of mucosal healing
2:1-23.
on the course of inflammatory bowel disease. J Crohns Colitis.
2011;5:477-83. 15. Travis SP, Stange EF, Lmann M, et al. European evidence-based
11. Podolsky DK. Inflammatory bowel disease. N Engl J Med. Consensus on the management of ulcerative colitis: Current
2002;347:417-29. management. J Crohns Colitis. 2008;2:24-62.
12. Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity 16. Van Assche G, Dignass A, Reinisch W, et al. The second European
indices and efficacy endpoints for clinical trials of medical evidence-based Consensus on the diagnosis and management
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10
cHAPTER
Irritable Bowel Syndrome
Monjur Ahmed
INTRODUCTION the pathogenesis of IBS. Small bowel manometry may show

prominent clustered contractions during phase 2 activity.
Irritable bowel syndrome (IBS) is a clinical diagnosis This may also occur in healthy individuals. But more patients
characterized by chronic or recurrent abdominal pain or with IBS with these contractions will be symptomatic than
discomfort associated with alteration of bowel habits. The healthy individuals with these contractions. In irritable bowel
symptoms cannot be explained by any structural lesion, syndrome with diarrhea (IBS-D), transit time through the
metabolic changes or infection of the gut. It is a functional small bowel is short whereas in irritable bowel syndrome with
disorder due to changes in motility, perception and sensation constipation (IBS-C), small bowel transit time is prolonged.
of the gut. No specific colonic dysmotility is found in IBS. High
There are several functional gastrointestinal disorders amplitude peristaltic contractions are more frequent after
described in Rome III classification, IBS being the most taking meals and before bowel movements. In IBS-D, colon
common (28% of outpatient gastroenterology practice and transit is rapid, and in IBS-C, colon transit is slow.
12% of primary care practice). It affects 820% of the adult
population in the western world with similar prevalence
reported in other parts of the world. The prevalence of
Visceral Hypersensitivity
IBS is higher among women although any socioeconomic Most of the patients with IBS have decreased pain threshold
group can be affected. Two-third of IBS patients do not seek in the gastrointestinal tract. How visceral hypersensitivity
healthcare although it varies from culture to culture. In Indian occurs in IBS is not exactly known. Painful and non-painful
subcontinent, self reporting of IBS symptoms is much less stimuli are transmitted from the gut to the brain via afferent
common than in the western world. Irritable bowel syndrome nerves. Many factors involve both peripheral and central
not only causes significant negative impact on the quality of neurons. The neurons in the myenteric plexus of the gut
life of the patients for years and years but also creates a huge may get exposed to a variety of inflammatory mediators and
economic impact on our society through direct healthcare cytokines (serotonin, prostaglandin, leukotrienes, histamine,
costs and negative productivity through workers absenteeism. reactive metabolites) during tissue injury. They act on the
nociceptor terminals and activate intracellular signaling
pathways, which upregulate the sensitivity of the gut. A
PATHOPHYSIOLOGY small percentage of patients with IBS give history of onset
of symptoms since an attack of gastroenteritis, as they have
The pathophysiology of IBS is not fully understood. The current developed hypersensitivity of the gut. Functional magnetic
thinking is that abnormal braingut control leads to visceral resonance imaging (MRI) studies suggested greater activation
hypersensitivity, and altered colonic and small bowel motility of middle and posterior dorsal cingulate gyri (responsible
and secretion. Multiple pathophysiologic mechanisms have for pain sensation) and less activity of supragenual anterior
been associated with IBS, and it seems reasonable that several cingulate cortex (responsible for pain inhibition) in response
mechanisms need to be present to manifest the disease. to rectal distention in IBS patients. This may implicate that
pain modulation may be altered in IBS patients.
Dysmotility of the Gut
Previously IBS was thought to be a purely motility disorder. Stress
But the motility disturbances seen in patients with IBS do Stress plays an important role in the pathogenesis and clinical
not always correlate with the symptoms and do not explain manifestations of IBS. Normal individuals may develop
Irritable Bowel Syndrome 95
abdominal cramps, diarrhea or constipation in response to CLINICAL MANIFESTATIONS

stress. This response is much more exaggerated in patients
with IBS. Stress is an acute threat (physical or psychological) Irritable bowel syndrome is commonly present in the younger
to the homeostasis of an individual. The response to stress is population as majority of the patients present below the age
mediated through hypothalamicpituitaryadrenal axis and of 45. The prevalence generally decreases with age. Females
the sympathetic nervous system. In IBS patients, this circuit are five to six times more frequently affected than males.
could be improperly functioning. Altered sympathetic activity Females are significantly more symptomatic, primarily with
or inadequate cortisol secretion may lead to persistence of less satisfied bowel movements and bloating. In one study,
gut inflammation despite eradication of infection leading to whites and African Americans had similar prevalence of IBS.
postinfectious IBS. Different stressful life events like accidents, Abdominal discomfort or pain is the main symptom of
death in the family, divorce, unemployment and financial IBS. Patients generally feel lower abdominal pain, but it
crisis may predispose and perpetuate the manifestations can be anywhere in the abdomen. The pain can be mild to
of IBS. Stress hormone like corticotrophin releasing factor severe, and is not well characterized, sometimes described
has been found to cause more colonic contractions and as crampy, sometimes gas-like, sometimes sharp, sometimes
more abdominal pain in patients with IBS than in normal dull and sometimes aching in nature. Onset of abdominal
individuals. pain is associated with change in bowel frequency or
consistency of stool. The pain is intermittent, aggravated by
taking food and generally relieved by defecation. Stressful life
Psychological Factors events precipitate the abdominal pain and change in bowel
Anxiety, depression, hypochondriasis, phobia, somatization habit. We generally follow Rome III diagnostic criteria, as they
and post-traumatic stress disorder are common in patients have high specificity for diagnosing IBS.
with IBS. In one study, 53% of women with IBS had a history of
abuse occurred during their childhood. These psychological
factors have been associated with increased visceral
Rome III Diagnostic Criteria for
perception leading to negative impact on the quality of life, Irritable Bowel Syndrome
increased doctors office visit and healthcare utilization,
Recurrent abdominal pain or discomfort at least 3 days per
ineffective coping skills and poor clinical outcome.
month in the last 3 months associated with two or more of the
following:
Enteric Infection and Gut Microbes Improvement with defecation
Onset associated with a change in the frequency of stool
Postinfective IBS can occur following bacterial infection Onset associated with a change in the form (appearance)
of the gut, the relative risk being 12%. Young female with a of stool
history of prolonged diarrhea but absence of vomiting as The symptoms should be present for at least 6 months
well as persons with anxiety, somatization and stressful life prior to diagnosis.
events before or during infection are at increased risk of Some of the symptoms we frequently find in patients with
developing IBS. Random colon mucosal biopsies may show IBS are not mentioned in Rome III criteria. These include
increased number of lymphocytes and enterochromaffin morning rush, i.e. repeated bowel movements in the morning
cells throughout the colon, and these changes may last for when stool form changes from solid to liquid, passage of
more than 3 months. Enterochromaffin cells can release mucus per rectum, abdominal bloating and gas sensation,
5-hydroxytryptamine (5-HT) in the postprandial period. visible abdominal distention and feeling of incomplete
Recently, it has been found that there is significant alteration evacuation of stool.
of fecal microflora in IBS patients. Those microflora may Irritable bowel syndrome is subtyped depending on
release proinflammatory cytokines. Increased prevalence the consistency of the stool. Subtyping is important for
(54%) of small intestinal bacterial overgrowth (SIBO) based therapeutic purposes as the treatment is directed toward
on lactulose or glucose breath test has been found in IBS symptoms. The Bristol Stool Form Scale (Fig. 1) is very helpful
patients. In another study, low concentration of bacteria in this situation. The stool form depends on colon transit
(>5,000 coliforms/mL) in jejunal culture was more frequently time, i.e. the more time stool remains in the colon, it becomes
found in IBS patients than in healthy controls (43% vs 12%). harder. Irritable bowel syndrome has four subtypes:
The significance of SIBO in the pathogenesis of IBS remains 1. IBS-C: Hard stools for more than 25% of the time and loose
uncertain. stools for less than 25% of the time.
post-traumatic stress disorder. Many IBS patients cannot

manage well their stressful life events and they become
more symptomatic during these stress situations
Extracolonic symptoms: Many patients with IBS complain
of nausea and dyspepsia. A significant numbers of IBS
patients seek medical attention for headache, backache,
insomnia and genitourinary symptoms like impotence,
dyspareunia, dysmenorrhea, increased frequency and
urgency of micturition, sensation of incomplete bladder
emptying and nocturia.
Comorbidities: Irritable bowel syndrome is significantly
found in certain disorders like fibromyalgia, chronic
fatigue syndrome, temporomandibular joint disorder, and
chronic pelvic pain.
A thorough history taking is pertinent to find out red
flags that may indicate presence of an organic disorder.
Red Flags
Age greater than 50 years, particularly in patients with new
onset of symptoms or change in symptoms
Male sex
Rectal bleeding
Fig. 1: the bristol stool form scale Anemia
Source: Reproduced by kind permission of Dr KW Heaton, Reader in Fever
Medicine at the University of Bristol. Documented weight loss
2000 produced by Norgine Pharmaceutical Limited, manufacturer Nocturnal symptoms with wake up from sleep
of MOVICOL Family history of colon cancer or inflammatory bowel
disease
2. IBS-D: Loose stools for more that 25% of the time and hard
stools for less than 25% of the time. PHYSICAL EXAMINATION
3. IBS-mixed (IBS-M): Hard stools for more than 25% of the
time and loose stools for more than 25% of the time. This Physical findings are generally normal. Sometimes, we
subtype constitutes 3050% of all cases of IBS. find left lower quadrant abdominal tenderness and intense
4. Unsubtyped IBS (IBS-U): Neither hard nor loose stools for discomfort on rectal examination. The patient may look
more than 25% of the time. This constitutes 4% of all cases anxious or depressed.
of IBS.
Sometimes we use the term alternators to those IBS
patients whose symptoms change from one subtype to DIAGNOSTIC TESTING
another over a period of time.

Although Rome III criteria and Bristol Stool Form Scale Extensive workup is generally not needed to establish the
help us diagnosing and subtyping IBS, few important points diagnosis of IBS in the absence of red flags as mentioned
should be considered in its clinical spectrum: above. Complete blood count, erythrocyte sedimentation
Psychological aspects: Anxiety and depression are rate (ESR) and thyroid stimulating hormone (TSH) are
commonly found in patients with IBS. Many IBS patients generally done routinely. Abnormalities in these tests may
are hypochondriac. There are significant numbers of suggest systemic disease. Serum tissue transglutaminase
patients who have history of physical and sexual abuse antibody should also be done in patients with IBS-D and
during their childhood and they are more symptomatic IBS-M as few studies have suggested increased chance of
with pain, disability and psychological distress. Irritable having celiac disease in suspected IBS. In patients with IBS-D,
bowel disease has been found to be associated with three loose stool samples should be collected on separate
days for ova, parasites and Giardia antigen (ELISA). Flexible MANAGEMENT
sigmoidoscopy should be considered in suspected IBS
patients to evaluate any colitis in diarrhea and distal colonic
obstruction in constipation.
General Approach
Colonoscopy is generally indicated for patients with age 50 After establishing the diagnosis of IBS, a strong physician
and above, family history of colon cancer, positive fecal occult patient relationship should be established. Patients under-
blood test or rectal bleeding, and refractory diarrhea. standing and concern about the illness should be determined
Additional diagnostic testing may be necessary if the and adequate explanation should be given. The severity of
patients clinical course does not improve or deteriorate after symptoms and the impact on the quality of life should be
about a month of symptomatic treatment. evaluated. The physician should ask how much improvement
Further tests are performed depending on the patients of symptoms patients expect and the physician should answer
predominant symptoms. If the patient has predominant diar- realistically with consistent limits.
rhea, bacterial overgrowth, lactose intolerance, microscopic Detailed dietary history should be taken as most of the
colitis, secretory or osmotic diarrhea and malabsorption patients with IBS relate their symptoms to intake of certain
food. Fat is known to aggravate visceral sensation and
should be excluded. To evaluate these conditions, further in-
gastrocolic reflex, and consequently abdominal cramping
vestigations would include lactulose or glucose breath test,
and diarrhea. Excessive coffee, alcohol, lactose, fructose and
lactose breath test, colonoscopy with random biopsies from
sorbitol can aggravate IBS symptoms. Therefore, in certain
both left and right colon, stool osmolarity, stool for sodium
IBS patients, they should be avoided.
and potassium to calculate the fecal osmotic gap: 300 2
(Na + K), and 3-day stool collection for quantitative fat assay.
If the patient has predominant constipation, then colon Pharmacological Approach
inertia and anorectal dyssynergia should be excluded.
Medications are generally given to treat the patients
Additional tests would include colon transit study (Sitzmarks),
predominant symptoms.
anorectal manometry and defecography.
If the patient has predominant pain, then pancreatitis,
hepatitis and any intra-abdominal pathology should be Constipation
excluded. Further tests to be done are liver function test,
Patients should be advised to take plenty fibers in the diet with
serum amylase and lipase, and CT or MRI of abdomen and
plenty of water. High fiber diet may include fruits, vegetables,
pelvis.
whole grains, nuts, and seeds. The fiber ingestion should be
gradually increased over few weeks to about 2025 gm/day.
If dietary fiber does not improve constipation, next step is
DIFFERENTIAL DIAGNOSIS to add fiber supplements to regularize bowel movements.
Commercially available fiber supplements include psyllium
Celiac disease (Metamucil, Konsyl), methylcellulose (Citrocel) and
Inflammatory bowel disease: Crohns disease, ulcerative polycarbophil (Fibercon, Equalactone). The main side effect
colitis of fiber therapy is gas formation. In that case, patients should
Microscopic colitis be advised to reduce their fiber intake including gas-forming
Infectious diarrhea: Giardia, Entamoeba, Campylobacter, foods, which include certain vegetables like cabbage and
Yersinia beans, and certain fruits like apples and grapes. Fiber therapy
Small intestinal bacterial overgrowth does not reduce patients abdominal pain.
Food intolerance: Lactose, sorbitol, monosodium gluta- If fiber therapy fails, osmotic laxatives should be given
mate, fructose first before trying stimulant laxatives. Osmotic laxatives
Endocrine: Hyperthyroidism, carcinoid syndrome, cause influx of water into the small bowel and colon and thus
ZollingerEllison syndrome, mastocytosis forms bulky stool. Commonly used osmotic laxatives include
Tumors: Colon cancer, villous adenoma lactulose, polyethylene glycol (Miralax), magnesium citrate
Medications: Laxatives, magnesium containing antacids and magnesium hydroxide. Stimulant laxatives increase
Malabsorption: Pancreatic insufficiency, tropical sprue, colonic contraction by stimulating the myenteric plexus.
Whipples disease They should be used with caution, as they may damage the
myenteric plexus permanently leading to cathartic bowel and Abdominal Pain and Global Symptoms
also for the potential for abuse. Commonly used stimulant
laxatives include bisacodyl, senna, and cascara. Antispasmodics are commonly used for the treatment of
If constipation still persists, chloride channel activator abdominal pain in IBS. Dicyclomine and hyoscyamine are
lubiprostone can be given. It causes active chloride secretion usually prescribed. They can be used regularly three to four
from the colon mucosa with obligatory secretion of sodium times a day about half an hour before meals or as necessary
and water making the stool hydrated. It improves constipation basis. They can improve abdominal pain as well as global
and global symptoms of IBS-C. The main side effect of symptoms of IBS. They can cause anticholinergic side effects
lubiprostone is nausea, which can be reduced if the pill is like dry mouth and constipation.
taken with food. Low-dose tricyclic antidepressants (TCA) have been found
The role of probiotics in IBS-C is not known. Limited data to be beneficial in improving the global symptoms of IBS. They
supports that Bifidobacterium animalis shortens colon transit reduce abdominal pain by acting on the central and periph-
and improves bowel movements. eral nervous system. They also reduce gut motility and so, they
Tegaserod (partial 5-HT4 receptor agonist) was efficacious are effective in patients with IBS-D. The medication should be
in relieving constipation as well as improving global started at a low dose and gradually increased over few weeks.
symptoms of IBS in women. But it was suspended from the It may take several weeks to get the effect of the tricyclics. Pa-
US market in 2007 because of its small but significant risk of tients may develop drowsiness and anticholinergic side effects.
ischemic cardiovascular events. Selective serotonin reuptake inhibitors (SSRIs) like
Recently, linactolide, a guanylate cyclase-C agonist has paroxetine, fluoxetine, and citalopram may improve global
been approved for IBC-C patients. It works by increasing symptoms of IBS, but they are not as good as tricyclics in
intestinal fluid secretion. It improves constipation and relieving abdominal pain.
reduces pain by decreasing visceral hypersensitivity. Another Serotonin-norepinephrine reuptake inhibitors (SNRIs)
5-HT4 receptor agonist, prucalopride, is under investigation. can be helpful in alleviating abdominal pain in IBS without
It has 150 times greater affinity on 5HT4 receptors than any anticholinergic side effects.
other 5HT receptors and, as a result, does not seem to have Few antibiotics have been investigated in the management
adverse cardiovascular events. Although it increases bowel of IBS as they can alter intestinal microflora. Neomycin was
movements in constipation, its role in IBS-C has not been found to improve global symptoms of IBS-C. But its side effects
formally evaluated. like neuromuscular blockade, ototoxicity and nephrotoxicity
limit us to use it very cautiously in IBS patients.
Diarrhea Rifaximin 550 mg three times a day for 2 weeks in
nonconstipated IBS patients was found to improve global
The common antidiarrheal agents used are loperamide and symptoms of IBS and bloating. The improvement was
lomotil (combination of diphenoxylate and atropine). Both maintained in 3-month follow-up.
loperamide and diphenoxylate are synthetic opoids, bind Probiotics are frequently used by IBS patients, although
to receptors on the myenteric plexus and thus reduce the there are only few studies. Bifidobacterium infantis 35624
gut motility. Cholestyramine (bile acid binder) has also been (Align) was found to improve abdominal pain, diarrhea,
used in IBS-D. As it works by binding bile acid in the colon, it bloating and global symptoms of IBS.
is more effective in IBS patients with rapid small bowel transit
or cholecystectomy.
Alosetron (5-HT3 antagonist) slows gastrointestinal Psychological Treatment
transit, reduces chloride and water secretion in the gut and
Patients with IBS can have other psychiatric comorbidities
diminishes visceral hypersensitivity. Alosetron has been
like anxiety, depression, panic attacks and substance abuse.
found to be helpful in reducing abdominal pain, diarrhea and
These patients need help from the psychiatrists. Besides
global symptoms in women with IBS-D. Alosetron 1 mg orally
these, if the patients symptoms are disabling, they should
twice a day in women with IBS-D was approved in USA in 2000
be referred for psychological assessment and treatment.
but in the same year it was taken off from the market because
Psychotherapy is commonly used to reduce symptoms.
it was infrequently associated with severe constipation and
ischemic colitis. Alosetron was reintroduced in the US market
in 2002 through a restricted access program0.5 mg twice Alternative Medicine
a day in women with IBS-D unresponsive to conventional
medical treatment. The chance of developing ischemic colitis A significant number of patients suffering from IBS also use
is rare, about 23 per 1,000 case over 6 months. alternative medicines, which include different vitamins,
Ayurvedic herbal medicine, homeopathic medicine, Chinese 6. Dickhaus B, Mayer EA, Firooz N, et al. Irritable bowel syndrome
herbal medicine and acupuncture. There are not many patients show enhanced modulation of visceral perception by
randomized placebo controlled trials with these alternative auditory stress. Am J Gastroenterol. 2003;98:135-43.
medicine therapies. The effectiveness of these therapies is 7. Drossman DA. Treatment of bacterial overgrowth in the irritable
unknown and safety is also a great concern as many herbal bowel syndrome. Ann Intern Med. 2006;145:626-8.
8. Drossman DA, Camilleri M, Mayer EA, et al. AGA technical review
medicines can cause drug-induced hepatitis. One randomized
on irritable bowel syndrome. Gastroenterology. 2002;123:
controlled trial showed better result with standard medical
2108-31.
therapy than Ayurvedic herbal medicine. 9. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial:
lubiprostone in patients with constipation-associated irritable
bowel syndromeresults of two randomized placebo-
CONCLUSION controlled studies. Aliment Pharmacol Ther. 2009;29:329-41.
10. Drossman DA, Thompson WG. The irritable bowel syndrome:
Irritable bowel syndrome is a common clinical problem review and a graduated multicomponent treatment approach.
in our day-to-day medical practice. It is a chronic disorder Ann Intern Med. 1992;116:1009-16.
with recurrent symptoms. Although it does not cause excess 11. Ford AC, brandt LJ, Young C, et al. Efficacy of 5-HT3 antagonists and
mortality, it has a huge impact on our society considering 5-HT4 agonists in irritable bowel syndrome: systematic review and
meta-analysis. Am J Gastroenterol. 2009;104:1831-43.
the patients sufferings and the economic burden. In the last
12. Ford AC, Chey WD, Talley NJ, et al. Yield of diagnostic tests for
few decades, extensive research has explored the potential
celiac disease in individuals with symptoms suggestive of
mechanisms responsible for the symptomatology of IBS and irritable bowel syndrome: systematic review and meta-analysis.
new medical therapies have been developed. The disorder Arch Intern Med. 2009;169(7):651-8.
cannot be cured completely, but the symptoms can be 13. Hammerle CW, Surawicz CM. Updates on the treatment of irritable
alleviated by different therapies. In mild cases, symptoms can bowel syndrome. World J Gastroenterol. 2008;14(17):2639-49.
be improved by dietary and lifestyle modifications and taking 14. Johnson JF, Wald A, Tougas G, et al. Effect of tegeserod in chronic
over-the-counter medications. Moderate-to-severe cases will constipation: a randomized double-blind, controlled trial. Clin
require prescription medications. But a good doctorpatient Gastroenterol Hepatol. 2004;2:796-805.
relationship will be essential to keep the symptoms under 15. Lind CD. Motility disorders in the irritable bowel syndrome.
control for longer period of time. Patients with refractory Gastroenterol Clin North Am. 1991;20(2):279-95.
16. Low K, Hwang L, Hua J, et al. A combination of rifaximin
symptoms should be considered for psychotherapy. Our
and neomycin is most effective in treating irritable bowel
current knowledge does not suggest the routine use of
syndrome patients with methane on lactulose breath test. J Clin
alternative medicine as the remedy for IBS. As the research Gastroenterol. 2010;44(8):547-50.
is continuing, large numbers of medications are in the 17. Marshall JK, Thabane M, Borgaonkar MR, et al. Postinfectious
developmental phase for the treatment of IBS. irritable bowel syndrome after a food-borne outbreak of acute
gastroenteritis attributed to a viral pathogen. Clin Gastroenterol
Hepatol. 2007;5:457-60.
BIBLIOGRAPHY 18. Matheis A, Martens U, Kruse J, et al. Irritable bowel syndrome and
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11
cHAPTER
Colorectal Carcinoma
Kaushal Kishor Prasad, Saroj Kant Sinha, Rakesh Kochhar
INTRODUCTION tumor-associated antigens have opened new horizon for the

immunotherapy of advanced CRC.
Colorectal carcinoma (CRC) is the third most commonly
diagnosed tumors in the Western countries, and recently
its incidence is increasing rapidly in Asia. These increased EPIDEMIOLOGICAL TRENDS IN ASIA
rates are the result of increase in the risk factors that are
associated with westernization of Asian populations. Colorectal carcinoma has become one of the leading causes
Epidemiologically, alcoholism, cigarette smoking, diabetes of death in many Asian countries. Epidemiologic studies have
mellitus, consumption of red and processed meat, physical demonstrated geographical variations in the incidence of
inactivity and obesity are associated with CRC. The changes CRC across ethnic groups and socioeconomic groups. There
in dietary pattern and lifestyle are linked to increase in CRC is an increasing trend in CRC, which is considered as typical
incidence in Asian populations; however, the interaction of economically developed countries. CRC incidences differ
between these factors and genetic makeups might also play a considerably between Western and non-Western countries.
pivotal role. At present the incidence, anatomical distribution In past few decades, a steep rise in CRC incidence has been
and mortality of CRC among Asian populations are not reported in several Asian countries. The rising trend in the
different compared with Western countries. The mortality incidence and mortality from CRC is much more in affluent
related to CRC is also rising in Asia, except in Japan and than in poorer societies and differs to a great extent in different
Singapore. For the prevention and early intervention various ethnic groups. In South-East Asia, CRC is now the third most
screening options for CRC are available. In Japan, Korea and common neoplastic disease in both sexes. Although there
Taiwan CRC screening by fecal occult blood tests (FOBT) is at are evidences of increasing incidence in North-Western and
present national policy. Full length colonoscopy is the most Central Asia, CRCs are still very infrequent.
commonly used modality for the diagnosis of CRC. Surgery
is the only way to potentially cure the disease and may be
accomplished in 7080% of newly diagnosed cases. However, INCIDENCE OF COLORECTAL
about half of patients who underwent surgery alone ultimately CARCINOMA IN ASIA
relapse and dies due to widespread metastasis. Surgery with
additional adjuvant therapy utilizing chemotherapy and/or Colorectal carcinoma has a global annual incidence of
radiotherapy improves the final outcome for high-risk CRC 1 million cases and an annual mortality of more than 500,000
patients. After surgical treatment surveillance programs are cases. The overall estimated new cases of CRC in USA in
widely accepted as an integral part of the treatment plan 2013 are 142,820. CRC comprises 9% of the overall cancer
provided to CRC patients. burden and is most frequent in North America, Australia,
The importance of the molecular biology and its New Zealand, and Europe. CRC is considered as a disease
methodology has been growing for both detection of the of the Western lifestyle. In past few decades, China, Japan,
CRC and the selection of the best treatment for the individual South Korea, and Singapore have experienced an increase
patient during the last decade. The genetic and epigenetic of two to four times in the incidence of CRC. The most
characteristics of CRC help predict the prognosis of the striking increase in CRC incidence has been observed in
disease and also select the best treatment, which extends Japan, a developed nation with a strong economy. In the
the disease-free and overall survival of the patient. The last 4 decades, two of three registries recorded an increased
cloning techniques utilizing to identify genes and peptides of incidence of CRC of more than 90%. During this period,
there has been a westernization of the Japanese diet with an the difference in the incidence of CRC amongst Asians of the
increased intake of dairy products, fat, and meat. It has been same racial origin (e.g. Indian) migrating to Southeast Asia
speculated that westernization may account for the major and to the North America. In Singapore and Malaysia the
shift in CRC incidence. The increase in incidence might be incidence of CRC is significantly lower among the Indian and
also due to actual increase in risk of CRC; however, it could be Malay populations than among the Chinese population. In
also due to increasing population or relative increase in the both these countries, the three major ethnic groups live in
high-risk groups, increased awareness, or availability of better the same environment. The lower incidence among Indians
diagnostic tools. The age-standardized rates (ASR) of CRC per and the higher incidence among Chinese living in South
100,000 men are 49.3 in Japan, 35.1 in Singapore, and 24.7 in east Asia reflect the incidence rates in the countries of origin
South Korea as compared to 44.4 in North America and 42.9 although both racial groups migrated few generations ago.
in Western Europe. Although overall ASR has increased in These evidences on racial differences indicate that the genetic
majority of Asian countries in the past few decades, there has makeup of a population is an important etiological factor in
been recent decrease in ASR in some countries, particularly in colorectal carcinogenesis.
those having younger population. In Singapore, CRC became
second most common carcinoma in both sexes, and similar
pattern has been observed in Hong Kong. The noticeable rises DISTRIBUTION ACCORDING TO AGE
in incidence of CRC have also been observed in China and AND SEX
Taiwan, but the reported data are not available from countries
like India, Indonesia, and Philippines. The observed overall The risk for onset of CRC increases with aging. In developed
incidence of advanced CRC in asymptomatic Asians is countries, 90% of CRC cases are 50 years or above. In the UK,
comparable with that of other developed countries. Figure 1 the peak age of onset is 70 years, while 510% of cases are 80
shows estimated ASR for CRC worldwide. years. The peak onset age in the USA is 75 years, while less
In many different ethnic groups in Asia, there are substantial than 6% of cases are under the age of 40 years. In Thailand,
differences in the incidence of CRC. The Japanese, Korean and the average age for patients of CRC is 61.2 years and 83.9% of
Chinese are found to have a higher risk of advanced colonic patients are above 50 years. In Philippines, the average onset
carcinoma than in the Indians, Thais and Filipinos. The age in patients of CRC is 55.3 years, while 17% of patients
genetic predisposition interacts with environmental factors are below 40 years. In Korea, the average onset age of colon
or lifestyle modification is substantiated by the evidence that carcinoma is 57.4 years and rectal carcinoma is 55.6 years. In
Fig. 1: Estimated age-standardized rates and mortality rates for colorectal carcinoma
Colorectal Carcinoma 103
Turkey genetic factors are thought to be playing an important CRC in many Asian countries. In Northwestern and Central
role as CRCs appear in younger age group more commonly Asia, there is a slight predominance of colon carcinoma over
than in Western populations. A similar pattern has been rectal carcinoma in both sexes and men have slightly higher
observed in Iran, where about 50% of CRC cases are also less incidence rates. Substantial increases of CRCs are observed
than 50 years of age and there is a family history in about 35% in Shiraz with no alteration in the ratio of right to left-sided
of cases. The apparent higher proportions of younger cases carcinomas, whereas in Tabriz a left shift of both colorectal
may also be due to relatively younger population in these adenomas and carcinomas are observed. In Turkey, colon
countries. carcinomas slightly outnumber those of the rectal carcinomas
Globally, CRC is the third most common carcinoma in men but the situation in Iran is unclear. Synchronous colonic and
and the second most common in women. More than 50% of rectal lesions may not be rare.
cases occur in developed countries and developed regions
of developing countries. The incidence rates vary between
10-folds in men and women, the highest rates estimated to be MORTALITY RATE FOR COLORECTAL
in Australia, New Zealand, and Western Europe, intermediate
in Latin America and the lowest in Africa (except Southern CANCER IN ASIA
Africa) and SouthCentral Asia. The incidence rates are higher
Deaths from CRC account for 8% of all cancer deaths, making it
in men than in women with overall sex ratio of the ASRs 1.4:1.
the fourth most common cause of death from cancer. Figure 1
The highest CRC incidence rates among men are observed
shows estimated mortality rates for CRC worldwide. The
in Europe, North America, and Oceania. In Asia, high rates
overall estimated deaths in USA from CRC in 2013 are 50,830.
are observed in Japan, Singapore, and Israel. Higher CRC
Similar to incidence, mortality rates are lower in women
incidence rates observed in these three countries recently and
than in men, except in the Caribbean. Globally there is less
are thought might be due to lifestyle or environmental factors.
variability in mortality rates, which are around sixfold in men
A slow rising trend in men has also been noted in Hong Kong.
and fivefold in women. The highest mortality rates in men
The highest CRC incidence rates among women are observed
and women observed in Central and Eastern Europe with
in New Zealand, Australia, and Israel. High CRC rates among
20.3 per 100,000 for men and 12.1 per 100,000 for women, and
women are also observed in Japan and Singapore; however,
rates for women are noticeably lower than those for men in the lowest rates in Middle Africa with 3.5 per 100,000 for men
these countries. The ASR of CRC among women in Hong Kong and 2.7 per 100,000 for women. A recent decreasing trends in
and Singapore had reached a plateau by 1995 and since then CRC in both sexes observed in USA, Australia, New Zealand,
it has downward trend, which has different trend from men. and the majority of Western Europe, including Germany,
The lower rates observed among women compared with men France, Austria, Ireland, and the UK. Increasing trends in CRC
may be associated with different lifestyle patterns in men and mortality rates recently observed in both sexes in Mexico,
women. Among both sex, the lowest CRC incidence rates Brazil, Chile, Ecuador, Romania, and Russia.
are observed in India, Oman, Egypt, Algeria, and Pakistan. The incidence of CRC in Asia has been increasing rapidly
In these developing countries, low CRC incidence rates may in recent decades, and mortality has also increased except
mirror a low prevalence of known CRC risk factors. in Japan and Singapore. The largest observed increase in
CRC deaths happened in Korean women, in past decades,
although mortality rates still remained relatively low (7.5 per
RIGHT SHIFT IN THE POSITION OF 100,000) in recent year. CRC mortality rates among Korean
men stabilized during recent time after increasing in past
COLORECTAL CANCER LESIONS decades. In Japan, death rates decreased in past decades in
both sexes; however, more marked in women.
A trend of relatively higher proportion of carcinomas in
ascending colon and cecum versus descending colon, sigmoid
colon and rectum (right shifting) has been observed in South
east Asia, including Japan, South Korea, and Hong Kong, COLORECTAL POLYPOID AND
which is not accountable by indications for colonoscopic NONPOLYPOID ADENOMA
examination or difference in age. The wider availability of
colonoscopy, aging populations and increasing trend of Colorectal polyps have conventionally been classified into two
right-sided CRC is accompanied by a continuous declining main types: neoplastic polyp, or adenoma, and hyperplastic
trend of rectal carcinoma in both sexes in all age groups polyp (HPP). Colorectal adenomas are precancerous
might explain in part the apparent increase in right-sided lesions for the CRCs; they have been classified into three
histologic types, with increasing malignant potential: are more likely to be missed on colonoscopic examination
tubular, tubulovillous and villous adenoma. The different than conventional adenomas, and the progression of SAs to
biological and metabolic processes have been implicated carcinoma may be at rapid pace. Therefore, it is of paramount
to adenoma pathogenesis. The adenomatous polyps are importance for both gastroenterologists and gastrointestinal
benign tumors that may undergo malignant transformation (GI) histopathologists to recognize SAs, and affected patients
and this transformation of adenoma to carcinoma occurs in must undergo surveillance and lesions must be identified and
only about 5% of cases. Early detection and removal of all resected.
adenomas decreases CRC incidence and mortality rates. The The majority of CRC progresses slowly through polypoid
pathological features are unable to accurately discriminate growth, the nonpolypoid (flat and depressed) colorectal
which adenomas will progresses to carcinomas from those neoplasms (NP-CRN) also contribute to the progression
which will not. Large size of adenoma, villous pathology of CRC. The NP-CRN lesions appear to be slightly elevated,
and the degree of dysplasia within the adenomas are highly completely flat or slightly depressed with respect to the
correlated with the potential to transform into carcinoma. surrounding normal mucosa. Large, flat and depressed
Understanding the pathobiology of carcinoma progression lesions are more likely to be severely dysplastic. The NP-CRN
will help better characterize high-risk adenomas, and further lesions, initially thought to primarily exist in Japan, recently
help in establishing triage tests which will allow to safely it have been observed globally. The NP-CRN seems to be
reserving colonoscopic examination only for cases at high more prevalent in Asian populations. Since NP-CRN is small
probability of having truly high-risk lesions. The screening lesions and there are no adenomatous lesions in their close
tests based on changes at molecular levels that affect relevant vicinity, they are termed de novo carcinomas as they appear
biological and metabolic processes hold promising future. not to originate from any precursor lesion. The NP-CRN is
Overall in Asian continent, 57% of polyps are distal, 30% are unlikely to have K-ras mutations compared to CRCs arising
proximal and 13% are synchronous. In the Western world, 49% from the adenoma-carcinoma sequence. The colorectal
of polyps are distal, 49% are proximal and 2% are synchronous.
NP-CRN have tendency to reach deeper layers of the bowel
However, the advanced neoplastic lesion distributions are not
wall early in the course of disease and having a higher grade
significantly different between the Eastern and the Western
of dysplasia and for this reasons they are more invasive
world. There is a trend toward the right-shift of colonic
compared to the polypoid adenomas. In Japan up to a third of
polyps in Asia. A right-shift of adenoma is also apparent in
CRCs identified to be arisen de novo. The aging populations
Korea. In Japan, a large cohort study consisted of consecutive
have highest incidence rate of these carcinomas. In Taiwan
asymptomatic subjects indicated that the phenomenon of
at least 30% of CRCs might be arising de novo. The absence
right-shifting is resulting from aging, and hence full-length
of polypoid growth preceding carcinoma poses difficulties
colonoscopies are of importance in aging population.
Although a typical small and distal HPP without associated in screening for early CRCs by radiological imaging or even
dysplasia has little malignant potential, but individual with by different endoscopic techniques. Recent significant
hyperplastic polyposis syndrome (HPS) has an increased advances in endoscopic resolution and the development of
potential for progression to CRC. The HPS presents with improved diagnostic techniques and modalities might play
extensive phenotypic heterogeneity not only with respect an important role in the early management of such lesions.
to the number and size of polyps, but also with regard to
presence of CRC, polyp histology, sex ratios, age of onset,
and the presence of a family history of CRC. Hyperplastic PATHOPHYSIOLOGY OF
polyps are only part of the spectrum of polyps known as COLORECTAL CARCINOMA
serrated adenomas (SAs). SAs are a heterogeneous group
of lesions having distinct morphologic, histologic and Colorectal carcinoma is caused by interplay between the
molecular genetic characteristics that can potentially environmental factors and host with accumulation of
undergo malignant transformation to CRC through the gene alterations (acquired or inherited), such as activation
serrated polyp pathway. Sessile SAs usually presents as of oncogenes and inactivation of suppressor genes, and
a large usually greater than 1 cm sessile polyp that lacks generally involves an adenomacarcinoma sequence.
conventional dysplasia. Traditional serrated adenoma (TSA) Carcinogenesis progresses with multifactor, multi-hit and
is a rare type of colorectal polyp that has the cytologic features multistage mechanisms. In addition to nutritional aspects,
of an adenoma and the architectural features that of a HPP. other environmental factors include physical exercise,
The serrated polyp pathway may contribute to metachronous energy intake, obesity and parity. Environmental factors
or missed carcinomas for the reason being serrated lesions are modifiable risk factors that are thought to contribute
substantially to the variation in incidence. Improved success The MSI is usually associated with absence of expression of
in the management of CRC requires a better understanding one or more of the MMR proteins like MSH2, MLH1, MSH6
of its development and biological behavior. The key for this is and PMS2. About 15% of CRCs are characterized by genomic
molecular genetics, which is explored in more detail below. MSI arising as a consequence of loss of MMR activity. The MSI
cancers are characterized by the changes in repeating units of
DNA that normally occur throughout the genome known as
MOLECULAR BIOLOGY: IS IT DIFFERENT DNA microsatellites. Nearly 80% of carcinomas harboring MSI
are sporadic with hypermethylation of the promoter region of
IN ASIANS? the MMR gene MLH1. The remainder occurs as part of the
Our level of understanding of the molecular events underlying HNPCC. Tumors with MSI tend to arise in the proximal colon
CRC is far greater than for other common solid tumors. CRC and have a slightly better prognosis than tumors without MSI.
is used as a model for investigating the molecular genetics In carcinogenesis epigenetic silencing of genes is
of carcinoma development and progression; this is in part considered as an important mechanism for inactivation of
due to the stepwise progression of mutations facilitates the tumor suppressor genes. In CRC epigenetic changes comprise
histological transition from normal mucosa to adenoma chromatin modifications, aberrant DNA methylation and
to carcinoma. It arises as a consequence of genomic expression of noncoding RNAs, especially microRNA (miRs).
instability with an accumulation of genetic errors resulting DNA methylation and histone modification are involved in the
in dysregulation of molecular pathways controlling cell maintenance of gene silencing that cause carcinogenesis. The
migration, differentiation, apoptosis and proliferation. CRCs DNA methylation of cancer-related gene promoters usually
result from a variable combination of inactivation of the starts early in the process of carcinogenesis that affect various
tumor suppressor genes adenomatous polyposis coli (APC), types of CRC to differing degrees. Histone modifications play
p53, transforming growth factor beta (TGF-), activation of a pivotal role in the process of gene silencing in CRC as it
oncogene pathways including K-ras, and activation of the, impinges on chromatin structure and gene expression. The
cyclooxygenase (COX)-2, epidermal growth factor receptor DNA hypermethylation also leads to inappropriate expression
and vascular endothelial growth factor (VEGF) pathways. and down-regulation of certain miRs which act like tumor
These changes are similar whether they occur in inherited suppressor genes. MicroRNAs are a class of noncoding small
disorders like APC and hereditary nonpolyposis colorectal RNAs with critical regulatory functions as post-transcriptional
cancer (HNPCC) or acquired cancer in the elderly. In regulators. The miRs regulate tumor progression and invasion
addition to chromosomal instability (CIN) and microsatellite via direct interaction with target messenger RNAs (mRNAs).
instability (MSI), a third pathway, epigenetic instability has Colorectal carcinoma is associated with the under expression
been implicated in progression to CRC. of miR143. Expression of miRs in CRC cells had different
Chromosomal instability is the most common pathway effects and the miRs interact with different mRNAs. miR28-
by which CRC develops and is present in 6570% of cancers. 5p and miR28-3p are transcribed from the same RNA hairpin
Main genomic alterations in CIN cancers include alterations and are downregulated in CRC cells. Overexpression of each
in chromosome number (aneuploidy), loss of portions of has different effects on CRC cell proliferation and migration.
chromosome 5q, 18q and 17p, and mutation of the K-ras Recently, the p53 tumor suppressor and K-ras has identified
oncogene. The losses are associated with instability at as targets of miRs. Both proteins are known targets for at least
the molecular and chromosomal level. The commonly two miRs species (p53: miR125a/b and K-ras: miRlet7a/143).
involved genes in chromosome losses are APC (5q), DCC/ Many tumor suppressor genes contain CpG islands in
MADH2/MADH4 (18q) and TP53 (17p), and chromosome. their promoters. CpG island DNA methylation and aberrant
Inactivation of the tumor suppressor gene, APC is an early methylation of genes drive the initiation and progression
initiating event. Activating mutations in of the K-ras oncogene of CRC. CpG island methylator phenotype (CIMP) refers
follow. Additional mutations including mutations in TGF- to a subset of CRC that occur through the epigenetic
and p53 drive subsequent malignant transformation. The instability pathway and that are characterized by widespread
temporal acquisition of these genetic changes is matched by hypermethylation of promoter CpG island loci, resulting in
the progression from normal colonic epithelium to adenoma the inactivation of several tumor suppressor genes or tumor-
formation and subsequently CRC. related genes. Among the common targets for aberrant DNA
The MSI cancers occur as a result of defects in the DNA methylation is the p16 gene. The p16 is a gene, which seems
mismatch repair (MMR) system and having mostly intact to play a major role in colorectal carcinogenesis. It is a tumor
chromosome component. This phenomenon may occur due suppressor gene, which is also known as MTS1, INK4a or
to germline or somatic mutations or epigenetic alterations. CDKN2A. Inactivation of the p16 gene is recognized as the
second most common molecular defect in human carcinoma metastasis-associated miRs like miR21, 135a, 335, 206 and
preferentially through de novo methylation of its 5-promoter- let7a expression levels in primary CRCs significantly correlates
associated CpG islands. The percentage of hypermethylation with the presence of metastatic disease. The circulating miRs
of the p16 gene ranged from 29 to 42% in Asian population. have potential as novel noninvasive biomarkers for carcinoma
Colorectal carcinomas can be classified by global genomic and other disease processes. Serum miR29a hold substantial
or epigenomic aberrations including CIN, MSI, and CIMP. potential as a novel noninvasive biomarker for early detection
Classification based on CIN has many problems because the of CRC with liver metastases.
methods or markers and criteria currently used for analysis of The identification of important CRC-related genes may
CIN are not uniform. The MSI and CIMP are relatively well- help facilitate the early diagnosis, prevention, and treatment
defined when compared with CIN; CRCs are usually classified of CRC. Genetic and epigenetic characteristics of the tumors
into four molecular subtypes on the basis of both CIMP and help to predict the prognosis of the disease and also select the
MSI statuses: CIMP+/MSI+, CIMP+/MSI, CIMP/MSI+ and best treatment, which extends the disease-free and overall
CIMP/MSI. There are differences between Western (United survival of the patient.
States and European Union) and Eastern (Korea and China)
populations in the number of CRC that are MSI+, and in the
number of MSI+ CRC that are CIMP+. The four molecular INHERITED SUSCEPTIBILITY TO
subtypes of CRC that are defined by their CIMP and MSI statuses
COLORECTAL CARCINOMA
are characterized by their own distinct clinicopathologic and
molecular features and precursor lesions. In particular, the About one-fourth of CRC cases are associated with a
clinicopathologic features of MSI+ CRC differ depending on family history of carcinoma. Up to 10% of CRC cases have
the CIMP status. Further understanding of the heterogeneity a true inherited susceptibility to CRC and these cases are
in CRC molecular pathways may help explain the diverse subdivided according to the presence or absence of colonic
morphologic features of CRC. The prevalence of MSI+ in polyps as a major disease manifestation. Those diseases
CRCs in Western populations is approximately 15% but tends having polyposis include familial adenomatous polyposis
to be lower in Korean populations. For CRCs in Western (FAP), MutY-homolog (MYH)-associated polyposis (MAP)
populations, approximately two-thirds of sporadic MSI+ CRCs and the hamartomatous polyposis syndromes including
are CIMP+. In contrast, approximately one-third of MSI+ CRCs Peutz-Jeghers syndrome and juvenile polyposis syndrome
are CIMP+ in CRCs in Korean populations. Environmental or (JPS). These conditions are all associated with a high risk of
ethnic differences between Eastern and Western populations developing CRC. Familial adenomatous polyposis and HNPCC
may account for this discrepancy. are dominantly inherited conditions with 100% and 80% life-
Colorectal cancer metastasis occurs in various organs, time risk of developing colorectal cancer, respectively. These
most frequently in liver. The liver metastases from many hereditary syndromes that predispose to CRC genesis have
cases of CRCs acquire genetic aberrations that are not present significantly contributed to our understanding of the genetic
in primary CRCs. These genetic alterations acquired by mechanisms underlying CRC formation. Occurrences of
metastatic tumors may be associated with either metastatic CRCs at younger age are one of the major clinical hallmarks of
process and/or adaption of metastatic cells to the liver this inherited susceptibility. The hereditary syndromes add a
microenvironment. The acquisition of metastatic aberrations wide range of risk, modes of inheritance, age at presentation,
predominantly consist of an increased frequency of genetic extracolonic manifestations, endoscopic appearances, and
alterations of chromosomes which are associated with histological findings. Inherited susceptibility should be
metastatic CRCs, including 1p, 7p, 8q, 13q, 17p, 18q and 20q suspected when CRCs occur in younger age, cases presenting
and acquisition of new chromosomal abnormalities like loss with synchronous or metachronous CRCs or adenomatous
of chromosomes 4 and 10q and gain of chromosomes 5p and polyps, or with a strong family history of CRC. The mutations
6p. In Taiwanese CRC patients UDP-glucuronosyltransferase in DNA MMR genes are most common and well-known
1A1 (UGT1A1): carriage of the variant-211 UGT1A1 allele, and predisposing factor for CRC that cause HNPCC or Lynch
also UGT1A7*3 allele represent a risk factor for development syndrome. The mutations in the base-excision repair (BER)
of metastases and also the determinant for metastases. gene MYH, and FAP which are due to mutations in the APC
The miRs are potential clinically useful prognostic tool as gene predispose to CRC in other hereditary syndromes.
Familial Adenomatous Polyposis: AFAP-related gene and encodes an enzyme DNA glycosylase,
MYH glycosylase, involved in oxidative DNA damage BER.
Classic and Attenuated The MYH gene is located on the chromosome 1p. Mutations
Familial adenomatous polyposis is one of the well- in this gene result in heritable predisposition to colon and
established and clearly understood of the all inherited stomach carcinoma. The MYH mutations are seen in 1020%
colon cancer syndromes. Majority of FAP cases are due to of classical FAP cases without an APC mutation and in 30% of
germline mutations of the APC gene on chromosome 5q21. AFAP cases. Polyps due to mutated MYH do not appear until
FAP is characterized by more than 100 adenomatous polyps adulthood and are less numerous than those found in patients
in the colorectum that usually appear during adolescence with APC gene mutations. MAP has broad range of clinical
or the third decade of life. It is associated with extracolonic presentations as the MYH genes has the ability to cause
manifestations in 70% of the cases that include congenital disease in its homozygous or compound heterozygous forms.
hypertrophy of the retinal pigment epithelium (CHRPE), The incidence of extracolonic cancers is significantly increased
which includes ovary, bladder, skin and breast cancers.
upper GI tumors, desmoid tumors, papillary carcinoma of
the thyroid, medulloblastoma, hepatoblastoma and soft
tissue tumors. This syndrome inevitably leads to CRC when Hamartomatous Polyposis Syndromes
left untreated and it is estimated that 1% of all CRC cases
are due to it. The risk of cancer is generally related to polyp PeutzJeghers syndrome is an autosomal dominant disorder
number. The risk of CRC development can be significantly characterized by the presence of hamartomatous polyps in
reduced when patients enter a screening-treatment program. the small intestine, together with dark-blue or dark-brown
freckling, especially around the mouth and on the lips, fingers,
Annual colonoscopy is indicated in individuals at risk of
or toes. Freckles generally appear in childhood and may fade
FAP from adolescence, followed by prophylactic colectomy
with age. There is a significantly higher risk of carcinoma
or proctocolectomy to eliminate the risk of subsequent
progression from the small intestinal polyps as well as breast
development of CRC only in those proven to have FAP.
cancer, CRC, and other types of cancer. The syndrome is
Attenuated FAP (AFAP) is a less severe phenotypic variant of
caused by germline mutations in the STK11 (LKB1) and
FAP characterized by an average 69% lifetime risk of CRC and
possibly other genes.
the presence of less than 100 polyps and a later onset of CRC.
Juvenile polyposis syndrome is another autosomal
AFAP is caused by autosomal-dominant inherited mutations
dominant disorder in which affected individuals are
in the APC gene which controls turnover of -catenin in the
predisposed to hamartomatous polyps occurring most
Wnt pathway. New or de novo APC mutations are responsible
commonly in stomach and colorectum. While the majority of
for approximately 25% of FAP cases. In 85% of classical
the polyps found in JPS are non-neoplastic, hamartomatous,
FAP families and in 2030% of AFAP cases, a germline APC self-limiting and benign, there is an increased risk of
mutation identified. The dense carpeting of colonic polyps adenocarcinoma progression to GI carcinoma occurs in
in classic FAP is associated with APC mutations that occur variable numbers (968%) of juvenile polyposis cases. Cases
between codons 169 and 1393. The sparse polyps are features with JPS are at an increased risk for developing specific types
of AFAP cases with mutations occur at the extreme ends of of cancer, including CRC, gastric, esophageal and pancreatic
the APC gene or in exon 9. APC mutations occurring between carcinoma. Germline mutations responsible for JPS have
codons 1445 and 1578 in Gardner syndrome characterized by been identified in the SMAD4 (DPC4), BMPR1A and PTEN
FAP with epidermoid cysts, osteomas, dental anomalies, and/ genes. There is a condition related to JPS that is also caused
or desmoid tumors. by alterations in the SMAD4 gene. This condition is known
as combined juvenile polyposis/hereditary hemorrhagic
telangiectasia syndrome (combined JPS/HHT syndrome). It
MutY-homolog-associated Polyposis is estimated that 1522% of people with a genetic alteration in
MutY-homolog-associated polyposis is an autosomal SMAD4 may have combined JPS/HHT syndrome. Mutations
recessive inherited polyposis syndrome. The MYH gene was in PTEN also account for Cowdens syndrome, which carries
first identified in 2002 in three siblings with multiple colonic an increased risk of early-onset breast cancer, thyroid cancer,
adenomas and CRC but no APC mutation. It is the second ovarian cancer and hamartomatous lesions of the skin.
Hereditary Nonpolyposis Colorectal MOLECULAR GENETICS OF SPORADIC

Carcinoma/Lynch Syndrome COLORECTAL CARCINOMA
Hereditary nonpolyposis colorectal carcinoma is an Among the various causes of CRC, approximately 75% can be
autosomal-dominant disease with a 6882% lifetime risk attributed to sporadic disease, in which there is no apparent
of CRC caused by germline to MSI, also known as MSI-H, family history. The multicentric genome-wide association
which is a hallmark of this condition. It accounts for 5% of studies (GWAS) identified the complex genetic architecture
all cases of CRC and it is characterized by younger age of of the sporadic CRC cases. High penetrance mutations in a
onset, excess synchronous and metachronous CRCs, right- small group of genes have been identified as the causal agent
sided predominance and extracolonic cancers, including of CRC in high risk families. APC-I1307K, HRAS1-VNTR and
endometrium, ovary, pancreas, stomach, small intestine, MTHFR variants represent the low penetrance susceptibility
hepatobiliary tract, upper urinary tract, brain and skin. alleles. Implies that they have considerable impact on CRC
HNPCC can be divided into Lynch syndrome I (familial incidence even though genotypic risks are modest. The
colon cancer) and Lynch syndrome II (HNPCC associated GWAS of CRC have identified rs6983267 and trs10505477
with other cancers of the GI tract or reproductive system. polymorphisms as key loci in the 8q24 region to be associated
The variations in the MMR genes, including MLH1, MSH2, with CRC. The rs6983267 G more than T polymorphism is a
MSH6, and PMS2 genes on chromosome 2 increase the risk of risk factor for CRC in Asians, Europeans and Americans with
developing HNPCC. Mutations of the EPCAM gene that result European ancestry. The NOD1/CARD4 and NOD2/CARD15
in hypermethylation and silencing of MSH2 is also seen in gene polymorphisms are also associated with altered risk of
HNPCC cases. The Amsterdam criteria and revised Bethesda CRC. NOD1/CARD4 and NOD2/CARD15 are members of
guidelines are used in clinical practice to identify individuals nod-like receptor family and located in cytosol that binds
at risk for HNPCC who require further evaluation. bacterial and viral ligands.
MuirTorre syndrome (MTS), a rare variant of HNPCC The somatic mutations spectrum that contributes to the
in which the features of HNPCC are present along with CRC pathogenesis is far more extensive. Each tumor has a
multiple cutaneous tumors including sebaceous adenomas, distinct mutational gene signature. A tumor can accumulate
sebaceous carcinomas and keratoacanthomas. The clinical an average of approximately 90 mutant genes. Sixty-nine
variability is common; however, skin lesions and CRC define genes are considered to be relevant to the CRC pathogenesis,
the phenotype. Like HNPCC, cases with MTS linked to and each CRC can harbor an average of nine mutant genes
mutations in either MSH2 or MLH1 gene. per tumor. Mutations in APC are seen in 7080% of sporadic
tumors, and often occur early in the development of CRC.
Familial Colorectal Carcinoma Other tumor suppressor genes involved in CRC include p53,
which is mutated in 75% of sporadic tumors and deleted in
Familial CRC is an autosomal dominant disease which colorectal cancer (DCC), which is mutated in 70% of CRCs.
accounts for up to 25% of cases. Affected patients have a The K-ras oncogene is mutated in 50% of all sporadic CRCs. In
family history of CRC, but the pattern is not consistent with around 15% of sporadic CRCs, MMR genes are inactivated. In
one of the inherited syndromes described above. Individuals most cases of the CRCs mutations occur in the Wnt/-catenin
from these families are at increased risk of developing pathway and these mutations lead to increased nuclear
CRC, although the risk is not as high as with the inherited accumulation of the transcriptional coactivator, -catenin
syndromes. About 710% of cases have a first-degree relative and it associates with T-cell factor/lymphoid enhancer
with CRC and about twice that many have either a first- factor (TCF/LEF) sequence-specific transcription factors in
degree or a second-degree relative with CRC. It increases the nucleus to activate target gene expression by recruiting
the risk of developing CRC 1.7-fold over that of the general multiprotein complexes that remodel or modify chromatin
population. The genetic abnormalities underlying familial into a transcriptionally permissive state. The -catenin/TCF4
CRC remain incompletely understood. A subset of families complexes directly associate with the Yes-associated protein
with MSI-negative familial colorectal tumor found to link (YAP) gene locus and that -catenin is required for YAP
to chromosome 9q22.2-31.2. Other three potential loci in expression in CRC cells. The Hippo pathway also contributes
familial CRC families linked to chromosomes 11, 14 and 22. to colorectal carcinogenesis. This pathway restricts cellular
growth by preventing nuclear accumulation of the YAP Table 1: List of risk factors for colorectal carcinoma in Asia
transcriptional coactivator. YAP expression is elevated in
Lifestyle
CRCs similar to Wnt/-catenin signaling. The Wnt/-catenin
and Hippo/YAP signaling pathways converge to promote Alcohol and smoking
CRC. Physical inactivity
The genetic pathway of colorectal carcinogenesis parallels Obesity
with histological transition from adenoma to carcinoma. Dietary factors
Although most of the CRCs develop through the adenoma- High fatty diet
carcinoma sequence with APC, K-ras, DCC and p53 mutations,
Low dietary fiber and starch
an admixed HPP or serrated adenoma have been linked to a
distinct serrated polyp pathway of colorectal carcinogenesis Red and processed meat
which is characterized by MSI and deficiency in DNA MMR. Low intake of vegetables and fruits
HPPs associated with alterations in the components of the Low intake of micronutrients
mitogen-activated protein kinase signaling pathway, notably Soy and phytoestrogens
the oncogenes K-ras and BRAF. The HPPs associated CRC Reproductive factor
are also linked to MLH1 protein, MSI and MLH1 promoter
Late age at first child birth
methylation. A high proportion of SAs and TSAs have BRAF
mutations and DNA methylation. Early menarche
In the case of CRC that results after radiation exposure Late menopause
may influence MSI status through MSI-related epigenetic Menstrual regularity
and genetic changes, which may occur in the early stage of Number of abortion(s)
colorectal carcinogenesis. Infectious disease
The mechanism whereby lifestyle and other factors may
Schistosomiasis
interact with the expression of the above molecular pathways
Helicobacter pylori
is explored in detail below.
Other specific diseases
Inflammatory bowel disease
RISK FACTORS Ulcerative colitis
Crohns disease
The risk of developing CRC is influenced by both our lifestyle
Diabetes mellitus
and the environment where we live in apart from our genetic
makeup. The GI tract is influenced by diets, alcohol and GI
microecology. The microbiome forms an integral part of the alcoholic beverages are causally related to CRC. The inactive
human organism. External force that impacts human health form of aldehyde dehydrogenase-2 (ALDH2), encoded by
and diseases. Other external factors, including sedentary life the gene ALDH2*1/2*2, which is prevalent in Asians, exposes
and tobacco consumption have also impact on the diseases of them to higher levels of acetaldehyde after drinking and
GI tract. The list of risk factors for CRC in Asia is summarized is an important risk factor for CRC. Alcohol consumption
in Table 1. combined with a diet low in methionine and folate has strong
impact on colorectal carcinogenesis through antagonism of
Lifestyle methyl group metabolism.
Smoking is a well-known cause of lung carcinoma, but
With rapid modernization, lifestyle changes have been some of the carcinoma-causing substances are swallowed
blamed for an increased incidence of CRC. Physical inactivity, and can cause CRC. Long-term smokers are more likely than
smoking and alcohol intake have been associated with nonsmokers to develop CRC. An increased risk of CRC among
development of CRC. smokers related to the number of cigarette consumption and
age at the starting of smoking. Both men and women are
equally affected. Current smokers have a higher risk than
Alcohol and Smoking ex-smokers. In comparison to the nonsmokers, smokers
Alcohol itself is not carcinogenic. However, its first metabolite have 1.52.5 times increased risk of CRCs. Smoking interacts
(acetaldehyde) has been shown to be a potent carcinogen in with alcohol consumption in an additive fashion in affecting
humans. High alcohol consumption increased the risk of CRC the risk of CRC. Approximately 50% of the CRC cases can be
by up to 60%. Epidemiological study has demonstrated that prevented by tobacco and alcohol control.
Physical Inactivity advanced colorectal adenoma. An elevated body mass index

(BMI) has been associated with both the development of
There is an inverse relationship between physical activity colonic adenomas and CRC in Japan, Korea, and China.
and risk of CRC. When those in the highest and lowest Visceral adiposity is a stronger risk factor for development of
categories of physical activity are compared, a reduction in CRC compared with BMI alone with an elevated risk of CRC in
the risk of CRC of up to 60% has been observed. High levels patients with higher waist-to-hip ratios. It is unclear whether
of physical activity have been associated with a lower risk of interventions to reduce weight could have an impact on the
colon carcinoma, but not rectal carcinoma in Western world development of CRC.
as well as in some Asian countries. A number of potential
mechanisms whereby physical activity could reduce the risk
of CRC have been described. Increase in GI transit time (with Dietary Factors
increased exposure of colorectal mucosa to fecal carcinogens), It is widely believed that environmental factors, particularly
altered immune function, increased prostaglandin levels dietary patterns, account for most of this marked variation in
and alterations in GI and pancreatic hormone profiles have
incidence rate of CRC. Differences in dietary habits have been
all been proposed to play a role. High levels of insulin and
implicated in the risk of developing CRC. Dietary factors are
insulin-like growth factor-1 (IGF-1) are associated with low
clearly linked to the development of CRC, and the increase
exercise levels. High levels of IGF-1 increase the risk of CRC.
in mortality from CRC over the last few decades in Asia has
Conversely, elevated levels of IGF-binding protein-3, which
been attributed to westernization of the diet. Diet influences
is associated with reduced levels of IGF-1, are associated
colonic microecology. High fruit and low meat containing
with a lower risk of CRC. It is interesting to note that genetic
diets have a protective effect by modulating the composition
mutations associated with development of CRC have been
of the normal nonpathogenic commensal microbiota,
linked to levels of physical activity. Mutations in both K-ras
thereby reducing the incidence of colorectal adenomas and
and p53 have been associated with reduced levels of physical
ultimately CRC.
activity. Colonic adenomas that develop in patients with
low levels of physical activity are also more likely to harbor
mutations in K-ras compared with individuals with higher High Fatty Diet
levels of physical activity.
Diet high in fat content leads to an excess of bile acid secretion
into the GI tract and is associated with CRC. The incidence
Obesity of CRC is related to the concentration of deoxycholic (DOC)
Obesity is one of the known strongest risk factors of CRC. The acid and secondary bile acids in the intestine. Bile acid
metabolic burden induced by excess adiposity accelerates can be transformed into carcinogenic compound known
uncontrolled cell growth and survival leading to increased as methylcholanthrene by enzyme. Bile acid promotes
risk of CRC genesis. Obesity raises the risk of CRC in both men synthesis of pentane in feces through bacteria. Toxic bile
and women, but the link seems to be stronger in men. Obesity acids accumulation induces oxidative damage and colorectal
causes metabolic stresses, including excessive reactive carcinogenesis, thereby some dietary antioxidants may
oxygen species production, increased gut permeability, ameliorate this carcinogenicity. High levels of serum high-
hyperinsulinemia and the elevated adipokine secretion. density lipoproteins are associated with a low risk of CRC.
The effect of hyperinsulinemia may be mediated by the IGF Long-chain -3 polyunsaturated fatty acids (PUFAs) and
system. Hyperinsulinemia is associated with elevated levels conjugated linoleic acid (CLA) have potential protective role
of IGF-1 which has itself been associated with an increased against CRC, whereas -6 PUFAs may promote carcinogenesis
risk of CRC. Obesity is associated with increased serum mediated in part through prostaglandin E2 (PGE2) production.
leptin levels and inversely associated with adiponectin
levels. Alterations in levels of these adipocytokines have
effects on cell proliferation, angiogenesis and promotion of
Red and Processed Meat
tumorigenesis in in vitro studies that could contribute to the A diet high in red and processed meats can increase risk
development of colorectal neoplasia in obese individuals. of CRC. Cooking meat at very high temperatures creates
A substantial increase in obesity among Asian populations chemicals that might increase cancer risk. The processed
has been associated with an increase in metabolic syndrome meat is associated with an increased risk of distal colon
and various GI carcinomas. In Korean patients with metabolic cancer. On the other hand, the intake of fish/-3 PUFAs
syndrome has an increased risk for proximal, multiple, and has long been considered as a factor decreasing the risk of
CRC. The heme content of red meat increases fecal levels of important molecular event leading to CRC. Supplementation
N-nitroso compounds. N-nitroso compounds are potentially of folate, methionine, riboflavin and vitamin B6 may prevent
carcinogenic and processed meat has also been found to aberrant DNA methylation, thereby prevent CRC.
contain N-nitroso compounds. Some classes of N-nitroso
compounds have alkylating agent properties and have been
demonstrated to induce GC to AT transitions at the second Soy and Phytoestrogens
base of codon 12 or 13 in K-ras gene. Red meats and haem Certain phytochemicals found in plant foods are known to
supplementation have also been associated with increased exert anticarcinogenic effects. Phytoestrogens, including
levels of DNA adducts within colonocytes. DNA adducts are isoflavones and lignin are associated with a significant
highly reactive agents that react with nucleophilic centers in reduction in colorectal adenoma and CRC. Phytoestrogens
DNA bases and have been recognized as playing a central role have molecular similarities to endogenous estrogens, which
in carcinogenesis. interact with estrogen receptors ER and ER. Both genomic
and nongenomic influences play role in anticarcinogenic
Low Dietary Fibers and Resistant Starch properties of phytoestrogens, including induction of apoptosis
and inhibition of tyrosine kinases and DNA topoisomerases.
The resistant starch (RS), non-starch polysaccharides (NSP) Far Eastern countries have lower incidence of CRC which in
and carotenoids are thought to be important protective part is attributable to high intake of soy products in their diet.
factors with a strong inverse relationship between RS
consumption and CRC incidence. RS and NSP reduces the
adverse effect of dietary fats and fecal bile acids by their Reproductive Factors
marked effect on composition and metabolic activity of large
Certain reproductive factors like early menarche, late age at
intestinal microflora, which affect gene expression and DNA
first childbirth, short duration of lifetime lactation and late
repair through excessive butyrate production. RS increases
menopause are associated with breast carcinoma and CRC.
fecal bulk as well as physically dilutes fecal contents by water
The exogenous female hormones use [i.e. oral contraceptive
absorption, reduces transit time thereby decreases exposure
and postmenopausal hormone (PMH)] reduces the mortality
of the colonic mucosa to carcinogens, reduces colonic pH
rates of CRC in women in many developed countries. Estrogen
which decreases conversion of primary bile salts to secondary
have protective effect against MSI carcinomas through
bile salts, increases short-chain fatty acids including butyrate,
acetate and propionate, decreases protein fermentation its effect on selected molecular targets. Postmenopausal
products like phenolic compounds, amines, ammonia, hormone therapy may reduce CRC risk through mechanisms
N-nitroso compounds and indoles; and reduces bile salts in beyond K-ras mutation status, but might provide greater
feces by binding bile acids and bile salts. benefits for K-ras mutation-negative than mutation-positive
tumors, at least in the distal colorectum.
Low Intake of Fruits and Vegetables

Drugs
Diets high in vegetables, fruits, and whole grains have been
associated with a reduced risk of CRC. Increased intake of The nonsteroidal anti-inflammatory drugs (NSAIDs), and
dry fruits, fruit juice and green leafy vegetables have been calcium have been associated with a lower risk of colorectal
associated with reduced risk of colonic adenoma and CRC adenomas and CRC. The NSAIDs act by inhibiting COX activity,
risk by altering the composition of colonic microflora. Both prostaglandin synthesis and the cascade of arachidonic acid
raw and green vegetables contain vitamins, dietary fibers and metabolites which are involved in cell transformation, tumor
phytochemicals which may exert anticancer effects. growth and metastasis. The NSAIDs like sulindac and the
selective COX-2 inhibitor, celecoxib significantly regresses
existing adenomas, whereas aspirin decreases CRCs that
Low Intake of Micronutrients overexpress COX-2 but not those with weak or absent COX-
Supplementation of micronutrients like calcium, vitamin 2 expression. The use of NSAIDs doubled during the past 2
D, folates, flavonoids, antioxidant vitamins (A, C and E) and decades in the USA and a similar trend occurring in many
selenium might have protective effect, whereas iron may Asian countries, which reduces risk of CRC in younger
potentiate risk of CRC. Aberrant DNA methylation is an populations.
Other Specific Diseases the risk of CRC in the younger population is decreasing, while
the prevalence of rhinitis, rhinoconjunctivitis and eczema
Chronic inflammation plays a role in the progression to increased significantly among school children.
cancer. The risk of CRC is increased in inflammatory bowel
diseases (IBDs) ulcerative colitis (UC) and Crohns disease
(CD). However, much more is known about the risk in UC. Environmental Carcinogens
The risk of CRC in UC depends upon the duration and extent Industrial workers who are in contact for many years with
of disease. The risk of CRC for cases with IBD increases by inorganic dust coming from plastic substances and fuel oil
0.51% yearly approximately 810 years after diagnosis. While could have a greater risk of developing CRC. Sometimes, a
cases with UC lesions extending to the hepatic flexure or seafood product (e.g. shellfish) accumulates diarrheic shellfish
more proximally (pancolitis) have the greatest risk of CRC, poisoning toxins (i.e. okadaic acid and its derivatives), which
whereas the disease limited only to rectum have lowest risk. are tumor promoters that could increase CRC risk.
The UC-associated colorectal carcinomas (UCACRCs) are
the most common in the rectum and sigmoid colon and the
CRC associated with CD is evenly distributed between the Infectious Disease
right colon and rectosigmoid. The carcinogenesis pathway in
Schistosomiasis is associated with bladder cancer and CRC.
colitis-associated colorectal cancer is less clearly understood
Schistosoma japonicum is particularly associated with CRC.
than its sporadic counterpart. The flat dysplasia-associated
The schistosomal colitis is commonly associated with earlier
lesion or mass (DALM) is considered to be the precursor
onset of CRC that presents at an advanced stage. Helicobacter
lesion for UCACRCs. Therefore, it is of utmost importance
pylori infection is also associated with modest increase in the
to identify DALM and NP-CRN to reduce the morbidity and
risk of colorectal adenoma and CRC.
mortality from UCACRCs. Genetically, UCACRCs appear
to be characterized by early TP53 mutations, together with
much lower frequencies of APC and K-ras mutations than in Gut Microbiota and Colorectal Cancer
sporadic CRCs. Epigenetic changes, such as DNA methylation
and histone modification are thought to play an increasingly One of the important factors associated with CRC is the
important role in the development of CARCs. Clonal expansion human gut microbiota. The composition of the luminal
of procarcinogenic mutations can lead to large fields of microbiota and mucosa-adherent microbiota are different in
mutant tissue from which CARCs can arise, this phenomenon CRC cases. The luminal microflora potentially influences CRC
is called field concretization. In contrast to Western countries, risk through cometabolism or metabolic exchange with their
the incidence of CRC among cases with UC is low in Asian host. However, mucosa-associated microbiota potentially
countries. However, the prevalence of UC has been increasing affects CRC risk primarily through direct interaction
in Japan in the last few decades, although it is still lower than with the host. Microbial dysbiosis leads to induced-
Western countries. The incidences in Japan, Korea, Taiwan as procarcinogenic pathways by converting procarcinogenic
well as other Asian countries are increasing. Recently, KASID dietary substances to carcinogens. Increase of opportunistic
study revealed that the cumulative incidence of UCACRCs in pathogens and reduction of butyrate producers constitute
Korea is comparable to that of Western countries. CRC in IBD a major compositional imbalance of gut microbiota in CRC
patients is frequently diagnosed at an advanced stage, a factor cases. Such variations may allow for future utilization of the
that contributes to poor prognosis. The risk of UCACRCs fecal flora as markers for screening and diagnosis of CRC.
has decreased over time which might be due to intensive Probiotics are of potential importance in CRC prevention as
chemoprevention and surveillance colonoscopy. the microbial metabolic activities might have effects on the
Increasing evidence suggests that a history of type 2 CRC prevention by scavenging toxic substances or preventing
diabetes mellitus (T2DM) is an independent risk factor for their generation in vivo.
CRC in both women and men, and insulin therapy for diabetes
may increase this risk. Women with T2DM had higher rates
of colorectal adenomas. This finding adds to the evidence CLINICAL FEATURES AND DIAGNOSIS
that T2DM is an important factor in the progression of
adenoma-carcinoma sequence. Cigarette smoking appeared Colorectal carcinoma can present in a variety of ways and
to positively modify DM-associated CRC risk. with any of several symptoms. The alarm features like
Allergic disorders, including asthma, hay fever and eczema rectal bleeding, altered bowel habits, microcytic anemia,
is inversely associated with incidental CRC. In Hong Kong, or palpable right-sided abdominal mass or rectal mass are
usually considered important for CRC diagnosis and are to ensure optimal control of disease during an attempt to
used to prioritize access to urgent investigation. The rectal minimize their toxicity. Majority of CRC cases ultimately
bleeding and altered bowel habit toward increased softness die of their disease in spite of the significant advances in
or increased stool frequency are considered as major therapeutic approaches to CRC.
single predictors of cancer. Some cases manifest as surgical
emergencies like bowel obstruction or perforation. On the
other hand asymptomatic CRCs cases are usually detected by Preventive Measures
a screening procedure and they have a better Dukes staging. In last few decades two to four times increase in the incidence
Colorectal carcinomas occur with different frequencies at of CRC have been observed in many Asian countries like
different sites because of developmental and physiological China, Japan, South Korea and Singapore. This rising trend
differences that exist between anatomic segments of the of CRC incidence and mortality is significantly more in
colorectum. The differences in presentation of colonic and affluent societies and differs among different ethnic groups.
rectal carcinomas affect their outcome. Colonic cancer Prevention is and will remain a major goal of medicine
presents later than rectal cancer. The proximal, distal and and gastroenterology, which are based on identifying a
synchronous CRCs are 35%, 59% and 6% in USA and 29%, 52% preneoplastic lesions and altering their outcome by the
and 19% in Asian population. introduction of early intervention. Colorectal screening with
Colorectal carcinoma is mainly a disease of adulthood but FOBT is at present a national policy in Asian countries like
children are not spared. It accounts for 2% of all malignancies Taiwan, Japan, and Korea. Sigmoidoscopy and colonoscopy
in children. Childhood CRCs are usually diagnosed at an are potentially effective screening modalities for diagnosing
advanced stage, with mucinous histology and tend to have a CRCs and neoplasms. The incidence and mortality of CRC in
poorer outcome. Asian populations have been rising due to alterations in their
The CRCs are diagnosed at any stage, from a surgical lifestyle and therefore acceptable and efficient screening
emergency, symptomatic carcinoma or to an asymptomatic programs is an important issue in the prevention of this widely
carcinoma detected by screening. Colonoscopy is the most prevalent neoplastic disease. The implementation of primary
effective in the diagnosis of CRC. A colonoscopy database and secondary prevention, chemoprevention and screening
review of 10,603 Chinese patients revealed that 181 of Chinese programs are of paramount importance for reduction of CRC
patients with CRC presented without features indicative of incidence and mortality. Surveillance programs as tertiary
tumor formation. The overall prevalence of CRC was 3%. The prevention are widely accepted as an integral part of the
phenomenon of its diagnostic delay often occurs. However, treatment plan provided to patients after surgical treatment
the delay is not a major cause for its advanced stage and a of CRC. The number of CRC cases in men and women are
poor outcome. Its inherent biological characteristics may be increasing and probably it will surpass that of lung carcinoma
more important. Fluorine-18 (F) fluorodeoxyglucose (FDG) in future. There is need to prioritize primary and secondary
positron emission tomography/computed tomography prevention to control CRC in Asian populations.
(PET/CT) is a safe imaging method that can be used in the
determination of CRC recurrence in patients with elevated
carcinoembryonic antigen (CEA) levels. There is a compelling Screening
need for the identification of a panel of novel biomarkers Screening is an important armamentarium in modern day
for early diagnosis of CRC. An integrated proteomics and preventive medicine. The modalities of CRC screenings
metabolomics approach will promote the translation of varies worldwide and are influenced by the cost and
biomarkers with clinical value into routine clinical practice. diagnostic resources availability in that country. Screening
tests for CRC can be broadly divided according to two
distinctly different aims: cancer prevention versus early
MANAGEMENT detection of cancer. Screening methods for cancer
prevention target the precancerous stage before it becomes
In the era of personalized cancer therapy and prevention, malignant through detection and removal of precursor
adopting a multidisciplinary approach should be considered lesions. The preventive CRC screening success depends on
in order to broaden our knowledge of the complex compliance of the population of that region, minimal or low
etiopathogenesis of CRC, and to improve individualized adverse events and skill in detecting the lesions. Screening
preventive and therapeutic approaches. In regard to the tests for CRC fall under two categories: fecal-based tests
advancement in chemotherapeutic and chemopreventive including guaiac-based (gFOBT), immunochemical tests
agents, molecular and phenotyping of CRC is important (iFOBT) and stool DNA panel (sDNA); and endoscopic and
radiologic tests including flexible sigmoidoscopy, flexible accurate identification of family members likely to have the
colonoscopy, optical colonoscopy, double-contrast barium faulty gene, enabling the targeting of screening and preventive
enema (DCBE) and computed tomography colonography surgery only to those at risk. Clinicians should discuss about
(CTC, also called virtual colonoscopy). The recommended prenatal testing with patients in childbearing age for either
CRC screening methods are flexible sigmoidoscopy and opting conventional prenatal diagnosis like amniocentesis
colonoscopy, and FOBTs including gFOBT and iFOBT. or chorionic villous sampling, or for preimplantation genetic
DCBE and CTC are not a commonly used screening method. diagnosis. Identification of individuals with Lynch syndrome
Colonoscopy is considered to be the gold standard for allows for increased surveillance of the affected individual
CRC screening; however, it requires skilled and dedicated and of potentially affected family members. A high index
personnel, involves high cost and is inconvenient to the of suspicion is required to detect cases and families who
patient. Colonoscopy is less protective for right-sided potentially have Lynch syndrome. Preliminary screening
tumors, which are more likely to be flat or depressed and tests can identify individuals unlikely to be affected by Lynch
are more affected by an inadequate bowel preparation. syndrome, thereby, reducing the need for full gene analysis.
Imaging technologies, such as chromoendoscopy and The familial clustering of CRC is usually seen in younger
narrow band imaging have been developed to improve probands and carcinomas are located in the proximal colon.
delineation of suspicious lesions during colonoscopy. The Every attempt should be taken to promote public awareness
iFOBT and sDNA tests may offer less invasive screening and screening strategies in those families with a member
options for patients who decline colonoscopy. Confocal affected by CRC, especially those at younger age or with
laser endomicroscopy (CLE) provides real-time, high- proximal colonic involvement. To diminish the incidence
resolution imaging at a micron level through endoscopes. of CRC, screening colonoscopy to the spouses of CRC
CLE and related technologies are termed virtual biopsy patients might be advised as married couples share home
as their images simulate to that are seen in conventional environments and lifestyle for years. The risk of developing
histology. Immediate potential applications of CLE are to neoplasia leading to CRC is significantly increased in UC and
guide biopsy sampling in CRC surveillance and evaluation most likely in CD. Patients with UC should not be denied the
of colorectal polyps. In underdeveloped resource poor benefits of a cancer surveillance program. The risk of colonic
countries, FOBT is the first choice for CRC screening. cancer is higher in patients with total colitis type and when
CRC screening should be initiated at the age of 50 years. has had the disease for more than 10 years. The cumulative
The smaller polyps measuring 59 mm in size should be incidence rates over 10 years and 20 years are 5.1% and 17.5%,
removed endoscopically and in case of follow-up negative respectively. Most of them are flat type poorly-differentiated
colonoscopic examination, a repeat colonoscopy should be adenocarcinomas. Therefore, patients with total colitis
performed every 10 years. type for more than 10 years should undergo colonoscopic
The carcinoma associated antigen in blood or feces, DNA surveillance.
MSI for family members at-risk, molecular techniques for fecal In North America, Europe, and Australia as well as New
oncogene or antioncogene, telomerase activity and exfoliative Zealand, there is a CRC screening guidelines but these
cytology for tumor marker are utilized but none of them are in guidelines are lacking in most Asian countries except Japan,
use for mass screening. Although hypermethylated genes in Korea, Singapore, Hong Kong, and Taiwan. Healthcare is
fecal samples have been used as biomarkers for the CRC or self-financed in most of the Asian countries (e.g. Brunei,
adenomas detection, the hypermethylated gene panels are China, India, Indonesia, Malaysia, Philippines, Thailand
not accurate enough to be used as a single test for colorectal and Vietnam) and national healthcare systems and health
neoplasia screening. Altered miRs expression is found in CRC insurance cover only minority of the Asian population.
and their expression patterns may serve as useful cancer In addition healthcare facilities access is limited in rural
biomarkers. areas and for the people of low socioeconomic status. Asian
In affected persons and family members at-risk initially continent has very heterogeneous population; therefore, it
requires early recognition of hereditary colon cancer is desirable to calculate risk stratification for people at the
syndromes followed by integration of genetic testing and highest CRC risk by considering age, gender, race and family
clinical examinations for effective cancer prevention. FAP history for prioritizing a screening program. Risk stratification
is a potentially preventable cause of CRC; clinicians should strategy using colonoscopy and CT colonography is utilized
have an adequate knowledge of it to identify the disease and in the Western world and this might be very useful in best
to manage the patient and family. After the identification utilization of limited resources in many Asian countries. A
of an index patient, genetic testing in combination with two-tier approach may reduce the colonoscopy work load
the detection of extracolonic manifestations allows more without jeopardizing the efficacy of screening program.
Chemoprevention the dietary guidelines have shown no protective effect on

overall carcinoma risk. However, good dietary adherence is
Efforts to prevent CRC have targeted early detection through associated with a reduced cancer-specific mortality.
screening and chemoprevention. Chemoprevention is
an intentional chemical interference with the process of
carcinogenesis by protecting against initiation or by arresting Health Education
or reversing later stages of carcinogenesis at various steps In most Asian countries population-based CRC screening
in the processes of promotion and progression. Primary program compliance rates are still far from the desirable rates
prevention is achieved by using chemopreventive agents to because of poor public knowledge about CRC, including
prevent carcinoma in apparently healthy individuals. Aspirin people above 50 years of age who may benefit from CRC
and other NSAIDs and calcium have shown significant screening. Compliance for CRC screening program requires
reductions of CRC risk. Traditional NSAIDs, as well as the considerable effort on the part of the individuals. The factors
new COX-2 selective inhibitors, such as rofecoxib and influencing population participation is crucial prior to
celecoxib, have a role in the setting of primary and secondary designing and launching a population-based CRC screening
prevention, and adjuvant therapy of both sporadic CRC as high levels of screening uptake are necessary for the
and FAP. Chemoprevention is possible through inhibition success of screening program. These influencing factors can
inducible nitric oxide synthase (iNOS/NOS-2), as it plays be classified as modifiable factors like knowledge about CRC
an important role as mediator of inflammation involved and its screening, attitudes of patient and healthcare providers
in early carcinogenesis. Indole-3-carbinol is a constituent or structural barriers for screening; and non-modifiable
of cruciferous vegetables like cabbages, cauliflowers and factors like demographic factors, education, health insurance
broccoli, which might be a chemopreventive agent for or income. Modifiable factors are of great importance as they
colorectal carcinogenesis. are plausible targets for health educational interventions to
The use of probiotics, prebiotics or synbiotics has potential increase the general populations knowledge about CRC and
to impact significantly on the development, progression its screening before implementation of population-based
and treatment of CRC. Probiotics and prebiotics alter the CRC preventive programs. To improve participation in CRC
intestinal microecology by reducing the levels of pathogenic screening, appropriate strategies must be directed toward
microorganisms and increasing concentrations of beneficial vulnerable populations, such as those with low socioeconomic
bacteria such as Lactobacillus and Bifidobacterium, which status and those above 50 years of age. Education and training
induces reduction in intestinal inflammation, enhancing for healthcare providers, including family doctors could also
immune function and antitumorigenic activity, binding to be an effective strategy to promote CRC screening.
potential food toxins, and a decrease in bacterial enzymes
including -glucuronidase which hydrolyze precarcinogenic
compounds. TREATMENT
It is beyond the scope of this chapter to discuss most forms
Vaccine of treatment modalities of CRC. The readers are referred
Cancer vaccine is a promising tool to achieve therapeutic reference works in the field for more complete information.
responses in patients by inducing antitumor immunity. Early stage of CRC detection and treatment with newer
Immunotherapy of patients with advanced carcinomas could effective agents would likely improve survival of high-risk
be possible by utilizing cloning techniques to identify genes CRC patients as most of CRC patients are in advanced stages
and peptides of tumor-associated antigens. Several cancer with poor prognosis. The important prognostic factors are
vaccine, including CEA, dendritic cells, human leukocyte stage of tumor, distant metastasis, grade of tumor and tumor
antigen-restricted peptides and epitope-encoding vectors size. A distinction between resectable, potentially resectable
have been tried for advanced CRC. Since their clinical impacts and unresectable CRCs should be made for establishing an
are still limited, extensive studies are underway in order to adequate therapeutic strategy. Complete surgical resection
identify more effective antigens. The cancer vaccines could with aggressive lymph node dissection is mainstay of
be a promising therapeutic option for CRC in future. treatment. The healthcare delivery systems difference affects
the treatment choices for unresectable CRC. Neoadjuvant
chemoradiation therapy is used for rendering unresectable
Dietary Guidelines tumors resectable. Active chemotherapeutic agents for CRC
Association between dietary guideline adherences and include fluorouracil, folinic acid (leucovorin), oxaliplatin,
overall cancer risk is inconclusive as good adherences to irinotecan, bevacizumab and cetuximab. Chemotherapy given
concomitantly to radiotherapy and combined before or after secondary CRC prevention. Newer molecular techniques
radiation significantly reduces the risk of local recurrence. The will help to understand the underlying mechanisms of CRC
sterilization of the tumor (complete pathological response) carcinogenesis and identify sensitive biomarkers for early
by chemotherapy is a favorable prognostic factor. diagnosis and advancement in therapeutic modalities.
Growing subsets of patients with metastatic CRC are
being considered for treatment with curative intent.
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12
cHAPTER
Gastrointestinal Lymphomas
Moiss Copelman, Natalia Balbi Flores, Cassiano Ribeiro Pires
INTRODUCTION have heterogeneous aspects with the presence of small

lymphocytes (often centrocytic looking) or lymphocytes with
Gastrointestinal (GI) tract represents 3040% of extranodal a monocytoid appearance. A variable number of large cells
lymphomas and forms 420% of all non-Hodgkins lymphomas (immunoblasts and centroblasts) are usually present.
(NHL) cases. The stomach is the most common extranodal An increased number of large cells in a MALT lymphoma
site of lymphoma and accounts for 6875% of GI lymphomas can, at times, create problems from a diagnostic point of view,
followed by the small and the large bowel. Involvement of the suggesting a histological transformation into a DLBCLa
esophagus is quite rare. The real increase of NHL incidence in transformation that is usually defined by the presence of
the GI tract cannot exclude a correlation with improvements in compact aggregates or a sheet-like proliferation of large cells.
diagnostic procedures over the last years. Several autoimmune High-grade primary gastric lymphomas are nearly always
disorders like rheumatoid arthritis, Sjgrens syndrome, of the B-phenotype and are characterized by an aggressive
Wegeners granulomatosis, systemic lupus erythematosus, clinicopathological presentation.
and acquired immunodeficiency syndrome (AIDS) have an Whether all diffuse large B-cell gastric lymphomas are
increased risk of GI-associated lymphoma. derived from previous low-grade MALT lymphomas is still an
open question that is not yet resolved unequivocally.
It should be remembered, however, that the cytogenetic
GASTRIC LYMPHOMAS alterations common in gastric MALT lymphomas are different
from those typical of large-cell primary lymphomas of the
Primary gastric lymphoma accounts for approximately 3% stomach (Figs 1A to D).
of gastric neoplasms and shows an apparently increasing
incidence worldwide.
The disease reaches its peak incidence between the ages Clinical Features
of 50 years and 60 years with a slight male predominance.
Two histological types are particularly frequent in primary
Signs and Symptoms
extranodal lymphoma: (i) a preponderance of diffuse large The initial symptomatology of a gastric lymphoma is often
B-cell lymphomas (DLBCLs) and (ii) the marginal zone quite unspecific and more evocative of gastritis or an
B-cell lymphomas of the mucosa-associated lymphoid tissue ulcerous condition rather than a neoplasm; for this reason,
(MALT) type (therefore extranodal by definition), which is an its diagnosis is often delayed. The most common presenting
indolent lymphoma that frequently presents with localized, symptoms are epigastric pain or discomfort, anorexia, weight
early stage disease. loss, nausea and/or vomiting, occult GI bleeding and early
satiety. Systemic B symptoms (fever and night sweats) are
extremely rare. Hematemesis or melena occurs at the outset
Histology in 2030% of patients, while gastric occlusion and perforation
In 1983, Isaacson and Spencer proposed, for the first time, are quite uncommon. The duration of symptoms preceding
the concept of a MALT-type lymphoma. These lymphomas the diagnosis is quite variable ranging from a few days to 6
represent the most frequent histotype in low-grade years.
malignant primary gastric lymphomas. This extranodal The physical examination is often normal but may reveal
lymphoma develops from B lymphocytes of the marginal a palpable mass and/or peripheral lymphadenopathy
zone and is characterized by a cellular population that can when the disease is advanced, especially in cases where the
A B
C D
Figs 1A to D: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma. (A) Small lymphocytes infiltrating the mucosa. Immuno
histochemical study shows (B) lymphoepithelial lesion CD20+; (C) low Ki-67 proliferation index; (D) cyclin D1-negative
Courtesy: Nilcimar Miranda, Rio de Janeiro, Brazil
histology is aggressive. Laboratory studies also tend to be is important in the diagnosis of illnesses that are unresponsive
normal at presentation. Anemia or an elevated erythrocyte to antibiotics, and this can be carried out by fluorescent in
sedimentation rate may be present in selected cases. situ hybridization on fixed material.
An endoscopic ultrasound (EUS) should determine the
depth of invasion and the presence of perigastric nodes. The
Diagnostic Evaluation pattern seen on EUS may correlate with the type of lymphoma
Diagnosis of gastric lymphoma is usually established during that is present.
upper endoscopy with biopsy. While it can be suggested
by findings on imaging, biopsy is required for a definitive
diagnosis.
Pathology
The most frequent sites of gastric lymphomas are at the The diagnosis of gastric lymphoma may be suggested by
pyloric antrum, corpus, and cardia. The extension of a lesion endoscopic and imaging findings, but must be confirmed
across the pylorus into the duodenum is highly suggestive, by biopsy. Both suspicious appearing lesions and normal
but again not pathognomonic of lymphoma; for this reason, appearing mucosa should be biopsied since gastric
verification through biopsy is always deemed necessary. lymphoma can occasionally present as multifocal disease
The findings on upper endoscopy are diverse and may with involvement of tissue that appears to be unaffected on
include any of the following: mucosal erythema, mass or initial visualization.
polypoid lesion with or without ulceration, benign-appearing Endoscopists should aim to attain the largest biopsy
gastric ulcer, nodularity, thickened, cerebroid gastric folds specimen possible. Conventional pinch biopsies may miss
(Figs 2A and B). Any of these findings should heighten the diagnosis, since gastric lymphoma can infiltrate the
suspicion of gastric lymphoma, but none is diagnostic. submucosa without affecting the mucosa; this problem is
Multiple biopsies should be obtained from the stomach, most likely to occur when no obvious mass is present. Jumbo
duodenum, gastroesophageal junction, and from abnormal biopsies, snare biopsies, biopsies within biopsies (well
appearing lesions. Identification of the t(11;18) translocation technique), and needle aspiration can all serve to increase
Gastrointestinal Lymphomas 123
A B
Figs 2A and B: Gastric lymphoma with ulcerations and erythema in corpus and antrum
the yield in such cases. Endoscopic ultrasound-guided fine Unilateral bone marrow biopsy and aspirate should be
needle aspiration biopsy (FNAB) or endoscopic submucosal performed in all patients with the possible exception of
resection may provide even greater diagnostic capability. those with localized gastric extranodal marginal zone
B-cell lymphoma
Additional studies [e.g. magnetic resonance imaging
Pretreatment Evaluation (MRI) of the orbit] should be reserved for selected patients
After a diagnosis of GI lymphoma is confirmed, a pretreatment who have findings on history and/or physical examination
evaluation determines the extent of disease. In addition to a concerning for involvement of additional sites.
history and physical examination, it is our practice to perform Men and women with childbearing potential should
the following pretreatment studies: receive counseling about the potential effect of treatment
Laboratory studies include a complete blood count on their fertility and options for fertility-preserving
with differential, human immunodeficiency virus (HIV) measures.
serology, chemistries with liver and renal function,
electrolytes and lactate dehydrogenase (LDH). Patients
should undergo serologic testing for hepatitis B and
Staging
hepatitis C The most widely accepted staging system is the Lugano that
A contrast-enhanced computed tomography (CT) scan of was developed to incorporate measures of distant nodal
the chest, abdomen, and pelvis should be performed to involvement. Early (stage I/II) disease includes a single
evaluate for distant disease. The use of positron emission primary lesion or multiple, noncontiguous lesions confined
tomography (PET) is controversial except in cases of to the GI tract that may have nodal involvement. There
DLBCL is no stage III in the Lugano system. Advanced (stage IV)
An endoscopic evaluation is performed based upon the disease displays disseminated extranodal involvement or
site of disease. Patients with gastric lymphoma should concomitant supradiaphragmatic nodal involvement.
undergo an esophagogastroduodenoscopy with EUS
to determine the depth of invasion and involvement of
perigastric lymph nodes Treatment
Patients with gastric lymphoma should be tested for Historically, therapeutic strategies in gastric lymphomas have
Helicobacter pylori (H. pylori), which can be detected by been, for a very long while, based on surgery, followed by
histologic specimen, biopsy urease test, urea breath test, radiotherapy or postoperative chemotherapy. This approach
stool antigen test or serology in the vast majority of gastric began to be questioned at the end of the 1980s when
MALT lymphomas (90%). In addition, fluorescence in situ several retrospective studies showed that surgery should
hybridization (FISH), or polymerase chain reaction (PCR) not necessarily be considered obligatory in all patients. At
testing for t(11;18) should be performed the same time, the demonstration of the effectiveness of
antibiotics in localized MALT lymphomas gave a further push H. pylori at the time of diagnosis. These patients should be
toward abandoning front-line surgery, even for lymphomas treated with radiation therapy (RT) administered with curative
with a low-grade malignancy histology, where surgery (with intent. Radiation therapy is also appropriate for patients
or without adjuvant radiotherapy or chemotherapy) was with tumors that demonstrate the t(11;18) translocation that
considered the gold standard. is typically unresponsive to H. pylori eradication therapy.
Other treatments, including immunotherapy, single agent
chemotherapy and multiagent chemotherapy, are reserved
Gastric MALT Lymphoma for patients failing or recurring after RT and those with
Gastric MALT lymphomas represent 78% of all B-cell advanced stage disease (i.e. Lugano stage IV).
lymphomas and approximately 50% of primary gastric The treatment of patients with advanced stage (Lugano
lymphomas. They originate from the lymphatic tissue in the IV) disease is not clearly defined. These patients are typically
stomach that, in association with the mucous membrane, treated with H. pylori eradication therapy, if they are H. pylori-
usually develops following chronic H. pylori infection (Figs positive, and then generally observed until the development
1A to D). of symptoms at which time they undergo treatment with
Although H. pylori infects over 50% of the worlds immunotherapy or chemotherapy (similar fashion to those
population, most patients with H. pylori do not develop with advanced stage follicular lymphoma).
lymphomas; therefore, it is commonly believed that additional While successful treatment with radiation usually results
environmental, microbial, or hostgenetic factors may play in the disappearance of B-cell clonality, treatment with H.
a role in gastric lymphomagenesis. Infection with H. pylori pylori eradication therapy often demonstrates persistent
strains that carry the cytotoxin-associated antigen A (cagA) B-cell clonality on molecular studies. The ultimate clinical
is linked to gastric carcinoma, and it has been suggested that significance of persistent clonality in these treatment settings
cagA-positive strains may also be associated with lymphoma is unclear.
development, but available data remain controversial. Gastric resection is reserved for patients with complications
Gastric MALT lymphomas have an indolent clinical- such as perforation or obstruction.
biological behavior pattern, with a tendency to remain After initial therapy, patients must be monitored with
localized at the onset site in 7080% of cases. At present, the serial endoscopies to evaluate for disease response and
most widely accepted initial therapy for localized disease recurrence. Treatment failures should be treated with local
is aimed at the eradication of H. pylori using regimens RT administered with curative intent.
combining antibiotics and proton-pump inhibitors. One of
the most commonly used regimens combines omeprazole
with clarithromycin and amoxicillin; nonetheless, the choice
Response Evaluation
of a treatment regime must take into account the local Patients with early stage H. pylori positive, initially treated
epidemiology of the infection and the possible resistance with H. pylori eradication therapy need to be evaluated after
to certain antibiotics. This therapeutic approach is the one the completion of treatment to determine whether the H.
that is mostly investigated and successfully verified in a large pylori was successfully eradicated and whether there has
number of clinical studies. been a tumor response.
Four-to-eight weeks after the completion of H. pylori
eradication therapy, urea breath test should be performed
Treatment to confirm eradication of infection. Up to 20% of patients
The treatment of gastric MALT lymphoma is dictated will require a second H. pylori eradication regimen to fully
primarily by the presence or absence of a concomitant H. eliminate the infection. After successful eradication of H.
pylori infection. pylori, patients should undergo periodic upper endoscopy
The majority of patients with gastric lymphoma present with multiple biopsies to evaluate for tumor response and
with early stage (Lugano I/II) H. pylori-positive disease. monitor for relapse.
Therapy aimed at the eradication of H. pylori is the favored Endoscopic examination with multiple biopsies should be
initial treatment for patients, because of its low side effect done every 6 months for the first 2 years and then yearly to
profile and demonstrated efficacy. With this approach, monitor histological remission.
5080% of patients with localized gastric MALT achieve a
histologic complete remission (CR), which will be maintained
long-term for the majority of patients.
Conclusion
A minority of patients with early stage (Lugano I/II) The general consensus is nowadays limited to using an
gastric MALT lymphoma will not demonstrate infection with antibiotic therapy for the initial treatment of MALT type, H.
pylori-positive lymphomas. In all other situations, the choice

between local therapy options (radiotherapy or surgery) and
systemic ones (chemotherapy and immunotherapy) must
be based on the characteristics of each individual patient
(histological type, stage, age, comorbidities and willingness
to undergo a rigorous endoscopic follow-up).
Diffuse Large B-cell Lymphoma

A B
Gastrointestinal DLBCL includes lesions previously called
high-grade MALT lymphoma. It can occur anywhere along
the GI tract and is the most common histology for primary
gastric lymphoma, representing approximately 50% of cases.
Compared with patients with low-grade lymphoma, these
patients tend to have more systemic symptoms, a more
advanced stage at diagnosis, and a worse prognosis.
Treatment options that have been evaluated in GI
DLBCL include surgery, RT, chemoimmunotherapy, H. C D
pylori eradication therapy, and combinations of the above.
Figs 3A to D: Gastric mantle cell lymphoma. (A) Mucosal infiltration
In general, most patients are treated with combination
with small lymphocytes. Immunohistochemistry shows (B)
chemoimmunotherapy regimens used for non-GI DLBCL.
lymphocytes CD20+; (C) moderated cell proliferation ndex/Ki-67; (D)
A few patients may be candidates for a trial of H. pylori positive D1 cyclin
eradication therapy. Surgery is reserved for patients with
Courtesy: Nilcimar Miranda, Rio de Janeiro, Brazil
complications, such as perforation, obstruction, or intractable
bleeding. This applies to both early stage and advanced
disease. nonspecific abdominal symptoms, which will depend on the
affected site, as well as tumor size and disease duration. The
most common is a subclinical form with an indolent course,
but if symptomatic, it can have a presentation from abdominal
SMALL INTESTINAL LYMPHOMAS pain to GI bleeding.
Histology and immunohistochemistry are similar to gastric
Mantle Zone Cell Lymphoma mantle cell lymphoma as seen in Figures 3A to D. The constant
Mantle zone cell lymphoma (MZL) is a rare disease of the GI and typical phenotypic features of the small cleaved tumor
tract recently identified, and it is estimated that its frequency cells are characterized as CD20+, CD5+, CD23-, CD43+ with
is between 4% and 9% of all GI B-cell NHL. It was originally a t(11;14) (q13;q32), and cyclin D1 overexpression of the bcl-1
called multiple lymphomatous polyposis (MLP) due to its gene on immunohistochemistry. The CD5 and CD43 markers
particular presentation, which looked to be of multiple are called aberrant, as they are products of T lymphocytes.
lymphomatous polyps involving the digestive tract, and in The treatment of this condition will depend on the stage of
some cases, more advanced extraintestinal dissemination the disease. Response to intensive chemotherapy is variable
was observed. and usually results in regression of gross and microscopic
Mantle cell lymphoma has been reported to involve the GI lesions. Surgery is indicated in some cases, especially
tract in 1530% of patients. Although any part can be affected, those who develop advanced disease with stenosis and
the most common site is in the ileocecal region, and in about consequently clinical obstruction. Even with good initial
90% of all patients who have GI involvement, it is through response to chemotherapy, it may not subsequently become
both distal small bowel and colon. responsive, with short remissions and median survival from 3
The disease usually arises from the sixth decade of life to 4 years.
with a slight predominance of male gender (2:1). Extranodal
involvement is relatively common, and in this situation, the
investigation of the spleen and bone marrow has become
Gastrointestinal Follicular Lymphoma
crucial. Most cases are usually present with generalized Gastrointestinal follicular lymphoma (GIFL) is a relatively
lymphadenopathy. Some patients may experience rare disease, representing only 13% of all GI tract B-cell NHL.
The most common sites of involvement are the duodenum malabsorption syndrome, and should be investigated at the
and terminal ileum, and it is quite common for patients to time of diagnosis of celiac disease, or when this is already a
have obstructive symptoms as an overt presentation that known condition, and the patient develops worsening of
often requires surgical management. It is usually an indolent symptoms, even with a free gluten diet.
lymphoma that responds well to chemotherapy. While The estimated prevalence of celiac disease is of up to
multiple treatments show good response rates, most patients 12% in developed countries, being much more common in
relapse. It is a low-grade lymphoma that usually develops Caucasian individuals. Detection of a T-cell type lymphoma
very slowly. Primary extranodal FL without peripheral more often leads to clinical suspicion of possible adult celiac
lymphadenopathy is uncommon. disease, but both B-cell and T-cell type lymphomas have
As in MZL, several markers that make it possible to been described in single individuals with celiac disease. The
differentiate from other strains of B-cell lymphoma are occurrence of this lymphoma is not very common, which is
expressed from B cells. The CD19, CD20 and CD22 are usually responsible for only 5% of all GI lymphomas. The diagnosis is
identified, while surface immunoglobulins like CD10, CD5, around 50 years old and males are affected slightly more than
CD43, and especially the cyclin D1 marker are usually not, females by a ratio of 2:1. When biopsies from proximal small
which becomes a useful tool in differentiating with the FL.
bowel were obtained in adults with celiac disease, the overall
In up to 85% of cases, there is a translocation that results in
lymphoma risk was about 810%.
rearrangement and overexpression of the bcl-2 gene. The
The EATL can be divided into two groups based on genetic,
B-cell bcl-2 protein expression is useful in discriminating
morphological, and immunohistochemical features: (1)
GIFL from florid follicular hyperplasia, in which it is not
Type I is a large cell lymphoma, which is highly associated
expressed.
with celiac disease, and this was the most commonly found.
The diagnosis of this condition can be a real challenge for
(2) Type II has no known association with celiac disease
many physicians and certainly diagnostic resources should
be widely used. In this context, some recent researches have and unlike type 1, with the predominant symptoms of
shown the role of double-balloon enteroscopy and the use malabsorption, may occur in more severe cases, including
of magnification. The endoscopic study of GIFL in the small small bowel obstruction.
bowel using the virtual chromoscopy was clarified as a coiled Chronic ulcerative jejunitis (CUJ) is another etiology of
or elongated vascular pattern by narrow band imaging (NBI), malabsorption syndrome, and it is important in the differential
and small or whitish nodules by Fuji intelligent chromo diagnosis with EATL. Differentiating these two conditions
endoscopy (FICE). becomes quite difficult in clinical practice, because they both
If the diagnosis set in a medical challenge, the decision have the same histological features like crypt hyperplasia,
to treat is also the same thing. Some authors advocate if the villous atrophy, and inflammatory cell infiltrate by T cell; not
patient has no symptoms, immediate treatment may not to mention, the CUJ can be transformed into lymphoma after
be necessary. So far, there are no reports in the literature of several years.
a standard treatment. Then, both the use of chemotherapy, The EATL can affect any part of the small bowel; however,
radiation and biological agents are the choices currently the most often reported site is the jejunum. The symptoms
available and their combinations will be individualized in are quite variable and are directly related to the extent of
each case according to the stage. involvement of the GI tract, as well as any atypical sites, such
Yamamoto S et al. recently published the results of a few as liver, brain and nasal sinus. Abdominal pain is considered
series on the long-term outcomes of patients with GIFL the most common symptom. Perforation and obstruction
treated with conventional therapy. In the group of patients have been described with much less frequency in cases of
undergoing treatment, the median free time of relapses type II EATL.
ranged from 31 to 45 months, while those who were only Currently, several resources are available to make the
observed, the mean time was very similar, almost 38 diagnosis of this condition, including endoscopy with or without
months. virtual chromoendoscopy, double-balloon enteroscopy, video
capsule enteroscopy, CT, 18F-fluorodeoxyglucose PET scan, and
Enteropathy-type Intestinal T-cell magnetic resonance enteroclysis. Regardless of the resources
available, in some situations, this is a difficult condition to
Lymphoma diagnose, mainly in those patients in which the enteropathy is
Enteropathy-type intestinal T-cell lymphoma (EATL) a condition not yet even known.
has a close relationship with celiac disease. It is part Immunophenotypic markers have been identified in this
of the investigative algorithm when a patient develops disease. Some T lymphocytes markers help identify the EATL.
The CD103 is seen quite often, while CD8 only in a minority of show thickening of folds with multiple small superficial
cases. ulceration, submucosal infiltration, diffuse dilation of
The therapy of EATL is not yet well defined, and duodenum and extensive nodularity involving antrum,
unfortunately, the prognosis is still poor with a 5-year survival duodenum and jejunum at upper GI endoscopy. Biopsy
rate of 820%. Often the patients nutritional status is a limit for findings include blunting or flattening of villi, dense mucosal
the proposed therapy, mainly because of the malabsorptive and submucosal cellular infiltrate with increase in lamina
syndrome experienced with hypoalbuminemia often present. propria lymphocytes.
The proposed treatment is in accordance with the stage of As noted above, there are several evidences that relate
disease and performance status of the patient, with a mix this particular form of lymphoma with infectious agents,
of chemotherapy (CHOP) and surgery. New therapies are primarily because of its high prevalence in regions where
developing and a monoclonal antibody, alemtuzumab, the number of cases of parasitic and bacterial infections
constitutes a relevant option in refractory celiac disease. are very high. Also, a satisfactory response when the use of
Through it all, the rates of complete remission for the disease antimicrobial agent is employed, and in this context, the
is around 58%, and less than 50% of patients completed Campylobacter jejuni is closely related to this condition. The
their planned chemotherapy courses, largely because of use of specific antibiotics for the eradication of C. jejuni like
complications of treatment. tetracycline (250 mg four times daily; 6 months to 2 years)
alone, especially in the early stages of disease, can achieve
remission rates of nearly 70%. Several studies have shown the
Immunoproliferative Small Intestinal presence of C. jejuni through PCR or other techniques as FISH
Disease assay. The FISH use an oligonucleotide probe directed at C.
jejuni 16S rRNA. In studies with mice, the C. jejuni has been
Immunoproliferative small intestinal disease (IPSID) is a
shown to persist in Peyers patches and mesenteric lymph
MALT lymphoma, with a strong geographic feature. This
nodes. So, this pathogen can stimulate IgA mucosal response
entity is well recognized in some underdeveloped regions,
and the chronic infection leads to sustained stimulation of
especially Mediterranean, Middle East, and African countries.
the mucosal immune system leading to IPSID.
It corresponds to about one-third of GI lymphomas in the
The staging for IPSID has not been uniformly defined,
Middle East, being the main site of extranodal lymphoma. Due
although the most commonly used system consists of early
to this regional landmark, it is also known as Mediterranean
benign (stage A), late benign (stage B), and lymphomatous
lymphoma and occurs rarely in western countries.
categories (stage C). Once malignancy develops, IPSID
This rare disease affects people with low socioeconomic
lymphoma can be divided into four stages of involvement: (i)
status and might have some relation with infectious agents. As
the intestine or the mesenteric lymph nodes, (ii) the intestine
is well documented in the literature regarding the association
and the mesenteric lymph nodes, (iii) retroperitoneal extra-
between H. pylori infection and gastric MALT lymphoma, the
abdominal lymph nodes, and (iv) noncontiguous non-
role of C. jejuni and IPSID appears to be very similar but, yet
lymphatic structures.
requires further analysis.
The main feature of this condition is an infiltrating plasma The identification of an association between C. jejuni and
cell population that secretes a monotypic immunoglobulin IPSID may lead to improvements in the management mainly
heavy chain (IgA), mainly observed in the early stages from patients in early stages (stages A and B) of the disease,
of the disease. This protein can be identified through the which can be eligible for treatment with antimicrobial
immunoassay in the serum of up to 70% of patients and also regimens, while for stage C patients, standard CHOP
can be isolated in the biopsy tissue. While IgA is directly chemotherapy was administered.
involved in the pathophysiological process, its serum levels
are very low. IgG and IgM can be found in high titers. The
disease usually affects younger people around the third
Others Types of Small Bowel Lymphoma
decade of life without gender preference. Less common types of lymphoma but with well-defined
The most affected region of the GI tract is the duodenum, clinical importance deserve a brief comment. Among these are
being reported in up to 62% of cases. The patients may the Malt lymphoma of B-cell type (MLB), Burkitt lymphoma
experience a wide variety of symptoms, but abdominal pain (BL), and natural killer of T-cell type (NKT) lymphoma.
is the most common. Similar to EATL, IPSID may present The MLB is a rare type of lymphoma with an approximately
with malabsorptive syndrome with significant diarrhea, 70% 5-year survival rate when an early diagnosis is achieved.
and progress with advanced signs and symptoms of poor As Malt lymphoma of the stomach, this lymphoma bears
nutrition. Fever may sometimes occur. Imaging studies can some similar histologic features. Like other lymphomas,
it can affect any part of the GI tract, and the most common will dictate the therapy. Resection is the standard therapy,
presentation is a solitary lesion. Surgical treatment is the best with adjuvant chemotherapy only for patients with aggressive
option, when it is feasible. histology.
Burkitts, lymphoma is one of the most aggressive
forms of lymphoma. Depending on the subtype, it is very
common in children, and despite the aggressiveness of the Biliary Tract
disease, it usually responds well to chemotherapy. Three Biliary lymphomas account for less than 1% of lymphomas.
forms are reported: (i) the endemic, (ii) an association with Extrahepatic biliary tree can be occasionally involved and
immunodeficiency, and (iii) the sporadic. Children are most often are mistaken for cholangiocarcinoma.
affected, and males have a twofold increased risk than women.
All subtypes have a predilection for the ileocecal region,
but any area can be affected. Therefore, the initial presentation Appendix
with intestinal obstruction is relatively common. Abdominal Appendiceal lymphoma accounts for approximately 2% of all
pain is also the main clinical symptom. Some viruses have a GI lymphomas. Patients usually present with an appendiceal
close relationship with some subtypes of BL. Infection with diameter of more than 2.5 cm and acute appendicitis.
Epstein-barr virus (EBV) is present in most sporadic BL and Appendectomy is the treatment of choice. If there is extension
immunodeficiency associated, while the HIV is related only of tumor onto the mesentery or cecum, right hemicolectomy
to the latter. As previously mentioned, although the nature is advised.
of tumor is malignant, response to chemotherapy is usually
good, with rates of remission of up to 90% at initial stages.
Natural killer of T-cell type is very rare. Unlike the T-cell Pancreas
lymphoma related to celiac disease, this condition does
The pancreas is an uncommon site of lymphoma, representing
not have any relation with gluten. There is no consensus
less than 12% of all pancreatic malignancies and less than
on standard treatment and the approach is individualized
1% of extranodal NHL. The diagnosis should be regarded
according to the stage and to the affected site. whenever a large mass is identified in the pancreas without
biliary obstruction, pain or weight loss. An elevated level
of serum LDH supports a diagnosis of lymphoma. Patients
OTHERS SITES may have a clinical presentation similar to that of pancreatic
adenocarcinoma with abdominal pain and obstructive
Less commonly, NHL can affect the oral pharynx, esophagus, jaundice. High accuracy in diagnosis is obtained in FNA
liver, pancreas, biliary tree, retroperitoneum, colon, and with flow cytometry. Histology shows usually diffuse large
rectum. Some of these sites have been explored below. B-cell lymphoma. The diagnosis of pancreatic lymphoma
is important because prognosis is much better than for
Retroperitoneum pancreatic adenocarcinoma and treatment is primarily
nonsurgical, although a few patients with small tumors
The most common neoplasms are lymphomas or lympho thought to represent carcinomas, have been treated with
sarcomas. surgery alone and have had excellent survival. Treatment
usually consists of a combination of chemotherapy and RT.
Patients with biliary obstruction may require a drainage
Colon procedure before chemotherapy to avoid excessive
Colorectal lymphoma is rare, occurring in about 14% of all chemotherapy-related toxicity. Cure rates near 30% are
GI lymphomas, and representing approximately 1% of all reported in the literature.
colon cancers. The cecum is the most common site (75%),
followed by the rectum.
Weight loss and abdominal pain are the most common
Hepatosplenic T-cell Lymphoma
presenting complaints, and approximately 50% of patients This extremely rare form of NHL predominantly affects
have an abdominal palpable mass. Burkitts lymphoma and young males, although its incidence is unknown. It is a nearly
DLBCL are the most common histological subtypes (4060%). universally fatal form and has been described in patients with
It is important a colonic evaluation in patients with mantle Crohns disease in the setting of combination therapy with anti-
cell lymphoma because of the association of this subtype, tumor necrosis factor (TNF) agents and immunomodulators,
with 88% rate of colonic involvement. Histology and stage and less frequently, with immunomodulators alone.
Liver Lymphoma Histology usually shows high-grade B-cell lymphoma,

most of them are of extranodal origin.
Primary hepatic lymphoma is an unusual site with diffuse Chemotherapy, surgery, radiotherapy, or combined
large cell lymphomas of B-cell origin being more frequently therapy have not substantially improved the survival of HIV
than T-cell or non-B, non-T-cell lymphomas. Patients with patients with GI lymphoma. On the other hand, highly active
primary lymphoma usually have evidence of mass lesions on antiretroviral therapy seems to have a protective effect against
imaging procedures that may mimic primary or metastatic the onset of NHL associated with HIV.
carcinoma. On the other hand, secondary lymphomatous
involvement of the liver is often only detected by histologic
evaluation.
Numerous reports of primary hepatic lymphoma of B-cell
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13
cHAPTER
Gastrointestinal Stromal Tumor
INTRODUCTION EPIDEMIOLOGY
Gastrointestinal stromal tumors (GISTs) are rare but known to There is dearth of worldwide epidemiological data about
be the most common mesenchymal tumors of the gut. Stout GIST likely due to the lack of a globally available clinical or
in 1962 described these tumors as morphologically similar morphological coding system. In one recent epidemiological
to smooth muscles and classified them among leiomyomas analysis in the United States from 1993 to 2002, the average
or leiomyosarcomas. Later, it became evident that some of annual GIST incidence was found to be 0.32 per 100,000
these tumors possess neural features or mixed (myogenic persons; 15-year limited-duration prevalence was 1.62 per
and neural) features or lack complete differentiation. 100,000 persons in 10 years. The incidence and prevalence
Subsequently, a more general term gastrointestinal stromal were more in the elderly population over 65 years. It was
tumor was suggested in 1986. It took a further decade very rare in children less than 5 years of age. There was no
for the definition of GIST as a biologically distinct tumor predilection for sex, race, or geographic region. Median
of the gastrointestinal (GI) tract, different from smooth overall survival was 58.7 months and 3-year survival was 73%.
muscle (leiomyomas and leiomyosarcomas) and neural In this observation, when controlling for age, gender, income
(schwannomas) tumors. The expression of KIT oncogene or and urban area, survival did not significantly differ by tumor
CD117 (proto-oncogene protein) became widely accepted as size (P = 0.117). The median recurrence-free survival (RFS)
the defining feature for the diagnosis of GISTs. for GIST cases was 44.9 months. Controlling for age, gender,
income and urban area, RFS did not significantly differ by
tumor size for tumors greater than 3 cm (P = 0.08).
HISTOGENESIS Gastrointestinal stromal tumors are usually sporadic;
however, familial GISTs have also been reported where
Interstitial cells of Cajal (ICC) known as GI pacemaker heritable mutations of the KIT gene have been illustrated.
cells control gut motility. Immunophenotypical (being There is a predisposition in such families to have patients with
CD117 positive) and ultrastructural resemblance with ICCs multiple gastric and intestinal GISTs.
suggest a possible histogenesis of GISTs from the ICCs. In an
earlier observation, the most common sites of occurrence
of sporadic GISTs were reported to be in the stomach (39%) CLINICAL FEATURES
and small intestines (32%), with the remainder in the rectum
(21%) and colon (11%). But notably, GISTs were also present Small GISTs can be asymptomatic and are found incidentally.
outside the bowel wall, albeit rarely, in the retroperitoneum The most common clinical presentations are GI bleeding,
or omentumsites normally devoid of ICCs. This could be abdominal mass and abdominal pain. Intestinal GISTs may
explained by the fact that the smooth muscle cells as well as be complicated with obstruction, perforation, bleeding or just
the ICCs originate from common intestinal mesenchymal present with vague symptoms. Metastatic GISTs may present
precursor cells but CD117 is typically required for their with symptoms corresponding to the sites of metastases
differentiation into ICCs. most commonly in the liver, omentum, and peritoneal cavity.
Gastrointestinal Stromal Tumor 133
Gastrointestinal stromal tumors in the retroperitoneum and eosinophilic or clear. Metaplastic bone formation has also
mesentery may be mistaken for metastatic deposits. been reported in GISTs.
IMAGING IMMUNOHISTOCHEMISTRY
Computed tomography (CT) or magnetic resonance The c-kit proto-oncogene is located on chromosome 4q11-
imaging (MRI) scans can suggest a diagnosis of GIST by the 21. The c-kit proto-oncogene protein, CD117, is a trans-
presence of a large exophytic tumor with heterogeneous membrane receptor for stem cell factor (SCF) or mast cell
contrast enhancement arising from the stomach or small growth factor (MCGF), and is expressed in the ICCs as well
bowel. Fluorine-18 fluorodeoxyglucose positron emission as in other tissues, such as hematopoietic stem cells, mast
tomography (18F-FDG-PET) is primarily used when there are cells, germ cells, and some of the epithelial cells.
inconsistencies between CT and clinical findings or when the CD117 expression is universal for almost all GISTs
CT findings are inconclusive. irrespective of their site of origin, histologic features and
In one study, PET imaging of malignant GISTs biologic behavior and hence regarded as their most suitable
demonstrated uptake of 18F-FDG, while nonmetastasizing defining feature. Though strong diffuse cytoplasmic positivity
GISTs did not. Positron emission tomography imaging may is their hallmark, dot positivity (so called golgi pattern)
also detect metabolic improvement early on and aid in within the cytoplasm is not unknown. Ordinarily, at least 90%
monitoring therapy. of cells in GISTs express CD117. But rarely, this proportion
Endoscopic ultrasound (EUS) allows clear imaging of the GI can be as low as 5%, accounting for the infrequent CD117
wall layers and precise evaluation of submucosal tumors and negativity in the small biopsy samples from tumors with
could be of use in diagnosing GISTs. Endoscopic ultrasound/ typical morphology of a GIST. All the same, it is now well
fine needle aspiration (FNA) should be performed for all known that a small group of GISTs fails to express CD117
hypoechoic solid tumors to confirm their nature. altogether. Approximately 6080% of GISTs express CD34
Contrast-enhanced harmonic EUS (CEH-EUS) is a novel (Figs 1 and 2).
sonographic technique that uses ultrasound contrast agents
and depicts intratumoral vessels in real time, which might
have a role in predicting the malignancy potential of GISTs. CYTOGENETICS
Contrast-enhanced multidetector CT and power-Doppler
EUS have significantly less sensitivities as compared to CEH- Greater than 90% of GISTs harbor a specific KIT or platelet-
EUS. derived growth factor receptor alpha (PDGFR-alpha or
HISTOLOGY
About 7080% of GISTs are characterized by spindle cells
with a storiform or fascicular growth pattern with oval
nuclei and less cytoplasmic eosinophilia compared to that
of smooth muscle tumors. Marked perinuclear vacuolation
is not uncommon, especially in gastric GISTs. Nuclear
palisading simulating nerve sheath tumors can also be
seen. Gastrointestinal stromal tumors found in the small
intestine may harbor eosinophilic, hyaline, periodic acid-
Schiff (PAS)-positive, diastase resistant, extracellular
globules, or elongated collagen fibers known as skeinoid
fibers.
Almost up to a third of GISTs may exhibit a packeted
architecture akin to a paraganglioma or a carcinoid tumor.
They are primarily composed of large round or polygonal
epithelioid cells with abundant cytoplasm, which is often Fig. 1: CD117 positive
gastric tumors with stable karyotypes and is associated with

a relatively favorable course. The 1p pathway pertains to
mainly intestinal GISTs, with propensity for cytogenetic
complexity and a more aggressive course. The 22q pathway,
though more closely associated with 1p than 14q, appears
to trigger the critical transition to an unfavorable cytogenetic
subpathway.
Molecular defects of other genes may also contribute to
the progression and/or malignant transformation of GISTs.
Loss of p16 (INK4A) gene on 9p and Hox11L1 gene on
chromosome 2 are examples.
KIT-NEGATIVE GISTs AND THEIR

ASSOCIATIONS
Fig. 2: CD34 positive
It is common for KIT-negative GISTs to express PDGFRA
mutations. Such tumors primarily originate in the omentum/
PDGFRA) gene mutation, which is of significance not only peritoneal surface and demonstrate epithelioid cell
for tumor phenotyping but also for determining the patient morphology. As KIT-negative GISTs may potentially bear
group who could benefit from targeted therapy using certain imatinib-sensitive KIT or PDGFRA mutations, such patients
tyrosine kinase inhibitors, such as imatinib mesylate. with apparent KIT-negative GISTs should not blindly be denied
Recognition of other genetic aberrations in GISTs may imatinib therapy.
potentially lead to the evolution of additional therapeutic The association of GIST with other tumors, such as
targets. neurofibromatosis type 1 (NF1), caused by mutations of the
KIT receptor tyrosine kinase (RTK) activation is known NF1 gene, is well described. Gastrointestinal stromal tumors
to be the crucial step in the development of almost every in NF1 patients are usually KIT-negative and likely to have
GIST. This is an outcome of oncogenic, gain-of-function, a different pathogenesis than sporadic GISTs, involving a
point mutations or in-frame deletions potentially involving somatic inactivation, which may include loss of heterozygosity
the juxtamembrane cytoplasmic or extracellular domains of (LOH) of the wild-type NF1 allele leading to inactivation of
the receptor enabling it to phosphorylate various substrate neurofibromin and subsequent activation of the mitogen-
proteins, thereby triggering signal transduction cascades activated protein (MAP)-kinase pathway.
which modulate cell proliferation, survival, chemotaxis and Carney triad is an exceptionally rare syndrome characterized
adhesion. by occurrence of GISTs, extra-adrenal paragangliomas and
KIT mutations are usually clustered in exons 9, 11, 13 and pulmonary chondromas. These GISTs are not only deficient
17, exon 11 (intracellular juxtamembrane domain) being in conventional KIT and PDGFRA mutations, but also lack the
the most common. Most exon 17 mutations are 2487T>A nonrandom loss of 14q and 22q, which is typical of sporadic
substitution resulting in A822L and is found mostly in small GISTs, suggesting an origin through a distinct pathogenetic
intestinal GISTs. Exon 13 mutation in gastric GISTs portends pathway.
a more aggressive course.
Gastric GISTs with PDGFRA mutations are associated with
a less malignant course but are resistant to treatment with PROGNOSTIC VALUE OF GENETIC
imatinib. The most common PDGFRA mutation is an A842V ABERRATIONS
substitution in exon 18.
In an attempt to simplify the cytogenetics of GISTs, Apart from holding a pivotal role in GIST pathogenesis, KIT
an oncogenetic tree model with three major cytogenetic mutation and activation may provide critical prognostic
pathways was designed utilizing comparative genomic information. KIT mutation-positive GISTs are more prone to
hybridization (CGH) data derived from 203 primary GISTs. metastasize to liver and carry a higher mortality compared
The first one initiated by 14q pathway primarily involves to KIT-negative GISTs. KIT exon 11 deletion has been
suggested to independently predict adverse prognosis though Imatinib Resistance

conflicting reports are available in literature.
More genetic abnormalities, including those of the The wide interpatient variability in the pharmacokinetics of
tumor suppressor genes, such as loss of the p16(INK4A) imatinib is of utmost clinical relevance as the progression-
gene on 9p have been implicated in the progression and/ free survival has been found to be correlated to imatinib
or malignant transformation of GISTs. There is also some trough levels.
Approximately 15% of patients exhibit resistance to
evidence to suggest that another gene FLJ10261(DOG1) may
imatinib during initial use (e.g. within the first 36 months
also be involved in the genesis of GIST. Thirty-six percent
of treatment) (primary resistance), whereas acquired
KIT-negative conventional GISTs express DOG-1. This gene is
or secondary resistance is ultimately observed in most
rarely expressed in other soft-tissue tumors.
patients who initially derive clinical benefit. With more
Low mRNA expression of the CDKN2A tumor suppressor
experience with this drug, primary and secondary resistance
pathway transcripts p16 and p14 whereas high mRNA
has been recognized as serious clinical challenges. Loss of
expression of CDK4, RB1, MDM2, TP53 and E2F1 are heterozygosity of the KIT gene is an important event that
associated with aggressive course and adverse prognosis. leads to imatinib resistance and metastatic progression of
GISTs. In cases where the presence of KIT exon 9 mutation
has been initially recognized as the prominent adverse
RISK STRATIFICATION prognostic factor for response to imatinib, treatment
with high-dose regimen (800 mg/day) has resulted in a
Several risk stratification systems have been proposed to significantly superior progression-free survival. Absence of
identify the malignant potential of GISTs. Features correlating KIT or PDGFRA mutations significantly worsens the relative
with prognosis like tumor size, anatomic site and mitotic risk of progression and death.
count in addition to tumor rupture have been used in various Secondary KIT mutations, usually point mutations,
systems for risk stratification. Recently, the International occurring in addition to the primary mutation may account
Union Against Cancer (UICC) TNM classification has been for the 40% of patients with GISTs who develop secondary
introduced for GISTs, but its clinical usefulness is yet to be resistance to imatinib. A limited number of codons in exons
determined. 13, 14, 17 and 18 of KIT and often PDGFRA are involved in
these point mutations. Such secondary mutations are rarely
seen in untreated GISTs. They make the KIT receptor less
TREATMENT OF GASTROINTESTINAL sensitive to imatinib, probably by hampering its binding to
the cytoplasmic tyrosine kinase domain.
STROMAL TUMORS Resistant clonal nodule can be defined as a new
Despite significant advancements in the medical treatment enhancing nodular focus enclosed within a preexisting GIST
of GIST, complete surgical excision remains the treatment mass. This emergence of imatinib-resistant clones in patients
who had an initial favorable response to imatinib should be
of choice for localized GISTs. The option of radiotherapy is
considered as progression of the disease.
restricted due to its potential for toxicity to the neighboring
structures, primarily the intestines. Medical therapy with
imatinib, which is a selective inhibitor of ABL, KIT and Treatment of Imatinib-resistant
PDGFR tyrosine kinases, has shown to be of clinical benefit in Gastrointestinal stromal tumors
most cases as most GISTs have an activating mutation of KIT
Sunitinib is a structurally distinct tyrosine kinase inhibitor
or PDGFRA tyrosine-kinase receptors. By inhibiting KIT, MAP
(TKI), which has been approved worldwide as the second-
and Akt phosphorylation, imatinib reduces glucose uptake by
line treatment of patients with GIST following imatinib
the tumor cells by effecting a reduction in the levels of plasma failure either due to resistance or intolerance. The structure
membrane-bound Glut4 (glucose transporter), and thereby of sunitinib enables it to interact with the drug-binding
inducing apoptosis and/or growth arrest. [adenosine triphosphate (ATP)-binding] site of the target
kinases differently from imatinib, enabling it to bind to 3. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to
certain KIT proteins with greater affinity than imatinib. imatinib in gastrointestinal stromal tumor occurs through
Although, sunitinib is generally well tolerated, it inhibits a secondary gene mutation. Clin Cancer Res. 2005;11:4182-90.
much broader spectrum of kinases than imatinib, and this 4. Casali PG, Blay JY; ESMO/CONTICANET/EUROBONET Consensus
multi-targeted inhibition may potentially lead to a variety Panel of Experts. Gastrointestinal stromal tumours: ESMO Clinical
of clinical adverse events (such as mucositis, hand-foot skin Practice Guidelines for diagnosis, treatment and follow-up. Ann
reactions, hypertension, hypothyroidism or cardiotoxicity). Oncol. 2010;21 Suppl 5:v98-102.
Furthermore, the benefits of sunitinib are often short 5. Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are
lasting, with emergence of further resistance in less than an correlated with clinical benefit in patients with unresectable/
year. metastatic gastrointestinal stromal tumors. J Clin Oncol.
Other TKIs currently in clinical trials include sorafenib, 2009;27(19):3141-7.
dasatinib, masitinib and regorafenib; some of them showing 6. Demetri GD. Differential properties of current tyrosine kinase
promising results in the first-, second-, third-, or even later- inhibitors in gastrointestinal stromal tumors. Semin Oncol.
line settings. 2011;38 Suppl 1:S10-9.
Other avenues are being explored for the treatment of 7. Desai J, Shankar S, Heinrich MC, et al. Clonal evolution of resistance
GISTs, which include inhibition of downstream targets to imatinib in patients with metastatic gastrointestinal stromal
of receptor tyrosine kinases using agents, such as pan- tumors. Clin Cancer Res. 2007;13:5398-405.
ClassI PI3K inhibitors, dual PI3K/mTOR inhibitors and Akt 8. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of
gastrointestinal stromal tumors: a consensus approach. Hum
inhibitors.
Pathol. 2002;33:459-65.
9. Gunawan B, von Heydebreck A, Sander B, et al. An oncogenetic
tree model in gastrointestinal stromal tumours (GISTs) identifies
CONCLUSION different pathways of cytogenetic evolution with prognostic
implications. J Pathol. 2007;211:463-70.
Gastrointestinal stromal tumors have unique immunological 10. Kaifi JT, Wagner M, Schurr PG, et al. Allelic loss of Hox11L1 gene
and histochemical characteristics, which distinguish it from locus predicts outcome of gastrointestinal stromal tumors.
other GI tumors. With the ongoing advancements in the Oncol Rep. 2006;16:915-9.
field of medicine and technology, better understanding of 11. Kee D, Zalcberg JR. Current and emerging strategies for the
the nature of this tumor has become possible. However, management of imatinib-refractory advanced gastrointestinal
surgical treatment remains indispensable especially for stromal tumors. Ther Adv Med Oncol. 2012;4:255-70.
localized tumors, given that medical therapy is often fraught 12. Kindblom LG, Remotti HE, Aldenborg F, et al. Gastrointestinal
with hurdles including the development of drug resistance. pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors
Recent insights into the widening array of genetic aberrations show phenotypic characteristics of the interstitial cells of Cajal.
in GISTs open up prospects for the development of novel- Am J Pathol. 1998;152:1259-69.
targeted medical therapies. 13. Lasota J, Corless CL, Heinrich MC, et al. Clinicopathologic profile
of gastrointestinal stromal tumors (GISTs) with primary KIT exon
13 or exon 17 mutations: a multicenter study on 54 cases. Mod
BIBLIOGRAPHY Pathol. 2008;21:476-84.
14. Lasota J, Miettinen M. Clinical significance of oncogenic KIT
1. Agaimy A, Pelz AF, Corless CL, et al. Epithelioid gastric stromal
and PDGFRA mutations in gastrointestinal stromal tumours.
tumours of the antrum in young females with the Carney
triad: a report of three new cases with mutational analysis Histopathology. 2008;53(3):245-66.
and comparative genomic hybridization. Oncol Rep. 2007;18: 15. Medeiros F, Corless CL, Duensing A, et al. KIT-negative
9-15. gastrointestinal stromal tumors: proof of concept and
2. Agaimy A. Gastrointestinal stromal tumors (GIST) from therapeutic implications. Am J Surg Pathol. 2004;28:889-94.
risk stratification systems to the new TNM proposal: more 16. Miettinen M, Lasota J. Gastrointestinal stromal tumors
questions than answers? A review emphasizing the need for definition, clinical, histological, immunohistochemical, and
a standardized GIST reporting. Int J Clin Exp Pathol. 2010;3(5): molecular genetic features and differential diagnosis. Virchows
461-71. Arch. 2001;438:1-12.
17. Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal with malignant gastrointestinal stromal tumors. Mod Pathol.
tumors: recent advances in understanding of their biology. Hum 2004;17:1364-71.
Pathol. 1999;30:1213-20. 21. Sakamoto H, Kitano M, Matsui S, et al. Estimation of malignant
18. Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal potential of GI stromal tumors by contrast-enhanced harmonic
tumour. Lancet. 2007;369:1731-41. EUS (with videos). Gastrointest Endosc. 2011; 73(2):227-37.
19. Rubin JL, Sanon M, Taylor DC, et al. Epidemiology, survival, and 22. Tzen CY, Wang MN, Mau BL. Spectrum and prognostication of KIT
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20. Sabah M, Cummins R, Leader M, et al. Loss of heterozygosity of 23. Yang J, Du X, Lazar AJ, et al Genetic aberrations of gastrointestinal
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14
cHAPTER
Acute Diarrheal Diseases
Sabyasachi Ray
DEFINITION ETIOLOGY
There is a wide variation of bowel frequency and consistency
Infective
in normal population ranging from three times per day to
three times per week and hard to semisolid. Usually increased Bacterial
stool frequency is termed as diarrhea. The word diarrhea
was derived from Greek word meaning flowing through. Salmonella
The World Health Organization (WHO) defined diarrhea Shigella
as having three or more loose or liquid stools per day, or as Escherichia coli
having more stools than is normal for that person. Clostridium difficile
Acute diarrhea lasts for less than 2 weeks. If persists for Yersinia
more than 2 weeks, it is called persistent diarrhea. If the Plesiomonas
duration is longer than 1 month, it is considered as chronic
diarrhea. Majority of acute diarrhea subside spontaneously Viral
without any specific medication unless the patient is
immunocompromised. Pseudodiarrhea or hyperdefecation Rotavirus
(frequency is more but weight of stool is not increased) and Adenovirus
fecal incontinence (involuntary expulsion of rectal content) Astrovirus
should not be regarded as diarrhea. Norovirus
Acquired immunodeficiency syndrome (AIDS)
EPIDEMIOLOGY Parasites
Diarrhea is a common cause of death in developing countries Giardia
and the second most common cause of infant death (16%) Entamoeba histolytica
after pneumonia (17%) worldwide in this age group. In Isospora belli
2004, approximately 2.5 billion cases of diarrhea occurred Microsporidia
worldwide, which resulted in 1.5 million deaths among Blastocystis hominis
children under the age of 5 years. More than half of these were Cyclospora
in Africa and South Asia. In 2009, diarrhea was estimated to Cryptosporidium
have caused 1.1 million deaths in children aged 5 years and
over and 1.5 million deaths in children under the age of 5
years. Among children in the United States, acute diarrhea
Noninfective
accounts for more than 1.5 million outpatient visits, 200,000 Inflammatory bowel disease
hospitalizations, and approximately 300 deaths per year. Bowel ischemia
Acute Diarrheal Diseases 139
Malabsorption MECHANISMS
Hormone (serotonin)-secreting tumor
Food allergy/intolerance
Alcohol abuse
Osmotic
Medications (discussed below) In this form of diarrhea, excessive water is drawn into
Idiopathic the bowel, e.g. gluten enteropathy, pancreatic disease.
Nutrients present in the gut lumen pulls in water. Laxatives
Medications Causing Diarrhea relieve constipation by drawing water inside the bowel.
Magnesium and lactose can cause diarrhea and distension
Gastrointestinal in the same fashion. Lactose intolerance can have difficulty
Laxative abuse absorbing lactose after high intake of dairy products.
Antacids-containing magnesium Fructose malabsorptionexcess fructose intake can also
Misoprostol cause diarrhea. Sorbitol (often found in sugar-free foods) is
difficult for the body to absorb and in large amounts, may
Cardiac lead to osmotic diarrhea. When the offending agent is not
consumed, diarrhea stops.
Hydralazine
Quinidine
blockers Secretory
Angiotensin-converting enzyme inhibitors
Digitalis Considerable enhancement of active secretion or inhibition
Diuretics of absorption occurs in secretory diarrhea but there is no
significant structural damage. The most common example
is cholera toxin. It causes diarrhea by stimulating anion
Antibiotics secretion mainly chloride ions. Sodium accompanies it to
Ampicillin maintain balance in the lumen. In this type of diarrhea,
Erythromycin intestinal fluid secretion is isotonic with plasma even
Cephalosporins during fasting. It continues even when there is no oral food
Clindamycin intake.
Lipid Lowering Inflammatory/Exudative

Clofibrate
Gemfibrozil Inflammatory Diarrhea
Lovastatin
Intestinal secretion containing protein cannot get absorbed
adequately and lost due to malfunctioning brush border of
Psychological inflamed intestinal mucosa. Probable causes are infective, i.e.
Lithium bacteria, virus, or parasites and autoimmune, i.e. blood itself
Fluoxetine when present in colon may initiate diarrhea. Tuberculosis or
carcinoma colon or food poisoning due to various agents may
Neurological often be responsible.
Valproic acid
Ethosuximide Dysmotility
L-dopa
In this disorder, intestine becomes hypermotile.
Consequently, food traverses rapidly and intestinal mucosa
Miscellaneous does not get sufficient time for absorption of nutrients and
Thyroxine water, e.g. hyperthyroidism, which causes pseudodiarrhea
Theophylline and occasionally diarrhea. Hypermotility may be seen
Nonsteroidal anti-inflammatory drugs following bowel resection allowing less total time for
Colchicine. absorption of nutrients.
Infections Campylobacter isolates susceptible to ciprofloxacin are

more likely to cause severe diarrhea requiring hospital-based
Infectious diarrhea may be caused by bacteria, viruses and management. Severity of infection is not related to resistance
parasites and is a significant contributor to morbidity and of fluoroquinolone.
mortality worldwide. Infections are classified as follows. Clostridium difficile is now considered to be one of the
most important organisms associated with health care. This
infection is not only a complication of antibiotic treatment but
Noninflammatory also emerging in the community and in animals consumed
Vibrio cholerae secretes enterotoxin, enterotoxigenic E. coli as food. Over the last 10 years, prevalence of C. difficile has
(ETEC) or viruses. Consequently, absorption and secretion increased significantly.
from the enterocytes deranged, but no acute inflammation or
any damage to the mucous membrane.
Shigellosis
Shigellosis is endemic globally. Over 120 million persons are
Inflammatory affected. Majority of cases are in developing countries and are
Noninvasive cytotoxin produced by bacteria like below 5 years. It is estimated that over 1 million deaths occur
enteroaggressive E. coli, enterohemorrhagic E. coli, C. difficile every year; of which, 60% are below 5 years. The organism is
adhere to the intestinal mucous membrane, cytokines transmitted by contaminated food and water, contact of one
stimulated and inflammatory mediators are secreted by the person to another and, rarely, by house flies. Poor population
mucosa. staying in overcrowded conditions with very little awareness
Invasive bacteria like Salmonella spp., Shigella spp., of hygiene and poor sanitation get of S. dysenteriae type 1
Campylobacter spp. and E. Histolytica activate cytokines, frequently.
which cause acute inflammation by inflammatory mediators. Bacillary dysentery is caused by three types of Shigella
All these pathogens evolve to evade and modulate the host species, i.e. S. sonnei, S. flexneri, and S. dysenteriae. S. boydii
defense systems. infection is milder form. Antigen specificity of O-polysaccharide
portion of their lipopolysaccharide determines the subtypes
of these species. In developed nations, Shigella sonnei (single
BACTERIA serotype) causes dysentery in 77% of population. Shigella
flexneri (14 serotypes and subtypes) is most common globally
Campylobacter, Salmonella, Shigella, and some strains of and endemic in developing countries (60%).
E. coli are common. Clostridium difficile produces a toxin The disease manifests with acute diarrhea, which may be
causing severe diarrheas. The patients sustain profound watery with dehydration or dysenteric with blood and mucus
loss of fluids as well as electrolytes due to reductions in in stool.
absorption from intestinal mucosa and activated secretory The acute phase may be complicated with septicemia and
process. peritonitis, particularly in children with malnutrition as well
Campylobacter infection is one of the most common as hemolyticuremic syndrome. Antibiotic-resistant Shigella
causes of diarrhea caused by food poisoning. This infection strains are increasing steadily throughout the world, as there
is common in the developing world, and travelers to is no effective vaccine available. Resistance of Shigella to
foreign countries are also at risk of becoming infected cotrimoxazole and amoxicillin was found in majority during a
with Campylobacter. Most people present with diarrhea, 4-year survey in 2000 in Indian subcontinent, South Asia and
abdominal pain or cramps, and pyrexia within 25 days after China.
exposure to the organism. There may be nausea, vomiting Shigellosis was found to be 4/1,000/year in children below 5
and blood in motion. Symptoms usually last for a week. years during study conducted in Thailand. A study in thailand
Occasionally, patients get serious and life-threatening illness amongst children below 5 years demonstrated shigellosis in 4
by septicemia. Diagnosis of Campylobacter requires special per 1000 per year. S. sonnei and S. Flexneri were found to be
laboratory culture of stool and blood. Milder infections 90% resistant to antibiotics like cotrimoxazole, tetracycline,
subside with supportive treatments, i.e. oral fluid. Severe ampicillin, and chloramphenico. Shigella secretes toxins
cases require fluroquinolone or erythromycin. causing enterotoxicity, cytotoxicity, and neurotoxicity
VIRUS diarrhea, nausea, vomiting pain abdomen and fever for

34 days which may continue up to 6 weeks. Stools become
Viral infection of the gut is the most common cause of greasy, but there is no blood or pus as giardiasis does not
diarrhea, which usually lasts for 2 days and sometimes cause dysentery. Watery diarrhea may be followed by soft
called intestinal flu or stomach flu. Enteric adenoviruses, stools and constipation. Upper gastrointestinal symptoms,
human adenoviruses have 47 serotypes and six subgenera, of i.e. acidity, heartburn, nausea, early satiety, bloating, egg-
which types 40 and 41 of subgenus F cause enteric infection smelling halitosis, etc. may be aggravated by food. Common
resulting in gastroenteritis. It primarily affects children below constitutional symptoms are malaise, fatigue and weight loss.
2 years with watery diarrhea, vomiting, mild pyrexia and often
dehydrated diarrhea.
Monoclonal-based enzyme-linked immunosorbent assays
Entamoeba histolytica
is very sensitive and specific for diagnosis of gastroenteritis This protozoan causes amebic dysentery. In severe infection,
caused by adenovirus and may be used routinely for it invades into the gut wall causing amebic colitis. This
developing countries. parasite often traverses through the blood to various
Astrovirus causes significant morbidity. Astrovirus organs, particularly in liver causing amebic liver abscess. It
is an important cause of outbreaks of diarrhea among is transmitted by fecaloral route, particularly in areas with
children attending daycare centers. Younger children are poor sanitation. This allows contamination of drinking water
more frequently infected and often produce asymptomatic and food with feces. In these areas, up to 40% of people with
infections. Outbreaks of astrovirus gastroenteritis are more diarrhea may have amebic dysentery. In developing nations,
common in daycare centers. mortality in patients with severe infection may reach 100,000.
Norovirus (previously known as Norwalk agent) is Presenting symptoms may vary from mild diarrhea to severe
responsible for majority of adult infections. It causes over 90% form with copious blood- and mucus-mixed stool. Infection
nonbacterial gastroenteritis epidemic globally. Transmission occurs by cyst of Entamoeba histolytica. Trophozoite form
occurs mainly by contaminated food and water. Norovirus is usually does not cause infection, as it dies quickly after
often responsible for causing infection in closed community, excretion in stool.
e.g. school, hostel, hospital, etc. Mode of transmission is Diagnosis is established by microscopic examination
usually contaminated food/drink or infection from one of stool and finding cyst and is practiced widely worldwide
person to another. However, Norovirus infection can be even now. At least three samples should be examined, as cyst
controlled by chlorine-based infection or by heating food. may not be excreted daily. Trophozoite (motile form) may be
found in fresh sample of stool. Serological test is positive after
2 weeks of contracting infection with high titer of antibodies,
PARASITES particularly in liver abscess. Amoeba DNA may be detected in
recently available kit.
Parasites are generally responsible for chronic diarrhea
except Giardia and occasionally E. histolytica.
Isospora belli
Giardia This protozoon is usually found in the small intestinal
epithelial cells. It causes villous atrophy and crypt hyperplasia.
The unique feature of Giardia lamblia is that the parasite Patient presents with watery diarrhea, abdominal pain, and
consists of solitary cell and responsible for causing giardiasis. steatorrhea. It is commonly associated with AIDS infection.
It is prevalent throughout the world. In developed countries, Detection of oocysts using carbol fuchsin stain on microscopic
23% of the population is affected. In developing nations, up examination confirms the diagnosis. It usually responds to
to 30% may be infected due to unhygienic preparation, food trimethoprim/sulfamethoxazole.
handling by infected person, and poor sanitation. Infection in
patients with immunosuppression may be fatal.
Giardiasis is transmitted by the ingestion of infective cysts. Microsporidia
Two trophozoites are created from one cyst. Trophozoites Microsporidia can cause infection in healthy hosts but is
are noninfective, as they can stay alive only for a short largely a pathogen of AIDS patients. There are many species
period outside the body. Venereal transmission happens that can cause a diarrheal illness. They are small and difficult
through fecaloral contamination. Infected persons manifest to detect in stool and tissue samples. Albendazole is an
symptoms after a week or so with sudden-onset watery effective medical treatment for some species.
Blastocystis hominis Vaccines

It causes diarrhea and abdominal pain. A second infection Molecular biology studies of rotavirus replication and
may be found in many patients with this parasite. The patients pathogenesis have identified unique viral targets that might
are exposed to contaminated food or water. Majority do not be useful in developing therapies for immunocompromised
require any specific treatment. If symptoms persist, the children with chronic infections.
patients are treated with metronidazole 750 mg three times Rotavirus vaccine has the potential to decrease rates of
daily for 10 days. diarrhea. There are currently two licensed vaccines against
rotavirus. Live-attenuated vaccines are available for prevention
of the disease burden. Prevention of rotavirus-induced
Dientamoeba fragilis diarrhea may be possible by this vaccination. Replication
It is associated with pinworm infection. The treatment is of rotavirus may be carried out by molecular biology study
diiodohydroxyquin in adults and metronidazole in children. and this knowledge will be useful in finding appropriate
treatment of children suffering from chronic infection and
have compromised immune system. New vaccines against
Food Poisoning rotavirus, Shigella, ETEC and cholera are under development,
Food-borne illness can occur from infection or preformed as well as other causes of infectious diarrhea.
toxins. The most common causes of food-borne toxic illness
are: Immunity for Shigellosis
Staphylococcus aureus: Preformed enterotoxin from this
organism causes an acute-onset illness of nausea and After one attack of shigellosis, infection with that specific
vomiting with a short incubation period (16 hours) and type again is very unlikely for at least several years.
duration of illness of 24 hours. Symptoms include fever, However, they can still get infected with other types of
cramps and diarrhea. Transmission occurs from food Shigella. Presumably, this immunity is due to secretory
handler to food (especially food with high salt or sugar IgA. Three approaches to Shigella vaccine development
concentration), where toxin is formed as the organism that are under active investigation are (i) Polysaccharide
grows in the warm food conjugate vaccine-O specific-administered parenterally, (ii)
Clostridium perfringens: This organism produces a toxin Shigella lipopolysaccharidesdelivered by nasal route, (iii)
as it grows in insufficiently cooked, bulk-cooked meat Shigella deletion mutantlive, attenuated and invasive
or poultry, and produces toxin. Symptoms are watery administered by oral route.
diarrhea and crampy pain with an incubation of 824 All serotypes of live-attenuated Shigella vaccines are quite
hours and duration of 2436 hours safe and effective and effective in producing immunogenic
Bacillus cereus: It is associated with foods kept warm for response even against virulent strains. Evaluation of live
prolonged periods. The patient presents with cramps, oral vaccine is being carried out to find its ability to provide
diarrhea, and vomiting. The incubation period is 614 bacterial antigen to the gut-associated lymphoid tissues as
hours with duration of 2036 hours. Fever is not common. multivalent mucosal vaccines.
Miscellaneous: Mushroom poisoning, cholera, botulism,
tetrodotoxin poisoning from puffer fish, ciguatera fish,
paralytic shellfish poisoning. MANAGEMENT
Replacement of Fluid and Electrolytes
PREVENTION
Oral Rehydration Therapy
Hand Washing In many cases of diarrhea, replacing lost fluid and salts is
Hand washing can interrupt the transmission of diarrhea- the only treatment needed. Oral rehydration therapy (ORT)
causing pathogens. A Cochrane review of studies found that includes rehydration and maintenance fluids with oral
in institutions and community, promotion of hand washing rehydration solutions (ORS) combined with continued age-
led to significant reductions in the incidence of diarrhea appropriate nutrition. The combination of oral rehydration
(about 30%). This significant reduction is comparable to the and early nutritional support has proven effective throughout
effect of providing clean water in low-income areas. the world in treating acute diarrhea.
Multiple randomized controlled trial (RCT) studies preventing antibiotic-associated diarrhea mainly in adults.
clearly suggest that the duration of the disease does not Used alongside rehydration therapy, probiotics appear to be
shorten withholding milk in a child with mild dehydration. safe and have clear beneficial effects.
Recommencement of both breast and bottle milk feed is Digestive enzymes: For those with lactose intolerance, taking
nutritionally beneficial (WHO). Limitations of ORT, ongoing digestive enzymes containing lactase when consuming dairy
research in the areas of micronutrient supplements and products is recommended.
functional foods are reviewed as well. If diarrhea persists,
nutritional therapy, including dietary manipulations, is a
very important aspect in its management. Rehydration may Treatment for Giardia, E. histolytica, or
be carried out either by oral or intravenous route, depending E. dispar
upon the degree of dehydration.
Nitazoxanide (500 mg twice a day for 3 days) could play an
important role in the management of diarrhea caused by
Medications enteric protozoa, by reducing morbidity and costs associated
with these diarrheal illnesses.
Antimotility Agents on the basis of meta-analysis and RCT with nitazoxanide,
Loperamide: It is an opioid receptor agonist and acts on/ metronidazole, mebendazole, and albendazole, tinidazole
in the myenteric plexus and reduces the activity of the has a higher clinical cure rate than these drugs. It also has a
large intestine. It allows for more water to be absorbed out comparable side-effect profile and requires only one dose. A
of the fecal matter, decreases colonic mass movements, single dose of tinidazole is the best treatment.
and suppresses the gastrocolic reflex. Thus, it is effective in Randomized clinical study of nitazoxanide compared to
reducing the frequency and duration of diarrhea. metronidazole in the treatment of symptomatic giardiasis
in children showed that a 3-day course of nitazoxanide
Bismuth compounds: They reduce the number of bowel
suspension was as efficacious as a standard 5-day course
frequency in patient with travelers diarrhea but have no
of metronidazole suspension. Paromomycin, a member of
effects on duration of illness. These should not be used if
aminoglycoside family is used for giardiasis. Usual dosage
blood is present in the stool.
is 100 mg four times a day for 710 days. It inhibits Giardia
Codeine phosphate: It is an opioid and has multiple actions, protein synthesis.
i.e. pain control, cough suppressant, and antidiarrheal. In For amebic dysentery, nitroimidazole group of drugs
treating diarrhea, codeine works by acting on the opioid like metronidazole 250 mg three times per day, tinidazole
receptors found in the muscle walls of the intestines and and ornidazole 500 mg twice/day, secnidazole 500 mg/day
slows down the peristaltic movement, thereby, reducing the usually for 5 days are commonly used. They are effective and
frequency of passage of stool. More time is given for water have lesser adverse effects.
to reabsorb back into the body, which gives a firmer stool.
Common adverse effects are constipation, nausea, vomiting,
dizziness, drowsiness, headache, dry mouth, dependence, BIBLIOGRAPHY
and rarely, respiratory depression, hypotension, and urinary
retention. 1. World Health Organization. Diarrhoea. [online]. Available from
http://www.who.int/topics/diarrhoea/en/ [Accessed January,
Zinc: Diarrhea-affected children are benefited significantly
2013].
by supplementation with zinc. It also reduces mortality 2. Allen SJ, Martinez EG, Gregorio GV, et al. Probiotics for treating
significantly in developing countries in infants over the age acute infectious diarrhoea. Cochrane Database Syst Rev.
of 6 months. This supports the WHO guidelines that severe 2010;(11):CD003048.
diarrhea can be controlled by zinc supplementation. Low 3. Greenberg HB, Estes MK. Rotaviruses: from pathogenesis to
osmolarity oral rehydration solution with reduced proportion vaccination. Gastroenterology. 2009;136(6):1939-51.
of glucose is used throughout the world. Over last 2 decades, 4. Haque R, Mondal D, Duggal P, et al. Entamoeba histolytica
zinc tablets and ORS together have cured over 50 million of infection in children and protection from subsequent amebiasis.
children globally. Infect Immun. 2006;74(2):904-9.
5. Kale-Pradhan PB, Jassal HK, Wilhelm SM. Role of Lactobacillus in
Probiotics: Probiotics may offer a safe intervention in acute the prevention of antibiotic-associated diarrhea: a meta-analysis.
infectious diarrhea, and study demonstrated that the use Pharmacotherapy. 2010;30(2):119-26.
of probiotics reduced the duration of symptoms and the 6. Kiser JD, Paulson CP, Brown C. Clinical inquiries. Whats the most
severity. Meta-analysis suggests that Lactobacillus helps in effective treatment for giardiasis? J Fam Pract. 2008;57(4):270-2.
7. Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. 11. Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection:
Cochrane Database Syst Rev. 2008;(3):CD005436. new developments in epidemiology and pathogenesis. Nat Rev
8. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel Microbiol. 2009;7(7):526-36.
disorders. Gastroenterology. 2006;130(5):1480-91. 12. Viswanathan VK, Hodges K, Hecht G. Enteric infection meets
9. Navaneethan U, Giannella RA. Mechanisms of infectious intestinal function: how bacterial pathogens cause diarrhoea.
diarrhea. Nat Clin Pract Gastroenterol Hepatol. 2008;5(11): Nat Rev Microbiol. 2009;7(2):110-9.
637-47. 13. Wilson ME. Diarrhea in nontravelers: risk and etiology. Clin Infect
10. Noda M, Fukuda S, Nishio O. Statistical analysis of attack rate in Dis. 2005;41 Supp 8:S541-6.
norovirus foodborne outbreaks. Int J Food Microbiol. 2008;122(1- 14. Zaat JO, Mank TH, Assendelft WJ. WITHDRAWN: Drugs for treating
2):216-20. giardiasis. Cochrane Database Syst Rev. 2007;(2):CD000217.
15
cHAPTER
Liver Immunology
Julio Csar Aguilar
INTRODUCTION The major role of the immune system in the healing of

liver chronic infections suggests that immunotherapeutic
Liver regulates the levels of most blood components, having approaches can be used for the development of novel
a relevant function in the intermediary metabolism of products. Knowledge on the liver as lymphoid organ should be
carbohydrates, lipids, and glycolipids as well as in the synthesis a matter of attention for scientist working in the development
and secretion of several plasmatic proteins, enzymes, and bile of novel immunotherapeutic treatments. In the last 10 years,
salts. In addition, toxic compounds ingested with the food are there has been an increasing development on the knowledge
transported to the liver from the intestines by the portal vein of innate immunity and signaling mechanisms. It is possible
for detoxification. to predict that those immunotherapeutic strategies that take
After the year 2000, the specialized defense mechanism into account the recently emerging information about the role
of liver against infectious agents, toxins, and other bacterial of the liver as lymphoid organ would have a higher impact.
products was better understood. In addition, its mechanism
of self-protection from undesired responses against dietary
proteins or malignant cells transported by the blood flow was MAIN LIVER CELLULAR TYPES RELATED
better recognized. The detoxification of potentially harmful
dietary compounds may release carcinogens able to generate TO THE IMMUNE RESPONSE
many mutations together with the high rate of cell turnover of
Conventional and nonconventional cellular types are
this organ, further requiring a specialized tumor surveillance
inserted in the immune response activation or inhibition in
mechanism.
the liver. Hepatocytes comprise roughly two-thirds of liver
The particularities of the liver immune system need to be
studied for designing novel immunotherapeutic approaches, cells, the rest are cells unrelated to liver parenchyma and with
especially in the case of chronic hepatitis B or C. Tolerance functions highly related to the defense of the organ. This last
and immune response induction mechanisms have evolved third can be subdivided into endothelial cells (50%), Kupffer
in a number of signaling pathways, simultaneously allowing cells (20%), lymphocytes (25%), bile cells (5%) and stellate
the control of pathogens as well as the organ adaptation as cells (less than 1%).
a venous blood receptor from the intestines, guaranteeing Lymphocytes are disseminated throughout the parenchyma
complex and vital functions. and portal tracts. The normal human liver contains
A first look to liver cellular components during chronic approximately 1010 lymphocytes. Conventional T cells comprise
infections provides a better understanding on the need for CD8+ and CD4+ T cells, both of them with diverse repertoire of
antiviral effector cells not only to be rescued from tolerogenic T cells with T cell receptors comprising the a and b subunits
status, but also to be migrated into the liver parenchyma in able to recognize antigens within the context of major
order to exert its functions and, at the same time, to overcome histocompatibility complex (MHC) type I and II molecules,
the immune tolerance environment of the liver. respectively. CD8+ T cells outnumber CD4+ T cells and the
Historically, interferon (IFN) has been used as an effector/memory cells ratio is higher than in blood.
immunomodulating treatment against chronic liver diseases. Unconventional T cells comprise several cell types that
The novel modulating agents used in therapeutic vaccination can be grouped attending to the presence of natural killer
against chronic hepatitis B demands a profound knowledge of (NK) cell markers (known as NKT cells) or its absence. At the
that signaling system, which favors under normal conditions same time, there are classical and nonclassical NKT cells.
the induction of tolerance or immune response in this organ. Classical NKT cells originate in the thymus. Its T-cell receptor
comprises Va24/Vb11 subunits that recognize antigens phagocytosis ability of LSEC as well as its antigen processing
within the context of CD1 molecules. These cells become and presenting properties are similar to those of DCs.
activated by a-galactosylceramide (a-GalCer), and they are Sinusoids are slightly wider than lymphocytes in diameter;
phenotypically CD4+/CD8- or CD4-/CD8-. this characteristic promotes the contact between lymphocytes
The nonclassical NKT cells represents up to 30% of the and APCs after minimal increase of the systemic venous
intrahepatic lymphocyte population, a more abundant pressure and perturbations of the sinusoidal flow. These
proportion compared to other organs. NK cells control NKT perturbations in the flow aid lymphocyte extravasations. The
cell migration into the liver and their expansion within this fenestrations of the LSEC allow the access of lymphocytes
organ. NK cells have cytolytic activity against tumor or virus- into the Disse space and their contact with the extracellular
infected cells; its function is regulated by activating and matrix, stellated cells, resident hepatic DCs, Kupffer and
inhibitory receptor with the inhibitory signal as the dominant endothelial cells, and hepatocytes. The liver-specific tissue
one. morphology (Fig. 1) facilitates direct and indirect sensitization
Unconventional T cells without NK cell markers comprise of lymphocytes, modulates the immune response against
the T-cell subset bearing gd subunits (gd T cells). These cells hepatotropic pathogens, and contributes to the immune
account for 1525% of intrahepatic T cells, being the liver response induced by this organ.
one of the main sources of gd T cells of the body. These cells Surrounding the central veins and portal tracts are located
bear invariant or oligoclonal T-cell receptors that recognize a the resident DCs. Such cells originate in the bone marrow.
limited range of antigens, such as stress proteins and antigens Under physiologic conditions DCs are predominantly in an
of nonprotein nature. immature state susceptible to capture and process antigens.
The intrahepatic antigen presenting cells (APCs) also Sinusoidal endothelial cells, together with Kupffer cells
evidence the complexity of the hepatic immune system. produce interleukin (IL)-10 and transforming growth factor
Several types of APCs can be found in the liver. Such cells are (TGF)-b; these cytokines are inducible in stellate cells and
able to capture antigens passing through sinusoids or those contribute to the unique cytokine environment of the normal
released when pathogen-infected hepatocytes are destroyed. livermaking tolerogenic the resident DCs.
Liver APCs include Kupffer cells, liver sinusoidal The tolerogenic DCs inhibit proliferation and cytokine
endothelial cells (LSEC)which represent an unusual production of infiltrating lymphocytes through cytotoxic
vascular endothelial cell type and dendritic cells (DCs). These T-lymphocyte antigen-4 and programmed death 1 receptors.
three APCs are involved in the induction of tolerance under
noninflammatory conditions.
Kupffer cells originated from bone marrow-derived
circulating monocytes are the main subset of resident
macrophages in the body. These cells are located throughout
the sinusoidal vascular space, predominantly in the periportal
space. In this place are strategically located for eliminating
blood endotoxins passing through the sinusoids, to phagocyte
cellular debris and also microorganisms. The migration of
Kupffer cells through the sinusoids is slow; this characteristic
frequently perturbs the blood flow facilitating the contact of
circulating lymphocytes with different cell types. Kupffer cells
are able to pass through the Disse space getting into direct
contact with hepatocytes and phagocytizing the apoptotic
ones.
Liver sinusoidal endothelial cells are lined up with the
Fig. 1: Hepatic sinusoidal and APCs. The liver has several APC types
sinusoid similarly to the arterial, and portal and central that uptake the antigens passing through the sinusoids or those
veins vascular endothelia. Nevertheless, their morphology released by hepatocytes dying of infection with pathogenic agents.
considerably differs by forming a filter-shaped fenestrated The resident APCs comprise Kupffer cells, LSEC, and DCs. It has been
endothelium. LSEC express molecules that promote antigen also considered that stellated cells resident at the endothelial Disse
assimilation like the mannose and scavenger receptors. space and hepatocytes or hepatic parenchymal cells can also act as
This cell layer also expresses molecules to promote antigen liver APCs
presentation, such as the costimulatory CD40, CD80, and Abbreviations: APCs, antigen presenting cells; LSEC, liver endothelial
CD86 molecules. The receptor-mediated endocytosis and sinusoidal cells; DCs, dendritic cells
Liver Immunology 147
However, when becoming activated, DCs downregulate these developer should overcome such mechanisms controlling
receptors and increase its capacity to migrate through the the immune response in the liver, in order to contribute to
Disse space into lymphatic vessels in the portal tracts, finally eliminate a persistent pathogen away from this organ.
reaching the extrahepatic lymph nodes.
Immunological Functions of Liver:

BIOLOGY OF THE LIVER IMMUNE Sinusoidal Endothelial Cells
RESPONSE Liver sinusoidal endothelial cells bear scavenger receptors
and efficiently capture and present circulating antigens. It has
The APC function is a property of several liver cell types; the been demonstrated in mice that these cells express low levels
list includes LSEC, hepatocytes, DCs, Kupffer cells, and stellate of MHC II and CD80/CD86 costimulatory molecules, also
cells. All of them present antigens to nave T cells; however, evidencing their ability for antigen presentation and cross-
Kupffer cells and LSEC are strategically located to interact presentation to CD4+ and CD8+ T cells, such properties favor
with nave T cells coming from blood and circulating within the induction of tolerance.
sinusoids. The APC role of such cells will be explored further. In response to antigens presented by LSEC the nave CD4+
T cells produce IL-4 and IL-10 instead of IL-2 and IFN-g.
Dominance of IL-10 in the liver is not only determined by
Role of Dendritic Cells CD4+ T cells, but also by Kupffer cells and by intrahepatic
Hepatic DCs are usually found within the portal tracts rather CD8+ T cells. This environment modifies the expression of
than in the sinusoids. It is improbable within this context chemokine receptors in DCs, reducing its migration toward
immature DCs getting into contact with circulating nave the draining lymph nodes. T-cell sensitization in the presence
lymphocytes in spite of evidence on DCs translocation of IL-10 reduces its capacity to produce cytokines and also its
through the sinusoids. Therefore, it is improbable that effector functions.
immature DCs could activate circulating nave CD8+ T cells. CD8+ T cells cocultured with LSEC have a reduced
LSEC interfere the presentation capacity of DCs, particularly capacity to produce IL-2 and IFN-g, low cytotoxicity, low
affecting its costimulatory function (required to activate proliferative response and are also prone to apoptosis. Such
CD8+ T cells) and IL12 secretion. In the absence of interaction results evidence that LSEC antigen presentation results in a
with LSEC, DCs fully recover their cellular capacity to induce telerogenic CD8+ T cell rather than inducing effector function.
proliferation. This LSEC property is absent in hepatocytes and These properties can be re-established by exogenously adding
B cells. LSEC are not only able to tolerogenize T cells directly IL-12 to the cocultures of CD8+ T cells and LSEC.
but also to suppress the capacity to induce T-cell immunity in In a noninflammatory environment-lacking IL-2-, LSEC
the neighboring DCs. However, DCs that are mostly located antigen presentation contributes to tolerance while within
at portal tracts are poorly stimulatory due to their immature a proinflammatory context, LSEC downregulates MHC
state rather than being tolerogenized during their passage expression reducing its tolerogenic effect.
through the hepatic sinusoid.
The T cells activated within lymph nodes acquire a complete
effector function and take part in immunity; however, the T Functions of Kupffer Cells
cells activated within the liver become unresponsive or are The systemic tolerance to antigens within the portal vein
eliminated in a process causing an antigen-specific tolerance. depends on these cells, being considerably reduced by
Freshly isolated DCs from the liver are relatively immature their elimination. Several bacterial stimuli, including
and less immunogenic than spleen DCs. Intrahepatic DCs lipopolysaccharides (LPS) and superantigens activate
are relevant to the tolerogenic function of the liver since Kupffer cells. Cytokines released by Kupffer cells are relevant
all liver DCs secrete high levels of IL-10 and TGF-b leading to modulate proliferation and differentiation of other cell
to a negative regulation of the immune response and to the types. These cells produce tumor necrosis factor (TNF)-a
induction of a regulatory T-cell response. and IL-10 in response to physiological concentrations of
This network of regulatory mechanisms acting on DCs LPS, downregulating receptor-mediated antigen uptake and
enables the control of the liver over a potentially harmful MHC II expression by the LSEC and DCs, contributing to the
cytolytic immune response. It has been hypothesized that reduction in the activation of T cells. Kupffer cells also produce
this mechanism is advantageously used by the pathogens prostanoids, nitric oxide, and reactive oxygen intermediaries,
to develop a persistent infection. A therapeutic vaccine which suppress T-cell activation.
Kupffer cells produce IL-12 and IL-18; these cytokines LIVER T-CELL RESPONSE
regulate NK cell differentiation and promote their local
expansion, resulting in NK cells secretion of large amounts AND POTENTIALITIES FOR
of the antiviral IFN-g. Other cytokines secreted by Kupffer IMMUNOMODULATING VACCINES
cells promote neutrophil infiltration and antimicrobial
activity. Several studies characterize the phenotype and function
of pathogen-specific T cells, both in blood and within the
liver; however, only a few have addressed the mechanisms of
Functions of Natural Killer Cells intrahepatic antigens to induce a T cell-mediated response
Through activating or inhibitory receptors the hepatic NK and the sites where they are presented to CD8+ T cells in vivo.
cells modulate the liver damage by equilibrating the local The T cell-mediated protection against hepatotropic viruses,
production of pro- and anti-inflammatory cytokines. The NK such as HBV or hepatitis C virus (HCV), requires an immune
cell receptors involved in NK cell activation and lysis of target response capable of controlling the emergence, distribution
cells become activated in the absence of inhibitory signals and and expansion of the pathogen.
the presence of type I IFNs and IFN-induced CC chemokine Classically, unprimed CD8+ T cells localized in secondary
ligand 3 ligands. Activation also implies the burst of IFN-g that lymphoid compartments require two independent signals
stimulates hepatocytes and LSEC to secrete the chemokine to become fully activated. The first signal is provided by
(C-X-C motif ) ligand 9 (CXCL9) chemokine responsible for the interaction with the peptide-MHC class I complex
recruiting T cells into the liver. through the specific T-cell receptor. The second signal, the
costimulatory one, is antigen receptor-independent and
critical for the full activation of CD8+ T cells. Primed CD8+
Functions of Natural killer T Cells T cells can be activated by any APC but only professional
Natural killer T cells recognize nonpeptide antigens, such and properly licensed bone marrow-derived APCs can
as lipids and glycolipids from microorganisms cell walls. initiate unprimed CD8+ T cell responses by expressing co-
Antigenic recognition of NKT cells is restricted to the CD1 stimulatory molecules. These cells carry the antigen from the
molecule that can be expressed by hepatocytes and APCs infection site into lymphoid organs.
(including DCs, macrophages and B cells). Most of the classic It is currently under discussion if the antigens can be
NKT cells are activated by IL-12 produced by DCs and NK, efficiently presented within the liver or at draining lymph
mostly resulting in a Fas-mediated destruction of the target. nodes. It is not excluded that the antigens of hepatotropic
It has been considered that these cells are related to the agents could be taken up by LSEC and Kupffer cells and
polarization of both the local and systemic adaptive immune further presented to unprimed T cells which recirculate
responses, either pro- or anti-inflammatory due to the NKT through hepatic sinusoids or those localized at lymphoid
cells capacity to produce high levels of IFN-g and IL-4. These aggregates within the portal tracts.
cells carry out a function relevant to liver infections, since It has been traditionally established that cells should
mice deficient of NKT cells or CD1d are more susceptible migrate and CD4+ / CD8+ lymphocyte activation must occur
to certain viral and bacterial infections. Besides, it was within the regional lymph nodes, where mostly unprimed
demonstrated in a transgenic mouse model that activation CD8+ T cells can be found. Once activated, antigen-specific
of NKT cells with the synthetic CD1d ligand a-GalCer lymphocytes enter the bloodstream and localize to the liver,
increases the production of IFN-g and downregulate HBV where they exert their effector functions.
replication. A recent study suggests that priming of CD8+ T cells within
This property of NKT cells and specifically the result the lymph nodes and in the liver results in qualitatively
obtained by Kakimi et al. opened a window of opportunity different effector functions. In a transgenic mouse model
to the use of NKT cell activation as therapeutic tool. More simultaneously expressing the same antigen both within the
recently, in 2008, it was reported that the coadministration of liver and the lymph nodes, CD8+ T cells induce hepatitis only
a-GalCer together with the surface antigen of HBV (HBsAg) when T cells are primed within the lymph nodes. A defective
enhanced the induction and proliferation of anti-HBsAg cytotoxic immune response and a decreased CD8+ T cell half-
cytotoxic T cells. lifetime were observed when they are primed within the liver.
Uninfected APCs have deficient direct priming of CD8+ to avoid a harmful immune response against dietary antigens
T cells, in this scenario, the way to initiate a CD8+ T cell directly reaching the intestine through the portal venous
response is through cross-priming. In this process, an antigen blood together with the LPS. The secretion of IL-10 by
within a cell is taken up, processed, and cross presented Kupffer cells modulates the host immune response against
by another cell, being displayed within the MHCI context the proinflammatory cytokines secreted by the same Kupffer
to CD8+ T lymphocytes for their priming. It is relevant to cells.
notice that particulated antigens are especially efficient for The binding of microorganism-derived ligands to their
cross-priming. The HBsAg and core antigen of HBV (HBcAg), respective TLRs on the cells of the innate immune system
currently used in the novel therapeutic formulation NASVAC, activates two different signaling pathways: (i) dependent
are antigens capable of being cross-primed by different APCs. on the myeloid differentiation factor 88 (MyD88), activation
The HBcAg induces cross-priming once assimilated by B of the NF-B transcription factor and the secretion of
cells, activating them as very efficient APCs able to prime proinflammatory cytokines and (ii) MyD88-independent
nave T-cell response without T-cell help. pathway in which the signal is transduced through the TRIF-
Virus-infected cells are not a simple source of antigens; IRF-3 complex responsible for the synthesis of type I IFNs and
they play an active role in the quality and specificity of the proinflammatory cytokines associated with the activation of
T-cell priming by delivering preprocessed antigens. An NF-B. Although, in both pathways, there is a stimulation of
enhancing effect can be attributed to the debris of dying or proinflammatory cytokine production through NF-B, the
already died cells. In this way, the balance between immune production of IFN is limited to the signaling through TRIF-
tolerance and the induction of immune response can be IRF-3.
modulated. Cell wall components of the gram-positive bacteria, such
This mechanism depends on the number and viability of as the lipoteichoic acid (LTA) are detected through TLR-2,
infected cells, the amount of endogenously-expressed antigen and those of gram-negative bacteria through TLR-4. The
and the inflammatory environment. A potent inflammatory TLR-2 pathway is strictly MyD88-dependent, while the TLR-
immune response may circumvent costimulatory 4 pathway uses both MyD88 and TRIF-IRF-3 pathways. Viral
requirements for CD8+ T priming; a weak one could fail to products are detected through the TLR3, which is strictly
effectively present some antigens to CD8+ T cells. MyD88 independent and uses TRIF-IRF-3.
In case of a therapeutic vaccine candidate comprising Freshly isolated liver sinusoidal leukocytes from live
both HBsAg and HBcAg, the presence of virus-like antigens donors of hepatic transplants were cultured in presence
with capacity to be cross-presented and bearing activators of of poly-IC and LPS. The IL-10 produced by Kupffer cells
the innate immunity favor a proinflammatory scenario. The through MyD88-dependent pathway attenuated the levels of
E. coli-derived RNA/DNA associated with the HBcAg particle IFN-g secreted by NK cells. The double-stranded RNA analog
as well as the presence of 180230 monomers per particle poly-IC, which is detected by the TLR-3 via TRIF-IRF-3, did
increases the efficiency of APC by the high number of antigens not induce a substantial synthesis of IL-10, causing a strong
assimilated in a single endocytic event as compared to the secretion of IFN-g by the liver NK cells.
assimilation of soluble proteins. These characteristics favor In response to stimulation through TLR-2 and 4, there is a
the efficiency of the presentation/cross-priming process. local immunological mechanism within the liver modulating
toward tolerance by secreting IL-10. Alternatively, the
mechanism for antiviral activity is mediated by the stimulation
of TLR-3 through a MyD88-independent signaling pathway.
TOLL-LIKE RECEPTORS AND INNATE The TLR-3 activation induces an inflammatory response
IMMUNITY ACTIVATION WITHIN THE mediated by NK-cell stimulation, with fast production of
LIVER IFN-g that stimulates hepatocytes and LSEC to secrete the
CXCL9 cytokine to recruit T cells into the liver, modulating
There is a reciprocal stimulation between Kupffer and NK the hepatic damage.
cells as a result of their activation through toll-like receptors It is considered that recently activated lymphoblasts are
(TLRs) by pathogen-derived antigens, initiating the innate localized at hepatic sinusoids, and these cells are eliminated
immune response. by Kupffer cells, decreasing the excess of activated T cells.
The liver is exposed to nonpathogenic dietary antigens This process, however, does not occur in memory cells,
and also to LPS from the intestinal flora. The LPS is a potent which can repopulate the systemic immunity. In this sense,
stimulus to the innate immunity as ligand of TLR-4, activating it is considered that the liver regulates peripheral immune
the professional APCs. The liver has developed a mechanism homeostasis.
The role of the liver in systemic immune response is still In support of these clinical observations, results from animal
a matter of research, since this organ is the second largest models suggest that nave T cells reactive against antigens
reservoir of CD8+ T cells in the body after spleen. Activated expressed within the liver are tolerogenized within the liver
CD8+ T cells are entrapped and undergo apoptosis in the liver or ignore their antigens. In addition, the immunoreactivity
during the development of a systemic immune response. The studies against components of solid peripheral organs, such
liver loses its capacity to sequester activated CD8+ T cells in as pancreatic islet cells, salivary glands or thyroid antigens
the absence of TLR-4 stimulation, with an inverse correlation indicate that B or T cells could not be enough by their own to
between the frequency of CD8+ T cells entrapped within the induce the disease. Proinflammatory signals are required for
liver and the frequency of these cells in the circulation. an efficient induction of the disease.
The constant exposure to endotoxins coming from Viral infections promote adaptive immune response and
commensal bacteria in the intestine acts through TLR-4 and proinflammatory responses due to their capacity to activate
promote the adhesion of activated T cells. In the absence of the innate immune system through TLRs. Inflammation
inflammation, TLR-4 ligands are relevant for the capacity of resulting from naturally occurring systemic infections
the liver to sequester activated CD8+ T cells. Therefore, the upregulate costimulatory molecules within the liver leading
immune response is regulated under basal conditions. to tolerance subversion.
The use in therapeutic vaccination of TLR-3 ligands allows The activation of TLR-3 and TLR-7 after double- and
inducing a type of proinflammatory response with a signal single-stranded RNA recognition, respectively, promote
opposed to the response produced by TLR-4 activation. autoimmunity in mice exhibiting a high frequency of
In summary, the immune response within the liver can be functional autoreactive CD8+ T cells. The appearance and
reshaped by elements of the local environment by detecting progression of the disease correlates with the production of
pathogen-associated molecular patterns. This mechanism is IFN-a.
optimized to preserve the balance between tolerance to the Although the immune-mediated protection or destruction
self and also the host defense. of the liver depends on sensitization of T cells for liver-
Given that the liver is constitutively exposed to bacterial expressed antigens, even at high levels of primed T cells in
products, including the ligands of TLRs-2 and 4, it is blood, very few of them migrate into the liver. The migration
inappropriate for these signals to promote inflammation or of T cells to the target organ is also a relevant factor because
innate immunity in the liver. In contrast, TLR-3 stimulation the liver does not attract antigen-specific cells as chemokines
occurs in response to signals coming from viral infections. are expressed at low levels.
Therefore, the immune response mediated by signaling A second line for immunoprivilege of the liver-based
through TRL-3 is appropriate due to its capacity to induce on signaling through the TLR-3 was demonstrated in a
proinflammatory cytokines. mouse model expressing a protein of the lymphocytic
choriomeningitis virus. The proinflammatory signals
triggered by the TLR-3 signaling can redirect CD8+ T cells
IMMUNOPRIVILEGED STATUS OF THE toward the liver and cause its destruction. The mechanism
mediating this process involved the upregulation of IFN-a
LIVER, TOLL-LIKE RECEPTORS, AND and TNF-a-dependent genes that resulted in CD8+ T cell
IMMUNOMANIPULATIONS relocation and migration.
The activation of the innate immunity affects the balance
Two observations lead to consider the liver as an between tolerance and immune response in the liver. The
immunoprivileged organ: (1) The capacity of this organ selection of the adjuvant strategy for therapeutic vaccine
liver to induce toleranceknown long ago in the field of candidate against chronic infections of the liver should take
transplantology. Briefly, even when some organs are rejected into account this knowledge to design a rational strategy of
under normal circumstances, during simultaneous liver immunotherapy.
transplantation, such solid organ transplants from the same Therapeutic vaccine candidates must fulfill the antigenic
donor are accepted. These findings suggest the existence of as well as immune systems requirements, filling the gaps on
mechanisms to protect this solid organ from the attack of the innate response to establish an immune response able
immune system. (2) The autoimmune hepatitis due to the to control a chronic infection, for example HBV. Including
attack by B and T cells is a rare manifestation of autoimmune ligands able to trigger proinflammatory stimulation through
disease; however, the markers for the diagnosis of TLR-3, may redirect CD8+ T cells toward the liver.
autoimmune hepatitis, such as antimitochondrial antibodies, Currently available adjuvants able to activate TLR-3 have
are found in healthy people. being assayed in the past, for example, poly-IC. Such molecules
The reinforcement of a Th1 pattern of response is desirable

for therapeutic vaccine candidates. Preliminary findings from
chronic patients demonstrate the elimination of the virus
with slight increases in transaminase levels, suggesting that
the control of the virus is established by mechanisms similar
in nature to that mentioned above but without cytolytic
processes.
In summary, the induction of CD8+ T cells after
immunotherapy is the primary step to eliminate or control
chronically infecting viruses, in addition, the stimulation
A B C
of adequate innate immunity receptors like TLR-3 and
Figs 2A to C: Study of the physical aspect, chromatographic profile and -7 may provide further support to the subversion of the
presence of nucleic acids associated with the HBcAg. (A) Transmission immunoprivileged status of the liver.
electron microscopy: bars represent 200 nm; (B) Study of the size and
homogeneity of the HBcAg particle by HPLC. The upper and lower
charts show the HBsAg and HBcAg chromatographic profiles. Runs
were made on TSK-6000 columns at a flow rate of 0.25 mL/minute CONCLUSION
in PBS, applying 100 mL of each protein. Detection was carried out
In liver antigenic environment and to preserve their multiple
at 280 nm. Both particles had a retention time of 73 minutes. The
second peak in the HBcAg chart belongs to a nonproteic component and essential roles this organ has evolved a particular
in the solution where the HBcAg was diluted (EDTA); (C) Detection of immunological system. Liver anatomical situation favors
the presence of nucleic acids associated with the HBcAg by agarose a constant exposure to dietary antigens and also to the
gel electrophoresis. Lane 1: DNA molecular weight marker; lane 2: degradation debris of commensal and pathogenic bacteria.
HBcAg; lane 3: HBcAg treated with RNAse (2 mg/mL) at 37C for 6 The liver has developed unusually abundant representation
hours. The HBcAg subjected to treatment was at 0.447 mg/mL of conventional and unconventional innate immune
Abbreviations: HBcAg, core antigen of HBV; HPLC, high performance cells compared to the systemic immune system. Antigen
liquid chromatography; HBsAg, surface antigen of HBV; PBS, presentation in liver is carried out by DCs and Kupffer cells,
phosphate-buffered saline; EDTA, ethylenediaminetetra-acetic acid in addition a subset of liver nonhematopoietic cells (which
include LSEC), stellated and parenchymal cells are also
involved in antigenic presentation. These cells present the
have caused adverse reactions that limit its use, among antigens in a context of immunosuppressive cytokines and
them: high fever in most of the volunteers, lymphopenia, inhibitory cell surface ligands, favoring tolerogenic immune
hypotension episodes, among the most frequent. response against the antigens.
The Center for Genetic Engineering and Biotechnology, Liver is under high influence of signals coming from the
have produced and developed the HBcAg, a virus like particle intestine (LPS and LTA). This organ has adapted to promote
nucleoprotein (Figs 2A and B) with an electron-dense core anti-inflammatory signals in response to such signals that
(Fig. 2A). This antigen contains an RNA nuclear component stimulate TLR-2 and -4. On the other hand, the stimulation
(Fig. 2C) that has been characterized as double- and single- of TLR-3 in response to signals of viral infections promotes
stranded RNA and a minor component of DNA nature. The inflammatory responses. This mechanism is optimized for
concomitant presence in time and space of both the antigen maintaining the balance between tolerance and host defense.
and the adjuvant in this 28 nm HBcAg particle favors that The understanding of this complex signaling system may
antigens and TLR-3,-7 and -9 ligands could colocalize within be useful to optimize current immunomodulatory agents
the same endocytic vacuole together. This is a very effective because hepatotropic pathogens, including the hepatitis B and
way to optimize the modulatory properties of HBcAg. The C viruses, exploit the tolerogenic environment of the liver to
presence of HBcAg and HBsAg aggregates in a novel vaccine evade immunity leading to persistent infections. The immune
candidate confers a marked enhancement and modulation of response or tolerance can be manipulated by administering
the immune response against both antigens. therapeutic vaccines based on the analysis of mechanisms
A mechanism called cytokine-mediated viral control is a able to induce immune responses similar to those naturally
way to preserve the physical integrity of liver cells and control shown as effective to control chronic infections. Immune
viral replication simultaneously, preventing a potentially system should be manipulated in such a way to use innate
devastating effect of cytolytic mechanisms on liver. An immune activators that resemble the effect of those normal
immunomodulatory therapy should eliminate the virus mediators of a real activation of liver immunity during the
without liver damage. healing process.
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16
cHAPTER
Inborn Errors of
Bilirubin Metabolism
Cristiane Alves Villela-Nogueira
INTRODUCTION hepatic bilirubin clearance. Nowadays, it is known that

most of them have a genetic basis. This chapter focuses on
Inborn errors of bilirubin metabolism are rare diseases, but these situations which, although uncommon, but may be
they must be considered in every newborn and child that implicated in the differential diagnosis of many liver diseases.
present jaundice as well as in young adults. Although it may
not be easily diagnosed, most of the diagnosis is made on
clinical basis. Other differential diagnoses like septicemia CLINICAL APPROACH TO A PATIENT
and cholestatic diseases of the newborn are necessary.
Hence, understanding the basis of bilirubin production
WITH HYPERBILIRUBINEMIA
and its metabolism may provide a clue to the diagnosis, Hyperbilirubinemia may be related to several reasons,
management, and treatment of neonates at risk for jaundice such as overproduction of bilirubin through excessive
complications. Red blood cell (RBC), hemoglobin accounts
breakdown of hemoglobin, impaired hepatocellular uptake,
for approximately 85% of all bilirubin. The degradation of
conjugation or excretion of bilirubin, or regurgitation of
heme to biliverdin is catalyzed by heme oxygenase (HO), the
unconjugated and conjugated bilirubin from damaged
rate-limiting step in bilirubin production. Further, biliverdin
hepatocytes or bile ducts. A jaundiced patient presents a
reductase converts biliverdin to bilirubin, which is bound to
total serum bilirubin level of at least 3.0 mg/dL but jaundice
plasma albumin. This way, unconjugated bilirubin is a product
itself does not allow distinguishing between conjugated
of heme catabolism that occurs in the reticuloendothelial
and unconjugated hyperbilirubinemia. The presence of
system. It is lipid soluble and insoluble in water. In order to
coluria may indicate the presence of bilirubinuria and thus
be transported into the blood, this unconjugated bilirubin
must be solubilized. Unconjugated bilirubin is noncovalent- conjugated hyperbilirubinemia. If the patient has an isolated
bounded to albumin in plasma and passes through the hyperbilirubinemia, and the use of drugs that can interfere in
fenestrations in the endothelium lining the hepatic sinusoids conjugation of bilirubin is excluded, a genetic etiology should
into the space of Disse, where it dissociates from albumin be suspected.
and is taken up by the hepatocytes via a protein-mediated
facilitated process. It is then bound in the cytosol to a Hemolysis
number of proteins, including proteins in the glutathione
S-transferase superfamily. It is then conjugated with An increased bilirubin load may be explained by the presence
glucuronic acid in the hepatocytes and the enzyme uridine- of hemolysis. Hemolytic disorders enhance bilirubin
5-diphosphate glucuronosyltransferase (UDP-GT) catalyzes production by increasing the amount of heme available for
this conjugation. Conjugated bilirubin is secreted into the degradation. Of the congenital hemolytic disorders that
bile and enters the duodenum. In the small bowel, some of contribute to enhanced bilirubin production, glucose-6-
the bilirubin is hydrolyzed to yield unconjugated bilirubin phosphate dehydrogenase (G6PD) deficiency, an X-linked
and glucuronic acid. Most unconjugated bilirubin is excreted disorder, is the most common. Neonatal jaundice in G6PD
in the stool, but some is reabsorbed and returned to the liver deficiency can result from hemolysis triggered by exogenous
for reconjugation (enterohepatic circulation). Inborn errors agents (e.g. naphthalene) or occur spontaneously. This,
of bilirubin reflect an imbalance of developmental changes later, may reflect an interaction between G6PD deficiency-
in bilirubin production and metabolism characterized by associated hemolysis and coinherited conjugation defects,
an increased bilirubin load on hepatocytes and decreased such as Gilberts syndrome, which has been discussed later
in this chapter. Other less common genetic conditions that serum bilirubin responds to phenobarbital (CriglerNajjar
may predispose to enhanced heme degradation include red type II) decreasing bilirubin levels. Genetic lesions in any of
blood cell (RBC) metabolic enzyme defects, e.g. pyruvate regions of the UDP-GT1A1 gene cause both CriglerNajjar
kinase deficiency, RBC membrane defects, e.g. hereditary type I and type II syndromes. The gene frequency for Crigler
spherocytosis and hemoglobinopathies. Najjar type I is estimated to be 1:1000. CriglerNajjar type I
syndrome is characterized by marked hyperbilirubinemia
and high risk for kernicterus and, consequently, have a higher
Decreased Hepatic Bilirubin Clearance mortality rate if left untreated. In contrast, CriglerNajjar type
The second mechanism that is related to hyperbilirubinemia II or Arias syndrome is characterized by less intense levels
is an impaired hepatocyte uptake of indirect bilirubin. In of indirect hyperbilirubinemia as well as low but detectable
newborns, the normal hemoglobin level is 1518 mg/dL, so hepatic bilirubin UDP-GT1A1 activity. In most cases, further
the physiologic rate of RBC destruction is high. The levels UDP-GT1A1 activity can be induced by phenobarbital
of UDP-GT are still low in the newborn and any increase in administration. In some cases, marked hyperbilirubinemia
the rate of bilirubin formation can overwhelm its capacity to occurs in CriglerNajjar type II making it difficult to
conjugate. distinguish this entity from CriglerNajjar type I syndrome.
Within the hepatocyte, unconjugated bilirubin is The gene frequency for CriglerNajjar type II syndrome is
conjugated with glucuronate via the enzyme activity of UDP- also estimated to be 1:1000. These rare but important clinical
GT. Unconjugated bilirubin is rapidly and selectively taken syndromes must be included in the differential diagnosis of
up across the basolateral membrane of the hepatocyte. prolonged marked indirect hyperbilirubinemia. Treatment
Mutations leading to cholestasis have been described in in CriglerNajjar type I syndrome is consisted of exchange
humans and animal models. One such mutation results in therapy immediately after birth and phototherapy that must
a deficiency of the canalicular multispecific organic anion be continued for years until liver transplantation which
transporter (cMOAT) also known as multidrug resistance should be considered in adolescence in most of the affected
associated protein-2 (MRP-2) is the cause of conjugated patients. For CriglerNajjar type II syndrome, a disease with a
hyperbilirubinemia in DubinJohnson syndrome. good prognosis, treatment consists of phenobarbital. Future
treatment may be the implementation of gene therapy.
Inborn Errors of Hepatic Bilirubin

Conjugation Gilberts Syndrome
Gilberts syndrome, originally described at the turn of the
There are congenital inborn errors of bilirubin UDP-
20th century, is characterized by mild, chronic or recurrent
GT1A1 expression, commonly referred to as the indirect
unconjugated hyperbilirubinemia in the absence of liver
hyperbilirubinemia syndromes. These include CriglerNajjar disease or overt hemolysis. Hepatic bilirubin UDP-GT activity
type I and type II (Arias) syndromes and Gilberts syndrome is reduced to approximately 30% of normal in affected
among others like galactosemia and biliary atresia; these last subjects and more than 95% of their total serum bilirubin
are not related to the inborn errors of bilirubin metabolism. is unconjugated. Typically, indirect hyperbilirubinemia
These are uncommon and result from biliary obstruction associated with Gilberts syndrome is seen during fasting or
or impairment of hepatic uptake, conjugation or canalicular its association with an ongoing illness. Gilberts syndrome
transport of bilirubin. Hyperbilirubinemia may be is common affecting approximately 9% of the population. A
unconjugated or conjugated, depending on whether the genetic basis for this disorder has recently been defined. It has
etiology is inadequate conjugation or inadequate biliary been observed that a mutation in the TATAA element in the
secretion. This type of disorder should be suspected if 5 promoter region of the UDP-GT gene results in reduction
jaundice is prolonged beyond the first week of life. in enzyme activity to approximately one-third of normal. It is
more common in males than in females. Although Gilberts
syndrome is most commonly diagnosed in young adulthood,
CriglerNajjar Syndrome investigators have long speculated that this disorder might
CriglerNajjar type I and type II syndromes are characterized contribute to indirect hyperbilirubinemia in the newborn
by a significant elevation of serum unconjugated bilirubin period. Identification of a molecular marker for Gilberts
(higher than 150400 mmol/mL). There are two types of the syndrome has provided investigators with an important tool
syndrome, one in which serum bilirubin does not respond to to study the role of Gilberts syndrome in the pathogenesis
phenobarbital (CriglerNajjar type I) and the other in which of neonatal jaundice. A genetic interaction between G6PD
Inborn Errors of Bilirubin Metabolism 155
Table 1: Clinical and genetic characteristics of Gilberts syndrome and CriglerNajjar syndrome types I and II
Clinical and genetic characteristics Gilberts syndrome CriglerNajjar type I syndrome CriglerNajjar type II syndrome

Total bilirubin (mg/dL) 15 1020 >20
UDP-GT activity 50% 0 10%
Kernicterus No yes Rare
Type of inheritance Variable Autosomal recessive Autosomal recessive
UDP-GT gene mutation Promoter region Coding region Coding region
Fenobarbital improvement Yes No Yes
deficiency and Gilberts syndrome can also contribute to bilirubin secretion is impaired owing to a deficiency of the
the development of neonatal hyperbilirubinemia. Studies in transporter protein MRP2, which is located in the canalicular
adults confirm that the Gilberts genotype in combination with membrane of the hepatocyte. In DubinJohnsons syndrome,
G6PD deficiency, and coinherited Gilberts and -thalassemia the serum conjugated bilirubin is around 5085 mmol/L
result in accentuated hyperbilirubinemia in this age group but can be elevated up to 385 mmol/L. It can be increased
as well. After the exclusion of the diseases associated with during pregnancy. Coproporphyrin isomer 1 is increased.
unconjugated hyperbilirubinemia, the diagnosis of Gilberts Hepatobiliary secretion of hydroxy iminodiacetic acid HIDA
syndrome might be reinforced upon a doubling in serum is increased. Routine liver function tests are normal. The
bilirubin upon fasting (400 kcal diet for 48 hours). This test lacks disease has a benign course with a good prognosis, and
specificity. The elevation of unconjugated bilirubin can also be treatment is not needed.
obtained by the administration of intravenous nicotinic acid. Patients with Rotor syndrome present with both conjugated
Phenobarbital can stimulate UDP-GT activity and reduces and unconjugated abnormal bilirubin. Different from Dubin
unconjugated bilirubin levels. The UGTA1* 28 genes related Johnsons syndrome, the liver biopsy is completely normal on
to Gilberts syndrome can be tested by a reverse transcriptase histology and the total urinary coproporphyrin is elevated.
polymerase chain reaction. In Gilberts syndrome, the It is a rare disease and a defect has not yet been identified.
mildly elevated indirect serum hyperbilirubinemia is of no Diagnosis should be suspected in patients with a predominant
clinical consequence and contrasts with that of Crigler mildly elevated conjugated bilirubin in whom liver function
Najjar syndrome. A comparison among Gilberts syndrome tests are normal. The prognosis is good. Treatment is not
characteristics and those of CriglerNajjar syndrome types I required.
and II are displayed in Table 1.
Increase of Conjugated Bilirubin: Dubin SUMMARY

Jonhsons and Rotor Syndrome The inborn errors of bilirubin are rare diseases that should
Regarding the inborn errors of bilirubin metabolism that be included in the differential diagnosis of a patient with an
present with conjugated hyperbilirubinemia, two diseases isolated hyperbilirubinemia mainly in the neonatal period
are described: (i) Dubin-Johnsons syndrome and (ii) Rotor and childhood. Nowadays, most of these diseases have a
syndrome. Dubin Johnsons syndrome is characterized by genetic-based physiopathology. Although genetic tests might
elevation of conjugated bilirubin in serum alone without any be applied to confirm the diagnosis, most of the time, it is
abnormality in liver function or serum enzymes. Remarkably, based on clinical and laboratory findings, such as the serum
a black lysosomal pigment is seen on liver biopsy, which leads level of bilirubin and its conjugated/unconjugated profile. In
to the black liver aspect and can be called the black liver general, these diseases cause no liver dysfunction and have a
jaundice. However, there is no correlation between the liver good prognosis except for CriglerNajjar type I syndrome. This
aspect and hyperbilirubinemia. It is an autosomal recessive is a severe disease with a high mortality rate if left untreated.
disease and the gene frequency in Japan is 1:800,000. In the future, it is possible that gene therapy may be useful to
The pathogenesis of this syndrome is that the conjugated diagnose and control these entities.
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UDP-glucuronosyltransferase in Gilberts syndrome. Lancet. canalicular multispecific organic anion transporter gene causes
1995;345:958-9. the Dubin-Johnson syndrome. Hepatology. 1997;25:1539-42.
2. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the 7. Sinaasappel M, Jansen PL. The differential diagnosis of
reduced expression of bilirubin. UDP-glucuronosyltransferase 1 Crigler-Najjar disease, types 1 and 2, by bile pigment analysis.
in Gilberts syndrome. N Engl J Med. 1995;333:1171-5. Gastroenterology. 1991;100:783-9.
3. Ciotti M, Obaray R, Martn MG, et al. Genetic defects at the UGT1 8. Valaes T. Bilirubin metabolism. Review and discussion of inborn
locus associated with Crigler-Najjar type I disease, including a errors. Clin Perinatol. 1976;3:177-209.
prenatal diagnosis. Am J Med Genet. 1997;68:173-8. 9. Watchko JF, Daood MJ, Biniwale M. Understanding neonatal
4. Fox IJ, Chowdhury JR, Kaufman SS, et al. Treatment of the Crigler- hyperbilirubinemia in the era of genomics Semin Neonatol.
Najjar syndrome type I with hepatocyte transplantation. N Engl J 2002;7:143-52.
Med. 1998;14:1422-6. 10. Wolkoff AW, Wolpert E, Pascasio FN, et al. Rotors syndrome.
5. Jansen PL. Genetic cholestasis and hyperbilirubinemia. In: A distinct inheritable pathophysiologic entity. Am J Med.
Arroyo V, Navasa M, Forns X, Bataller R, Snchez-Fueyo A, Rods 1976;60:173-9.
17
cHAPTER
Hepatitis A and E Viruses
P Karayiannis
INTRODUCTION HEPATITIS A VIRUS

Hepatitis A and E viruses (HAV, HEV) are the causative
Virion Structure and Physical Properties
agents of type A and E viral hepatitides, respectively.
They share a common route of transmission, namely The virus belongs to the picornaviridae family of viruses and
the fecaloral one and have the same outcome in that is the only member of the hepatovirus genus. The virion lacks
infection culminates in complete resolution of disease. an outer envelope, measures 27 nm in diameter and has an
Epidemiology of infection for both the viruses has been outer capsid which consists of 60 capsomeres, each made
changing since their discovery, because of improvements up of the same structural viral proteins, namely VP1, VP2,
in public and domestic sanitary conditions and rising VP3 and perhaps VP4. This encloses the RNA genome of the
living standards. Although still a problem in the areas of virus which is single stranded and of positive polarity, being
developing world where they are endemic, sporadic cases approximately 7500 nucleotides in length (Fig. 1).
and small outbreaks do occur in developed countries The virus is resistant to bile acids and can persist in the
from time to time. In the case of HEV, such cases are not environment including surfaces, seawater, fresh water,
restricted to travelers who visit endemic areas, but it seems and soil for long periods. It survives on human hands and
that they are due to autochthonous zoonotic infections, as fomites, and can be inactivated by heat (>85C), formalin, and
at least two HEV genotypes are present in pig populations. chlorine.
There is an effective HAV preventative vaccine, which is
highly antigenic and immunogenic. A vaccine has been
trialed in Nepal for HEV prevention and although shown
Genome Organization
to be effective, it has not as yet become commercially It contains a single large open reading frame (ORF) that
available. encodes for a polyprotein that is post-translationally
Fig. 1: Genome organization of hepatitis A virus. The polyprotein open reading frame (ORF) is divided into the structural (P1) and nonstructural
regions (P2 and P3), which after processing yield the mature products as indicated. 2A is involved in viral morphogenesis, 2B is a host range
determinant, whilst the function of 3A remains unknown. The 5 noncoding region (NCR) contains the internal ribosome entry site (IRES) and
attached to it the VPg protein. The 3 NCR ends with a poly-A tail
processed by the viral protease mostly to yield a number replication of HAV RNA as detailed above. Progeny positive
of precursors and mature viral proteins. The polyprotein is sense RNA strands synthesized from the negative sense
divided into three regions; P1-2A which yields the structural replicative intermediate are packaged into virus particles
proteins from its amino-terminal end, and 2BC and P3 which with the assembly of the structural proteins into a capsid
cover the remainder two-thirds of the polyprotein from which after the late processing by a cellular protease probably of the
the nonstructural proteins involved in the replication of the cleavage between VP1 and 2A and the maturation cleavage of
virus are derived. The ORF is flanked at the 5 and 3 ends of VP0 to form VP2 and VP4. Whether the latter forms part of
the genome by stretches of nucleotides that do not encode the capsid, remains unclear. The mature virions are trafficked
proteins and are referred to as noncoding regions (NCR), with through vesicles and secreted into bile canaliculi and from
critical roles in the translation and replication of the genome their through bile to the small intestine.
respectively. The 5 NCR forms an internal ribosome entry site
(IRES) for cap-independent translation of the ORF. Instead,
covalently linked to this end of the genome is a small protein
Laboratory Detection
referred to as VPg or 3B which is uridylylated, and therefore The infection is typically acute in nature and the incubation
likely responsible for priming negative sense RNA synthesis period is between 15 days and 50 days following exposure.
(replicative intermediate) initiated at the extreme end of Viral shedding in the feces precedes the rise in serum alanine
the 3 NCR, which is polyadenylated. VPg is also involved in aminotransferase (ALT) levels and overlaps with the acute
subsequent positive-sense progeny RNA synthesis using the illness, but this wanes as antibody against the virus appears
negative strand as template. Of the non-structural proteins, (Fig. 2). The appearance of serum IgM anti-HAV is diagnostic
most important are 3C or the cysteine protease, which is of acute infection. This antibody persists for 26 months and
responsible for the processing of most of the polyprotein rarely, in low titer, for up to 1 year. It gives way to IgG anti-HAV,
cleavages to yield a number of precursor and mature products, which indicates neutralizing immunity against the virus and
and the 3D or RNA-dependent RNA polymerase responsible lifelong protection from re-exposure.
for viral replication. Biochemical tests other than ALT include measurement
Three genotypes of the virus appear to be circulating in of bilirubin and alkaline phosphatase levels, as well as
the human population as revealed by sequencing studies of prothrombin time. Transaminase levels can reach very
isolates from different parts of the world. Each genotype is high levels (up to 10,000 IU/L), bilirubin 510 mg/dL and
further subdivided into two subgenotypes. prothrombin time ranges between 11 seconds and 15 seconds.
Life Cycle of the Virus Epidemiology

The virus enters the body through the gastrointestinal tract The protracted shedding of the virus in feces and its resistance
following ingestion of contaminated food or water, and in the to desiccation in ambient temperatures and stability at low pH,
marmoset animal model, there is suggestive evidence that it ensure its persistence in the environment. These properties
replicates in the gut mucosa. This is followed by a brief period facilitate its transmission through contaminated food and
of viremia when the virus infects and replicates within the water in endemic areas of the world with poor sanitary
hepatocytes as the liver is the main site of virion production. conditions. Ingestion of improperly cooked clams and oysters
The cell receptor that may be involved in virus uptake remains from sewage contaminated sea waters is a well-documented
to be identified although there are suggestions that attachment risk and was responsible for the Shanghai outbreak which
may involve the asialoglycoprotein receptor via IgA-virus affected over 292,000 people in 1988. Similarly, fruit and
complexes or the HAVCR1/TIM (T cell immunoglobulin vegetables washed with contaminated water, or frozen soon
mucin) receptor with its IgA1 lambda ligand, which has a after, have been the source of HAV outbreaks in the Western
synergistic effect on virus-receptor interaction. The virus, World. Transmission can also occur with close personal
possibly as an immune complex, is also seen in Kupffer cells. contact with an infected person, whilst in developed countries
Following internalization and uncoating, the viral genome is groups at risk include men who have sex with men, illicit drug
directly translated into the polyprotein which is co- and post- users, holiday makers to endemic areas, people in contact with
translationally processed by the 3C protease to the mature infected children in daycare centers and employees working
products, except for the further cleavage of two resulting there, and rarely by transfusion of blood. The disease occurs
capsid protein precursors, namely VP0 (VP4-VP2 or 1A-1B) sporadically or in epidemics, and in children under the age
and VP1-2A. All the nonstructural proteins form a replicase of 15 years, it is largely asymptomatic, whilst in adults overt
complex, which is membrane bound and is involved in the disease may occur in more than 70% of cases.
Hepatitis A and E Viruses 159
Fig. 2: Temporal relationship following hepatitis A virus infection between serological and biochemical markers detected over time
The incidence of HAV infection in the early 1990s varied Clinical Course
from 5 cases per 100,000 population in Northern Europe and
Japan to 9.1 in the USA and 60 per 100,000 in Africa and parts In children, the disease is frequently subclinical, but in adults,
of South America. This incidence has been dropping steadily it is more serious and prolonged. Fulminant hepatitis and
as a result of improved sanitary conditions, and in those death are rare complications (0.3% of cases in the US in 2006).
countries that have instituted childhood vaccination against Symptoms include abrupt onset of fever, malaise, anorexia,
HAV, the drop has been more dramatic. nausea, vomiting, abdominal pain, and headache. Icterus is,
accompanied by the appearance of pale, clay-colored stools
and jaundice. A relapse in hepatitis occurs in about 1020%
Pathogenesis of symptomatic patients, which lasts for several months and
The virus is not thought to be directly cytopathic and is accompanied with persistent fever, pruritus, jaundice,
hepatocellular damage is likely the result of immune mediated diarrhea and weight loss, whilst biochemical markers remain
responses; the mechanisms responsible for this are poorly deranged. Such patients maintain low levels of IgM anti-HAV
characterized. Following infection, the virus effectively blocks and may continue to shed virus in the stools. There is no
the activation of interferon regulatory factor 3 (IRF-3) which chronic carrier state.
is effected by signaling through the retinoic acid-inducible
gene I (RIG-I) pathway of the innate immune response. Prevention
RIG-I interaction with double stranded RNA normally leads
to activation of a signal transduction pathway culminating Protection against HAV infection can be achieved through
in the phosphorylation of IRF-3, a transcription factor that passive and active immunization. Immune serum globulin
translocates to the nucleus and induces transcription of (ISG) efficacy depends on the antibody concentration and
interferon b mRNA. This allows the virus to replicate at high hence the source of the plasma. ISG must be given within 2
levels during the incubation period causing no obvious weeks following exposure (0.02 mL/kg IM). In this situation,
liver pathology. The latter becomes obvious with the rise in it is 8090% effective.
transaminases and the activation of the adaptive immune For preexposure prophylaxis, the HAV vaccines consist
response. Apart from the humoral immune response that of tissue culture virions, which have, after purification, been
includes the production of IgM and IgG anti-HAV antibodies, inactivated with formaldehyde treatment. The vaccine also
secretory IgA is also produced, but its role in protection contains alum adjuvant. There are two HAV vaccines, HAVRIX
is limited. Recruitment in the liver of virus-specific HLA- (GSK Biologicals) and VAQTA (Merck), whilst TWINRIX
restricted T lymphocytes has been documented, and these (GSK) is in combination with the hepatitis B virus vaccine.
cells may be responsible for clearance of infected cells and, The vaccine is safe and highly immunogenic, eliciting near
therefore, for liver injury. 100% immunity in vaccinated individuals. Elicited antibodies
are broadly reactive against the single serotype of the virus Virion Structure and Physical Properties
and long lasting, persisting for up to 25 years as kinetic
models indicate. A single 1 mL dose of vaccine in adults Hepatitis E virus has recently been assigned to a new family of
is followed by a booster 612 months later (1440EL.U of viruses, namely the hepeviridae, under the genus hepevirus.
HAVRIX or 50U of VAQTA). Children 12 months (minimum The virion measures approximately 3234 nm in diameter and
age) to 18 years of age receive 0.5 mL of the vaccine under the does not possess an outer envelope. The outer coat or capsid
same immunization schedule (CDC recommendations). The of the virus which consists of a single protein has icosahedral
TWINRIX vaccine is administered on a 0-, 1-, and 6-month symmetry and encloses the viral RNA genome. This is single-
schedule in persons aged more than or equal to 18 years and stranded, of positive polarity, and has a total length of 7.2 kb.
elicits antibody responses to both HAV and HBV comparable As in the case of HAV, it withstands the acidity of the stomach
to their single-antigen counterparts. and the bile salt action in the small intestine, from where it is
A live attenuated HAV vaccine has given subcutaneously taken up into the circulation and transferred to the liver.
has been in use in China for a while and shown to be safe and
effective in preventing overt disease.
Travelers to areas where the virus is endemic or where
Genome Organization and Molecular
sanitary conditions are poor should be vaccinated, as should Biology
military personnel, missionaries and aid workers stationed The genome has at its extreme 5 end a 7-methylguanosine
in such regions. High-risk groups that should be vaccinated cap, a short 5 NCR which is then followed by a coding region
include intravenous drug users, promiscuous gay men, that is divided into three open reading frames (ORF1, 2 and
patients with clotting factor disorders, and patients with 3) and finally a short 3 NCR terminating in a poly(A) tract
chronic viral liver disease as such patients run the risk of (Fig. 3). The 5 and 3 NCRs of about 26 and 6875 nt in length,
developing fulminant hepatitis if superinfected with HAV. respectively are highly conserved, playing essential roles in
Finally, food handlers, sewage workers, and personnel at replication and/or replication as is the case in many other
daycare centers may also be vaccinated. In the United States RNA viruses. The three ORFs are arranged in the order ORF1-
regions with recommendations for childhood vaccination ORF3-ORF2, with ORF3 largely overlapping with ORF2.
against HAV have seen a dramatic drop in reported HAV ORF1 encodes a polyprotein (186 kDa) which is thought to
cases. As a result, CDC now recommends universal childhood be the precursor of the nonstructural proteins of the virus and
vaccination against HAV. Other countries, however, have not is translated directly from the genomic RNA. The proteolytic
introduced universal childhood vaccination yet, basing their processing of this polyprotein remains unclear but appears
decision on costbenefit reasons, as the vaccine is expensive to contain regions with amino acid sequence motifs that
for them. are associated with methyl transferases (consistent with
the presence of a cap), papain-like cysteine proteases, RNA
helicases and RNA-dependent RNA polymerases.
HEPATITIS E VIRUS Recent work in a replicon system has indicated that
both ORF2 and ORF3 proteins are translated from a single
Hepatitis E virus is also transmitted through the fecal-oral bicistronic subgenomic mRNA. ORF2 encodes the 660 amino
route, commonly by contaminated water supplies, and shares acid long capsid protein. The protein has an arginine rich
many of the epidemiological and clinical characteristics region likely involved in interactions with the negatively
of HAV infection. Thus, it causes a self-limiting disease charged viral RNA. The capsid protein carries in addition
presenting as acute, icteric hepatitis with eventual complete antigenic epitopes that are useful in virus detection and
recovery. The virus has been in the past 50 years responsible appear to elicit a neutralizing antibody response.
for major outbreaks of infection in many developing countries The ORF3 encoded protein is thought to be about 114
in Asia, Africa, and Latin America. Since the first documented amino acids long, but whether the protein constitutes a
epidemic of the virus which occurred in Delhi, India in structural or a nonstructural protein is still not known. ORF3
19551956, there followed others in subtropical and tropical protein expressed in eukaryotic cells associates with the
regions of the world which have occurred in conditions of cytoskeleton and thus likely involved in virus assembly. It also
poor sanitation, overcrowding, and flooding. interacts with cellular proteins involved in cell signaling.
Fig. 3: Genome organization of hepatitis E virus. Open reading frame 1 (ORF1) and its translated products are encoded by the positive-sense
genomic RNA. ORF3 and 2 are contained in the bicistronic subgenomic mRNA, encoding for a protein of unknown function and the capsid
protein, respectively. Also shown are the CAP, 5 and 3 noncoding regions (NCRs) and the poly-A tail
Nucleotide sequence analysis of isolates from epidemic The virus can be detected in feces of infected patients
and sporadic cases from all over the world has identified four in the period preceding the rise in transaminases. Reverse
genotypes of the virus; genotype 1 and 2 are found in humans, transcription polymerase chain reaction (RT-PCR) using
and genotype 3 and 4 in humans as well as swine, whilst each primers from the polymerase and ORF2 regions can be
genotype is subdivided into a number of subtypes. There is used most efficiently in the detection of HEV-RNA in stools
only one recognized serotype in the mammalian viruses. and serum samples from patients, animals, as well as
environmental samples. Detection of HEV-RNA in serum is of
shorter duration and does not often extent beyond the acute
Viral Life Cycle phase (Fig. 4).
The viral receptor on the hepatocyte membrane has not
been identified so far. Replication occurs in the cytoplasm
and proceeds through a negative strand RNA intermediate
Epidemiology
synthesized by the RNA polymerase/helicase complex using The virus is transmitted through the fecaloral route, primarily
the genomic RNA as template. The negative strand is then by drinking sewage contaminated water. Other modes of
itself used as template for the synthesis of the subgenomic transmission such as person-to-person and intrafamilial
mRNA (2.2 kb) for ORF2 and ORF3 translation, but also for spread are distinctly uncommon. To this day, infection in
positive strand genomic RNA synthesis for progeny virions. endemic regions of the world appears to be the result of large
HEV is excreted in the bile. outbreaks involving in some instances many thousands of
people. Outbreaks have been recorded apart from the Indian
subcontinent, from South-east Asia, Southern Russia, as well
Laboratory Detection as from North and East Africa and coincide with heavy rains
Acute infection is characterized by the presence of IgM that result in flooding that may lead to contamination of
anti-HEV in serum, and this is used preferentially for drinking water with sewage.
diagnostic purposes. IgG anti-HEV detection is associated In these same regions, children and adults may contract
with convalescence or past infection and has been shown to HEV infection sporadically also. In India, 5070% of all cases
persist for many years in about half of the patients. Diagnostic of sporadic viral hepatitis are thought to be due to HEV
tests employ recombinant proteins or synthetic peptides from infection. HEV outbreaks in Western industrialized countries
ORF2 proteins for the detection of antibodies. IgM anti-HEV have not been reported, whilst sporadic cases have been as a
appears in the serum of infected patients with the onset of rule associated with travel to endemic areas. However, recent
symptoms, preceding the IgG response, and wanes from 2 reports with increased frequency suggest transmission of
months to 5 months later, but may remain detectable in up to HEV in the absence of foreign travel. Such cases appear to
40% of patients up to 1 year late. IgG anti-HEV appears shortly be associated with contact with swine (and other animals),
after the IgM response and increases thereafter though the as well as consumption of inadequately cooked meat.
acute and convalescent phases, remaining detectable for Seroepidemiological evidence of HEV infection in developing
many years in most exposed subjects. countries, as determined by detection of anti-HEV IgG, has
Fig. 4: Temporal relationship following hepatitis E virus infection between serological and biochemical markers detected over time
consistently shown that seroprevalence increases in direct Immunosuppressed individuals including HIV positive
proportion with increasing age. subjects may be at risk of developing chronic HEV infection if
exposed to the virus.
Liver histological findings show ballooning of hepatocytes,
Clinical Features acidophilic body formation and focal or confluent hepatocyte
After an incubation period of between 15 days and 60 days necrosis. Cholestatic hepatitis is found in about 50% of
from exposure, clinical symptoms in icteric cases can include cases prominent feature characterized by canalicular bile
a short flu-like prodrome with fever, mild chills, abdominal stasis. Heavy inflammatory infiltrates are evident in lobules
pain, anorexia, nausea, vomiting, clay-colored stools, dark and portal tracts. Massive and submassive necrosis is seen
or tea-colored urine, diarrhea, arthralgias, asthenia and a in fulminant cases and bridging necrosis is the prominent
transient macular skin rash, which are followed by jaundice. feature of subacute hepatitis.
Enlargement of the liver becomes obvious and splenomegaly
may also be present. The illness is self-limiting, leading to
resolution of symptoms within 14 weeks, and full recovery.
Prevention
Liver function tests become deranged prior to onset of Preventative measures include provision of clean water,
symptoms and these normalize over a 6 week period after better sanitation and hygiene education. Early studies in
appearance of symptoms. rhesus macaques have indicated that a preventative vaccine
Hepatitis E virus infected persons exhibit a wide clinical was possible on the basis of recombinant technology
spectrum, ranging from asymptomatic infection to fulminant that was used to express the capsid protein of the virus
hepatitis. Epidemic HEV infection has been associated encoded by ORF2. A virus neutralizing immune response
with mortality rates of up to 1%, rising to 20% in pregnant was elicited in immunized animals. A human vaccine
women, particularly in the third trimester of pregnancy. The utilizing a truncated form of the capsid protein (56 kDa)
more severe outcome in pregnancy appears to be related that retains the conformational neutralization epitope of
to diminished cellular immunity and hormonal factors. the protein underwent field trials in Nepal and showed
Sporadic HEV infection of pregnant women does not appear a 95.5% antibody response rate after three doses given at
to have the same high mortality rate. 0, 1 and 6 months, and an 87% efficacy rate. However, the
Finally, it has recently been reported that chronic infection likely low demand in Western countries and the high cost
has been observed in two post-liver transplantation patients of the vaccine to endemic regions of the world have put
where HEV-RNA persisted for 57 years. Both patients were into question its economic viability. It remains to be seen
retransplanted and reinfection of the new liver graft occurred whether the vaccine becomes commercially available in the
in one of them, whilst antibodies developed in the other. near future.
CONCLUSION 8. Karayiannis P, Jowett T, Enticott M, et al. Hepatitis A virus

replication in tamarins and host immune response in relation to
Since the discovery of the viruses, our knowledge of the pathogenesis of liver cell damage. J Med Virol. 1986;18:261-76.
epidemiology, serology, molecular biology, clinical picture 9. Khuroo MS, Rustgi VK, Dawson GJ, et al. Spectrum of hepatitis E
virus infection in India. J Med Virol. 1994;43:281-6.
and outcome of disease, as well as preventative vaccination
10. Koff RS. The case for routine childhood vaccination against
has progressed significantly. Both diseases are preventable
hepatitis A. N Engl. J Med. 1999;340:644-5.
and their eventual eradication is not beyond reach, if a 11. Lu L, Li C, Hagedorn CH. Phylogenetic analysis of global hepatitis
worldwide concerted effort is made. E virus sequences: genetic diversity, subtypes and zoonosis. Rev
Med Virol. 2006;16:5-36.
12. Martin A, Lemon SM. Hepatitis A virus: from discovery to
BIBLIOGRAPHY vaccines. Hepatology. 2006;43(Suppl 1):S164-72.
13. Meng XJ. From barnyard to food table: The omnipresence of
1. Aggarwal R, Naik SR. Epidemiology of hepatitis E past, present hepatitis E virus and risk for zoonotic infection and food safety.
and future. Trop Gastroenterol. 1997;18:99-56. Virus Res. 2011;161(1):23-30.
2. Center for Disease Control. Prevention of hepatitis through 14. Purcell RH, Emerson SU. Hepatitis E: An emerging awareness of
active or passive immunization, recommendations of the an old disease. J Hepatol. 2008;48:494-503.
Advisory Committee of Immunization Practices (ACIP). MMWR. 15. Reyes GR, Purdy MA, Jungsuh PK, et al. Isolation of a cDNA from
1999;48:1. the virus responsible for enterically transmitted non-A, non-B
3. Cristina J, Costa-Mattioli M. Genetic variability and molecular hepatitis. Science. 1990;247:1335-9.
evolution of hepatitis A virus. Virus Res. 2007;127:151-7. 16. Shrestha MP, Scott RM, Joshi DM, et al. Safety and efficacy of a
4. Gordon SG, Reddy KR, Schiff L, et al. Prolonged intrahepatic recombinant hepatitis E vaccine. N Engl J Med. 2007;356:895-903.
cholestasis secondary to acute hepatitis A. Ann Intern Med. 17. Tam AW, Smith MM, Guerra ME, et al. Hepatitis E virus (HEV):
1984;101:635-7. molecular cloning and sequencing of the full-length viral
5. Haagsma EB, van den Berg AP, Porte RJ, et al. Chronic hepatitis genome. Virology. 1991;185:120-31.
E virus infection in liver transplant recipients. Liver Transpl. 18. Tami C, Silberstein E, Manangeeswaran M, et al. Immunoglobulin
2008;14:547-53. A (IgA) is a natural ligand of hepatitis A virus cellular receptor
6. Halliday ML, Kang LY, Zhou TK, et al. An epidemic of hepatitis A 1 (HAVCR1), and the association of IgA with HAVCR1 enhances
attributable to the ingestion of raw clams in Shanghai, China. J virus-receptor interactions. J Virol. 2007;81:3437-46.
Infect Dis. 1991;164:852-9. 19. Thomas DL, Yarbough PO, Vlahov D, et al. Seroreactivity to
7. Innis BL, Snitbhan R, Kunasol P, et al. Protection against hepatitis hepatitis E virus in areas where the disease is not endemic. J Clin
A by an inactivated vaccine. JAMA. 1994;271:1328-34. Microbiol. 1997;35:1244-7.
18
cHAPTER
Hepatitis B Virus
Narendra Choudhary, Ajay Duseja
INTRODUCTION protein HBsAg. It is structurally and functionally divided into

the pre-S1, pre-S2, and S regions. The C ORF has the precore
About 350 million persons worldwide are chronically and core regions; it encodes the viral nucleocapsid antigen
infected with hepatitis B virus (HBV). About 1540% HBV (hepatitis B core antigen) (translation initiated from the core
carrier patients develop serious sequel of infection, including region) and hepatitis B e antigen (HBeAg) (translation initiated
cirrhosis and hepatocellular carcinoma (HCC). Global from the precore region). HBeAg has been implicated as an
prevalence of HBV carrier state varies and countries can be immune tolerogen. The P ORF encodes polymerase enzyme.
dened as having a high, intermediate, and low prevalence The X ORF encodes HBxAg with multiple functions, including
of HBV infection based on a prevalence of HBsAg carriers of signal transduction, transcriptional activation, DNA repair
more than 8%, 27%, and less than 2%, respectively. Highly and inhibition of protein degradation (Fig. 1). Replication
endemic areas include Southeast Asia (excluding Japan), of HBV occurs through an RNA intermediate that requires
China and much of Africa, areas of intermediate prevalence an active viral reverse transcriptase/polymerase enzyme.
are some parts of Europe, Middle East, Japan, the Indian Mutation rate is higher for HBV because reverse transcriptase
subcontinent, most of the former Soviet Union, and Northern lacks proofreading function.
Africa. Regions of low prevalence are North America, Western
Europe, certain parts of South America, and Australia. The
prevalence rates are dependent on the modes of transmission
and determine the lifetime risk of acquiring HBV infection.
MOLECULAR BIOLOGY OF
THE HEPATITIS B VIRUS
The human HBV is a member of the hepadnaviridae family.
Humans and higher primates are the only known hosts for
human HBV. Serum of patients with HBV infection exhibit
three types of particles when seen by electron microscopy;
largest (42 nm spherical structure with a lipid bilayer) is called
Dane particle and it represents the intact virion, other smaller
particles are spherical (20 nm diameter) and filamentous (22
nm diameter) forms of hepatitis B surface antigen (HBsAg)
which are secreted in abundance over intact virion. The HBV
genome is a partially double-stranded circular DNA of 3.2
kb in length. There are four open reading frames (ORF); core
(C), polymerase (P), surface (S), and X that partially overlap
with each other (Fig. 1). The S ORF encodes surface envelope Fig. 1: Genomic structure of hepatitis B virus
Hepatitis B Virus 165
VARIOUS ANTIGENS AND ANTIBODIES C Taiwan, China, Korea and Southeast Asia, Australia,
Philippines, Vietnam
OF HEPATITIS B VIRUS D Africa, Europe, Mediterranean countries, India
E West Africa
Hepatitis B surface antigen is an outer envelope protein;
F Central and South America
it is formed from S ORF. There are several different HBsAg
G France, Germany, and the United States
subdeterminants and a common group reactive antigen,
H Central America
a shared by all HBsAg isolates. In addition to this, HBsAg
I Vietnam and Laos
may contain one of several subtype-specific antigens (d or
J Ryukyu, Japan.
y, w or r and several others). Clinical course and outcome
are independent of the subtype. Depending on the site of
translation initiation, three potential HBsAg gene products
are synthesized. S gene is translated as HBsAg (major protein), MODES OF HEPATITIS B VIRUS
S region plus the adjacent pre-S2 region produce middle TRANSMISSION
protein, and pre-S1 plus pre-S2 plus S regions produce large
protein. Compared with the smaller spherical and tubular Modes of transmission for HBV include vertical (mother to
particles of HBV, complete 42 nm virions are enriched in baby, transmission rate is 6090% for HBeAg positive and
the large protein. HBV vaccines contain HBsAg that leads to 1520% for anti-HBeAg positive, HBeAg negative mothers),
protective antibody (anti-HBs) production. The intact virion household contact with HBV carrier, hemodialysis, exposure
contains a 27 nm nucleocapsid core particle; the C gene codes to infected healthcare workers, percutaneous, and mucous
for these nucleocapsid proteins. The antigen expressed on the membrane exposure to infectious body fluids, tattooing and
surface of the nucleocapsid core is referred to as hepatitis B receipt of blood products or organs.
core antigen (HBcAg), and its corresponding antibody is anti-
HBc (IgM anti-HBc for acute hepatitis B and IgG anti-HBc for
chronic hepatitis B); it is product of C ORF (when translation DISEASE MANIFESTATIONS OF
begins with the core region), HBcAg has no signal peptide,
so it is not secreted in serum. HBeAg is another product of C
HEPATITIS B VIRUS
ORF (when translation begins at precore region); it has signal Hepatitis B virus is responsible for causing acute viral
peptide to be secreted from cells into serum. Loss of HBeAg hepatitis (AVH), acute liver failure (ALF), subacute hepatic
and appearance of anti-HBe usually marks a transition from failure (SAHF), chronic hepatitis, cirrhosis and HCC in
active disease state to inactive carrier state in majority of significant proportion of patients and uncommonly can have
patients and is associated with low DNA levels. extrahepatic manifestations as well.
GENOTYPES OF HEPATITIS B VIRUS Acute Hepatitis B

After an incubation period ranging from 1 month to 6 months,
Hepatitis B virus has ten genotypes (A to J, I and J are recently
about two-thirds of patients with acute infection have mild
identified) based on an intergroup difference of 8% or more
subclinical illness that usually remains undetected. Rest of
in the genome. Various geographical regions have different
the patients with acute hepatitis B develops clinical hepatitis
predominant genotype. Genotyping has some clinical
that rarely can lead to ALF.
associations like HBeAg seroconversion and probability of
Earlier serum markers are HBV DNA followed by the
HBsAg loss (B < C); response to interferon- (INF-) (A > B
appearance of HBsAg and HBeAg. After few weeks of
C > D); precore mutation are not selected with A and F, liver
appearance of these viral markers, aspartate aminotransferase
disease activity and risk of progression (B < C); evolution to
and alanine aminotransferase (ALT) rise, and there is
chronic liver disease (A < D) and HCC risk (B > C in younger
appearance of jaundice. HBV DNA usually persists in serum
age group in Taiwan but B < C in older age group in Japan).
for the duration of symptoms and may be cleared with
Geographic distributions of hepatitis B genotypes: recovery. Antibody to core antigen (anti-HBc, initially IgM
A Sub-Saharan Africa, Northern Europe, Western Africa, then IgG class) generally appears shortly before onset of
India clinical illness, anti-HBe appears shortly after clearance of
B Japan, East Asia, Taiwan, China, Indonesia, Vietnam, HBeAg. Anti-HBs rise late during infection during recovery
Philippines, Alaska, Northern Canada, Greenland or convalescence after clearance of HBsAg (Fig. 2). Around
Fig. 2: Viral markers in acute hepatitis B
1015% of patients who recover from acute hepatitis B does indicated for acute hepatitis B as only 5% of adults progress
not develop detectable anti-HBs and have anti-HBc alone as to chronic hepatitis B. Though the datum is not convincing,
a marker of previous infection. there may be a place of antiviral drugs in patients with
Diagnosis of acute hepatitis B is made in presence of severe acute hepatitis. Kumar et al. found lower HBV DNA
suggestive clinical presentation, positive HBsAg, and positive levels in patients with HBV-related severe acute hepatitis
IgM anti-HBc. However, in endemic areas sometimes it may treated with lamivudine with no difference in clinical
be difficult to differentiate acute hepatitis B from acute flare of or biochemical recovery. Treatment with antiviral drugs
chronic hepatitis B. Acute exacerbations of chronic hepatitis may be beneficial for those patients having ALF (discussed
may constitute about 50% of cases diagnosed as primary later).
infections. IgM anti-HBc titers more than 1:1000, sample/cut Chronicity after episode of acute exposure to HBV depends
off ratio more than 10 and DNA less than 1,41,500 copies/mL on the age of patient at the time of acquiring HBV infection
are suggestive of acute hepatitis B rather than acute flare of (Table 1).
chronic hepatitis B.
Complications of acute hepatitis B include ALF in about 1%
of patients, acute on chronic liver failure (ACLF) in a patient
with underlying chronic liver disease (defined as acute hepatic Acute Liver Failure
insult manifesting as jaundice and coagulopathy, complicated Hepatitis B-related ALF occurs in about 1% of patients with
within 4 weeks by ascites and/or encephalopathy in a patient acute hepatitis B and survival without liver transplantation
with previously diagnosed or undiagnosed chronic liver occurs in 2853% of patients. HBV is responsible for ALF in
disease) and SAHF (defined as development of ascites after around 1146% of patients in India, 13.4% in Bangladesh, 27%
4 weeks of onset of jaundice, without any preexisting liver in China and approximately 41% in Japan. Acute exacerbation
disease). HBV is an important cause of both ACLF and SAHF of chronic HBV infection can present as ALF. There are
in areas where HBV is highly endemic but is less common a insufficient data regarding treatment with anti-HBV drugs
cause in areas with low or intermediate prevalence. in hepatitis B-related ALF. Tillmann et al. showed significant
survival benefit with lamivudine in patients with severe acute
hepatitis or ALF as compared to historic controls. Recently,
Treatment of Acute Hepatitis B a study of six patients with HBV-related ALF found good
General treatment of patients with HBV-related AVH is response to entecavir with seroconversion to anti-HBs in five
no different from other causes. Antiviral treatment is not out of six patients.
Table 1: Chronicity of hepatitis B virus infection after acute exposure
Mode of transmission Age at infection Risk of acute icteric Risk of chronic HBV Lifetime risk of hepatocellular
hepatitis infection carcinoma with chronic hepatitis B
Perinatal (HBeAg positive mother) Birth <1% 90% 1540%
Perinatal (HBeAg negative mother) Birth 5% <15% 1540%
Horizontal Between birth and 2 years <10% 50% 1540%
Horizontal 25 years 9% 30% 1525%

Horizontal 510 years 10% 16% 1525%
Horizontal >10 years 1033% 714% Unknown
Table 2: Interpretation of serologic testing
HBsAg Anti-HBs HBeAg Anti-HBe Anti-HBc HBV DNA (copies/mL) ALT
Inactive HBsAg carrier + + + Negative- < 104 Normal

Immune-tolerant + + + >10 7
Normal
Chronic hepatitis B (HBeAg-positive) + + + >105 Elevated
Chronic hepatitis B (HBeAg-negative) + + + >104 Elevated (persistently/intermittently)
Acute hepatitis B + + IgM Positive Elevated

Resolved infection +/ +/ +/ Negative Normal
(or very low levels)
Immunized +
HBeAg seroconversion, patients enter a remission or inactive

phase characterized by low serum HBV DNA (<2,000 IU/mL),
normal ALT and near normal liver histology (inflammation
Chronic Hepatitis B and fibrosis reversal) (Table 2). In patients with inactive phase
Viral persistence beyond a period of 6 months is defined spontaneous HBsAg seroclearance occur at an annual rate
as chronic HBV infection. Course of patients with chronic of 0.52%. Patients with HBeAg-positive or HBeAg-negative
HBV infection can be divided into three phases: (i) immune hepatitis have a 24% annual incidence of cirrhosis. Risk of
tolerant phase, (ii) immune clearance phase and (iii) developing cirrhosis is more in patients with male gender,
residual or inactive phase. Perinatal or early childhood age more than 40 years, alcohol intake, smoking, coinfection
transmission results in immune tolerant phase characterized with hepatitis C virus (HCV), hepatitis D virus (HDV), and
HBeAg seropositivity with high viral loads (>107108 copies/ human immunodeficiency virus (HIV); basal core promoter
mL), normal serum alanine transaminase (ALT), and near mutation, HBV DNA more than 20,000 IU/mL in persons
normal liver histology (Table 2). Immune tolerant phase is more than 40 years. Incidence of HCC is less than 1% per
absent or very short if infection is acquired in childhood. year in patients with chronic hepatitis B and around 36% in
Immune clearance phase is characterized by intermittent patients with cirrhosis.
or continuing hepatitis activity or episodic acute flares that
can cause hepatic decompensation, liver histology showing
inflammation and fibrosis, HBeAg may be positive or negative
Reactivation of Hepatitis B Virus
and HBV DNA levels more than 20,000 IU/mL (Table 2). In The covalently closed circular (cccDNA) is responsible for
majority of patients, immune clearance phase results in durability of HBV infection. It resides in the nucleus of infected
HBeAg seroconversion to anti-HBe or undetectable HBV hepatocytes as a stable, nonintegrated episomal DNA; cccDNA
DNA (annual rate of 215%) depending on age, gender, is not replicated by the host DNA replication machinery. As
baseline ALT, and severity of hepatitis. After spontaneous cccDNA persists in liver, it can cause reactivation of HBV once
immunity is lowered. Hepatitis B reactivation occurs in the Who Requires Treatment in Chronic
setting of solid organ or bone marrow transplantation, HIV
Infection, withdrawal of antiviral therapy, immunosuppressive Hepatitis B?
treatment including chemotherapy or it can be spontaneous. Decision of treatment of chronic hepatitis B patients depends
Typical reactivation has three phases, DNA rises initially on serum ALT levels, HBV DNA levels and findings of liver
followed by rise of ALT and jaundice; finally resolution biopsy if available. Decision to treat is further modified by
once immunosuppression is reduced. Prophylactic antiviral patient age, HBeAg status, occupational requirements and
therapy should be given for HBV carriers at the onset of cancer
patient preference. While immediate treatment is indicated
chemotherapy or immunosuppressive therapy. In patients with
in patients with life-threatening disease (ALF or severe
baseline HBV DNA less than 2,000 IU/mL, treatment should
hepatitic flare, although data are not robust in these patients)
be given for 6 months after completion of chemotherapy/
or advanced disease (compensated or decompensated
immunosuppressive therapy; treatment end points are similar
cirrhosis), patients with quiescent disease can be monitored
to chronic hepatitis B in patients with baseline HBV DNA more
than 2,000 IU/mL. Lamivudine or telbivudine can be used on the other hand. Treatment with antiviral drugs is associated
if the anticipated treatment is less than 12 months otherwise with improvement of histology in patients with compensated
tenofovir or entecavir are preferred. IFN should not be used as cirrhosis and stabilization of liver disease in patients with
it causes bone marrow suppression. decompensated disease. Patients with immunotolerant or
inactive carrier stage of disease should not be treated, as these
patients do not have significant liver disease. If patient is a
Immunopathogenesis of HBV-related healthcare worker, he can be treated on lower DNA threshold
Hepatic Injury as per local guidelines.
Recommendations for treatment and doing liver biopsy as
Hepatitis B virus itself is not pathogenic to cause liver injury
given by various guidelines are given below in Table 3.
except in cases of fibrosing cholestatic hepatitis (high levels
of HBV replication in immunocompromised host). ALF due
to acute hepatitis B may be caused by massive necrosis and How to Treat Patients with Chronic
activation of coagulation system after activation of immune
cells. Neonates develop chronic infection because they have
Hepatitis B?
immature immune system, HBeAg has tolerizing effect (soluble Various drugs approved by US Food and Drug Administration
HBeAg crosses placenta), and there is T cell exhaustion and/or (FDA) for the treatment of chronic hepatitis B include
clonal deletion. In adults, prolonged T-cell activation caused conventional IFN-, peginterferon -2a, lamivudine, adefovir
by high levels of viral antigens may result in T-cell exhaustion dipivoxil, entecavir, telbivudine, and tenofovir (Table 4).
and anergy or even clonal deletion. The extent of these
immune inhibitory pathways defines the course of chronic
HBV infection from immune tolerance to immune active and Treatment with Interferon
healthy carrier state as well as hepatitis flares. HBV infection Interferons are a multigene family of inducible cytokines.
triggers several innate and adaptive immune responses. HBV IFNs are divided into two types: type I IFNs (known as viral
does not trigger the type I IFN response during acute infection, IFNs) and include IFN- (synthesized by leukocyte) and
but can induce other innate immune subsets (e.g. natural killer IFN- (synthesized by broblast); these INFs are induced by
cells). As for adaptive immunity, CD8 T cells play a critical role viral infection. Type II IFN (known as immune IFN, IFN-)
in HBV clearance, whereas they are functionally suppressed is synthesized only by certain cells of the immune system.
during chronic HBV infection via multiple immune regulatory Pegylated INFs are INF bound to a molecule of polyethylene
mechanisms that involve activation of inhibitory receptors glycol (PEG) of varying length, which increases the half-life
[programmed death 1 (PD-1) and CTL-associated antigen 4 and reduces the volume of distribution of INF thus once
(CTLA-4)] on T cells to suppress their activation and immune weekly dose can be used. Pegylated INFs are associated
suppression through CD 25+ T regulatory cells (Tregs). with uniform plasma concentrations and enhanced viral
suppression. Binding of IFN to its cell surface receptor activates
the downstream IFN signaling pathway that ultimately leads
Treatment of Chronic Hepatitis B to the induction of IFN stimulated genes that mediate a wide
Important questions, which need to be answered in the array of biologic activities (e.g. antiviral, immune modulatory,
treatment of chronic hepatitis B, are who and how to treat antiproliferative, antiangiogenic and antitumor effects). Type
patients with chronic hepatitis B. I IFNs can affect all phases of the viral life cycle, including
Table 3: Recommendations for liver biopsy and treatment
Recommendation for Liver biopsy AASLD APASL EASL

HBeAg+, ALT persistently 12 ULN Detectable HBV DNA and ALT Raised ALT or HBV DNA >2,000 IU/mL
or age >40
HBeAg-, HBV DNA High normal ALT and age >40 years
2,00020,000 IU/mL, ALT
persistently 12 ULN
Recommendation for treatment
HBeAg+ patients ALT persistently >2 ULN, Moderate HBV DNA > 20,000 IU/mL and ALT > 2 HBV DNA >2,000 IU/mL or ALT >
or greater, inflammation or fibrosis on ULN If persistently elevated or concern 1 ULN and moderate or greater
biopsy about hepatic decompensation or inflammation or fibrosis on biopsy
moderate or greater inflammation or
fibrosis on biopsy
HBeAg- patients ALT >2 ULN and HBV DNA > HBV DNA >2,000 IU/mL and ALT
20,000 IU/mL. Moderate or greater persistently >2 ULN, or concerns of
inflammation or fibrosis on biopsy hepatic decompensation. Moderate
or greater inflammation or fibrosis on
biopsy
Patients with cirrhosis Decompensated- DNA + Decompensated Decompensated
Compensated- HBV DNA >2,000 IU/ Compensated and HBV DNA
mL, HBV DNA <2,000 IU/mL if raised >2,000 IU/mL
ALT
Abbreviations: AASLD, American Association for the Study of Liver Disease; ALT, alanine aminotransferase; APASL, Asian Pacific Association for
the Study of the Liver; EASL, European Association for Study of Liver; ULN, upper limit of normal
Table 4: Food and Drug Administration-approved treatment for in 8050% of cases. Indicators of response on treatment are
chronic hepatitis B infection HBV DNA decline, HBeAg concentration decline and HBsAg
concentration decline. Baseline predictors of sustained
Drug Year of approval
virological response are higher baseline ALT levels, lower
Interferon 1991
baseline HBV DNA concentrations (<109 copies/mL), and
Lamivudine 1998 lower concentrations of HBeAg in case of HBeAg positive
Adefovir dipivoxil 2002 chronic hepatitis B and younger age, female gender, higher
Peginterferon -2a 2005 ALT levels, lower baseline HBV DNA and HBV genotype in
Entecavir 2005 cases of HBeAg negative chronic hepatitis B. Response to
INF- is different among various genotypes in order of A > B
Telbivudine 2006
C > D; so young patients with genotype A infection, higher
Tenofovir 2008
ALT and lower HBV DNA levels may be good candidates for
IFN treatment.
entry/uncoating, transcription, RNA stability, translation,
maturation, assembly, and release. Oral Drugs for the Treatment of Chronic
Both standard INF- and peginterferon- are available
for treatment of chronic hepatitis B. Pegylated INF may be
Hepatitis B
better than conventional INF. Duration of therapy is 16 weeks Lamivudine: Lamivudine is L nucleoside analogue. It gets
(standard INF-) or 48 weeks (peginterferon-) in cases incorporated into growing DNA chains and causes premature
of HBeAg positive disease and 1 year in HBeAg negative chain termination thus inhibiting HBV DNA synthesis. The
disease (both standard and PEG IFN). Sustained virological recommended dose of lamivudine for adults is 100 mg orally
response are present in approximately 30% of HBeAg positive daily, except in patients with renal dysfunction where it may
and 40% of HBeAg negative cases (when dened as HBeAg require dose modification. Treatment with lamivudine for
seroconversion and/or DNA levels below 20,000 copies/ 48 weeks produces loss of HBV DNA in 4044% of patients,
mL, respectively) 6 months after completion of a 48-week HBeAg loss in 1732% patients, HBeAg seroconversion in
treatment with peginterferon -2a with durable response 1621% of patients with durability of response in 5080% of
patients in HBeAg positive chronic hepatitis B patients. For in 22% of patients with durability of response in near 80%
HBeAg negative chronic hepatitis B patients durability of of patients. Telbivudine selects for mutations in the YMDD
response is less than 10% only. Development of resistance is motif. To date, only M204I (but not M204V) has been
main fear with use of lamivudine and genotypic resistance can observed. Peripheral neuropathy and myopathy have been
be detected in 1432% after 1 year and in 6070% after 5 years reported with telbivudine.
of use. The most common mutation involves substitution Tenofovir: Tenofovir treatment at 48 weeks in HBeAg
of methionine for valine or isoleucine (rtM204V/I) in the positive patients results in HBV DNA loss in 76% and HBeAg
tyrosine-methionine-aspartate-aspartate (YMDD) motif of seroconversion in 21% of patients. Tenofovir has been
the HBV DNA polymerase. reported to cause Fanconi syndrome, renal insufficiency as
Adefovir dipivoxil: Adefovir dipivoxil is an orally bioavailable well as osteomalacia and decrease in bone density.
prodrug of adefovir, a nucleotide analog of adenosine Entecavir and tenofovir are associated with greater DNA
monophosphate. It is least potent among oral antiviral suppression and greater histological improvement than
drugs to suppress HBV DNA. It acts by inhibiting both the other drugs. Emtricitabine and clevudine are other available
reverse transcriptase and DNA polymerase activity and is oral L-nucleoside analogs against HBV; not approved in the
incorporated into HBV DNA causing chain termination. United States or Europe. Entecavir and tenofovir are high
Adefovir is effective against lamivudine-resistant strains. genetic barrier (number of mutations needed by virus in order
It results in seroconversion in 12%, HBeAg loss in 24% and to replicate efficiently) drugs as compared to other drugs.
DNA loss in 21% of patients after 48 weeks of treatment. Nucleos(t)ides drugs are generally well-tolerated but since
Durability of response is near 90% with almost no resistance. almost all are excreted by renal route, a dose modification is
Main adverse event is renal dysfunction, which appears in necessary in patients with renal disease.
nearly 3% of patients after 45 years of treatment. For HBeAg
negative chronic hepatitis B patients durability of response
is 5% only. Resistance occurs at a slower rate during adefovir How to Choose between IFN and Oral Drugs
treatment compared to lamivudine, with almost no resistance in Chronic Hepatitis B?
after 1 year of treatment, though asparagine to threonine
Interferon for treatment of chronic hepatitis B has several
substitution (N236T) and alanine to valine or threonine
advantages like finite duration of therapy and better
substitutions (A181V/T) have been described with adefovir.
seroconversion and HBsAg loss than oral drugs but is more
Entecavir: Entecavir is a carbocyclic analog of 2 costly and is associated with more side effects; on the
deoxyguanosine; it inhibits HBV replication at three other hand, oral drugs are well-tolerated but has no finite
different steps: the priming of HBV DNA polymerase, reverse duration of therapy and are less effective than INF regarding
transcription of the negative strand HBV DNA from the seroconversion and HBsAg loss; generally oral drugs are given
pregenomic RNA and the synthesis of the positive strand HBV till specific end point of therapy is achieved. A comparison of
DNA. Entecavir is more potent than lamivudine and adefovir INF and oral drugs is given below in Table 5.
and is effective against lamivudine and adefovir-resistant
strains. Dose used is 0.5 mg daily in lamivudine naive patients
and 1 mg daily in lamivudine-resistant patients. Side effects Monitoring during Treatment
are similar to lamivudine. Forty-eight weeks of treatment Renal functions should be monitored in case of adefovir/
with entecavir results in HBV DNA loss in 67%, HBeAg loss tenofovir use and dose modification of most of the drugs
in 20% and seroconversion in 21% of patients with durability is needed in case of renal insufficiency. During treatment,
of response in 69% of patients with HBeAg positive chronic ALT, HBeAg and HBV DNA should be monitored every 3
hepatitis B. For HBeAg negative chronic hepatitis B patients, months; after completion of treatment, ALT and HBV During
durability of response is 3% only. Resistance to entecavir treatment, ALT, HBeAg and DNA should be monitored every 3
appears to occur through a two-hit mechanism with initial months; after completion of treatment, ALT and DNA should
selection of M204V/I mutation followed by amino acid be monitored monthly for 3 months to detect early relapse in
substitutions at other site, so lamivudine-resistant patients patients with cirrhosis.
are at a higher risk for developing resistance and dose used in
them is 1 mg daily.
Telbivudine: Telbivudine is L-deoxythymidine (L-nucleoside
When to stop Treatment?
compound). Forty-eight weeks treatment in HBeAg positive End points of treatment for chronic hepatitis B are not well-
chronic hepatitis B patients results in HBV DNA loss in 60% defined. HBsAg loss is ideal, end point that is rarely achievable
of patients, HBeAg loss in 26% and HBeAg seroconversion with present available treatment; suppression of viral
Table 5: Advantages and disadvantages of interferon and oral nucleos(t)ide drugs
Interferon Nucleos(t)ides
Route Percutaneous Oral
Tolerability Poor Good
Monitoring Needed Less intense
Effective in high HBV DNA (>109 IU/mL) Rarely Usually
1-year HbeAg Seroconversion 30% 20%
HBsAg loss year 1 34% 03%

Duration of therapy 1 year Generally indefinite
Cost More
Cirrhosis Not recommended for compensated, Tolerated
contraindicated in decompensated
Resistance None Present
Table 6: Recommendations for stopping antiviral drugs
Drug HBeAg status APASL AASLD

Conventional interferon HBeAg + 46 months 16 weeks
HBeAg 1 year 1 year
Peginterferon HBeAg + 6 months 48 weeks
HBeAg 1 year 1 year
Oral drugs HBeAg + HBeAg seroconversion with undetectable DNA on Undetectable DNA and at least 6 months of
two separate occasions at least 6 months apart additional treatment after appearance of anti-HBe
HBeAg Duration? End point not defined
Treatment discontinuation can be considered if Best end point-HBsAg clearance
undetectable HBV DNA documented on three
separate occasions 6 months apart
Abbreviations: AASLD, American Association for the Study of Liver Disease; APASL, Asian Pacific Association for the Study of the Liver
replication, as measured by HBV DNA levels is the present at 1 year and 65% at 5 years, for adefovir it is 29% at 5 years,
goal of therapy particularly if maintained off therapy. End for telbivudine it is 22% at 2 years, for tenofovir and entecavir
point of therapy is HBeAg seroconversion in case of HBeAg it is negligible at 5 years, but in patients with lamivudine
positive disease and not defined in case of HBeAg negative resistance entecavir resistance is near 50% at 5 years.
disease (as HBsAg loss is rare). Patients with compensated
cirrhosis should receive long-term treatment; however,
treatment may be stopped with similar end points as given for Terminologies used in Drug Resistance
chronic hepatitis B. Close monitoring is needed if treatment Primary nonresponse: It is defined as the inability of the
is stopped. For patients with decompensated cirrhosis or
antiviral agent to reduce serum HBV. DNA by less than 1 log10
recurrence post liver transplantation, lifelong treatment is
IU/mL within the first 6 months (first 12 weeks according
indicated (Table 6).
to Asian Pacific Association for the Study of the Liver) of
treatment. It is an indication to change therapy to a new drug.
Antiviral Drug Resistance Virological breakthrough: It is defined as an increase in serum
As HDV DNA polymerase lacks proofreading activity, HBV DNA by more than 1 log10 IU/mL above a nadir on two
combined with high rate of replication, virus can have drug or more consecutive occasions at least 1 month apart in a
resistance in treatment of naive patients. Resistance to various compliant patient after initial response. If DNA level exceeds
drugs increases with the usage time: for lamivudine it is 24% pretreatment levels, it is called viral rebound.
Table 7: Sites of drug resistance and susceptibility to various drugs
Pathway Amino acid substitutions Lamivudine Telbivudine Entecavir Adefovir Tenofovir

Wild-type S S S S S
L-nucleoside M204I/V R R I S S
(lamivudine, telbivudine)
Acyclic phosphonate N236T S S S R I
(adefovir, tenofovir)
Shared A181T/V I R S R I
D-cyclopentane L180M+M204V/I R R R S S
(entecavir) +I169+T184
+S202+M250
Keys: I, intermediate sensitivity, R, resistant, S, sensitive
Biochemical breakthrough: It is defined as an elevation in ALT mothers. Administration of standard passive and active
level while on treatment after achieving normalization in a immunoprophylaxis with hepatitis B immunoglobulin
compliant patient. Biochemical breakthrough lags behind (HBIg) and hepatitis B vaccination decreases the risk of
virological breakthrough. transmission to 510%. Issues regarding antiviral treatment
Genotypic resistance: It refers to the detection of amino acid during pregnancy are development of resistance, flares
substitutions in the reverse transcriptase region of the HBV following treatment cassation after delivery, side effects for
genome that have been shown to confer resistance to antiviral baby (in pregnancy and during lactation). Regarding safety
drugs in a phenotypic assay during antiviral therapy. in pregnancy, no antiviral drug has FDA category A status.
Various sites of amino acid substitutions causing drug Tenofovir and telbivudine are in category B and lamivudine,
resistance and the susceptibility of resistant virus to different adefovir, entecavir and INF are categorized as category C.
drugs are shown in Table 7. INF has antiproliferative effects, so should not be used in
pregnancy. A proposed algorithm to prevent mother to
child transmission is to check HBV DNA at 28 weeks and
Management of Drug Resistance to start treatment at week 32 with lamivudine, tenofovir
or telbivudine if HBV DNA more than 108 copies/mL or 106
The policy for managing drug resistance is either to add a
copies/mL (if previous child had vertical transmission).
new drug or to switch to a new drug. The choice of new drug
Baby should receive HBIg and vaccination (three doses as
depends on the resistance profile and the drug used. In case
scheduled) followed by antibody titers check (should be more
of lamivudine or telbivudine resistance, tenofovir (or adefovir
than 10 IU/mL), in case of inadequate titers, vaccination
if tenofovir not available) can be added as these drugs have
course should be repeated. If mother has risk of severe liver
different resistance profile. In case of entecavir resistance,
disease, treatment is recommended.
tenofovir can be added. In case of adefovir resistance,
tenofovir and a second drug without cross-resistance can be
added. In case of tenofovir resistance, entecavir, lamivudine,
telbivudine or emtricitabine can be added depending on the HEPATITIS B VIRUS AND
resistance profile. HEPATOCELLULAR CARCINOMA
Possible mechanisms of HCC pathogenesis in chronic
PREGNANCY AND HEPATITIS B hepatitis B are integration of HBV-DNA into chromosomes
of hepatocytes (integration within or near functional cellular
Acute hepatitis B has no predilection for pregnancy. Course genes) and inflammation and regeneration associated with
of pregnancy is not changed by chronic hepatitis B in majority chronic HBV infection. HBx protein is a transcriptional
of patients but exacerbations may occur, particularly after activator and activates the Ras-Raf-MAPK pathway and
delivery. In majority, transmission of HBV from mother to interacts with p53 tumor suppressor gene.
child occurs at the time of labor. Hepatitis B vaccine is safe American Association for the Study of Liver Disease
in all trimesters of pregnancy. Risk of vertical transmission Recommendations for Hepatocellular Carcinoma Surveil
is 7090% and 1040% for HBeAg positive and negative lance among HBsAg Carriers.
Asian males over the age of 40 years Other immune-mediated hematological disorders, such as
Asian females over the age of 50 years essential mixed cryoglobulinemia and aplastic anemia have
All patients with cirrhosis who are seropositive for HBsAg been described as part of the extrahepatic manifestations of
Those with a family history of HCC HBV infection, but their association is not as well-dened;
Those who were born in Africa and are over the age of 20 therefore should not be considered etiologically linked to
years HBV. Primary endpoint of treatment is suppression.
Patients with high serum levels of HBV DNA and ongoing
hepatic injury.
Several factors are associated with increased risk of HEPATITIS B VACCINATION
development of HCC; these factors can be grouped into host
factors (old age, male sex, Asian and African, family history of Hepatitis B vaccines contain HBsAg and induces protective
HCC, environmental factors like aflatoxin exposure, lifestyle anti-HBs antibody. There are two types of hepatitis B
and health-associated factors (alcohol, smoking, diabetes, vaccines; plasma derived or recombinant vaccines. There is
obesity), clinical factors (presence of cirrhosis, hepatitis C, no difference in efficacy of plasma derived or recombinant
hepatitis D and HIV coinfection) and hepatitis B viral factors vaccines. Small dose by intradermal route (1 g or 2 g) is
(HBeAg positive, higher HBV DNA, precore mutation and less efficacious than high dose (10 g or 20 g) intramuscular
deltoid and is associated with higher incidence of local
basal core promoter mutation). Tertiary prevention with INF
adverse events. Intramuscular injection in gluteal region is
or lamivudine may prevent recurrence of HCC after curative
less efficacious than intramuscular injection in deltoid region.
ablation.
Vaccination schedule at 0, 1 and 6 months is better than 0-,
1- and 2-month rapid schedule. Role of booster injections
in nonresponder patients is not clear. Protective anti-HBs
EXTRAHEPATIC MANIFESTATIONS OF response rates after HBV vaccination exceeds 90%. Antibody
HEPATITIS B VIRUS titers up to 10 mIU/mL are seroprotective in most instances,
anti-HBs titers decrease to nonprotective levels in at least
Hepatitis B infection produces extrahepatic manifestations 2550% of recipients over a period of 510 years, response
in 110% of patients. Serum sickness-like syndrome may rates are lower in presence of smoking, obesity, injection
occur in the setting of acute hepatitis B due to high levels of into the buttock, chronic liver disease, extremes of age,
circulating immune complexes containing HBV antigens and immunocompromised state, chemotherapy or hemodialysis.
complement components. It presents with fever, skin rash, Hyporesponders to vaccine may benefit from higher dose
and polyarteritis, and often precedes jaundice. Polyarteritis (double dose is recommended for immunosuppressed or on
nodosa is an immune-mediated vasculitis that can involve hemodialysis patients at 0, 1, 2 and 6 months).
large, medium and small arteries and can present with
multisystem involvement. Thirty to fifty percent patients of
polyarteritis nodosa are HBV carriers. POSTEXPOSURE PROPHYLAXIS
Papular acrodermatitis (GianottiCrosti syndrome) is
a skin manifestation of acute HBV infection in childhood Previously unvaccinated: HB immune globulin (HBIg) 0.06
characterized by maculopapular, erythematous nonpruritic mL/kg and hepatitis B vaccine series
lesions involving face and extremities. Previously vaccinated: No treatment if Anti-HBs titer more
Hepatitis B virus infection is associated with several types than 10 mIU/mL; HBIg 1 dose and vaccine booster dose
of glomerular lesions. membranous glomerulonephritis and (if prior antibody response unknown) or revaccination (if
membranoproliferative glomerulonephritis are the most nonresponse earlier) if anti-HBs titer less than 10 mIU/mL.
common and nephrotic syndrome is the most common
presentation. Renal biopsy shows glomerular deposits of one
or more HBV antigens by immunohistochemistry. In children,
disease resolves over months to years while in adults natural
COINFECTION WITH HEPATITIS C VIRUS,
history of hepatitis B-associated glomerulonephritis is not HEPATITIS D VIRUS, AND HUMAN
well-defined. Often, resolution occurs in conjunction with IMMUNODEFICIENCY VIRUS
HBeAg seroconversion but renal failure may ensue rarely.
Long-term control of HBV replication by INF or oral drugs is Patients with concurrent HCV, HDV, or HIV infections have
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19
cHAPTER
Viral Factors and Host Immune

Response to Hepatitis B Virus
Andrew Vaillant
INTRODUCTION viral particles (virions) in the blood is the source of HBV DNA
and is accompanied by the relase of HBeAg into the blood,
Hepatitis B virus (HBV) infection is hepatotrophic and HBsAg is by far the most abundant viral product present in the
typically results in hepatic inflammation and/or necrosis, blood of infected patients, with the overwhelming majority of
which can vary in its impact on liver function. Acute HBsAg being derived from the noninfectious subviral particles,
infection ranges from 60 to 180 days and typically varies in which are typically produced in 1,00010,000-fold in excess
its presentation from asymptomatic infection to cholestatic over virions. Within 18 weeks after the appearance of HBV
hepatitis with jaundice and in rare cases, liver failure. While viremia in the blood, antibodies to the HBV core antigen (anti-
the majority of acute HBV infections are self resolved, a HBc), also known as the HBV capsid protein appear, followed
significant proportion of infected individuals develop chronic by the emergence of anti-HBeAg antibodies (anti-HBe). The
HBV infection. The risk of chronic infection is elevated in initial production of these antibodies can be accompanied
two main patient populations: (i) those acquiring their by varying increases in serum transaminases and may also be
infection when they are young or old and (ii) those whe are accompanied by other symptoms of liver dysfunction, such
immunocomproprised at the time of infection. In many as jaundice and cholestasis. Liver failure can occur, but this is
cases, HBV infection in the liver is able to persist over many a very rare event occurring in less than 1% of reported acute
years (chronic HBV), and while the chronic HBV infected infections. From the onset of liver dysfunction (typically 2
patient population is for the most part asymptomatic, 1030% months after infection) and for the next 3 months, patients that
of patients develop liver cirrhosis and many of these patients go on to resolve their infection typically see a steady drop in
can go on to develop hepatocellular carcinoma (HCC).
transaminase levels as well as improvement in other symptoms
The resolution of acute HBV infection and establishment
of liver dysfunction. During this time the production of anti-HBc
of chronic HBV infection are all greatly influenced by the
and anti-HBe increases and is accompanied by sharp declines
interplay of viral replication and the host immune system. This
in serum HBeAg. HBV DNA levels also begin to drop from peak
chapter focuses on interactions between the host immune
levels observed in the initial months after inoculation. By about
response and HBV in infected individuals. More specifically,
5 months following inoculation, HBsAg levels also sharply
the current understanding of how the innate and adaptive
decline, which can precede or occur simultaneously with the
immune responses react to HBV infection in the acute and
detection of antibodies to HBsAg (anti-HBs). The detection of
chronic phases of the disease and the potential role of viral
factors in modulating these responses is presented. anti-HBs is considered to be a reliable marker for the resolution
of acute infection. By this time, HBV DNA is also undetectable
in the blood. This adaptive immune response to acute HBV
infection can persist for several years in the life of the infected
ACUTE INFECTION patient and is suffictent to provide prophylactic protection
Evidence of HBV infection can be observed as early as 6 weeks against future HBV infections.
following inoculation. By this time, both the surface antigen
(HBsAg) and e-antigen (HBeAg) proteins can be detected in Delayed and Slowly Activated Innate
the blood by standard enzyme-linked immunosorbent assay
(ELISA)-based tests as well as HBV DNA (the viral genome Immune Response during Acute Infection
in infectious HBV virions), detected using polymerase chain For most viruses, infection and subsequent replication
reaction (PCR)-based tests. While the release of infectious typically result in activation of the innate immune response,
Viral Factors and Host Immune Response to Hepatitis B Virus 177
which is characterized by the induction of interferon (INF)- such as CMV and HIV. This delayed onset of viral replication,
a/b by infected cells. This cytokine in turn induces the combined with the lack of a strong immediate innate immune
expression of a number of INF response genes in infected response may also explain the variable symptomology of
cells, which have direct antiviral activity. HBV infection acute HBV infection.
appears fundamentally different from other viral infections
in that its replication does not appear to be cytopathic and
also does not result in the induction of a typical INF response Adaptive Immune Response during
in the infected host. Significant work done in HBV infected Acute Infection
chimpanzees has demonstrated that HBV infection can
Adaptive response to HBV infection is likely initiated by
become established in almost all hepatocytes without any
detectable liver dysfunction. Moreover, the initial stages of a Th1 type T cell response, which evokes the production of
HBV infection in chimpanzees are devoid of any detectable multispecific antibodies that complex with virions and subviral
INF response unlike hepatitis C infection, which rapidly particles in the blood, and removes them from circulation
evokes an INF-mediated innate immune response. The or prevents subsequent reinfection of nave hepatocytes.
absence of this immediate immune response to HBV infection This response may be sustained by natural killer (NK) and
may be due to that fact that HBV replication within the cell or NK-T cells, which may themselves be triggered by CD4+
restricts transcriptional templates to the nucleus, utilizes and CD8+ T-cell independent stress responses from infected
mRNA, which harbors the same structural elements as host hepatocytes or dendritic cells or even by direct recognition of
mRNA and shields the final replication of its genomic material viral components (Fig. 1). Acute infection in individuals who
inside capsids. Also, for reasons not yet elucidated, the early eventually resolve their infection is characterized by an initial
phase of viral replication of HBV in the host does not appear to increase in circulating NK cells consistent with the onset of
occur nearly as rapidly as observed for other human viruses, the peak of viremia, followed by a strong HBV specific CD4+
Fig. 1: Immune responses to HBV infection. HBV infection activates both the innate and adaptive immune responses as depicted. The major
source of viral antigen is derived from subviral particles (the predominant source of serum HBsAg) and secreted HBeAg. Smaller amounts of
HBsAg and HBcAg are also derived from virions. Via antigen presenting cells, these antigens activate HBV specific CD4+ T cells, which go on to
stimulate the activation and proliferation of B cells (and production of antibodies to these viral antigens). Infected hepatocytes are targeted
directly via CD8+ T cells and NK cells, which act to directly suppress viral replication within the infected hepatocyte without compromising the
hepatocyte itself or to eliminate infected hepatocytes cytolytically.
Abbreviations: MHC, major histocompatibility complex; HBV, hepatitis B virus; INF, interferon; TNF, tumor necrosis factor; NK, natural killer;
HBsAg, hepatitis B surface antigen; HBcAg, hepatitis B core antigen; HBeAg, hepatitis B e-antigen; cccDNA, covalently closed circular DNA (the
stable extrachromosomal HBV DNA reservoir in the nucleus).
Fig. 2: Patterns of virology and serology in (A) acute resolving and (B) chronic HBV infection. Chronic infection most importantly differs from
acute resolving infection in the absence of a strong T cell response, which is typically accompanied by a significantly weaker flare of liver
dysfunction as measured by ALT. In acute infection, the more robust immune response leads to the successful elimination of serum antigens
and the successful elimination of HBV infection from hepatocytes. In resolving cases, HBV-specific immunity is maintained long-term and
provides durable control over de novo infection. In chronic infection, both anti-HBc and anti-HBe can be detected, with the latter taking some
years to develop with no apparent effect on the long-term control of infection. The persistence of infection and the absence of free anti-HBs
in the serum of patients are well correlated with the poor initial T cell response, chronic prevalence of HBV DNA and most notably with the
persistence of HBsAg, and suggest that HBsAg may be critical for the chronicity of HBV infection.
Abbreviations: HBV, hepatitis B virus; ALT, alanine transaminase; HBsAg, hepatitis B surface antigen; HBcAg, hepatitis B core antigen; HBeAg,
hepatitis B e-antigen
and CD8+ T cell response after viremia reaches its nadir and viral clearance. While the CD4+ T cell response is responsible
results in the accumulation of HBV-specific T cells in the for the stimulation of CD8+ T cell and B cell proliferation, it
liver. While this T cell-mediated immunity appears to provide is still unclear what role this CD4+ T cell response plays in
durable protection from de novo infection, the fact that it the resolution of liver infection. On the other hand, CD8+ T
appears relatively late in the acute phase of infection suggests cells appear to play an essential role in viral clearance by two
that it may not be sufficient to elicit the early clearance of different pathways: (i) directly by stimulating the apoptosis
HBVDNA observed in successfully resolved acute infections of infected cells, giving rise to the liver pathology (elevated
(Fig. 2). transaminase levels and jaundice), which occurs during acute
infection and (ii) indirectly via the production of antiviral
cytokines (INFs) of the innate immune response. In this
Resolution of Acute Infection and the INF-g- and tumor necrosis factor (TNF)-a-mediated process,
Innate Immune Response assembly of HBV capsids in the cytoplasm is inhibited in
a proteosome and kinase dependent process, viral RNAs
CD4+ T cell proliferation and production of antibodies are destabilized and covalently closed circular DNA
for HBV antigens in response to HBV infection appears to (cccDNA), the extrachromosomal replication source of HBV,
correlate with the onset of acute hepatitis and subsequent accumulation is halted and even reversed, all without any
apparent harm to the host hepatocyte (Fig. 1). Thus, the onset toll-like receptors (TLRs) important in the immune response
of liver dysfunction observed before or during the peak of (including TLR-2) were found to be significantly lower in
viremia is consistent with the influx of T cells into the liver and peripheral blood mononuclear cells (PBMCs) from CHB
further suggests that cytolytic activities of the innate immune patients; and the ability of PMBCs from CHB patients to
response may be in play during this period. However, the fact produce anti-HBs in response to antigen stimulation appears
that the majority of viral clearance in resolving acute HBV severely degraded in comparison to PMBCs from patients in
infection takes place in the absence of or during the waning the acute phase of infection. There is also evidence to suggest
of liver dysfunction argues that noncytolytic viral clearance that at least some of these immunological deficits are more
mediated by innate immunity also plays a significant role in severe in the liver as T cells isolated from the livers of patients
the resolution of acute infection. with CHB showed significantly reduced secretion of INF-g
and TNF-a upon stimulation with HBV-specific peptides as
compared to T cells isolated from the blood, which showed
CHRONIC INFECTION normal secretion of these cytokines with similar stimulation.
Moreover, these immunological deficits may not be limited
Patients who do not resolve their HBV infection within 68 only to HBV-specific T cells as immunological deficits have
months after inoculation are considered to have entered also been observed in non-HBV-specific CD8+ T cells in CHB
the chronic phase of HBV infection. This is characterized patients.
by continued prevalence of HBsAg and inability to detect
antibodies to HBsAg in the blood and significant HBV
DNA titers, although the steady state levels of HBV DNA EFFECT OF HEPATITIS B VIRAL
in chronically infected patients are typically lower than in
acutely infected patients. While the appearance of anti-HBe COMPONENTS ON IMMUNE FUNCTION
and subsequent elimination of HBeAg is observed in some
Several viral proteins produced by hepatocytes after HBV
patients after several years of infection, this does not appear to
infection have the ability to directly or indirectly suppress
have any positive benefit on the patients ability to eliminate
both innate and adaptive immunity. This is the likely the
the infection.
reason why active HBV replication can persist so long in
The transition to chronic infection appears to be correlated
infected patients, even though this virus is known to be highly
with weak initial CD4+ and CD8+ T cell responses and weak
immunogenic. The specific roles these HBV proteins play in
activation of innate immunity. This is consistent with the
immunosuppression are described below.
young/elderly and immunocompromised patients being the
most likely to develop chronic HBV infection.
Although HBV-specific CD8+ T cells continue to persist in HBX Protein
chronic infection, they appear unable to clear HBV infection
HBX is the smallest HBV protein and has been suggested to
by themselves from hepatocytes. This is likely caused by the
continual production of viral antigens (see below), which directly induce the apoptosis of infected hepatocytes by both
over time can lead to a loss of CD8+ T cell function, deletion p53 dependent and independent mechanisms. However,
of virus-specific T cells and other immunoinhibitory effects. HBX can inhibit proteosome activity inside the cell, resulting
In fact, the size and activity of the CD8+ T cell population in impaired immune function and antigen presenting ability
in chronically infected patients is inversely correlated with and may have an immunotolerizing activity on CD8+ T cells
the extent of their viremia. The weakened functionality in the liver.
and reduced prevalence of these CD8+ T cells may actually
result in their contributing to the pathogenic nature of the
chronic disease state as a result of their continual stimulation
HBeAg
of ineffective cytolytic and noncytolytic responses in an HBeAg is a secreted form of the capsid (or core) antigen and
attempt to eliminate the liver infection. In addition, there are is produced in large excess during the initial stages of HBV
other reported immunological deficits in chronic hepatitis infection. It has been shown to have both immunogenic and
B (CHB), which suggest a general pattern of erosion of immunotolerizing effects and may be at least partly responsible
immune functionality with continued presence of infection: for the poor HBeAg and HBcAg antibody response in HBeAg+
dendritic cells in patients with CHB have been observed to patients via Fas-mediated apoptosis of CD4+ T cells. HBeAg can
be dysfunctional with an immature phenotype and reduced also interfere with the expression of TLR-2 on monocytes, which
capacity to interact with T cells; the expression of several can block the secretion of TNF-a. The resulting imbalance in
Th1/Th2 responses has been shown to suppress the immune Such enormous amounts of HBsAg serve to effectively
response in HBeAg/HBcAg-specific CD8+ T cells. This is sequester all available anti-HBsAg antibodies in the sera of
consistent with the observation that vertical transfer of HBV infectious patients, effectively shutting down the adaptive
infection from mother to child is more likely to result in resolved immune response to HBsAg (Fig. 3). In fact, this may be
infection in the child when the mothers HBV infection is HBeAg the reason for the delay or absence of anti-HBs detection
negative. In addition, HBeAg may also inhibit p38 mitogen- during acute and chronic infection as commonly used
activated protein kinase (p38 MAPK) and nuclear factor- clinical assays for detecting anti-HBs antibodies cannot
kappaB (NF-B) signaling (also important components in the detect immunocomplexed IgG. In this context, the absence
immune response) as these signaling deficits are observed in of anti-HBs merely demonstrates the absence of free anti-
PBMCs from HBeAg positive patients but not in HBeAg negative HBsAg antibodies, not the lack of seroconversion. In fact,
patients. Interestingly, there is a region on HBeAg, which shows studies, which have specifically looked at the prevalence
significant homology with Toll/interleukin-1 receptor (TIR) of immunocomplexed anti-HBs IgG have discovered that
antibody is actually present in 93% of acute HBV infections and
domains (conserved activation domains in all TLR receptors)
40% of chronic infections, suggesting that the majority if not
and this suggests that HBeAg may also have a broad ability to
all patients acquiring HBV infection become seroconverted
block TLR-mediated signaling (Fig. 3).
relatively early on during the infection but that the detection
of anti-HBs is masked by the presence of HBs in significant
HBsAg molar excess in the blood. This chronic neutralization of
available anti-HBsAg may be the underlying factor in the
Originally termed the Australian antigen, HBsAg was the first immune exhaustion, which is known to occur in CHB.
component of HBV infection to be characterized and is by In addition to neutralizing the adaptive response by
far the major viral protein component in the sera of infected IgG sequestration, several groups have demonstrated the
patients. In fact, HBV appears to have evolved to produce a direct inhibitory effect of HBsAg on the ability of humoral
large excess of defective particles (1,00010,000-fold in excess and liver cells to mount both adaptive and innate immune
of infectious particles), which are essentially the delivery responses to HBV infection. These effects have been shown
vehicle by which infected hepatocytes deliver enormous to include inhibition of TLR-9-mediated activation and
amounts of HBsAg into the blood. INF-a production in plasmacytoid dendritic cells, the
Fig. 3: Impact of secreted viral antigens on the host immune response to HBV infection. The immunosuppressive actions of HBsAg and HBeAg
are depicted. The effects of HBsAg are emphasized owing to the significant concentrations of this antigen, which are maintained by the
constitutive secretion of large quantities of subviral particles by infected hepatocytes.
Abbreviations: HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e-antigen; TLR, toll-like receptors
development of a tolerogenic phenotype in myeloid dendritic and was predicted to occur with greater frequency only
cells with reduced capacity to produce INF-g and induce after more than 10 years of therapy. It is important to note
T cell proliferation, and the blockade of NF-B-mediated that these poor HBsAg clearance rates are concurrent with
cyclooxygenase-2 (COX-2) expression and interleukin (IL)- rapid and universal reductions of HBV DNA and significant
18 production in monocyte cell lines. Most strikingly, the HBeAg seroconversion rates in these patient populations,
administration of purified HBsAg to primary cultures of which suggests that although the HBV DNA and HBeAg
mouse hepatocytes completely shut down TLR-mediated seroconversion endpoints may be convenient for following
antiviral activity, which was correlated with the suppression the activity of nucleoside analogs, they are inadequate
of INF-b secretion, suppression of interferon regulatory prognostic indicators for a curative response in patients with
factor-3 (IRF-3), NF-B and extracellular signal-regulated CHB. This further suggests that the overall role of infectious
kinase (ERKS)-1 and -2 (this was observed with HBeAg as particles or HBeAg in suppressing immune function is
well). Moreover, activation of HBV infection in HBV-met marginal. The failure of polymerase inhibitors to achieve
cells blocked their expression of TNF-a, IL-6 and IRF-3, significant SVR rates even with several years of treatment
while suppression of HBV infection by small interfering may be linked to the poor HBsAg seroclearance rates in these
RNA (siRNA) led to restoration of these proinflammatory patients. This is consistent with the fact that while polymerase
cytokines and transcription factors. These studies and the inhibitors inhibit the replication of HBV genomes during viral
fact that HBsAg is the predominant viral protein in the blood particle maturation, they do not directly affect the levels of
point to this protein as having a major role in the suppression cccDNA in the nucleus, which is the source of transcription
of adaptive and innate immune responses to HBV infection of mRNA for the synthesis of HBsAg. As such, the effects of
and may be the key mechanism whereby HBV maintains its polymerase inhibitors on reductions in serum HBsAg are
chronic liver infection in patients with CHB. gradual and only moderate at best, which may be the reason
for the poor SVR rate in these patients. New technologies that
can directly affect the production or release of HBsAg may
IMPLICATIONS FOR CURRENT AND have the potential to achieve significantly improved rates of
seroconversion by removing the immunological suppression
FUTURE HEPATITIS B VIRUS TREATMENTS in patients with CHB.
Patients with CHB infection typically require some form of Recently, a novel family of HBV antiviral agents (nucleic
medical intervention because these patients eventually develop acid polymers or NAPs) was characterized in the duck HBV
liver fibrosis, which often progresses to more severe liver (DHBV)-infected Pekin duck model of HBV infection. NAPs
damage (cirrhosis) and may be accompanied by onset of liver appear to be of inhibitors of HBV subviral particle release
cancer. These complications are the results of a liver infection, and one NAP (REP 2055 or REP 9AC) has been evaluated in
which can persist for decades. In large longitudinal studies of a small cohort of HBeAg positive patients with CHB. REP
patients with CHB, loss of detectable HBsAg is associated with 2055 has proven to be able to rapidly clear HBsAg from
improved survival and reduced risk of HCC. Recent reports from patients after 4 months or less of treatment, depending on the
CHB patients treated with INF have noted that the loss of HBsAg treatment regimen. With continual maintenance of HBsAg
in these patients is correlated with and is highly predictive seroclearance, 3 out of 5 of these patients have gone on to
of a sustained virologic response (SVR), which consists of the achieve control of their infections after only 56 months of
appearance of protective levels of anti-HBs and the absence of treatment (serum HBV DNA <400 copies/mL, no detectable
detectable HBV DNA 48 weeks after the end of treatment. These HBsAg or HBeAg and significant anti-HBsAg and anti-HBeAg
recent reports suggest that HBsAg clearance may be the primary titers). Of significant importance is that these three patients
endpoint for predicting SVR in patients with CHB.
are currently maintaining a durable sustained virologic res
Current drugs approved for the treatment of CHB only
ponse up to 12 months after treatment and that these SVRs
achieve marginal rates of HBsAg clearance. Forty-eight
were achieved in a relatively short timespan after HBsAg
weeks of treatment with INF results in approximately 17% of
seroclearance. These preliminary findings suggest that HBsAg
patients clearing their surface antigen at the end of treatment
compared to 1% with lamivudine alone. Even longer duration may indeed be the critical viral component responsible for
treatment with nucleoside analogs (96 weeks) only results in the chronicity of HBV infection and further suggest that the
surface antigen clearance in 2.8 and 5.1% of patients treated inhibition of production of this protein (or its rapid removal
with lamivudine or entecavir respectively. In comparable from the serum of infected patients) may be an effective
studies, appearance of free anti-HBs with lamivudine therapy approach to achieving an improved curative response in
was rare and reported only after 6571 months of therapy patients with CHB.
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20
cHAPTER
Hepatitis C
Amna Subhan Butt, SM Wasim Jafri
INTRODUCTION The journey in search of this novel discovery continued.

Dr Michael Houghton who characterized the human
Hepatitis C is a global health issue that affects almost every interferon-beta (IFN-) gene migrated from UK in 1982 to set
region across the world. It is well recognized as the leading up a laboratory at a newly formed biotechnology company
cause of end-stage liver disease and primary liver cancer. called Chiron. Thereafter, the works conducted largely
Moreover, the endemicity and chronicity of hepatitis C virus in Dr Houghtons laboratory at the Chiron Corporation
(HCV) infection leading to major complications have made between 1982 and 1989 led to the identification of HCV. Key
HCV a major healthcare burden globally. colleagues included Dr Qui-Lim Choo (Chiron); he was able
to identify the unique positive clone derived from the genome
of HCV, Dr George Kuo (Chiron), Dr Daniel Bradley [Centers
DISCOVERY OF NOVEL HEPATITIS C for Disease Control and Prevention (CDC)]; he provided
VIRUS biological samples from the NANBH chimpanzee model.
Subsequently, the same group was able to develop an assay
Since the beginning of viral hepatitis field during 195060s for circulating antibodies. This innovative discovery facilitated
as infectious and serum hepatitis, a lot of works have the development of effective diagnostics tests and promising
been done to recognize different viral isolates and to develop drugs to control this global pathogen. The first-generation
their diagnostic assays. This journey had led to the discovery blood test was available in 1990 that prevented the majority of
of hepatitis A virus (HAV) by Dr Stephen Feinstone et al., transfusion-associated hepatitis C infection afterwards.
hepatitis B virus (HBV) by Dr Baruch Blumberg et al., and Now, we recognize this novel NANBH virus as hepatitis C
the development of serological tests to detect these viruses in virus, which is an enveloped, single-stranded RNA virus of 9.5
mid-70s. However, due to the failure to detect HAV and HBV kb, 50 nm in diameter, and belongs to a genus Hepacivirus
in most cases of parenterally transmitted hepatitis, efforts and family Flaviviridae. Humans are the only known
were directed to isolate the attributable organism, which was reservoir/host; however, in chimpanzees experimental
initially named as Non-A, Non-B hepatitis (NANBH) in 1975. transmission of hepatitis C has been demonstrated.
Subsequently, Dr Harvey Alter and other groups were
able to transmit experimentally the NANBH virus from
human material to the chimpanzees. They also established GLOBAL BURDEN OF HEPATITIS C
that NANBH was actually not due to a single agent; instead,
probably multiple agents were involved. It was mid-1980s Currently, HCV is endemic to most part of the world. However,
when Dr Bradley suggested that this NANBH could be a its prevalence varies widely with the geographical locations
small enveloped virus belonging either to family flaviviridae, as well as within the populations. The existing data regarding
togaviridae or it could be a novel type of enveloped virus. HCV prevalence from most part of the world inherit the lack
In subsequent years, many scientists, including Dr Harvey of population-based studies and mainly consist of estimated
Alter, Dr Dienstag, Dr Hoofnagle, and Dr Seeff verified the prevalence from a selected group of population, i.e. blood
progression to cirrhosis among up to 20% of individuals donors. This might had led to the underestimation of actual
affected by NANBH. Meanwhile, it has also been demonstrated HCV prevalence.
that the transmission of this virus is attributable to blood The World Health organization (WHO) has compiled the
transfusions. available data regarding epidemiology of HCV in 1997 that
Hepatitis C 185
was updated subsequently. Out of 266, 166 studies were largely. Furthermore, evaluation by testing HCV RNA revealed
identified that cover 116 countries using preselected criteria 1.3% or 3.2 million cases of chronic hepatitis C (CHC). In
of representativeness. According to the WHO estimates in Latin America and Canada, in general, HCV seroprevalence is
general, 3% or 170 million individuals are affected by HCV 1.23% (range 0.23.4%) and 0.8%, respectively. The national
globally and more than 350,000 individuals die annually due Enhanced Hepatitis Strain Surveillance System established
to HCV-related liver disease. Even in developed regions, the the decline in incidence of HCV from 3.3 to 2.1 cases/100,000
burden of HCV is significant. Europe is an example of it where individuals from 1998 to 2004, which was mainly credited to
4 million HCV carriers have been reported making HCV safe blood transfusion practices.
five times more prevalent than human immunodeficiency
virus (HIV). Taking into account the geographical locations,
countries were divided into six WHO-regions of the world:
WHO African Region
Americas, Africa, Eastern Mediterranean, Europe, South-east Approximately 5.3% or 31.9 million individuals are affected by
Asia, and Western Pacific regions. Furthermore, according to hepatitis C in Africa. However, variability in different regions
estimated HCV prevalence, these regions were divided into has been found: 6%, 2.4% and 1.6% HCV prevalence has been
regions with (i) very low prevalence (where estimated HCV reported from Central Africa, West Africa, and East Africa,
prevalence was <1%), (ii) low prevalence (where estimated respectively. Additionally, clusters of higher prevalent areas
HCV prevalence was between 1% and 1.9%), (iii) intermediate have been notified, e.g. Burundi with 11.3% and Cameroon
prevalence (where estimated HCV prevalence was between with 13.8% HCV prevalence.
2% and 2.9%), and (iv) high prevalence (where estimated HCV
prevalence was >2.9%). Among WHO-regions, the overall
highest HCV prevalence of 5.3% was reported from Africa
WHO Eastern Mediterranean Region
followed by 4.6% from Eastern Mediterranean region, while There are 21 member countries in this region, including Egypt,
the lowest HCV prevalence of 1.03% was found in Europe Iran, Saudi Arabia, Afghanistan, and Pakistan. Over all up to
(Table 1). Whereas among countries, Egypt was found to 4.6% (21.3 million) of population is affected by HCV in this
have the highest HCV prevalence (1520%), while UK and region, and Egypt is the highly affected country pertaining
Scandinavia acquired the lowest (0.011%) HCV burden. to 1520% HCV prevalence. However, variability has been
Moreover, up to 75% individuals who were seropositive for notified in HCV prevalence across the Egypt per se, i.e. 8% in
HCV were found to have chronic infection with HCV. However, Cairo and Alexandria, 816% in middle and upper Egypt, and
taking into consideration the absence of data from 57 countries, 15% in lower Egypt or rural areas of Nile Delta.
one can expect that the actual number of individuals infected
might be higher than what has been estimated. The additional
information about the epidemiology of HCV among different WHO Southeast Asia Region
WHO regions is described below. A total 11 countries, including India, Bangladesh, Indonesia,
Korea, Sri Lanka, etc. are included in this region. In general, up
to 2.1% (32.3 million) individuals are affected by HCV in this
WHO Region of the Americas region. Among the member countries, HCV seroprevalence
According to the National Health and Nutrition Examination was found to be 2.9%, 2.4%, 1.3%, 1.2%, 2.5%, 1.8%, 1.1%, 1.6%,
Survey (NHANES) conducted in 19992002 in USA by CDC, and 1.4% in Thailand, Bangladesh, Bhutan, India, Indonesia,
1.6% or 4.1 million people were found HCV seropositive. Men, Maldives, Nepal, Korea, and Sri Lanka, respectively. The
non-Hispanic blacks and Mexican Americans were affected existing data from this region carry major limitation due to
Table 1: Estimated hepatitis C prevalence in WHO region
WHO regions Hepatitis C prevalence (%) Number of infected population (millions)

Africa 5.3 31.9
Eastern Mediterranean 4.6 21.3
Western Pacific 3.9 62.2
South-east Asia 2.15 32.3
America 1.7 13.1
Europe 1.03 8.9
lack of large population-based studies. In India, where most of among males and birth cohort of 19501970. Moreover, higher
available data originated from blood donors, major difference HCV prevalence was found in London (1.27%), and Eastern
in HCV prevalence was found among commercial blood (1.41%) and South West (1.25%) regions of UK. Injection drug
donors (55.387.3%) as compared to voluntary blood donors users have been notified to be at the highest risk to acquire
(1.54.3%). Up to 3.331.5% cases of cirrhosis and 15.142% HCV in UK.
cases of hepatocellular carcinoma (HCC) are attributed to Coming to the Western Europe, 5 million are seropositive
HCV in India. for hepatitis C. The estimated HCV prevalence in France is
Pakistan is placed in Eastern Mediterranean region by 1.1-1.2% and approximately 80% of them have been found to
WHO. However, geographically, it is recognized as the part have chronic HCV infection. Injection drug users, inmates,
of South Asia; hence, we discuss it in current section. Like and HIV infected patients are the most vulnerable to acquire
other countries of Southeast Asia, the overall prevalence of HCV.
hepatitis C is increasing. In general, most of the prevalence Hepatitis C virus is highly endemic in certain regions. Egypt
estimates for HCV range between 2.4% and 6.5% among adults is highly affected by hepatitis C leading to high morbidity and
and between 0.44% and 1.6% among children. Recently, a mortality from cirrhosis and HCC as compared to rest of the
countrywide survey was conducted by the Pakistan Medical world. The strong homogeneity of HCV subtypes in Egypt
Research Council in 20072008 to get the actual prevalence of (mostly 4a) correlates to the epidemic spread of HCV mainly
hepatitis B and C. The survey estimated that 4.9% (8.8 million) with past practice of parenteral therapy for schistosomiasis.
of population in Pakistan is affected by hepatitis C. This had led to the pooling of large reservoir of chronic HCV
infection, which is responsible for the continued endemic
WHO Western Pacific Region transmission of HCV in Egypt today. Variable HCV prevalence
was reported from Italy, i.e. greater than 5% in some
There are 27 member countries included in this region, including communities and 12.6% from others. Individuals greater
Australia, Cambodia, China, Japan, Malaysia, Mongolia, Nauru, than 60 years of age contribute to higher HCV prevalence in
New Zealand, Philippines, Korea, Singapore, and Vietnam. Italy, which could be attributable to the use of glass syringes
Overall, HCV prevalence is 3.9% (62.2 million) in this region.
for medical treatment or history of dental therapy before
Moreover, the estimates of 2001 from Australia reported
1970. Again in Japan use of nondisposable syringes for
210,000 individuals affected by HCV with 16,000 incident cases
immunizations in 1950s lead to endemicity of HCV.
diagnosed every year. National survey of China (19921995)
reported 3.2% HCV seroprevalence in general population with
highest prevalence (61.4%) among injection drug users (IDUs).
Hepatitis C virus affects 2% Japanese population and is the INCIDENCE
leading cause of HCC in Japan.
It is very difficult to ascertain the actual incidence of
The other member country, i.e. Samoa HCV prevalence of
hepatitis C as acute hepatitis C remains asymptomatic in the
0.20.6% has been reported that is probably due to the low
majority of cases and well-established surveillance systems
rate of IDUs. While in Korea, 1% of general population is
seropositive for HCV. are limited. However, the incidence data that are available
from few developed countries reported 150,000 new HCV
cases annually from the US and Western Europe, and about
WHO European Region 350,000 from Japan. However, in US, estimated annual HCV
The World Health Organization included 57 countries in incidence has been declined by greater than 80% since
European region. Considering WHO estimates, 1.1% (7.3 1980. Likewise, decreasing trends have been reported from
million) individuals were seropostive for HCV; higher rates European countries like France and Italy. Conversely, steady
(>1.25%) in Southern and Eastern European countries increase in HCV prevalence was reported from 1961 to 2001
and lower rates of less than or equal to 0.1% were found in in Australia. The declining incidence could be attributed to
Northern Europe. Nonetheless, more than 86,000 deaths were the implementation of safe blood transfusions and universal
attributed to HCV-related cirrhosis and HCC in 2002. precautions. However, unsafe therapeutic injections,
In England, hepatitis C affects 0.6% of adult population. especially in developing countries and needle sharing
It has been estimated that by 2010, 6,000 and 1,500 affected for IDUs and inmates are still responsible for new cases.
individuals will develop cirrhosis and end-stage liver disease However, one should not forget the fact that the actual annual
or HCC, respectively, and further increase in these rates are incidence might be much higher owing to underreporting
expected in next decades. Higher HCV prevalence was notified and asymptomatic infection in most of the cases.
Hepatitis C 187
RISK FACTORS FOR HCV TRANSMISSION countries, more than 50% of HCV cases are acquired through
illegal drug use mainly IDUs followed by intranasal cocaine
Being a blood-borne pathogen, the primary mode of especially among IDUs. In different studies, 5094% of IDUs
transmission for HCV is via parenteral exposure to have been found to be affected by hepatitis C. The risk of
contaminated blood or blood products. Sharing of acquiring HCV is correlated to the duration of drug use. In
contaminated needles, equipment and sharp objects like Thailand, 8692.5% and 9.5% hepatitis C have been reported
razors are common sources leading to iatrogenic spread in IDUs and commercial sex workers, respectively, hence,
of hepatitis C especially in developing countries. One of representing these factors next to unsafe injection practices
the major examples of this is Egypt where the highest HCV and blood transfusion.
prevalence has been reported due to the reuse of needles for Inmates are challenging population and are considered to
schistosomiasis vaccination program. The implementation be at greater risk of blood-borne infections, including hepatitis
of regular screening of blood and blood products started C due to high-risk related behaviors during and prior to
in 1991 had led to a significant decrease in the incidence imprisonment. The global HCV prevalence among prisoners
of transfusion-associated HCV in developed countries. ranges from 2 to 65%. Even in US, 39% of all Americans with
However, in developing countries, due to lack of regular HCV infection have a history of incarceration. In a study
screening of blood and blood products, transfusion-related conducted in 2002, all new entrants into the Maryland
transmission of HCV is still the primary mode. According to Division of Correction and the Baltimore City Detention
the recent WHO estimates, the probability of acquiring HCV Center were evaluated between January 28, 2002 and March
infection via transfusion of unsafe blood is expected to be 28,2002. Out of 3,914 inmates and detainee, 29.7% were
92%. found to be affected by HCV. Moreover, 44% of 418 homeless
Therapeutic injection given by used syringes is one of veterans were found HCV seropositive in another study that
the most common risk factor for hepatitis C in developing was significantly associated with history of substance abuse
countries. It is mainly due to peoples belief in the quick [odds ratio (OR) 6.86, P < 0.001] and services during the
action of injections and lack of awareness about their risks Vietnam era (OR = 4.66, P = 0.01). Furthermore, approximately
that lead to overuse of therapeutic injections. Furthermore, 38%, 34%, and 30% of HCV prevalence have been reported
injections given by unqualified practitioners and reuse of from Italy, Australia, and Iran, respectively. Recently, we
syringes augment the risk. According to the estimates of conducted a study in Central Prison, Karachi, Pakistan. Out
WHO, use of contaminated syringes for therapeutic injections of 750 adult inmates 18.4% inmates in total and 84.2% IDUs
is responsible for 2 million new cases of hepatitis C every year. were found to be HCV seropositive. Therapeutic injections
In contrast to developing countries, currently intravenous given by glass syringes, IDU, sharing of razors, and illiteracy
drug user (IVDU) and percutaneous exposure due to high- were the significant associated factors for HCV. However, one
risk sexual behaviors are the major factors responsible for should not ignore the possible underestimation of overall
HCV spread in developed countries. HCV prevalence globally due to underrepresentation of
Though it is less frequent among monogamous couples, incarcerated and homeless individuals in existing data.
mucosal exposures to blood or serum-derived fluids Needle-stick injuries are the source of nosocomial
through sexual contacts lead to transmission of HCV. In transmission of hepatitis C in the healthcare setting. In various
certain studies, 45% HCV seroprevalence have been found studies, up to 10% transmission rate has been documented
among household and sexual partners, but these results after a needle-stick injury involving contaminated blood.
are suspected to be confounded by possible concomitant However, the risk of HCV transmission after needle-stick
exposure to other risk factors. However, mucosal spread of injury is influenced by the size of inoculum, size of the needle,
HCV among HIV-infected men who have sex with men (MSM) and the depth of inoculation.
is one of the common causes in high-risk population, and Traditional folk remedies and other needle practices like
the risk correlates with the numbers of sexual partners and acupuncture, tattooing, body piercing via contaminated
high-risk sexual practices. Vertical transmission of hepatitis needles are also found to be responsible for the transmission
C is estimated to be less than 5%, although this risk increases of HCV.
greater than twofolds, if the mother is coinfected with HCV Transplantation of infected tissue or organ grafts,
and HIV. hemodialysis, and needle-stick injuries that expose the
Intravenous drug use has emerged as another major healthcare workers in an occupational setting are also
risk factor for acquisition of HCV, especially in high-risk recognized as attributable factors for the acquisition of
population like inmates and habitual drug users. In developed hepatitis C.
POPULATION AT HIGHER RISK PATHOGENESIS AND VIRAL

Currently, the prevalence of HCV is found highest in CHARACTERISTICS
IDUs (>70%), hemophiliacs (up to 98%) and patients with
Hepatitis C virus is an RNA virus that targets hepatocytes
thalassemia, and high but highly variable in hemodialysis
and possibly B lymphocytes. The RNA dependent, RNA
patients (<1090%). Moreover, HCV prevalence is higher
polymerase enzyme, which is responsible for HCV
among heterosexuals with multiple sexual partners,
replication, actually lacks a proofreading function. Hence,
homosexual men, HIV coinfection and in healthcare workers
HCV undergoes rapid evolution with time, giving rise to a
and family contacts of HCV-infected persons (15%). The
collection of multiple, diverse but related quasispecies within
most new infections are due to high risk drug behavior or
an infected individual. Moreover, the replication of HCV is
unsafe injection practices in developed countries.
very vigorous, and in general, more than 10 trillion virion
Despite availability of effective screening of blood and
particles are produced every day, even in the chronic phase
blood products with second and third generation enzyme
of infection.
immunoassays (EIAs), transfusion-associated hepatitis C is
still a major risk factor in developing countries due to lack and Hepatitis C virus mainly consists of:
inappropriate blood screening. A single open reading frame
Two untranslated regions (UTRs), i.e. 5UTR and 3UTR.
It encodes a single polyprotein of 3,011 amino acids, which
GENOTYPES: DISTRIBUTION is then processed into 10 mature structural and regulatory
proteins. The parent polyprotein is cleaved by:
ACROSS THE WORLD A host signal peptidase into single proteins in the
structural region
On the basis of the heterogenicity in genomic sequence
HCV-encoded proteases in the nonstructural (NS) region.
of HCV, 11 HCV genotypes (genotypes 111) and many
subtypes (a, b, c, and so forth) have been recognized. This The HCV genome has two regions:
variability of genetic sequence is distributed throughout 1. Structural region contains:
the genome; however, the coding for envelopes E1 and E2 The core protein
is the most variable one. The most prevalent genotypes Two envelope proteins (E)
are 1a and 1b that constitute up to 60% of HCV cases i. E1
across the world. However, there is some variability in ii. E2: In E2, there are two hypervariable regions 1 and
their distribution; genotype 1a is largely prevalent in 2 (HVR 1 and HVR 2). These HVRs show extreme
Northern Europe, North and America, while genotype 1b sequence variability that is thought to be the
is mostly found in Southern-eastern Europe and Japan. consequence of selective pressure by virus-specific
Genotype 2 is the predominant genotype in Europe. antibodies. This E2 region also encompasses the
Genotype 3 is endemic in Southeast Asia, and genotype 4 is binding site for CD81, which is assumed to be the
characteristic for the Middle East, Egypt and central Africa. HCV receptor or coreceptor on cells.
The phylogenetic analysis indicates that HCV genotype 2. Nonstructural proteins (NS), which function as:
3 appeared in Pakistan in 1920s, and further rapid spread Proteases (e.g. NS2, NS3, and NS4A)
occurred in 1950s. Genotype 5 is almost entirely prevalent Helicase (e.g. NS3)
in South Africa, and genotypes 611 are mostly dispersed RNA-dependent RNA polymerase (e.g. NS5B)
in Asia. The identification of genotype is important with However, the functions of other proteins (e.g. p7) are less
respect to the response to the treatment, as genotypes 2 and well described. Although the exact worth is not known, a
3 are known to have best response with antiviral therapy. region in NS5A has been found to be associated with response
genotype 1 has poorer response, while genotype 4 usually to the treatment with IFN- and named as interferon
has intermediate response. sensitivity-determining region (ISDR).
The influence of HCV genotypes directly in the progression However, the relevance and importance of this region are
of disease is still controversial, although the genetic, still unclear. In general, the NS proteins are found to have
environmental, and immunological factors are responsible crucial role in the lifecycle of HCV and represent attractive
for the differences in disease progression. targets for antiviral therapy. Likewise, being involved in
Hepatitis C 189
viral replication the UTRs could be the potential therapeutic not integrate into the host genome; hence, it is not directly
targets. oncogenic. Hepatitis C virus might lead to repeated cycles of
The HCV genome is highly mutable due to HVR (located hepatocyte destruction and regeneration over many years,
near N-terminus of E2). This region maps at the surface loop which subsequently lead to neoplastic changes and then
of E2 protein containing a B cell epitope that undergoes HCC. Globally, up to 27% cases of cirrhosis and 25% cases of
antigenic evolution over time. The rapid mutation in HCV HCC have been estimated to be due to HCV. Moreover, HCV
genome makes it able to escape host immunologic detection is accountable for approximately 20%, 70%, and 30% cases
and elimination that leads to chronic infection. Moreover, of acute hepatitis, chronic hepatitis, and liver transplants,
due to existing heterogeneity, the HCV vaccine development respectively. Nonetheless, 796,000 and 616,000 deaths were
is really a great challenge (as vaccine antigens from multiple attributed to cirrhosis and primary HCC in 2002, and perhaps,
serotypes are essential for global protection). up to 20% of these deaths were linked to HCV infection. These
Hepatitis C virus infects hepatocytes and leads to liver figures are alarming even for industrialized countries where
injury by direct cytopathic effect or a host immune-mediated the accesses to healthcare facilities are relatively easy. On the
cytolytic response. As a consequence, portal inflammation, other hand, the number of untreated patients, morbidity and
periportal hepatocellular necrosis, and fibrosis occur. Mean mortality due to underlying HCV cirrhosis are continuously
intervals between the onset of acute post-transfusion hepatitis growing. This is in general due to inadequate detection,
and detection of chronic hepatitis (10 years), cirrhosis (20 unavailability of antiviral therapy, and considerably high
years), and HCC (30 years) are reported in separate Japanese cost incurred to antiviral therapy, especially in developing
and American studies. countries. Hence, endemicity and chronicity of HCV infection
leading to major complications have made HCV a major
healthcare burden globally.
CLINICAL CHARACTERISTICS AND
NATURAL HISTORY OF THE DISEASE
WHO SHOULD BE SCREENED FOR
Hepatitis C can manifest as acute or chronic infection. The HEPATITIS C?
incubation period for HCV is 420 weeks. In general, acute
hepatitis C presents as milder disease and only up to 2030% Considering the risk of acquiring HCV and associated
individuals develop symptoms that include insidious onset morbidity, and mortality, it is essential to evaluate all
of fatigue, anorexia, nausea, vomiting, vague abdominal individuals for behaviors that could expose them at risk
discomfort, and fever. Jaundice appears in up to 25% cases; to acquire HCV. Those who are at risk should be tested for
however, HCV-related fulminant hepatic failure is rare. HCV. According to the recommendation of CDC, following
Although after acute hepatitis C, spontaneous recovery individuals should be screened for hepatitis C:
occurs in 1520% cases only, the disease takes a variable Injection drug users, including single time injection drug
course. Elevated alanine transaminase (ALT) with fluctuating users
pattern is the most characteristic feature. One may have Individuals experience conditions that could be associated
normalization of ALT followed by ALT elevations that specify with higher risk to acquire HCV infection, e.g.
progression to chronic disease. Individuals with HIV infection
Up to 80% of cases with acute hepatitis C develop chronic Individuals with hemophilia who received clotting
infection defined as the persistence of disease without factor concentrates prior to 1987
improvement for at least 6 months. It is characterized by Individuals who have ever been on hemodialysis
asymptomatic disease in 6080% individuals along with Individuals with unexplained abnormal aminotran
persistently elevated or fluctuating ALT indicating active sferase levels
liver disease as surrogate marker. However, so far no clinical Past recipients of transfusions or organ transplants prior to
or epidemiological factor has been found that could predict July 1992 including:
progression to chronic liver disease. Subsequently, up to 20% Recipients of blood from a donor seropositive for HCV
individuals develop cirrhosis within 2030 years. Patients Recipients of blood or blood products
with CHC usually become symptomatic, once develop Individuals who received an organ transplant
complications of cirrhosis. Following the development of Children born to HCV-infected mothers
cirrhosis, there is a significant risk (35% per year) to develop Healthcare, and emergency medical and public safety
HCC. In contrast to hepatitis B, it is very rare to develop workers after a needle-stick injury or mucosal exposure to
HCC in the absence of cirrhosis. Hepatitis C virus does HCV-positive blood
Current sexual partners of HCV-infected persons Molecular Assays

Individuals with high-risk sexual behaviors
The individuals who are carriers or have CHC should be The molecular assays detect HCV RNA (qualitative assays)
counseled about following protective measures to avoid HCV or quantify HCV RNA (quantitative assays) or detect
transmission to others: HCV genotypes (genotype assays). Following are the
Avoid sharing of sharp objects, e.g. shaving equipment, different qualitative assays approved by the Food and Drug
razors, and toothbrushes Administration (FDA) and used for the diagnosis and disease
Cover any bleeding wound to avert exposure of their blood monitoring:
to others 1. Amplicor HCV v2.0 [Roche Molecular Systems, manual
Stop using illicit drugs. If still continues to inject drugs, real-time polymerase chain reaction (RT-PCR) method]:
they should be counseled to: Detects HCV RNA up to 50 IU/mL.
Avoid reusing or sharing syringes, needles, water, cotton, 2. Cobas Amplicor HCV v2.0 (Roche Molecular Systems,
or other paraphernalia semi-automated RT-PCR method): Detects HCV RNA up
Clean the injection site with a new alcohol swab to 50 IU/mL.
Dispose syringes and needles safely after single use 3. Ampliscreen (Roche Molecular Systems, semi-automated
Do not donate blood, body organs or other tissue, or RT-PCR method): It can detect HCV PCR up to less than 50
semen. IU/mL and is used for blood screening.
As the risk of sexual transmission is low for monogamous 4. Versant HCV RNA qualitative assay [Siemens Healthcare
couple, it does not require barrier precautions, and others Diagnostics, semi-automated transcription-mediated
should always practice safer sex. amplification (TMA) method]: Detects HCV RNA up to 50
IU/mL.
5. Procleix HIV-1/HCV assay (Chiron Corporation, Manual
DIAGNOSTIC WORKUP TMA method): It can detect HCV PCR up to less than 50
IU/mL and is used for blood screening.
There are two types of assays available for hepatitis C:
Moreover, the following quantitative assays are available
1. Serological assays.
currently:
2. Molecular assays.
1. Amplicor HCV monitor (Roche Molecular Systems):
These assays have no role in the assessment of disease
Dynamic range of HCV PCR is 600500,000 IU/mL.
severity or prognosis.
2. Cobas Amplicor HCV Monitor V2.0 (Roche Molecular
Systems): Dynamic range of HCV PCR is 600500,000 IU/
Serologic Assays mL.
3. Versant HCV RNA 3.0 Assay (bDNA) (Siemens Health Care
These are the tests that detect specific antibodies to hepatitis C
Diagnostics): Dynamic range of HCV PCR is 6157,700,000
(anti-HCV) in serum or plasma and are used essentially for the
IU/mL.
screening and diagnosis of HCV. There are different modalities
of these assays: (i) EIAs, e.g. Abbott HCV EIA 2.0 (Abbott 4. LCx HCV RNA-Quantitative Assay (Abbott Diagnostics):
Laboratories, Abbott Park, IL) and ORTHOHCV Version Dynamic range of HCV PCR is 252,630,000 IU/mL.
3.0 ELISA (Ortho-Clinical Diagnostics, Raritan, NJ), (ii) 5. SuperQuant (National Genetics Institute): Dynamic range
enhanced chemiluminescence immunoassay (CIA) VITROS of HCV PCR is 301,470,000 IU/mL.
Anti-HCV assay, (Ortho-Clinical Diagnostics, Raritan, NJ). 6. Cobas Taqman HCV Test (Roche Molecular Systems):
Although the current EIAs are very accurate (specificity Dynamic range of HCV PCR is 4369,000,000 IU/mL.
> 99%), one can get false-positive results in the presence of 7. Abbott RealTime (Abbott Diagnostics): Dynamic range of
severe immunosuppression (e.g. HIV, solid organ transplant HCV PCR is 12100,000,000 IU/mL.
recipients, hypo- or aggammaglobulinemia), individuals on Hence, RT-PCR-based assays and TMA assays, with
hemodialysis, or if the HCV prevalence is low in the population. sensitivities of 1050 IU/mL and 9899% specificity are highly
Moreover, in the presence of these accurate assays, the utility appropriate for monitoring of antiviral treatment.
of previously available recombinant immunoblot assay, Hepatitis C virus RNA testing should be done for individuals
Chiron RIBA HCV3.0 strip immunoblot assay (SIA) (Chiron with positive anti-HCV antibody, where antiviral treatment
Corporation, Emeryville, CA) is limited. is being considered, immunocompromised individuals with
Hepatitis C 191
unexplained liver disease whose anti-HCV test is negative or ECONOMIC BURDEN OF HEPATITIS C
when suspecting acute HCV infection.
The predisposition to develop cirrhosis and subsequent
complications, including HCC and improvement in sustained
Genotyping Assays viral response with currently available pegylated interferon
The detection of HCV genotype has a crucial role in (Peg-IFN) and ribavirin (RBV) therapy justifies early detection
determining the optimal duration of therapy and predicting and treatment of HCV infection. Addition of new drugs, i.e.
the likelihood of response and should be done in all cases. protease inhibitors, e.g. telapravir are expected to increase
Several commercial assays are available to determine HCV the treatment response further especially among difficult to
genotypes using direct sequence analysis of the 5 noncoding treat population, including HCV genotype 1. However, this
region. However, in less than 3% cases, major genotypes could combination treatment is costly, and perhaps, it will not
be typed incorrectly and in less than 5%, genotype could not be affordable especially for the underdeveloped countries.
be detected due to issues with the PCR amplification step of Moreover, liver transplantation improves the survival for
the assay, or extreme nucleotide variability within the HCV patients with decompensated cirrhosis and HCC. However,
genome. the cost of antiviral therapy, managing end-stage liver disease,
and liver transplantation per se is very high and overblown
due to referrals from developing countries to transplant
Liver Biopsy centers in other regions. Only in 1995, 27,000 hospitalizations
The liver biopsy is the gold standard for defining the severity were due to HCV-related liver disease in US. Again, the
of liver disease, assessing grade and stage of the liver injury, estimated cost incurred to treat HCV was $ 693 million in 1998
and providing information about other histological features with $1$1.3 billion total expenditure per year that was quite
that might have a bearing on liver disease progression high. However, the differences exist in healthcare delivery
(e.g. steatosis). Liver biopsy should be considered where systems, economical status and availability of facilities to treat
information is required regarding fibrosis stage for prognostic HCV with or without complications; hence, it is difficult to
purposes or to make a decision regarding treatment or other approximate whether these costs are equivalent to or higher
hepatic diseases. Otherwise, liver biopsy is not mandatory as than the cost for other countries. Furthermore, most of such
part of regular CHC assessment. estimates incur direct costs but ignores indirect costs that
The liver biopsy provides information about (i) grade, include cost for work loss due to illness or early mortalities
which defines the extent of necroinflammatory activity and related to HCV liver disease. Hence, the actual costs could
(ii) stage, which provides information about the extent of be much higher if these indirect costs are taken into account,
fibrosis or the presence of cirrhosis. There are several scoring especially in case of developing countries.
systems that are used commonly, including French METAVIR,
the Batts-Ludwig, and International Association for the Study
of the Liver (IASL), and the Ishak scoring systems. TREATMENT
Beside its benefits, liver biopsy is not free of risks. It
carries the risk of pain, bleeding, perforation of other organs, What are the Goals of Treatment for
sampling error, high cost, and lower acceptability by patient.
The experts recommend initiating treatment earlier for those
Hepatitis C?
who have more advanced fibrosis stage, i.e. greater than or It is expected that the eradication of HCV can prevent the
equal to 3 and one can delay antiviral treatment, if fibrosis complications and ultimately mortality due to consistent
score is less than or equal to 2 on liver biopsy. liver injury by persistent viremia. However, the data based
Other tests for assessing chronic liver disease, e.g. liver upon long-term studies addressing such preventive aspect
synthetic function (albumin, prothrombin time), disclosure of antiviral therapy is lacking. The current goal of therapy is
of portal hypertension (platelets, ultrasonography) should be eradication of virus and achievement of sustained virological
done. In the absence of liver biopsy, liver fibrosis estimation response (SVR). The response to the treatment could also
using noninvasive markers (serum fibrosis indexes or be assessed by biochemical response (normalization of
elastometry) could be done. Moreover, all patients with HCV- ALT) and histological response (>2-point improvement in
cirrhosis should be screened for HCC. necroinflammatory score with no worsening in fibrosis score).
How can the Response during and after Evidence of chronic hepatitis with significant fibrosis
(bridging fibrosis or higher) on liver biopsy
the Treatment be Assessed? Individuals with compensated cirrhosis [(total serum
Following are the virological responses that are recommended bilirubin <1.5 g/dL; INR 1.5, serum albumin >3.4 g/dL,
to assess the response during and after treatment: platelet count 75,000 mm3, in the absence of hepatic
Rapid virological response (RVR): It is defined as decompensation (hepatic encephalopathy or ascites)]
undetectable HCV RNA at week 4 of antiviral therapy using Hemoglobin 13 g/dL for men and 12 g/dL for women;
a molecular assay with a lower limit of detection of 50 IU/ neutrophil count 1,500/mm3
mL. It predicts a high likelihood of achieving an SVR. Serum creatinine less than 1.5 mg/dL
Achievement of RVR may allow shortening of therapy for Willing to be treated and to adhere to treatment
genotypes 2 and 3 and possibly genotype 1 with low viral requirements
load No other contraindications for the treatment.
Early virological response (EVR): It is defined as a greater According to the AASLD guidelines, the HCV treatment
than or equal to two log reduction or complete absence should be individualized for the following group of patients:
of serum HCV RNA at week 12 of therapy compared with Nonresponder and relapser to prior treatment with
the baseline level. Failure to achieve an EVR is the most standard IFN with or without RBV or Peg-IFN monotherapy
accurate predictor of not achieving an SVR Acute hepatitis C
End of treatment response (ETR): It is defined as Current users of illicit drugs or alcohol who are willing to
undetectable virus at the end of either a 24-week or but willing to abstain (such individuals should be abstinent
48-week course of antiviral therapy. An ETR does not for at least 6 months)
accurately predict that an SVR will be achieved Mild or no fibrosis on liver biopsy
Sustained virological response: It is defined as the absence HIV coinfection
of HCV RNA from serum by a sensitive PCR assay 24 Younger patients less than 18 years of age
weeks following discontinuation of therapy. It is the Chronic renal disease (either requiring or not requiring
most important parameter and a surrogate marker for hemodialysis)
virological cure. Although HCC has been identified years Decompensated cirrhosis
after achievement of SVR, especially in those cases where Recipients of liver transplant.
cirrhosis was present at the time of achieving an SVR However, the HCV treatment is contraindicated in:
Nonresponder: It is defined as failure to clear HCV RNA Age less than 2 years
from serum after 24 weeks of therapy Pregnant ladies or those who are reluctant to adequate
Null responder: It is defined as failure to decline in HCV contraception
RNA less than two logs after 24 weeks of therapy Uncontrolled major depressive disorders
Partial responder: It is defined as persistence of HCV RNA Untreated/uncontrolled thyroid disorders
but with greater than or equal to two log reduction after 24 Individuals who had solid organ transplant (renal, heart or
weeks of therapy lung)
Virological breakthrough: It is defined as reappearance of Individuals with autoimmune hepatitis or other
HCV RNA during antiviral therapy autoimmune disorders that could be exacerbated by Peg-
Virological relapse: It is defined as reappearance of HCV IFN and RBV
RNA after completion of treatment. Severe uncontrolled hypertension/coronary heart disease,
heart failure or poorly controlled diabetes
Indications and Contraindications for Chronic obstructive pulmonary disease (uncontrolled)
Known hypersensitivity to antiviral therapy.
HCV Therapy Moreover, cautiousness is essential in the following
According to the American Association for the Study of situations while considering antiviral therapy:
Liver Diseases (AASLD) and Asian Pacific Association for Older age (>70 years)
the Study of the Liver (APASL) guidelines, the treatment for Neutropenia (neutrophil count <1,500 cells/mL3)
hepatitis C should be considered in the following groups of Thrombocytopenia (platelet count <85,000/mL3)
patients: Organ transplantation
Individuals greater than or equal to 18 years of age History of autoimmune disease and presence of thyroid
Detectable HCV RNA positive in serum autoantibodies
Hepatitis C 193
Predictors of Treatment Response for 6585 kg, 1,200 mg for >85105 kg and 1,400 mg for >105
kg). Therapy should be discontinued for those who are null
Age less than 40 years, female gender, lower body weight responders or partial responders with persistence of viremia
(<75 kg), non-African-American race, absence of insulin at week 24. Those partial responders who have viral clearance
resistance, metabolic syndrome and bridging fibrosis or during weeks 12 and 24, their treatment should be extended
cirrhosis, elevated ALT, genotypes 2 and 3, viral load less than till week 72.
600,000 IU/mL are the factors found to be associated with
higher rates of SVR in various studies.
HCV Genotypes 2 or 3
Role of Interleukin-28B Polymorphism Twenty-four-week treatment with weight-based RBV is
sufficient for most HCV genotype 2 and 3 patients.
In 2009, a set of polymorphism in interleukin-28B (IL-28B)
gene were found to be associated with HCV clearance in
HCV genotype 1 patients receiving Peg-IFN + RBV therapy. HCV Genotypes 5 and 6
Furthermore, IL-28B was found to be associated with Due to the limited geographical locations HCV genotypes 5
spontaneous viral clearance in untreated patients as well. and 6 are underrepresented in majority of the clinical trials.
This discovery may have an impact on making decision However, based upon available data, 48 weeks of treatment
regarding antiviral therapy, prognosis and might be a target with Peg-IFN and RBV is effective for genotype 6.
for new drugs. The most of the newely developed direct-acting antivirals.
Direct-acting antivirals (DAAs): for HCV target are the NS3/4A
Treatment for Nave Chronic Hepatitis C protease, the NS5A protein, and the NS5B polymerase.
Boceprevir (BOC) and telaprevir (TVR) are NS3/4A oral
Patients protease inhibitors (PIs) that have been used in combination
Treatment should be individualized on the basis of the with the PEG-IFN/RBV and are recently approved for HCV
severity of liver disease, likelihood of response, potential genotype. The cure rate for HCV genotype 1 with these tripple
for adverse effects, and patients acceptance. The current therapy has been reported from 70 to 80% with significant
standard of treatment is a combination of Peg-IFN-alfa and reduction in treatment duration (Chang MH, Gordon LA,
RBV, which has been found superior to the combination of Fung HB. Boceprevir: a protease inhibitor for the treatment of
standard IFN-alfa and RBV. Two types of Peg-IFN has been hepatitis C. Clin Ther 2012;34:2021-38; Forestier N, Zeuzem
licensed in the US: S. Telaprevir for the treatment of hepatitis C.Expert Opin
1. Peg-IFN-alfa-2b (Peg-Intron, Schering Plough Corp., Pharmacother 2012;13:593-606). However,there are certain
Kenilworth, NJ), having 12-kd linear polyethylene glycol limitation of BOC and TVR; poor tolerance, inconvenient
(PEG) linked to standard IFN-alfa-2b molecule. dosing frequency, expensive and only indicated for
2. Peg-IFN-alfa-2a (Pegasys, Hoffmann-La Roche, Nutley, genotype1 till now. Hence, in search of better regimens with
NJ) having 40-kd branched PEG molecule attached to pan-genotypic coverage, better efficacy newer DAAs are being
standard IFN-alfa-2a. developed which are targetting at the NS3/4A protease, NS5A
According to a recent clinical trial, SVR rates and tolerability protein, NS5B RNA-dependent RNA polymerase or NS4B
of treatment were not found significantly different between or p7. these newer agents are still in experimental phase.
peg-IFN-alfa 2a and 2b. The duration of therapy varies with The ultimate goal in HCV research is to develop a broadly
HCV genotypes, stage of liver disease, and response during efficacious, IFN-free all-oral therapy (Aghemo A, Francesco
treatment. RD. New Horizons in Hepatitis C Antiviral Therapy with
Direct-Acting Antivirals. Hepatology. 2012;58(1):428-38).
HCV Genotypes 1 and 4

Retreatment of Nonresponders or
In general, 48-week therapy is required. The dose of Peg-
IFN-alfa-2a is fixed, i.e. 180 g/week subcutaneously with
Relapsers to Prior Treatment
weight-based RBV (1200 mg for >75 kg, 1,000 mg for 75 kg Retreatment of patients who were nonresponders or relapsers
and 800 mg for <65 kg in two to three divided doses), while the to standard IFN and RBV or Peg-IFN monotherapy can be
dose of Peg-IFN-alfa-2b is weight based, i.e. 1.5 g/kg/week considered with Peg-IFN plus RBV, especially in the presence
subcutaneously along with RBV (800 mg for <65 kg, 1,000 mg of bridging fibrosis or cirrhosis. However, retreatment with
Peg-IFN plus RBV after complete course of Peg-IFN + RBV These patients frequently require supportive therapy with
is not recommended. Moreover, the maintenance therapy growth factors and erythropoietin. All cirrhotics should also
with Peg-IFN with the objective of delaying or preventing be screened for HCC periodically.
progression to cirrhosis and/or hepatic decompensation
is not recommended for patients with bridging fibrosis or
cirrhosis. Retreatment with same regimen is associated SVR HCV Treatment Pre- and Post-liver
in less than 5% patients only, hence not recommended. Again Transplantation
switching to an alternative IFN, e.g. consensus IFN is not
For patients who have recurrence of hepatitis C for more than
effective, especially in case on nonresponders.
6 months after liver transplant (especially in the presence of
histological evidence for severe disease), antiviral therapy
Treatment of Special Population Groups should be initiated with caution and under the supervision
of a physician experienced in transplantation. The preferred
Acute Icteric Hepatitis regimen is Peg-IFN-alfa with RBV for 48 weeks. However,
except for those who develop fibrosing cholestatic hepatitis,
According to the available data treatment with Peg-IFN (with IFN is not recommended currently for the recipients of heart,
or without RBV) during the acute hepatitis will reduce the lung and kidney grafts.
progression to chronic disease in 10% cases only. Furthermore, For patients with decompensated cirrhosis due to HCV
spontaneous resolution of acute hepatitis C is expected and candidate for liver transplantation, careful antiviral
within first 12 weeks. Hence, the treatment could be delayed therapy by an experienced hepatologist could be considered
for 812 weeks after acute onset of hepatitis C. The Peg-IFN is provided that the ChildPugh score is less than or equal to 7,
the drug of choice. However, standard IFN 510 million units model for end-stage liver disease (MELD) score is less than or
per day could be used (SVR 83100%). The treatment should equal to 18, and platelet count is greater than 60,000. However,
be given for at least 12 weeks in case of genotypes 2 and 3 but the dose of Peg-IFN and RBV should be low at the initiation
could be continued for 24 weeks in case of genotypes 1 and 4. of therapy that could be increased later. Concomitantly,
In case of HIV-positive patient, antiviral treatment should be supportive therapies to prevent variceal bleeding, infections,
considered before week 12. and correct cytopenia are recommended.
HIV-positive Patients Chronic Renal Failure or End-stage

The SVR rates in patients with concomitant HIV and HCV Renal Disease
are 1129% and 4373% in case of genotypes 1, and 2 and 3
Considering the risk of nosocomial infection while on
respectively after treatment with Peg-IFN + RBV.
regular dialysis, regular screening of such patients and the
dialysis staff for HCV is indicated. Patients with CHC and
HCV in Children chronic kidney disease (CKD) with glomerular filtration
rate (GFR) greater than 60 mL/min could be treated with
Considering the passive transmission of HCV antibodies from same dose of Peg-IFN and RBV like patients without CKD.
HCV infected mother, routine testing for anti-HCV for child Those who have severe CKD but not on dialysis could be
born to HCV infected mother is not recommended till greater treated with reduced dose of Peg-IFN (alpha-2a, 135 mc
than or equal to 18 months of age. However, HCV PCR could or alpha-2b, 1 g/kg weekly) and RBV (200800 mg/day
be tested at 12 months of age in such infants to make an early in divided doses). However, those who require regular
diagnosis. The criteria for selecting children aged 217 years dialysis, monotherapy with standard IFN or Peg-IFN is
are similar to adults. However, the dose of Peg-IFN-2b will be recommended, while the use of RBV is mainly limited to
60 g/m2/week along with RBV 15 mg/kg for 48 weeks. clinical trials. However, IFN therapies are contraindicated
in postrenal transplant unless they develop fibrosing
cholestatic hepatitis.
HCV Cirrhosis
Individuals with compensated HCV cirrhosis, especially For Patients with Cryoglobulinemia
those with childs class A could be treated well with Peg-IFN
+ RBV for 48 weeks. Those with decompensated cirrhosis and In cases of mild-to-moderate proteinuria and slowly
those listed for liver transplant could be treated with low-dose progressive kidney disease, standard IFN or reduced doses of
IFN therapy along with close monitoring by an expert person. Peg-IFN-alfa and RBV could be given.
Hepatitis C 195
In cases of marked proteinuria with progressive kidney further decrease the risk of HCV transmission. However,
disease or an acute flare of cryoglobulinemia, rituximab, such strategies would probably be unaffordable in most
cyclophosphamide plus methylprednisolone, or plasma of the developing countries. Unintentional needle-stick
exchange followed by IFN-based treatment, once the acute injuries among healthcare professional should be avoided.
process has subsided, could be considered. Identification, proper counseling and providing health
education to individuals who are at higher risk to acquire HCV
like IDUs, those who practice unprotected sex with multiple
Thalassemia and Hemophilia partners will help eliminate the risk for transmission of HCV,
According to the APASL guidelines, patients with thalassemia especially in developed countries. Community-based needle
or hemophilia who have chronic HCV infection should exchange program, drug and sexually transmitted diseases
treatment services would help reduce high-risk behaviors
be considered HCV treatment and Peg-IFN should be
and associated risk of transmission. Hence, the primary
considered. The benefits of RBV in this group of patients are
prevention strategies could have a great impact to decrease
not established yet. For those who underwent bone marrow
incident cases and ultimately the disease burden.
transplantation, HCV treatment should be considered after
the completion of immunosuppression therapy.
Secondary Prevention
Active Injection Drug Users Those who have already acquired HCV infection, proper
diagnosis and provision of appropriate treatment, including
According to the AASLD guidelines for management of
antiviral therapy would reduce the risk for chronic disease and
hepatitis C, those IDUs who are willing for HCV treatment
their subsequent complications. Effective treatment with Peg-
and to practice contraception, antiviral therapy for HCV
INF and RBV is the standard of care globally. Moreover, the
could be considered. However, a constant support from drug response rate after treatment is not optimal, especially in case
abuse and psychiatric counseling services is essential for of HCV genotype 1 and in the presence of advanced disease.
such patients while receiving HCV treatment. Addition of new drugs, i.e. protease inhibitors, e.g. telapravir, are
expected to increase the treatment response further, especially
among difficult to treat population. Proper counseling of HCV-
STRATEGIES TO PREVENT AND infected persons to reduce or abstain from alcohol intake may
CONTROL HEPATITIS C prevent the synergistic hepatic injury and disease progression.
Due to its ability to mutate rapidly, HCV behaves as a

genetically heterogeneous virus. It escapes to detection CHALLENGES
by immune system, and in general, the knowledge in the
Incident cases of HCV due to transfusion of blood and
protective immune response following infection is limited.
blood products continue to occur in resource poor settings.
Hence, the development of vaccine gets complicated,
Establishment and strict implementation of proper screening
and so far, no effective vaccine is available for hepatitis strategies for blood and blood products is a real challenge.
C. Immunoglobulins are not effective for postexposure Likewise, community-based campaigns to educate individuals
prophylaxis. Considering these facts, we are left with primary as well as healthcare providers about use of sterile syringes,
prevention to reduce exposure to HCV and secondary establishing and implementing a law require cost, human
prevention activities that reduce the risk to develop chronic resources and large efforts. Similarly, implementation of
disease and its complications. community-based programs to decrease high-risk behaviors,
including needle exchange programs, and health educations
Primary Prevention for IDUs is important. Implementation of screening and
treatment for HCV and health education for inmates would
Stringent strategies are required to reduce the risk of be a great challenge for countries where these facilities are not
exposures to the factors that could lead to the transmission available. There is also a desperate need to develop effective
of HCV. Implementation of regular practices to screen blood vaccine for hepatitis C and alternate or adjuvant treatment
and blood products, use of sterile syringes, needles, medical for nonresponders and relapsers to standard antiviral
and dental equipment are essentially required, especially therapy. Furthermore, there is need to refocus the research
in developing countries. Introduction of molecular testing priorities across the world to identify attributable factors and
via PCR method to screen blood and blood products would interventions to reduce the burden of disease.
CONCLUSION 8. Babudieri S, Longo B, Sarmati L, et al. Correlates of HIV, HBV, and

HCV infections in a prison inmate population: results from a
Hepatitis C is indeed a global problem. The incidence in multicentre study in Italy. J Med Virol. 2005;76(3):311-7.
the industrialized world is falling due to better screening 9. Balogun MA, Murphy N, Nunn S, et al. Prevalence and incidence
of blood products and healthcare infrastructure. However, of hepatitis C in injecting drug users attending genitourinary
medicine clinics. Epidemiol Infect. 2009;137(7):980-7.
in the developing world, both incidence and prevalence of
10. Brook G, Soriano V, Bergin C. European guideline for the
hepatitis C are rising at an alarming rate. Since the disease
management of hepatitis B and C virus infections, 2010. Int J STD
is chronic under most of the circumstances, it is imperative
AIDS. 2010;21(10):669-78.
that public awareness regarding the spread of hepatitis C 11. Brown RS, Gaglio PJ. Scope of worldwide hepatitis C problem.
should be one of the major campaigns both in the electronic Liver Transpl. 2003;9(11):S10-3.
and print media. The transfusion services have to be better 12. Butt AA. Hepatitis C virus infection: the new global epidemic.
organized and should follow the international norms Expert Rev Anti Infect Ther. 2005;3(2):241-9.
of practice. Campaigns should be started for safe blood 13. Butt AS, Jafri W, Janjua N, et al. Seroprevalence and risk factors for
transfusion especially in low economic countries. Through hepatitis C infection among male prisoners in karachi, pakistan.
public education and education of primary care physicians, Am J Gastroenterol; 2010;105(1):S112.
unnecessary therapeutic injections must be stopped. A 14. Butt AS, Mumtaz K, Aqeel I, et al. Sustained virological response
major obstacle in handling of hepatitis C is nonavailability of to pegylated interferon and ribavirin in patients with genotype
vaccine, and the current know how about the developmental 3 HCV cirrhosis. Trop Gastroenterol. 2009;30(4):207-12.
stages are not very encouraging either. Therefore, under such 15. Calleri G, Cariti G, Gaiottino F, et al. A short course of pegylated
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16. Champion JK, Taylor A, Hutchinson S, et al. Incidence of hepatitis
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21
cHAPTER
Emerging and Re-emerging

Factors about Hepatitis Virus
Control in Developing Countries
Sheikh Mohammad Fazle Akbar, Mamun-Al-Mahtab
INTRODUCTION liver diseases. Hepatitis E virus infection during pregnancy

usually follow a downhill course.
Liver receives blood supply from both systemic circulations Infection with HBV and HCV may remain nonsymptomatic,
as well as from portal system. Thus, many viruses may enter or there may be acute hepatitis. In considerable numbers of
the liver on a regular basis. Some of them are localized in the patients, HBV and HCV cause chronic infection without or
liver. Hepatocyte or liver cells also allow their replication. with progressive liver diseases. They usually enter human
Even some of them integrate in the genome of hepatocytes. body through contaminated blood or infected syringes and
In general, these viruses are not cytopathic in nature. They needles, but these viruses may also infect human being
cannot destroy liver cells directly. Destruction of liver cells through other routes.
and progression of liver diseases due to infection with The nature of antigens and antibodies to HBV and HCV is
hepatotropic viruses are mediated by host immunocytes quite different from that of HAV and HEV. Patients with HBV
that are produced during hostvirus interaction. Both acute infection may express hepatitis B surface antigen (HBsAg)
and chronic liver diseases by hepatotropic viruses constitute or hepatitis B e antigen (HBeAg) in the sera. Hepatitis B core
serious public health problems. antigen (HBcAg) can be also detected in the liver of these
Among the hepatotropic viruses, hepatitis A virus (HAV), patients. Regarding expressions of HBV-related antibodies,
hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis HBV-infected patients may express anti-HBs (antibody to
E virus (HEV) are etiological agents of different types of liver HBsAg), anti-HBe (antibody to HBeAg), or anti-HBc (antibody
diseases. The numbers of patients with clinical evidences to HBcAg). The clinical significances of these antigens and
of liver diseases also do not reflect the real magnitude of antibodies are diverse. People expressing anti-HBs in the
infections with these viruses. Hepatitis A virus and HEV sera are regarded as protected from HBV infection, but this
usually enter human body through oral route, although is not true in all situations. Persons expressing anti-HBs may
blood-borne transmission of HEV has been reported by also harbor HBV deoxyribonucleic acid (DNA) and develop
some investigators. These viruses usually cause an acute and progressive liver diseases in some cases. Anti-HBe and anti-
transient infection. In fact, majority of patients infected with HBc are not protective antibodies to HBV. Regarding HCV
HAV and HEV do not show any evidence of hepatitis or liver infection, the nature of protective antibody is not known. On
inflammation. They mostly remain unaware of their infection. the contrary, presence of HCV-related antibodies is used as a
Epidemiological data have shown that almost all children of marker of ongoing HCV infection.
certain countries and localities are infected with HAV during Several investigators are involved in exploring different
their early life, and antibody to HAV (anti-HAV) is detected in virological, immunological, and pathological features of these
their sera before they become 10 years old. Anti-HAV provides viruses. Many investigators also provide updated information
protection against HAV, and anti-HAV-positive subjects are about these viruses, the nature of diseases they cause, and their
not infected with HAV during rechallenge with the HAV later in management strategies. Many international organizations
their life. Hepatitis E virus, a virus causing acute hepatitis E, is and liver-related professional organizations also provide
comparable to HAV regarding nature of disease pathogenesis. recommendation about control and management against
About 45% of apparently healthy individuals of different these viruses. Also, commercial vaccines are available against
countries express evidences of previous infection with HEV. HAV and HBV. A vaccine against HAV is recommended for
Only a few of them develop features of acute hepatitis. There people traveling to endemic areas. This has considerably
is no convincible evidence about chronic infection with HEV; reduced the incidence of HAV in many developed countries.
however, some reports indicate that HEV may cause chronic HBV is one of the most successful vaccines in the history of
vaccinology that provides protection to about 90% HBV- countries before 23 decades. Now, similar situation would
uninfected subjects. Most of the developing countries are be found in developing countries. Thus, the public health
also signatories of universal vaccination against the HBV. authorities should be prepared to tackle acute hepatitis
Appropriate public health measures and HB vaccines have due to HAV in increased proportion of comparative elderly
reduced the incidence and prevalence of HBV in developed subjects in developing countries.
countries. However, this has not been duplicated in most
developing countries.
Although 90% or more hepatitis virus-infected subjects Vaccines against Hepatitis A Virus and
are localized in developing countries of the world, updated Vaccine Candidate
information about these viruses is not properly transmitted
As the epidemiology of HAV infection is showing shift in
to the physicians of developing countries. An extensive
different countries, serious consideration should be provided
description about hepatitis viruses has been provided in
about vaccination against HAV in developing countries.
different chapters of this book. This chapter is intended to
The peak age of seroprevalence of HAV is shifting from
provide some emerging information about HAV, HEV, HBV,
first decade of the life to the second and third decades.
and HCV to the readers of this book.
If this epidemiological shift occurs in a community in a
homogeneous manner, vaccination against HAV may be one
of the options to contain HAV infection in that particular area,
HEPATITIS A VIRUS but this usually happens mostly in heterogeneous manner in
most developing countries. Thus, recommendation of HAV
Changing Epidemiology and Emerging vaccination should be made after analyzing local conditions.
Challenges Shifting of HAV seroprevalence from first decade to second
or third decade will also make children at preprimary and
Hepatitis A virus infection is global in nature. It is highly primary school children more susceptible to HAV infection.
prevalent in the developing countries of the world. Studies In order to contain HAV infection and their effects in
have shown that almost all children of some countries community levels, constant surveillance would be required.
are infected with HAV and express anti-HAV in their sera The main challenge is to find out risky pocket in each country
before the age of 10 years. However, recent investigations and to address these challenges with proper strategies.
have shown that proportion of persons with anti-HAV has
been declining in most parts of the world. This may be
partly attributable to the improvements in socioeconomic
conditions and increased access to clean water and better
HEPATITIS E VIRUS
sanitation. Thus, the children are not infected with HAV
during childhood, but a gradual shift in the age of acquiring Prevalence and Diagnosis
HAV infection from early childhood to adulthood should At present, HEV infection is the most frequent cause of acute
not be considered as a positive trend. If pure supply of water viral hepatitis infection around the world. In many developing
and food can be ensured in different countries of the world, countries, HEV has replaced HAV as the main etiological
then low anti-HAV prevalence in a community or country agent of acute hepatitis. Also, HEV has been found to be one
is an encouraging matter from public health viewpoint. of the main triggers of acute on chronic liver failure (ACLF).
However, safe food and drinking water are available to The real global burden of HEV infection has not been well-
certain groups of people of developing countries. Thus, one characterized. But, it is estimated that one-fourth of the total
group of children would be infected with HAV and develop population of developing countries may have been exposed
anti-HAV antibody. On the other hand, another group to HEV. Anti-HEV prevalence is about 2045% among general
of children of the same country or locality would not be population of Asian and African countries (> 20% of anti-HEV
infected with HAV during their childhood and they would seroprevalence among the general population of China, about
remain vulnerable to HAV in their adulthood. HAV infection 45% in rural areas of Malaysia, about > 20% in India, about 26%
is usually asymptomatic and HAV-infected children develop in Egypt and about 17% in Saudi Arabia). The seroprevalence
protective anti-HAV without any evidence of clinical liver of HEV in Bangladesh and many developing countries has not
damages. On the other hand, most HAV-infected adults been properly assessed, but sporadic studies show that about
present with jaundice and other serious symptoms of liver 30% people of these countries have been infected with HEV.
damages. Some of these patients also develop fulminant Infection with HEV is usually assessed by presence of
hepatitis. This scenario has been shown in developed antibody to HEV (anti-HEV) and a decision of recent infection
Emerging and Re-emerging Factors about Hepatitis Virus Control in Developing Countries 201
or past infection with HEV is usually judged by the nature of 2 are restricted to humans and associated with epidemics
anti-HEV (IgM type for ongoing and acute infection and IgG in developing countries, whereas genotypes 3 and 4 are
type for previous HEV infection). However, attention should zoonotic and infect humans and several other animals
be given to the following points about anti-HEV antibody. in both developing and industrialized countries. Besides
Anti-HEV antibodies are detectable 13 weeks after acute humans, strains of HEV have been genetically identified
infection of immune-competent persons (IgM and IgG). On from swine, chickens, sika deer, mongeese, and rabbits.
the contrary, in immune-suppressed patients, seroconversion The identification and characterization of animal strains of
might be delayed by up to 610 months. Thus, if the patient is HEV from pigs and chickens and the demonstrated ability
immune suppressed, a combination of serology and nucleic of cross-species infection by swine HEV raise public health
acid testing may be required to confirm a diagnosis of HEV concerns for zoonosis. More studies are required, if HEV are
infection. The period of detectable HEV ribonucleic acid present in domestic animals of developing countries. Also,
(RNA) in serum may be short-lived (1030 days after the it is necessary to assess whether these domestic animals are
onset of symptoms), but fecal shedding of the virus may last capable of infecting human or not.
for up to 23 months. A combination of anti-HEV assay with
estimation of HEV RNA would be helpful to determine HEV
infection. But, mechanisms have not been developed for HEPATITIS B VIRUS
assessment of HEV RNA in most developing countries.
An open question remains about the management of
severe HEV infection today. Specific treatments are lacking,
Blood Transfusion and Hepatitis B Virus
and therapy is supportive. Since the majority of infections Monitoring
are self-limited, specific interventions may be needed only in
About 2 billion people of the world are infected with the HBV
the infrequent severe, life-threatening cases. Hepatitis E virus
and about 370 million are regarded as chronic HBV carriers.
infection during pregnancy may have fatal outcome. Also,
Chronic HBV carriers imply a condition in which HBV
HEV induces ACLF in many patients. Data are lacking about
replication continues with production of HBsAg and their
the scope of antiviral therapy in these critical cases. Hepatitis
expression in the sera. In fact, many HBV-infected persons
E virus may cause persistent infection in immune-suppressed
also allow HBV replication without expressing HBsAg in
subjects. Pegylated interferon has been used to treat some of
the sera. The entity of HBsAg-positive and HBsAg-negative
these patients with inconclusive outcome.
chronic HBV carriers may not be scientifically differentiated
on the basis of viral replication only. Several factors may be
Vaccine against Hepatitis E Virus and related to this.
Hepatitis B virus is transmitted from HBV-infected
Their Utility mothers to their offspring during or around birth. In
A vaccine containing a genotype 1 recombinant capsid protein addition, HBV may be transmitted through blood transfusion
buffered with aluminum hydroxide has been developed and or use of contaminated syringe and needle. Accordingly,
this vaccine has shown a good protection, with an efficacy two strategies have been adopted in developed countries to
of 95% after three doses and 85.7% after two doses over a curtain further transmission of HBV: safe delivery and safe
median follow-up of 2.5 years. Another anti-HEV vaccine blood transfusion. Also HB vaccine has given protection to
called vaccine 239 is a recombinant HEV capsid protein that huge numbers of HBV-uninfected subjects. Although these
is truncated to 239 amino acids absorbed with aluminum strategies have been adopted in developing countries,
hydroxide has shown safety and immunogenicity with a dose- the qualitative aspects of these approaches have not been
finding design. The levels of protection of vaccine 239 are also maintained to a satisfactory level. We would first discuss
good. Hepatitis E virus vaccines would be recommended about safe blood transfusion in developing countries. In
for people of low endemicity area during traveling to high this respect, Bangladesh would be regarded as an example.
endemic area, but the utility of this vaccine in developing Bangladesh is a country with 160 million population. The
country with high HEV endemicity is debatable. overall prevalence of HBsAg among general population is
about 27%. If HBV prevalence is 5%, there would be around
8 million HBsAg-positive persons in Bangladesh. HBsAg
Hepatitis E Virus Infection and Zoonosis is checked in donor blood in almost all health facilities
Hepatitis E virus genotypes and zoonosis of HEV should of Bangladesh. It is assumed that HBsAg-negative blood
be explored in developing countries. At least four major is safe for transmission. In fact, HBsAg-negative blood is
genotypes of HEV have been recognized: genotypes 1 and transfused without further assessment of HBV infection to
healthy individuals. This is almost a common practice in many of them will not develop adequate levels of anti-HBs
most developing countries. However, epidemiological data due to HB vaccination
indicate that about 40 million people of Bangladesh may Due to specific human leukocyte antigen (human
have been infected with HBV at some point of their life. A leukocyte antigen of hepatitis B vaccine nonresponders)
study found that 5.8% of general population was expressing and other factors, about 510% apparently normal subjects
HBsAg in their sera, whereas 22.6% of these populations (without HBsAg-positivity) will not develop anti-HBs after
were expressing anti-HBc in their blood. Another study from HB vaccination
Bangladesh showed that 24.1% apparently healthy people The response rate of HB vaccine in patients with liver
were positive for anti-HBc. Anti-HBc positivity was much diseases and HCV-infected patients is low (may be as low
higher among high-risk population like prostitutes (73%) at as 30%)
Bangladesh. However, it has not been explored about HBV Patients receiving immune-suppressor drugs may not
DNA positivity of HBsAg-negative but anti-HBc-positive produce anti-HBs due to HB vaccination.
subjects at Bangladesh and most developing countries. Based on these facts, about 2540% of Bangladeshi people
Indeed, anti-HBc-positive blood is potentially infective would not develop anti-HBs after HB vaccination. This is
and transfusion of anti-HBc-positive blood caused post- more or less same in most developing countries. But all HB
transfusion hepatitis B in recipients. However, it is not clear vaccinated persons assume that they are protected from HBV
about prevalence of HBV DNA in HBsAg-negative, anti-HBc- infection. They donate blood and take little care during delivery.
positive patients. Some of these patients express anti-HBs, To develop an effective HB vaccination program, these facts
whereas, others harbor only anti-HBc. A drastic overhaul should be considered by policy makers and physicians.
has been made in blood transfusion program in many
developed countries during last two decades. Blood samples
are tested for anti-HBc, alanine aminotransferase (ALT) and HEPATITIS C VIRUS
HBV DNA before transfusion in many developed countries.
Nucleic acid testing (NAT) may be a time-consuming Prevalence of Hepatitis C Virus Infection
approach in developing countries, but anti-HBc testing and
ALT assessment for donor blood should be introduced in in Developing Countries
these countries for containment of HBV infection. Anti-HBc Hepatitis C virus is notorious for causing chronic infection. It
screening program and NAT testing can be done as pilot also causes progressive liver diseases and their complications
projects in some tertiary institutions of some developing like liver cirrhosis and hepatocellular carcinoma.
countries. Also, a voluntary blood donation system should be Epidemiological studies have shown that the prevalence
developed to get adequate amounts of blood for transfusion. of HCV is significantly lower in most developing countries
compared to that of HBV. In 2000s, HCV prevalence has been
Outcome of Vaccination against increased in some developing countries and surpassed that of
HBV. Egypt is an example of this. Hepatitis C virus prevalence
Hepatitis B Virus is much higher in Egypt than HBV prevalence. This has
In most developing countries, HB vaccination is given to a been shown in Pakistan as well. In some parts of India, HCV
person without any prior test. Also, no serological assessment is more prevalent than HBV. However, inconclusive data
is done to assess if they have developed adequate levels of has emerged about HCV prevalence in most developing
protective antibody due to HB vaccination. In this context, countries, including Bangladesh. Extremely low prevalence of
following facts should be considered: HCV has been reported by some, whereas, others have shown
About 510% of apparently healthy subjects of developing considerably higher prevalence of HCV in these countries.
countries are HBsAg-positive. Hepatitis B vaccination is Less than 1% HCV prevalence has been shown in apparently
not going to induce protective anti-HBs in these subjects. healthy individuals of Bangladesh by some studies, at least
In the context of Bangladesh, about 8 million people of two groups have documented more than 5% prevalence of
Bangladesh would not develop anti-HBs if all Bangladeshi HCV among apparently healthy population of Bangladesh.
people are vaccinated today The discrepancy is yet to be solved and these factors unveil a
About 2050% people are anti-HBc positive and many of need of nationwide survey for HCV in these countries.
them would harbor replicating HBV in their liver. There is In addition, high prevalence of HCV has been shown in risky
a lack of information about response of anti-HBc-positive population, such as injection drug users in many countries,
person to HB vaccination in different parts of the world. In including Bangladesh. The reality is that few facilities can
Bangladesh, about 30% harbor anti-HBc and it is likely that assess HCV markers in most developing countries.
Emerging and Re-emerging Factors about Hepatitis Virus Control in Developing Countries 203
Also, little is known regarding risk factor of HCV infection BIBLIOGRAPHY

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effort of physicians, public health personals and policy World J Gastroenterol. 2009;15(45):5647-53
makers are needed for containment of these viruses in near 13. Walz A, Wirth S, Hucke J, et al. Vertical transmission of hepatitis
future. Also, some pilot studies should be done in developed B virus (HBV) from mothers negative for HBV surface antigen
countries to develop real extent of problems with hepatitis and positive for antibody to HBV core antigen. J Infect Dis.
viruses in these countries. 2009;200(8):1227-31.
22
cHAPTER
Nonalcoholic Fatty Liver Disease
Taranjeet S Jolly, Arun J Sanyal
INTRODUCTION and relative lack of exercise associated with a modern lifestyle.

Most recent reports from the Centers for Disease Control and
Nonalcoholic fatty liver disease (NAFLD) is the most common Prevention indicate that 66% of adults in the United States
cause of chronic liver disease and elevated liver enzymes in are overweight, and out of these, half are obese. A study using
North America. It is closely linked to obesity, which, in the proton-magnetic resonance spectroscopy (MRS) to measure
United States and other developed nations, has become a hepatic triglyceride content found out that the prevalence of
major public health hazard. It encompasses a broad histologic hepatic steatosis (5.5% or more fat) in the United States was
spectrum ranging from simple steatosis, without any evidence 31%. In other countries, the prevalence of ultrasound-defined
of inflammation to nonalcoholic steatohepatitis (NASH) with NAFLD in the general population ranges from 9.3 to 29% in
inflammatory activity and hepatocellular ballooning, which Asia, 16% in Mexico, 23% in Italy, and 30% in Israel. It is pro-
can further progress to liver fibrosis and cirrhosis. All of the jected that up to 45% of Americans will be obese by 2025. This
phenotypes of NAFLD have in common the accumulation is particularly of concern given the rising incidence of obesity
of fat in the hepatocytes. In NASH, the fat accumulation is in children.
associated with varying degrees of inflammation, cytologic The predilection for NAFLD is related to age, gender, and
ballooning and scarring (fibrosis) of the liver. The reason that ethnicity.
NAFLD is prefaced by the word nonalcoholic is because
the results of liver biopsies from people with NAFLD are Gender
frequently identical to those from people with alcoholic
liver disease. Yet, people with NAFLD do not have a history The influence of gender in determining the severity of NAFLD
of alcohol use in quantities considered to be injurious to the is still under evaluation. Contrary to the earlier belief, current
liver. Typically, the cutoff values used are 20 grams per day studies of NAFLD indicate that men are more commonly
for women and 30 grams per day for men. Fatty liver may be affected. It is also known that women with polycystic ovarian
the end result of various causes with different mechanisms, disease often have aggressive NASH.
natural histories and response to treatment. In this chapter
we will review the key aspects of NAFLD that a practising Weight (Including Fat Distribution)
clinician should be knowledgeable about.
In patients who were eligible for bariatric surgery [i.e. body
mass index (BMI) 40 kg/m2 or 35 kg/m2] with significant
medical comorbidities such as type 2 diabetes showed several
EPIDEMIOLOGY important results. It was found that 76% (range 3399%)
of these patients had steatosis, 37% (range 9.872.5%) had
Prevalence NASH, 23% (range 7.349%) had fibrosis, and 5.8% (range
The prevalence of NAFLD is increasing in parallel with the 1.610%) had cirrhosis.
prevalence of obesity and both these processes are closely
linked to insulin resistance. The WHO has also recently iden- Diabetes
tified the increasing prevalence of obesity and the metabolic
syndrome in the developing nations as a cause of public It is estimated that approximately 336% of the general
health concern. The worldwide epidemic of obesity and the American population has NAFLD, with increased risk up to
prevalence of NAFLD are significantly contributed by the diet 95% in patients with obesity and 70% for patients with T2DM.
Nonalcoholic Fatty Liver Disease 205
Within these groups, it has been reported that 2030% have of lipolysis. There is a progressive worsening of peripheral
NASH and a subgroup with increased risk for development of insulin resistance with progression to fatty liver and then to
cirrhosis and hepatocellular carcinoma. NASH. In other cases, diet could play a role although studies
Several studies have described a higher prevalence of of diet in NAFLD have not shown that these are different from
NAFLD among people with type 2 diabetes compared with obese subjects who do not have NAFLD. De novo lipogenesis
nondiabetics, with prevalence estimates ranging from 40% is under the control of insulin and while there is peripheral
to 69.5%. It is projected that the percent increase in type 2 insulin resistance, there is retained sensitivity to the lipogenic
diabetes mellitus will be around 32% in Europe, 72% in the activity of insulin in the liver. The key transcriptional factors
United States, and greater than or equal to 150% in sub-Saharan involved in mediating de novo lipogenesis are the sterol
Africa, India, and the Middle East by the year 2030. In a recent response element binding protein-1c. It is also enhanced by
case-control study using proton-MRS, it was demonstrated activation of the orphan nuclear receptor liver X receptor.
that people with type 2 diabetes have on average 80% more Conversely, farnesoid X receptor activation can improve
liver fat than age-, weight-, and sex-matched controls. This insulin sensitivity and reverse hepatic steatosis. A fatty liver
difference was not explained by the type of medications used. is also associated with an accumulation of free cholesterol in
Furthermore, aspartate aminotransferase (AST) and alanine the liver as well as diacylglycerol.
aminotransferase (ALT) underestimated liver fat content
among people with diabetes; for any given ALT or AST level,
adults with type 2 diabetes had 40200% more liver fat than Hepatocyte Injury
nondiabetic adults. Patients with type 2 diabetes not only have This manifests itself as cytologic ballooning and apoptosis. The
a higher prevalence of NAFLD, but also appear to have more precise mechanisms underlying ballooning are not known. It
severe forms of the disease, including NASH and fibrosis. is however known that ballooning is associated with Mallorys
hyaline which is the accumulation of ubiquitinated heat
shock proteins that fail to undergo proteasomal degradation.
PATHOGENESIS OF FATTY LIVER AND Failure of proteasomal degradation is thus a key aspect of cell
NONALCOHOLIC STEATOHEPATITIS injury. We have recently shown that NASH is associated with
a failure to activate ER-dependent mannosidases (EDEM)
The key histologic features of NAFLD are macrovesicular which are critical for activation of proteasomes and transport
steatosis, cytologic ballooning, inflammation, apoptosis, of proteins targeted for destruction to these organelles. This
and fibrosis. The current understanding of the mechanisms may be due to abnormal microRNAs that inhibit translation
underlying the development of these findings is reviewed of EDEM mRNA. Other mechanisms of hepatocyte injury
here. include oxidative stress, mitochondrial injury, accumulation
of toxic lipids, such as ceramides and the unfolded protein
response. Recently, autophagy has been implicated as another
Hepatic Steatosis mechanism of cellular injury where organelles are digested to
The principal lipid that accumulates in the liver of subjects provide substrate for energy in NASH where mitochondrial
with NAFLD is triglyceride (TAG). This is derived from fatty injury prevents normal adenosine triphosphate repletion.
acids that are taken up from circulation or synthesized de novo
in the hepatocyte. Fatty acids in circulation are derived from
either diet or from peripheral lipolysis. Using incorporation
Apoptosis
of labeled precursors into TAG, it has been shown that Apoptosis has mainly been linked to lipotoxicity. Free fatty
peripheral lipolysis plays an important role in driving hepatic acids, released from peripheral adipose tissues, can activate
fat content. De novo lipogenesis normally accounts for 58% toll-like receptors and downstream proapoptotic pathways.
of hepatic TAG content; in subjects with NAFLD this accounts They have also been shown to cause translocation of the
for as much as 20% of the fat content. Nonalcoholic fatty liver proapoptotic factor bax to lysosomes, which release cathepsin
disease may also be associated with a defect in the ability to and induce cell death. The accumulation of ceramides also
secrete very low-density lipoproteins. contributes to apoptosis. Finally, cytokines, such as tumor
Peripheral lipolysis is determined by the insulin sensitivity necrosis factor-alpha (TNF-) are increased in insulin-resistant
of adipose tissues. Normally, insulin has a lipogenic effect states and NASH and can induce cell death with TNF-receptor
and under insulin-resistant conditions, there is a net increase mediated pathways. There are thus a multitude of pathways by
in lipolysis due to impaired insulin-mediated suppression which cell death can occur in subjects with NASH.
Fig. 1: Pathogenesis of hyperinsulinemia
Inflammation NAFLD, one needs to exclude other factors like viral disease,
autoimmune disease, genetic disease, drug-induced liver
Nonalcoholic steatohepatitis is associated with activation disease and most importantly alcoholic liver disease (Fig. 1).
of proinflammatory pathways, such as c-Jun N-terminal On the basis of histology, Matteoni et al. classified NAFLD
kinases and mitogen-activated protein kinase. These are into four categories:
upstream of many genes involved in inflammatory signaling Type 1: Fat alone/steatosis
and are key modulators of inflammation. Nuclear factor Type 2: Fat/steatosis plus inflammation
kappa-light-chain-enhancer of activated B cells is another Type 3: Fat/steatosis plus ballooning degeneration
key proinflammatory transcriptional factor that has been Type 4: Fat/steatosis plus ballooning degeneration plus Mallory
implicated in the inflammation associated with NASH. body or fibrosis
Out of these, types 3 and 4 are considered to be NASH,
Fibrosis which is the most severe form of NAFLD.
Fibrosis results from activation of hepatic stellate cells and

production of matrix in excess of the livers capacity to resorb CLINICAL FEATURES
the matrix. Stellate cell activation can occur from products of
inflammation and cell injury from surrounding hepatocytes. A big majority of the patients suffering from NAFLD
Stellate cell activation may also occur from exposure to toxic remain asymptomatic (45100%). Patients can present
lipids in the NASH milieu. with fatigue, malaise and right upper quadrant fullness/
discomfort; in children nonspecific abdominal pain is a
common presentation. On physical increased abdominal
NATURAL HISTORY OF DISEASE circumference (>40 inches in men, >35 inches in women),
markers of insulin resistance like acanthosis nigricans and
Nonalcoholic fatty liver disease occurs most commonly in biochemical markers like fasting glucose greater than 110 mg/
middle-aged obese women; however, it is also seen in children dL, TAGs greater than 150 mg/dL, high-density lipoprotein
and men without weight issues. To arrive at a diagnosis of less than 40 mg/dL in men and less than 50 mg/dL in
women, blood pressure greater than or equal to 130/80 mm Serum Chemistries

Hg are some indicators that suggest a diagnosis of NAFLD.
In cases presenting late can present with complications like Increased values of aminotransferases up to two- to
ascites, variceal hemorrhage, subacute bacterial peritonitis fivefold have been noted in patients with NASH
and carcinoma. Other incidental findings are hepatomegaly The AST/ALT ratio is less than 1 in 6590% of NAFLD
(found in up to 85% patients on ultrasound and abnormal patients. A value greater than 1 usually suggests advanced
liver function tests. fibrotic disease, whereas a ratio greater than 2 may also
suggest an alcohol-related etiology
In up to 50% of the cases serum alkaline phosphatase has
RISK FACTORS FOR ADVANCED been found to be elevated. The degree of elevation is rarely
greater than twofold
DISEASE Serum albumin and bilirubin levels are almost always
close to normal unless patient has advanced cirrhosis
Conditions like obesity, type 2 diabetes, and lipid metabolism
disorders are the common risk factors for NAFLD. In In several studies increased level of serum ferritin (in
addition, family history of cryptogenic cirrhosis, metabolic up to 50% of NAFLD patients) and increased levels of
diseases, western diet, sedentary lifestyle, and certain genetic serum transferrin-iron saturation has been seen, without
factors predispose to this condition. Apart from this age, increased hepatic iron levels
hypertension, AST/ALT ratio, TAG levels, extent of steatosis, In 1046% of cases, antinuclear antibody have been found
grade of inflammation, and high insulin resistance index to be positive.
are other factors, which either alone or in combination
with others become strong predictors of NAFLD and its Radiological Tests
progression (Table 1).
Ultrasound
Out of all the imaging diagnostic modalities available,
DIAGNOSIS ultrasound is the most common imaging modality used for
The diagnosis of NAFLD depends on reliable histology along evaluating NAFLD. On ultrasound patients with NAFLD
with relevant clinical history to rule out alcohol intake, so it mostly present with hepatomegaly and liver appears
is basically a diagnosis of exclusion. The various tests used to hyperechoic due to increased parenchymal reflectivity
confirm diagnosis are as follows. caused by intracellular accumulation of fat. Studies have
demonstrated that ultrasonography has a sensitivity of
6094% and a specificity of 6695% in detecting fatty liver.
Clinical Presentations Several studies have demonstrated that ultrasound cannot
A large proportion of NAFLD patients are asymptomatic reliably distinguish between fibrosis and steatosis. Some
(45100%). At times, patients present with vague right other studies have concluded that it is possible to differentiate
upper quadrant pain or fullness, malaise, and fatigue. On between fibrosis and hepatic steatosis, at least at higher
examination, patients may also have hepatomegaly (in degrees of fibrosis leading to an increase in coarse echoes
up to 75% of the patients), which is seen on ultrasound without posterior beam attenuation. Most ultrasound studies
examination. use a three or more point scoring system for fatty liver (mild,
moderate and severe). One major weakness of ultrasound
Table 1: Risk factors for NAFLD and its progression is its operator dependency and inter- and intraobserver
variability. In a study comparing needle biopsy, ultrasound
Obesity and MRI findings in a fatty liver indicated that ultrasound
Diabetes may be unreliable in the discrimination of slight alterations
Age (>45 years) in hepatic fat content. Ultrasound is an established tool and
Hypertension used as a screening modality with acceptable sensitivity and
specificity in detecting fatty liver. However, the drawbacks of
AST/ALT >0.8
this technique like inaccuracy in differentiating fibrosis from
Increased triglyceride levels
steatosis, in reproducibility and in exact quantification of fat
High grade of inflammation accumulation make it a much debated diagnostic tool. Other
High insulin resistance index available modalities are CT scan, MRI, MR spectroscopy, but
these are less specific and are more costly. The most important standard. In contrast-enhanced CT images, assessment of
role of CT in NAFLD patients is quantitative assessment of fatty liver is more specific and skeletal muscle is used as a
the severity of steatosis by measurement of the liverspleen standard reference; however, it is useful only if the degree of
attenuation ratio. The presence of advanced fibrosis reduces fatty infiltration is severe. The recent introduction of dual-
the sensitivity of both ultrasound and CT for the detection of source/dual-energy CT scanners can be used for measuring
moderate-to-severe histological steatosis in NASH patients. the extent and grade of fatty liver; however, its role in clinical
The sensitivity of ultrasound and CT for advanced fibrosis assessment needs to be further evaluated. Although CT scan
gets decreased markedly in patients with severe steatosis is a good tool to evaluate not only diffuse but also focal fatty
and obese patients, and this decrease is more marked for infiltrations of the liver parenchyma, it has various limiting
ultrasound. factors like radiation exposure, misdiagnosis in cases of
underlying diffuse liver diseases like hemochromatosis,
variations across different manufacturers and different
Computed Tomography Scan generation of scanners and its limitations in detecting mild
Hepatic steatosis is best visualized in nonenhanced CT and moderate steatosis.
images. It presents with decreased attenuation values of
the parenchyma (i.e. hypodense liver) due to the inverse
relationship between hepatic fat content and hepatic
Magnetic Resonance
attenuation (Figs 2A and B). Measurement of attenuation This modality is based on the principle of chemical shift,
values are given in Hounsfield units (HUs). the difference which means that the difference of resonance frequencies
in attenuation values between liver and spleen as well as between hydrogen protons bound to methylene groups of
the calculation of the spleen-to-liver attenuation ratio are TAGs and water protons amounts to approximately 220 Hz at
the three values usually used to assess hepatic steatosis. 1.5 tesla (T) magnetic field strength [or 3.3 parts per million
Normal attenuation value for liver is 5075 HU. Attenuation (ppm)]. This difference is very small in comparison to the
values less than 40 HU or 10 HU lesser than that of spleen absolute resonance frequency of approximately 64 MHz and
are highly predictive of hepatic steatosis. Spleen-to-liver is given usually in dimensionless units (ppm). This chemical
attenuation ratio greater than 1.1 is suggestive of moderate shift effect is directly visible in MR spectra, displaying signals
hepatic steatosis. In a study using absolute and relative in dependence on their resonance frequency. Test modalities
CT attenuation-based methods of quantifying the degree using this principle are proton-MRS, fat sensitive MR imaging
of hepatic steatosis in transplant donors it was found that techniques based on signal phase or based on frequency
diagnostic performance of nonenhanced CT provided selective excitation. The limitations of using these techniques
high performance in qualitative diagnosis of higher (> are the high cost involved, and contraindication in patients
30%) degrees of hepatic steatosis with 100% specificity and who are claustrophobic or have metallic implants in their
82% sensitivity using histologic analysis as the reference body.
A B
Figs 2A and B: CT Scan of fatty liver. (A) No contrast; (B) Contrast-enhanced
Liver Biopsy Inflammation (Fig. 5)

Steatosis
It is considered the gold standard for diagnosis of NAFLD and Stage 1: 533%
is the most sensitive and specific method for differentiating Stage 2: 3466%
steatosis from steatohepatitis with or without fibrosis (Figs Stage 3: Greater than 66%
3 to 6). Biopsy is an invasive method with the risk of post- Lobular inflammation
interventional hemorrhage and bleeding, although the post- Stage 0: None
interventional complication rate seems to be quite low with the Stage 1: Less than 2 foci/20x field
mortality rate between 0.1% and 0.01%. It must also be taken Stage 2: 24 foci/20x field
into account that biopsy-based quantification of steatosis is Stage 3: Greater than 4 foci/20x field
derived from a small tissue sample and may, therefore, be Portal inflammation
misleading in cases of uneven fat distribution in the liver. A Fibrosis
liver biopsy is the only way to diagnose steatohepatitis and to Pericellular fibrosis (Fig. 6)
accurately stage the disease. Stage 0: None
A B C
Figs 3A to C: Macrovesicular steatosis. (A) Grade 1: 533%; (B) Grade 2: 3466%; (C) Grade 3: >67%
A B C
Figs 4A to C: Ballooning degeneration. (A) 0; (B) 1; (C) 2
A B
Figs 5A and B: Inflammation
mainstay of therapy for obesity-induced NAFLD. Body weight

reduction leads to loss of adipose tissue, improves both
peripheral and hepatic insulin sensitivity. Several diets have
been proposed for the treatment of obesity and metabolic
syndrome. Studies in NAFLD patients have shown that gradual
weight loss caused by exercise along with calorie-restricted
diet improve liver enzymes. However, rapid weight loss can
precipitate liver failure and is discouraged. It is recommended
that weight loss should not exceed 1.52 kg per week. However,
compliance with lifestyle changes is poor and only a minority
of subjects can maintain these changes. The rise in the
consumption of fast food may have particular relevance in the
rising obesity epidemic today. The key to dietary management
of NAFLD is modest caloric restriction to produce a negative
caloric balance of 500 cal/day. In those who are not overweight,
the focus is on keeping saturated fats to less than 30% of calories
Fig. 6: Pericellular fibrosis
and avoiding foods with a high glycemic index.
Exercise: Exercise is a key factor in weight loss programs.
Stage 1: Lobular Guidelines from the American College of Sports Medicine
Stage 2: Portal recommend 30 minutes of moderately intense exercise at
Stage 3: Bridging least 5 days per week. This may not be practical for obese
Stage 4: Cirrhosis. sedentary subjects. In such cases, a slowly ramped up program
of physical activity is recommended. It is also important to
establish realistic goals of treatment.
MANAGEMENT
Management of NAFLD can be broadly divided into medical Pharmacological Treatment
and surgical methods. Pharmacological treatment of NAFLD can be broadly
classified as:
Medications for weight loss
Medical Treatment
Medications for treating hyperlipidemia
Initial Approach Insulin sensitizing agents
Antioxidants
Diet: Basic lifestyle modifications, such as body weight Cytoprotective agents
management along with nutritional counseling are the Pentoxifylline.
Medications for weight loss: Anorectics are the medications Table -2:Studies on the effect of vitamin E in patients with NAFLD
that increase satiety and thus suppress appetite and food
Comparison Duration Histology ALT Authors
intake and lead to weight loss. They can be broadly classified (years)
into four categories:
Pioglitazone 2 + + Sanyal et al. 2010
1. Noradrenergic weight loss medications (n = 80) or vs Placebo
Schedule II: Amphetamine, dextroamphetamine vitamin E (n = 83)
(currently not approved by FDA for this indication) Vitamin E 0.5 + + Yakaryilmaz et al.
Schedule III: Benzphetamine, phendimetrazine 2007
(approved for short-term use) Vitamin E vs 1 - + Bugiansi et al.
Schedule IV: Phentermine, diethylpropion (approved metformin or diet 2005
for short-term use). Vitamin E vs 0.5 + - Sanyal et al. 2004
2. Serotonergic drugs vitamin E +
Nonselective serotonin reuptake inhibitors: Fenflura pioglitazone
mine, dexfenfluramine (removed from US market) Vitamin C + vitamin 0.5 - - Harrison et al.
Selective serotonin reuptake inhibitors: Sertraline, E (n = 30) 2003 vs Placebo
fluoxetine (not approved by FDA for this indication). (n = 22)
3. Dopamine-serotonin-norepinephrine reuptake inhibitor:
Sibutramine (continuous use up to 2 years). muscles and decreases liver lipid content in ob/ob mice
4. Pancreatic lipase inhibitors: Orlistat (continuous use up to models. Pioglitazone and rosiglitazone studies in animals
2 years). have been shown to improve hepatic steatosis, decrease
Of these, orlistat has been used for NASH. It is however hepatic TAGs, serum TNF- levels, procollagen levels
associated with gastrointestinal side effects including and TGF- levels. Virtually all studies using glitazones
incontinence especially in those who consume fatty foods. demonstrate an increase in insulin sensitivity, normalization
There are no data on the safety and the efficacy of the other of aminotransferase levels, histological improvements in
drugs. liver, including steatosis and ballooning, with or without
Medications for treating hyperlipidemia: Drugs were used improvement in fibrosis (Table 2). However, glitazones have
and their effects were noted by follow-up study on serum also been found to be associated with side effects, such as
aminotransferase levels and histopathology. In the earlier increased fatigue, mild lower extremity edema, weight gain,
trials, clofibrate and gemfibrozil were used, where clofibrate and increased risk of congestive heart failure.
showed no improvement, whereas gemfibrozil improved Antioxidants: Antioxidants have been a keen area of focus for
serum aminotransferase levels. HMG-CoA reductase the treatment of NAFLD, as chronic oxidative stress caused
inhibitor, Atorvastatin, was used for 1 year in a dose of 1030 by oxidation of free fatty acids with upregulation of cytokines
mg, follow-up liver biopsies showed improvement in hepatic has been found to be a key factor in depleting intracellular
steatosis and fibrosis. Probucol, a lipid lowering agent with antioxidants and hepatocyte injury. The various antioxidants
antioxidant properties was also used in a study which showed that have been used and studied are vitamin E, vitamin
improvement in aminotransferase levels. C, betaine, and N-acetyl-cysteine. Other than vitamin E,
Insulin-lowering agents: Metformin, a biguanide, acts by controlled studies have not uniformly demonstrated benefit
decreasing hepatic glucose output, increasing insulin- from these agents when compared with control groups treated
mediated glucose utilization by activating 5 AMP-activated with diet and weight loss alone, and measurement of reliable
protein kinase signaling and lowering serum free fatty acid histologic endpoints is limited. These agents may show benefit
concentration. Although several animal study models have in NAFLD through future larger controlled studies.
shown an improvement in liver abnormalities in animal Vitamin EIt is a fat-soluble vitamin with potent antioxidant
models of NAFLD, studies in human do not demonstrate any properties. It stabilizes biological membrane by preventing
meaningful effects on NASH. oxidation of unsaturated fatty acids and subsequent radical
Thiazolidinediones (pioglitazone, rosiglitazone) is another formation. In most of the studies either RRR--tocopherol
class of oral antidiabetic drugs that acts by activating form or a racemic mixture was used. Vitamin E has clearly
peroxisome proliferator-activated receptor gamma. The been shown to improve liver histology and reverse NASH.
therapeutic effects of pioglitazone in NASH are caused by It has been reported that vitamin E may be associated with
upregulation of adiponectin and later improved insulin an increase in all-cause mortality. However, these findings
sensitivity. Adiponectin increases fatty acid oxidation in are controversial. Vitamin E has not been studied in diabetic
Table 3: Randomised controlled trials comparing various insulin inflammation and ballooning; however, the data await
sensitisers in patients with NAFLD validation. Pentoxifylline might be considered a second-line
drug for the patients who have not responded to the first-line
Comparision Duration Histology ALT Author
(years) treatment.
Pioglitazone (n = 2 + + Sanyal et al. 2010
80) or E (N = 84) vs
placebo (N = 83)
Vitamin
Surgical Treatment
Metformin (n = 22) 1 + NA Omar et al. 2010 National Institutes of Health recommends surgical treatment
vs Rosiglitazone (n = of obesity for patients with BMI greater than 40, or BMI
20) or metformin + greater than 35 if other obesity-related health conditions are
rosiglitazone (n = 22)
present. Bariatric surgery involves either gastric restriction or
Rosiglitazone (n = 32) 1 + - Ratziu et al. 2008 impairing intestinal absorption.
vs Placebo (n= 31)
Metformin (n = 55) vs 1 + + Bugiansi et al. 2005
vitamin E (n = 28) or Procedures for Restriction
diet (n = 27)
Gastric stapling/gastroplasty: This involves restricting the
Vitamin E + .5 + - Sanyal et al,
pioglitazone vs 2004(64) capacity of the stomach either horizontally or vertically.
vitamin E Vertical banding has been found to be better than horizontal
Metformin (n = 17) vs 1 - + Uygun et al. 2004 one with lesser complications associated with the earlier one;
Diet (n = 17) however, gastroplasty is not considered a good method of
treatment as it does not have good long-term results.
Gastric banding: It has two modifications: (i) adjustable and (ii)
subjects as those with cirrhosis, and it is recommended that
nonadjustable. Banding can be performed laparoscopically,
it should not be used without histological documentation of
and thus, in minimally invasive procedure also, it does not
the liver disease. It is currently recommended for nondiabetic
and noncirrhotic subjects with active NASH (Table 3). alter the functional structure of stomach and can be adjusted
as per the requirement and is fully reversible.
Betaine: It is part of metabolic cycle of methionine, which leads
to the formation of S-adenosyl-methionine. This compound Gastric bypass: This is considered as the gold standard
acts as a methyl donor in several metabolic reactions and for antiobesity operations and is also the most effective
is proposed to have a beneficial role in NASH patients. In one. It has been associated with weight loss up to 60%
several small pilot studies using betaine for treating patients of the body weight. Early complications include wound
with steatosis and fibrosis, marked improvement in serum infections or complications; late complications are stenosis,
aminotransferases and hepatic steatosis were seen. These ulceration, bleeding, development of volvulus, obstruction,
findings await validation. micronutrient deficiency, and gallstone formation.
Cytoprotective agentsUrsodeoxycholic acid: It is a
hydrophilic bile acid, which displaces hydrophobic, toxic Procedures for Malabsorption
bile acids by competitive inhibition that decreases toxicity,
oxidative stress, and hepatic injury. Initial studies using They include:
ursodeoxycholic acid (UDCA) showed its beneficial effects Jejunoileal bypass
in patients of NASH; however, in subsequent large double- Biliopancreatic diversion
blind placebo-controlled study, it showed no significant Duodenal switch.
improvement in liver enzymes and histology of patients on These procedures have been found to be very effective
UDCA. There is currently no role for UDCA in the treatment in morbid obesity cases with BMI as high as over 50. these
of NASH. Clinical trials with high-dose UDCA are underway. procedures create selective malabsorption for fatty food
Pentoxifylline: Pentoxifylline, which is a TNF- antagonist and decrease oral intake by limited gastrectomy. However,
has shown improvement in insulin resistance and liver they have been associated with vitamin deficiencies, protein
enzymes in NASH patients in two different studies. In another malnutrition and bone diseases; hence, they are not very
small-pilot study, there was improvement in the steatosis, preferred procedures today.
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Dis. 2007;11(1):37-54. 21. Palmentieri B, de Sio I, La Mura V, et al. The role of bright liver echo
8. Chavarria-Arciniega S, Lopez-Alvarenga JC, Uribe-Uribe NO, et al. pattern on ultrasound B-mode examination in the diagnosis of
Relationship between morphological diagnosis of NASH (non- liver steatosis. Dig Liver Dis. 2006;38(7):485-9.
alcoholic steatohepatitis) and liver function tests in a group of 22. Park SH, Kim PN, Kim KW, et al. Macrovesicular hepatic steatosis
patients with morbid obesity. Rev Invest Clin. 2005;57(4):505-12. in living liver donors: use of CT for quantitative and qualitative
9. de Oliveira CP, de Mello ES, Alves VA, et al. Changes in assessment. Radiology. 2006;239(1):105-12.
histological criteria lead to different prevalences of nonalcoholic 23. Puri P, Mirshahi F, Cheung O, et al. Activation and dysregulation
steatohepatitis in severe obesity. Ann Hepatol. 2007;6(4):255-61. of the unfolded protein response in nonalcoholic fatty liver
10. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty
disease. Gastroenterology. 2008;134(2):568-76.
acids stored in liver and secreted via lipoproteins in patients with
24. Solga SF, Clark JM, Alkhuraishi AR, et al. Race and comorbid
nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343-51.
factors predict nonalcoholic fatty liver disease histopathology in
11. Fishbein M, Castro F, Cheruku S, et al. Hepatic MRI for fat
severely obese patients. Surg Obes Relat Dis. 2005;1(1):6-11.
quantitation: its relationship to fat morphology, diagnosis, and
ultrasound. J Clin Gastroenterol. 2005;39(7):619-25. 25. Strassburg CP, Manns MP. Approaches to liver biopsy techniques-
12. Gholam PM, Flancbaum L, Machan JT, et al. Nonalcoholic fatty -revisited. Semin Liver Dis. 2006;26(4):318-27.
liver disease in severely obese subjects. Am J Gastroenterol. 26. Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic
2007;102(2):399-408. fatty liver disease and its association with cardiovascular disease
13. Hamer OW, Aguirre DA, Casola G, et al. Imaging features of among type 2 diabetic patients. Diabetes Care. 2007;30(5):
perivascular fatty infiltration of the liver: initial observations. 1212-8.
Radiology. 2005;237(1):159-69. 27. Wolf AM, Busch B, Kuhlmann HW, et al. Histological changes in
14. Harnois F, Msika S, Sabate JM, et al. Prevalence and predictive the liver of morbidly obese patients: correlation with metabolic
factors of non-alcoholic steatohepatitis (NASH) in morbidly parameters. Obes Surg. 2005;15(2):228-37.
23
cHAPTER
Alcoholic Liver Disease
Hamizah Razlan, Rosmawati Mohamed
INTRODUCTION and polymorphonuclear cell infiltration with or without

fibrosis. Alcoholic hepatitis is clinically important because
Alcohol is a widely available hepatotoxin, which accounts patients with severe alcoholic hepatitis have a high risk of
for 3.5% of the global disease burden, a higher percentage progression and short-term mortality rates ranging from 30 to
as compared to the 2.6% disease burden related to tobacco. 50%. Development of alcoholic hepatitis increases the risk of
Alcoholic liver disease (ALD) is a major cause of chronic progression to cirrhosis by ninefolds as compared to patients
liver disease and liver-related mortality worldwide. In many with fatty liver alone. It has been reported that up to 40% of
countries, the per capita alcohol consumption is closely patients with alcoholic hepatitis had evidence of cirrhosis in a
related to the prevalence and incidence of ALD as well as repeat biopsy performed 5 years after diagnosis. For those that
mortality rates due to cirrhosis. Alcoholism is a condition of progress to cirrhosis, it is typically micronodular (Laennecs
physical dependence in which a person has impaired control cirrhosis). Mixed micronodular and macronodular is also
and craving for alcohol, develop tolerance, and suffer from seen occasionally.
withdrawal symptoms upon abstinence. Excessive alcohol A number of risk factors such as host attributes and
drinking is considered harmful, if it leads to physical and/or comorbidities influence the development and progression
social consequences, such as damage to organs, accidents of liver disease. The most important risk factor is the amount
of alcohol consumed, a measure of both daily alcohol
due to intoxication, job loss or marital difficulties. An
consumption and duration of use. A threshold of 4080 g/day
estimated 3.8% of mortality worldwide is related to alcohol.
of alcohol consumption in males and 2040 g/day in females
Alcoholic cirrhosis is the second most frequent indication for
for an average of 1012 years increases the risk of developing
liver transplantation in western countries.
significant liver injury and progression to cirrhosis occurs in
641% of cases. The type of alcohol consumed and pattern
of drinking also influences the progression of liver disease.
DISEASE SPECTRUM AND RISK It has been reported that drinking beer and spirits increases
FACTORS the likelihood of developing liver disease as compared to
wine. Binge drinking (defined as consumption of at least five
The histological stages of alcohol-related liver injury include alcoholic drinks at any one time) and drinking outside of
fatty liver or simple steatosis, alcoholic steatohepatitis, and mealtimes also increase the likelihood of developing ALD.
chronic hepatitis with fibrosis or cirrhosis. Fat accumulation The risk of ALD is higher in Hispanic males, obese and
in the liver, which is the earliest and most common feature, is overweight subjects, and patients with hepatitis C. Patients
seen in 90% of drinkers that consumed more than 60 g/day of with ALD and who are coinfected with hepatitis C virus
alcohol. However, it can also occur in drinkers who consumed (HCV) have an increased tendency to develop more severe
less than 60 g/day. Generally, fatty liver is a benign condition liver disease and at a younger age. The risk of cirrhosis
and is completely reversible with alcohol abstinence for increases 1030-folds among patients with ALD and HCV.
68 weeks. Despite abstinence, up to 15% of patients can The risk of hepatocellular carcinoma also increases 24
potentially progress to fibrosis and cirrhosis. times among patients with alcoholic cirrhosis and HCV than
Approximately 1035% of heavy drinkers develop those with alcoholic cirrhosis alone. Numerous studies have
alcoholic hepatitis, a clinical syndrome predominantly shown that ALD develops in women after a shorter duration
caused by alcoholic steatohepatitis; the latter is defined of drinking and at lower alcohol quantity. The risk of cirrhosis
histologically by fat infiltration, ballooning of hepatocytes, increases with alcohol consumption of more than 20 g/day.
Alcoholic Liver Disease 215
This difference in gender is due to several factors, such as of liver damage clinically and/or biochemically. However,
lower levels of gastric alcohol dehydrogenase and a higher patients who abuse alcohol often have denial of their condition
proportion of body fat in women amongst others. and may under-report the amount of alcohol consumed.
Therefore, clinicians who have a high clinical suspicion of ALD
may need to get further history from family members or apply
PATHOGENESIS questionnaires designed to screen these patients.
During history taking, the important questions to ask for
The factors involved in the pathogenesis of alcohol-induced alcohol abuse or dependence are on the amount and frequency
steatosis include increased fatty acids and triglyceride of alcohol consumed, past injuries and visits to the Emergency
synthesis secondary to increased production of NADH by Department. There are various questionnaires, which have
alcohol oxidation, influx of free fatty acids, and chylomicrons been developed and validated to screen for risky drinking
into the liver and inhibition of mitochondrial B-oxidation and alcohol dependence. The CAGE questionnaire has been
of fatty acids. For those who continue to drink excessive widely used for screening patients suspected to have alcohol
amounts of alcohol, progression from simple steatosis to abuse or dependence. It is simple, short, easily administered,
alcoholic steatohepatitis may occur. and sensitive to diagnose patients with an alcohol dependency
Several factors play an important role in the pathogenesis syndrome. Unfortunately, the questionnaire does not take into
of alcoholic steatohepatitis. Acetaldehyde, the major account of the amount of alcohol consumed and focuses on
metabolite of alcohol metabolism, binds to protein and the consequences of excess alcohol ingestion.
DNA to form protein adducts and interferes with normal cell Currently, the gold standard is the AUDIT questionnaire
function. This will then lead to the formation of autoantigens (Alcohol Use Disorders Identification Test) that was developed
which will activate the immune system. Acetaldehyde also by the World Health Organization to identify drinkers at risk
interferes with mitochondrial glutathione transport which of alcohol dependence or abuse. It consists of 10 questions
promotes oxidative stress and apoptosis. that explore the amount of alcohol consumed, alcohol
Acetaldehyde is a highly reactive and potentially toxic dependence and related problems. It is easily administered
compound and is responsible for systemic symptoms, such in the primary-care setting and has a high sensitivity and
as nausea, flushing, and headaches. The Oriental flush specificity.
syndrome is common in individuals from East Asia who had Clinicians who have a high index of suspicion of possible
inherited the ALDH22 allele, which encodes an inactive form alcohol abuse should proceed to administer these screening
of ALDH2, resulting in impaired metabolism of acetaldehyde. questionnaires. If the questionnaires were positive, the
Another contributing factor in the pathogenesis of clinicians should proceed to further tests and investigations.
alcoholic steatohepatitis is the formation of reactive oxygen
species (ROS), leading to lipid peroxidation. Chronic alcohol
exposure promotes CYP 2E1 upregulation, which will enhance
History and Physical Examination
the formation of free radicals and the metabolism of alcohol Most patients with underlying fatty liver are asymptomatic
to acetaldehyde. ROS is also generated from other sources, or present with nonspecific symptoms. The most common
such as NADH-dependent cytochrome reductase, xanthine physical finding is hepatomegaly, which is present in 75% of
oxidase and mitochrondrial electron transport system of the cases regardless of disease severity.
respiratory chain. Patients with alcoholic hepatitis may present with mild and
In ALD, inflammatory pathways are activated to generate nonspecific symptoms, such as nausea and vomiting, anorexia
inflammatory mediators, such as tumor necrosis factor and weight loss, and abdominal pain and distension. They
(TNF-), chemokines (interleukin-8), and osteopontin. can also present more severely with hepatic encephalopathy
Chronic alcohol consumption also leads to the generation and liver failure. Some patients develop high-grade fever,
of lipopolysaccharides, which will induce the inflammatory which can persist for weeks.
pathways and expression of profibrogenic cytokines leading Patients with alcoholic cirrhosis may present with
to infiltration of polymorphonuclear cells in the hepatocytes, decompensation without a prior history of fatty liver or
formation of ROS, progressive liver damage, and fibrogenesis. alcoholic hepatitis. These patients can also be diagnosed
concurrently with acute alcoholic hepatitis. Examination
findings include those related to alcohol abuse and liver
DIAGNOSIS injury, such as spider nevi, palmar erythema, Dupuytrens
contractures, parotid gland enlargement, and those related
Alcoholic liver disease is diagnosed through a combination to underlying portal hypertension, such as splenomegaly,
of a history of significant alcohol consumption and evidence ascites, abdominal wall collaterals, and venous hum.
It is important to emphasize that no single physical finding Mallory bodies, micronodular pattern of cirrhosis, and iron
is 100% specific or sensitive for ALD. Therefore, physical deposition. Histological features of alcoholic steatohepatitis
examination alone is unable to diagnose ALD or exclude include centrilobular ballooning of hepatocytes, neutrophilic
other causes of liver cirrhosis. infiltration, Mallory-Denk hyaline inclusions, steatosis and
a chicken-wire like pattern of fibrosis. Other common
features seen include bridging necrosis, fatty changes, bile
Laboratory Features duct proliferation, cholestasis, and perivenular fibrosis.
A number of laboratory abnormalities have been reported Liver biopsy is an invasive procedure with morbidity and
in patients with ALD, which includes elevation of aspartate mortality risks. Therefore, the decision to perform liver biopsy
aminotransferase (AST) and alanine aminotransferase (ALT). needs to be individualized and benefits versus risks should be
The most common pattern of enzyme elevation is AST greater discussed in detail with the patient. For patients with alcoholic
than ALT with neither usually elevated greater than seven hepatitis, a liver biopsy is beneficial in assessing the severity of
times the upper limit of normal. The likelihood of diagnosis of the disease, and it predicts the response to steroid treatment.
ALD increases as the AST/ALT ratio increases. The presence of severe inflammation (polymorphonuclear
Gamma glutamyl transferase is the most common cell infiltration) and cholestatic changes correlate with
marker used to detect chronic alcohol consumption. It is increasingly poor prognosis in this group of patients.
easy to measure and cheap but has low sensitivity (6973%)
and specificity (6580%) to diagnose underlying ALD.
Macrocytosis is also usually seen in individuals that abuse PROGNOSIS
alcohol, but again, it has a low sensitivity level (2752%) for
The prognosis of patients with ALD is dependent on the
the diagnosis of ALD.
underlying pathological injury, patients nutritional status,
Carbohydrate deficient transferrin is another serum
presence of complications of liver cirrhosis and other
marker that is used to detect alcohol abuse. It has a sensitivity
comorbidities, such as HCV infection. Patients with fatty
of 69% for detection of significant alcohol consumption with
liver alone usually have a good prognosis and the disease is
a high specificity of 92%.
nonprogressive that improves with abstinence. Studies have
Advanced alcoholic liver cirrhosis is suspected once the
shown that the presence of perivenular fibrosis, mixed macro/
serum albumin is reduced, prothrombin time is prolonged.
microvesicular fat and giant mitochondria were independent
Other laboratory abnormalities observed are increased
histological predictors of progression of alcoholic fatty liver
serum bilirubin levels and thrombocytopenia secondary to
disease. The extent of hepatic inflammation appears to be
portal hypertension and hypersplenism.
the single most important prognostic histological factor
for increased mortality in alcoholic hepatitis. The presence
Hepatic Imaging of alcoholic hepatitis in cirrhotic patients indicated a poor
prognosis with increased 1- and 5-year mortality rates of 27%
In patients who abuse alcohol, imaging modalities, such and 47%, respectively compared to those without hepatitis.
as abdominal ultrasound, computed tomography scan In patients with alcoholic hepatitis, it is crucial to stratify
or magnetic resonance imaging may be used to diagnose the severity of liver disease. Maddrey and Boitnott invented a
presence of fatty liver or liver cirrhosis, but more importantly, simple formula called Maddrey discriminant function (MDF),
these imaging modalities can exclude biliary tract obstruction which was calculated as 4.6 (patients prothrombin time -
or malignant diseases of the liver as a cause of raised liver control prothrombin time) + total bilirubin (mg/dL). This
enzymes . prognostic score is useful to identify patients with poor short-
term survival rates. It has been shown in three prospective
studies that patients with a score of greater than or equal to
Liver Biopsy in Alcoholic Liver Disease 32 had the worst prognosis with mortality rates of 3545% at
A liver biopsy is useful in establishing the diagnosis and 1 month.
histological severity of ALD and determining other causes of Other scoring systems that had been proposed to
liver disease, as up to 20% of patients with alcohol abuse have prognosticate patients with alcoholic hepatitis includes
concomitant etiology for liver disease. the MELD (model for end-stage liver disease) score, the
The features that are strongly suggestive of alcohol-related Glasgow alcoholic hepatitis score, the combined clinical and
injury on liver biopsy include fatty liver with perivenular laboratory index of the University of Toronto, and the Beclere
fibrosis, giant mitochondria, spotty hepatocyte necrosis, model.
THERAPY FOR ALCOHOLIC LIVER >32, hepatic encephalopathy, high MELD score) should be
considered for more aggressive medical therapy.
DISEASE
Abstinence is strictly recommended in all patients with Nutrition Therapy
ALD. Abstinence improves hepatic steatosis, and prevents
ongoing liver injury as well as progression to cirrhosis. Veldt Protein calorie malnutrition is a common problem in patients
et al. demonstrated that 66% of patients admitted for severe with alcoholic hepatitis. It has been shown in one study that
alcoholic cirrhosis had improvement in their ChildPugh all patients with alcoholic hepatitis have some degree of
score after 3 months of abstinence and, therefore, did not malnutrition, which correlated with the severity, prognosis
require liver transplantation. However, abstinence is less and development of serious complications of the disease.
likely to occur among females. Following abstinence, the Among patients with alcoholic hepatitis, the mortality rate
patients are at risk of recidivism. Miguet et al. demonstrated is 76% in those with severe malnutrition compared to 14% in
that relapse rates, defined as any alcohol consumption those with mild malnutrition.
following transplantation, were 11% at 1 year and 30% at 2
years. Corticosteroids
Several drugs have been used to sustain abstinence,
including naltrexone and acamprosate (N-acetyl homo Although corticosteroid has been the most widely studied
taurine). Naltrexone is a pure opioid antagonist that therapy in patients with alcoholic hepatitis, randomized
controls the craving for alcohol and significantly reduces controlled trials using steroids have yielded inconsistent
the risk of relapse. However, it has been shown to cause results. Mathurin et al. performed a meta-analysis using
liver injury. Acamprosate reduces withdrawal symptoms patients with similar disease severity (MDF 32 or
possibly by blocking the inhibitory neurotransmitter gamma encephalopathy) and demonstrated that the 28-day survival
aminobutyric acid. It is useful in reducing the relapse rates in improved significantly in patients taking steroids compared
detoxified alcohol-dependent patients in combination with to noncorticosteroid-treated patients (80% versus 66%,
counseling and support. However, a study demonstrated that respectively). Prednisolone is usually given at a dose of 40
it did not confer any additional benefit compared to naltrexone mg/day for 4 weeks then tapered over a period of 24 weeks
or to intensive counseling in maintaining abstinence. (i.e. 20 mg daily for 7 days, followed by 10 mg daily for 7 days).
Patients with ALD have a wide spectrum of nutritional However, it is also important to be aware that steroids in
abnormalities ranging from morbid obesity to severe patients with severe alcoholic hepatitis, concomitant sepsis,
malnutrition. Obese patients with ALD are also susceptible to acute pancreatitis, and gastrointestinal bleeding may be
the nutritional deficiencies related to alcohol similar to those harmful. In patients with MDF greater than 54, the mortality
who are malnourished. Nutritional deficiencies including rate has been shown to be higher in corticosteroid-treated
vitamin and mineral deficiencies should be identified, and patients.
treated aggressively in patients with ALD.
The management of complications of cirrhosis (ascites,
encephalopathy, and variceal bleeding) is similar in alcoholic
Anticytokine Therapy
and nonalcoholic liver disease. Pentoxifylline, a phosphodiesterase inhibitor, has been
shown to reduce the production of cytokines, including
TNF-. A study in patients with severe alcoholic hepatitis
Treatment of Alcoholic Hepatitis (MDF 32) showed a 41% reduction in the mortality
The mainstay of therapy for alcoholic hepatitis is complete rates among pentoxifylline-treated patients compared to
abstinence. In this group of patients, no threshold of alcohol those given placebo. The reduction of mortality rate was
consumption can be considered safe as alcoholic hepatitis attributed to the renoprotective effects of pentoxifylline with
can persist and recur even after one episode of drinking. It is a significant reduction in the risk of developing hepatorenal
also important to note that the risk of developing cirrhosis still syndrome, which accounted for 50% and 92% of deaths in
exists despite absolute abstinence, albeit lower than those the pentoxifylline-treated and placebo-treated patients,
who continue to drink. respectively.
Patients with low risk of complications are usually given Infliximab (a monoclonal antibody against TNF-), anti-
supportive care and will tend to improve spontaneously TNF etanercept (a fusion protein, which inhibits TNF) are
over time. Those with high risk of complications (MDF score other anticytokines that have not been shown to be beneficial
and, therefore currently not recommended in alcoholic Liver Transplantation for Alcoholic Liver
hepatitis.
Disease
Liver transplantation is a definitive treatment option for end-
Combination Therapy and Other stage alcoholic cirrhosis with survival rates comparable to
Treatments nonalcohol-related liver transplant recipients. Identifying
Sequential therapy by using steroids followed by pentoxifylline suitable candidates for liver transplantation is crucial and
therapy was shown in one study to confer no survival should include a formal evaluation of the likelihood of long-
benefits compared to steroid monotherapy in patients with term abstinence. The risk of resuming alcohol consumption
severe alcoholic hepatitis. Other older studies looked at the post-liver transplantation is high, but only small numbers of
combination therapy of steroids and nutritional intervention. patients revert to heavy alcohol use or abuse. The reported
Many other trials using various other medications, including rates of recidivism defined as any amount alcohol drinking
antioxidants, such as vitamin E and silymarin, colchicine after liver transplant vary between 3% and 49%. In the hope
and calcium channel blockers have not shown unequivocal to reduce the recidivism rate post-liver transplantation, the
beneficial effects. requirement in most transplant centers for patients with
decompensated alcoholic cirrhosis is a period of abstinence
of at least 6 months before listing for transplant. However, the
Long-term Management of Alcoholic 6-month abstinence rule has been questioned, as there is lack
Liver Disease of an association between the duration of at least 6 months
preliver transplant abstinence and post-liver transplantation
Nutritional Therapy recidivism.
A period of abstinence prior to liver transplant as a
Malnutrition, a common problem in chronic alcoholics, is prerequisite is important to manage the problems related
predictive of survival in patients with established ALD. During to chemical dependency and to allow adequate time for
hospitalizations for acute decompensation of ALD, aggressive recovery from medical therapy to occur, obviating the need
nutritional therapy (either enterally or parenterally) should be for transplant.
started to ensure that the patients nutritional requirements The role of liver transplantation for patients with severe
are being provided. Enteral feeding in hospitalized, severely alcoholic hepatitis not responsive to intensive medical
malnourished or decompensated cirrhotic patients resulted therapy will need to be evaluated on a case to case basis.
in improved serum bilirubin levels, hepatic encephalopathy,
ChildPugh score and survival compared to the group who did
not receive enteral nutrition. Patients with alcoholic cirrhosis
should be encouraged to have frequent interval feedings with
SUMMARY
daily dietary intakes of 1.21.5/kg of protein and 3540 kcal/ Alcoholic liver disease remains a major cause of chronic
kg body weight. Bedtime nutritional supplements have been liver disease globally. The disease spectrum ranges from
shown to improve the total body protein stores in patients fatty liver to alcoholic hepatitis and cirrhosis. Fatty liver is
with cirrhosis. the most common histological finding, which is found in
up to 90% of patients who drink excessively. The amount of
alcohol consumed (daily alcohol consumption and duration
Medical and Other Therapy of use), the pattern of drinking (the type of alcohol and
The use of propylthiouracil (decreases cellular metabolism binge drinking), host attributes (female gender and genetic
and hence the hypermetabolic state induced by alcohol), differences) and comorbidities (obesity and coinfection with
colchicines (antifibrotic and anti-inflammatory), silymarin hepatitis C) have been reported to influence the development
(antioxidant properties) and S-adenosyl L-methionine (a and progression of ALD.
precursor to glutathione) have not shown convincing benefits Alcoholic hepatitis is a distinct clinical entity, which carries
in terms of survival, complications of liver disease, liver tests a poor prognosis with high mortality rates.
or histology, and is currently not considered as standard Several scoring models have been developed to
treatment for patients with ALD. determine the outcome in patients with alcoholic hepa
titis. Abstinence is the cornerstone of therapy for ALD 8. McCallum S, Masterton G. Liver transplantation for alcoholic liver
and is the dominant factor determining the prognosis disease: a systematic review of psychosocial selection criteria.
with clinical and histological improvement seen even Alcohol Alcohol. 2006;41(4):358-63.
in patients with underlying cirrhosis. The first line of 9. McCullough AJ, OConnor JF. Alcoholic liver disease: proposed
therapeutic intervention in malnourished patients with recommendations for the American College of Gastroenterology.
ALD is nutritional support. Corticosteroids have also been 1998;93(11):2022-35.
shown to improve short-term survival in patients admitted 10. McCullough AJ, OShea RS, Dasarathy S. Diagnosis and
management of alcoholic liver disease. J Dig Dis. 2011;12(4):
with severe alcoholic hepatitis. Pentoxifylline have shown
257-62.
promising results in alcoholic hepatitis particularly in
11. Menachery J, Duseja A. Treatment of decompensated
patients with hepatorenal syndrome. Liver transplantation
alcoholic liver disease. Int J Hepatol. 2011:219238. doi:10.4061/
is an established treatment modality for abstinent alcoholic
2011/219238.
cirrhotic patients. 12. Miguet M, Monnet E, Vanlemmens C, et al. Predictive factors of
alcohol relapse after orthotopic liver transplantation for alcoholic
liver disease. Gastroenterol Clin Biol. 2004;28(10 Pt 1):845-51.
BIBLIOGRAPHY 13. OShea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease.
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Hepatology. 2000;32(1):36-42. 15. Savolainen VT, Liesto K, Mannikko A, et al. Alcohol consumption
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M, Friedman LS, Brandt LJ. Sleisenger and Fordtrans Gastroin effects of ethanol. Alcohol Clin Exp Res. 1993;17(5):1112-7.
testinal and Liver Disease. Pathophysiology/Diagnosis/
16. Savolainen V, Perola M, Lalu K, et al. Early perivenular fibrogenesis
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3. Gao B, Bataller R. Reviews in basic and clinical gastroenterology
17. Singal AK, Duchini A. Liver transplantation in acute alcoholic
and hepatology. Gastroenterology. 2011;141:1572-85.
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4. Kearns PJ, Young H, Garcia G, et al. Accelerated improvement of
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1992;102(1):200-5. 18. Stewart S, Jones D, Day CP. Alcoholic liver disease: new insights
5. Leevy CM. Fatty liver: a study of 270 patients with biopsy proven into mechanisms and preventative strategies. Trends Mol Med.
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1962;41:249-76. 19. Teli MR, Day CP, Burt AD, et al. Determinants of progression
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24
cHAPTER
Primary Sclerosing Cholangitis
Roger W Chapman
INTRODUCTION Table 1: Causes and mimics of secondary sclerosing cholangitis
Surgical trauma to bile ducts (with associated cholangitis)

Primary sclerosing cholangitis (PSC) is a chronic disease of
Ischemic injury, e.g. hepatic artery thrombosis following transplantation,
the intra- and/or extrahepatic bile ducts. It is characterized
HHT, PVT, hepatic arterial chemotherapy, e.g. floxuridine
by a concentric, obliterative fibrosis that leads to bile duct
Intraductal gallstones/choledocholithiasis (may be due to MDR3 mutation)
strictures (Fig. 1). In many patients, this in turn progresses
to biliary cirrhosis and hepatic failure. Approximately Viral or bacterial infection, e.g. CMV or cryptosporidiosis, severe sepsis in
ICU
one-third of patients will develop cholangiocarcinoma.
Primary sclerosing cholangitis is frequently associated Caustic injury, e.g. formalin treatment of hydatid disease
with inflammatory bowel disease (IBD) usually ulcerative IgG4-associated autoimmune pancreatitis
colitis (UC) and those with Crohns disease predominantly Conditions mimicking sclerosing cholangitis on cholangiographic imaging
affecting the colon. Approximately three quarters of the Malignancy, e.g. metastatic carcinoma
Northern European population with PSC have concomitant
Hypereosinophilic syndrome
IBD particularly extensive UC. Patients, usually with IBD,
Choledochal cyst, polycystic liver disease
who have normal cholangiography but typical histological
Carolis disease
features on liver biopsy are diagnosed as small duct PSC. Cystic fibrosis
The term secondary sclerosing cholangitis (SSC) is used
Cirrhosis
for a disease with similar morphological features to PSC
but where a direct causative agent for biliary disease can be Abbreviation: CMV, cytomegalovirus; HHT, hereditary hemorrhagic
established (Table 1). telangiectasia; PVT, portal vein thrombosis
EPIDEMIOLOGY
Little is known about the incidence and prevalence of PSC,
as good epidemiological studies are extremely difficult to
perform.
The true prevalence of PSC associated with IBD is
unknown; the estimated prevalence of PSC in patients with
UC is 2.57.5%. The prevalence of PSC in the United States has
been estimated by extrapolation to be 27 cases per 100,000
population, based on a prevalence of UC of 40225 cases per
100,000. These findings, however, probably underestimate the
Fig. 1: Endoscopic retrograde cholangiogram showing dilatation and actual prevalence of PSC, as the disease can occur in patients
stricturing of the extra- and intrahepatic biliary treethe typical with normal serum levels of alkaline phosphatase, and 20
changes of primary sclerosing cholangitis 30% of patients with PSC have no associated IBD.
Primary Sclerosing Cholangitis 221
Population studies from the Northern Hemisphere have Both the development of PSC and its outcome are
shown an annual incidence of PSC of 0.91.3/100,000 years independent of the activity of colitis. It may even occur after
and point prevalence of 8.513.6/100,000, which appears proctocolectomy and likewise IBD may present many years
to be increasing. The study from a population in Olmsted after liver transplant for PSC. The natural history of IBD in
County, MN in the United States estimated a prevalence of patients with PSC, although usually involving the whole colon
20.9 per 100,000 men and 6.3 per 100,000 women. In a similar has a more benign course than in those patients with IBD alone.
report from South Wales, UK, the incidence was calculated at Colitis associated with PSC may be a separate disease
0.91 cases per 100,000 person-years and the point prevalence entity as there is a higher prevalence of rectal sparing (52%
was 12.7 cases per 100,000 persons, both very similar to the versus 6%) in those with PSC than in those with UC alone,
US data. the same goes for backwash ileitis (51% versus 7%). All
The higher prevalence of PSC found in more recent patients given a diagnosis of PSC not already known to have
studies might be attributed to a more complete capture IBD should undergo colonoscopy with multiple biopsies as
of incident and prevalent cases and to a higher rate of liver coexisting IBD may be asymptomatic.
transplantation among prevalent cases (ascertainment bias) It is not known why patients with PSC who have undergone
rather than reflecting a true increase in prevalence. It may pouch surgery for their UC have a higher rate of pouchitis
also, in part, be due to the easier access to cholangiography than those without PSC (63% versus 32%).
provided by magnetic resonance cholangiography (MRC) Likewise the explanation for colonic resection prior to
scanning. liver transplant eliminating the risk of recurrent PSC (rPSC) is
Small duct PSC occurs in about approximately 10% of unknown.
a PSC population. Recently, a study involving the Calgary
health region in Canada has shown an incidence of small
duct PSC as 0.15/100,000. In children, the incidence rate was ETIOLOGY AND PATHOGENESIS
0.23/100,000 compared with 1.11/100,000 in adults.
Immunogenic Factors
Smoking It has been suggested that PSC results from a maladaptive
Cigarette smoking has been recognized as a protective factor immune/autoimmune response a hypothesis supported by
against the development of UC. Recent reports have suggested the association with human-specific leucocyte antigen (HLA)
that cigarette smoking may also additionally protect against haplotypes and polymorphisms of other genes involved in the
the development of PSC [unlike primary biliary cirrhosis immune response, autoantibodies in serum and the link with
(PBC)]. This protective effect was more marked in patients IBD and the consequent leaking gut syndrome.
with PSC than UC and interestingly was observed in patients There is an increased frequency of the HLA A1 B8 DR3
with and without IBD. The mechanism of protection in both DRW 52A haplotype in PSC compared with healthy controls.
disorders remains unknown. Human-specific leucocyte antigen DR2 and HLA DR6 are also
associated with PSC. Human-specific leucocyte antigen DR4
appears to be less common in PSC populations and may be
protective (Table 2).
PREVALENCE OF PRIMARY
SCLEROSING CHOLANGITIS IN Table 2: Key human leukocyte antigen haplotypes associated with
INFLAMMATORY BOWEL DISEASE primary sclerosing cholangitis (PSC)
Haplotype Significance in PSC

In Scandinavia, UK and the United States 7080% of those
B8-TNF*2-DRB3*0101-DRB1*0301- Strong association with disease
with PSC also have coexisting IBD. In reports from Spain,
DQA1*0501-DQB1*0201 susceptibility
Italy, India, and Japan the prevalence of IBD in PSC is 3750%
DRB3*0101-DRB1*1301- Strong association with disease
although very few underwent total colonoscopy and colonic DQA1*0103-DQB1*0603 susceptibility
biopsy. DRB5*0101-DRB1*1501- Weak association with disease
Conversely only 27.5% of those with IBD have PSC. DQA1*0102-DQB1*0602 susceptibility
However, this is very likely an underestimate as patients DRB4*0103-DRB1*0401-DQA1*03- Strong association with protection
with PSC proven on radiological imaging may have normal DQB1*0302 against disease
liver biochemical tests. Inflammatory bowel disease can be MICA*008 Strong association with disease
diagnosed at any time before or after the diagnosis of PSC. susceptibility
Table 3: Serum autoantibodies in primary sclerosing cholangitis The association of PSC with IBD led to the hypothesis
that colonic bacteria plus activated lymphocytes enter
Antibodya* Prevalence (%)
the portal circulation through a leaky mucosa in IBD.
Antinuclear antibody 777 Chemokines and cytokines released from within the liver
Antismooth muscle antibody 1320 attract macrophages/monocytes, lymphocytes, activated
Antiendothelial cell antibody 35 neutrophils and fibroblasts to the site of inflammation. In
Anticardiolipin antibody 466 those genetically susceptible individuals, bacterial antigens
Thyroperoxidase 716
may act as molecular mimics and cause an immune reaction
responsible for initiating PSC.
Thyroglobulin 4
Rheumatoid factor 15
*Antimitochondrial antibody is only rarely detected in PSC (<1%). CLINICAL FEATURES
This is useful in differentiating primary sclerosing cholangitis from
primary biliary cirrhosis Nowadays most individuals diagnosed with PSC are
asymptomatic. Symptoms when present are nonspecific and
relate to cholestasis, e.g. pruritus, right upper abdominal
There are other genes outside the HLA region that may play quadrant pain, fatigue and weight loss. In a few patients,
a role in the pathogenesis of PSC. Genome wide association episodes of fever and chills are predominant. Few present
studies are currently in progress to identify possible for the first time with decompensated cirrhosis and
susceptibility genes for PSC. portal hypertension, i.e. ascites and variceal hemorrhage.
No specific autoantigens have been identified in relation Nevertheless, hepatomegaly and splenomegaly are the most
to PSC although smooth muscle antibodies, antinuclear frequent abnormal physical findings at clinical examination
antibodies and antineutrophil cytoplasmic antibodies at the time of diagnosis in PSC. Osteopenic bone disease is
(p-ANCA) are often detected in serum. A high prevalence of both a complication of advanced PSC and IBD. Steatorrhea
p-ANCA (detected in 3388% of patients with PSC) but these and malabsorption of fat-soluble vitamins occur only with
autoantibodies are not specific to PSC. They are found in prolonged cholestasis with jaundice. Presentation with
UC alone (6087%) and in patients with type I autoimmune jaundice is uncommon and it is often associated with the
hepatitis (AIH) (5096%) and PBC, and thus, it is unlikely this presence of underlying cholangiocarcinoma. IgG4-associated
antibody is involved in the pathogenesis of PSC (Table 3), and sclerosing cholangitis may also present with jaundice, and
it is not a useful screening test. should be actively excluded by serology and/or histological
Primary sclerosing cholangitis is associated with other assessment.
autoimmune conditions (25%), such as diabetes mellitus,
celiac and autoimmune thyroid disease (Graves disease).
Rheumatoid arthritis has also been described in association DIAGNOSIS
with PSC and may be a clinical marker for those at high risk of
rapid progression to cirrhosis. Laboratory Investigations
One hypothesis to explain the association between
colonic and liver disease is that PSC is mediated by long- Primary sclerosing cholangitis is usually associated with IBD
lived memory T cells derived from the inflamed gut which and thus its diagnosis is frequently suggested by observing
enter the enterohepatic circulation and thus reach the liver. an elevation in liver biochemistries with a cholestatic picture
Aberrant expression of chemokines and adhesion molecules suggested by an elevated alkaline phosphatase and gamma
on liver endothelial cells may cause recruitment of these T GT in an asymptomatic individual. Blood tests typically
cells. This in turn may lead to biliary inflammation, fibrosis fluctuate over time and some may even return completely to
and bile duct stricturing. normal. The introduction of noninvasive imaging techniques
[magnetic resonance cholangiopancreatography (MRCP)]
has greatly facilitated the diagnosis of PSC (in patients with
Infections IBD).
Potentially infectious agents could mediate development of Autoantibody tests are of little diagnostic significance. IgM
PSC, but to date, there is no evidence for any putative infectious concentrations are increased in about 50% of patients with
agent studied, including viruses and parasitic organisms. advanced PSC. A serum IgG4 level should be measured in
all patients with suspected PSC as it is detected in about 10% biopsy but who have a normal cholangiogram) are described
and associated with a worse outcome if left unrecognized and as having small duct PSC; 616% of the PSC population has
thus untreated. small duct disease. For most part their course of disease is
milder than for large duct disease and favorable prognosis
with regard to patient survival, need for transplantation and
Radiological Features for Most Causes of the development of cholangiocarcinoma may be given. To
Sclerosing Cholangitis date no cases of cholangiocarcinoma have been reported in
small duct disease. Over 10-year follow-up, a quarter of these
The diagnosis of PSC and SSC depends on typical abnormalities
patients subsequently develop typical changes of large duct
shown on cholangiography. The typical cholangiographic
PSC on sequential cholangiography.
findings are diffuse stricturing of intrahepatic and
extrahepatic bile ducts with dilatation of the areas between
strictures causing a beaded appearance of the biliary tree. Autoimmune Hepatitis and Sclerosing
Magnetic resonance cholangiopancreatography (MRCP)
is the investigation of choice over endoscopic retrograde
Cholangitis
cholangiopancreatography (ERCP). Magnetic resonance Patients with simultaneous or sequential PSC and AIH
cholangiopancreatography is noninvasive and does not have been described. This has been reported more often in
involve radiation and is comparable to ERCP for diagnosis children than adults. Overlap should be considered if the
of PSC with good interobserver agreement. Endoscopic aminotransferase level is greater than twice the upper limit of
retrograde cholangiopancreatography should be reserved normal and the serum IgG is elevated. The diagnostic feature
for either therapeutic purposes or to facilitate diagnosis of of prominent interface hepatitis will be seen on the liver
cholangiocarcinoma in those with suspicious lesions on biopsy. Immunosuppression particularly in children appears
MRC. It may still have a place in patients where the diagnosis to be helpful.
remains uncertain after MRCP.
Histology IgG4-associated Cholangitis

Histological examination of the liver is not required to make a Some patients with autoimmune pancreatitis (AIP)/(an
confident diagnosis of primary or secondary cholangitis if the IgG4-associated systemic disease) have biliary strictures
radiological findings support this diagnosis. similar to PSC (IgG4-associated cholangiography). In this
The characteristic early pathological findings of PSC are male predominant disease, serum IgG4 levels are variably
periductal onion-skin fibrosis and inflammation, with increased. Importantly, the disease is responsive to steroids.
portal edema and bile ductular proliferation resulting in A retrospective study showed elevated IgG4 levels in a small
expansion of portal tracts. The early changes of any cause of (9%) proportion of patients with PSC. This untreated subgroup
sclerosing cholangitis may be focal and nonspecific. Later, the appears to have a more severe disease course with higher
fibrotic process progresses leading to the end-stage of biliary bilirubin and a normal alkaline phosphatase and shorter time
cirrhosis, but the severity of fibrosis varies throughout the to transplant, than PSC patients with a normal IgG4 level. It
liver and thus staging degree of fibrosis with liver biopsy is is possible that these patients really have IgG4-associated
very unreliable. In advanced cases loss of bile ducts can lead systemic disease and therefore may respond to corticosteroid
to a vanishing bile duct syndrome. Histology is diagnostic therapy, but this needs further study.
in only one-third although in another third there may be IgG4-associated disease is a multisystem disorder, which
findings suggestive of biliary disease. Patients with small may also involve the kidneys, lungs, thyroid, retroperitoneal
duct sclerosing cholangitis have normal cholangiograms with lymph nodes, salivary glands and aorta.
characteristic liver histology of PSC.
Special Populations MANAGEMENT OF COMPLICATIONS

The management of the nonhepatic complications of
Small Duct Primary Sclerosing Cholangitis cholestasis, which may occur in PSC (pruritus, fatigue, and
Patients who have cholestatic liver biochemistries and features osteoporosis) are discussed elsewhere (see chapter 25:
consistent with the diagnosis of sclerosing cholangitis on liver primary biliary cirrhosis).
Dysplasia and Cancer Table 4: Relative risk for first cancer after diagnosis of primary
sclerosing cholangitis (excluding first year after its diagnosis)
Patients with UC have an increased risk of colorectal cancer,
Site of cancer Relative risk 95% confidence ratio
associated with the longevity of disease and the extent of
colitis. The risk of colonic dysplasia and colorectal cancer is Esophagus 0.0 034.2
enhanced in those with coexistent PSC. Thus patients with Stomach 2.5 0.114.1
UC and PSC should undergo regular annual surveillance Small intestine 0.0 056.8
colonoscopy once the diagnosis of PSC is made. This risk Colorectal 6.8 2.714
continues after liver transplantation and increases with time.
Hepatobiliary 106.9 72.6151.7
Ursodeoxycholic acid (UDCA) treatment in patients with
Pancreas 9.7 228.4
PSC and UC may decrease the risk of colorectal dysplasia and
colorectal cancer. Source: Modified from Bergquist A, et al. 2002.
Cholangiocarcinoma (CCA) will complicate the clinical
course in 830% of adult patients with PSC, and can develop in Other Biliary Complications of
either the intra- or extrahepatic bile ducts. A third of patients
with PSC who develop cholangiocarcinoma are diagnosed
Sclerosing Cholangitis
within 1 year of the diagnosis of their PSC. The incidence of
CCA is approximately 0.51.5% per year in those with large
Biliary Strictures
duct PSC. Dominant strictures of major bile ducts may develop in
Symptoms of CCA are nonspecific and include jaundice, patients with PSC and with time they may cause biliary
weight loss, abdominal pain, and rarely with recurrent obstruction and severe cholestasis, but the exact prevalence
cholangitis. Early detection of cholangiocarcinoma is difficult. is unknown there being no population-based studies.
Unfortunately, computed tomography, ultrasonography Endoscopic retrograde cholangiopancreatography can be
and MRCP have poor sensitivity for detection of CCA. An used for balloon dilatation or stent placement in the treatment
elevated CA19-9 (>200U/L), weight loss as well as presence of of dominant strictures providing relief of symptoms and
a dominant bile duct stricture are suggestive of malignancy. possibly to improved survival without transplant. Dominant
However, CA19-9 has no role in cancer surveillance in PSC strictures are associated with recurrent bacterial cholangitis as
as CA19-9 can be elevated in benign biliary disease as well as well as biliary stones. Patients should be given preprocedure
other malignancies including pancreas, colon, stomach, and antibiotics, such as the quinolone, ciprofloxacin 750 mg given
gynecological cancers. by mouth approximately 2 hours before the investigation, as
Cholangiocarcinoma may be indistinguishable on injecting contrast into an obstructed duct with poor drainage
cholangiogram from a benign dominant stricture. Diagnosis could precipitate acute cholangitis. Other risks at ERCP
is difficult and brush cytology and endoscopic biopsy may include pancreatitis, hemorrhage, or bile duct perforation.
need to be performed. Survival is poor with a median time
to death of 7 months from diagnosis. Most patients are
treated palliatively, which may include biliary stenting and
Recurrent Bacterial Cholangitis
photodynamic therapy. It is rare in PSC in the absence of previous biliary
Other hepatobiliary malignancies particularly of the gall interventional procedures. It should be treated with the
bladder and hepatocellular carcinoma are frequently seen immediate administration broad-spectrum antibiotics such
in PSC (Table 4). Gallbladder polyps are a risk factor for as ciprofloxacin. Prophylaxis using oral quinolones may
gall bladder cancer in PSC. Hepatocellular carcinomas are decrease the frequency of episodes in those with recurrent
treated conventionally within the accepted criteria. The risk attacks. All patients should know to rapidly report to casualty
of pancreatic carcinomas may also be increased in PSC. (emergency room) should they develop fever and/or chills.
Hepatobiliary malignancy is only detected in a proportion
of those in whom it is suspected: this needs to be taken into
account when performing and interpreting cholangiograms. Biliary Stones
Additional risk factors for hepatobiliary cancer include Choledocholithiasis probably occurs secondary to chronic
smoking, long duration of IBD and male sex. bacterial contamination of bile and characteristically the
stones are small brown bile pigment bile stones. Stones and the great variability of the disease, models are of less use
sludge may be removed by therapeutic ERCP. in individual cases than in primary biliary cirrhosis. These
models do not identify the patient with cholangiocarcinoma.
MEDICAL TREATMENT
HEPATIC TRANSPLANTATION
Generally medical therapies including, immunosuppressive
agents and antifibrotic therapy have proved to be Liver transplantation is still the only treatment option for
disappointing in the treatment of PSC. PSC in those who develop advanced disease. Indications
Ursodeoxycholic acid is a naturally occurring bile acid that and timing of transplantation is difficult as the disease
improves liver biochemistries in PSC, but its effect on survival course is unpredictable. Traditionally the presence of
remains controversial. A recent randomized control study cholangiocarcinoma is a contraindication to transplant; it
employing higher doses 2530 mg/kg UDCA in patients with is usually diagnosed late and patients often have advanced
advanced PSC was prematurely halted because of greater liver disease. One study shows a 5-year-survival post-
need for liver transplant and death in the UDCA group. transplant for those with cholangiocarcinoma of around
Ursodeoxycholic acid may however decrease the risk of 35% in whom CCA was discovered incidentally at operation,
developing colorectal dysplasia in patients with PSC and UC. but the prior diagnosis of CCA is considered an absolute
The use of UDCA may reduce the incidence of biliary tract contradiction to liver transplantation, unless the tumor is
cancers but this needs further study. small and brachytherapy has been given. Recurrent PSC
There is little evidence that steroids are beneficial in following liver transplantation is well-recognized and seen
patients with PSC, except for those patients with features of in 1020% of those who undergo transplantation within 5
both PSC and AIH, which is more commonly observed in years; it is more common in males with an intact colon or
children. in those who require high-dose prednisone therapy early
Steroids are beneficial in those with IgG4-associated AIP/ post-transplant. However, adequate immunosuppression
AIC; hence, the need to screen for this in all with presumed should be maintained after orthotopic liver transplantation
PSC. as rejection is a risk factor for recurrent disease. There are no
known therapies to delay the onset or slow the progression of
rPSC, but it is rarely responsible for failure of the transplanted
PROGNOSIS organ.
The results of liver transplantation are good with a
The estimated median survival from diagnosis to death or liver 5-year-survival post-transplant of 7580%. Gastrointestinal
transplant is 9.612 years in all patients with PSC. Patients symptoms present post-transplantationthey rarely improve
who are asymptomatic at diagnosis, the majority of whom will and in most they worsen or stay stable. Ulcerative colitis may
develop progressive disease, have a mean survival rate of 88% even develop de novo in patients with PSC post-transplant.
at 5 years and greater than 70% at 16 years after diagnosis. Inflammatory bowel disease may become more severe post-
Those who are symptomatic at diagnosis have shorter transplant prompting proctocolectomy and 510% of those
survival. A persistently raised serum bilirubin for more than 3 with IBD develop colorectal cancer after liver transplantation.
months duration from diagnosis is an independent risk factor Thus annual surveillance colonoscopy is recommended in
correlating with poor outcome and high risk of CCA. this particularly high-risk group.
Survival models have been used to evaluate therapy, to
stratify patients in clinical trials and to define the time for
liver transplantation. The Mayo Clinic model is based on 406 SECONDARY SCLEROSING
patients and uses serum bilirubin, histological stage and the
presence of splenomegaly. It may be particularly useful in CHOLANGITIS
early cases. The Swedish prognostic model is based on 305
There are multiple causes, the most common of which are as
patients and uses age, serum bilirubin and histological stage
follows.
as bad prognostic features. Cholangiocarcinoma was found
at surgery in 8%, and 44% were asymptomatic at the time of
diagnosis. Vascular Cholangitis
A simple Child-Pugh classification was found to be a
The bile ducts are richly supplied by the hepatic artery, which
satisfactory alternative to disease-specific models in both
forms a peribiliary vascular plexus. Interference with blood
research studies and clinical decision-making. Because of
flow in these very small vessels leads to ischemic necrosis

of the bile ducts, both extra- and intrahepatic, and to their
ultimate disappearance. Injury to hepatic arterial branches,
for instance during cholecystectomy or hepatic artery
thrombosis or ischemic reperfusion injury post-transplant
leads to ischemia of the duct wall, damage to the ductal
mucosa and entry of bile into the duct wall so causing fibrosis
and stricture.
Biliary ischemia secondary to intimal thickening of hepatic
arterioles is a rare feature of chronic allograft rejection in
man.
Diffuse small vessel arteritis, part of a systemic vasculitis,
can be followed by bile duct loss. Other causes of reduced
blood flow in the hepatobiliary plexus include portal vein
thrombosis, hereditary hemorrhagic telangiectasia and
patients with severe sepsis in the ICU.
Floxuridine (5-FUDR) can be infused by pump into Fig. 2: Histologyliver biopsy showing typical onion skin periductal
the hepatic artery for the treatment of colorectal hepatic fibrosis, typical of sclerosing cholangitis
metastases. Biliary strictures can follow. The picture
resembles PSC. Immunodeficiency-related
Opportunistic Cholangitis
Bacterial Cholangitis
Opportunistic organisms can invade the bile ducts causing
Bacterial cholangitis is rare in the absence of mechanical, the picture of sclerosing cholangitis. There is usually a
usually partial, biliary obstruction. The primary source background of immunodeficiency, which may be congenital
of infection is often unknown. The damaged ducts show or acquired.
infiltration of their walls with neutrophils with destruction In the neonate, cytomegalovirus and reovirus type III have
of the epithelium. Ultimately, the bile duct is replaced by a a tropism for bile epithelium and an obliterative cholangitis
fibrous cord. Causes include choledocholithiasis, biliary results.
strictures and stenosis of biliary-enteric anastomoses. The Associated immunodeficiency syndromes include familial
bile duct loss is irreversible and a point comes when, even combined immunodeficiency, hyperimmunoglobulin
if the cause of the biliary obstruction can be removed, for M immunodeficiency, X-linked immunodeficiency and
instance common duct stones, the bile duct destruction with immunodeficiency with transient T-cell abnormalities. The
biliary cirrhosis persists. usual causative organism is cytomegalovirus or cryptosporidium
If the common bile or hepatic duct is surgically alone or in combination. Cryptococcus, Candida albicans and
anastomosed to a stagnant loop of duodenum, continued Klebsiella pneumoniae may be associated.
access of the biliary system to gut organisms can result in Abnormalities of the biliary system are associated with
bacterial cholangitis without biliary obstruction (sump AIDS. In one series, 20 of 26 patients with AIDS and biliary
syndrome). A similar sequence may follow sphincteroplasty. problems had markedly abnormal cholangiograms. In 14
The sclerosing cholangitis associated with infection by of these, the pattern was that of intrahepatic sclerosing
the Chinese liver fluke (Clonorchis sinensis) is related to cholangitis with or without papillary stenosis. The combined
secondary infection, usually with E. coli, following biliary occurrence of intrahepatic duct disease with papillary
obstruction by the fluke. Multiple pyogenic abscesses, stenosis is unique to AIDS cholangiography and has not been
particularly problematic in those with recurrent pyogenic reported in PSC.
cholangitis may lead to cholangiographic similarities with Primary sclerosing cholangitis and AIDS cholangiopathy
sclerosing cholangitis (Fig. 2). differ according to the inflammatory infiltrate surrounding
the diseased bile ducts. In PSC, it is rich in T4-lymphocytes, 10. Charatcharoenwitthaya P, Lindor KD. Recurrence of primary
the subpopulation specifically depleted in patients with AIDS. sclerosing cholangitis: what do we learn from several transplant
centres? Liver Transpl. 2008;14(2):130-2.
11. Cholongitas E, Shusang V, Papatheodoridis GV, et al. Risk factors
Drug-related Cholangitis for recurrence of primary sclerosing cholangitis after liver
Caustic cholangitis is caused by the injection of a scolicidal transplantation. Liver Transpl. 2008;14(2):138-42.
solution into a hydatid cyst. Only a part of the biliary tree is 12. Kaplan GG, Laupland KB, Butzner D, et al. The burden of large
usually affected. Within months the strictures can result in and small duct primary sclerosing cholangitis in adults and
jaundice, biliary cirrhosis, and portal hypertension. children: A population-based analysis. Am J Gastroenterol.
2007;102(5):1042-9.
13. Lindor KD, Kowdley KV, Luketic VA, et al. High dose
Histiocytosis X ursodeoxycholic acid for the treatment of primary sclerosing
cholangitis. Hepatology. 2009;50(3):808-14.
A cholangiographic picture identical with that of sclerosing
14. Loftus EV, Harewood GC, Loftus GC, et al. PSC-IBD: a unique
cholangitis may complicate histiocytosis X. The biliary
form of inflammatory bowel disease associated with primary
lesions progress from a hyperplastic to a granulomatous,
sclerosing cholangitis. Gut. 2005;54(1):91-6.
xanthomatous and, finally a fibrotic stage. Clinically, the
15. MacLean AR, Lilly L, Cohen Z, et al. Outcome of patients
picture resembles PSC.
undergoing liver transplantation for primary sclerosing
cholangitis. Dis Colon Rectum. 2003;46(8):1124-8.
16. MacFaul GR, Chapman RW. Sclerosing cholangitis. Curr Opin
BIBLIOGRAPHY Gastroenterol. 2004;20(3):275-80.
17. Maggs JR, Chapman RW. An update on primary sclerosing
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25
cHAPTER
Primary Biliary Cirrhosis
Nurdan Tzn, Murat Saru
INTRODUCTION The reason for gender imbalance is unknown. There may

be an increased exposure to disease triggering infections,
Primary biliary cirrhosis (PBC) is a chronic cholestatic altered response to various antigenic stimuli or a difference
liver disease characterized by gradual destruction of determined by sex hormones leading from the loss of
small and medium size intrahepatic bile ducts: a process tolerance to the autoantigen to overt liver disease, in women.
which eventually leads to progressive cholestasis and end- Chromosomal abnormalities have also been suggested.
stage liver disease. It is assumed to be a T lymphocyte- Epidemiological data about the prevalence and incidence
mediated autoimmune disease which mostly affects of PBC worldwide is scarce. An incidence of 0.749 per
middle-aged women. The serologic hallmark of PBC is the million-population per year and a prevalence of 6.7402 per
antimitochondrial antibody (AMA), which may be detected million-population have been reported in recent studies
in 9095% of the patients. There is marked variation in the incidence and prevalence
Giovanni Battista Morgagni first described the of PBC worldwide. The disease is more prevalent in the
histopathological features of biliary cirrhosis in 1761. The northern parts of Europe and the United States but less
name of PBC was coined by Dauphine and Sinclair in 1942. common in Asia and populations of African descent. The
In 1950, Ahrens further defined the features of the disease as continent with the lowest prevalence is Asia with estimated
progressive jaundice with pruritus and hepatosplenomegaly annual incidence of 0.340.42 per 100,000 population and a
in middle-aged women. Rubin revealed that main histological prevalence of 2.0 per 100,000 population in Japan
lesion was nonsuppurative destructive cholangitis in 1965. The highest rates for PBC were reported from a Spanish
Walker identified disease-specific serological marker AMA in area, Sabadell. The race difference may have an impact on
the same year. The diagnosis of the disease became easier and disease occurrence. No particular environmental agent has
more confident after these discoveries. Despite all studies been detected in areas where the disease showed geographical
carried out so far, the etiology of the disease is still unclear. clusters.
PBC is often considered a model autoimmune disease related A recent review indicates that incidence and prevalence
to multiple factors, which include genetic, environmental, of PBC have increased worldwide. However, this fact may
and autoimmune processes. be linked to earlier detection of the disease, improvement
in diagnostic technologies, increased awareness of the
physician, and increased number of elderly people under
EPIDEMIOLOGY the risk of developing the disease. Furthermore, recent
studies also suggest that due to early diagnosis and successful
Primary biliary cirrhosis is a rare disease with a prevalence management of the condition, the number of liver transplants
of less than 1/2,000, but it is an important cause of chronic for PBC is falling both in Europe and North America.
cholestatic liver disease. It is most frequently a disease of Natural history of PBC encompasses a wide spectrum of
women in various ethnic and racial populations. Women conditions ranging from asymptomatic, stable, or slowly
account for 7590% of patients with PBC with a 10:1 female- progressive disease to rapidly progressive clinical picture. In
to-male ratio. Male patients with PBC have similar disease asymptomatic patients with AMA positivity, the progression
course to that of females with the exception that males are of the disease is relatively slow even if they have histologic
more likely to develop hepatocellular carcinoma. PBC is features compatible with PBC at the time of diagnosis. When
generally observed between the ages of 3065, but younger the patient develops symptoms and remains untreated, the
cases or elderly patients over 90 years have been reported. It median survival usually ranges from 5 to 12 years. Moreover,
is rarely observed in teenagers. the median survival from the time of diagnosis is 7.5 years for
symptomatic and 16 years for asymptomatic patients. Many Environmental factors may also have some effect on the
authors believe that ursodeoxycholic acid (UDCA) therapy development of PBC. In some geographic regions, such as
has considerably improved the natural history of PBC. Northeast England and New York City, the disease may have
much higher prevalence rates, which may be associated with
toxic environmental exposure. Smoking rates have been
ETIOLOGY AND PATHOPHYSIOLOGY found higher in patients with PBC than in controls. Lifestyle
may affect the development of the disease. Other external
The exact pathogenic mechanism of the disease and the bile environmental factors, such as xenobiotics, infections, toxins
duct damage is incompletely understood but appears to (halogenated hydrocarbons) may stimulate T lymphocyte
involve environmental triggers and genetic factors. cytokine response. Cross reactivity with self-antigens may
In a recent review Selmi et al. mentioned three important develop in circulation in response to a variety of infections
observations related to the pathogenesis of PBC: causing molecular mimicry. General anesthesia, previous
1. Antimitochondrial antibody positivity appears before urinary tract infections, previous history of tonsillectomy
liver disease develops, which implicates that loss of and cholecystectomy, nail polishes, toxic wastes, and repro
tolerance to mitochondrial autoantigen is an early event ductive hormone replacement all have been suggested to be
and could be independent of the development of liver associated with the development of PBC.
disease. There is a genetic predisposition, which is evidenced by
2. Mitochondrial autoantigen exists in all nucleated body the family clustering and high concordance of monozygotic
cells but the immune response in PBC targets only the twins. Studies have shown that the prevalence of the disease
epithelial cells of the intrahepatic bile ducts. is 100 times higher in first degree relatives than in the general
3. After transplantation, the disease may recur supporting population. When the disease affects different generations,
the fact that autoantigenicity of bile duct epithelial cells is the second generation usually presents earlier and tends to
not restricted to PBC. have a more rapidly progressive course. On the other hand,
Table 1 shows the evidences supporting the association healthy family members of PBC patients are more likely to
of PBC with an autoimmune background, and Table 2 sum have an impaired T-cell regulation and increased number of
marizes the evidences against autoimmune pathogenesis. circulating autoantibodies than controls.
Several candidate genes have been investigated to show
Table 1: Evidences supporting autoimmune mechanism* any association with disease susceptibility, progression
and prognosis. Major histocompatibility complex (MHC)
Humoral and cellular immune system abnormalities (elevated serum levels class I molecules are not associated with susceptibility
of immunoglobulins, mainly immunoglobulin M) to PBC. In contrast, allelic variations in MHC class II
Presence of autoantibodies (antimitochondrial antibody positivity) (DR, DQ) components of the innate and of the adaptive
Presence of regional lymph nodes immune systems have been shown to be associated with the
Appearance of granulomas in the liver susceptibility to PBC. Briefly, it has been assumed that like any
Impaired regulation of B and T lymphocytes (autoreactive T cells)
other autoimmune disease, PBC is based on two factors: (i)
genetic susceptibility and (ii) a triggering event that initiates
Autoimmune comorbidities (Sjgren syndrome, scleroderma, CREST
syndrome, thyroiditis)
the autoimmune attack on bile duct cells. Table 3 lists the data
supporting genetic predisposition.
Molecular mimicry model which seems to be important in the pathogenesis
The pathognomonic serological hallmark of PBC is the
Association of major histocompatibility complex with primary biliary AMA. This highly disease-specific autoantibody is found in 90
cirrhosis
Female predominance
*Features shown according to Witebskys criteria, as modified by Rose and Table 3: Data supporting the genetic predisposition
Bona
High disease concordance in monozygotic twins
Table 2: Evidence against autoimmune pathogenesis in primary Family clustering of the disease
biliary cirrhosis
Increased prevalence of other autoimmune conditions in PBC patients and
In animal model, PBC cannot be developed by autoantibody transfer their family members
No correlation exists between the titer of autoantibody and disease severity Different prevalence of the disease between races
No therapeutic benefit from immune-suppressive agents Allelic variations in major histocompatibility complex class II (DR, DQ),
which affect the development and progression of the disease
*Features shown according to Witebskys criteria, as modified by Rose and
Bona Genetic variability in disease progression
Primary Biliary Cirrhosis 231
95% of patients with PBC with specificity close to 100% when are progressively destroyed and there is concomitant
tested with recombinant antigens but less than 1% of normal development of fibrosis leading to cirrhosis within 1020
controls. AMA can be detected in circulation at the preclinical years.
phase years before the advent of any clinical manifestation or A second form is characterized by features of autoimmune
laboratory findings. They target four principal autoantigens hepatitis (AIH) and a more severe course resulting in early
known as the M2 subtype of mitochondrial autoantigens: development of cirrhosis.
1. E2 subunits of the pyruvate dehydrogenase complex In the third form called premature ductopenic variant
(PDC-E2). which affects 510% of patients, there is a very rapid onset
2. Branched chain 2-oxo-acid dehydrogenase complex. of ductopenia and severe icteric cholestasis, which rapidly
3. Ketoglutaric acid dehydrogenase complex. progresses to cirrhosis in less than 5 years.
4. Dihydrolipoamide dehydrogenase-binding protein. Fatigue and pruritus are the two most common symptoms
These autoantigens participate in oxidative phosph in patients with PBC.
orylation (a process occurring in the inner mitochondrial Fatigue is the first reported symptom and can be present
membrane by which ATP is formed) and have a great deal in up to 80% of patients. It is a nonspecific symptom and
of homology. The major autoepitope recognized by both T can be associated with a variety of clinical conditions, such
and B cells is the inner lipoyl domain of the PDC-E2. The as depression and obsessivecompulsive behavior. There
M2 epitope is detectable in cholangiocytes undergoing is no correlation between fatigue and the stage of the liver
apoptosis, and in the luminal domain of the biliary cells disease, the magnitude of liver enzyme elevation or the
of the small bile ducts. Anti-M2 is the most used subtype duration of therapy. Fatigue can cause severe disability in
in regular diagnostic tests. Other AMAs (anti-M4, anti-M8, some patients. Its etiology is unclear. It has been linked
and anti-M9) previously described and linked with the to sleep abnormality (daytime somnolence), autonomic
severity of the disease are most likely artefacts of the dysfunction (hypothalamicpituitaryadrenal axis), anemia,
methods used to detect them. hypothyroidism, muscle impairment, altered manganese
The activated immune system and autoimmunity cause homeostasis within the CNS, increased production of
the destruction of small and medium size bile ducts. This proinflammatory cytokines and depression (decreased
process is mediated by activated CD4 and CD8 lymphocytes. release of serotonin).
After bile ducts are destroyed, it is well-established that Pruritus is seen in 2070% of patients with PBC. It is a
the regeneration of bile ducts is either not possible or more specific symptom for PBC and usually occurs months
inefficient. Impairment of normal bile flow causes retention to years earlier than jaundice. Pruritus can be local or diffuse.
of toxic substances, which are normally excreted into bile. The According to estimates, 10% of patients experience severe
retention of toxic substances, such as bile acids and copper pruritus impairing the patients quality of life. It is usually
can cause a further destruction of the bile ducts and the worse at night than daytime and often exacerbated by heat and
hepatocytes. After loss of bile ducts, intrahepatic retention contact with coarse garments. Pregnancy can make it worse.
of detergent bile acids occurs and causes liver damage by Pruritus may cause sleep deprivation and severe emotional
destructing cell organelles and membranes. The progressive disturbance sufficient to necessitate liver transplantation.
loss of intrahepatic bile ducts leads to cholestasis, cirrhosis The underlying cause of this symptom is not known. Several
and liver failure over the years. hypotheses have been proposed. The most notable ones
are bile acid accumulation and increased opioidergic tone.
Pruritogenic substances are thought to be produced in the
CLINICAL MANIFESTATIONS liver and excreted in bile which is impaired in cholestasis.
However, in many patients with cholestasis and elevated
Primary biliary cirrhosis can nowadays be diagnosed at an bile acid levels, there is no pruritus. Likewise, pruritus may
earlier stage due to the improvement of diagnostic technology subside despite high levels of bile acids. So pruritus appears
and widespread use of checkup programs. Most of the unrelated to the deposition of bile acids in the skin. It has
patients with PBC are incidentally diagnosed during a routine been claimed that increased opioidergic tone appears to be
blood evaluation when elevated alkaline phosphatase level is the major mechanism. The height of the bilirubin level is
detected. Fifty-to-sixty percent of patients have no symptoms proportionally related to the production of these peptides.
at the time of diagnosis. In some patients, the diagnosis is Opioid antagonists have been shown to alleviate pruritus in
made in the workup of other autoimmune diseases. some studies. Pruritus may diminish over time, especially
Three major forms of PBC have been described in the after development of cirrhosis and liver failure. Finally, an
literature. In the typical or classical form small bile ducts important association between pruritus and circulating
concentrations of the extracellular lysophospholipase auto DISEASES ASSOCIATED WITH PRIMARY

taxin has been recently reported.
Once cirrhosis develops, symptoms related to portal BILIARY CIRRHOSIS
hypertension and liver failure are observed. The development
Primary biliary cirrhosis has been associated with some
of hepatocellular carcinoma in PBC patients with cirrhosis is
other autoimmune diseases including the tissues of secretory
similar to other types of cirrhosis and warrants surveillance
systems, such as Sjgrens syndrome and chronic thyroiditis.
according to guidelines.
Thyroid dysfunction often predates the diagnosis of PBC. In
Other uncommon symptoms of PBC include right
that sense PBC has been referred to as a dry gland syndrome.
upper quadrant discomfort, rheumatic symptoms with
Other conditions commonly associated with PBC are:
classical rheumatoid arthritis developing in 510% of cases,
Sicca syndrome with xerophthalmia, xerostomia
keratoconjunctivitis (dry eyes) and/or xerostomia (dry
Dental caries
mouth), cutaneous calcinosis, Raynauds phenomenon, and
Dysphagia
dysphagia. Cognitive impairment has also been reported in
Tracheobronchitis
PBC patients.
Dyspareunia
Physical examination is usually normal if liver cirrhosis
CREST syndrome (calcinosis cutis, Raynauds pheno
is absent. In the early stages, examination findings are
menon, esophageal dysmotility, sclerodactily and telang
nonspecific. At advanced stages, excoriations of the skin,
iectasia) rarely seen in PBC patients
xanthelasma, xanthoma or stigmata of advanced liver disease
Reflux disease and related complications
such as arterial spider, palmar erythema, ascites, temporal
Celiac disease, often asymptomatic, present in 6% patients
and proximal muscle wasting, and peripheral edema may be
Raynauds syndrome
present. Jaundice is a later manifestation of the disease but
Arthritis with rheumatoid factor positivity (15%)
may be seen at presentation in some patients. On occasion
Inflammatory bowel disease, namely ulcerative colitis.
patients may present for the first time with a variceal
hemorrhage due to portal hypertension of noncirrhotic
or cirrhotic origin. Nodular regenerative hyperplasia is
associated with obliteration of the portal venules and may SPECIAL CASES
lead to portal hypertension in some of these patients. Physical
examination may reveal hepatomegaly, hyperpigmentation, Antimitochondrial Antibody-negative
splenomegaly, arterial spiders and jaundice. Hepatomegaly Primary Biliary Cirrhosis
can be found even in asymptomatic patients but splenomegaly
is less common and usually occurs in late stages secondary Five percent of the patients who have clinical, biochemical
to portal hypertension. As stated above, patients with PBC and histologic features of PBC, but who are negative for
may have Sicca syndrome (xerophthalmia: dry eyes and AMA are named AMA-negative PBC. This group of patients
xerostomia: dry mouth) in about 5075% of cases and very almost always has antinuclear antibody (ANA) and/or anti-
rarely Kayser-Fleischer rings. smooth muscle antibodies (ASMA) positivity and identical
Metabolic bone disease can occur in PBC. Both osteoporosis disease course with AMA-positive PBC patients. This category
and osteomalacia can be observed but osteoporosis is the has been referred by a variety of terms, including immune
most frequent bone disorder occurring in up to one-third of cholangiopathy, autoimmune cholangiopathy, immune
the patients. The relative risk of osteopenia, i.e. osteoporosis cholangitis, and autoimmune cholangitis.
greater than expected for gender and age, is 4.4. Both Some authorities do not accept the concept of overlap in
decreased osteoblastic activity and increased osteoclastic this situation and consider this syndrome to be AMA-negative
activity contribute to the development of osteoporosis in this PBC. Furthermore, some of these patients have detectable
setting. Vitamin D metabolism is normal in patients with PBC AMA when using the most sensitive assays. A liver biopsy is
except in patients with advanced disease and cholestasis, but mandatory to diagnose AMA-negative PBC. The finding of
malabsorption of both calcium and vitamin D may occur. granulomas on liver biopsy specimen confirms the diagnosis.
On the other hand, once jaundice is present, fat-soluble Circulating Immunoglobulin M (IgM) levels are lower in
vitamin deficiency and malabsorption (e.g. steatorrhea AMA-negative PBC compared to AMA-positive patients.
and weight loss) may occur and patients may experience The disease course and concordant autoimmune
symptoms related to these conditions. conditions in both AMA-positive and AMA-negative PBC are
usually identical. Biochemical pattern of cholestatic enzymes Table 4: Diagnostic criteria of primary biliary cirrhosis
and histopathological findings are also very similar in this
Biochemistry: Biochemical evidence of cholestasis for at least 6 months
group. A recent study has shown that there was no difference
(high ALP levels)
between AMA-negative and positive patients in terms of
Serology: Presence of antimitochondrial antibody
response rates to UDCA treatment.
A group of patients with positive AMA (>1/40) and normal Pathology: Histopathological evidence of nonsuppurative cholangitis and
destruction of small- or medium-sized (interlobular) bile ducts on liver
alkaline phosphatase values have been reported in a small
biopsy
study. In 10-year follow-up, 82% of these patients developed
cholestasis, and 75% became symptomatic. Patients with AMA
and normal biochemical tests are at risk of developing true PBC.
to-moderate elevation of the aminotransferases (ALT and
These patients are recommended to be followed prospectively
AST) may be found in most patients. If transaminase levels
on annual basis with reassessment of biochemical testing.
are 10 times normal or higher with elevated ALF the overlap
syndrome (AIH plus PBC) should be considered in the
Overlap of Autoimmune Hepatitis with differential diagnosis. In patients with both features of AIH
and PBC, IgG levels are markedly increased. In the premature
Primary Biliary Cirrhosis ductopenic variant, cholestasis is rapidly progressive and
Overlap of AIH with PBC refers to simultaneous occurrence there is associated elevation in both high-density lipoprotein
of AIH in a patient who was previously diagnosed as AMA- (HDL) and low-density lipoprotein (LDL) fractions, as well
positive PBC. The condition can be diagnosed by using a as the nonatherogenic lipid particle lipoprotein X. Elevated
scoring system to support the presence of AIH/PBC overlap. If immunoglobulin levels, mainly IgM are also found in PBC.
two of the three criteria are present, the diagnosis of AIH/PBC Cholesterol levels may be increased. Interestingly, HDL is the
overlap can be confirmed. These three criteria are: (i) ALT most prominent fraction. Elevated HDL levels may explain why
elevation more than five times the upper limit of normal, (ii) PBC patients do not have an increased risk for atherosclerosis
IgG elevation more than two times upper limit of normal and/ even though they have much more elevated cholesterol levels
or the presence of ASMA, and (iii) liver pathology disclosing than patients with atherosclerosis. Serum bilirubin levels are
periportal or periseptal inflammation. usually within normal limits at the early stages but with disease
Recent studies suggest that response to UDCA therapy is progression both direct and indirect fractions are increased.
similar in both groups of patients with AIH/PBC overlap and Serum bilirubin is an excellent predictor of survival and plays
PBC alone. a major role in the timing of transplantation. Patients with PBC
have also high erythrocyte sedimentation rate. When cirrhosis
develops, an elevated bilirubin level, a prolonged prothrombin
DIAGNOSIS time, and a decreased albumin level can be found. Cytopenias
(especially thrombocytopenia) in complete blood counts,
Before establishing the diagnosis of PBC the symptoms of the indicate the development of portal hypertension. Elevated
patients should be carefully evaluated and the patients should levels of ceruloplasmin, bile acids, and serum hyaluronate may
be questioned about the use of medications which may cause rarely be seen in the course of the disease. Rising hyaluronate
cholestasis and mimic PBC. The most common drugs that levels correlate with the serum bilirubin and histologic
cause cholestasis are phenothiazines, synthetic androgenic worsening of the disease.
steroids, trimethoprim-sulfamethoxazole, tolbutamide, and Antimitochondrial antibody is the serological hallmark
occasionally diclofenac, oxacillin and ampicillin. The diagnosis and pathognomonic laboratory finding of PBC. This
of PBC is based on the three criteria which are shown in Table 4. marker is found in nearly 95% of patients. Apart from
The expert consensus recommends that the diagnosis of immunofluorescence test, which is more operator-dependent
PBC is established when two of the three criteria are present. and can give false-positive or false-negative results, most
assays are 95% sensitive and 98% specific for PBC. Monitoring
the AMA titer is not useful in assessing the response to therapy
Laboratory Findings in PBC. ANA and ASMA can also be positive. They are found
in almost half of the patients with PBC, and this fact may force
Liver Biochemical Tests the clinician to consider overlap syndromes in the differential
Significant elevation of cholestatic liver enzymes, namely diagnosis of the condition. The presence of ANA in PBC has
ALP, 5 nucleotidase and -glutamyl transpeptidase is almost been linked to a poorer prognosis and severity of the disease
always seen in patients with classical PBC. In addition, mild- but this statement needs to be confirmed in further studies.
Imaging Table 5: Histological stages of primary biliary cirrhosis
Ultrasound imaging of the liver and biliary tree is necessary Stage 1 (portal stage): Portal inflammation, bile duct abnormalities or both
are present
in patients who have biochemical evidence of cholestasis. If
the biliary system is normal on ultrasound and the patient is Stage 2 (periportal stage): Periportal fibrosis is present, with or without
found to be AMA positive, then no further imaging modality is periportal inflammation or prominent enlargement of the portal tracts
with seemingly intact, newly formed limiting plates. This histologic picture
required. If the diagnosis is not certain, cholangiography may is compatible with stage 2 primary biliary cirrhosis.
be needed to rule out primary sclerosing cholangitis or other
Stage 3 (septal stage): Septal fibrosis with active inflammatory, passive
diseases of the biliary tract. Computed tomography scanning or
paucicellular septa, or both are present
magnetic resonance imaging with cholangiopancreatography
may be useful to evaluate liver and biliary tree when the Stage 4 (cirrhosis): Regenerative nodules with various degrees of
inflammation are present
diagnosis is uncertain.
PATIENT MANAGEMENT AND

Histopathology TREATMENT
Liver biopsy is not mandatory when the other two less invasive
diagnostic criteria are fulfilled. However, it is generally agreed There are up-to-date guidelines from the European Association
that liver histology gives the clinician more information for the Study of Liver Diseases and the American Association
about the stage of the disease, its prognosis and helps in the for the Study of Liver Diseases for the management of PBC.
management of the condition. It also enables to rule out other
liver diseases with common signs and symptoms, such as
AIH, nonalcoholic steatohepatitis or drug-induced hepatitis. Medical Therapy
Primary biliary cirrhosis is histopathologically chara The goals of the treatment are to control the symptoms and
cterized by asymmetric nonsuppurative, destruction of to counteract the immunologic attack, which damages the
the interlobular and septal bile ducts within the portal small interlobular bile ducts. A PBC patient with abnormal
tracts and portal tract inflammation with macrophages, liver biochemistry, is a candidate for treatment Specific
polymorphonuclear cells (especially eosinophils) infiltration. therapies may be needed to treat complications of PBC. Liver
The damage first occurs to the basement membrane of the bile
transplantation is the only curative treatment.
ducts accompanied by reactive hyperplasia of the epithelial
Ursodeoxycholic acid is the mainstay of therapy and the
lining. Epithelioid aggregates or granulomas may be found
only disease-modifying agent. UDCA is a hydrophilic bile acid
especially around the bile ducts. Eosinophils and granulomas
that acts through several mechanisms on disease progress.
are also characteristic but not pathognomonic of PBC. Fibrosis
and cirrhosis develop later. The size of the biopsy sample is It expands the hydrophilic bile acid pool and has direct
important. An efficient biopsy sample must have at least 1015 choleretic, anti-inflammatory, and antiapoptotic properties
portal tracts to evaluate cholangitis and ductopenia. Histologic on hepatic epithelia. It is claimed that UDCA may also have
lesions are classified into four stages. Among various staging some immunomodulatory effects. Patients with early disease
systems, which have been developed the most commonly benefit most from UDCA. This improvement is seen in all
used two systems are the ones developed by Ludwig et al. and clinical, biochemical, and histologic parameters. UDCA has
Scheuer et al. Table 5 outlines the histological stages of PBC. been shown to slow the progression of the disease, decrease
In Scheuers classification, stage 1 is referred to as the florid the need for transplantation, and prolong the interval until
duct lesion or chronic nonsuppurative destructive cholangitis. liver transplantation or death. This is further evidenced by
in stage 2, there is proliferation of the small bile ductules. stage the fall in the number of liver transplants for PBC in North
3 is characterized by fibrosis or scarring, and stage 4 is cirrhosis. America and Europe in parallel with the use of UDCA therapy.
If two or more stages are present within the same liver The clinical efficacy and therapeutic effect of UDCA in PBC
sample, then the patient is classified as belonging to the more have been the subject of debate but a recent meta-analysis
severe stage. Figures 1A to C shows histopathological findings addressed these issues and revealed that the risk of death or
in PBC. liver transplantation was reduced by 32% in patients treated
with UDCA compared to placebo.
Studies about the appropriate dose of UDCA in PBC
Endoscopy have shown that the 1315 mg/kg/day doses was superior
When cirrhosis and portal hypertension develops, an upper with respect to biochemical response and Mayo risk score
gastrointestinal endoscopy should be performed to confirm compared to low doses. The therapeutic effect of 1315 mg/
the presence of esophageal varices. kg/day was similar to higher doses.
A B C
Figs 1A to C: Pathologic findings in primary biliary cirrhosis: (A) Lymphoid cells infiltrate and damage interlobular hyperplastic bile duct with
several apoptotic biliary cells; (B) The epithelium is disrupted and the bile ducts are gradually attenuated; (C) Small epithelioid granulomas in
the parenchyma can appear. (H & E X200)
Courtesy: Prof. Hale Kirimlioglu
The efficacy of this medication in late stages is questionable. pruritus by sequestering bile salts in the intestine. But its
The response to UDCA was defined as serum bilirubin lower effect is relatively slow. There may be a gap period between
than 1 mg/dL, AST less than two times the upper limit of normal, the initiation of the medication and improvement of pruritus.
and alkaline phosphatase less than three times the upper limit of The recommended dose of cholestyramine ranges from 4 to
normal at the end of the first year of therapy. Patients who reach 16 g per day. If cholestyramine is used, 4 hours should elapse
these end points at the end of 1 year of treatment have a similar between cholestyramine intake and UDCA administration
survival rate to the matched control population. There are no and the drug should preferentially be taken before and after
data indicating that UDCA is teratogenic. Indeed there, are the breakfast when the greatest amount of bile is likely to be
many reliable data about UDCA use in pregnancy, which come available for binding. Rifampicin (300600 mg/day) can also
from the experience in patients with intrahepatic cholestasis of be used in the short-term for unresponsive cases, but the
pregnancy. However, in the latter condition, UDCA is mostly mechanism of action is unclear.
used in the third trimester. If a pregnancy is being planned, it Opioid antagonists, such as intravenous naloxone (given
may be wise to stop the drug during the first trimester. UDCA
as a bolus of 0.4 mg followed by 0.2 mcg/kg per minute for 24
therapy does not improve all symptoms of PBC, notably bone
hours), oral nalmefene (60120 mg daily), and oral naltrexone
disease, pruritus and fatigue. One in three patients with PBC
(12.550 mg daily) have been used with success in alleviating
does not respond to UDCA therapy. These nonresponders
cholestatic pruritus. The major inconvenience has been the
may require alternative or additional treatments. Steroids,
opioid withdrawal-like reaction that can occur with this
azathioprine, mycophenolate mofetil, methotrexate,
type of medication. Long-term use of these drugs has also
colchicine, silymarin, budesonide, and bezafibrate (a fibric
acid derivative used to treat hypercholesterolemia) have all been associated with a chronic pain syndrome. American
been used as alternative or adjuvant therapies in such group Association for the Study of Liver Diseases guideline 2009
of PBC patients. However, larger studies with longer follow-up also recommends the use of sertraline, a serotonin reuptake
periods are necessary to assess their efficacy on PBC. There inhibitor (75100 mg daily) if other measures fail. Finally
are other drugs that have been studied but found to be either plasmapheresis has also been performed for patients with
ineffective or toxic. Examples are penicillamine, chlorambucil, severe pruritus intractable to medical treatment.
malotilate, cyclosporine, and thalidomide. In refractory and incapacitating pruritus, a liver
Pruritus is a specific and devastating symptom of transplantation should be contemplated.
PBC. Pruritus is the hardest symptom to treat and mostly Fatigue may be multifactorial in PBC and no established
refractory to medical therapy. Pruritis usually impairs effective treatment exists. Recent studies have shown that
patients quality of life significantly. Cholestyramine and modafinil that is a drug approved for narcolepsy may be effective
antihistamines are used for patients with mild-to-moderate in treating fatigue in patients with PBC. The recommended
pruritus. They should be used with caution in patients with dose of 400 mg/day was found to be well-tolerated and very
encephalopathy. Cholestyramine is effective in improving effective in patients with fatigue and day-time somnolence.
Hypercholesterolemia can be successfully treated by Ultrasound and alpha-fetoprotein in patients with known
statins. On the other hand, UDCA can also decrease total and or suspected cirrhosis
LDL cholesterol levels.
Osteoporosis, which is the most common bone disorder
associated with PBC, can occur up to a third of patients. Expectations for the Future
It should be treated appropriately with calcium, vitamin
D and bisphosphonates. Dry eyes and dry mouth of the In recent years, the pathogenesis and etiology of PBC
sicca syndrome can be treated with artificial tears, anti- have been better understood. Ursodeoxycholic acid has
inflammatory, and immunosuppressant agents. substantially improved the natural history of the disease, but
Treatment of portal hypertension and its complications is some patients with PBC do not respond to treatment. Many
the same as for other cirrhotic patients and liver transplantation novel therapeutic approaches are needed for patients with
should be considered in end-stage cirrhosis. Patients with no or incomplete biochemical response to UDCA. Recently,
cirrhosis have also increased risk for hepatocellular carcinoma, trials with peroxisome proliferator-activated receptor alpha
and they should be screened with ultrasound (and CT if
agonists, farnesoid receptor agonists, biotherapies, such
needed) every 612 months with or without serum alpha
fetoprotein measurement. as anti-CD20, GLP1 receptor agonists and estrogen-alpha
receptor agonists seem to be promising, but further studies
are needed to find alternative treatment modalities in this
Surgical Management of
refractory group.
Primary Biliary Cirrhosis
Liver transplantation is the only effective treatment for PBC
patients with decompensated cirrhosis or liver failure. It CONCLUSION
has considerably improved the survival rates of end-stage
PBC patients. PBC is the sixth leading indication for liver Primary biliary cirrhosis, which is a progressive cholestatic
transplantation in USA. When the disease progresses to liver disease, affecting mostly middle-age women is
cirrhosis or is refractory to medical therapy as evidenced by
nowadays better understood and earlier detected than the
elevated bilirubin level, prolonged prothrombin time and
decreased albumin level, a liver transplantation must be past due to developed diagnostic techniques and awareness
contemplated. In premature ductopenic variant of PBC about the disease. Considered as an autoimmune disease
which is unresponsive to the treatment and progresses rapidly where the main target is the interlobular small bile ducts,
to cirrhosis early transplantation before decompensation the disease has been linked to genetic and environmental
should be planned. Approximately one-fifth of patients will factors. More than half of the patients with PBC are
have a PBC recurrence at 5-year post-transplant. UDCA incidentally diagnosed during a routine blood evaluation.
improves biochemical parameters in PBC patients with
Fatigue and pruritus are two most common symptoms in
evidence of recurrent disease after transplantation but its
PBC patients. For the diagnosis of PBC, two out of three
effect on delaying histological progression is unclear.
criteria must be present: (i) biochemical evidence of
cholestasis with the elevation of alkaline phosphatase for
Long-term Follow-up at least 6 months duration, (ii) presence of AMA, and (iii)
Recommendations from the American Association for the histopathological evidence of nonsuppurative cholangitis
Study of Liver Diseases for PBC patients can be summarized and destruction of small or medium-sized bile ducts on
as follows:
liver biopsy. UDCA with the dose of 1315 mg/kg/day is
Liver tests every 36 months
the major medication and first-line therapy used to slow
Thyroid status (thyroid stimulating hormone) annually
Bone mineral densitometry every 24 years the progression of the disease. Pruritus, osteoporosis, sicca
Monitor vitamin A, D, K annually if bilirubin is greater syndrome, and end-stage liver disease and its complications
than 2.0 mg per dL must be treated accordingly. Transplantation is the
Upper endoscopy every 13 years if cirrhosis or a Mayo risk treatment of choice for the patients with end-stage cirrhosis
score of greater than 4.1 or liver failure.
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26
cHAPTER
Autoimmune Hepatitis
Khin Maung Win
INTRODUCTION CLASSIFICATION
Autoimmune hepatitis (AIH) is an inflammatory condition The classification of AIH into different types is based on serum
of the liver, which can affect patients of all ages, sexes, and autoantibody profiles.
races. It is a rare disease with an estimated prevalence of
approximately 1050 per 100,000 in the Western population
with a strong predominance in middle-aged women. The
Type 1 AIH
disease occurs globally and has an unknown cause. The It is characterized by the presence of antinuclear antibody
pathogenetic understanding is that external triggers like a virus (ANA), antismooth muscle antibody (SMA) or both, and AIH
or an environmental agent induce a chronic self-perpetuating type 1 constitutes 80% of AIH cases. About 25% have cirrhosis
inflammatory process, which may lead to cirrhosis and death at presentation, and association with other autoimmune
or, where available, liver transplantation. The pathogenetic diseases is common (celiac disease, ulcerative colitis, autoim
principle is a loss of tolerance against the patients own liver mune thyroid disease).
and an immune-mediated necroinflammatory condition
of the liver that primarily targets hepatocytes. The clinical,
biochemical, and histological features are heterogeneous. If
Type 2 AIH
untreated, AIH can lead to cirrhosis, liver failure, and death. It is characterized by the presence of anti-liver kidney
Recently published the American Association for the Study microsomal (anti-LKM)-1 and/or anti-LKM-3 and/or anti-
of Liver Diseases (AASLD) 2010 practice guidelines and liver cytosol-1 (LC-1) antibodies. Most patients are children;
British Society of Gastroentrology (BSG) 2011 guidelines for acute severe presentation can occur, and progression to
management of AIH described the etiology, diagnosis, and cirrhosis commonly ensues. Type 2 AIH is a pediatric disease.
treatment of AIH comprehensively. The differences between type 1 and type 2 AIH have been
compared in Table 1.
EPIDEMIOLOGY Type 3 AIH

Autoimmune hepatitis affects both adults and children, Most of these patients are women and have clinical features
presenting more acutely and having a more aggressive course similar to, perhaps more severe than, those of patients with
in the latter. Women are affected more frequently than men type 1 AIH. These patients lack ANA and anti-LKM-1, but have
(sex ratio, 3.6:1) and the disease is seen in all ethnic groups. circulating antibodies to soluble liver antigen/liver pancreas
Autoimmune hepatitis affects 100,000200,000 persons in the antigen (anti-SLA/LP). Soluble liver antigen has recently been
USA and accounts for 4% of transplant recipients in Europe renamed SEPSECS [Sep (O-phosphoserine) tRNA synthase]
and 5.9% in the USA. selenocysteine synthase. Anti-SLA are occasionally found in
Autoimmune hepatitis type 1 (classical AIH) represents patients with AIH who are negative for ANA, SMA and anti-
the most common form of AIH, whereas AIH types 2 and 3 are LKM1. Therefore, these patients might be reclassified as
rare entities. AIH type 3. However, the International AIH group and the
Table 1: Differentiating features of autoimmune hepatitis (AIH) types Pathogenic Pathways

1 and 2 based on autoantibody profiles of patients
The first step in the autoreactive pathogenic immune pathway
Features Type 1 AIH Type 2 AIH
is the selection of autoantigens, which is to be presented to
Characteristic ANA Anti-LKM-1 the CD4+ T lymphocytes. The antigen is cradled in the antigen
autoantibodies ASMA antibody
binding group of the major histocompatibility complex
Anti-actin antibody Anti-LC-1 antibody
Anti-SLA/LP (MHC) class II molecules on the surface of the antigen
antibodies presenting cells (APC).
25% of patients with The CD4+ T helper cell is the principal effector of AIH. It is
negative ANA activated by two signals. The first signal is the presentation of
Geographical variation Worldwide Worldwide the autoantigen by class II molecule of the MHC. The second
Age at presentation All ages Usually childhood and signal is coupling of the CD28 molecule.
young adulthood Activation of the CD4+ T lymphocytes produces cytokines
Sex (F:M) 3:1 10:1 that leads to clonal expansion of liver, infiltrating CD8
Clinical phenotype Variable Generally severe cytotoxic T cell (type 1 cytokine pathway). The activated
CD4+ T lymphocytes also stimulate plasma cells to produce
Histopathological Broad range: mild Generally advanced,
features at disease to cirrhosis inflammation/ antibodies (type 2 cytokine pathway). Both cytokine pathways
presentation cirrhosis cause immune-mediated injuries on the hepatocytes
Treatment failure Rare Common resulting in AIH.
Regulatory (CD4+, CD25+) T cells are important
Relapse after drug Variable Common
withdrawal modulators of the immune response. These regulatory T cells
have suppressor activity on the CD8+ T cell proliferation and
Need for long-term Variable Approximately 100%
maintenance cytokine production with inhibitory actions on the cytokine
pathways. However, regulatory T cells are decreased in
Although immunofluorescence is the traditional method for
number and function in AIH and their failure to modulate
measuring the repertoire of conventional autoantibodies in AIH,
CD8+ T cell proliferation and cytokine production may
many laboratories (especially those in the USA) are increasingly using
ELISA-based methods, especially for anti-LKM antibodies. In relation promote liver injury.
to anti-LKM-1 antibodies, these may be erroneously reported as It is clear from the above description of the current concept
detectable antimitochondrial antibodies. of pathogenic pathways of AIH (Fig. 1) that autoantigens,
Abbreviations: ANA, antinuclear antibody; ASMA, anti-smooth environmental triggers and failure of immune tolerance
muscle antibody; anti-LC, anti-liver cytosol; anti-LKM, anti-liver mechanisms (defect in the Treg cells) in a genetically
kidney microsomal antibody; SLA/LP, soluble liver antigen/liver susceptible host are the key factors of immunopathogenesis.
pancreas antigen; ELISA, enzyme-linked immunosorbent assay Final result of the pathogenic pathway is development
of unregulated T cell-mediated immune attack against
autoantigens and hepatocytes.
Essential components of the immunopathogenesis of AIH
clinical practice guidelines committee of the AASLD have not can be grouped under the following titles:
come into agreement about whether anti-SLA characterize a Autoantigens and autoantibodies
distinct subgroup of AIH as its serologic marker (anti-SLA) is Molecular mimicry
also found in type 1 AIH and type 2 AIH. Genetic factors
Defects in numbers and function of regulatory cells.
IMMUNOPATHOGENESIS Autoantigens and Autoantibodies

Autoimmune hepatitis is characterized by chronic The autoantigens associated with AIH include various
inflammation of the liver, interface hepatitis (based on cytoplasmic enzymes (Table 2). The autoantigen of type 2
histologic examination), hypergammaglobulinemia and AIH is the cytochrome monooxygenase CYP2D6, and it has
production of autoantibodies. It results from the development homologies with many viral proteins.
of an immune response against normal self-antigens (or Many other autoantigens are recognized and reacted by
foreign antigens that resemble self-antigens) that disrupts the autoantibodies associated with AIH resulting in the expansion
immune regulatory network. of autoreactive T cells and autoimmune disease.
Autoimmune Hepatitis 241
Fig. 1: Putative pathogenic pathways of autoimmune hepatitis (AIH)

Abbreviations: MHC, major histocompatibility complex; APC, antigen presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen 4; TNFA, tumor
necrosis factor-alpha; NK, natural killer; TNFRSF6, tumor necrosis factor receptor superfamily member 6
Source: Modified from Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis.
Gastroenterology. 2010;139:58-72.
As discussed earlier, two types of AIH (type 1 and type disease predisposition, clinical phenotype, response to
2) have been categorized basing upon the autoantibodies. therapy and prognosis. The MHC controls the presentation
Autoimmune hepatitis type 1 has ANA or SMA or both, of antigens to the immune system and thereby immune
whereas AIH type 2 has anti-LKM-1 and/or anti-LC-1. Anti- activation. DRb is a polypeptide chain of the class II MHC
SLA can be present in type 1 and type 2 AIH. molecules, which presents antigen to CD4+ T lymphocytes.
Susceptibility to AIH is associated with genes withiwn the
human leukocyte antigen (HLA) region on the short arm of
Molecular Mimicry chromosome 6, in particular allelic variants of DRB1. Alleles
Molecular mimicry is the phenomenon of antigens sharing conferring susceptibility to AIH-1 are HLA DRB1*0301 and
similar epitopes and therefore, all these antigens can activate DRB1*0401 in European and North American populations,
immunocytes. In AIH with molecular mimicry, multiple and DRB1*0405 and DRB1*0404 in Japanese, Argentinean
autoantigens and environmental triggers with the same or and Mexican populations. Susceptibility to AIH-2 is conferred
similar epitopes can activate CD4+ T cells. This activation by HLA DRB1*0701 and DRB1*0301; patients who have the
leads to expansion of liver-infiltrating cytotoxic T cells that DRB1*0701 gene have a more severe prognosis.
can cause liver injury (type 1 cytotoxicity) and antigen-
sensitized plasma cells that produce autoantibodies (type 2 Defects in Numbers and Function of
cytotoxicity).
Regulatory Cells
Prevention of autoimmunity is achieved through the
Genetic Factors interaction of professional APCs, T effector and T regulatory
Multiple genetic associations with AIH have been described (Treg) cells. Regulatory T cells (CD4+CD25+ Treg cells)
in different ethnic groups. Amongst all the genetic factors modulate proinflammatory cytokine producing CD8+ T cell
in AIH, MHC seems to be the most important factor for the proliferation by suppressing production of interferon gamma
Table 2: Autoantibodies in the diagnosis of AIH
Antibody Target Antigen(s) Liver disease Value in AIH
ANA* Multiple targets including: AIH Diagnosis of type 1 AIH

Chromatin
Ribonucleoproteins PBC
Ribonucleoprotein complexes PSC
Drug-induced
Chronic hepatitis C
Chronic hepatitis B
Nonalcoholic fatty liver disease
SMA* Microfilaments (filamentous Same as ANA Diagnosis of type 1 AIH
actin) and intermediate filaments
(vimentin, desmin)
LKM-1* CYP2D6 Type 2 AIH Diagnosis of type 2 AIH
Chronic hepatitis C
LC-1* FTCD Type 2 AIH Diagnosis of type 2 AIH
Chronic hepatitis C Prognostic implications
Severe disease
pANCA (atypical) Nuclear lamina proteins AIH Diagnosis of type 1 AIH
PSC Reclassification of cryptogenic chronic
hepatitis as type 1 AIH
SLA tRNP(SER)Sec AIH Diagnosis of AIH
Chronic hepatitis C Prognostic implications
Severe disease
Relapse
Treatment dependence
LKM-3 Family 1 UGT1A Type 2 AIH Diagnosis of type 2 AIH
Chronic hepatitis D
ASGPR Asialoglycoprotein receptor AIH Prognostic implications
PBC Severe disease
Drug-induced hepatitis Histological activity
Chronic hepatitis B, C, D Relapse
LKM-2 Cytochrome P450 2C9 Ticrynafen-induced hepatitis None, does not occur after withdrawal of
ticrynafen
LM Cytochrome P450 1A2 Dihydralazine-induced hepatitis Diagnosis of APECED hepatitis
APECED hepatitis
*Antibodies highlighted as bold letters indicate the conventional serological repertoire for the diagnosis of AIH. The other autoantibodes may
be useful in patients who lack the conventional autoantibody markers.
Abbreviations: AIH, autoimmune hepatitis; ANA, antinuclear antibody; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy; ASGPR, antibody to asialoglycoprotein receptor; CYP2D6, cytochrome P450 2D6; FTCD, formiminotransferase cyclodeaminase;
LC-1, liver cytosol type-1; LKM, liver kidney/microsome; LM, liver microsome; pANCA, perinuclear anti-neutrophil cytoplasmic antibody;
PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SLA, soluble liver antigen; SMA, smooth muscle antibody; UGT, uridine
diphosphate (UDP) glucuronosyl transferase
and increasing secretion of interleukin (IL)-4, IL-10 and CLINICAL FEATURES

transforming growth factor.
Autoimmunity primarily results from failure of natural Seventy five percent of patients with AIH are female. Type1
Treg generated in the thymus to prevent initial reactions AIH affects all age groups, but with two peaks: (i) one in
against autoantigens. The number and functions of Treg cells childhood or adolescence, and (i) the other in adulthood
are decreased in AIH (Fig. 1). around the age of 40. About 20% of patients present after the
age of 60. Type 2 AIH mainly affects children and young adults. The diagnosis of AIH is established by the exclusion of
About 4060% of adult patients with AIH-1 have a chronic other causes of chronic hepatitis. As for the laboratory tests,
disease course characterized by nonspecific symptoms, such serum autoantibodies are the mainstay of diagnosis of AIH.
as fatigue, nausea, abdominal pain, and arthralgia. The serum autoantibodies detected in AIH are shown in
The common presentation of AIH is similar to other forms of Table 2. Autoimmune hepatitis is typically diagnosed by
chronic hepatitis. Usually, the onset of the disease is insidious demonstrating the presence of SMA, ANA or anti-LKM type 1
presenting with constitutional symptoms, such as fatigue, in patients in whom other diagnoses have been excluded.
anorexia, weight loss, and general ill health lasting for months However, there is no single diagnostic test for AIH. Even
or years. However, AIH can also present with acute hepatitis the typical histological feature of AIH, i.e. interface hepatitis is
with fulminant hepatic failure. About 25% of the patients not diagnostic of AIH. Therefore, International Autoimmune
are asymptomatic at the time of diagnosis. In any patient Hepatitis Group (IAIHG) developed scoring system for the
having persistently raised alanine aminotransferase (ALT) diagnosis of AIH in 1993 and revised in 1999 (Table 3). The
and aspartate aminotransferase (AST) without any obvious revised 1999 IAIHG diagnostic criteria were complex and
cause, the possibility of AIH should be considered. Some simplified criteria for the diagnosis of AIH were developed in
of the patients may have cirrhosis of the liver with hepatic 2008 by IAIHG (Table 4).
decompensation at the time of diagnosis. Some patients may The revised original scoring system is a comprehensive
have features of AIH as well as other autoimmune disorders template that grades multiple clinical, laboratory and
like primary biliary cirrhosis (PBC), primary sclerosing histological features, and the simplified scoring system assesses
cholangitis (PSC) or autoimmune cholangitis, which can four features deemed important by multivariate analyses. Both
be termed as variant syndrome. The natural history of AIH the revised original and simplified diagnostic scoring systems
is quite diverse from mild asymptomatic disease to severe render diagnoses of either definite or probable AIH.
symptomatic hepatitis, which can lead to hepatic coma and
death. Rarely, hepatocellular carcinoma can develop as a late
complication.
TREATMENT
The goal of treatment is to obtain early complete remission
DIFFERENTIAL DIAGNOSIS in order to prevent disease progression and to maintain
it long-term on the lowest possible dose of medication.
The clinical features of AIH can be very similar to other
Prednisolone alone or the combination of prednisolone
causes of acute or chronic hepatitis. Therefore, AIH needs
and azathioprine remains the mainstay of AIH treatment.
to be differentiated from viral hepatitis, drug-induced liver
Although immunosuppressive treatment is effective, it is not
diseases [(drug-induced liver injury (DILI)], nonalcoholic
necessary to treat all cases of AIH.
steatohepatitis (NASH), alcohol-induced hepatitis, genetic
hemochromatosis, Wilsons disease or cryptogenic hepatitis.
Autoimmune hepatitis, PBC and PSC all have very similar Treatment Indications
features, and sometimes, it is very difficult to obtain diagnosis
properly. According to the AASLD 2010 practice guidelines (Table 5), the
treatment should be instituted in patients with serum AST or
ALT levels greater than tenfold upper limit of normal (ULN),
at least fivefold ULN in conjunction with serum g-globulin
DIAGNOSIS level at least twofold ULN, and/or histological features of
The diagnosis of AIH is based on a combination of clinical, bridging necrosis or multilobular necrosis.
biochemical, immunological, and histological features. Liver
biopsy is required to confirm the diagnosis and to evaluate
the severity of liver damage. Interface hepatitis is typical
Standard Treatment
of, though not exclusive to, AIH. The AST, ALT, and IgG Corticosteroid therapy is effective for all forms of AIH.
levels neither reflect the extent of tissue inflammation nor Prednisone (or prednisolone) alone or a lower dose in
indicate the presence or absence of cirrhosis. Viral hepatitis combination with azathioprine ameliorates symptoms and
B and C, Wilsons disease, nonalcoholic steatohepatitis, and improves the laboratory and histologic manifestations of
drug-induced liver disease, which may share serological liver inflammation in most patients. There is 50% 5-year
and histological features with AIH, need to be excluded by mortality for symptomatic patients, and somebody with
appropriate investigations. untreated severe disease is likely to die within 6 months.
Table 3: Revised scoring system for the diagnosis of AIH Table 4: Simplified scoring system of the International Autoimmune
Hepatitis Group*
Parameters/Features Score Notes*
Female sex +2 Component Result Points
Autoantibodies
ALP:AST (or ALT) ratio
ANA or SMA >1:40 +1
<1.5 +2 1
ANA or SMA >1:80 +2
1.53.0 0 Antibodies to liver kidney microsome >1:40 +2
>3.0 2 type 1
Serum globulins or IgG above normal Antibodies to soluble liver antigen Positive +2
>2.0 +3 Absent autoantibodies None 0
1.52.0 +2 Immunoglobulin level
1.01.5 +1 Immunoglobulin G >ULN +1
<l.0 0 >1.1 ULN +2
ANA, SMA or LKM-1 Normal 0
>1:80 +3 2 Histological findings
1:80 +2 Morphological features of AIH Compatible +1
Typical +2
1:40 +1 Incompatible 0
<1:40 0 Viral Disease
AMA positive 4 Absence of viral hepatitis No viral markers +2
Hepatitis viral markers Viral markers present 0
Positive 3 3 Pretreatment aggregate score: definite >7
Negative +1 diagnosis
Drug history Probable diagnosis 6
Positive 4 4 Abbreviations: ANA, antinuclear antibodies; SMA, smooth muscle
Negative +1 antibodies; ULN, upper limit of normal range. *Adapted from Hennes
Average alcohol intake et al.
<25 g/day +2
>60 g/day 2 Table 5: Indications for immunosuppressive treatment
Liver histology
Interface hepatitis +3 Absolute Relative None
Predominant lymphoplasmacytic +1 Serum AST Symptoms (fatigue, Asymptomatic with
infiltrate >tenfold ULN arthralgia, jaundice) normal or near normal
Rosetting of liver cells +1 serum AST and -globulin
None of the above 5 levels
Biliary changes 3 5
Other changes 3 6 Serum AST Serum AST and/or Inactive cirrhosis or mild
Other autoimmune disease(s) +2 7 >fivefold ULN and -globulin less than portal inflammation
Optional additional parameters: -globulin level absolute criteria (portal hepatitis)
Seropositivity for other defined +2 8 >twofold ULN
autoantibodies +1 9 Bridging necrosis Interface hepatitis Severe cytopenia (white
HLA DR3 or DR4 10 or multiacinar blood cell counts <2.5 x
Response to therapy necrosis on 109/L or platelet counts
Complete +2 11 histological <50 x 109/L) or known
Relapse +3 examination complete deficiency
of TPMT activity
Interpretation of aggregate scores
precludes treatment with
Pretreatment >15
azathioprine
Definite AIH 1015
Probable AIH Incapacitating Osteopenia, emotional Vertebral compression,
Post-treatment symptoms instability, hypertension, psychosis, brittle
Definite AIH >17 12 diabetes or cytopenia diabetes, uncontrolled
Probable AIH 1217 (white blood cell counts hypertension,
<2.5 x 109/L or platelet known intolerances
Abbreviations: AIH, autoimmune hepatitis; ALP, alkaline phosphatase;
counts <50 x 109/L) to prednisone or
AST, aspartate aminotransferase; ALT, alanine aminotransferase; ANA, azathioprine
antinuclear antibodies; SMA, smooth muscle antibodies; LKM 1;
type 1 liver-kidney microsomal antibodies; AMA, antimitochondrial Abbreviations: AST, aspartate aminotransferase le; ULN, upper limit
antibodies of normal range; TPMT, thiopurine methyltransferase
On the contrary, AIH has good prognosis with treatment remission on the above treatment schedules. In some
the 5-year mortality drops to 21% in cirrhotics and to 3% in patients whohave adverse effects to steroids, it is possible
noncirrhotics. Therefore, it is essential to diagnose early and to maintain remission with azathioprine alone at a dose
start treatment until remission is obtained. of up to 2 mg/kg daily. Treatment can be safely continued
during pregnancy.
Corticosteroid-related side effects are the most common
Induction of Remission causes for premature drug withdrawal in AIH. Treatment is
Standard induction treatment regimens are prednisolone (60 discontinued in 13% of patients because of complications,
mg daily) or a lower dose of prednisolone (30 mg daily) in and 47% of these have intolerable cosmetic changes or
conjunction with azathioprine (50 mg daily). Detail tapering obesity. Twenty-seven percent have osteoporosis with
of doses is shown in Table 6. The AASLD practice guidelines, vertebral compression, and 20% have brittle diabetes.
published in 2010, recommended either an initial dose of 30 Azathioprine has no reported teratogenic effects in
mg prednisolone combined with 12 mg of azathioprine per humans, but women who are particularly concerned about
day, or monotherapy with prednisolone at a starting dose of its use can be treated with steroids alone. Adverse effects of
4060 mg daily in adults. Combination therapy is generally azathioprine (cholestatic hepatitis, veno-occlusive disease,
preferred, because it allows for the reduction of prednisolone pancreatitis, nausea and vomiting, rash, bone marrow
dose frequently to below 10 mg/day, thereby, reducing the suppression) affect lesser than 10% of patients and usually
steroid-associated side effects. subside upon drug withdrawal.
Treatment should be given until normal liver test results
(AST, ALT, bilirubin and g-globulin levels) and normal liver
tissue, so that the frequency of relapse after drug withdrawal
Management of Relapse
is reduced from 86 to 60%. Relapsethe return of inflammatory activity determined
by the reappearance of interface hepatitis in liver tissue
samplesis the most common challenge for the management
Maintenance of Remission of AIH. Relapse, characterized by an increase of serum AST
Immunosuppressive therapy with azathioprine alone or and ALT levels, is common, occurring in 4080% of patients
combination with prednisolone is generally recommended and requiring a temporary increase in steroid dose. Relapse
for at least 2 years. Prednisolone withdrawal should is often associated with attempts to withdrawal treatment.
proceed gradually over a period of 36 months. Most Nonadherence to treatment, which is particularly common in
patients, including those with cirrhosis, achieve complete adolescents, also has an important role in relapse.
Table 6: Immunosuppressive treatment regimens for adults in autoimmune hepatitis
Combination Therapy
Monotherapy Azathioprine
Prednisone only* (mg/day) Prednisone* (mg/day) USA (mg/day) EU (mg/kg/day)
Week 1 60 30 50 12
Week 2 40 20 50 12
Week 3 30 15 50 12
Week 4 30 15 50 12
Maintenance until end-point 20 and below 10 50 12
Reasons for preference Cytopenia Postmenopausal state

Thiopurine methyltransferase Osteoporosis
deficiency Brittle diabetes
Obesity
Pregnancy malignancy short Acne
course (<6 months) Emotional lability
Hypertension
*Prednisolone can be used in place of prednisone in equivalent doses.

Table 7: Feasible molecular and cellular interventions in AIH
Intervention Rationale Precedents Feasibility

Blocking synthetic peptides Block autoantigen presentation by MHC molecules Low; target antigen(s) uncharacterized;
class II Murine models of rheumatoid uncertain mimicry effects
arthritis
CTLA-4Ig Blocks second co-stimulatory signal Success in rheumatoid arthritis, High; soluble fusion molecule available;
for immunocyte activation by mismatched marrow transplants, approved by FDA for rheumatoid arthritis
impairing multiple sclerosis
CD28-B7 ligation
Anti-TNF-a Impairs cytotoxic type 1 cytokine Effective in Crohns disease, Low; diverse serious toxicities
pathway rheumatoid arthritis Multiple preparations
Recombinant IL-10 Counteracts type 1 cytokine Crohns disease High; only mild reversible side effects
response; effective in viral hepatitis
Anti-CD20 Impairs activated B cells and type 2 Limited human experience Low; rare but late serious side effects
cytokine response
Autoantigen tolerization Desensitize disease-triggering Effective in diverse disease models Low; human trials disappointing; too many
antigen variables
T regulatory cell adoptive Intensify immune suppressive Deficient numbers and function High; can be expanded or freshly generated
transfer actions in AIH in culture
CD8? T cell vaccination Eliminates principal liver-infiltrating Prevents or attenuates AIH in Low; pathogenic clone unidentified; mainly
effector cells animal models preventive effect
Gene silencing Blocks genetic promoters of Multiple known genetic promoters; Low; key genetic targets unidentified in AIH
disease severity used in animal models
Abbreviations: AIH, autoimmune hepatitis; MHC, major histocompatibility complex; CTLA-4Ig, cytotoxic T-lymphocyte antigen 4; FDA, food
and drug administration; TNF, tumor necrosis factor
Alternative Treatments CONCLUSION

The AASLD 2010 practice guidelines reviewed the alternative Recently, there has been a progress in the development
medications that have been used empirically for treatment
of animal model of AIH, and the immunopathogenesis of
failure in adults that included cyclosporine, tacrolimus,
AIH is more clearly understood. This opens the emerging
ursodeoxycholic acid, budesonide, 6-mercaptopurine,
methotrexate, cyclophosphamide, and mycophenolate opportunities for site-specific molecular and cellular
mofetil, and it has been mentioned that all the drugs are interventions in AIH (Table 7). Treatments using tacrolimus,
not effective. Moreover, the guidelines stated that treatment mycophenolate mofetil, cytotoxic T-lymphocyte antigen 4
failure should be managed with high-dose prednisolone (60 (CTLA-4) Ig, recombinant IL-10 and T-regulatory cells by
mg daily) or prednisolone (30 mg daily) in combination with adoptive transfer are at the top of the list of candidates for the
azathioprine (150 mg daily) before considering other drugs research and development of newer drugs for AIH.
such as cyclosporine, tacrolimus or mycophenolate mofetil.
Liver Transplantation BIBLIOGRAPHY

For those patients who present with fulminant hepatic failure 1. Baeres M, Herkel J, Czaja AJ, et al. Establishment of standardised
(grades IIIV encephalopathy) and for those who progress to SLA/LP immunoassays: specificity for autoimmune hepatitis,
end-stage liver disease despite immunosuppression (around worldwide occurrence, and clinical characteristics. Gut.
2002;51:259-64.
1020% of patients), liver transplantation is the treatment of
2. Candia L, Marquez J, Espinoza LR. Autoimmune hepatitis and
choice. Recurrent AIH, characterized by high AST and ALT
pregnancy: a rheumatologists dilemma. Semin Arthritis Rheum.
levels, presence of autoantibodies, interface hepatitis and/ 2005;35:49-56.
or steroid dependence, affects some 20% of transplanted 3. Czaja AJ, Freese DK. Diagnosis and treatment of autoimmune
patients. hepatitis. Hepatology. 2002;36:479-97.
4. Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis, 14. Ma Y, Bogdanos DP, Hussain MJ, et al. Polyclonal T-cell responses
and management of autoimmune hepatitis. Gastroenterology. to cytochrome P450IID6 are associated with disease activity
2010;139:58-72. in autoimmune hepatitis type 2. Gastroenterology. 2006;130:
5. Czaja AJ. Autoimmune hepatitis. Part A: pathogenesis. Expert 868-82.
Rev Gastroenterol Hepatol. 2007;1:113-28. 15. Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and
6. Czaja AJ. Comparability of probable and definite autoimmune
management of autoimmune hepatitis: AASLD practice
hepatitis by international diagnostic scoring criteria.
guidelines. Hepatology. 2010;51:2193-213.
7. Czaja AJ. Current and future treatments of autoimmune hepatitis. 16. Manns MP, Vergani D. Autoimmune hepatitis. Semin Liver Dis.
Expert Rev Gastroenterol Hepatol. 2009;3:269-91. 2009;29:239-40.
8. Czaja AJ. Emerging opportunities for site-specific molecular 17. Montano-Loza AJ, Carpenter HA, Czaja AJ. Improving the end
and cellular interventions in autoimmune hepatitis. Dig Dis Sci. point of corticosteroid therapy in type 1 autoimmune hepatitis
2010;55:2712-26. to reduce the frequency of relapse. Am J Gastroenterol.
9. Czaja AJ. Safety issues in the management of autoimmune 2007;102:1005-12.
hepatitis. Expert Opin Drug Saf. 2008;7:319-33. 18. Poulsen LO, Thulstrup AM, Mellemkjaer L, et al. Mortality and
10. Duclos-Vallee JC, Sebagh M, Rifai K, et al. A 10-year follow up study causes of death in patients with lupoid hepatitis. A long-term
of patients transplanted for autoimmune hepatitis: histological follow-up study in Denmark. Dan Med Bull. 2002;49:263-5.
recurrence precedes clinical and biochemical recurrence. Gut.
19. Terrabuio DR, Abrantes-Lemos CP, Carrilho FJ, et al. Follow-up
2003;52:893-7.
of pregnant women with autoimmune hepatitis: the disease
11. Gleeson D, Heneghan MA. British Society of Gastroentrology
(BSG) guidelines for management of autoimmune hepatitis. Gut. behavior along with maternal and fetal outcomes. J Clin
2011;60:1611-29. Gastroenterol 2009;43:350-6.
12. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the 20. Vergani D, Mieli-Vergani G. Autoimmune Hepatitits. Nat Rev
diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169-76. Gastroenterol Hepatol. 2011;8:320-9.
13. Longhi MS, Ma Y, Bogdanos DP, et al. Impairment of CD4(+) 21. Vergani D, Mieli-Vergani, G. In: Mackay, IR, Rose NR (Eds). The
CD25(+) regulatory T-cells in autoimmune liver disease. J Autoimmune Diseases, 4th edition. Amsterdam: Elsevier
Hepatol. 2004;41:31-7. Academic Press; 2006. pp. 767-77.
27
cHAPTER
Amebic Liver Abscess
Premashis Kar
INTRODUCTION of the amebic liver abscesses present as acute illness for less
than 2 weeks duration but, sometimes, present as chronic
Amebic liver abscess is the extraintestinal infestation of indolent disease when it becomes difficult to distinguish
amebic infection. In this disease there is inflammation space from hepatocellular carcinoma potentially in elderly. Most
occupying lesions of liver caused by Entamoeba histolytica. of the patients present with history of abdominal pain, fever,
The overall incidence of amoebic liver abscess varies from 3 to and anorexia. Abdominal pain could be localized in right
9% of all infections of ameba seen in India where this disease hypochondrium or epigastrium. Sometimes, presentation
is endemic. With the advancement of imaging and molecular is characterized by diffuse abdominal pain, pleuritic chest
techniques the diagnosis has become more objective. Today a pain and radiation of right hypochondrial pain to right
large number of patients of amebic liver abscess present with shoulder joint epigastric pain at presentation is usually seen
variable manifestations and, therefore, the clinical picture with left lobe abscess. Some patients present with history of
need to be readdressed from time to time. The understanding high fever with chills. Some of the patients of amebic liver
of the pathogenesis and long-term follow-up of patients abscess may have developed basal atelectasis, and they
has helped clinicians to identify the risk factor affecting the may have cough with or without expectoration and pleuritic
healing pattern. It is important to classify patients of high risk chest pain. Clinical jaundice during course of illness may
where intervention is required. be seen in one-third of patients, which is usually due to
large abscess, multiple abscess, or abscess located at porta
hepatis.
PATHOLOGY By far and large, amebic liver abscess usually occurs in
right lobe of liver and is solitary in nature (3070%); however,
The amebic liver abscess occurs due to necrotic lysis of liver unusual presentations include multiple abscess, left lobe
tissues which vary in size from few centimeters to large lesions. abscess rupturing into the adjacent viscera. All this type of
Mostly the abscess is often single and located in the posterior atypical presentation needs to be looked into since they are
superior aspect of right lobe. The wall of the abscess is usually curable if intervention is done at the right time or potentially
welldemarcated and contains chocolate color brown anchovy fatal if untreated. Around 15% of patients may have multiple
like material, bile, fat necrotic tissue, and other common abscess, and they may present with fever, toxemia, deep
products. The amebic puss is usually sterile but can become jaundice and encephalopathy. They could be an element of
secondarily infected. Grossly, the liver is enlarged, has bacterial superinfection. The bacterial culture of puss may
smooth surface, soft in consistency, and tender to touch. If show isolates of E. coli and klebsiella. In such cases, it is
untreated, it can rupture into the plural cavity, peritoneum difficult to distinguish between pyogenic and liver abscess,
and pericardium. If the abscess is located in left lobe of the and if, the test for amebic serology is positive, it support, the
liver, it is at high risk to give rise to cardiac tamponade. diagnosis of amebic liver abscess.
In 35% of patients with left lobe abscess, half of this may
have an associated lesion in right lobe but remaining may
CLINICAL PRESENTATION have only solitary left lobe. This may have longer duration of
disease and needs to be differentiated from hepatoma and
Amebic liver abscess is usually seen in age group of 2045; pseudocyst of pancreas. Such cases need to be treated with
however, the disease could be seen in extreme of age. The needle aspiration and anti-entamebic drug, because they are
disease is believed to be nine times common in males. Most prone to complications like peritonitis and toxemia.
Amebic Liver Abscess 249
It is important to maintain that amebic liver abscess

located in right lobe in liver can present with hepatic outflow
obstruction characterized by obstructive jaundice, and
presence of hepatomegaly. The clinical, radiological (MR
venography), and serological test demonstrates compression
of hepatic vein or IVC. These features disappear once the
abscess is aspirated.
Various samples of amebic liver abscess include rupture
of abscess into pleural cavity with empyema thoracis, rupture
into peritoneal cavity, and biliary tree have been reported.
Sometimes, a subhepatic collection can occur, but such
presentations are rare.
DIAGNOSIS
Ultrasound is useful for diagnosis of amebic liver abscess Fig. 2: Ultrasound demonstrating hepatic abscess
(Figs 1 and 2). In a classical case of amebic liver abscess, the
ultrasound imaging shows a sonolucent or hypoechoic area cannot differentiate from remote to acute infection in areas of
usually with fine internal echoes and a well-defined margin high endemicity.
with posterior acoustic enhancement.
Computed tomography scan is not needed for amebic liver
abscess but, sometimes, may be indicated for differentiating Newer Methods
complicated cases of amebic liver abscess from hepatocellular Recently an enzyme-linked immunosorbent assay kit has
carcinoma. been developed that helps in the detection of amebic lectin
antigen in serum sample in patients with amebic liver abscess
and is considered to be 95% sensitive.
Serology
The ELISA test for amebic serology is positive in 8095% of
cases, and in the context of clinical features of suspicious liver MEDICAL THERAPY
abscess, positive serological test supports diagnosis of amebic
infection. But since the serum antibodies to E. histolytica Amebicidal drugs, which are currently used include
persist for many years, the ELISA or indirect hemagglutination nitroimidazole derivatives: metronidazole, tinidazole
and ornidazole. Oral or intravenous administration of
metronidazole, tinidazole remains drug of choice for
management of amebic liver abscess because they lead to
rapid clinical improvement. But this should be followed with
luminally active drug. The pharmacotherapy for E. histolytica
in adults is discussed as follows.
It has been shown that nitroimidazole, which includes
metronidazole is effective in greater than 90% case. It is
recommended that therapy be continued for at least 10 days. If
there is evidence of relapse or incomplete response treatment
should be continued for 3 months. The recommended dose of
nitroimidazole is 40 mg/kg/day in divided doses. Tinidazole
can be administrated for 1.2 mg/kg/day for 7 days. Other drugs
like chloroquine, emetine and dehydroemetine are rarely
used these days. It has been observed that they yield excellent
results and use of alternative drugs is rarely indicated. The
clinical response becomes evident between 48 hours and
Fig. 1: Hepatic abscess 72 hours of starting of the treatment. There is evidence of
improvement of toxemia and constituting syndromes like BIBLIOGRAPHY

abdominal pain, fever and anorexia.
1. Aucott JN, Ravdin JI. Amebiasis and nonpathogenic intestinal
protozoa. Infect Dis Clin North Am. 1993;7(3):467-85.
ASPIRATION OR DRAINAGE OF 2. Haque R, Mollah NU, Ali IK, et al. Diagnosis of amebic liver abscess
and intestinal infection with the TechLab Entamoeba histolytica
ABSCESS II antigen detection and antibody tests. J Clin Microbiol.
Most of the cases of liver abscess where aspiration is required 2000;38(9):3235-9.
may be indicated in the following situations: 3. Haque R, Huston CD, Hughes M, et al. Amebiasis. N Engl J Med.
No improvement in 4872 hours 2003;348(16):1565-73.
Left lobe of abscess 4. Irusen EM, Jackson TF, Simjee AE, et al. Asymptomatic intestinal
Thin rim of liver tissue around abscess (<10 mm) colonization by pathogenic Entamoeba histolytica in amebic
Evidence of impending rupture. liver abscess: prevalence, response to therapy and pathogenic
It has also been proved that needle aspiration combined potential. Clin Infect Dis. 1992;14(4):889-93.
with antiamebic therapy is not indicated in patients of 5. Kapoor OP, Joshi VR. Multiple amoebic liver abscess. A study of
uncomplicated amoebic liver abscess. 56 cases. J Trop Med Hyg. 1992;75(1):4-6.
6. Khokhani RC, Garud AD, Deodhar KP, et al. Treatment of amebic
liver abscess with tinidazole and metronidazole. Drugs. 1978;15
Suppl 1:23-5.
SURGICAL INTERVENTION 7. Li E, Stanley SL. Protozoa. Amoebiasis. Gastroenterol Clin North
Surgical drainage is really indicated in the following situations: Am. 1996;25(3):471-92.
When there is clinical deterioration after needle aspiration 8. Patterson M, Healy GR, Shabot JM. Serologic testing for
Complicated amebic liver abscess amoebiasis. Gastroenterology. 1980;78(1):136-41.
A large abscess with poor yield on needle aspiration. 9. Perez JY. The management of amoebic hepatic abscess. Drugs.
Since surgery carries high mortality, therefore surgery 1978;15 Suppl 1:49-52
should be considered only when evidence of liver abscess 10. Petri WA, Singh U. Diagnosis and management of amebiasis. Clin
rupturing into adjacent viscera or peritoneum. Infect Dis. 1999;29(5):1117-25.
11. Sharma MP, Ahuja V. Management of amebic liver abscess. Arch
Med Res. 2000;31(4 Suppl):S4-5.
LONG-TERM FOLLOW-UP 12. Sharma MP, Dasarathy S, Sushma S, et al. Long term follow-
up of amebic liver abscess: clinical and ultrasound patterns of
The patients can be followed up as outpatient on basis resolution. Trop Gastroenterol. 1995;16(3):24-8.
of clinical assessment, liver function test, and periodic 13. Sharma MP, Dasarathy S, Verma N, et al. Prognostic markers in
sonographic assessment, which could be done every 3 amebic liver abscess: a prospective study. Am J Gastroenterol.
months for a period of 1 year. It is believed that disappearance 1996;91(12):2584-8.
of sonographic abnormality takes around 69 months. The 14. Sharma MP, Dasarathy S. Amoebic liver abscess. Trop
factors, which influence the healing of abscess are as follows: Gastroenterol. 1993;14(1):3-9.
Size of abscess cavity at the time of admission 15. Sharma MP, Sarin SK. Interior vena caval obstruction due to
Hypoalbuminemia and anemia amoebic liver abscess. J Assoc Physicians India. 1990;30(4):
The clinical improvement usually does not correlate with 243-4.
ultrasonography resolution. 16. Sharma MP, Acharya SK, Verma N, et al. Clinical profile of multiple
liver abscesses. J Assoc Physicians India. 1990;38(11):837-9.
17. Sharma MP, Dasarathy S. Amebic liver abscess. Trop Gastroenterol.
PROGNOSTIC MARKER 1993;14(1):3-9.
18. Stanley SL. Amoebiasis. Lancet. 2003;361(9362):1025-34.
It has been shown bilirubin levels greater than 3.5 g/dL, 19. Thorsen S, Rnne-Rasmussen J, Petersen E, et al. Extra-intestinal
encephalopathy, volume of abscess cavity, and albumin amebiasis: clinical presentation in a non-endemic setting. Scand
levels less than 2 g/dL indicates high-risk mortality. J Infect Dis. 1993;25(6):747-50.
28
cHAPTER
Pyogenic Liver Abscess
Furqan Ahmed
INTRODUCTION Bacteria can gain access to the liver through a variety of

routes. Ascension from the biliary tree occurs in patients
Pyogenic liver abscess (PLA) occurs when there is bacterial with benign or malignant obstruction of the biliary tree.
infection of the liver parenchyma resulting in the formation Biliary tree obstruction can be due to choledocholithiasis,
of a collection of pus. cholangiocarcinoma, primary sclerosing cholangitis, and
congenital biliary anomalies like Carolis disease. Biliary
procedures, including stent deployment and stricture dilation
EPIDEMIOLOGY can result in the introduction of bacteria into the biliary
system.
Incidence of PLA varies among different geographic regions. Hematogenous spread from a distant focus is another
Published data have shown an annual incidence of PLA source of infection in PLA. Hematogenous spread of infection
of 2.3/100,000 in Canada and 1.0/100,000 in Denmark. to the liver can occur via the hepatic artery or the portal
A nationwide study from Taiwan reported an increasing system. Prior to the introduction of antibiotics, seeding of the
incidence of PLA from 11.15/100,000 in 1996 to 17.59/100,000 portal venous system frequently occurred in patients with
in 2004. Another study from Taiwan reported a crude appendicitis and diverticulitis. Inflammatory bowel disease
incidence rate of PLA of 446.1/100,000 hospital admissions. may also result in portal venous bacteremia. In infants and
Multiple studies have shown differences in the children, PLA is seen in the setting of umbilical vein infections,
epidemiology of PLA in Asia versus that in the West. Studies which can reach the liver via the portal vein.
from Southeast Asia report a growing prevalence of Klebsiella Streptococcus bovis, an uncommon cause of PLA, warrants
pneumoniae PLA, whereas studies from the United States an endoscopic evaluation to exclude an occult colonic
and Europe report a predominance of Escherichia coli PLA. malignancy. However, the incidence of colon cancer in these
Klebsiella pneumoniae PLA was initially reported in Taiwan in patients is low.
the 1980s but is now being reported in other regions as well. Secondary infection of an amoebic abscess, metastatic
Studies from Taiwan, Korea, and Singapore have reported lesions, or intrahepatic hematoma may also lead to the
this emerging Klebsiella PLA. A study from South Korea has formation of PLA. Direct extension into the liver can also
shown a dramatic rise in the proportion of K. pneumoniae occur, for example in cases of pneumonia or subphrenic
liver abscesses from 0% in 19551969 to 78.2% in 20042005. abscess. Aggressive treatment of hepatobiliary malignancies
Furthermore, at least some studies in patients with Klebsiella may result in post-procedure PLA occurring after liver
PLA in the United States have shown a predominance of transplantation, transarterial chemoembolization, ethanol
patients of Asian origin. injection and radiofrequency ablation of malignant tumors,
and percutaneous transhepatic cholangiography. Liver
trauma may also result in the abscess formation. Pyogenic
PATHOGENESIS liver abscess may be a complication of liver transplant surgery.
Finally, penetrating injuries to the liver may result in the
When bacteria reach the liver parenchyma, endotoxins direct introduction of bacteria into the hepatic parenchyma.
are released which then induce Kupffer cell proliferation However, in a significant proportion of PLA the etiology is
and release of proinflammatory mediators that trigger an unknown, or cryptogenic.
inflammatory response. Sinusoidal obstruction and rising Abscesses arising from portal vein bacterial seeding are
hydrostatic pressure leads to hepatic ischemia and pus usually limited to the right lobe whereas those of hepatic
accumulation. artery origin often involve both lobes. Multiple abscesses are
seen in 40% of the PLA patients. In PLA the right lobe of the shoulder pain. Older patients are more likely to have a
liver is more commonly involved than the left lobe. nonspecific clinical presentation of PLA. Patients with large
In Southeast Asia, K. pneumoniae PLA is associated with abscesses may develop portal vein thrombosis which can then
diabetes or a cryptogenic etiology. Klebsiella pneumoniae is lead to cavernous transformation and portal hypertension.
rarely associated with intra-abdominal pathology. Western A subphrenic abscess may develop in approximately 3% of
studies have found a much lower prevalence of diabetes in cases.
PLA patients. Risk factors previously associated with PLA Braiteh et al. have described three distinct K. pneumonia
reported from the West include underlying hepatobiliary liver abscess syndromes: the monomicrobial cryptogenic
disease, biliary fistulas, gallbladder empyema, systemic liver abscess, the polymicrobial liver abscess and the
infections, malignancy (hepatocellular carcinoma, pancreatic monomicrobial cryptogenic invasive K. pneumoniae-
cancer, ampullary carcinoma, gall bladder carcinoma, associated liver abscess (CIKPLA) syndrome. The CIKPLA
cholangiocarcinoma and liver metastases), renal disease, and syndrome is most commonly seen in diabetic patients,
pneumonia. predominately in Southeast Asia, and is complicated by septic
Virulence factors of K. pneumoniae have been studied to spread to other organs.
identify the pathogenic mechanisms by which this organism
causes liver abscess. Identified virulence factors include
the lipopolysaccharide, which contains the O antigen and MICROBIOLOGY
the capsular polysaccharide, which contains the K antigen.
The K1 capsular serotype is more common in Taiwan than Asian studies have reported a high prevalence of
in the West and this has been shown to be a major factor in K. pneumoniae. Klebsiella pneumoniae has been described
the development of K. pneumoniae liver abscesses. More as a globally emerging infectious disease. In contrast,
specifically, the magA (mucoviscosity-associated gene A), Western studies have shown E. coli to be the major pathogen
which is a K1 antigen-specific polymerase, is responsible isolated. Western studies have shown a 515% prevalence of
for the pathogenic features of K. pneumoniae by conferring K. pneumoniae in their PLA cases. Other bacteria seen include
resistance to neutrophil phagocytosis. Enterococcus faecalis, Streptococcus milleri and Pseudomonas
species (Table 1).
Recent Western studies have shown a high frequency
CLINICAL MANIFESTATIONS of polymicrobial infections, which may be more common
in patients with underlying malignancy. Salmonella is
Clinical manifestations of PLA may include fever, chills, right seen in immunocompromised individuals. In children,
upper quadrant abdominal pain, nausea, vomiting, anorexia, Staphylococcus aureus is the most common microorganism
loss of appetite and jaundice. Due to the nonspecific seen. Streptococcus bovis, an uncommon cause of PLA,
symptoms and signs associated with PLA, diagnosis requires warrants an endoscopic evaluation to exclude an occult
a high index of suspicion. At presentation, patients usually colonic malignancy. Fungi can be seen in patients with
report a 2-week duration of symptoms. One study reported previous manipulation of the biliary tree, for example
a fever in only half of PLA patients. In contrast, another study after endoscopic retrograde cholangiopancreatography or
found fever to be the most consistent clinical symptom. percutaneous transhepatic cholangiography.
Patients with sepsis or abscess rupture may present with
shock or altered mental status. Table 1: Organisms cultured from pyogenic liver abscesses
Hepatomegaly and right upper quadrant abdominal
Gram-negative rods Gram-positive cocci Anaerobic bacteria
tenderness are the most common findings on physical
Escherichia coli Streptococcus viridans Bacteroides species
examination. Signs attributable to localized peritoneal
group
irritation are found only in 1555% of the patients. Although
Klebsiella pneumoniae Staphylococcus aureus Fusobacterium species
mild ascites is common and is seen in up to 30% of the patients,
ascites that is clinically detectable is rare. Other studies have Enterobacter Enterococcus Clostridium species
also reported the frequent lack of clinical abdominal findings Proteus species Actinomyces
in patients with PLA. Pyogenic liver abscess should always Pseudomonas species Eubacterium
be considered in the evaluation of patients with fever of Listeria Propionibacterium
unknown origin.
Yersinia
Direct extension into the pleural cavity or lung may also
Pasteurella
occur and these patients may present with cough or right
Pyogenic Liver Abscess 253
DIAGNOSIS
Laboratory analysis in PLA demonstrate nonspecific
abnormalities that reflect the underlying infective process
including leukocytosis with a neutrophil predominance
and elevated erythrocyte sedimentation rate and C-reactive
protein levels. Hypoalbuminemia is frequently seen and is an
indication of a systemic inflammatory response. Liver enzyme
abnormalities are frequently seen, and there is neither a
predominance of a cholestatic nor a hepatocellular pattern.
Prolongation of the prothrombin time may also occur.
Microbiological studies are the gold standard in making a
diagnosis of PLA. One-third of PLAs are caused by anaerobic
bacteria, one-third by aerobic bacteria, and the final third are Fig. 2: Computed tomography scan shows appearance of a pyogenic
a mixture of aerobes and anaerobes. Blood cultures should be liver abscess
obtained because bacteremia is often seen in K. pneumoniae
PLA. Ideally an ultrasound or computed tomography (CT)- is suspicion of associated biliary tract pathology. The CT
guided diagnostic aspiration should be performed before appearance of multiple small abscesses coalescing into a
starting antibiotic therapy. Pyogenic liver abscess aspirates single larger abscess is called a cluster sign. Kim et al. have
should be cultured in aerobic and anaerobic media and in described the following characteristic intra-abscess features
carbon dioxide rich media for Streptococcus milleri. of K. pneumoniae PLA on CT imaging: air-fluid levels, no
The reported sensitivity and specificity of gram staining of rim enhancement, hairball-like contents, septal breakage
liver abscess aspirates is 90% and 100% for gram-positive cocci and turquoise-like structure. These features were less seen in
and 32% and 94% for gram-negative bacilli. The sensitivities non-K. pneumoniae PLA.
of blood cultures are 30% for gram-positive cocci and 40% for Gadolinium-enhanced magnetic resonance imaging
gram-negative bacilli. Furthermore, 35% of blood-cultured can differentiate hepatic abscesses from other focal hepatic
organisms are not seen in abscess aspirate cultures. Cultures lesions. Chest X-rays are abnormal in up to 50% of PLA
of abscess aspirate are positive in approximately 75% of cases; patients with findings of an elevated and immobile right
blood cultures are positive in one-half of cases. hemidiaphragm or an air-fluid level in an abscess cavity in the
Ultrasonography is the first imaging modality that should liver.
be performed in a patient with a suspected liver abscess
(Fig. 1). Computed tomography scanning with intravenous
contrast may confirm an ultrasonographic diagnosis or DIFFERENTIAL DIAGNOSIS
make the diagnosis in a patient with a high level of suspicion
but an inconclusive ultrasound. It can detect abscesses as In developing countries, the most important differential
small as 5 mm which may be missed on ultrasound (Fig. 2). diagnosis is amebic liver abscess. This distinction is very
Computed tomography imaging is also helpful when there important because treatment and prognosis of the two are
very different. Imaging characteristics of PLA and amebic
liver abscesses are similar and the diagnosis is based
on serologic markers, and aspirate characteristics, and
cultures (Table 2).
TREATMENT
The cornerstone of PLA treatment is intravenous antibiotics.
Broad-spectrum empirically based antibiotic administration
according to the local prevalent bacteriology should be
instituted early and can be refined based on the culture
and sensitivities of an aspirate. Antibiotic therapy should
Fig. 1: Ultrasound appearance of a pyogenic liver abscess be initiated immediately after culture specimens have been
Table 2: Differentiation between amebic and pyogenic liver abscesses invasiveness and the lack of a need for an indwelling catheter
and catheter care.
Features Amebic liver abscess Pyogenic liver abscess
Drainage is most effectively accomplished when the
Age Younger (2040 years) Older (6070 years) pus is well-liquefied and completely evacuated. Relative
Comorbidities Absent Present contraindications to percutaneous drainage include
Diabetes Infrequent Frequent coagulopathy and ascites. Uncommon, but reported,
E. histolytica serum >1:512 <1:512 complications of percutaneous intervention include
titer biliary fistula, leakage, hemorrhage, hemoperitoneum and
E. histolytica cysts in Present Absent peritonitis. Percutaneous needle aspiration is considered to
stool have failed when the patient does not improve clinically or
Jaundice Uncommon Common radiologically after the second aspiration. Factors reported to
Dysentery Frequently present Absent
be associated with failure of percutaneous therapy include the
presence of yeast, hypoalbuminemia, and communication
Pulmonary findings Absent Frequently present
with an untreated biliary obstruction.
Abscess number Solitary Can be multiple If biliary obstruction due to stones, tumors or strictures
Aspirate No bacteria Bacteria present of the bile duct is the cause of the PLA, it must be relieved
by endoscopic retrograde cholangiopancreatography.
Biliary drainage promotes abscess drainage when there
is communication between the abscess and the biliary
system. Endoscopic ultrasound-guided drainage of hepatic
obtained. Initial antibiotic coverage should cover gram- abscesses has been described for abscesses not accessible to
negative bacilli, streptococcus and anaerobic bacteria. percutaneous drainage, for example those in the caudate lobe
Generally, first-line therapy consists of a third generation or the gastrohepatic space.
B-lactam inhibitor. Second-line therapy, for those with In a study of nearly 1,000 patients, 56% (540/966)
intolerance to B-lactam inhibitors, would be fluoroquinolone. responded to medical therapy and 44% (426/966) required
A 46-week course of antibiotic therapy should begin with adjunctive percutaneous aspiration. Factors predicting the
intravenous antibiotics. Antibiotic therapy can be switched to need for aspiration included age greater than 55 years, abscess
oral agents after 2 weeks of intravenous therapy and when the size greater than 5 cm, involvement of both lobes of the liver
patient demonstrates a favorable response. Data suggest that and symptom duration of greater than 7 days. Other studies
antibiotics alone, given for 46 weeks, can be curative for PLA from large Asian medical centers have reported that 87100%
if the abscess is solitary and without loculations, no greater of PLA patients are amenable to medical and/or radiological
than 5 cm in diameter, and if a diagnostic aspirate was done treatment alone.
to culture the offending microorganism and determine its Input from a hepatobiliary surgeon is often helpful in
sensitivities. patients with a PLA. In an early published series of PLA cases,
Both percutaneous needle aspiration and percutaneous surgery was considered essential for the successful treatment
catheter drainage are effective treatment options for PLA. of PLA and the only modality that would avoid mortality. With
Published literature does not yet establish superior efficacy the introduction of image-guided percutaneous modalities,
of one over the other. Although an early randomized study the need for surgical intervention has been substantially
suggested that catheter drainage had a higher success rate reduced. Surgery is currently indicated in patients with
than percutaneous aspiration, a more recent randomized medical treatment failure, catheter drainage failure or
study did not find a statistically significant difference between abscess rupture. Surgical drainage may also be required in the
the two approaches. presence of renal failure or ascites, abscesses of the left lobe of
Abscesses that are most amenable to percutaneous the liver, or when the abscess is not accessible to radiological
drainage are those that are adherent to the abdominal wall intervention. Patients with abscesses greater than 5 cm in
and peripheral abscesses of the right lobe of the liver. Needle diameter and those with multiloculated abscesses have better
aspiration should be performed with an 18-gauge needle. In outcomes when treated with surgical drainage, as compared
multiloculated abscesses, the needle tip should be inserted to those who received percutaneous drainage. One author
into the various compartments to ensure maximal drainage. has reported that hepatic resection in patients with PLA and
Advantages of needle aspiration include reduced cost and acute physiology and chronic health evaluation (APACHE)
Pyogenic Liver Abscess 255
II scores of greater than 15 lead to better clinical outcomes Risk factors associated with increased mortality include
than other treatment approaches. the presence of multiple hepatic abscesses, polymicrobial
Factors now associated with failure of nonsurgical infections, disseminated intravascular coagulation, septic
management include abscess multiloculation, abscess shock and underlying renal disease. Mortality rates remain
rupture, unresolving jaundice, renal impairment and high for patients with an underlying malignancy. Prognosis
biliary communication with the abscess. In such patients, is also made worse by delayed diagnosis, pleural effusion and
laparoscopic abscess drainage has been successfully reported. old age. The APACHE II scoring system can be used to predict
The need for salvage surgery, however, is associated with a mortality in PLA patients.
higher mortality. Surgical management is increasingly being There is conflicting data on the impact of diabetes on
limited to those patients who fail medical and radiological mortality due to PLA. In a study from Taiwan, diabetes was
management and for the management of complications. associated with a ninefold increase in the incidence of PLA
Published mortality rate after surgical intervention ranges but a decrease in mortality. This phenomenon has also been
from 27 to 41%. reported by others. Studies have shown that diabetic patients
Follow-up imaging is required to assess response to with PLA tend to have longer hospitalizations.
therapy, to help guide the duration of antibiotic therapy, and
to evaluate the need for further drainage. After successful
treatment, K. pneumoniae PLA recurrence is infrequent. SUMMARY
Pyogenic liver abscess is a potentially life-threatening disease
COMPLICATIONS that requires a high index of suspicion and prompt abdominal
imaging studies to make a rapid diagnosis. Delayed diagnosis
Complications associated with PLA include septic metastasis of a PLA due to its nonspecific clinical presentation can
leading to meningitis, endophthalmitis, septic pulmonary also lead to increased morbidity and mortality. There are
emboli and brain abscesses. K. pneumoniae PLA is more distinct differences in the microbiological spectrum which
likely to spread than polymicrobial PLA. Acute respiratory imply different risk factors and clinical courses. Klebsiella
distress syndrome and pleural effusions may also occur. pneumoniae PLA is predominately seen in Southeast Asia
Diabetic patients are more susceptible to metastatic foci. in patients likely to have diabetes mellitus and the cause
Perihepatitis may develop, which can lead to adhesion
of infection is often cryptogenic. In the West, E. coli is the
formation.
frequent cause of PLA and these patients commonly have
In a study from Taiwan, the presence of K. pneumoniae
underlying hepatobiliary pathology or a malignancy. Early
liver abscess and diabetes were predictors of septic
institution of broad-spectrum intravenous antibiotics, ideally
metastatic lesions from PLAs. It has been suggested that
after a diagnostic image-guided aspiration, is the mainstay
poor glycemic control leading to impaired neutrophil
chemotaxis and phagocytosis may be responsible for the of therapy. Morbidity and mortality have reduced in recent
greater frequency of septic metastases seen in diabetic decades due to the introduction of percutaneous radiological
patients. As mentioned previously, the CIKPLA syndrome is drainage by aspiration and catheter introduction. Surgery
associated with diabetes. is now reserved for those patients who have failed medical
and radiological therapy and for those with complications.
A multidisciplinary approach involving a gastroenterologist,
infectious disease specialist, microbiologist, interventional
MORTALITY radiologist, and surgeon provides the most optimal
Although the incidence of PLA has risen, the mortality has management for these complex patients.
significantly declined. An early study from Denmark reported
a 50% mortality rate. More recently, studies have shown
mortality rates of approximately 10%. There is a trend toward BIBLIOGRAPHY
a lower mortality over the past 2030 years and this has been
1. Barakate MS, Stephen MS, Waugh RS, et al. Pyogenic liver abscess:
attributed to better antibiotics, the introduction of cross-
a review of 10 years experience in management Augst. NZJ syrs.
sectional imaging, the introduction of percutaneous abscess 2999;69:205-9.
aspiration and catheter drainage, and to the rise of Klebsiella 2. Braiteh F, Golden MP. Cryptogenic invasive Klebsiella pneumoniae
which responds well to medical care. liver abscess syndrome. Int J Infect Dis. 2007;11(1):16-22.
3. Butler TJ, McCarthy CF. Pyogenic liver abscess. Gut. 1969;10(5): 11. Lodhi S, Sarwari AR, Muzammil M, et al. Features distinguishing
389-99. amoebic from pyogenic liver abscess: a review of 577 adult
4. Chemaly RF, Hall GS, Keys TF, et al. Microbiology of liver abscesses cases. Trop Med Int Health. 2004;9(6):718-23.
and the predictive value of abscess gram stain and associated 12. Noh SH, Park do H, Kim YR, et al. EUS-guided drainage of hepatic
blood cultures. Diagn Microbiol Infect Dis. 2003;46(4):245-8. abscesses not accessible to percutaneous drainage (with
5. Chung DR, Lee SS, Lee HR, et al. Emerging invasive liver abscess videos). Gastrointest Endosc. 2010;71(7):1314-9.
caused by K1 serpype Klebsiella pneumoniae in Korea. J Infect. 13. Podschun R, Ullmann U. Klebsiella spp. as nosocomial pathogens:
2007;54:578-83. epidemiology, taxonomy, typing methods, and pathogenicity
6. Khan R, Hamid S, Abid S, et al. Predictive factors for early aspiration factors. Clin Microbiol Rev. 1998;11(4):589-603.
in liver abscess. World J Gastroenterol. 2008;14(13):2089-93. 14. Rajak CL, Gupta S, Jain S, et al. Percutaneous treatment of liver
7. Kim SB, Je BK, Lee KY, et al. Computed tomographic differences abscesses: needle aspiration versus catheter drainage. AJR Am J
of pyogenic liver abscesses caused by Klebsiella pneumoniae Roentgenol. 1998;170(4):1035-9.
and non-Klebsiella pneumoniae. J Comput Assist Tomogr. 15. Tsai FC, Huang YT, Chang LY, et al. Pyogenic liver abscess as endemic
2007;31(1):59-65. disease, Taiwan. Emerg Infect Dis. 2008;14(10):1592-600.
8. Lee SS, Chen YS, Tsai HC, et al. Predictors of septic metastatic 16. Wong WM, Wong BC, Hui CK, et al. Pyogenic liver abscess:
infection and mortality among patients with Klebsiella retrospective analysis of 80 cases over a 10 year period. J
pnemoniae liver abscess. Clin Infect Dis. 2008;47(5):642-50. Gastroenterol, Hepatol. 2002;17:1001-7.
9. Liew KV, Lau TC, Ho CH, et al. Pyogenic liver abscess--a tropical 17. Yeh KM, Lin JC, Yin FY, et al. Revisiting the importance of virulence
centres experience in management with review of current determinant magA and its surrounding genes in Klebsiella
literature. Singapore Med J. 2000;41(10):489-92. pneumoniae causing pyogenic liver abscesses: exact role in
10. Lin JC, Siu LK, Fung CP, et al. Impaired phagocytosis of capsular serotype K1 capsule formation. J Infect Dis. 2010;201(8):1259-67.
serotypes K1 or K2 Klebsiella pneumoniae in type 2 diabetes 18. Yu SC, Ho SS, Lau WY, et al. Treatment of pyogenic liver abscess:
mellitus patients with poor glycemic control. J Clin Endocrinol prospective randomized comparison of catheter drainage and
Metab. 2006;91(8):3084-7. needle aspiration. Hepatology. 2004;39(4):932-8.
29
cHAPTER
Hydatid Cyst of Liver
Fazal Karim, Salimur Rahman
INTRODUCTION Dogs are the definitive hosts for E. granulosus. They harbor
the tapeworm in their small intestine. Sheep, goats and cows
Hydatid cyst disease dates back to first millennium. Among the are the major intermediate host. These animals become
first noted incident of hydatid cyst was by Hippocrates more infected feco-orally by Echinococcus eggs shed into the
than 2,000 years ago. Also known as cystic echinococcossis, environment with feces of infected dogs. Life cycle is closed
affects intermediate hosts generally herbivores and when dogs are infected by viable cyst-containing organs of
occasionally humans. slaughtered livestock. In the intestine of the dog, protoscoleces
develop into adult tapeworms. Humans become accidental
intermediate hosts by ingesting vegetables and foods
EPIDEMIOLOGY contaminated by Taenia eggs excreted with infected dogs
feces. Factors associated with infection include the number
Echinococcosis is prevalent worldwide. However, this of owned dogs, frequency of contact with dogs, feeding dogs
diseases more frequently found in bovine (mainly sheep) with infected offal, infrequent administration of praziquantel
raising nations of Africa, Mediterranean Europe, Middle East, to dog. The common practices of slaughtering cattle in open
South America, and Oceania (Fig. 1). spaces and of feeding dogs on offal containing hydatid cysts
facilitate the life cycle of the parasite.
Fig. 1: Global distribution of zoonotic strains of Echinococcus granulosus

Source: Adapted from Eckert and Deplazes; 2004.
TRANSMISSION retrograde cholagiopancreatography. Symptoms include

high fever, sepsis syndrome, and tender liver.
After oral ingestion Echinococcus eggs hatch in the intestinal Like in liver abscess, antibiotics and drainage are the
mucosa of the intermediate host and transform into principles of treatment. Rupture into biliary tree presents with
oncospheres, which penetrate bowel wall. Through the portal obstructive features and cholangitis. Endoscopic retrograde
circulation it reaches major filtering organs like liver where cholangiopancreatography with removal of membranes is the
cysts develop. Cystic lesions (CLs) are mostly seen in liver; recommended treatment.
however, these are also found in lung, brain and other viscera.
Oral ingestion portal vein liver liver cyst
The cyst layer can be segregated into three layers. The outer DIAGNOSIS
layer, adventitial layer is host derived also known as pericyst. It
is followed by worm-derived layers, i.e. intermediate acellular Diagnosis is made by combining clinical suspicion, imaging
layer and inner germinal layer. and serology. Routine laboratory tests, including a full blood
The inner germinal layer produces brood capsules and count and liver function tests are not specific. Less than 15%
protoscoleces. It secretes clear fluid. The brood capsules of cases have eosinophilia, which generally occur only if there
generate daughter cysts by invagination. is leakage of antigenic material.
Imaging
CLINICAL FEATURES
Ultrasound is most widely used imaging tool, because it is
Mostly asymptomatic easy to perform and less expensive. WHO Working Group
Mechanical effects due to compression of adjacent organs on echinococcosis has classified liver hydatid cyst according
No specific symptom. Majority are asymptomatic. to sonographic findings into CL, which is cyst without wall,
Symptoms depend on the site and size of cysts leading to CE1 cyst with wall, CE2 multiseptated, multivesicular cysts,
pressure or obstructive symptoms. CE3a cyst with detached membrane, CE3b daughter cyst
The liver is affected in around 6070% of patients, the with echogenic matrix, CE4 heterogeneous hyperechoic or
lungs in 25% patients, and other organs, including the brain, hypoechoic mass, CE5 cysts with calcified wall (Table 1). CL,
muscle, kidney, bone, heart and pancreas involved in a small CE1, CE2 are active cysts; CE3 is transitional; CE4, CE5 are
proportion of patients. Usually single organ involvement (85 inactive cysts (Figs 2A to C). Plain radiography may reveal
90%) and more than 70% have only one cyst. calcified cyst, but cannot detect uncalcified cyst. Computed
In liver right lobe is affected in majority (6085%) of cases.
tomography (CT) scanning and magnetic resonance imaging
Right upper abdominal pain, due to the mass effect of the
(MRI) are also used to detect hydatid cysts and to evaluate
enlarging cyst, is the most characteristic symptom. Significant
their characteristics.
symptoms are unusual before the cyst has reached at least 10
cm in diameter.
Serologic Methods
A number of serological techniques are currently
COMPLICATIONS employed. These include complement fixation test, indirect
The most severe complications are: hemagglutination (IHA), indirect immunofluorescence, latex
Anaphylactic shock agglutination, double diffusion immunoelectrophoresis,
Cyst infection counter-current immunoelectrophoresis, radioimmunoassay,
Rupture into the biliary tree. enzyme-linked immunosorbent assay (ELISA), etc.
Spontaneous or traumatic cyst rupture during surgery may Indirect hemagglutination and ELISA are most common
lead to anaphylactic shock. However, such incidences are initial screening tests using antigens. Sensitivity of these
rare. Lack of immediate diagnosis and appropriate treatment serological tests for liver cysts is 8090% and specificity is
may lead to fatality. 8896%; sensitivity is much reduced when other organs are
Seeding of cyst content into the peritoneal cavity due to involved. For 1015% cases serology may not be positive,
cyst rupture leads to secondary hydatidosis. especially in well-encapsulated cysts and pulmonary
Cysts may become infected through bacteremia or via cysts. Hence, a negative test does not exclude diagnosis of
communicating bile ducts, especially during endoscopic echinococcosis.
Hydatid Cyst of Liver 259
Confirmatory tests using specific antigens can then be TREATMENT

performed, such as arc-5 immunoelectrophoresis and
immunoblotting Currently, three treatment options are available:
Testing for specific antibodies such as IgG subclasses has 1. Surgery
been introduced to increase sensitivity. Specificity of IgG1 2. Medical treatment
and IgG4 is high for echinococcosis (Table 2) 3. Percutaneous treatment.
The Casoni skin test, used in the past, is nonspecific and no
longer recommended
Microscopic examination of cyst fluid confirms the Surgery
diagnosis, but it is not a recommended modality for Considered gold standard as it removes cyst along with
diagnosis. its wall. Different types of surgery are done starting from
partial hepatectomy to cystectomy. The preferred surgical
Table 1: Sonographic classification of liver hydatid disease approach is pericystectomy, in which the entire cyst and
the surrounding fibrous tissue are removed. Surgery though
Cyst type Status and imaging features
curative has considerable morbidity and is expensive. In
Cystic Status: If CE: active recent years laparoscopic treatment of liver echinococcosis
lesion Unilocular, cystic lesion(s) without cyst wall. Usually round,
has become increasingly popular. Laparoscopic treatment
sometimes oval. Size variable.
CE1 Status: active
Unilocular, cystic lesion with wall. Usually round, sometimes Table 2: Sensitivities of various assays for antibody detection in
oval. Size variable. patients with confirmed cystic echinococcosis
CE2 Status: active
Test Organ sites of cysts and number of patients (N)
Multivesicular, multiseptated cysts. Cyst septations produce
wheelike, rosette-like or honeycomb-like structure. Liver (N: Lung (N: Liver and Others
Usually round, sometimes oval. Size variable. 41) 79) lung (N: 7)
(N: 49)
CE3 Status: transitional
3a: Cyst with detached membranes (water-lily sign) Sensitivity (%)
3b: Cyst with daughter cysts having echogenic area Latex agglutination 80 58 88 57
representing disrupted membranes. Shape and size variable.
Indirect 80 61 90 57
CE4 Status: inactive hemagglutination
Cyst with heterogeneous hypoechoic or hyperechoic contents.
No daughter cysts. Present as ball of wool sign indicative of Immunoelectrophoresis 68 51 71 50
degenerating membranes. Size variable. IgG-ELISA 93 83 96 93
CE5 Status: inactive *of 165 patients 79 (48%) had one cyst and 86 (52%) had more than
Cyst wall calcified. Calcification variable either partial or
one cyst
complete. Size variable.
A B C D
Figs 2A to D: WHO informal working groups on echinococcosis classification of ultrasound images of cystic echinococcosis cysts: (A) Cystic:CE,
(B) Active: CE1 and CE2; (C) Trasitional: CE3; (D) Inactive: CE4 and CE5
includes partial or total pericystectomy and cyst drainage Contraindications of Medical Therapy
with omentoplasty. Laparoscopic techniques in appropriately
selected patients, such as those with anteriorly located Inactive or calcified cysts
hepatic cysts, have high success rates, low complication rates, Decompensated chronic liver diseases
and low recurrence rates. Bone marrow depression
Pregnancy.
Medical Treatment
Percutaneous Treatment
Antihelmintics benzimidazoles like mebendazole, albend
azole are used. Benzimidazoles inhibit the assembly of Risk of anaphylaxis and intraperitoneal seeding is minimal
tubulin into microtubules, thus, impairing glucose absorption during percutaneous puncture of hydatid cysts as experiences
through the cyst wall. This causes glycogen depletion and from accidental and intended puncture of incumbent hydatid
degeneration of the endoplasmic reticulum and mitochondria cysts has proved it to be uneventful. Hence, the most widely
of the germinal layer, leading to an increase in lysosomes practiced percutaneous treatment in hepatic echinococcosis
and subsequent cellular death. Albendazole is preferred is PAIR.
to mebendazole. Albendazole is given in 3-month cycles Puncture-aspiration-injection-reaspiration or puncture,
interrupted after 28 days for 2 weeks. Medical treatment aspiration, injection and reaspiration is a newer option. It is a
using interrupted cycles appeared to be parasitostatic rather process of aspiration of substantial amounts of cyst fluid and
than parasiticidal. Therefore, continuous daily treatment injection of protoscolicidal agent (usually hypertonic saline
for a 3-month period is preferred. Recommended dosage of or ethanol) into cyst cavity guided by ultrasound or CT. This is
albendazole is 400 mg bid. followed by cyst reaspiration after at least 15 minutes.
Adverse effects of the drug include hepatotoxicity (16%), It is combined with oral albendazole to enhance response.
bone marrow changes or leukopenia (2.44%), gastrointestinal WHO recommends that medical therapy should be initiated
symptoms (4%), and other less frequent ones as alopecia, skin at least 4 days prior to a PAIR procedure and should be
reactions, or headaches. Consequently, when monitoring the continued for at least 1 month (albendazole) or 3 months
patients on this drug, periodic laboratory testing must be (mebendazole) after the procedure.
performed, especially including complete blood count and
liver function tests. Albendazole is curative in one-third of
patients (complete and permanent disappearance of cysts)
Indications for PunctureAspiration
and 3050% responds with significant regression of cyst size InjectionReaspiration
and alleviation of symptoms. The efficacy of albendazole Cysts greater than or equal to 5 cm in size (CE1)
(82%) is superior to that of mebendazole (56%). Relapse rate Cysts with detachment of membranes (CE3a)
is 25% in both treatment groups. Infected cysts
Another antiparasitic agent that has proven to be useful in Pregnancy
treating this condition is praziquantel (PZQ). Publications on Children 3 years or older
PZQ in human hydatidosis are scarce. Non-response to chemotherapy
Medical therapy should be used for: Non-response to surgery
Small cyst less than 5 cm (CE1, CE3a) Relapse after surgery
Inoperable or unfit for surgery
Multiple cysts in two or more organs
Multiple small liver cysts or inaccessible locations Contraindications for PunctureAspiration
Peritoneal cysts InjectionReaspiration
Relapse after surgery
Noncooperative patient
As secondary prevention in spontaneous rupture, surgery
Inaccessible or risky locationsuperficial cyst or located
or aspiration of cysts [punctureaspirationinjection
in spine, brain, heart
reaspiration (PAIR)]
Inactive or calcified cyst (CE4)
Medical treatment alone is not effective in cysts more than
Cysts communicating with biliary tree, abdominal cavity,
5 cm or multiseptated cyst (CE2, CE3b). Here, combination
urinary tract.
with percutaneous aspiration or surgery is recommended
Punctureaspirationinjectionreaspiration has been used
where applicable.
predominantly for cysts in the liver, although cysts in other
Hydatid Cyst of Liver 261
sites (e.g. abdominal cavity, spleen, kidney) occasionally On CT or MRI, degenerating cysts are often surrounded by
have been treated in this fashion. Complications have been a dense halo.
observed more frequently when PAIR is used for pulmonary Serologythe use of serologic titers to monitor therapy has
cysts, therefore not recommended in pulmonary cysts. also been assessed. Titers usually fall 12 years after successful
Percutaneous drainage has gained much acceptability surgery and will rise again if recurrence or secondary lesions
because of minimal invasiveness, low morbidity, less develop. Specific IgE antibody titers, IgG4 antibody and arc
hospitalization time. 5-based tests have been shown to be more sensitive than other
tests. However, no serologic test has consistently proven to be
The potential risks of PAIR procedure are: reliable in monitoring patients on chemotherapy for hydatid
Same risks as any puncture (hemorrhage, mechanical disease and antibodies may remain elevated even many years
lesions of other tissues, infections) after successful cyst removal.
Anaphylaxis
Secondary echinococcosis (spillage)
Chemical (sclerosing) cholangitis (biliary communication) PREVENTION
Biliary fistulas
Persistence of satellite daughter cysts Prevention of cystic echinococcosis often can be achieved
Systemic toxicity of alcohol or hypertonic saline (in case of simply by avoiding close contact with dogs. Careful washing
large cysts). of vegetables reduce the incidence of infection. Prohibition
The overall complication rates in percutaneous drainage of open slaughtering of sheep, goats and cows also prevent
vary from 15 to 40%. Major complications like anaphylactic dogs from consuming infected viscera, thus disrupting the life
shock range from 0.1 to 0.2%, and minor complications cycle of the parasite.
(urticaria, itching, hypotension, fever, infections, fistula, and Monitoring of the dog population, control of dog-transmitted
zoonoses, improvement of slaughtering procedures and
rupture in biliary system) vary from 10 to 30%.
destruction of infected viscera, health education, and inter-
professional cooperation are all measures that may reduce the
Monitoring the Response to Therapy incidence of CE.
Evaluating the success of any form of therapy is difficult and
usually requires follow-up imaging at 36 month intervals.
Ultrasoundradiologic changes seen on ultrasound that BIBLIOGRAPHY
seem to correlate with effective therapy include: 1. Chin J. Echinococcosis. In: Control of communicable diseases
Reduction in cyst size and volume manual. Washington, DC: American Public Health Association;
Separation of the endocyst from the pericyst and 2000. pp. 176-9.
detachment or collapse of membranes leading to a split 2. Eckert J, Deplazes P. Biological, epidemiological, and clinical
wall (water lily sign) (seen in PAIR procedure) aspects of echinococcosis, a zoonosis of increasing concern. Clin
Decrease in size or number of daughter cysts and/or Microbiol Rev. 2004;17(1):107-25.
rupture of vesicles in multivesicular cysts 3. Guidelines for treatment of cystic and alveolar echinococcosis in
humans. WHO Informal Working Group on Echinococcosis. Bull
Decrease in fluid within the cyst and increase of the solid
World Health Organ. 1996;74(3):231-42.
component, leading first to the development of internal
4. Khan M, Rahman S, Brunette E, et al. Percutaneous Aspiration
echoes within the cyst (heterogeneous echo pattern) and
of Echinococcal Cysts (PAIR). Ultrasound International.
then to obliteration of the cyst cavity by echogenic material 2004;10(4):144-9.
(pseudotumor echo pattern) 5. Orduna A, Zarzosa P, Abad R, et al. Influence of factors related
Thickening and irregularity of the cyst wall to cysts in the sensitivity of six serological tests for diagnosis of
Complete disappearance of the cyst. human hydatid disease. Arch Int Hydatid. 1997;32:280-6.
Relapse is suggested on ultrasound by the development 6. Vuitton DA, Meslin F, MacPherson C, (Eds). World Health
of new cysts, increase in the volume of the cyst, appearance Organization Informal Working Group on echinococcosis. PAIR:
or increase of the liquid component of the matrix, and an option for the treatment of cystic echinococcosis. Bull World
disappearance of a visibly detaching membrane. Health Organ; 2002.
30
cHAPTER
Leptospirosis
Izazul Haque, Fazal Karim
INTRODUCTION RISK FACTORS

Leptospirosis is a zoonosis caused by bacteria of the genus Risk factors for infection include exposure to contaminated
Leptospira. It is globally distributed and is a major zoonotic environment by:
health problem in developing countries. Weil reported this High risk profession: farmers, veterinarians, sewer
biphasic illness (consistent with leptospirosis) in 1886, and it workers, laboratory workers, etc.
is now termed Weils disease. Recreational: fresh water swimming
Leptospirosis is also known as Weils disease, Swineherds Natural disaster: flooding, etc.
disease, autumn fever, swamp fever, mud fever, hemorrhagic Occupational exposure to farmers, ranchers, abattoir
jaundice, Stuttgart disease, and even canicola fever. workers, veterinarians, sewer workers, rice field workers,
But that is not all. It is also referred as Andaman military personnel and laboratory workers
hemorrhagic fever in India, Fort Bragg fever in United States, Recreational activities like fresh water swimming
7 day fever in Japan, rice field leptospirosis in Indonesia and Household exposure to pet dogs, livestock, rainwater and
cane cutters disease in Australia. infestation by infected rodents.
Leptospirosis in humans is commonly seen in teenage
children and young adults but can occur in all age groups.
EPIDEMIOLOGY Person to person transmission is extremely rare. Cases
are seen sporadically throughout the year but outbreaks
The majority of leptospirosis cases occur in the tropics, usually occur during the rainy season due to widespread
although cases are also observed in temperate regions. contamination of water by urine of infected rodents.
Mammals (other than human) are natural host of
this organism. Exposure to animal urine contaminated
environment is believed to be one of the main reasons MICROBIOLOGY
behind human infection. The organism infects a wide range
of mammals; both domestic and wild; however, rodents, Leptospira consists of two species, L. interrogans and L.
bovines, swine, and dogs appear more in numbers. biflexa, only the former is known to cause human disease.
The most frequent hosts are small rodents especially Twenty-three serogroups and more than 200 serovars
the common rat and once infected, the organism persist of L. interrogans have been identified so far. Particular
indefinitely in their convoluted tubules of kidney. There they serogroups are associated with characteristic animal hosts;
multiply and secrete offspring through urine continuously or L. icterohaemorrhagiae is the classical parasite of rats, L.
in spells contaminating soil, water, etc. where, the organism canicola of dogs, L. hebdomadis of cattle and L. pomona of
can remain active for days to months. Abraded skin, mucous pigs.
membranes are usual entry point of organism to new hosts. Leptospira are tightly coiled, thin, flexible aerobic spirochetes
Infection through contaminated food is rare. However, 515 mm long, with very fine spirals 0.10.2 mm wide, which are
whether Leptospira has the ability to penetrate skin is actively motile by rotating and bending. The name interrogans
unknown. has been given to the organism because one or both ends of
Leptospirosis 263
this single cell organism are bent or hooked, resembling a leads to jaundice. Aseptic meningitis can be documented in
question mark. These are best viewed by dark field, silver stain 5085% of patients if CSF is examined after 7 days of illness.
or fluorescent microscopy. Blood, urine and cerebrospinal fluid The meningitis is thought to be secondary to a host immune
(CSF) are required to grow Leptospiral interrogans in laboratory. response to the organism rather than to direct infection.
Individual special media, i.e. fletchers, ellinghausens or
polysorbate 80 is required for isolation; hence, it is a better
approach to inform laboratory technician in advance if the isolate CLINICAL MANIFESTATIONS
Leptospira is desired. Growth may be observed within 2 weeks;
however, in some rare cases it may take up to 3 months. Clinical course of leptospirosis is variable. It usually presents
as a self-limiting febrile illness followed by seroconversion
or rarely as severe, potentially fatal illness entwined with
PATHOGENESIS multiorgan failure. The incubation period is usually 712
days (range 220 days) (Fig. 1). In 510% of cases the disease
After entry, the organism multiplies in the blood. They then evolves into severe jaundice, also known as Weils disease.
distribute throughout the body; organs mostly affected are The natural course of leptospirosis falls into two distinct
the kidneys, liver, meninges, and brain. The mechanism of phases: septicemic and immune.
tissue injury is uncertain since it is often associated with lysis
of the organisms rather than their multiplication. There are
three main pathogenic form of the disease: hemorrhagic, Septicemic Phase
icteric, and renal. But pathological changes may occur in The name of the first phase is derived from the fact that the
other organs like lungs, heart, brain, and eyes. organism may be isolated from blood cultures, CSF and
In kidney involvement the organism travels to interstitium, tissues. In this initial stage, lasting 47 days, patient may
renal tubules, tubular lumen and causes interstitial nephritis experience varying degrees of flu like illness with fever, chills,
and tubular necrosis. Renal failure is primarily triggered by weakness, headache, malaise and myalgias affecting calf
tubular damage but in cases hypovolemia from dehydration muscles, back and abdomen. Less common presentations
and altered capillary permeability may also contribute. are diarrhea, vomiting, sore throat, cough, chest pain,
Liver involvement is seen as centrilobular necrosis with hemoptysis, rash and photophobia. Conjunctival congestion
proliferation of Kupffer cells. Hepatocellular dysfunction is the only notable physical sign. Patient may experience 13
Fig. 1: Clinical and laboratory profile of leptospirosis

days of brief improvement when the temperature will fall, DIFFERENTIAL DIAGNOSIS
with physical well-being. However, fever may recur, indicating
onset of second phase. Leptospirosis is often confused with a number of different
infectious diseases. Hence, it is important to remember
that conjunctival suffusion is one of the most reliable
Immune Phase distinguishing features, due to the fact that it rarely occurs in
This phase results from bodys immunologic response to other illnesses.
infection. Lasting from few days to few weeks, it often results Differential diagnosis includes common febrile illness like
in specific organ failure. The meninges, liver, eyes, and malaria, dengue, and rickettsial disease like scrub typhus,
kidneys are most common organs affected. Fever, myalgia like Salmonella typhi and influenza.
nonspecific symptoms are less severe in this phase.
In the immune anicteric stage, aseptic meningitis is the
most important clinical syndrome. Classically it is associated
with L. canicola infection and is very difficult to distinguish
LABORATORY DIAGNOSIS
from viral meningitis. Almost half of the patients develop Common laboratory tests are nonspecific and noncon
meningeal symptoms. Cranial nerve palsies, encephalitis clusive.
and changes in consciousness are less common, presenting Identification of leptospirosis depends on isolation of
with mild delirium. Meningitis usually lasts from few days to the organism, serological tests or the detection of specific
2 weeks. DNA.
Uveitis can develop in any phase of the disease. However,
iridocyclitis and chorioretinitis are related with late
complications and often persist for years. Up to 90% patients Blood
develop subconjunctival hemorrhage. These symptoms first
manifest 3 weeks to 1 month after exposure. White blood cell counts generally show polymorphonuclear
Pulmonary manifestations are characterized by leukocytosis; in about two-thirds of the patients, a shift to
hemoptysis, dyspnea, respiratory failure, and patchy lung the left is seen. Elevated creatine kinase can be a useful
infiltrates on chest X-ray. Total bilateral lung consolidation clue for diagnosis since it is found in approximately 50%
and acute respiratory distress syndrome (ARDS) develops in of patients. Approximately 40% patients have minimal
fatal cases. Pulmonary hemorrhage is the main cause of death to moderate elevations of hepatic transaminases. The
due to leptospirosis in some countries. bilirubin concentration reaches 6080 mg/dL occasionally,
Weils disease is the severe form of leptospirosis and is while jaundice is only observed in patients with Weils
a dramatic life-threatening event, characterized by fever, disease. Prothrombin time may be a little prolonged.
severe jaundice, renal impairment, pulmonary dysfunction, Thrombocytopenia is often seen in severe infection.
and hemorrhagic manifestations. It occurs at the end of the Pancytopenia has been reported as the presenting
first stage and peaks in the second stage; however, the patient manifestation in case reports with complete resolution
may deteriorate suddenly at any time. Fever may be marked following treatment with penicillin. Hyponatremia is common
during the second stage. Conjunctival suffusion is a frequent in severe leptospirosis.
feature. Hemorrhagic manifestations include erythematous
rash, purpura, and ecchymosis. In severe cases, there may be
epistaxis, hematemesis and melena. Urine
Cough, dyspnea, chest pain, blood-stained sputum,
Urine analysis results frequently come up with proteinuria,
hemoptysis and respiratory failure are part of pulmonary
pyuria, granular casts and occasionally red blood cells.
manifestations. Patients with severe Weils disease are more
prone to develop renal failure, hemorrhagic manifestations
and cardiovascular collapse. During the second week of
illness, hypovolemia and decreased renal perfusion may
Cerebrospinal Fluid Study
cause oliguric or anuric acute tubular necrosis. Other Upon analysis CSF shows a neutrophilic or lymphocytic
presentations are multiorgan failure, rhabdomyolysis, adult pleocytosis with varied level of elevated protein
respiratory distress syndrome, hemolysis, splenomegaly, concentrations and normal glucose. Low CSF glucoseconc
congestive cardiac failure, myocarditis, and pericarditis. entration is rare.
Leptospirosis 265
Imaging amoxicillin (2550 mg/kg in three equally divided doses) is

recommended.
X-rays of chest may show small nodular densities but has the For hospitalized adult patients with severe disease,
potential to progress to confluent consolidation or ground intravenous therapy with penicillin G 6 million units daily,
glass appearance. These represent alveolar hemorrhage, ceftriaxone 1 g daily or cefotaxime (1 g every 6 hours) is the
ARDS or pulmonary edema pathologically. recommended modality. It is especially effective if started
within the first 4 days of illness. JarischHerxheimer reactions
Culture may occur during treatment but usually mild. Azithromycin is
also active, but clinical experience is limited.
Culture of the organism in appropriate media can confirm Uveitis is treated with systemic antibiotic and local
presence of leptospirosis. During the first 10 days blood corticosteroid.
and CSF specimens are positive. In almost 50% of the cases Other than specific treatment, supportive care in critically
isolation of organism from blood is successful. Urine cultures ill patient is important. Hemorrhagic manifestation should
become positive only from second week of illness and persist be treated by prompt blood transfusion. Renal damage is
for up to 30 days after the resolution of symptoms. essentially reversible and peritoneal dialysis or hemodialysis
may be life-saving. Patients with multiorgan failure should be
treated in intensive care unit.
Serology
Serological tests are mostly used for diagnosis. These
are microscopic agglutination test (MAT), macroscopic PROGNOSIS
agglutination test, indirect hemagglutination, microcapsule
agglutination test, compliment fixation test and enzyme- Prognosis depends on the virulence of the infecting strain
linked immunosorbent assay (ELISA). and immunity of the host. Without jaundice, the disease is
Among the mentioned serological tests, MAT is considered almost never fatal and most patient recovers. With jaundice,
most reliable for diagnosis of leptospirosis. MAT is most the mortality rate is 5% for those under age 30 years and 30%
specific when a fourfold or greater rise in titer is detected for those over age 60 years. Long-term prognosis after acute
between acute and convalescent serum specimens. However, renal failure and meningitis is good. Severe disease with
a single titer of greater than 1:800 is strongly suggestive of pulmonary syndrome or with multiorgan dysfunction can be
current or recent infection with Leptospira. associated with very high mortality (>50%).
Serology becomes positive at the end of second week.
Commercially available rapid tests are available like
microplate IgM ELISA and IgM dot-ELISA dipstick test. PREVENTION
Difficulty in eradication of leptospirosis from wild animals
Molecular Methods leads to continuous infection of domestic animals. This has
Molecular techniques, such as polymerase chain reaction made prevention of leptospirosis a very tough call. Among
(PCR), show great promise as a rapid and specific means of the practiced preventive measure includes, control of
diagnosis of leptospirosis. PCR can detect leptospiral DNA in livestock infection with good sanitation, immunization and
blood in early symptomatic disease and positive in urine from proper veterinary care, preventing infected animals from
the eighth day and for many months afterward. urinating in waters where humans have contact, disinfecting
contaminated working places, training workers, practicing
good personal hygiene, and using personal protective
TREATMENT equipment, etc.
Leptospira is sensitive to moist heat and pasteurization
Majority of infections with Leptospira are self-limiting. and is killed by house-hold disinfectants and diluted
Recommended regimens include doxycycline, tetracycline, bleach solution. Among the public health measures are
intravenous penicillin, and third generation cephalosporins. identification of contaminated water supplies, rodent control
Doxycycline is given in oral dose of 100 mg twice daily for and prohibition of swimming in lakes where risk of infection
7 days. Tetracycline 2 g orally is an alternative and has the are considered high or critical. It is also imperative to inform
advantage of eliminating the organism from the kidney. In people of such risk when theyre involved in recreation
children less than or equal to 8 years or pregnant women, activities like fishing.
Prophylaxis with doxycycline, 200 mg orally once weekly, 8. Im JG, Yeon KM, Han MC, et al. Leptospirosis of the lung:
can be given during periods of possible exposure. radiographic findings in 58 patients. AJR Am J Roentgenol.
In some European and Asian countries high-risk individuals 1989;152(5):955-9.
are offered vaccination. However, vaccines are not in use in 9. Jena AB, Mohanty KC, Devadasan N. An outbreak of leptospirosis
United States. These human vaccines are serovar-specific and in Orissa, India: the importance of surveillance. Trop Med Int
Health. 2004;9(9):1016-21.
needs to be repeated annually. Vaccine given should contain
10. Johnson WD, Silva IC, Rocha H. Serum creatine phosphokinase in
the serovars known to be prevalent in the area.
leptospirosis. JAMA. 1975;233(9):981-2.
Doxycycline may be given to prevent the disease from
11. Karande S, Gandhi D, Kulkarni M, et al. Concurrent outbreak of
spreading when exposed since at the dose of 200 mg
leptospirosis and dengue in Mumbai, India, 2002. J Trop Pediatr.
every week the drugs has a efficacy of 95%. However, this
2005;51(3):174-81.
regimen is recommended only to those with short-term
12. Katz AR, Ansdell VE, Effler PV. Assessment of the clinical
exposure and is not for repeated exposure over protracted
presentation and treatment of 353 cases of laboratory-
periods.
confirmed leptospirosis in Hawaii, 1974-1998. Clin Infect Dis.
2001;33(11):1834-41.
13. Merien F, Portnoi D, Bourhy P, et al. A rapid and quantitative
BIBLIOGRAPHY method for the detection of Leptospira species in human
1. Acha PN, Szyfres B. Leptospirosis. In: Zoonoses and leptospirosis. FEMS Microbiol Lett. 2005;249(1):139-47.
Communicable Disease Common to Man and Animals, 3rd Pan 14. Rathinam SR, Rathnam S, Selvaraj S, et al. Uveitis associated
American Health Organization. Washington, DC; 2001. pp. 157. with an epidemic outbreak of leptospirosis. Am J Ophthalmol.
2. Bovet P, Yersin C, Merien F, et al. Factors associated with clinical 1997;124(1):71-9.
leptospirosis: a population-based case-control study in the 15. Romero EC, Billerbeck AE, Lando VS, et al. Detection of Leptospira
Seychelles (Indian Ocean). Int J Epidemiol. 1999;28(3):583-90. DNA in patients with aseptic meningitis by PCR. J Clin Microbiol.
3. Carvalho CR, Bethlem EP. Pulmonary complications of 1998;36(5):1453-5.
leptospirosis. Clin Chest Med. 2002;23(2):469-78. 16. Sanford JP. Leptospirosis--time for a booster. N Engl J Med.
4. Cetin BD, Harmankaya O, Hasman H, et al. Acute renal failure: 1984;310(8):524-5.
a common manifestation of leptospirosis. Ren Fail. 2004;26(6):
17. Segura ER, Ganoza CA, Campos K, et al. Clinical spectrum
655-61.
of pulmonary involvement in leptospirosis in a region of
5. Chawla V, Trivedi TH, Yeolekar ME. Epidemic of leptospirosis: an
ICU experience. J Assoc Physicians India. 2004;52:619-22. endemicity, with quantification of leptospiral burden. Clin Infect
6. Dupont H, Dupont-Perdrizet D, Perie JL. Leptospirosis: prognostic Dis. 2005;40(3):343-51.
factors associated with mortality. Clin Infect Dis. 1997;25(3): 18. Sejvar J, Tangkanakul W, Ratanasang P, et al. An outbreak of
720-4. leptospirosis, Thailand--the importance of the laboratory.
7. Farr RW. Leptospirosis. Clin Infect Dis. 1995;21(1):1-6. Southeast Asian J Trop Med Public Health. 2005;36(2):289-95.
31
cHAPTER
Cirrhosis of Liver
Anil Arora, Ashish Kumar
INTRODUCTION Table 1: Etiology of cirrhosis
Category Agent
Cirrhosis is one of the leading causes of mortality and morbidity
and is an enormous worldwide healthcare problem. One- Drugs and toxins Alcohol
Methotrexate
year mortality due to cirrhosis can range from 1% in early
Isoniazid
cirrhosis to 57% in decompensated cirrhosis. The occurrence Methyldopa
of complications of cirrhosis increases the mortality in
Infections Hepatitis B and C viruses
these patients; therefore, early detection and treatment of Schistosoma japonicum
complications of cirrhosis is of major importance.
Autoimmune/immune-mediated Primary biliary cirrhosis
Liver cirrhosis is defined as the histological development of Autoimmune hepatitis
regenerative nodules surrounded by fibrous bands in response Primary sclerosing cholangiitis
to chronic liver injury, which leads to portal hypertension Metabolic Wilson's disease
and end-stage liver disease regardless of etiology. Cirrhosis Hemochromatosis
is a frequent consequence of the long clinical course of most 1-antitrypsin deficiency
chronic liver diseases of any etiology. Alcohol abuse and viral Glycogen storage diseases
hepatitis are the most common causes of cirrhosis, although Biliary obstruction Cystic fibrosis
nonalcoholic fatty liver disease is emerging as an increasingly (secondary biliary cirrhosis) Biliary atresia
Biliary strictures
important cause (Table 1).
The pathological pathway in the development of cirrhosis Vascular Chronic right heart failure
Budd-Chiari syndrome
is through the initiation and maintenance of fibrosis pathways
Veno-occlusive disease
and development of regenerating nodules. Cirrhosis is said
Miscellaneous Nonalcoholic steatohepatitis
to occur when the fibrotic liver disease becomes irreversible.
Sarcoidosis
Once cirrhosis occurs, even with the removal or control of the Cryptogenic (unknown)
inciting stimulus, the presence of architectural distortion may
still lead to consequences of cirrhosis (e.g. portal hypertension
and esophageal varices) that may not be directly related to the cirrhosis. It results from an increased intrahepatic resistance
primary disease etiology. However, now there is accumulating due to distorted architecture of liver combined with increased
evidence that even comparatively advanced fibrosis and portal blood flow. Portal hypertension is conventionally
cirrhosis can be reversed if the inciting stimulus for fibrosis is measured by hepatic venous pressure gradient (HVPG) and a
removed. value over 5 mm Hg signifies portal hypertension. When the
One of the fundamental functions of the liver is the HVPG is above 10 mm Hg, it is known as clinically significant
detoxification of potentially harmful substances received portal hypertension (CSPH) as most of the complications of
from the splanchnic circulation, especially the bacterial end portal hypertension begin to appear above this level.
products. With failure of this function in cirrhosis, the bacterial Cirrhosis is said to be compensated when complications,
endotoxins are not neutralized, leading to the establishment such as variceal bleeding, ascites, or jaundice have not
of a systemic proinflammatory state which further accelerates occurred. When any of these complications have occurred, the
the disease progression. patient is said to have decompensated cirrhosis. In advanced
Portal hypertension is the most important consequence stages of cirrhosis, other organ systems of the body, such
of cirrhosis, and it underlies most of the complications of as nervous system, excretory system, respiratory system,
circulatory system, and hematological system frequently get Regardless of the nature of the initial insult, the cellular
affected, and thus, cirrhosis becomes systemic illness and not mechanisms leading to cirrhosis are common. Initially, the site of
just a disease of the liver. injury within the liver lobule may vary with etiology: viral hepatitis
In liver cirrhosis there is a constant stimulus for initially causes periportal inflammation, while alcoholic liver
hepatocellular regeneration in a microenvironment of disease initially causes pericentral damage. Continued injury
chronic inflammation and tissue fibrosis. This presents an with the inciting agent eventually lead to panlobular cirrhosis.
ideal breeding ground for the development of liver cancer or Fibrosis and cirrhosis represent a continuous pathological
hepatocellular carcinoma (HCC). spectrum, characterized not only by an increase in total
collagen and other matrix proteins compared to normal, but
also qualitative change in their nature and distribution within
PATHOGENESIS OF CIRRHOSIS the liver. The hepatic stellate cell (HSC) is the major cell type
involved in the pathogenesis of liver fibrosis and cirrhosis
Cirrhosis is a diffuse process characterized by tissue fibrosis (Fig. 1). HSCs have primary role in retinoid storage and are
and the conversion of normal liver architecture into structurally situated in the subendothelial space of Disse. When there is
abnormal nodules. The key morphological features of cirrhosis liver injury, HSCs proliferate, lose their retinoid droplets and
include: diffuse hepatic fibrosis, regenerative nodules, altered are activated to a myofibroblast-like phenotype. The activated
lobular architecture and establishment of intrahepatic vascular HSCs are the major source of collagen and noncollagenous
shunts between afferent (portal vein and hepatic artery) and matrix proteins leading to fibrosis. The majority of excess matrix
efferent (hepatic vein) vessels of the liver. Other relevant protein that accumulates in liver fibrosis is of type I and type
characteristics include: capillarization of sinusoids and III collagen deposited by the activated HSCs, with virtually
perisinusoidal fibrosis, vascular thrombosis and obliterative no contribution by the liver parenchymal cells. The other
lesions in portal tracts and hepatic veins, under-perfusion of function of HSCs is to express a repertoire of enzymes from
lobular parenchyma and consequent tissue hypoxia. the metalloproteinase family, which degrade excess collagens.
Fig. 1: Pathogenesis of cirrhosis (from Gressner OA, Weiskirchen R, Gressner AM. Evolving concepts of liver fibrogenesis provide new
diagnostic and therapeutic options. Comp Hepatol. 2007;6:7.)
Cirrhosis of Liver 269
Metalloproteinase activity decreases fibrosis, and it has been Table 2: Presentation of cirrhosis
shown that various specific tissue metalloproteinase inhibitors
Asymptomatic
are increased during liver fibrosis. Thus, the development
Nonspecific symptoms
of cirrhosis represents an aberrant balance between matrix
synthesis and degradation. Lethargy, malaise and abdominal pain
Kupffer cells (hepatic macrophages) are one of the main Symptoms of portal hypertension
players in HSC activation during injury. Growth factors, Gastrointestinal bleeding
particularly transforming growth factor beta 1 (TGF-1), Ascites
have been implicated in the mechanisms underlying the
Symptoms of hepatocyte dysfunction
stimulatory effects of Kupffer cells. The parenchymal cell
Coagulation abnormality
contribution to HSC activation comes from the injured cell
membranes of the necrosed parenchymal cells which produce Pruritus
lipid peroxidases and the apoptotic parenchymal cells which Pigmentation
release the insulin-like growth factor. Both these factors Jaundice
contribute to HSC activation. The activated HSCs express Hepatic encephalopathy
numerous cytokines, including platelet-derived growth
Liver failure
factor, a potent proliferative cytokine for HSC, and TGF-1,
Acute-on-chronic liver failure
a potent fibrogenic mediator, thus sustaining activation and
proliferation of HSCs and persistent fibrogenesis. The matrix Decompensated end-stage liver disease
is initially laid down in the space of Disse causing endothelial Liver cancer
cells to lose their fenestrae leading to capillarization of
the space of Disse. Liver parenchyma gets distorted with jaundice. Unfortunately, often many patients present only
formation of fibrous septae, as the disease progresses. when they have developed serious complications of cirrhosis.
Ultimately, the vascular structures become linked, leading to Altered mentation may indicate hepatic encephalopathy while
the grossly distorted architecture of cirrhosis. The nodules of presentation with gastrointestinal bleeding due to esophageal
regenerating parenychmal cells expanding against a capsule varices occurs when portal hypertension has advanced. Rapid
of fibrotic bands further worsen the hepatic architecture. The development of liver failure may occur in a syndrome called
histological classification of cirrhosis depends on the size acute-on-chronic liver failure where cirrhosis has been
of the regenerating nodules, with micronodular cirrhosis complicated by an acute precipitating event, such as acute viral
being defined as having uniform nodules of less than 3 mm in hepatitis or sepsis. In decompensated end-stage liver disease
diameter, whereas in macronodular cirrhosis, the majority of there is a slow but steady decline in liver functions eventually
nodules are greater than 3 mm in diameter. However, often a leading to liver failure. In rare cases, liver cancer may be the
mixed nodularity may exist. first presentation of cirrhosis.
Parenychmal dysfunction and portal hypertension develops
with advanced cirrhosis. Hepatocyte dysfunction occurs, in
part, as a result of altered cell-matrix interactions, which result DIAGNOSIS
from replacement of the normal basement membrane-like
matrix with fibrotic matrix. Although cirrhosis is a histological diagnosis, however
at present times, histology is rarely required to diagnose
cirrhosis. Most often diagnosis of cirrhosis is based on
CLINICAL PRESENTATION clinical presentation and basic laboratory and radiological
investigations.
Clinical presentation of liver cirrhosis depends on the stage of Physicians should inquire about risk factors that predispose
the disease. In the initial stages, cirrhosis may be asymptomatic patients to cirrhosis, such as history of alcoholism, hepatitis
and discovered incidentally on routine clinical or laboratory B and C transmission, and personal or family history of
evaluation (Table 2). In the later stages the symptoms may autoimmune or hepatic diseases. Physical examination of
vary depending on the etiology of cirrhosis, stage, and whether patients with cirrhosis may reveal a variety of findings that
liver cell dysfunction or portal hypertension predominates. should lead to a targeted hepatic workup. These findings
Presentation may be with nonspecific symptoms, such as, include: ascites, icterus, asterixis, splenomegaly, hepatomegaly,
lethargy, malaise and abdominal pain, or the symptoms may testicular atrophy, gynecomastia, clubbing, abdominal
be liver-specific, such as, pruritus, pigmentation, ascites or wall vascular collaterals (caput medusa), palmar erythema,
Cruveilhier-Baumgarten murmur (a venous hum in patients

with portal hypertension), Dupuytrens contracture, parotid
enlargement, fetor hepaticus, and vascular spiders (spider
telangiectasias, spider angiomata).
Liver Function Tests

When a liver abnormality is suspected or identified, a liver
panel, a complete blood count (CBC) with platelets, and a
prothrombin time test with international normalized ratio
(INR) should be performed. Common tests in standard liver
panel or liver function tests (LFTs) include the serum enzymes
aspartate transaminase (AST), alanine transaminase (ALT),
alkaline phosphatase, and gamma-glutamyltransferase; total,
direct, and indirect serum bilirubin; and serum albumin. LFTs
cannot diagnose cirrhosis, however, they are helpful screening Fig. 2: Transient elastography (FibroScan) machine and probe
tools to detect hepatic dysfunction, to estimate the severity of
hepatic disease, and for the follow-up of liver diseases. Since
liver performs a variety of functions, no single test is sufficient tissue. The ultrasound transducer then detects the propagation
alone to provide complete estimate of function of liver. Effective of the shear wave through the liver by measuring its velocity
interpretation of the hepatic function panel requires knowledge at a depth from 25 to 65 mm below the skin surface. The shear
of underlying pathophysiology and the characteristics of wave velocity is directly related to the liver stiffness, with a
panel tests. Moreover, because laboratory testing is routine, higher velocity equating to higher stiffness, corresponding to
an abnormal serum transaminase or alkaline phosphatase increasing severity of fibrosis. The test is performed with the
in patients without clinical symptoms is not uncommon. patient lying in the supine position, with the probe placed
Whilst LFTs can theoretically remain within normal limits in at the intercostal space overlying the liver. Ten validated
cirrhosis, they serve as a useful baseline and may provide a measurements are required, with the median value taken as
pointer toward etiology. When cirrhosis is advanced leading the final result, which is expressed in units of kilopascals (kPa).
to hepatic synthetic dysfunction, serum albumin levels and The range of possible liver stiffness values obtained with TE is
INR becomes abnormal. The ALT is thought to be the most from 2.5 to 75.0 kPa, with the normal liver stiffness value for
cost-effective screening test for identifying metabolic or drug- healthy individuals being around 5.5 kPa. The age of the subject
induced hepatic injury, but like other liver function tests, it is does not affect liver stiffness, and males tend to have a slightly
of limited use in predicting degree of inflammation and of no higher liver stiffness value compared to females. TE has been
use in estimating severity of fibrosis. shown to be highly reproducible with minimal inter- and intra-
observer variability. TE is an excellent tool for early detection
of cirrhosis and evaluation of portal hypertension, for which it
Elastography may have prognostic value as well. Cirrhosis is diagnosed when
Elastography is a noninvasive imaging modality that maps the TE values are above 13 to 17 kPa, depening on the etiology. The
elastic properties of soft tissue and is used for the assessment advantages of TE are that the results are immediately available,
of hepatic fibrosis in patients with chronic liver disease by and the procedure is painless, rapid (approximately 5 minutes
measuring liver stiffness. This modality emerged in the last per patient), and easy to perform. Limitations include failure
decade and it includes ultrasound based elasticity imaging (no value) in around 5% of cases, mainly in patients with
and magnetic resonance based elasticity imaging. The most substantial thoracic fat or significant ascites.
widely used ultrasound based elastography modality is the Acoustic Radiation Force Imaging (ARFI) is another
Transient Elastography (TE, FibroScan) which is a technique ultrasound based noninvasive procedure that is similar to
that uses both ultrasound (5 MHz) and low-frequency (50 Hz) TE and is used to assess liver fibrosis. It uses short, high-
elastic waves, whose propagation velocity is directly related to intensity pulses of acoustic radiation to displace tissue in the
elasticity. The probe consists of an ultrasound transducer which body. These high intensity pulses are followed by a series of
is located at the end of a vibrating piston (Fig. 2). The piston diagnostic pulses which assess the magnitude of displacement
produces a vibration of low amplitude and frequency, which at multiple locations. Images are displayed as a grayscale map
generates a shear wave that passes through the skin and liver of relative tissue elasticity; bright regions represent tissue
sensitive manner. The accuracy of CEUS is comparable with

helical-CT or MRI, and CEUS is very useful in the evaluation
of response to ablation therapy of hepatocellular carcinoma.
Computed tomography (CT) scanning complements
ultrasound imaging. In addition there may be classical
appearances in some diseases, e.g. hemochromatosis where
the excess iron deposition causes a dramatic increase in hepatic
density. Magnetic resonance imaging (MRI) shows promise
and is particularly valuable in determining the nature of focal
lesions, such as hepatic metastases or nodular regeneration,
which can be difficult to differentiate from cirrhosis by
Fig. 3: Magnetic resonance elastography images ultrasound.
that is less stiff. MR elastography (MRE) is a noninvasive MRI Liver Biopsy

based elastography technique which is performed by using a Needle biopsy of the liver is considered the gold-standard
vibration source to generate low frequency mechanical waves for diagnosis of hepatic fibrosis and cirrhosis. However, in
in tissue, imaging the propagating waves using a phase contrast todays medical practice, cirrhosis is less often diagnosed by
MRI technique, and then processing the wave information to liver biopsy. When physical examination or standard laboratory
generate quantitative images showing mechanical properties tests reveal clear-cut signs of portal hypertension, liver biopsy
such as tissue stiffness. In this color-coded image, areas toward will seldom add useful information. Similarly, when imaging
the red end of the spectrum are stiffer and therefore contain studies provide compelling evidence of cirrhosis and portal
more fibrosis than areas toward the violet end of the spectrum hypertension, needle biopsy is not warranted. Liver biopsy is
(Fig. 3). The disadvantages of MRE are its limited availability not risk-free, lacks accuracy, and is poorly accepted by some
and high costs. patients.
Despite aforementioned advances in imaging and
Imaging laboratory investigations, percutaneous liver biopsy may
remain the cornerstone of management in following situations:
Ultrasound (US) allows for a quick, precise, noninvasive when there is diagnostic uncertainty (e.g. in patients with
and safe examination of the liver parenchyma, the vascular atypical features); when there are coexisting disorders (e.g.
structures, the biliary tract, and the abdominal cavity. Apart human immunodeficiency virus [HIV] and hepatitis C virus
from the diagnosis of portal hypertension in liver cirrhosis infection, or alcoholic liver disease and hepatitis C); when
a portal vein thrombosis should be detected or excluded in there is an overlapping syndrome (e.g. primary biliary cirrhosis
cases of new or refractory ascites. Optimized US technique with autoimmune hepatitis); when hereditary disorders
is crucial for accurate diagnosis of the cirrhotic liver and its (e.g. hemochromatosis, alpha-1 antitrypsin deficiency,
complications. Various ultrasound techniques are already and Wilson disease) are suspected; when in autoimmune
in routine use, such as grey-scale imaging, Doppler US, and hepatitis a physician is considering reducing or discontinuing
contrast-enhanced US (CEUS). Grey-scale imaging may immunosuppressive therapy (to monitor the plasma cell score
demonstrate changes, such as volume redistribution, capsule on histology which may help predict relapse); and after liver
nodularity, parenchymal nodularity, and echotexture changes. transplantation to assess for rejection and the presence and
Importantly, it also provides a practical and widely available intensity of disease recurrence.
means of excluding biliary obstruction in patients who present Liver biopsy procedure is quick and simple to perform in
with jaundice. The Doppler findings in the hepatic and portal a cooperative patient with a normal international normalized
veins, hepatic artery, and varices allow assessment of hepatic ratio (INR) and platelet count. The risks of hemorrhage, biliary
circulatory changes in cirrhosis and portal hypertension. peritonitis, hematoma and perforation of other viscera, are
Low mechanical index CEUS plays an important role in the rare in experienced hands. Several large series have reported
assessment of complications of cirrhosis, such as hepatocellular mortality rates between 0.01% and 0.1%. Percutaneous biopsy
carcinoma and portal vein thrombus. There is a considerable of focal lesions can be performed in conjunction with either
improvement in the differential diagnosis of focal liver lesions ultrasound or CT imaging. Transjugular liver biopsy is an
especially due to CEUS. Using phase-inversion harmonic extremely useful technique in patients with clotting disorders,
sonography it is possible to detect tumor vascularity in a very in which the risk of intraperitoneal bleeding is greatly reduced.
TREATMENT OF CIRRHOSIS overload in 90% of patients with cirrhosis and ascites. Evidence
also indicates that sodium-restricted diets improve survival.
Since high blood ammonia levels is the predominant cause of
Causal hepatic encephalopathy, dietary changes, such as the use of
Treating the cause that lead to cirrhosis is likely to retard vegetable protein instead of animal protein, may help lower
progression of cirrhosis to end stage liver disease and to blood ammonia levels. Plant-based diets have more dietary
reduce the incidence of HCC. There is some evidence that fiber, which may reduce ammonia-related encephalopathy
causal treatment may even reverse cirrhosis, a fact that was in two ways: first, by enhancing the use of nitrogen by colonic
not believed till recently. Abstinence is the most important bacteria; and second, by facilitating nitrogen removal from
treatment for patients with alcoholic cirrhosis as continued the body by speeding food remnants through the intestines.
alcohol consumption favors hepatic fibrogenesis and Vegetable protein sources are also higher in arginine, an
decompensation. Patients who stop drinking may reduce or amino acid that decreases blood ammonia levels through
normalize portal pressure, have a reduction of ascites, and increasing urea synthesis. They are also lower in methionine
improve liver fibrosis. Patients with compensated cirrhosis and tryptophan, amino acids that exacerbate encephalopathy
due to hepatitis C virus, benefit from interferon-based antiviral through gut conversion to neurotoxic metabolites (mercaptans
treatment. Viral eradication and a consequently lowered risk of and oxyphenol, respectively). Clinical studies show that
hepatic decompensation and HCC can be achieved in up to 40 vegetarian diets increase the results of standard tests (e.g.
70% of patients. In a recent meta-analysis, 75 out of 153 biopsy- number connection score), improve nitrogen balance and
proven cirrhotics showed reversal of cirrhosis on biopsy after electroencephalogram (EEG) results, and lower blood
successful treatment, but results need confirmation in view ammonia concentrations.
of biopsy sampling variability. Similarly, long-term treatment Probiotic treatments may have a similar effect. An
with oral nucleoside and nucleotide inhibitors of hepatitis B imbalance in gut flora and bacterial translocation in cirrhosis
virus (HBV) polymerase may not only retard or reverse cirrhosis patients contributes significantly to ammonia production,
but are also shown to prevent complications of end-stage liver resulting in varying degrees of encephalopathy. Providing
disease. The data on reversibility and stabilization of other these patients with supplemental combinations of probiotics
causes of cirrhosis is less well defined. Cohort studies showed reduces blood concentrations of ammonia and endotoxin;
that some cirrhotic patients with autoimmune hepatitis showed reduces proinflammatory cytokine production, markers of
regression after long-term treatment with corticosteroids, and lipid peroxidation; and improves liver function tests. Patients
venesection of patients with hereditary hemochromatosis with liver disease treated with a combination of probiotics
could decrease the development of complications of portal (Lactobacillus plantarum) and fiber also had a lower rate of
hypertension. postoperative bacterial infections than those treated with
selective intestinal decontamination, indicating a beneficial
effect on the prevention of bacterial translocation.
Nutrition Nutrition therapy, particularly with branched-chain amino
Malnutrition, a common complication in liver cirrhosis, is acids, can also help support patients who are losing weight
associated with poorer outcome. Impaired dietary intake as a due to poor appetite and may improve survival. Cirrhotic
consequence of anorexia, nausea, protein restriction and often patients have significant reductions in antioxidant enzymes
an unpalatable low sodium diet is almost certainly the principal and lower blood levels of certain antioxidant nutrients, such as
cause of malnutrition in cirrhotics. There is, however, also carotenoids, vitamin E, and zinc. Oxidative stress contributes
evidence that cirrhosis itself leads to metabolic abnormalities significantly to liver damage. Poorer folate status is also found
and nutritional deficiencies. Several studies have documented in persons with cirrhosis. Due to a reduction in food intake
poor calorie and protein intake in cirrhotics. Iron deficiency and documented deficiencies of several nutrients in cirrhosis,
anemia often secondary to occult gastrointestinal blood loss, patients should take at least a multiple vitamin with minerals
and multiple vitamin deficiencies as a result of poor intake, that meets 100% of the dietary allowance for all vitamins and
decreased absorption and abnormal metabolism are also minerals.
common.
Consequently, a sodium-restricted diet that provides 2540
kcal/kg body weight with 1.21.5g/kg protein daily is usually
Liver Transplantation
prescribed. Protein restriction is no longer recommended in The ultimate therapy for cirrhosis and end-stage liver disease
most patients. A 2000 mg sodium-restricted diet is effective, is liver transplantation. Indications and contraindications
when combined with diuretic therapy, for controlling fluid for liver transplant are given in Table 3. For certain diseases,
Table 3: Indications and contraindications for orthotopic liver are recurrent disease in the transplant, particularly HCV, and
transplantation long-term consequences of immunosuppressive agents, such
as hypertension, hyperlipidemia and renal disease. Recently,
Indications Relative Absolute
contraindications contraindications there has been an interest at the prospect of reducing or
stopping immunosuppressants in long-term transplant
Advanced chronic liver HIV seropositivity Extrahepatic malignancy
failure Methadone AIDS patients. A small study has suggested that this may be possible
CPT score >7 dependence Cholangiocarcinoma in a significant number of patients, although the concept
Qualifying MELD Stage 3 HCC Severe, uncontrolled remains experimental at present.
score for organ systemic infection Liver transplantation has transformed the clinical outcome
allocation Multiorgan failure
of patients with decompensated cirrhosis, with many centers
Acute liver failure Advanced cardiopul
Unresectable hepatic monary disease now reporting excellent results. With careful patient selection,
malignancy Active substance abuse 5-year survival for chronic liver disease of all etiologies usually
Inherited metabolic exceeds 80%, with patients enjoying a good quality of life. The
disorders most recent survival data from the United Network of Organ
Abbreviations: MELD, model for end-stage liver disease; HIV, human Sharing (UNOS) indicates a 1-, 5- and 10-year graft survival
immunodeficiency virus; HCC, hepatocellular carcinoma; AIDS, rates of liver transplant recipients who were younger than 65
acquired immunodeficiency syndrome years as 82.1%, 67.8% and 52.6%, respectively; for recipients
who were 65 years or older as 77.5%, 59.7% and 41.2%,
there are established models to predict the stage at which respectively. Survival is best in patients who are at home at the
transplantation should be considered before complications time of transplant compared to those who are in the hospital
arise that may adversely affect survival. In other situations, the or in the ICU. Thus, it is important to remember that the timing
decision as to whether transplantation is a suitable treatment of transplantation is critical.
option can be more difficult. Age itself is not a contraindication, Liver transplantation in alcoholic liver disease is
although obviously the patients overall condition must be controversial. Most centers insist on a period of abstinence of at
considered. least 6 months and carefully assess an individuals psychosocial
The actual procedure, both the donor operation and situation before considering transplantation. Because alcoholic
the orthoptic transplantation, are well established. Newer hepatitis is often coexistent with cirrhosis, abstinence may
developments include reducing techniques and segmental result in an improvement in liver function, possibly obviating
transplantation from living donors in response to the the requirement for transplantation. Concerns regarding drug
shortage of size-matched donors for children. Auxiliary liver compliance and other coexistent alcohol-related pathologies
transplantation in which a segment of donor liver is implanted are often cited; however, results of liver transplantation in
in addition to the recipients own (when there is a strong carefully selected alcoholic patients are at least as good as in
possibility that native liver function may recover) is another patients with liver disease of other etiologies.
new development. To date this technique has predominately
been used in acute liver failure, and although its role may
increase it is unlikely to be of benefit in cirrhotics. COMPLICATIONS OF CIRRHOSIS AND
Although animal studies have suggested that the liver is less ITS MANAGEMENT
susceptible to rejection than other organs, acute and chronic
rejection remain important causes of morbidity and mortality,
with the need to balance the risk of rejection against the risk
Variceal Bleeding
of opportunistic infections (e.g. cytomegalovirus) being an Bleeding from gastroesophageal varices is a frequent
ongoing clinical problem. The introduction of cyclosporin A complication of cirrhosis. When portal pressure increases
in 1980s led to a dramatic improvement in long-term graft portosystemic anastomoses form at several anatomical sites,
survival. In 1994, a new immunosuppressant, tacrolimus, was the most important of which is in the lower esophagus leading
introduced. Two multicenter trials have shown tacrolimus to be to esophageal varices. Large prospective studies have shown
superior to cyclosporin A in terms of both acute and refractory that 2540% of cirrhotic patients with esophageal varices
rejection, but to be associated with a higher rate of side eventually experience an episode of acute variceal bleeding
effects. A great advance in liver transplantation has been the with the potential for serious and fatal complications. In last
improvement in immunosuppressive regimens so that allograft 2 decades, mortality from a variceal bleeding episode has
loss from rejection is now relatively rare. The major issues decreased from 40% to 15-20%, probably as a result of improved
that remain in care of the patient post-liver transplantation general management (with prophylactic antibiotics) and more
effective therapies (endoscopic variceal ligation and vasoactive before they are discharged from the hospital. A combination
drugs). of pharmacologic therapy (with nonselective beta-blockers)
Initial treatment of acute variceal bleeding should include with endoscopic variceal ligation is the secondary prophylactic
adequate fluid resuscitation and transfusion to maintain therapy of choice. A meta-analysis showed that rates of
hemoglobin around 78 g/dL, and prophylactic antibiotics rebleeding (from all sources and from varices) are lower with
(norfloxacin or ceftriaxone). It is currently recommended that a a combination of endoscopic therapy plus drug therapy than
vasoactive drug (terlipressin, somatostatin or analogs, such as with either therapy alone, but without differences in survival.
octreotide or vapreotide) be started as soon as variceal bleeding Patients who have rebleeding despite combined treatment with
is suspected. Vasoactive therapy should be maintained for up endoscopic variceal ligation and drugs at the recommended
to 5 days to prevent early rebleeding. Endoscopic therapy must doses and schedule should undergo placement of a TIPSS or
be performed within the first 12 hours after admission as soon surgical creation of a shunt; the two shunts are equally effective.
as the patient is stable. Endoscopic variceal band ligation is the Regarding the primary prevention of variceal bleeding,
endoscopic treatment of choice; however, endoscopic injection nonselective beta-blockers should be the first-line therapy in
sclerotherapy is an alternative if band ligation is technically all patients with medium to large varices and in patients with
difficult or not available. Despite this standard of care, 1020% small varices associated with high-risk features such as red
of patients may still exhibit initial failure to control bleeding or wale marks and/or advanced cirrhosis. EVL should be offered
early rebleeding within the first 5 days. In mild early rebleeding in cases of intolerance or side effects to beta-blockers.
a second course of endoscopic therapy may be attempted. If
rebleeding is severe, placement of transjugular intrahepatic
portosystemic shunt (TIPS) using covered stents is the first- Hepatic Encephalopathy
choice rescue treatment. Although TIPS is used as rescue Hepatic encephalopathy or portosystemic encephalopathy
treatment, however, it may be used as a primary treatment is a syndrome of largely reversible impairment of brain
for acute variceal bleeding for a patient who has a high risk function occurring in patients with acute or chronic liver
of treatment failure with conventional treatment. Indeed, a failure (advanced cirrhosis) or when the liver is bypassed by
recent trial has shown that placement of TIPS, using covered portosystemic shunts. This leads to a spectrum of neurological
stents, within 72 hours of admission in patients at high risk of impairments ranging from subclinical brain dysfunction to
treatment failure (i.e., those Child B with active bleeding or coma.
Child C less than 14 points) markedly decreased rebleeding The pathogenesis of hepatic encephalopathy remains
and improved survival. If TIPS is not available, patients with unclear; several hypotheses have been proposed, and it is
intractable bleeding may need to be considered for emergency possible that the underlying mechanism maybe multifactorial.
surgery, either esophageal transection or surgical shunting. The first and the most importanta hypothesis is the ammonia
Bleeding from fundal varices is more severe and is hypothesis which postulates that intestinal neurotoxins
associated with a higher rate of death than bleeding from such as ammonia, mercaptans and short-chain fatty acids,
gastroesophageal varices. Endoscopic variceal obturation with along with other products are not adequately detoxified in
the use of tissue adhesives such as N-butyl-2-cyanoacrylate, the blood (due to a combination of portosystemic shunting
along with the use of vasoactive drug, is the treatment of choice and hepatocellular failure). They cross the blood-brain
for bleeding from fundal varices. A TIPSS is also effective in barrier causing impaired central nervous system function
patients with bleeding fundal varices. and thus hepatic encephalopathy. Ammonia taken up by
A Sengstaken-Blakemore (SB) tube can be used to control the brain is incorporated into glutamine thus depleting
bleeding for short periods in difficult situations until alternative cerebral glutamate levels and leading to disturbances in
treatments are available. Effective tamponade can be achieved glutamatergic transmission and thus accounting for the
in 90% of cases in experienced hands, but with the risk of neuroinhibition of hepatic encephalopathy. According to
a relatively high complication rate in unskilled hands. The the false neurotransmitter hypothesis there is an imbalance
commonest severe complications result from pressure necrosis between aromatic amino acids and branched chain amino
of the esophagus or airways obstruction by the esophageal acids seen in patients with advanced liver disease. It has been
balloon or accumulated secretions. suggested that hepatic encephalopathy may be precipitated
Following an episode of acute variceal bleeding, the risk by an increase in cerebral aromatic amino acids, which are
of rebleeding is approximately 6080% over a 2-year period, precursors to false neurotransmitters. An increase in the
with a mortality of approximately 20% per episode. Given the latter may in turn cause a reduction in neural excitement and
high recurrence rate, patients who survive an acute variceal an increase in neural inhibition. According to yet another
hemorrhage should receive therapy to prevent recurrence hypothesis the gamma-aminobutyric acid (GABA) levels of
have been shown to be elevated in the peripheral blood of Thus, patients with ascites should generally be considered
patients with hepatic encephalopathy. GABA is an important for referral for liver transplantation. There is a clear rationale
inhibitory neurotransmitter with a cognate receptor closely for the management of ascites in patients with cirrhosis, as a
related to the benzodiazepine receptor. The increased successful treatment may improve the outcome and symptoms.
cerebral GABA level leads to the development of hepatic The aim of the medical treatment of ascites is the mobilization
encephalopathy. of intra-abdominal fluid through creation of a negative sodium
Therapeutic measures against hepatic encephalopathy balance. This can be achieved most simply by bed rest, fluid
are aimed at removing the precipitating cause, and reducing restriction and a low sodium diet. The aldosterone antagonist
production or decreasing the absorption of intestinal spironolactone is usually the first-line diuretic of choice, but
neurotoxins. The protein intake should be adequate but not if the ascites is severe, a loop diuretic, such as frusemide may
excessive. Nonabsorbable disaccharides, such as lactulose be used judiciously. Diuretic dosage is increased to achieve
or lactitol can be used orally or as enemas, both of which a target weight loss of approximately 0.50.75 kg/day, with
prevent constipation and alter nitrogen handling within the careful monitoring of electrolytes and renal function.
bowel. Nonabsorbable antibiotics, e.g. rifaximin or neomycin, In those patients who do not respond to diuretics (510%)
can also be used. Branched chain amino acids have also paracentesis is an alternative. Paracentesis is the treatment
been used in the treatment of hepatic encephalopathy in of choice for tense ascites, as it has been shown to be both
an attempt to correct the balance; however, the results of more effective and to have a lower complication rate than
randomized controlled trials are somewhat heterogenous. If high dose diuretic treatment. Large volume paracentesis is a
hepatic encephalopathy proves intractable, this may itself be safe procedure provided intravenous infusion of 20% human
an indication for liver transplantation. albumin solution is undertaken concurrently. Albumin
infusion (68 g/L ascites drained) prevents hemodynamic,
vasoactive and neurohumeral disturbances. Following
Ascites paracentesis, measures should be undertaken to prevent the
Ascites is the most common complication of cirrhosis, and reaccumulation of ascitic fluid.
about 60% of patients with compensated cirrhosis develop Refractory ascites is defined as ascites that cannot be
ascites within 10 years during the course of their disease. The mobilized or the early recurrence of which (i.e., after LVP)
development of ascites is the first sign of decompensation in cannot be satisfactorily prevented by medical therapy. There
many cirrhotic patients and thus a poor prognostic sign. are two categories of refractory ascites: diuretic-resistant ascites
The precise mechanism by which ascites forms in cirrhosis is an ascites that cannot be mobilized or the early recurrence
is not fully understood and may well be multifactorial. Ascites of which cannot be prevented because of a lack of response
is related to portal hypertension which leads to splanchnic to sodium restriction and diuretic treatment; and diuretic-
arteriolar vasodilatation. This leads to underfilling of intractable ascites is an ascites that cannot be mobilized or the
the vascular compartment and activation of arterial and early recurrence of which cannot be prevented because of the
cardiopulmonary volume receptors, and homeostatic activation development of diuretic-induced complications that preclude
of vasoconstrictor and sodium-retaining systems (i.e., the the use of an effective diuretic dosage. To diagnose refractory
sympathetic nervous system and the reninangiotensin ascites the patient must be on intensive diuretic therapy
aldosterone system). Any reduction in hormonal clearance by (spironolactone 400 mg/day and furosemide 160 mg/day) for
the liver will result in an increase in their half-life, in the case at least 1week and on a salt-restricted diet of less than 90 mmol/
of aldosterone, promoting sodium and water retention. There day. Lack of response to diuretics is defined when mean weight
is also an increased production of antidiuretic hormone. Thus loss of <0.8 kg over 4 days and urinary sodium output less than
there is an inability to excrete an adequate amount of sodium the sodium intake. Ascites is said to have an early recurrence
into urine, leading to a positive sodium balance. Renal sodium when there is reappearance of grade 2 or 3 ascites within 4
retention leads to expansion of the extracellular fluid volume weeks of initial mobilization. Diuretic-induced complications
and formation of ascites and edema. There is also evidence comprisesof diuretic-induced hepatic encephalopathy
of sinusoidal hypertension with changes in hepatic lymph (development of encephalopathy in the absence of any other
flow and altered hydrostatic forces favoring net loss of fluid precipitating factor); diuretic-induced renal impairment
from mesenteric capillary varices. Reduced oncotic pressure (increase of serum creatinine by >100% to a value >2 mg/dl
secondary to hypoalbuminemia will increase any tendency for (177 mol/L) in patients with ascites responding to treatment);
ascites to form. diuretic-induced hyponatremia (decrease of serum sodium by
The development of ascites is associated with a poor >10 mmol/L to a serum sodium of <125 mmol/L); and diuretic-
prognosis and impaired quality of life in patients with cirrhosis. induced hypo- or hyperkalemia (a change in serum potassium
Table 4: Criteria for diagnosis of hepatorenal syndrome in cirrhosis the most important trigger for the development of type 1 HRS
is bacterial infection; and renal function can be improved by
Cirrhosis with ascites
drug therapy.
Serum creatinine >1.5 mg/dl (133 mol/L) Patients with type 1 HRS are generally better managed in an
Absence of shock intensive care or semi-intensive care unit. Bacterial infection
Absence of hypovolemia as defined by no sustained improvement of renal should be identified early, by blood, urine and ascitic fluid
function (creatinine decreasing to <133 mol/L) following at least 2 days of cultures, and treated with antibiotics. All diuretics should be
diuretic withdrawal (if on diuretics), and volume expansion with albumin stopped in patients at the initial evaluation and diagnosis
at 1 g/kg/day up to a maximum of 100 g/day
of HRS. Terlipressin (1 mg/46 hour intravenous bolus) in
No current or recent treatment with nephrotoxic drugs combination with albumin should be considered the first
Absence of parenchymal renal disease as defined by proteinuria <0.5 g/ line therapeutic agent for type 1 HRS. The aim of therapy is to
day, no microhematuria (<50 red cells/high powered field), and normal improve renal function sufficiently to decrease serum creatinine
renal ultrasonography
to less than 133 mol/L (1.5 mg/dl) (complete response). If
serum creatinine does not decrease at least 25% after 3 days, the
to <3 mmol/L or >6 mmol/L despite appropriate measures). dose of terlipressin should be increased in a stepwise manner up
Methods for treatment of refractory ascites include large to a maximum of 2 mg/4 hour. Contraindications to terlipressin
volume paracentesis with albumin administration, continuing therapy include ischemic cardiovascular diseases. Patients on
diuretic therapy (if effective in inducing natriuresis), insertion terlipressin should be carefully monitored for development of
of transjugular intrahepatic portosystemic shunt (TIPS), and cardiac arrhythmias or signs of splanchnic or digital ischemia,
liver transplantation. and fluid overload, and treatment modified or stopped
accordingly. Potential alternative therapies to terlipressin
include norepinephrine or midodrine plus octreotide, both
Hepatorenal Syndrome in association with albumin. Renal replacement therapy may
Hepatorenal syndrome (HRS) is defined as the occurrence be useful in patients who do not respond to vasoconstrictor
of renal failure in a patient with advanced liver disease in the therapy, and who fulfill criteria for renal support. Terlipressin
absence of an identifiable cause of renal failure. Thus, the plus albumin is effective in 6070% of patients with type 2 HRS.
diagnosis of HRS is essentially one of exclusion of other causes Liver transplantation is the best treatment for both type 1 and
of renal failure. The diagnostic criteria for HRS are shown in type 2 HRS. HRS should be treated before liver transplantation,
Table 4. since this may improve post-liver transplant outcome.
There are 2 types of HRS. Type 1 HRS is a rapidly progressive To prevent HRS patients who present with SBP should be
acute renal failure that frequently develops in temporal treated with intravenous albumin since this has been shown
relationship with a precipitating factor for a deterioration to decrease the incidence of HRS and improve survival. There
of liver function together with deterioration of other organ are some data to suggest that treatment with pentoxifylline
function. It commonly occurs in severe alcoholic hepatitis or in decreases the incidence of HRS in patients with severe
patients with end-stage cirrhosis following a septic insult, such alcoholic hepatitis and advanced cirrhosis and treatment
as SBP, although in some patients it may occur in the absence of with norfloxacin decreases the incidence of HRS in advanced
any identifiable triggering event. Type 2 HRS occurs in patients cirrhosis, respectively.
with refractory ascites and there is a steady but moderate
degree of functional renal failure, often with avid sodium
retention. Patients with type 2 HRS may eventually develop
Spontaneous Bacterial Peritonitis
type 1 HRS either spontaneously or following a precipitating Spontaneous bacterial peritonitis (SBP) is a very common
event, such as SBP. bacterial infection in patients with cirrhosis and ascites with
The hemodynamic changes in HRS are thought to be an associated mortality of approximately 20%. All patients
similar to those postulated in ascitic formation, but there with cirrhosis and ascites are at risk of SBP and the prevalence
is a paradoxical increase in renal vascular resistance and a of SBP in outpatients is 1.53.5% and 10% in hospitalized
marked decrease in renal cortical blood flow, with reduction patients. Patients with SBP may have one of the following: (i)
in the glomerular filtration rate and low urinary sodium, local symptoms and/or signs of peritonitis: abdominal pain,
making HRS in some ways analogous to acute prerenal failure. abdominal tenderness, vomiting, diarrhea, ileus; (ii) signs of
Vasodilatation mainly occurs in the splanchnic arterial bed; systemic inflammation: hyper or hypothermia, chills, altered
the cardiac output in patients with HRS may be low or normal white blood cell count, tachycardia, and/or tachypnea; (iii)
(infrequently high), but insufficient for the patients needs; worsening of liver function; (iv) hepatic encephalopathy; (v)
shock; (vi) renal failure; and (vii) gastrointestinal bleeding. anaerobic flora (selective intestinal decontamination). Given
However, it is important to point out that SBP may be the high cost and inevitable risk of developing resistant
asymptomatic, particularly in outpatients. organisms, the use of prophylactic antibiotics must be strictly
The diagnosis of SBP is based on diagnostic paracentesis restricted to patients at high risk of SBP. Three high-risk patient
and it should be carried out in all patients with cirrhosis and populations have been identified: (i) patients with acute
ascites at hospital admission to rule out SBP. A diagnostic gastrointestinal hemorrhage; (ii) patients with low total protein
paracentesis should also be performed in patients with content in ascitic fluid and no prior history of SBP (primary
gastrointestinal bleeding, shock, fever, or other signs of prophylaxis); and (iii) patients with a previous history of SBP
systemic inflammation, gastrointestinal symptoms, as well as (secondary prophylaxis). In patients with gastrointestinal
in patients with worsening liver and/or renal function, and bleeding and severe liver disease ceftriaxone is the prophylactic
hepatic encephalopathy. The diagnosis of SBP is based on antibiotic of choice, whilst patients with less severe liver disease
neutrophil count in ascitic fluid of >250/mm3 as determined may be given oral norfloxacin or an alternative oral quinolone
by microscopy. Ascitic fluid culture is frequently negative even to prevent the development of SBP. In patients with ascitic fluid
if performed in blood culture bottles and is not necessary for protein lower than 15 g/L and without prior SBP norfloxacin
the diagnosis of SBP, but it is important to guide antibiotic (400 mg/day) reduces the risk of SBP and improves survival.
therapy. Blood cultures should be performed in all patients These patients should be considered for long-term prophylaxis
with suspected SBP before starting antibiotic treatment. Some with norfloxacin. In patients who recover from an episode of
patients may have an ascitic neutrophil count less than 250/ SBP the administration of prophylactic antibiotics reduces
mm3 but with a positive ascitic fluid culture. This condition is the risk of recurrent SBP. Norfloxacin (400 mg/day, orally)
known as bacterascites. If the patient exhibits signs of systemic is the treatment of choice. Alternative antibiotics include
inflammation or infection, the patient should be treated with ciprofloxacin (750 mg once weekly, orally) or cotrimoxazole
antibiotics. When culture is positive (40% of cases), the most (800 mg sulfamethoxazole and 160 mg trimethoprim daily,
common pathogens include Gram-negative bacteria (GNB), orally), but evidence is not as strong as that with norfloxacin.
usually Escherichia coli and Gram-positive cocci (mainly Patients who recover from SBP have a poor long-term survival
streptococcus species and enterococci). and should be considered for liver transplantation.
Empirical antibiotics should be started immediately following
the diagnosis of SBP. The first line antibiotic treatment are
third-generation cephalosporins, while, alternative options Hepatocellular carcinoma
include amoxycillin/clavulanic acid and quinolones such as Hepatocellular carcinoma is the sixth most prevalent cancer
ciprofloxacin or ofloxacin. SBP resolves with antibiotic therapy and the third most frequent cause of cancer-related death.
in approximately 90% of patients. Resolution of SBP should be Worldwide, the single largest risk factor in the development of
proven by demonstrating a decrease of ascitic neutrophil count HCC is cirrhosis of any etiology, which is present in 70 to 90%
to <250/mm3 and sterile cultures of ascitic fluid, if positive of those who have HCC. HCCs detected when symptomatic
at diagnosis. A second paracentesis after 48 hour of start of are associated with a poor prognosis and ones detected on
treatment may help guide the effect of antibiotic therapy. Failure surveillance fare as well as incidentally found ones. Early
of antibiotic therapy should be suspected if there is worsening detection by surveillance is the only way to diagnose HCC
of clinical signs and symptoms and/or no marked reduction or when curative treatments are feasible in at least 50-70% of
increase in ascitic fluid neutrophil count compared to levels at these early detected cases. Hence, all patients of cirrhosis at
diagnosis. Failure of antibiotic therapy is usually due to resistant risk of developing HCC and who are eligible for HCC therapy
bacteria or secondary bacterial peritonitis. Once secondary are candidates for regular HCC surveillance. Six-monthly
bacterial peritonitis has been excluded, antibiotics should be ultrasound abdomen by experienced personnel is the
changed according to in vitro susceptibility of isolated organisms, recommended surveillance test.
or modified to alternative empiric broad spectrum agents. HRS When a nodule is detected in the liver by ultrasonography
occurs in approximately 30% of patients with SBP treated with and HCC is suspected a triphasic or four phasic CT scan or MRI
antibiotics alone, and is associated with a poor survival. The are the radiologic procedures of choice to confirm the diagnosis
administration of albumin (1.5 g/kg at diagnosis and 1 g/kg on of HCC. On dynamic (triphasic or four-phasic) CT or MRI scan,
day 3) decreases the frequency of HRS and improves survival. features typical of HCC are characterized by hypervascularity
Since most episodes of SBP are thought to result from the of the nodule in arterial phase and washout in portovenous
translocation of enteric GNB, the ideal prophylactic agent should phase. However, when dynamic CT or MRI shows atypical
be safe, affordable, and effective at decreasing the amounts of imaging pattern, a histological confirmation maybe required
these organisms from the gut while preserving the protective for the diagnosis of HCC.
Fig. 4: The Barcelona Clinic Liver Cancer (BCLC) staging system
Once HCC is diagnosed, staging is essential to guide further signalling and VEGF, PDGF, and c-Kit. It has antiproliferative
therapy. The Barcelona Clinic Liver Cancer (BCLC) is the most and antiangiogenic activity and delays tumor progression.
widely used staging system for HCC (Fig. 4). The best treatment
for HCC depends on the stage. Patients should be considered
for liver transplantation if the lesion is single and less than 5 CONCLUSION
cm or three lesions smaller than 3 cm each and there is no
evidence of vascular invasion or extrahepatic spread. Liver There have been numerous advances in the management of
resection may be considered for small lesions when the liver cirrhosis with the emergence of specific therapies for several
has early cirrhosis with no signs of clinically relevant portal conditions, notably viral hepatitis, and advances in the
hypertension (defined as presence of varices, splenomegaly, techniques used to manage the complications of cirrhosis.
platelet count <100,000 or a hepatic vein pressure gradient >10 The advent of successful liver transplantation offers effective
mm Hg). If resection or liver transplantation is not possible, treatment for patients with even end-stage liver disease. It is
patients may be considered for local ablative therapies for therefore imperative that individuals with established liver
lesions smaller than 4 cm in diameter. The local ablative fibrosis or conditions that may lead to it are identified and
procedure of choice is radiofrequency ablation (RFA), referred to a hepatologist for assessment. As the only treatment
however, alcohol injection is a good alternative when RFA is for advanced cirrhosis is liver transplantation, what is urgently
not available. Transarterial chemoembolization (TACE) is an needed is strategies to prevent transition to decompensated
excellent palliative option for multifocal nonresectable lesions. stages.
Knowledge of molecular events that govern tumor
progression and dissemination has allowed the development
of targeted treatments that aim to abrogate these disrupted
pathways. Several monoclonal antibodies and small molecules
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32
cHAPTER
Ascites
Gourdas Choudhuri, Ajesh Goyal
INTRODUCTION ETIOLOGY
Ascites is the accumulation of uid in the peritoneal cavity. Many diseases can lead to the accumulation of fluid within
The word ascites is from Greek derivation askos meaning a the peritoneal cavity. They can be grouped into two major
leather bag used to carry wine, water, or oil. categories depending on whether they directly affect the
peritoneum (Table 1).
Cirrhosis is the most common cause of ascites accounting
Table 1: Causes of ascites for approximately 85% of cases, with malignancy, cardiac and
other causes accounting for the other cases (Table 2). Ascites is
Diseases not involving peritoneum Peritoneal diseases
the most common manifestation of hepatic decompensation
Portal hypertension Malignant ascites in patients with cirrhosis; hepatic encephalopathy and
Cirrhosis Peritoneal mesothelioma
variceal hemorrhage are second and third most common,
Alcoholic hepatitis Peritoneal carcinomatosis
Fulminant hepatitis respectively. Approximately 50% of patients with compensated
Subacute hepatitis cirrhosis develop ascites within 10 years. Ascites, regardless of
Hepatic veno-occlusive disease the cause, has great prognostic significance. Survival is only
Massive liver metastasis 50% after 2 years or 5 years in patients with alcoholic cirrhosis
Congestive heart failure
or chronic hepatitis C, respectively. Ascites during fulminant
Constrictive pericarditis
Budd-Chiari syndrome hepatic failure is associated with 80% mortality, and patients
with malignant ascites usually survive for only a few weeks.
Hypoalbuminemia Infectious peritonitis
Nephrotic syndrome Tuberculosis
Protein-losing enteropathy Chlamydia trachomatis
Malnutrition Fungal and parasitic peritonitis
Candida albicans
PATHOGENESIS
Histoplasma capsulatum
Coccidioides immitis Cirrhotic Ascites
Cryptococcus neoformans
Schistosoma mansoni The most recent theory of ascitic fluid formation, the
Strongyloides stercoralis peripheral arterial vasodilation hypothesis combines both
Entamoeba histolytica underfill as well as overfill hypothesis of ascites formation
Miscellaneous disorders Other peritoneal diseases (Fig. 1). According to peripheral arterial vasodilation
Myxedema Sarcoidosis
Ovarian disease Starch granulomatous peritonitis Table 2: Most common causes of ascites
Carcinoma Barium peritonitis
Benign tumors Vasculitis Cause %
Ovarian hyperstimulation Systemic lupus erythematosus
Cirrhosis (with or without infection) 85
syndrome Henoch-Schnlein purpura
Pancreatic ascites Eosinophilic gastroenteritis Miscellaneous portal hypertension-related disorder
8
Bile ascites Whipples disease (including 5% with two causes)
Chylous ascites Cardiac disease 3
Nephrogenic ascites
Acquired immunodeficiency Peritoneal carcinomatosis 2
syndrome Miscellaneous nonportal hypertension-related disorders 2
Ascites 281
Fig. 1: Pathogenesis of ascites formation in patients with cirrhosis
hypothesis, portal hypertension results from increased production of proteinaceous fluid by tumor cells lining the
intrahepatic resistance to portal blood flow and is a peritoneum. Extracellular fluid enters the peritoneal cavity
prerequisite for the development of ascites in patients with to re-establish oncotic balance.
liver disease. In response to increased portal venous pressure, In massive liver metastases, fluid accumulates because
there is increased production of vasodilators, such as nitric of portal hypertension caused by stenosis or occlusion of
oxide, in the splanchnic vascular bed. Neuroendocrine portal veins by tumor nodules or tumor emboli.
compensation for the vasodilation results in renal fluid In hepatocellular carcinoma, ascites arises because of the
retention, increased plasma volume and increased cardiac underlying cirrhosis-related portal hypertension, tumor-
output (underfill theory of ascites). However, eventually these induced portal vein thrombosis or both.
compensatory mechanisms are unable to fully compensate as Chylous ascites in patients with malignant lymphoma
portal hypertension worsens and effective blood volume falls. appears to be caused by lymph node obstruction by tumor
As a result, there is activation of vasoconstrictor mechanisms and rupture of chyle-containing lymphatics.
and antinatriuretic mechanisms in the kidney to retain Heart failure (high-output or low-output) or nephrotic
sodium and water. The combination of portal hypertension, syndrome: As in cirrhosis, effective arterial blood volume
increasing plasma volume, splanchnic vasodilation and appears to be decreased, and the vasopressin, renin-
reduced plasma osmotic pressure results in increased aldosterone and sympathetic nervous systems are activated.
permeability of the intestinal bed and translocation of fluid These changes lead to renal vasoconstriction and sodium
into the peritoneal cavity (overfill theory of ascites). and water retention. Fluid then weeps from congested
hepatic sinusoids as lymph as in cirrhotic ascites.
Tuberculosis, Chlamydia infection and coccidioidomycosis
Noncirrhotic Ascites probably cause ascites through the production of
The mechanism of fluid retention in patients with malignancy- proteinaceous fluid as in peritoneal carcinomatosis.
related ascites depends on the cause of ascites. In pancreatic or biliary ascites, fluid accumulates by
Peritoneal carcinomatosis causes ascites through the leakage of pancreatic juice or bile into the peritoneal cavity
or forms secondary to a chemical burn of the perit A history of heart failure may raise the possibility of cardiac
oneum. ascites
After abdominal surgery, especially extensive retro Tuberculous peritonitis usually manifests as fever and
peritoneal dissection, lymphatics may be transected and abdominal pain
may leak lymph for varying amounts of time. Ascites may occur in patients with acute pancreatitis
with necrosis or a ruptured pancreatic duct from chronic
pancreatitis or trauma
EVALUATION AND DIAGNOSIS Patients in whom ascites and anasarca develop in the
setting of diabetes mellitus should be suspected of having
The initial evaluation of patient with ascites has been depicted nephrotic ascites
in Figure 2. As the most common cause of ascites is cirrhosis, Ascites in a patient with symptoms and signs of myxedema
patients with ascites should be questioned about risk factors should prompt assessment of thyroid function.
for liver disease like alcohol, injection drug abuse, blood
transfusions, sex with a same-gender partner, acupuncture,
tattoos, ear piercing, life-time maximum body weight, etc. PHYSICAL EXAMINATION
Patients with a long history of stable cirrhosis and sudden
development of ascites should be suspected of harboring The presence of a full, bulging abdomen should lead to
a hepatocellular carcinoma. Patients with ascites who percussion of the flanks. The presence of shifting dullness
have a history of cancer should be suspected of having has 83% sensitivity and 56% specificity in detecting ascites.
malignancy-related ascites Approximately 1,500 mL of fluid must be present before flank
Malignancy-related ascites is frequently painful, whereas dullness is detected. If no flank dullness is present, the patient
cirrhotic ascites is usually not, unless bacterial peritonitis has less than 10% chance of having ascites. The fluid wave
or alcoholic hepatitis is superimposed and puddle sign are cumbersome and perform less well when
Fig. 2: Initial evaluation of patient with new onset ascites

Abbreviations: SAAG, serum-ascites albumin gradient; Asc prot, ascites protein; HVPG, hepatic venous pressure gradient; TJLB, transjugular
liver biopsy
Ascites 283
compared to shifting dullness. Ultrasonography can detect as Samples from patients with hepatocellular carcinoma
little as 100 mL of fluid in the abdomen. are often bloody
One should look for signs of liver disease and portal About 10% of samples from patients with peritoneal
hypertension like palmar erythema, spider nevi, large carcinomatosis are red
abdominal wall collateral veins and fetor hepaticus. Other Less than 5% of tuberculous samples are hemorrhagic
physical findings that might suggest nonhepatic causes Chylous fluid: Samples have a triglyceride concentration
of ascites include abnormal jugular venous distension or greater than 200 mg/dL (2.26 mmol/L). Most patients with
a pulsatile liver in patients with right-sided heart disease, chylous or opalescent ascites have cirrhosis.
presence of lymphadenopathy or firm nodules in patients with Dark-brown fluid: Biliary perforation if bilirubin concen
underlying malignancy, large veins on the back in patients tration is greater than that of serum; deeply jaundiced
with Budd-Chiari syndrome or vena cava obstruction, and patients have bile-stained ascitic fluid, but the bilirubin
generalized anasarca in patients with nephritic syndrome. level and the degree of pigmentation are visually less than
those of the corresponding serum. Pancreatic ascites may
be pigmented because of the effect of pancreatic enzymes
Indications of Abdominal Paracentesis on red blood cells. Black ascitic fluid may be found in
To diagnose the cause of ascites patients with malignant melanoma.
Cirrhotic patients admitted to the hospital with ascites
Cirrhotic patients with ascites and unexplained clinical
deterioration
Laboratory Tests on Ascitic Fluid
On the basis of cost analysis, tests can be classified as routine,
optional, unusual and unhelpful (Table 3).
Contraindications
Coagulopathy should preclude paracentesis only when
clinically evident fibrinolysis or disseminated intravascular
Cell Count
coagulation is present. There is no role of transfusion of blood Cell count is the single most helpful ascitic fluid test. Only
products (fresh frozen plasma or platelets) routinely before approximately 10 L of fluid is required for a standard
paracentesis in cirrhotic patients with coagulopathy. manual hemocytometer count. Therefore, if only one drop of
fluid can be obtained, it should be sent for cell count. More
fluid is almost always obtainable; however, fluid should
Ascites Fluid Analysis be submitted in an anticoagulant-containing tube, i.e.
After diagnostic tap, fluid should be sent for analysis in the ethylenediaminetetraacetic acid (EDTA) to prevent clotting.
laboratory. The WBC count in uncomplicated cirrhotic ascites is usually
less than 500 cells/mm3 (0.5 109/L). During diuresis in
patients with cirrhotic ascites, the WBC count can concentrate
Gross Appearance to more than 1,000 cells/mm3 (1.0 109/L). Common causes
Transparent: Non-neutrocytic [i.e. ascitic fluid polymor of elevated ascitic fluid WBC are given in Table 4.
phonuclear neutrophil (PMN) count less than 250/mm3
(0.25 x 109/L)] ascitic fluid is transparent and is usually SerumAscites Albumin Gradient
slightly yellow
Cloudy: Fluid with a count greater than 5,000/mm3 (5.0 The difference between the serum and ascitic fluid albumin
109/L) is quite cloudy concentrations correlates directly with portal pressure.
Pink: If RBC is greater than 10,000/mm3 (10.0 109/L)
Table 3: Ascitic fluid laboratory tests
In traumatic tap, ascitic fluid specimen is blood streaked
and clotted unless the fluid is transferred immediately Routine Optional Unusual Unhelpful
to the anticoagulant-containing tube for cell count. By Cell count Amylase Bilirubin Cholesterol
contrast, nontraumatic or remotely traumatic blood-
Albumin Culture Cytology Fibronectin
tinged ascitic fluid is homogeneous and does not clot
TB smear, culture
Some patients with portal hypertension have bloody Total protein Glucose Lactate
and PCR test
hepatic lymph, resulting in bloody ascitic fluid
Gram stain Triglycerides pH
perhaps because of rupture of lymphatics that are
under high pressure Abbreviations: PCR, polymerase chain reaction; TB, tuberculosis
Table 4: Common causes of elevated ascitic fluid WBC Table 5: Classification of ascites by serum-ascites albumin gradient
(SAAG)
Spontaneous bacterial peritonitis (SBP)
Tuberculous peritonitis High gradient Low gradient
1.1 g/dL (11 g/L) <1.1 g/dL (11 g/L)
Peritoneal carcinomatosis
Traumatic tap Alcoholic hepatitis Biliary ascites
Budd-Chiari syndrome Bowel obstruction or infarction
Cardiac ascites Nephrotic syndrome
Serum-ascites albumin gradient (SAAG) is calculated by
Cirrhosis Pancreatic ascites
subtraction and is not a ratio.
Fatty liver of pregnancy Peritoneal carcinomatosis
SAAG = S. albumin Albumin in ascites
Fulminant hepatic failure Postoperative lymphatic leak
Massive liver metastases Serositis in connective tissue
Clinical implications diseases
Mixed ascites Tuberculous peritonitis
If SAAG is 1.1 g/dL (11 g/L) or greater, the patient can be
Myxedema
considered to have portal hypertension with an accuracy
of approximately 97%. Portal vein thrombosis
If SAAG is less than 1.1 g/dL (11 g/L), the patient is unlikely Sinusoidal obstruction
to have portal hypertension (Table 5). syndrome
The SAAG will be falsely low if:

Patient with cirrhosis has a serum albumin level of less 80% if the fluid is inoculated into blood culture bottles at the
than 1.1 g/dL (11 g/L) bedside and prior to administration of antibiotics.
When specimens of serum and ascites are not obtained
nearly simultaneously as both serum and ascitic fluid
albumin concentrations change over time; however, these Total Protein
values change in parallel, so the difference is stable The ascitic fluid total protein concentration does not increase
Arterial hypotension may result in a decrease in the portal during spontaneous bacterial peritonitis (SBP); it remains
pressure and narrowing of the SAAG stable before, during and after infection. During a 10kg
Serum hyperglobulinemia [serum globulin level greater diuresis, the ascitic fluid total protein concentration doubles.
than 5 g/dL (50 g/L)]. A narrowed gradient caused by high In cardiac ascites, the ascitic fluid protein concentration is
serum globulin levels occurs in only approximately 1% of greater than 2.5 g/dL (25 g/L) with high SAAG. The high SAAG
ascitic fluid specimens. To correct the SAAG in the setting of cardiac ascites is presumably the result of high right-sided
of a high serum globulin level, the following formula is cardiac pressures. However, in patients with cardiac ascites,
used: the SAAG may narrow with diuresis; such narrowing does not
Corrected SAAG = Uncorrected SAAG x 0.16 x (S. globulin in happen in patients with cirrhosis.
g/dL + 2.5)
SAAG may be falsely high in chylous ascites as lipid
interferes with albumin estimation. Glucose
Mixed ascites: Approximately 5% of patients with ascites Concentration of glucose in ascitic fluid is similar to that in
have mixed ascites, i.e. two causes of ascites. Most of these serum, unless glucose is being consumed by ascitic fluid
patients have portal hypertension from cirrhosis as well as WBCs or bacteria.
another cause of ascites, such as tuberculous peritonitis or
peritoneal carcinomatosis. The albumin gradient is high [1.1
g/dL (11 g/L) or greater] in mixed ascites as a reflection of the Amylase
underlying portal hypertension. In uncomplicated ascites in the setting of cirrhosis, the ascitic
fluid amylase concentration is usually one half that of the
serum value, approximately 50 U/L. In patients with acute
Culture pancreatitis or intestinal perforation (with release of luminal
When ascitic fluid has PMN count greater than 250 cells/ amylase into the ascitic fluid), the fluid amylase concentration
mm3 (0.25 x 109/L), bacterial growth occurs in approximately is elevated markedly, usually greater than 2,000 U/L.
Ascites 285
Cytologic Examination Grade 3 ascites is large or gross ascites with marked

abdominal distension.
The sensitivity of cytology in detecting peritoneal
carcinomatosis is 96.7% if three samples are sent and
processed promptly; the first sample is positive in 82.8% and Diuretic-resistant Ascites
at least one of two samples is positive in 93.3%. The sensitivity Ascites that cannot be mobilized or the early recurrence of
of cytology is approximately 100% for detecting peritoneal which cannot be prevented because of a lack of response to
carcinomatosis but much lower for detecting malignancy- dietary sodium restriction and intensive diuretic treatment is
related ascites caused by conditions other than peritoneal diuretic-resistant ascites.
carcinomatosis. Because hepatocellular carcinoma rarely
metastasizes to the peritoneum, a positive ascitic fluid
cytology in a patient with hepatocellular carcinoma is not Diuretic-intractable Ascites
expected.
Ascites that cannot be mobilized or the early recurrence of
which cannot be prevented because of the development of
Bilirubin diuretic-induced complications that preclude the use of an
effective diuretic dosage is diuretic-intractable ascites.
The bilirubin concentration should be measured in ascitic
fluid that is dark brown. An ascitic fluid bilirubin level greater
than 6 mg/dL (102 mol/L) and greater than the serum level Recidivant or Recurrent Ascites
of bilirubin suggests biliary or proximal small intestinal
This type of ascites recurs on at least three occasions within
perforation into ascitic fluid.
a 12-month period despite dietary sodium restriction and
adequate diuretic doses.
Adenosine Deaminase
Measurement of adenosine deaminase in ascites has been Massive or Tense Ascites
proposed as a useful test for detecting peritoneal tuberculosis.
This type of ascites causes respiratory/abdominal discomfort.
In a study from India, in patients with tubercular ascites,
It can by no means be considered as refractory, as the failure
sensitivity and specifity of adenosine deaminase was 97% and
to respond to treatment has to be demonstrated.
94%, respectively.
DEFINITIONS OF SOME COMMONLY COMPLICATIONS

USED TERMS Ascitic Fluid Infection
Chylous Ascites Ascitic fluid infection can be classified into five categories
based on ascitic culture results, absolute neutrophil count
It develops when intra-abdominal lymphatics containing (ANC), and presence or absence of a surgical source of
chyle rupture. Cirrhosis is the cause of chylous ascites in more infection (Table 6).
than 90% of the patients with chylous ascites. In addition,
retroperitoneal surgery and radical pelvic surgery in patients
with cancer can transect lymphatics and, thereby, lead to Pathogenesis of Spontaneous Bacterial
chylous ascites. Peritonitis
Spontaneous forms of ascitic fluid infection are the result
Uncomplicated Ascites of overgrowth of a specific organism in the intestine,
This type of ascites is not infected and is not associated with translocation of that microbe from the intestine to
the development of hepatorenal syndrome (HRS). mesenteric lymph nodes, and resulting spontaneous
Grade 1 ascites is mild ascites only detectable by ultrasound bacteremia and subsequent colonization of susceptible
examination ascitic fluid. Low-protein ascitic fluid, e.g. protein content
Grade 2 ascites or moderate ascites is manifested by less than 1 g/dL (10 g/L) is particularly susceptible to SBP. The
moderate symmetrical distension of abdomen endogenous antimicrobial (opsonic) activity of human ascitic
Table 6: Classification of ascitic fluid infection Differential Diagnosis from Secondary

Infection type ANC (cells/mm3) Bacterial culture Peritonitis
Spontaneous bacterial >250 Positive (1 organism)
peritonits Intestinal perforation can be suspected and pursued if
a specimen of ascites is neutrocytic and meet two of the
Culture-negative neutrocytic >250 Negative
bacterascites following three criteria:
1. Total protein greater than 1 g/dL (10 g/L).
Monomicrobial <250 Positive (1 organism)
nonneutrocytic bacterascites 2. Glucose less than 50 mg/dL (2.8 mmol/L).
3. Lactate dehydrogenase greater than the upper limit of
Secondary bacterial >250 Positive (polymicrobial)
peritonitis normal for serum.
In the setting of a perforated viscus, cultures of ascitic
Polymicrobial bacterascites <250 Positive (polymicrobial)
fluid nearly always disclose multiple organisms, except in
ANC, absolute neutrophil
gallbladder rupture, which is usually monomicrobial.
count.
An ascitic fluid amylase level that is greater than fivefold
that of the serum level may also be indicative of intestinal
rupture (but not gallbladder rupture) with the release of
fluid correlates directly with the protein concentration of the luminal amylase.
fluid. Patients with deficient ascitic fluid opsonic activity are
predisposed to SBP.
Treatment of Ascitic Fluid Infection
Symptoms and Signs Antibiotic therapy is not necessary for patients with bloody
fluid unless the corrected ascitic fluid PMN count is 250 cells/
Although 87% of patients with SBP are symptomatic at the mm3 (0.25 109/L) or greater. Table 7 describes the treatment
time the infection is diagnosed, the symptoms and signs of of various subtypes of ascitic fluid infection.
infection are often subtle, such as a slight change in mental
status. Without prompt paracentesis, the diagnosis and Other intravenous antibiotics: Amoxicillin-clavulanic acid has
treatment of infected ascites may be delayed, often resulting been shown to be as effective as cefotaxime in a randomized
in the death of the patient. trial.
Bacteriology Table 7: Treatment of subtypes of ascitic fluid infection

Escherichia coli, streptococci (mostly pneumococci) and
Diagnosis Treatment
Klebsiella cause most episodes of SBP in patients who are not
receiving selective intestinal decontamination. Spontaneous Cefotaxime 2 g every 8 hours empirically followed by
bacterial more specific therapy as per culture/sensitivity. Total
peritonitis duration of therapy is 5 days
Risk Factors for Spontaneous Bacterial Monomicrobial Five days of intravenous antibiotic to which the
non-neutrocytic organism is highly susceptible, if the patient is
Peritonitis bacterascites symptomatic or persistently culture-positive; not all
patients with bacterascites require treatment
Low ascitic fluid total protein concentrations, as well as
Culture-negative Five days of intravenous third-generation
the phagocytic (both motile and stationary) dysfunction
neutrocytic ascites cephalosporin (e.g. cefotaxime 2 g every 8 hours)
associated with cirrhosis
Secondary Surgical intervention plus approximately 2 weeks
Gastrointestinal hemorrhage: The cumulative probability
bacterial of intravenous cephalosporin (e.g. cefotaxime 2 g
of infection during a single hospitalization for bleeding peritonitis every 8 hours) plus an antianaerobic drug, such as
is approximately 40%. The risk appears to peak 48 hours metronidazole
after the onset of hemorrhage. The high risk of infection Polymicrobial Intravenous third-generation cephalosporin (e.g.
probably is mediated by a shock-induced increase bacterascites cefotaxime 2 g every 8 hours) plus an antianaerobic
in the translocation of bacteria from the intestine to drug, such as metronidazole
extraintestinal sites. Duration is determined by clinical response and
serial ascitic fluid PMN counts and cultures
Urinary tract infections
Ascites 287
Role of Albumin Table 8: Prevention of spontaneous bacterial peritonitis (SBP)
Renal impairment occurs in 33% of episodes of SBP. Indication Drug Results

Spontaneous bacterial peritonitis leads to increased Prior SBP Norfloxacin 400 mg 66% reduction in
intraperitoneal nitric oxide production, which in turn further orally once daily recurrence
until death or liver
increases systemic vasodilatation and promotes renal failure.
transplantation
Intravenous albumin (1.5 g/kg of body weight at the time
Cirrhosis with Norfloxacin 400 mg 73% reduction in
the infection is detected and 1.0 g/kg on day 3) can increase
gastrointestinal orally twice daily for infection
intravascular volume, and in combination with cefotaxime, hemorrhage 7 days
has been shown in a large randomized trial to reduce the risk of Ceftriaxone 1 g 67% reduction in
renal failure and improve survival compared with cefotaxime intravenously per infection as compared
without albumin. However, a confirmatory randomized day for 7 days to norfloxacin
trial is needed. Because of the survival advantage, use of Cirrhosis with ascitic fluid Norfloxacin 400 89% reduction in
intravenous albumin as an adjunct to antibiotic treatment has total protein <1.5 g/dL mg/day orally for SBP; 32% reduction
been recommended. and either Child-Turcotte- 1 year in hepatorenal
Pugh score 9 and total syndrome; 52%
bilirubin 3 mg/dL, or increase in 3-month
Prognosis creatinine 1.2 mg/dL, or
blood urea nitrogen 25
survival; 25% increase
in 1-year survival
The most recent series report the lowest mortality rates (less mg/dL, or serum sodium
than 5% if antibiotics are administered in a timely fashion), 130 mEq/L
probably because of earlier detection and treatment of Cirrhosis with ascitic fluid Ciprofloxacin 500 31% reduction
infection, as well as the avoidance of nephrotoxic antibiotics. total protein <1.5 g/dL mg orally daily for in infection; 30%
1 year improvement in
In fact, spontaneous ascitic fluid infection is a good marker
survival
of end-stage liver disease and has been proposed as an
indication for liver transplantation in a patient who is
otherwise a candidate.
Without surgical intervention, the mortality rate for subjected to hydrostatic pressures different from those that
secondary peritonitis in hospitalized patients with ascites affect the portal bed. The total protein concentration is higher
approaches 100%. When secondary peritonitis is diagnosed by approximately 1.0 g/dL (10 g/L) in the pleural fluid than in
early and treated with emergency laparotomy, the mortality ascitic fluid.
rate is approximately 50%.
Treatment of Hepatic Hydrothorax

Prevention Sodium restriction plus use of diuretics with intermittent
Norfloxacin, 400 mg per day orally, has been reported to thoracentesis is the safest and most effective first-line
reduce the risk of SBP in patients with low-protein ascites and therapy of hepatic hydrothorax
those with previous SBP (Table 8). Norfloxacin, 400 mg orally Transjugular intrahepatic portosystemic shunt (TIPS)
twice daily for 7 days, helps prevent infection in patients placement has been reported to be successful and
with variceal hemorrhage and is cost-effective in preventing constitutes reasonable second-line treatment (Fig. 3)
recurrent SBP. If the patient is a candidate for liver transplantation,
proceeding with a transplantation evaluation may be the
best approach
Hepatic Hydrothorax Some authors have recommended chest tube insertion
Sympathetic pleural effusions are common in patients with and sclerosing of the pleurae with tetracycline; however,
cirrhotic ascites. They are usually unilateral and right-sided, chest tubes inserted to treat hepatic hydrothorax are
but occasionally may be bilateral and larger on the right usually difficult to remove; moreover, shortness of breath
side than on the left. A unilateral left-sided effusion suggests may recur when the tube is clamped, and fluid may leak
tuberculosis. A large effusion in a patient with cirrhotic around the insertion site of the tube
ascites is designated hepatic hydrothorax. The analysis of A peritoneovenous shunt can be considered when the
uncomplicated hepatic hydrothorax fluid is similar, but not patient with hepatic hydrothorax has large-volume ascites,
identical to that of ascitic fluid because the pleural fluid is but the shunt usually clots after a short time
Direct surgical repair of the diaphragmatic defect can be alcohol can result in healing of the reversible component of
considered, but the patients typically are poor operative alcoholic liver disease, and the ascites may resolve or become
candidates. more responsive to medical therapy. Similarly, patients
with other forms of treatable liver disease (e.g. autoimmune
hepatitis, hemochromatosis, Wilsons disease) should receive
TREATMENT OF ASCITES specific therapy for these diseases.
Appropriate treatment of ascites depends on the cause of

fluid retention. Treat the Precipitating Cause
Determining the immediate precipitant of ascites (e.g. dietary
indiscretion or nonadherence to therapy with diuretics) may
Treatment of Low SAAG Ascites be of value. Ascites may be precipitated by saline infusions
Peritoneal carcinomatosis is the most common cause given perioperatively or to treat variceal hemorrhage or by
of low-albumin-gradient ascites. Peripheral edema in sodium bicarbonate tablets; in such cases the ascites may
affected patients can be managed with diuretics. By resolve without the need for long-term treatment.
contrast, patients without peripheral edema who receive
diuretics lose only intravascular volume, without loss
of ascitic fluid. The mainstay of treatment of nonovarian Diet Education
peritoneal carcinomatosis is outpatient therapeutic Fluid loss and weight change are related directly to sodium
paracentesis balance in patients with portal hypertension-related ascites.
Ascites caused by tuberculous peritonitis (without The dietary sodium restriction recommended is 2,000 mg
cirrhosis) is cured by antituberculosis therapy sodium (88 mmol of sodium) or 5 gm of NaCl (common salt)
Pancreatic ascites may resolve spontaneously, require per day. Protein is not restricted unless the patient has hepatic
endoscopic placement of a stent in the pancreatic duct encephalopathy.
or operative intervention, or respond to treatment with
somatostatin
A postoperative lymphatic leak from a distal splenorenal No Role of Fluid Restriction
shunt or radical lymphadenectomy may also resolve Indiscriminate restriction of fluid in the treatment of cirrhotic
spontaneously, but occasionally may require surgical ascites is inappropriate, and may result in hypernatremia.
intervention or placement of a peritoneovenous shunt Chronic hyponatremia usually seen in patients with cirrhotic
Chlamydia peritonitis is cured by tetracycline ascites is seldom morbid. Attempts to correct hyponatremia
Ascites caused by lupus serositis may respond to rapidly in this setting can lead to more complications than
glucocorticoids those related to the hyponatremia. A study of 997 patients with
Dialysis-related ascites may respond to aggressive dialysis. cirrhosis and ascites demonstrates that the serum sodium
is less than or equal to 120 mmol/L in only 1.2% of patients
Treatment of High SAAG Ascites and less than or equal to 125 mmol/L in only 5.7%. Unless
the decline in sodium concentration is rapid, symptoms of
Cirrhosis is the most common cause of liver disease that leads hyponatremia usually do not develop in cirrhotic patients
to high-albumin-gradient ascites. Reducing the quantity until serum sodium concentration is below 110 mmol/L.
of fluid in the abdomen can improve patients comfort, Preliminary data suggest that aquaretic drugs have the
and prevent hepatic hydrothorax and hernias. Also, by promise of correcting hyponatremia. An oral preparation
concentrating the ascitic fluid, diuresis increases the opsonic tolvaptan increases serum sodium in patients who have
activity of ascitic fluid tenfold and theoretically may be of pretreatment values less than or equal to 130 mmol/L.
value in preventing spontaneous ascitic fluid infection. Tolvaptan has been used in fewer than 100 patients with
cirrhosis and hyponatremia, and most of the safety data the
Food and Drug Administration (FDA) relied upon is from
Manage Causative Factors patients with congestive heart failure. Therefore, it remains
In a patient with alcoholic liver disease, convince the patient to unclear how safe this drug is in patients with cirrhosis. Cost-
stop drinking alcohol. In a period of months, abstinence from effectiveness also warrants investigation.
Ascites 289
Diuretics Dose: The initial oral dose of furosemide is usually 2040

mg/d, and is generally adjusted upward every few days up to
Diuretics are the mainstay of treatment for patients with a maximum of 160 mg/d.
cirrhosis and ascites. Various diuretics used are as follows.
Side effects:
Potassium depletion
Antimineralocorticoids Metabolic hypochloremic alkalosis
Hyponatremia
Secondary hyperaldosteronism is a major factor promoting Hypovolemia leading to renal dysfunction.
renal sodium retention in the distal tubules and collecting
ducts of the nephron. Both controlled and uncontrolled
clinical trials have shown that spironolactone is the drug of Other Diuretics
choice for the initial treatment. Spironolactone achieves a
Metolazone and hydrochlorothiazide have also been
better natriuresis more often than loop diuretics, such as
used to treat ascites. Hydrochlorothiazide can cause
furosemide. The half-life of spironolactone is approximately
rapid development of hyponatremia when added to the
24 hours in normal control subjects, but is markedly prolonged
combination of spironolactone and furosemide.
in patients with cirrhosis; almost 1 month is required to reach
Eplenerone is a new aldosterone antagonist that has been
a steady state. In view of its long half-life, dosing the drug
used in heart failure. It has not been studied in the setting of
multiple times per day is unnecessary. A loading dose may be
cirrhosis and ascites.
appropriate but has not been studied.
Dose: The recommended initial dose of spironolactone is
100200 mg once daily. When severe hyperaldosteronism, Combination of Antimineralocorticoids and
i.e. severe sodium retention is present, the dose may be Loop Diuretics
increased to 400 mg/d. A therapeutic response is observed in
75% of patients. The usual diuretic regimen consists of single morning doses
of oral spironolactone and furosemide, beginning with 100
Side effects:
mg of the former and 40 mg of the latter. Initial combination
Gynecomastia is the main side effect of spironolactone.
treatment shortens the time to mobilization of moderate
Patients may be shifted to other potassium-sparing
ascites. An alternative approach would be to start with single-
diuretics like amiloride.
agent spironolactone, in particular in the outpatient setting.
Metabolic acidosis with or without hyperkalemia may
The doses of both oral diuretics can be increased
occur with renal impairment.
simultaneously every 35 days (maintaining the 100:40 ratio)
if weight loss and natriuresis are inadequate. In general, this
Other Potassium-sparing Diuretics ratio maintains normokalemia. Usual maximum doses are
400 mg/day of spironolactone and 160 mg/day of furosemide.
Amiloride and triamterene act in the distal tubule. Amiloride Furosemide can be temporarily withheld in patients
(1040 mg/day) can be substituted for spironolactone in presenting with hypokalemia; this is very common in the
patients with tender gynecomastia. However, amiloride is setting of alcoholic hepatitis.
more expensive and has been shown to be less effective In the largest (involving around 4,000 patients),
than an active metabolite of spironolactone in a randomized multicenter, randomized controlled trial performed in
controlled trial. patients with ascites, dietary sodium restriction and a dual
diuretic regimen with spironolactone and furosemide has
Loop Diuretics been shown to be effective in more than 90% of patients in
achieving a reduction in the volume of ascites to acceptable
Loop diuretics, such as furosemide, are used as an adjunct levels.
to spironolactone therapy. Furosemide should be given once
An issue is whether diuretics should be withheld when a
a day. Furosemide may be preferred over spironolactone patients blood pressure is low. No data exist to support this
in patients with parenchymal renal disease (e.g. diabetic practice in the setting of cirrhosis. Baseline blood pressure,
nephropathy or immunoglobulin A nephropathy or mental status and creatinine must be factored into the decision
those having undergone liver transplantation) because of to continue, hold or discontinue diuretics. The baseline blood
hyperkalemia. pressure is usually low (e.g. 70100 mm Hg systolic in a patient
with cirrhotic ascites). Unless, it has dropped significantly or urine sodium-to-potassium ratio greater than 1 probably are
the patient has confusion or azotemia, diuretics should be not adherent to the diet.
given.
Prostaglandin inhibitors (e.g. nonsteroidal anti-inflam
matory drugs) should be avoided in patients with cirrhosis Role of Therapeutic Paracentesis
and ascites because they inhibit diuresis, may promote renal
failure and may cause gastrointestinal bleeding.
Indications
Ascites that has not responded to medical therapy
To resolve large-volume ascites rapidly
Indications of Cessation of Diuretics To enable easier ultrasound examination in patients with
Uncontrolled or recurrent encephalopathy massive ascites
Serum sodium less than 120 mmol/L despite fluid To periodically treat refractory ascites.
restriction Frequency of paracentesis provides insight into the
Serum creatinine greater than 2.0 mg/dL (180 mol/L). patients degree of compliance with the diet. The sodium
concentration of ascitic fluid is approximately equivalent
to that of plasma in these patients, i.e. 130 mmol/L. A 6 L
Assessing the Response to Diuretics paracentesis removes 780 mmol of sodium (130 mmol/L
The mobilization of ascites is best assessed by daily weighing 6 L = 780 mmol). A 10 L paracentesis removes 1,300 mmol.
of the patient using accurate standardized weighing protocols. Patients consuming 88 mmol of sodium per day, excreting
Loss of body weight: The rate of weight loss should be 0.5 kg/d approximately 10 mmol/day in nonurinary losses and
in the absence of edema. In the presence of edema, rate of excreting no urinary sodium retain a net of 78 mmol/day.
weight loss should not exceed 1 kg/d. Therefore, a 6 L paracentesis removes 10 days (780 mmol or
78 mmol/day) of retained sodium and a 10 L paracentesis
Urine sodium excretion: Measurement of urinary sodium removes approximately 17 days of retained sodium (1,300
excretion is a helpful parameter to follow when rapidity of
mmol or 78 mmol/day = 16.7 days) in patients with no
weight loss is less than desired. Random urinary sodium
urinary sodium excretion. Patients with some urinary sodium
concentrations are of value when they are 0 mmol/L or
excretion should require paracenteses even less frequently.
greater than 100 mmol/L, but are much less helpful when
Patients requiring paracenteses of approximately 10 L more
they are intermediate because of lack of uniformity of sodium
frequently than every 2 weeks are clearly not complying with
excretion during the day and lack of knowledge of total urine
the diet.
volume, which may vary from 300 mL to greater than 3,000
mL. Twenty-four-hour collections of urine for determination
of sodium excretion are much more informative than Trials of Paracentesis Versus Diuretic
random specimens. The completeness of urine collection
can be assessed by measuring urinary creatinine excretion There have been five randomized controlled trials comparing
(1520 mg/kg per day in male and 1015 mg/kg per day in therapeutic paracentesis with diuretics in cirrhotic patients
female; excretion of less creatinine indicates an incomplete with ascites. These studies compared repeated large volume
collection). Total nonurinary sodium excretion is less than paracentesis (5 L/d) with albumin infusion (68 g/L of ascites
10 mmol/day in afebrile patients with cirrhosis without removed) and showed that paracentesis was more effective
diarrhea. One of the goals of treatment is to increase urinary than diuretics in eliminating ascites and shortened the
excretion of sodium so that it exceeds 78 mmol/day (88 mmol duration of hospitalization.
intake/day - 10 mmol nonurinary excretion per day). Patients
who are adherent to an 88 mmol per day sodium diet and who
excrete more than 78 mmol per day of sodium in the urine
Paracentesis-induced Circulatory
should lose weight. If the weight is increasing despite urinary Dysfunction
losses in excess of 78 mmol per day, it means that the patient The diagnosis of paracentesis-induced circulatory dysfunction
is consuming more sodium than is prescribed in the diet. (PICD) is based on an increase in plasma renin activity (PRA)
Urine sodium-to-potassium ratio: Random urine sodium-to- of 450% of the pretreatment value to above 4 ng/mL/h on the
potassium concentration ratio greater than 1 predicts that 6th day after paracentesis. Changes in PRA may also predict
the patient should lose weight if a sodium-restricted diet is postparacentesis hyponatremia Changes in blood circulation
followed. Patients who do not lose weight despite a random following paracentesis include:
Ascites 291
Acute increase of cardiac output and a lowering of systemic paracentesis. these patients may be more sensitive to
vascular resistance, leading to a modest reduction of blood paracentesis-related volume depletion than are patients
pressure with advanced cirrhosis
Pulmonary capillary wedge pressure decreases about 6 In patients with tense ascites, paracentesis (45 L) to relieve
hours postparacentesis. intra-abdominal pressure and diuretics to eliminate the
Right atrial pressure falls acutely following the onset of remainder should be used
paracentesis, secondary to a reduction of intrathoracic To remove all fluid by paracentesis when most of it can
pressure. be removed with diuretics seems inappropriate, partly
Paracentesis-induced circulatory dysfunction may persist because paracentesis removes opsonins, whereas diuresis
for months and may be associated with adverse clinical concentrates opsonins
events, such as an increased rate of recurrent ascites, the Chronic therapeutic paracenteses should be reserved for
development of HRS and/or hyponatremia in 20% of cases 10% of patients in whom diuretic treatment fails to relieve
and reduced survival. These events likely result from the the ascites.
activation of the neurohumoural systems. Because of the risk
of complications, many but not all experts believe that it is
necessary to use a treatment that prevents PICD in patients Role of Transjugular Intrahepatic
receiving large-volume paracentesis. Portosystemic Shunt
Prevention of PICD: Transjugular intrahepatic portosystemic shunt, in which a
Use of plasma expanders: An analysis of data from all self-expanding shunt is inserted to create a shunt between the
published studies suggests that albumin is more effective hepatic vein (low pressure) and portal vein (high pressure),
in the prevention of hyponatremia (8% of 482 patients) as can lead to an improvement of renal function and sodium
compared to other plasma expanders (17% of 344 patients). excretion, and the resolution of ascites. Circulatory changes
Role of vasoconstrictors: As vasodilation plays a crucial following TIPS are:
role in the development of PICD, administration of a Marked increase of cardiac output, right atrial pressure
vasoconstrictor (e.g. terlipressin or midodrine) might and pulmonary artery pressure
prevent PICD. A randomized pilot study compared the Secondary decrease of systemic vascular resistance
effects of terlipressin and albumin on PICD showing Increase in pulmonary vascular resistance and effective
similar levels of post-paracentesis PRA in patients arterial blood volume
receiving terlipressin or albumin. However, this study was Sodium excretion and renal function improve over 4
underpowered and thus larger trials are needed to confirm weeks. It is indicated in diuretic resistant ascites.
the effectiveness and safety of terlipressin.
Complications
Controversy of Volume Expansion
Immediate complications include:
There have been five randomized controlled trials comparing Capsule puncture
volume expansion with albumin with other forms of plasma Intra-abdominal bleeding.
expanders, including dextrans, collagen-based colloids, and
Late but common complications include:
hydroxyethyl starch. All studies have shown that synthetic
Shunt thrombosis and stenosis: TIPS stenosis occurs in
plasma expanders are as effective as albumin in preventing the
up to 70% of patients with a bare TIPS within the first
clinical complications of paracentesis, namely hyponatremia
year. TIPS stenosis can be treated by balloon dilatation of
or renal impairment. A colloid that specifically should be
the stent, and if this is not successful, a new stent can be
avoided is hetastarch, which can accumulate in Kupffer
inserted. Polytetrafluoroethylene (PTFE)-covered stents
cells and cause portal hypertension in patients without pre-
have significantly reduced the incidence of TIPS stenosis,
existing liver disease.
as they avoid bile leakage into the shunt lumen because of
their decreased porosity, and also permit a more uniform
Approach to Patients with Ascites endothelial growth owing to a smoother internal lining
Hepatic encephalopathy: The incidence of new or
Salt restricted diet (5 gm table salt/day)
worsening hepatic encephalopathy after TIPS insertion
Patients with early cirrhosis and diuretic-sensitive ascites
is 2030%. Only in a very small proportion of patients,
should be managed with diuretics, not large-volume
encephalopathy is refractory to medical management.
Table 9: Large-scale randomized controlled trials of TIPS versus serial large-volume paracentesis
Author Inclusion criteria Method of randomization N Control of Survival Encephalopathy

and analysis ascites
Rossley Tense ascites and failure of 4 No details 60 61% vs 18% 69% vs 52% 58% vs 48%*
weeks of therapy (P = 0.006) (P = 0.11)
Gines Ascites refractory to medical Sealed opaque envelope 70 51% vs 17% 41% vs 35%* All 77% vs 66% (P = 0.29)
therapy Intention to treat (P = 0.003) Severe 60% vs 34% (P = 0.03)
Sanyal Refractory ascites No details; intention to treat 109 58% vs 16% 40% vs 37%* Moderate-severe 38% vs 12%
(P < 0.001) (P = 0.058)
Salerno Refractory or No details 66 79% vs 42% 77% vs 52% Severe (P = 0.039)
recidivant (P = 0.0012) (P = 0.021)
*P value not significant
In such cases, occlusion or reduction of the shunt size is Structural abnormalities such as multiple hepatic cysts, as
mandatory to control the encephalopathy the insertion of TIPS may be technically unfeasible.
Intravascular hemolysis: This is particularly evident with
bare stents, occurring in approximately 10% of patients.
Although hemolysis can be quite severe, in most cases, Controlled Trials Comparing TIPS with
it is self-limited and decreases as the stent becomes Paracentesis
endothelialized in 1215 weeks. Patients with severe
Four large-scale randomized trials in diuretic-resistant patients
hemolysis may require blood cell transfusions for support.
have demonstrated consistent superiority of TIPS over repeated
With the advent of PTFE-covered stents, the incidence of
paracentesis but no survival advantage (Table 9).
intravascular hemolysis should decrease, but no data are
Transjugular intrahepatic portosystemic shunt was
yet available on this issue
effective in about two-thirds of patients in eliminating ascites,
Other serious complications include the development of
and was superior to repeated large-volume paracentesis,
cardiac failure (2.5%), renal failure (4.3%) and liver failure
which controlled ascites in only 23% of patients.
(1.9%)
Bacterial infection of the stent itself or endotipsitis is
an uncommon complication, occurring in about 1.5% Role of Peritoneovenous Shunt
of patients, but it is a very serious event because it often
cannot be successfully treated. Due to fatal complications following shunt insertion and
randomized trials demonstrating no survival advantage have
led to the relegation of this procedure to third-line therapy
Contraindications for TIPS in patients with cirrhosis and ascites (Fig. 3). Indications of
peritoneovenous shunt are as follows:
Transjugular intrahepatic portosystemic shunt should not be
Patients who are not candidates for liver transplantation
performed in the following:
Patients who have a scarred abdomen that is not amenable
Elderly patients with a history of recurrent hepatic
to repeated paracenteses
encephalopathy
Patients who are not candidates for TIPS, or
Patients with cardiac dysfunction or pulmonary hyper
Patients in whom an attempt at TIPS placement has failed.
tension and patients with renal failure. Although TIPS
has been used as a treatment for HRS type-1 with an
improvement of renal function post-TIPS, worsening of Role of Liver Transplantation
renal function post-TIPS has also been reported
All patients receiving TIPS should be free of infections Liver transplantation should be considered among the
and should receive an antibiotic prophylaxis during the treatment options for patients with cirrhosis and ascites
procedure whether the fluid is diuretic-sensitive or diuretic-refractory.
Presence of intrahepatic malignancy, as this can dissem The 12-month survival rate for patients with ascites refractory
inate the tumor to medical therapy is only 32%. The survival rate for liver
Patients with portal vein thrombosis transplantation is much higher.
Ascites 293
First-line treatment Second-line treatment Third-line treatment

Fig. 3: Algorithm for the treatment of patients with cirrhosis and ascites
Table10: Selective studies from India in the management of ascites
Author Treatment modality No. of patients Clinical results

Sen et al. Spironolactone alone vs with 20 Decrease in portal pressure with combination therapy in propranolol-refractory
propranolol patients
Singh et al. Terlipressin vs albumin 40 Similar effectiveness in preventing circulatory dysfunction from paracentesis
Amarapurkar et al. Covered vs uncovered TIPS 23 Less stent dysfunction with covered stent without increasing hepatic
stent encephalopathy. No survival benefit.
Abbreviations: TIPS, transjugular intrahepatic portosystemic shunt
In patients who are candidates for liver transplantation, an insufficient natriuretic effect of diuretic medications, or
procedures that could make transplantation difficult should more often, to the development of diuretic-related severe side
be avoided. Surgery in the right upper quadrant causes effects, which compel the patient to discontinue the diuretic
adhesions that become vascularized and difficult to remove treatment.
during transplant surgery. Even peritoneovenous shunting The revised diagnostic criteria of refractory ascites by
can lead to the formation of a cocoon in the right upper International Ascites Club are shown in Table 11.
quadrant that can involve the bowel and liver.
Clinical Consequences of Refractory

Indian Data on the Management of Ascites
Ascites Refractory ascites is frequently associated with HRS type-2,
Indian data on the management of ascites has been given in SBP, dilutional hyponatremia, muscle wasting and pleural
Table 10. effusion.
It also implies an ominous prognosis, as the 2-year
probability of survival among patients with refractory ascites
REFRACTORY ASCITES is about 30%, while at least 40% of patients with responsive
ascites are alive at 5 years.
Five to ten percent of ascitic patients per year become Thus, the onset of refractory ascites requires specific
refractory to standard medical treatment, because of either therapeutic measures and dictates that the patient be rapidly
Table 11: Revised diagnostic criteria of refractory ascites Conditions Leading to Transient or
Treatment duration: Patients must be on intensive diuretic therapy Apparent Refractoriness to Diuretic
(spironolactone 400 mg/day and furosemide 160 mg/day) for at least
1 week and on a salt-restricted diet of less than 90 mmoles/day or 5.2 Therapy
g of salt/day
There are, however, several other conditions of no or
Lack of response: Mean weight loss of 0.8 kg over 4 days and urinary
sodium output less than the sodium intake
insufficient response to diuretic treatment that cannot be
properly defined as refractory ascites.
Early ascites recurrence: Reappearance of grade 2 or 3 ascites within 4
weeks of initial mobilization An inappropriate diuretic therapy like patients treated
only with loop diuretics
Diuretic-induced complications:
Diuretic-induced hepatic encephalopathy: Development of encepha Diuretics have evoked an exaggerated response (over
lopathy in the absence of any other precipitating factor diuresis) leading to a negative fluid balance in excess of
Diuretic-induced renal impairment: Increase of serum creatinine by 900 mL/day with too rapid weight loss. Prerenal azotemia
> 100% to a value > 2 mg/dL in patients with ascites responding to ensues in these cases and refractoriness is actually induced
treatment
Diuretic-induced hyponatremia: Decrease of serum sodium by > 10
by the treatment itself. This condition requires diuretic
mmol/L to a serum sodium of < 125 mmol/L withdrawal, plasma volume expansion and a cautious
Diuretic-induced hypo- or hyperkalemia: Change in serum potassium restoration of a gradually increasing diuretic therapy to
to < 3 mmol/L or > 6 mmol/L despite appropriate measures doses lower than those that caused prerenal azotemia
Transient refractoriness of ascites can also occur when the
renal function is impaired by other iatrogenic causes or
evaluated for possible liver transplantation if not carried out
concurrent, but reversible, complications like:
before.
Administration of nonsteroidal anti-inflammatory
drugs, which impair renal function by inhibiting the
Mechanisms of Refractory Ascites synthesis of vasodilating prostaglandins
Administration of angiotensin-I-converting enzyme
Two mechanisms act simultaneously. inhibitors or angiotensin receptor antagonists, which
1. The severity of renal sodium retention increases throughout
can impair the renal blood perfusion and reduce the
the natural history of cirrhosis, because of the progression
glomerular filtration rate in patients with cirrhosis and
of systemic and portal hemodynamic abnormalities and
ascites
the associated activation of neurohumoral vasoactive
Administration of nephrotoxic drugs, such as amino
systems leading to avid renal reabsorption of sodium and
glycosides
water. At the same time, renal perfusion and glomerular
Complications precipitating renal failure including
filtration rate progressively decline. As a result, sodium
fluid loss through vomiting, diarrhea or bleeding.
reabsorption at the proximal convoluted tubule markedly
In these cases, withdrawal of the offending drug or
increases and its delivery to distal segments of the nephron
is markedly reduced. Thus, renal sodium retention resolution of the complication combined with an
mainly occurs proximally to the site of action of both appropriate plasma volume expansion may restore
antimineralocorticoid and loop diuretics, and this can responsiveness to the standard treatment of low sodium
explain why diuretic treatment becomes unsuccessful in intake and diuretics.
some patients. Bacterial infections, such as SBP, which can intensify
2. Reduced cardiovascular responsiveness to vasoconstrictor arterial vasodilatation, and therefore, worsens the
systems perpetuates the relative underfilling of the mismatch between the intravascular volume and the
effective arterial blood volume and this compounds vascular capacitance. Treatment of SBP will lead response
the hypovolemic effects of diuretics. In such a situation, to standard diuretic therapy
diuretic-related side effects frequently occur, precluding the Noncompliance to low sodium diet: Patient may not
continuation of effective dosages of diuretics. Accordingly, comply with a low sodium diet. A 24-hour urinary sodium
refractoriness to diuretic treatment is the consequence of excretion and a quick calculation using the amount of
the hemodynamic abnormalities characterizing advanced weight gained will allow one to tell whether or not the
cirrhosis. patient is compliant with sodium restriction.
Ascites 295
Treatment 7. Gines P, Cardenas A, Arroyo V, et al. Management of cirrhosis and

ascites. N Engl J Med. 2004;350:1646-54.
Options for patients refractory to routine medical therapy 8. Gines P, Uriz J, Calahorra B, et al. Transjugular intrahepatic
include: portosystemic shunt versus paracentesis plus albumin for
Serial therapeutic paracenteses refractory ascites in cirrhosis. A multicenter randomized
Liver transplantation comparative study. Gastroenterology. 2002;123:1839-47.
TIPS 9. Gunawan B, Runyon B. The efficacy and safety of epsilon-
aminocaproic acid treatment in patients with cirrhosis and
Peritoneovenous shunt
hyperfibrinolysis. Aliment Pharmacol Ther. 2006;23:115-20.
Novel treatments.
10. Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic
liver diseases: from the patient to the molecule. Hepatology.
Novel Treatments 2006;43:S121-31.
11. Koconis KG, Singh H, Soares G. Partial splenic embolization in
Novel treatment options for patients with refractory ascites the treatment of patients with portal hypertension: a review
include: of the English language literature. J Vasc Internvent Radiol.
Weekly infusions of intravenous albumin 2007;18:463-81.
Ascites reinfusion 12. Planas R, Montoliu S, Balleste B, et al. Natural history of
patients hospitalized for management of cirrhotic ascites. Clin
Ultrafiltration
Gastroenterol Hepatol. 2006;4:1385-94.
Partial splenic artery embolization.
13. Rossle M, Ochs A, Gulberg V, et al. A comparison of paracentesis
More data are needed before these treatments can be and transjugular intrahepatic portosystemic shunting in patients
advocated. with ascites. N Engl J Med. 2000;342:1701-7.
14. Runyon BA. Management of adult patients with ascites caused
by cirrhosis. Hepatology. 2004;39:841-56.
PROGNOSIS 15. Salerno F, Badalamenti S, Incerti P, et al. Repeated paracentesis
and IV albumin infusion to treat tense ascites in cirrhotic patients.
Cirrhosis complicated by ascites is associated with significant A safe alternative therapy. J Hepatol. 1987;5:102-8.
morbidity and mortality related, in part, to the severe 16. Salerno F, Badalamenti S, Lorenzano E, et al. Randomized
underlying liver disease and, in part, to the ascites per se. comparative study of hemaccel vs. albumin infusion after
When ascites appears in cirrhosis, the expected mortality rate total paracentesis in cirrhotic patients with refractory ascites.
Hepatology. 1991;13:707-13.
is approximately 50% in just 2 years with liver transplantation;
17. Salerno F, Badalamenti S. Drug-induced renal failure in cirrhosis.
survival is improved dramatically. In: Arroyo P, Gine`s J, Rodes RW, Schrier (Eds). Ascites and Renal
Dysfunction in Liver Disease, 2nd edition. Oxford, UK: Blackwell
Science; 2005. pp. 372-8.
BIBLIOGRAPHY 18. Salerno F, Merli M, Riggio O, et al. Randomized controlled study
of TIPS vs. paracentesis plus albumin in cirrhosis with severe
1. Amarapurkar DN, Punamiya S, Patel ND. An experience with ascites. Hepatology. 2004;40:629-35.
covered transjugular intrahepatic portosystemic shunt for 19. Sanyal A, Gennings C, Reddy KR, et al and the North American
refractory ascites from western India. Ann Hepatol. 2006;5: Study for Treatment of Refractory Ascites. A randomized
103-8. controlled study of TIPS versus large volume paracentesis in
2. Angeli P, Wong F, Watson H, et al. Hyponatremia in cirrhosis: the treatment of refractory ascites. Gastroenterology. 2003;124:
results of a patient population survey. Hepatology. 2006;44: 634-43.
1535-42. 20. Sanyal AJ, Freedman AM, Luketic VA, et al. The natural history of
3. Barrio J, Ripoll C, Banares R, et al. Comparison of transjugular portal hypertension after transjugular intrahepatic portosystemic
intrahepatic portosystemic shunt dysfunction in PTFE-covered shunts. Gastroenterology. 1997;112:889-98.
stent grafts versus bare stents. Eur J Radiol. 2005;55:120-4. 21. Sanyal AJ, Freedman AM, Purdum PP, et al. The hematologic
4. Bernardi M, Domenicali M. The renin-angiotensin-aldosterone consequences of transjugular intrahepatic portosystemic
system in cirrhosis. In: Schrier RW, Arroyo V, Rodes J, Gines P shunts. Hepatology. 1996;23:32-9.
(Eds). The Liver and the Kidney. Malden, MA: Blackwell Science 22. Sanyal AJ, Freedman AM, Shiffman ML, et al. Portosystemic
Publication; 2005. pp. 43-53. encephalopathy after transjugular intrahepatic portosystemic
5. Cardenas A, Gines P, Runyon BA. Is albumin infusion necessary shunt: results of a prospective controlled study. Hepatology.
after large volume paracentesis? Liv Int. 2009;29:636-40. 1994;20:46-55.
6. DAmico G, Garcia-Tsao G, Pagliaro L. Natural history and 23. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective
prognostic indicators of survival in cirrhosis: a systematic review oral vasopressin V2-receptor antagonist, for hyponatremia. N
of 118 studies. J Hepatol. 2006;44:217-31. Engl J Med. 2006;355:2099-112.
24. Sen S, De BK, Biswas PK, et al. Hemodynamic effect of 26. Silva RF, Arroyo PC, Duca WJ, et al. Complications following
spironolactone in liver cirrhosis and propranolol-resistant portal transjugular intrahepatic portosystemic shunt: a retrospective
hypertension. Indian J. Gastroenterol. 2002;21:145-8. analysis. Transplant Proc. 2004;36:926-8.
25. Sharma SK, Tahir M, Mohan A, et al. Diagnostic accuracy of
ascitic fluid IFN-gamma and adenosine deaminase assays in 27. Singh V, Kumar R, Nain CK, et al. Terlipressin versus albumin in
the diagnosis of tuberculous ascites. J Interferon Cytokine Res. paracentesis-induced circulatory dysfunction in cirrhosis: a
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33
cHAPTER
Hepatic Encephalopathy
Cihan Yurdaydin, Ramazan Idilman
INTRODUCTION precipitating event. Persistent HE is likely to be due to a large

spontaneous or iatrogenic portosystemic shunt.
Hepatic encephalopathy (HE) is defined as a reversible
metabolic encephalopathy occurring in patients with acute,
subacute or chronic liver disease. As such, two clinical entities CLINICAL SIGNS AND CLINICAL
associated with chronic liver disease, namely acquired
hepatocerebral degeneration and hepatic myelopathy,
IMPORTANCE OF HEPATIC
should be differentiated from HE since both conditions do ENCEPHALOPATHY
not suit with metabolic encephalopathy and are associated
with organic sequel. Acquired hepatocerebral degeneration, Hepatic encephalopathy reflects a spectrum of
with symptoms ranging from dementia, dysarthria, ataxia, neuropsychiatric abnormalities ranging from mHE to deep
intention tremor to choreoathetosis, has been associated coma. Minimal hepatic encephalopathy will be covered
with microcavitation in the cortex and white matter and separately. Clinical signs and neuropsychiatric abnormalities
spongy appearance of gray matter. Hepatic myelopathy is that can be detected during routine assessment are
secondary to pyramidal tract demyelination and may lead classified as overt HE. In overt HE, clinical signs can range
to transverse myelitis associated with spastic paraparesis. from personality changes, attention deficits and apathy to
Standard measures of HE management are without effect in deep coma depending on the stage of the HE spectrum.
both conditions whereas liver transplantation may offer some Traditionally, these stages are differentiated using the West
benefit. Both conditions have been associated with large Haven criteria (Table 1A). Stage 1 HE may be difficult to
spontaneous or iatrogenic portacaval shunts. differentiate from normal as assessment is subjective. For
Clinically, it was common to classify HE occurring in a follow-up and assessment of advanced stages of HE the
patient with cirrhosis as acute and chronic. The former was Glasgow coma scale serves as a practical easy-to-use tool
related frequently to a precipitating event and would most (Table 1B). Diagnosis of HE is important not only for its
of the time subside by simply managing the precipitating proper management but also for its prognostic implications.
event and the latter would be related to a large spontaneous Besides the reported clinical observations that cirrhotic
or iatrogenic portacaval shunt. HE in a patient with acute patients with HE did worse than those without HE, the natural
liver disease on the other hand would justify a diagnosis of history of patients after a first episode of HE is not known to
fulminant hepatic failure and herald an ominous prognosis. the extent we know the natural history of compensated and
However, it was observed that even experts put different decompensated cirrhosis. However, the few studies which
meanings to the terms acute and chronic HE. Hence, a panel of investigated the natural history after a first episode of HE
experts came together and decided upon a new nomenclature clearly have shown an ominous prognosis with 13 year
of defining HE aiming to avoid the confusion. Accordingly HE survival rates as low as 40% and 20%, respectively, and this
developing in acute liver failure was defined as type A HE, appears to have not changed in the last 34 decades. Further,
HE occurring in patients with cirrhosis was defined as type C a recent study suggests that HE affects patient survival
HE and finally HE occurring in patients with a portosystemic independent of the model for end-stage liver disease (MELD)
bypass with no intrinsic liver disease was classified as type B score; thus it may increase the accuracy of the MELD score
HE. Type C HE is further classified as episodic, persistent and in predicting survival. Finally, patients with pretransplant HE,
minimal HE (mHE). Episodic HE refers to the most frequently may have a worse prognosis post-transplant than patients
encountered form of overt HE which is often triggered by a without pretransplant HE.
Table 1A: The West Haven criteria for the differentiation of the stages
of hepatic encephalopathy
Grade of hepatic Clinical features

encephalopathy
0 No abnormality detected
1 Slight euphoria, anxiety, lack of awareness, shortened
attention span, difficulty with arithmetic
2 Lethargy, disorientation for time, change of personality,
uncharacteristic or inappropriate behavior
3 Somnolence to semistupor but response to stimuli,
gross disorientation
4 Coma
Table 1B: Glasgow coma scale (patients with a score of 8 or less are Fig. 1: Precipitating factors for hepatic encephalopathy
in coma)
Eye opening spontaneously 4 tool. Venous ammonia levels may be as reliable as arterial
to speech 3
ammonia levels but despite more than 100 years of availability
the test may still pose a challenge in routine clinical practice.
to pain 2
Diagnosis of HE should include identification of a possible
none 1 precipitating event (Fig. 1) as this is important for optimal
Verbal response orientated 5 management of the patient.
confused 4
inappropriate 3
incomprehensible 2 MINIMAL HEPATIC ENCEPHALOPATHY
none 1
This condition is defined as abnormal brain functioning
Motor response obeys commands 6 detected by psychometric or electrophysiologic testing in
localizes to pain 5 patients with advanced liver disease who show no clinical
withdraws from pain 4 signs of overt HE and appear to have a normal neurologic
flexion to pain (decorticated flexion) 3 examination. The prevalence of mHE has been reported in
extension to pain (decerebrate extension) 2
various studies as between less than 1550% of patients with
cirrhosis, depending on the criteria used for diagnosing mHE
none 1
and the stage of liver cirrhosis where patients with advanced
Maximum score 15 (Child B/C cirrhosis) were more likely to have mHE. It is
characterized by psychomotor slowing, deficits in attention,
DIAGNOSIS visual perception and visuoconstructive abilities. Verbal
abilities are preserved. Minimal hepatic encephalopathy has
Hepatic encephalopathy was and remains a clinical replaced the term subclinical HE, the latter of which was felt
diagnosis. A physician encountered an unconscious patient to underestimate the clinical importance of the condition. The
in the emergency room of a hospital needs first to do a clinical significance of mHE is highlighted through various
physical examination, which includes a thorough neurologic observations: in patients with mHE quality of life appears to
examination to rule out other causes of encephalopathy. be impaired; these patients may be unfit to drive a car; mHE
Patients with liver cirrhosis depict a tendency for bleeding may predict overt HE and may predict survival. It may resolve
which however, does not constitute clinical importance except with treatment. However, the diagnosis of mHE continues
that subdural hematoma is more frequently encountered to be a challenge. One problem is to differentiate between
in these patients. Especially in patients not responding to normal and abnormal. In a given population and for a
conventional management of HE this possibility needs to be particular test values outside the 2 standard deviation range
considered. Measurement of plasma ammonia levels should are generally considered abnormal. Several psychometric,
not be seen as a diagnostic tool but rather as a screening neurophysiologic and computerized tests have been
Hepatic Encephalopathy 299
Table 2: Psychometric tests for diagnosis of minimal hepatic by Haussingers group is a new concept that however, also
encephalopathy serves as an umbrella concept where both ammonia and
GABA or better the GABA/benzodiazepine receptor complex
Paper-pencil tests
NCT-A are the key players. Its strength lies also on the fact that the
NCT-B low-grade cerebral edema concept appears to give answers to
Block design test how precipitating factors of HE can lead to the development
Digit symbol test of HE. The concept of low-grade cerebral edema was first
Line tracing test
suggested by nuclear magnetic resonance spectroscopy
Serial dotting test
Repeatable battery for assessment of neuropsychological status data which showed an increase of the glutamine/glutamate
peak. This was accompanied by a depletion of myo-inositol.
Computerized tests
Inhibitory control test These data were further supported by newer magnetic
Cognitive drug research resonance techniques such as magnetization transfer ratio
Steinberg paradigm or scan test measurements. Ammonia detoxification in the central
Neurophysiological tests nervous system takes place in astrocytes where ammonia is
electroencephalogram converted to glutamine, a reaction catalyzed by the enzyme
Visual evoked potentials glutamine synthetase. Glutamine serves as an osmolyte and
Auditory evoked potentials
water moves inside the cell leading to astrocyte swelling,
Brainstem auditory evoked potentials
P300 event-related potentials a benchmark of low-grade cerebral edema. Methionine
sulfoximine, an inhibitor of glutamine synthetase, has been
Critical flicker frequency test
shown to prevent ammonia-induced astrocyte swelling in the
Abbreviations: NCT, number connection tests rat. As a compensatory mechanism to glutamine excess, other
Source: Adapted from Bajaj et al. osmolytes such as myo-inositol and taurine are released from
the cell leading to the depletion of intracellular myo-inositol,
serving as a homeostatic mechanism. This homeostatic
proposed and assessed for its diagnosis (Table 2). These are mechanism may be of crucial importance. It is suggested
too many and confusing for the practicing physician. Further, that patients with a normal liver tolerate precipitating
with psychometric paper-pencil tests normal values may be factors of HE since their osmolyte pool such as myo-inositol
affected by factors such as age, socioeconomic and cultural and taurine are not exhausted in contrast to the situation
background, education and repeat testing. Thus, normal in liver cirrhosis. In line with this reasoning, patients with
values of one cohort or society may not be applicable to cirrhosis with low brain myo-inositol were found to be prone
another society. The psychometric hepatic encephalopathy for the development of HE. In several studies, astrocyte
score had been proposed as a standard battery of tests but swelling could be induced not only by ammonia but also by
still needs validation. Newer approaches such as critical hyponatremia, inflammatory cytokines and benzodiazepines.
flicker frequency testing and computerized psychometric In the case of hyponatremia, it needs to be mentioned that
testing are approaches toward simplification; their universal glial cells selectively swell but neurons do not, suggesting the
applicability needs to be seen. Thus, mHE seeks for a simple existence of glia-specific water pores, namely aquaporin-4
diagnostic workup for it to be discovered by the daily and aquaporin-1 water channels. Astrocyte swelling may
practicing physician. upregulate peripheral benzodiazepine receptors which would
lead to the synthesis of neurosteroids such as pregnenolone.
Neurosteroids are potent positive allosteric modulators of
PATHOGENESIS the GABAA/benzodiazepine receptor complex and would
enhance GABAergic tone, the consequence of which is neural
The modern concept of HE had started with Sherlocks inhibition characteristic for HE (Fig. 2).
landmark paper delineating a gut-liver-brain connection Another important aspect of the pathogenesis of HE is
and emphasizing the importance of gut-derived nitrogenous the Trojan horse hypothesis by Albrecht and Norenberg.
substances, the main being ammonia, on the development of The Trojan horse here is glutamine which on the one hand
HE. A second step forward was reached when Schafer and Jones appears to detoxify ammonia in the brain but on the other
suggested the potential importance of gamma aminobutyric hand initiates ammonia toxicity in the brain. Accordingly
acid (GABA), the principal inhibitory neurotransmitter of glutamine formed in the cytoplasm enters the mitochondrial
the central nervous system, in the pathogenesis of HE. The matrix where breakdown of glutamine by phosphate-
current concept of low-grade cerebral edema put forward activated glutaminase to glutamate and ammonia occurs, the
antibiotic with broad spectrum activity and minimal intestinal

absorption, appears to be a safe and valid alternative. In a meta-
analysis of studies in patients with overt HE, rifaximin was
found as effective as nonabsorbable disaccharides. Ornithine-
aspartate infusion may also be effective in patients with overt
HE by promoting ammonia detoxification in muscle and liver.
Nonabsorbable disaccharides, rifaximin and ornithine-aspartate
were also found to be effective in improving mHE. However, a
general recommendation of treating patients with mHE does not
exist currently.
Persistent overt HE is likely due to spontaneous or
Fig. 2: Schematic representation of the low-grade cerebral edema iatrogenic portosystemic shunting. If this is due to transjugular
hypothesis of the pathogenesis of hepatic encephalopathy intrahepatic portosystemic shunt placement, shunt closure
Abbreviations: NH4, ammonium; BZD, benzodiazepines; PBR, or reduction of the shunt diameter is an effective strategy
peripheral type benzodiazepine receptor; PGN, pregnenolone; which may be justified in patients not responding to medical
GABA-R, gamma-aminobutyric acid receptor
therapy. Similarly, in patients with persistent HE due to a
spontaneous portosystemic shunt, embolization of the shunt
may be considered however, a large shunt may pose technical
latter of which interferes with mitochondrial function through difficulties.
excessive production of reactive oxygen species. These free An important aspect of the management of HE is
radicals also induce astrocyte swelling. It has been shown the prevention of its occurrence. Both nonabsorbable
however, that astrocyte swelling per se leads to oxidative and disaccharides and rifaximin have been explored in this regard
nitrosative stress and the sequence of events is still a matter of and found to be effective. In the long-term management of
debate. HE, another important aspect is nutrition. Patients with
cirrhosis should receive a high protein diet as suggested also
by the European Society for Parenteral and Enteral Nutrition.
Patients intolerant to meat protein should receive vegetable-
TREATMENT based protein. Finally, long-term administration of branched
The most frequently encountered and also clinically most chain amino acids is most likely of additional value, as two
relevant form of HE is type C episodic HE. The optimal large recent studies have shown.
management in such a patient begins with the identification
of a precipitating event. If such an event is recognized it should
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34
cHAPTER
Hepatocellular Carcinoma
Sachin Gupta, YK Chawla
INTRODUCTION most of the Indian studies. These varied age patterns of HCC
incidence in different areas are likely related to the prevalence
Hepatocellular carcinoma (HCC) is a major cause of of dominant hepatitis virus in the population, age at which
morbidity and mortality. Over last few decades, advancement viral infection is acquired, presence of other risk factors, and
in molecular and cellular biology and genomics made us some cohort effects. In Japan, the dominant virus is HCV;
wiser in understanding of risk factors and pathways leading while in China, it is HBV. Most of the patients infected with
to liver cancer. Advances in treatment modalities, radiological HCV acquire infection when they are adults while most of the
interventions, surgical methods, and progress in the field of HBV-infected persons acquire infection at childhood.
liver transplantation also led to better treatment of HCC.
Awareness for HCC prevention, surveillance, and early
diagnosis has also been increased. Unfortunately, lack of
Sex
surveillance, availability of advanced imaging, and treatment Men have two to four times more risk of development of
modalities, including liver transplantation are less in the HCC in comparison to females. The reason is not completely
regions where the disease burden is more. understood, but may be partly explained by the sex-specic
prevalence of risk factors. Males are more commonly infected
with HBV and HCV, consume more alcohol, smoke cigarettes,
EPIDEMIOLOGY and have increased iron stores.
Hepatocellular carcinoma incidence varies with the region.

Liver cancers most commonly occur (>80%) in either some ENVIRONMENTAL RISK FACTORS
part of Africa or in Eastern Asia, with China alone, accounting
for more than half of the cases of the world. Western countries The major risk factors are chronic infection with HBV or HCV,
have lower incidence (<5 cases/year/100,000), while dietary exposure to aatoxin B1 (AFB1) and consumption
Asian countries have either an intermediate (515 cases/ of alcohol. It is estimated that HBV and HCV infections are
year/1,000,000) or high (>15 cases/year/100,000) incidence causally associated with over 80% of HCC all around the
of HCC. India has low incidence of HCC, i.e. less than 5 cases/ world.
year/100,000 despite having high prevalence of HBV and
HCV-related chronic liver disease, possibly this is related to
underreporting. Hepatitis B Virus
Approximately 5% of the worlds population is chronically
infected with HBV; majority of whom live in the Asia and
DEMOGRAPHIC FACTORS Africa, which are high in high incidence HCC regions, cirrhosis
is closely associated with chronic HBV infection and cirrhosis
Age precedes most of the cases of HCC. In high incidence HCC and
HBV areas, about 70% of HBV infections are acquired either in
Age distribution of HCC varies by incidence, gender and, the perinatal period or in early childhood. Studies have shown
possibly, also by etiology. Female incidence peaks 5 years that HBV carriers born to HBV-infected mothers are at higher
higher than the peak age of males. In low-risk populations, the risk of HCC than other HBV carriers. The increased risk is likely
highest age-specic rates occur among persons aged 80 years to be related to a longer period of infection. Carcinogenesis
and greater. Fifty-two years was the mean age of patients in of HCC is considered to be a multistep process. HBV
Hepatocellular Carcinoma 303
infection causes HCC via both direct and indirect pathways. four principal aatoxins, B1, B2, G1, and G2, AFB1 is the
Indirectly, continual necrosis of hepatocytes accompanied most potent for carcinogenesis. From a Chinese study, it was
by regeneration leads to accumulation of mutations and estimated that AFB1 increased the risk of HCC fourfold, HBV
selection of cells with malignant phenotype. Directly, HBV increased the risk sevenfold, and the combination of AFB1
DNA and HBx cause alteration in different cellular processes and HBV increased the risk sixtyfold.
which stimulate the process of hepatocarcinogenesis. It is
obvious that, prevention of infection with HBV reduces the
risk of development of HCC. Alcohol
The evidence in support of a positive association between
alcohol consumption and HCC led International Agency
Hepatitis C Virus for Research on Cancer to conclude in 1988 that there was
Similar to HBV, HCV usually causes chronic infection, and a causal relationship. The mechanism by which alcohol
leads to slowly evolving liver disease. HCV infection is usually increases risk is not well understood. Data also suggest that
acquired in the adulthood. Japan has highest incidence alcohol is associated with HCC even in the absence of either
of HCC. Before the identication of HCV, Okuda et al. HBV or HCV infection. Alcohol causes cirrhosis and cirrhosis
hypothesized that a non-A, non-B virus caused a signicant is present in 6090% of HCCs. Whether alcohol is related to
proportion of HCC in Japan. Data on the risk of HCC in HCC independent of cirrhosis is not clear.
Japan were reported in a study of approximately 2,900 HCV
patients. The annual incidence of HCC among patients with
concomitant cirrhosis was 8% while the incidence was only Iron
0.5% among patients with little or no brosis. HCV has been There is evidence that higher body iron stores increase the
reported as a cause of HCC from all over the world and it risk of HCC. Persons with inherited metabolic disorders
depends upon the age at which infection was acquired, length which are associated with hepatic iron loading (e.g.
of follow-up and prevalence of cirrhosis. hemochromatosis, porphyria cutanea tarda) are at increased
The exact mechanism of HCC occurrence in chronic HCV risk of HCC. Similarly, iron overload in Africans, unrelated to
infection is not very clear. Although it was initially suggested hemochromatosis, has been associated with an increased risk
that HCV-enhanced mutagenesis in liver cells as a result of HCC. Moreover, studies have shown that in persons who
of chronic inammation and hepatocyte regeneration, are at high-risk of HCC due to infection with HBV and HCV or
it was questioned whether liver inammation itself is exposure to alcohol, iron may be a cofactor.
capable of causing HCC. The role of inammation alone
in hepatocarcinogenesis is questionable because patients
who have persistent severe inammation in the course of Endogenous and Exogenous Hormones
autoimmune hepatitis rarely develop HCC. A transgenic It is well known that oral contraceptive (OC) use can lead to
mouse model has demonstrated that the core protein of the benign hepatic adenoma. The evidence suggests that there is
virus plays an important role in the development of HCC. It also a relationship between OC use and HCC. Case control
was recently proposed that the HCV core protein may have studies have found increased risk with long-term (>5 years)
oncogenic properties that allow omission of some of the usual of OC use. There is some evidence that suggests that anabolic
multiple steps required during the process of carcinogenesis. steroids may cause HCC, but no epidemiologic study of
There are several factors that increase the likelihood of anabolic steroids and HCC has yet been reported. Animal
development of liver cirrhosis and HCC in patients who studies have shown a role of androgens in hepatocellular
have chronic HCV infection, and these include, older age carcinoma, but whether androgens are also a risk factor
at the time of the onset of HCV infection, male gender, in humans is not clear. In studies from Taiwan, Yu and
accompanying infection with HBV or HIV, heavy consumption Chen reported a positive association between increased
of alcohol, diabetes mellitus, obesity, transfusion-acquired testosterone levels and HCC among men who were chronically
HCV infection, and genotype 1b of HCV. In most of the cases, infected with HBV. Among women, several studies found that
cirrhosis precedes the development of HCC. HCC risk increased with increasing parity.
Aatoxin Diet
Aatoxin B1 is a mycotoxin elaborated by fungi of the Few dietary items have been extensively examined in human
Aspergillus species. The fungi grow on foodstuffs, such as studies; decreased risks of HCC have been reported in
corn and peanuts, stored in warm, damp conditions. Among association with selenium, tea, and vegetable consumption.
Selenium has been most widely studied in China due to a of obesity reported to date, Calle et al. reported signicantly
geographic correlation between high HCC rates and low increased risk of HCC.
serum selenium levels. Green tea consumption has been
shown to lower the risk of development of HCC. In various
studies, coffee has been shown to reduce the risk of HCC. Diabetes Mellitus
More than 20 studies of diabetes mellitus and HCC were
Toxins reported between 1970 and 2004 and over three-fourths
reported positive associations. Many of the studies of
Exposure to some toxins like thorotrast, vinyl chloride diabetics also noted a relationship between diabetes and
and arsenic is a known risk factor for development of cirrhosis. Insulin resistance is known to be associated with
angiosarcoma and intrahepatic cholangiocarcinoma. There is cirrhosis; hence, it is possible that the diabetes-cirrhosis
a weak association with heavy exposure of these toxins and and diabetes-HCC relationships are a consequence of the
development of HCC. brotic process. Recently, the role of insulin-like growth
factor (IGF) axis in HCC has been illustrated in HCC cell lines
and in animal xenograft models. This evidence provides an
HOST FACTORS indication that all four components of IGF axis are involved
in the carcinogenic and metastatic potential of HCC. Several
Cirrhosis strategies targeting this system, including monoclonal
antibodies against the IGF-1 receptor (IGF-1R) and small
Most of the HCCs are associated with cirrhosis. Chronic liver
disease of all etiologies is characterized by varying degrees molecule inhibitors of the tyrosine kinase function of IGF-1R
of inammation and brosis. The degree or stage of brosis are under active investigation.
appears to correlate best with prognosis. Only few studies
have been done to demonstrate the presence of cirrhosis in Nonalcoholic Steatohepatitis
HCCs, because, cirrhosis is diagnosed denitively by liver
biopsy. Velazquez et al. followed 463 patients with Child A It is clear that incidence of HCC is increased in most forms of
or B cirrhosis for the development of HCC. During a mean cirrhosis. The risk of HCC among patients with nonalcoholic
follow-up of 3.2 years, 38 patients were diagnosed with HCC, steatohepatitis (NASH) is not yet clearly dened. However,
with a mean annual incidence of 2.95%. Other studies have several case-reports and case-series of HCCs arising in NASH
also shown that the annual risk of HCC among patients with patients have been reported. A more denitive estimate of
cirrhosis is about 3%. HCC risk awaits prospective studies of NASH patients.
Hemochromatosis and Other Inherited NATURAL HISTORY OF

Metabolic Diseases HEPATOCELLULAR CARCINOMA
Hemochromatosis has been shown to be associated with
great risk of HCC. Recent studies have demonstrated the Hepatocellular carcinomas begin as solitary nodules, which
risk to be closer to 20. The risk is increased in the presence can occur anywhere in the liver. The right lobe is more
of a variety of cofactors, including male sex, age greater than frequently involved than the left. This may be related to its
50 years, drinking, smoking, and HBV and HCV infections. larger size. HCC commonly invade the portal and hepatic
Porphyria, alpha 1 antitrypsin deficiency and tyrosinemia venous systems, producing tumor thrombi in the portal
also have increased risk of HCC development. vein and its tributaries. The time from initial infection
with hepatitis B or C viruses to the development of HCC
is 28 decades. During this long interval, many changes
Obesity may occur in the liver, including chronic inammation,
Obesity increases risk of HCC. Obesity is associated with brosis, cirrhosis, increased hepatocyte death rates and
conditions which increase the risk of HCC, like diabetes regeneration. Studies of experimental hepatocarcinogenesis
mellitus and nonalcoholic steatohepatitis. Obesity may in animals reveal a sequence of events beginning with foci of
be responsible for a signicant proportion of cryptogenic phenotypically altered hepatocytes, proceeding to dysplastic
cirrhosis associated with HCC. In one of the largest studies foci and nodules.
SURVEILLANCE des--carboxyprothrombin and the percentage of AFP-L3, as

a marker for detection of early-stage HCC. The researchers
Ultrasonography is recommended every 612 months for suggested that an AFP level of 10.9 ng/mL (which had a
individuals at high risk of developing HCC (Table 1). The sensitivity of 66% and specificity of 82%) was optimal for
serum tumor marker -fetoprotein (AFP) is frequently used detection of early-stage HCC. However, AFP levels have a
in combination with ultrasonography for HCC surveillance low sensitivity in populations with a low pretest probability
in clinical practice. A randomized, controlled trial in China of HCC (as in the surveillance setting); moreover, the cutoff
reported improved overall survival (a reduction in mortality value suggested in this study pertained to diagnosis rather
of 37%) in the group of patients who underwent surveillance than surveillance.
with ultrasonography and measurement of AFP levels every
6 months, compared with the group of patients assigned to
no surveillance. Findings of a multicenter study in the US CLINICAL MANIFESTATIONS
demonstrated that AFP levels had the best area under the
receiver operating characteristic curve, followed by levels of Because most HCC cases appear in the setting of cirrhosis, a
major part of the findings will be indistinguishable from the
Table 1: Individuals for whom surveillance for hepatocellular clinical picture observed in patients with advanced cirrhosis.
carcinoma is recommended Patients may present with jaundice, ascites, encephalopathy,
or bleeding due to ruptured esophageal varices. In regions of
Surveillance recommended low incidence, HCC commonly develops as a complication
Population group Threshold incidence for Incidence of HCC of cirrhosis, and the patient has few, if any, symptoms
efficacy of surveillance attributable specifically to the tumor. If the tumor is small
(>0.25 LYG) (%/year)
(as it often is in a cirrhotic liver), it may not be obvious in
Asian male hepatitis B 0.2 0.40.6%/year the presence of advanced cirrhosis. One circumstance that
carriers over age 40
should alert the clinician to the possibility that HCC has
Asian female hepatitis B 0.2 0.30.6%/year supervened in a cirrhotic liver is a sudden unexplained
carriers over age 50
change in the patients condition: He or she may complain
Hepatitis B carrier with 0.2 Incidence higher of abdominal pain or weight loss; ascites may become more
family history of HCC than without
family history
severe, the ascitic fluid may become blood-stained, or the
condition may become more difficult to treat; the liver may
African/North American 0.2 HCC occurs at a
Blacks with hepatitis B younger age
enlarge rapidly or develop an arterial bruit or hepatic failure
may ensue. Moreover, because of the functional reserve of the
Cirrhotic hepatitis B 0.21.5 38%/year
carriers
liver, jaundice and other signs of hepatic dysfunction do not
appear until a large part of the organ has been replaced by
Hepatitis C cirrhotic 1.5 35%/year
tumor.
Stage 4 primary biliary 1.5 35%/year The ease of recognizing HCC clinically also differs among
cirrhosis
geographic regions. In regions in which HCC is common,
Genetic hemachromatosis 1.5 Unknown, but clinicians are especially mindful of the tumor and its diverse
and cirrhosis probably >1.5%/
year
presentations. Consequently, they are likely to recognize HCC
early than that for clinicians in regions where the tumor is rare.
Alpha 1-antitrypsin 1.5 Unknown, but
deficiency and cirrhosis probably >1.5%/
Patients with HCC often are unaware of its presence until the
year tumor has reached an advanced stage. The most common, and
Other cirrhosis 1.5 Unknown
first, symptom is pain in the right hypochondrial or epigastric
region (Table 2). Although sometimes severe, the pain usually
Surveillance benefit uncertain
is a dull continuous ache that becomes more intense in the
Hepatitis B carriers 0.2 <0.2%/year later stages of the illness. It may be accompanied by weakness
younger than 40 (males)
or 50 (females)
and weight loss. Less common complaints are an awareness
of a lump or fullness in the abdomen, loss of appetite, early
Hepatitis C and stage 3 1.5 <1.5%/year
fibrosis
satiety or discomfort after eating, generalized abdominal
swelling, diarrhea and constipation. Jaundice is an infrequent
Noncirrhotic NAFLD 1.5 <1.5%/year
initial complaint. When jaundice is deep, the cause is likely to
Abbreviation: NAFLD, nonalcoholic fatty liver disease be biliary obstruction.
Table 2: Symptoms and signs of hepatocellular carcinoma key pathologic factors for differential diagnosis is the vascular
supply of the lesion. Imaging techniques may establish the
Symptom Frequency Sign Frequency
(%) (%)
diagnosis of HCC in nodules larger than 1 cm showing arterial
hypervascularization and venous wash-out. In lesions that
Abdominal pain 5995 Hepatomegaly 5498
do not show a typical pattern, biopsy is recommended.
Weight loss 3471 Hepatic bruit 625 Contrast-enhanced ultrasound, spiral computed tomography
Weakness 2253 Ascites 3561 or dynamic magnetic resonance imaging are required for
Abdominal swelling 2843 Splenomegaly 2742 characterization of lesions in cirrhotic liver. However, during
Jaundice 435 the development of HCC, significant histological changes
Nonspecific 2528 Wasting 2541
are present with or without an evident arterial supply of the
gastrointestinal symptoms nodule. If ultrasonography reveals suspicious liver lesion
Fever 1154
in a patient with cirrhosis, contrast-enhanced CT or MRI is
the next diagnostic step. Biopsy is indicated when lesions
Jaundice 526
greater than 1 cm develop in a patient without cirrhosis or
if dynamic imaging modalities show inconclusive results
(Fig. 1). However, percutaneous biopsy to be used with
DIAGNOSIS AND STAGING caution, especially in patients who are eligible for curative
treatment (resection or liver transplantation), because of the
Despite advances in imaging technologies, imaging in cirrhotic 23% risk of tumor seeding along the biopsy needle track.
patients remains a challenge, since preneoplastic lesions, Numerous staging systems for HCC have been described,
such as dysplastic nodules, mimic a small HCC. One of the including the Barcelona Clinic liver Cancer (BCLC), Cancer
Fig. 1: Diagnostic algorithm for suspected hepatocellular carcinoma

Abbreviations: CT, computed tomography; MDCT, multidetector CT; MRI, magnetic resonance imaging;
US, ultrasound
of the liver Italian Program, tumor-node-metastasis, Okuda Table 5: Cancer of the liver: Italian program scoring system
and Japanese Integrated staging score systems (Tables 3 to
Variables Points
5). The BCLC system is currently endorsed by the American
association for the study of liver diseases and European 0 1 2
Association for the study of the liver, and is considered Child-Pugh class A B C
the standard staging system for clinical practice. It has Tumor morphology Single nodule Multiple and Massive or
the advantage that tumor staging is linked with treatment and extension extension extension
recommendations, as described below (Fig. 2). 50% 50% >50%
Alpha-fetoprotein <400 400
Table 3: Okuda staging for hepatocellular carcinoma (ng/mL)
Portal vein No Yes
Variables Points thrombosis
0 1
Tumor size < 50% of liver > 50% of liver
Ascites No Yes
Albumin (g/dL) 3 <3
Metroticket calculator is an online calculator proposed
Bilirubin (mg/dL) <3 3
by international liver transplant society. It is an easy way of
Okuda stage I 0 points; stage II 12 points; stage III 34 points predicting the 5-year survival of any given patient on the
basis of morphological and biological characteristics: size
Table 4: Tumor-node-metastasis stage as proposed by American Joint of the total nodules, size of the largest nodule and vascular
Committee on Cancer invasion. The calculator gives survival prediction and also
gives information where the patient fits on an HCC weather
Primary tumor (T)
forecast chart: the blue zone is synonymous of good weather
TX Primary tumor cannot be assessed and therefore good survival, while the red zone of bad weather
T0 No evidence of primary tumor of poor prognosis. Recently in a study 95 patients of HCC were
T1 Solitary tumor without vascular invasion studied, out of which 82 underwent liver transplantation and
T2 Solitary tumor with vascular invasion or multiple tumors none more metroticket calculator was applied in them to predict survival.
than 5 cm in greatest dimension Metroticket calculator was found to be an accurate predictor
T3 Multiple tumors more than 5 cm in greatest dimension or tumor of post-transplant survival in this cohort of predominantly
involving a major branch of the portal or hepatic veins HBV-related HCC. Further studies are needed to validate this
T4 Tumor(s) with direct invasion of adjacent organs other than the calculator in different cohort of patients.
gallbladder or with perforation of visceral peritoneum.
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed TREATMENT
N0 No regional lymph node metastasis
Treatment options for HCC are resection, liver transplantation
N1 Regional lymph node metastasis for early stages, locoregional therapies for intermediate
Distant metastasis (M) stage and sorafenib for advanced stage. BCLC staging
MX Distant metastasis cannot be assessed system is followed most widely for staging and treatment of
M0 No distant metastasis HCC. Curative treatment (resection, liver transplantation,
or percutaneous local ablative treatment) is primarily
M1 Distant metastasis
appropriate for asymptomatic patients with very early and
Stage groupings
early (BCLC stage A) HCCs. Transarterial chemoembolization
Stage I T1 N0 M0 (TACE) is primarily indicated for patients with asymptomatic,
Stage II T2 N0 M0 multinodular HCC (intermediate or BCLC stage B), whereas
Stage IIIA T3 N0 M0 chemotherapy with sorafenib is the only recommended
Stage IIIB T4 N0 M0 treatment for patients with advanced (BCLC stage C)
HCCthose with invasive or extrahepatic tumors. The best
Stage IIIC Any T N1 M0
supportive care is recommended for patients with terminal
Stage IV Any T Any N M1
(BCLC stage D) HCC.
Fig. 2: The Barcelona Clinic liver Cancer staging system for hepatocellular carcinoma
Abbreviations: M, metastasis classication; N, node classication; PS, performance status; RFA, radiofrequency ablation; TACE, transarterial
chemoembolization; CLT, cadaveric liver transplantation; LDLT, living donor living transplantation; HCC, hepatocellular carcinoma
Resection approach to postresection tumor recurrence has not been

well-studied, repeat resection is rarely ideal, as recurrences
Surgery is a potentially curative treatment for HCC. However, often have multifocal presentations reflecting their likely
the patients residual liver remains at risk of developing dissemination from the primary tumor. Instead, patients with
cancer and the 5-year risk of recurrence is more than 70%. a postresection recurrence may be more suitable for salvage
Therefore surgical resection should be done only after liver transplantation or other locoregional therapies, with
thorough evaluation of underlying liver function and tumor or without oral multikinase inhibitors. Among patients with
extent. Hepatic reserve can be assessed by the indocyanine more advanced disease (multiple tumor foci or a possibility of
green retention test, and clinical signs of portal hypertension metastasis) or patients with significant cirrhosis and impaired
(namely, thrombocytopenia, splenomegaly and varices) functional status, surgical resection is less beneficial and may
and elevated bilirubin. A model for end-stage liver disease actually contribute to the development of liver failure.
score less than or equal to eight shows well-preserved liver
function and is a strong predictor of both low perioperative
mortality and long-term survival. Vascular invasion and/or Transplantation
tumor metastasis are contraindications for surgical resection. Liver transplantation is considered the definitive treatment
Although large sizes and increased numbers of tumors
for HCC because it removes not only the malignancy but also
are associated with a great risk of recurrence after surgical
the whole diseased liver, which would otherwise have a high
resection, the presence of these characteristics should not
risk of cancer recurrence; however, the resources are limited.
preclude surgical resection in patients with resectable tumors
Milan criteria is being used for liver transplantation in HCC (a
and a reasonable hepatic reserve. Among patients with
cirrhosis or multiple tumor foci, resection may not always be single tumor less than 5 cm in diameter or up to three lesions
the most ideal treatment option. with the largest number more than 3 cm in diameter).
As resection is the main problem, preoperative evaluation The University of California San Francisco criteria for liver
must therefore consider recurrence risk via assessment of transplantation for HCC (a single nodule no larger than 6.5
overall risk profile and tumor characteristics in order to offer cm, or up to three lesions, the largest of which is 4.5 cm or
appropriately targeted therapy for patients. While the best smaller with the sum of the diameters up to 8.0 cm), and more
recently the up to seven criteria (seven being the sum of the 72%, respectively. Subsequent studies, including two further
size and number of tumors) have been proposed as expanded randomized controlled trials, showed that RFA has similar
selection criteria for liver transplantation in this setting. efficacy to surgical resection in the treatment of early-stage
These are more expanded transplantation criteria, compared HCCs, and is associated with lower complication rates and
with the Milan criteria, without compromising the long-term costs than resection.
outcome.
Down staging (to reduce tumor size and number) can be
done through local or locoregional therapies for patients who Transarterial Chemoembolization
do not meet Milan criteria. Living donor liver transplantation As HCC is a highly vascular tumor, TACE performed by
was pioneered in Asian countries for HCC, because of the infusion of a mixture of chemotherapeutic agents and gel-
shortage of livers from cadaveric donors. This has been foam particles into the hepatic artery branch that supplies
successfully replicated worldwide, despite the considerable the tumor is an effective treatment strategy for HCC (Table
risks of morbidity (520%) and mortality (0.28%) in the donor 6). TACE is primarily indicated for patients with unresectable
and an increased risk of HCC recurrence in the recipient HCCs without vascular invasion or metastasis. TACE
(515%) in deceased donor transplantation versus 2030% in improves overall survival in the intermediate time frame,
living donor transplantation. when compared with symptomatic supportive care alone.
It is not clear why living donor transplantations are In two randomized, controlled trials, 2-year overall survival
associated with high HCC recurrence. It appears to be higher was 3163% in the TACE groups versus 1127% in the control
because a short waiting period enables patients to receive groups. TACE is considered an alternative treatment option
transplantation even when the patient has an aggressive in patients with early-stage HCC when ablative treatment
tumor, in which case the patient would not have been eligible cannot be performed safely owing to the tumor location. It is
to receive deceased donor liver transplantation. Patients also frequently used as a bridging treatment or to downsize
undergoing living donor transplantation also tend to have tumors before liver transplantation. Patients with poor
more extensive tumors than patients undergoing deceased liver function or HCC invasion of the portal vein should not
donor liver transplantation. In addition, the humoral be treated with TACE owing to the high risk of acute liver
environment of liver regeneration from a partial liver graft decompensation after this treatment. New evidence suggests
seems to increase the risk of recurrence in living donor that TACE with doxorubicin eluting beads is superior to
transplantations. In spite of the higher risk of recurrence, conventional TACE, in terms of reduced adverse event rates
living donor transplantation is often used, owing to the and improved survival. These beads are impregnated with
limited availability of deceased donors, particularly in Asian doxorubicin, which is slowly released after being infused into
countries. the tumor vessels allowing a delivery of high intratumoral
concentrations with a low serum doxorubicin level.
Locoregional Therapies
Transarterial Radioembolization
Radiofrequency and Percutaneous Ablation
Transarterial radioembolization (TARE) with 90Y-impregnated
Percutaneous ablation, which is usually performed with glass microspheres is increasingly being used to treat patients
radiofrequency ablation (RFA) or percutaneous absolute with unresectable, multifocal HCC, including tumors with
alcohol injection, is a potentially curative treatment for small portal-vein invasion. TARE seems to achieve equivalent
tumors, usually less than 3 cm in size, in patients who are not clinical outcomes to those of TACE, with acceptable safety
eligible for liver transplantation or resection because of either and improved tolerability. Additional randomized studies are
comorbidities, liver dysfunction or limited surgical resources. required to evaluate the long-term efficacy and adverse-effect
Percutaneous ethanol injection (PEI) has an excellent profile of TARE.
outcome in patients with small tumors, as complete necrosis
is achieved in most HCCs less than 2 cm in diameter. However,
RFA is currently more frequently used than PEI in most of the Pharmacological and
countries. Randomized controlled trials have demonstrated
that treatment success is more in patients treated with RFA
Chemotherapeutic Agents
than those treated with PEI: with the rate of complete tumor Hepatocellular carcinoma is mostly chemoresistant and
necrosis, 96% versus 88%; 3-year recurrence-free survival, 34 moreover these patients poorly tolerate chemotherapy
49% versus 1243%, and overall survival 6278% versus 36 because of underlying liver dysfunction in most of the patients.
Table 6: Summary of therapeutic modalities for hepatocellular carcinoma and their outcomes
Treatment Survival Special issues
Surgical resection 1 year: 97% Choice of therapy for patients without cirrhosis (low morbidity)
3 years: 84% 5%15% of HCC, patients eligible
5 years: 26%57% Right hepatectomy has higher risk than left hepatectomy
Pre/postresection adjunct therapy not recommended
Transplantation (LT) 1 year: 91% Curative treatment for chronic disease and HCC
2 years: 75% MELD exception points for HCC
5 years (MILAN): >70% Effective corresponding to UNOS criteria (1 tumor <5 cm; up to 3 tumors <3 cm)
5 years (extended): ~50% Liver donor LT considered for HCC progression outside MILAN criteria
UCSF criteria not implemented in current MELD exception allocation policy

Radiofrequency ablation (RFA) 1 year: 90% Effect is more predictable in all tumor sizes than following PEI
3 years: 74% Superior to PEI larger tumors; equivalent in small tumors
5 years: 40%50% Requires fewer treatment sessions
Percutaneous ethanol injection (PEI) 1 year: 85% Early HCC patients not suitable to resection of OLT or RFA nto available or
containdicated
3 years: 50% Highly effective for small HCC (<2 cm)
5 years: 40%50% Low rate fo AEs
Transarterial chemoembolization (TACE) 1 year: 82% Non surgical patients with large/multifocal HCC w/o vascular invasion or extrahepatic
2 years: 63% spread
Abbreviations: HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease; UNOS, united network for organ sharing; UCSF;
University of California San Francisco; PEI, percutaneous ethanol injection; OLT, orthotopic liver transplantation; RFA, radiofrequency ablation
Several important molecules and pathways have, however, PREVENTION

been implicated in liver carcinogenesis, including receptor
tyrosine kinases, wntb-catenin signaling, the ubiquitin- The aim of chemoprevention has been to prevent cirrhosis
proteasome system, epigenetic DNA modification (promoter because prevention of HCC in non-HCV-related cirrhosis
methylation and histone acetylation), the PI3K-AKT-mTOR has been unachievable. Among HCV-infected individuals,
pathway, proangiogenic molecules and telomerase. Agents the efficacy of interferon in reducing HCC risk has been
that target these pathways are under active investigation. demonstrated, even among patients who did not achieve
Sorafenib, an oral multikinase inhibitor that targets the Raf a sustained response. Unfortunately, interferon appears to
kinase, vascular endothelial growth factor-receptor and have little effect in diminishing HBV-associated HCC risk.
platelet-derived growth factor receptor signaling pathways, Whether therapy with nucleoside or nucleotide inhibitors
is approved for the treatment of patients with advanced will reduce the risk of HCC among HBV-infected patients is
HCC (BCLC stage C). In a phase III, randomized, placebo- unknown, but the improvement in liver histopathology with
controlled trial in 602 patients with advanced HCC (SHARP prolonged treatment with these drugs is encouraging. Several
trial), overall survival was 10.7 months in the sorafenib other chemopreventive agents are at preclinical or early
group versus 7.9 months in the placebo group. Sorafenib phase clinical stages of development.
treatment was associated with acceptable profiles of adverse As chronic viral hepatitis and the resultant liver cirrhosis
effects, such as fatigue, diarrhea, and hand-foot skin reaction together constitute the most important cause of HCC, the most
(a known treatment-related adverse effect of sorafenib). effective measure to avert HCC is the prevention of HBV and
Another trial conducted in the Asia-Pacific region also HCV infections. The gradual introduction of HBV vaccination
showed that sorafenib therapy was associated with improved began in 1984 and by 2006 universal HBV vaccination (that is,
overall survival and a tolerable adverse effect profile. The use of all newborn babies regardless of maternal hepatitis B surface
of sorafenib after potentially curative resection or RFA (in the antigen status) had been implemented in 164 of 190 WHO
STORM study), and in combination with TACE (in the SPACE member states. These vaccination programs have resulted in
study) are currently under investigation (Table 7). dramatic decreases in the incidence of HBV infection. A study
Table 7: Pharmacological and chemotherapeutic agents of hepatocellular carcinoma
Target Drug (trade name) Stage of development
EGFR pathway inhibitors Eriotinib (Tarceva, Roche, Switzerland) Phase II/III

EGFR Cetuximab (Erbitux, Merck/Schering, Germany) Phase II
EGFR Lapatinib (Tykerb, Glaxo SmithKline, UK) Phase II
EGFR, HER2
VEGF/VEGFR pathway inhibitors Bevacizumab (Avastin, Roche, Switzerland) Phase II

VEGF-A Vandetani (Zactima, AstraZeneca, UK) Phase II
VEGFR-2, EGFR AZD171 (Recentin, AstraZeneca, UK) Phase II
VEGFR-1-3 Phase II/III Sunitinib (Sutent, Pfizer, USA) Phase II/III
VEGFR-1-3, PDGFR, C-KIT, FLT-3
Ras/Raf/MEK pathway inhibitors Lonafarnib (Sarasar, Merck/Schering, USA) Phase II

Ras Sorafenib (Nexavar, Bayer, Germany) Approved for advanced HCC
Raf-1, VEGFR-2 Phase II/III in combination
and -3, PDGFR, c-KIT
MEK AZD6244 (AstraZeneca, UK) Phase II

P13K/Akt/PTEN Sirolimus (Rapamune, Pfizer, USA) Phase I/II
pathway inhibitors mTOR Phase III liver transplantation
mTOR Everolimus (Novartis, Switzerland) Phase I/II
Enhancing apoptosis
TRAIL-R1 Mapatumumab (Human Genome Science, USA) Phase I
Proteasome inhibitors
Proteasomes Bortezomib (Velcade, Millenium, USA) Phase I
HDAC inhibitors
HDAC LBH589 (Novartis, Switzerland) Phase I
HDAC Vorinostat (Zolinza, Merck et co., USA) Phase I
Abbreviation: EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth
factor receptor; PDGFR, platelet derived growth factor receptor; FLT-3, FMS-like tyrosine kinase 3; c-KIT, another member of the receptor
tyrosine kinase subclass III family; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; PTEN, phosphatase with tensin homology; mTOR,
mammalian target of rapamycin; TRAIL-R1, tumor necrosis factor-related apoptosis inducing ligand receptor; HDAC, histone deacetylase;
mTOR; mammalian target of rapamycin
from Taiwan showed that, after adjustment for age and sex, hepatitis before transfusion, the use of disposable needles and
the relative risk of HCC was 0.31 among children aged 619 other incidental supplies (for example, intravenous tubing
years in the vaccinated cohort, compared with similar-aged sets or lancets for checking blood glucose), and thorough
children in unvaccinated cohorts. Universal vaccination of sterilization of surgical instruments, should be implemented.
newborn babies will lead to a substantial reduction in the These measures should be the primary focus of HCC
global incidence of HCC, especially in regions where HBV prevention, especially in low-resource countries where
has a high incidence. Unfortunately, no vaccine against unsafe medical practices are not uncommon and resources
HCV is yet available, owing to difficulties related to the high for treatment of viral hepatitis and HCC are often inadequate.
mutation rate of HCV ribonucleic acid viral replication. A key Encouraging avoidance of high-risk behaviors through public
need remains, therefore, for recognition and prevention of education and social awareness is an effective measure
HCV transmission in the healthcare setting as well as in other to prevent HCV-induced HCC. Avoidance or mitigation of
high-risk practices, such as individuals receiving treatment modifiable risk factors for HCC, such as heavy alcohol use,
from unlicensed practitioners. Infection control measures, diabetes mellitus, obesity and smoking, are also important,
such as screening potential blood donors and recipients for especially in patients with chronic viral hepatitis.
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35
cHAPTER
Portal Hypertension:
Pathophysiology and Management
Debashis Misra, Abhijit Chowdhury
INTRODUCTION by the union of splenic and superior mesenteric veins, carries

venous blood from the intestine, spleen and pancreas: organs
Portal hypertension (PH) is a common clinical syndrome that provide vast capillary surface area and are concerned
characterized by pathological increase in portal pressure with digestion, absorption and metabolic activities. It is
gradient and commonly occurs as a complication of connected in series with the hepatic arteriesa high pressure,
cirrhosis of liver. In addition, it can be present in a wide high flow territoryforming the vascular inflow circuit to the
variety of noncirrhotic liver diseases that cause obstruction/ liver and the two systems are conjoined at the sinusoids. The
distortion in the vascular architecture of the liver as well sinusoids behave as effective vascular cushions and dampen
as in extrahepatic portal venous obstruction (EHPVO), as any trend toward precipitous increase in portal pressure
primary or predominant feature. The pathophysiology and related to changes in flow as long as its structure and function
clinical outcome of portal hypertension (PH) vary depending remain unimpaired. Hepatic veins are the effluent tract of the
on whether or not cirrhosis is present. However, presence liver, is a low pressure, low flow system and drains into the
and bleeding from esophageal and/or gastric varices (GV) inferior vena cava (IVC). Portal hypertension, of whatever
is the classical clinical manifestation of PH. As a result, cause, is associated with transformation of the portal territory
prevention and treatment of variceal hemorrhage is the focus to a higher pressure and higher flow system at a cost-
of management in PH. In addition, PH causes or contributes development of aberrant collateral vessels called varices that
to ascites, renal dysfunction and cerebral abnormalities in attempts ineffectively to decompress the portal system along
cirrhosisapart from widespread hemodynamic, vascular with other hemodynamic and metabolic consequences that
and metabolic consequences. impair function of the other organs of the body.
Most efficient management of PH is the treatment of the Thus, PH is defined as an increase in the pressure in the
cause of chronic liver disease. Regression of fibrosis in chronic portal vein and its territory. In normal, fasted subjects at rest
liver diseases that can happen with successful treatment of the and in the supine position, the portal pressure ranges from
etiology of chronic hepatitis and cirrhosis have been shown 7 mm Hg to 12 mm Hg. Direct measurement of the portal
to diminish portal pressure, improve the pathophysiological pressure is an invasive procedure and is not performed in
derangements and potentially reduce the occurrence of clinical circumstances. Instead, a less invasive procedure
clinical events in the management of PH. At the present time, of hepatic vein catheterization under radiologic guidance
such definitive therapy of PH cannot be undertaken in the is undertaken for hemodynamic assessment of PH. This
majority and is still evolving. Therefore, current management procedure, measurement of the hepatic venous pressure
of PH primarily involve different drugs, endoscopic therapies, gradient (HVPG), is best accomplished with the use of a
transjugular intrahepatic portosystemic stent (TIPS) balloon catheter, usually taking triplicate readings and when
placement and surgical shuntstargeted at altering the measured with a proper technique, is very reproducible and
natural history of evolution and bleeding from varices. reliable. It measures the pressure gradient between the portal
vein territory [wedged hepatic venous pressure (WHVP)] and
the vena cava territory [free hepatic venous pressure (FHVP)]
PORTAL VEIN AND PORTAL and provides a value for the sinusoidal pressure. The FHVP
HYPERTENSION is subtracted from the WHVP to correct for intra-abdominal
pressure to provide an accurate measure of the portal vein
Under normal conditions the portal vein is a low pressure, high pressure. The normal portal venous pressure as measured by
flow vascular bed that is rich in O2 and nutrients. It is formed HVPG is less than 5 mm of Hg. Portal hypertension is said to be
present when this measurement of HVPG goes above normal. Table 1: Classification of portal hypertension according to the
Since it is a measure of sinusoidal pressure, the HVPG will be anatomic site
elevated in intrahepatic causes of PH, such as cirrhosis, but
Prehepatic
will be normal in prehepatic causes of PH, such as portal vein
Splenic vein thrombosis
thrombosis (PVT). Clinically significant portal hypertension
(CSPH)portal pressure predictively associated with the Portal vein thrombosis
development of varicesis defined as 10 mm of Hg of HVPG. Congenital stenosis of the portal vein
Bleeding from varices occurs at HVPG above 12 mm of Hg and Extrinsic compression of the portal vein
reduction of HVPG below this value or more than 20% of the Arteriovenous fistulae
baseline value is predictive of reduced probability of variceal
IntrahepaticPresinusoidal
bleeding. Mortality after variceal bleed is high when HVPG is
Partial nodular transformation
above 20 mm of Hg. Measurement of HVPG as a reliable and
reproducible surrogate of portal pressure, therefore, has value Nodular regenerative hyperplasia
in the management of PH. Polycystic disease
Noncirrhotic portal fibrosis/Idiopathic portal hypertension
Intrahepaticsinusoidal
ETIOLOGY Cirrhosis (viral, alcoholic, biliary, metabolic)
Granulomatous diseases (schistosomiasis, sarcoidosis, tuberculosis, PBC)
Pathological conditions those bring about changes in blood
flow in portal venous system resulting in PH can be divided in Congenital hepatic fibrosis
three groups based on their anatomic location: Peliosis hepatis
1. Prehepatic: conditions involving mesenteric, splenic and Hypervitaminosis A
portal vein. Arsenic, copper sulfate, vinyl chloride monomer poisoning
2. Hepatic: liver diseases.
Amyloidosis
3. Posthepatic: conditions involving hepatic venous outflow
Mastocytosis
including heart diseases (Table 1).
Cirrhosis of liver is by far the most common cause of PH all Rendu-Osler-Weber syndrome
over the world (Fig. 1). Liver infiltration in hematologic diseases
Acute fatty liver of pregnancy
Prehepatic Cause of Portal Hypertension Severe acute viral and alcoholic hepatitis
Cyanamide toxicity
Conditions giving rise to this subgroup of PH are those causing
Veno-occlusive disease
obstruction to blood flow, mostly in portal vein itself and less
Posthepatic
commonly in splenic or mesenteric vein. Underlying condition
can be congenital, but more commonly they are acquired. Hepatic vein thrombosis (Budd-Chiari syndrome)
Congenital malformations and thrombosis of the inferior vena cava
Constrictive pericarditis
Portal Vein Thrombosis
Tricuspid valve diseases
This is the most common cause of prehepatic PH. This can
have both acute (less common) and chronic (more common)
presentation. Omphalitis and umbilical vein catheterization
are the predisposing factors in the children, whereas in
bosis that usually present with upper gastrointestinal bleeding
adults, thrombophilic factors in isolation or in combination
(from GV) and splenomegaly.
with local factors are the contributory factors. PVT is noted in
cirrhosis (in absence of hepatocellular carcinoma) in around
0.526% of the cases. Intrahepatic Cause of Portal
Hypertension
Splenic Vein Thrombosis These causes are traditionally classified according to the
Chronic pancreatitis, pancreatic carcinoma, retroperitoneal different values of parameters studied in hepatic vein
infection/fibrosis are the usual causes of splenic vein throm catheterization.
Portal Hypertension: Pathophysiology and Management 315
Fig. 1: Causes of portal hypertension
Presinusoidal causes: having normal WHVP supply. The differential blood supply is the outcome of PVT
Sinusoidal causes: increased wedged (WHVP) and normal that leads to PH.
free pressure (FHVP)
Post-sinusoidal causes: increased wedged (WHVP) and
free pressure (FHVP). Cirrhosis of various etiologies is by Noncirrhotic Portal Fibrosis/Idiopathic
far the most common cause of sinusoidal PH. Portal Hypertension
This syndrome is known in different names, such as
Nodular Regenerative Hyperplasia Bantis syndrome, noncirrhotic portal fibrosis (NCPF) and
This condition is characterized by the formation of nodules hepatoportal sclerosis. Nearly 2530% of all patients with PH
in liver without intervening fibrosis with some nodule being in India who undergo surgery or sclerotherapy, have NCPF.
hypertrophic as a result of greater blood supply and some Noncirrhotic portal fibrosis is usually a disease of young
nodules being atrophic as a result of diminished blood Indian men. Patients of NCPF usually present following one
or more well-tolerated upper gastrointestinal bleed along flow and high resistance in an intrinsically low pressure system
with mass in left hypochondrium (splenomegaly). Ascites maintain and worsen PH. Increased intrahepatic vascular
and signs of liver failure are transient following bleed. resistance initiates PH in cirrhosis. In cirrhosis, the sinusoids
Exposure to toxins or infective episode in childhood has are the primary site of this increased resistance. This is caused
been postulated to be the etiologies behind these entities by fibrosis, nodular regeneration and distorted lobular
without confirmation. Interestingly, the liver on gross architecture that disables the sinusoids from discharging
appearance looks to have a nodular surface despite liver their pressure transducing functions. This fixed structural,
function being almost normal. fibrotic-nodular component of increased resistance is
amplified by a dynamic functional element in PH due to
contraction of the stellate cells and portal myofibroblasts
Posthepatic Cause of Portal that occur in cirrhosis. These are the primary cells in hepatic
Hypertension fibrosis and are sensitive to and generate cytokines that alter
their contractile properties in an autocrine, self-perpetuating
Inferior Vena Cava Obstruction fashion and are strategically situated in sinusoids to influence
its functions. Approximately 2030% of the increased
Thrombosis, tumor, cyst, abscess can create mechanical
vascular resistance in cirrhosis is contributed by these
obstruction to outflow of blood from liver at the level of IVC.
dynamic factors and modifying it by means of drugs provide
Similarly, fibrous web at the junction of hepatic veins and
a potential target for the development of novel therapies for
IVC can create such obstruction. Both extra- and intrahepatic
PH. In noncirrhotic PH and in EHPVOstructural factors
obstructive causes fall under this subgroup with similar
causing narrowing of the intrahepatic (noncirrhotic portal
presentation of painful hepatomegaly, ascites, variceal
fibrosis) or extrahepatic (PVT or EHPVO) portal vasculature
bleeding, and subcutaneous venous collaterals. Membranous
are nearly solely responsible. The role of dynamic factors
obstruction is the dominant etiology in the Asian countries
need further evaluation in both these conditions and is not
whereas thrombotic occlusion is more common in western
as clear as in cirrhosis. The reverse occur in the vast capillary
countries.
bed of the splanchnic vessels, where vasodilation occur along
with diminished response to endogenous vasoconstrictors
Heart Disease expanding the capacitance of the vascular tree. The systemic
vascular tree also has similar features accompanying the
Constrictive pericarditis, valvular heart disease with tricuspid hemodynamic changes in PH so that systemic vascular
regurgitation or cardiomyopathy are associated with elevated resistance falls. The splanchnic and systemic vasodilation
right atrial pressure that in advanced stage of the heart diminishes the overall peripheral vascular resistance while
disease, gets transmitted to hepatic sinusoids and portal vein increasing the heart rate and cardiac output. Despite the
and ultimately leads to ascites and hepatocyte dysfunction. increased cardiac index, the widened splanchnic capillary
Esophageal varices are conspicuously absent in these tree results in effective hypovolemia and underfilling, so
conditions. that the different neurohormonal mechanism for fluid and
pressure hemostasis gets activated. These include renin-
angiotensin system, sympathetic nervous system and the
PATHOPHYSIOLOGY OF PORTAL antidiuretic hormones (ADH). These retain Na+ and water,
HYPERTENSION IN CIRRHOSIS enlarges the capacitances ineffectively, increases cardiac
index furtherputting additional burden on the cardiac
Intrahepatic Vasoconstriction and muscles, already in stress due to impaired contractility and
inotropy. While splanchnic and systemic vasodilation occur in
Peripheral Vasodilation progressive cirrhosis-related PHvasoconstriction in organ
These are the key events that set in motion the widespread systems, particularly renal, cerebral and pulmonary, develop
vascular and organ dysfunction in cirrhosis. As in any other in response to systemic underfilling and guard the blood flow
vessel, the pressure within the portal vein is determined by the in these vital organs through local autoregulatory circuits.
product of blood flow and resistance to its egress, as defined Kidneys are particularly vulnerable and local vasodilatory,
by Ohms law P (pressure) = Q (blood flow) R (resistance). counterbalancing mechanisms therein regulate the renal
Portal hypertension is initiated by increased resistance to blood flow. With progressive liver dysfunction and advancing
portal venous outflow. As the condition progresses, there is a PH, such accommodative machinery falters and together
rise in portal blood flow, and this combination of increased with a falling cardiac output due to cirrhotic cardiomyopathy,
Table 2: Pathogenesis of portal hypertension The classical features of PH include splenomegaly and
varices: esophageal and gastric. However, these may be
Portal hypertension is initiated by increased outflow resistance at a
presinusoidal (intra- or extrahepatic), sinusoidal, or postsinusoidal level
considered as just one facet of a wider spectrum of clinical
derangements that include vascular abnormalities in
In the latter part, there is a rise in portal blood flow; in combination with
the above, it maintains and worsens the portal hypertension
gastric and intestinal mucosa, anemia, leucopenia and
thrombocytopenia, skin changes, such as warm skin
In cirrhosis, liver in the primary site of increased resistance to portal
venous blood flow due to intraheptic vasoconstriction
with bounding pulses and palmar erythema, ascites,
spontaneous bacterial peritonitis, hepatorenal syndrome,
Mesenteric arterial vasodilation contributes to both increased portal
venous inflow and a system hyperdynamic circulatory state
hepatopulmonary syndrome and portopulmonary syndrome,
cirrhotic cardiomyopathy as well as hepatic encephalopathy,
Collateral vessels that open up due to portal hypertension, also
contribute to increased resistance to blood flow in latter part of the
and hepatocerebral degeneration. Anemia is due to blood loss
disease process from varices and portal gastropathy as well as enteropathy.
Splenomegaly often causes sequestration and reduced life
span of the formed elements (hypersplenism), and this causes
intense renal vasoconstriction ensues that leads to renal leukopenia, thrombocytopenia and contributes to anemia.
functional impairment characteristic of hepatorenal Liver failure and immune dysfunction also contribute to
syndrome. Hepatorenal syndrome can, therefore, be viewed impaired hemopoiesis in cirrhotic PH.
as a failure of the compensatory vascular arrangements and Ascites occurs in cirrhotic PH. In noncirrhotic PH ascites
indicative of poor prognosis in cirrhosis of liver (Table 2). is a transient phenomenon and can occur with intercurrent
infections, bleed and other events that compromise liver
function. Sodium and water retention are the classical fluid and
Sinusoidal Remodeling and electrolyte abnormalities in cirrhosis. As cirrhosis progresses,
Angiogenesis total body sodium increases along with water. Diminished
free-water clearance leads to hypo-osmolality, a tendency to
Hepatic stellate cell density and activation increase in move fluid out of the vascular compartment and finally when
advancing cirrhosis. They occupy more space in its strategic compensation fails in advanced cirrhosis, to hyponatremia.
microvascular locationspace of Dissein cirrhosis Sinusoidal PH increases the sinusoidal hydrostatic pressure
as compared to a normal liver, in an arborising network and drives the hypo-osmotic fluid out into the peritoneal
that interspersed with collagen fibers that they elaborate. cavity. Capillarization of sinusoids diminishes the size of the
Activation of stellate cell is associated not only with this fenestrae allowing solute movement and impedes movement
fibrogenesis but also thrombosis in the microvasculature that of larger molecules into the space of Disse. As a result, ascitic
can potentially lead to vascular extinction and angiogenesis. fluid in cirrhosis is low in protein.
Angiogenesis is a hypoxia driven, growth factor-dependent Portal hypertension facilitates the translocation of gut
phenomenon, wherein new vessels develop from existing bacteria through the intestinal wall. This, together with the
ones and also at new sites. Many molecules and pathways immunological dysfunction, allows bacteria to house in
take part but VEGF functioning through its xxx receptor the low-protein ascites and cause spontaneous bacterial
is the most significant. Angiogenesis plays an important peritonitis.
role in the development of varices and mesenteric vascular The renal vasculature participates in the progressive
readjustments. hemodynamic and endothelial dysfunction in cirrhosis.
Initially, renal vasoconstriction in the face of effective
hypovolemia maintains the intrarenal circulation as a
CLINICAL SEQUELAE OF PORTAL compensatory mechanism. As liver dysfunction progresses
HYPERTENSION and cardiac output also starts falling, this compensation fails.
The end result is hepatorenal syndrome, a functional renal
The pathophysiological abnormalities in PH are initiated failure.
within the hepatic microvasculature but involve multiple Vasodilation in the pulmonary circulation leads to
organs when fully evolved, particularly in cirrhosis. The ventilation-perfusion mismatch, arteriovenous shunts and
systemic manifestations are also present in noncirrhotic PH hypoxemia in the syndrome named hepatopulmonary
and often in extrahepatic PH, albeit at a much lesser degree syndrome. Clubbing of the fingers and hypoxemia while
and frequency, depending on the extent liver parenchymal breathing 100% O2 are the characteristic features. In addition,
dysfunction and portosystemic shunting of blood. angiogenesis can occur in the lung which together with
endothelial dysfunction can give rise to another syndrome dysfunction in the absence of florid signs of liver failure or
called portopulmonary syndrome characterized by marked PH. Such patients often may not have esophageal or GV but
increase in pulmonary vascular resistance and pulmonary develop large retroperitoneal and other collaterals which
hypertension. Increased cardiac index is a feature of PH. drain the portal blood away into the systemic circulation
Increased pulse pressure, heart rate are early features, whereas (Table 3). Long-standing portosystemic encephalopathy can
QT abnormalities and impaired myocardial contractility in the often present with features of rigidity and other long tract
face of physiological and pharmacological stimuli can develop signs: an entity called hepatocerebral degeneration (Fig. 2).
in the long-terman entity called cirrhotic cardiomyopathy.
In the end stages of cirrhosis, the cardiac output falls and Development and Natural History of
exacerbates the systemic abnormalities in cirrhosis of liver
including renal failure. Sepsis, inflammatory cytokines Esophageal Varices
abound in advancing cirrhosis are some of the factors that Esophageal varices are the hallmark of PH. They develop,
cause or contribute to the myocardial dysfunction in cirrhotic enlarge, bleed and often rebleed as portal pressure
cardiomyopathy. progressively increase. Thus, a HVPG of 10 mm of Hg is the
In cirrhosis, hepatic encephalopathy occurs due to the threshold when varices develop, 12 mm of Hg when they
portosystemic shunting of blood through collaterals. Some bleed and 20 mm of Hg within 24 hours of a bleed when the
subjects may present with prominent neuropsychiatric chances of bleed-associated mortality are high. While, varices
Fig. 2: Systemic effects of portal hypertension

Abbreviations: SNS, sympathetic nervous system; ADH, antidiuretic hormone: increased, decreased; RAS, renin-angiotensin system
Table 3: Sites of portal-systemic collaterals
Transition zones between squamous and glandular epithelium, e.g.

gastroesophageal junction, anus, ileostomies, etc.
Obiterated fetal circulation in the falciform ligament, e.g. umbilical and
periumbilical veins
Retroperitoneal channels originating in the splenic vein and anast
omosing with the adrenal gland or renal veins, especially the left renal
vein
Retroperitoneal parts of the gastrointestinal tract where the organ
surface is not covered by peritoneum, e.g. duodenum; descending,
ascending and sigmoid colon, spleen, liver, etc.
are meant to decompress the hypertensive and overflowing

portal venous system proper by providing alternative
channels, they are also sites of increased resistance in PH
making the entire process an ineffective, potentially harmful
phenomenon. They can drain up to 8090% of portal inflow
and can rupture based on the pressureelasticity relationship
prevailing within the varices. Although the esophageal varices
are the most frequent, gastric and other ectopic varices can
develop and become clinically significant (Fig. 3).
Gastric Varices
Gastric varices develop in ~20% of patients with PH.
GV are classified according to location and relationship
to esophageal varices. The most common type of GV is
indeed the continuation of esophageal varices below the Fig. 3: Natural history of variceal bleed
gastroesophageal junction along the lesser curvature. GV Abbreviations: CPT, Childs Pugh Turcotte; HVPG, hepatic venous
account for 510% of all upper digestive bleeding episodes in pressure gradient
patients with cirrhosis. Bleeding is more common from GV
located in the fundus of stomach. The risk of gastric variceal revealing diminished mucosal blood flow and mucosal
bleeding is lower compared to esophageal varices, but gastric hypoxia contributing to these changes.
variceal bleeding tends to be more severe, requiring more Prevalence of this condition in cirrhosis is around 80% and
transfusions, and is associated with a higher mortality rate. In it correlates with the duration of disease, presence and size of
most cases of GV, following obliteration of esophageal varices, esophagogastric varices, and a previous history of endoscopic
contiguous GV also disappear. Persistence of GV despite variceal sclerotherapy. Gastropathy can progress from mild to
obliteration of esophageal varices is associated with higher severe and vice versa or even disappear completely. About
mortality. 2.5% of the cases of PHG account for acute bleeding and
10.8% for chronic bleeding. The bleeding-related mortality
rate is 12.5%.
Portal Hypertensive Gastropathy
Portal hypertensive gastropathy (PHG) is a significant cause
of bleeding from the stomach. PHG is characterized by the
Ectopic Varices
endoscopic finding of mosaic-like pattern of the gastric Ectopic varices are those portosystemic venous collaterals,
mucosa (mild PHG), red-point lesions, cherry red spots, which are located outside the esophagus and stomach. They
and/or black-brown spots (severe PHG). These lesions, account for 15% of all variceal-related bleeding (Table 4).
however, are not entirely specific. Pathogenesis of this entity Ectopic varices are usually found in duodenum and in colon.
is a matter of debate with some study suggesting increased They commonly manifest with melena or hematemesis.
gastric mucosal blood flow in the presence of PH while others Manifestation may be unusual, and include hemoperitoneum,
Table 4: Varices: the source of blood loss in patients with portal While determining whether a liver function derangement
hypertension is acute or chronic
Approaches available for the evaluation of PH are (i)
Esophageal varices are the most common type of varices encountered in
clinical practice clinical assessment, (ii) ultrasonography and Doppler, (iii)
endoscopy, (iv) angiographicparticularly measurement of
Varices are the markers of advanced portal hypertension
HVPG, (v) other radiological modalities like CT scan, MRI,
Gastric varices bleed less commonly, but, such bleeding is associated with
and (vi) emerging techniques, such as transient elastography
higher mortality
(TE) and videocapsule endoscopy.
Portal hypertensive gastropathy is a source of chronic blood loss
Ectopic varices should considered in patients of obscure gastrointestinal
bleeding Clinical Assessment
This is the simplest approach and provides clues to the
presence of PH if splenomegaly, abdominal wall and back
hemobilia, or hematuria. Duodenal varices are more veins and/or ascites are present. While these signs are
prevalent in patients of extrahepatic PH except in the western suggestive and mandate the need for further investigations,
hemisphere where cirrhosis is a more common cause of only approximately 70% patients of cirrhosis will have
duodenal varices. The other common site of ectopic varices is splenomegaly at some time point.
around the stomatal opening, in patients with inflammatory
bowel disease and primary sclerosing cholangitis who have
undergone a proctocolectomy with creation of an ileostomy. Ultrasonography
Ultrasonography with duplex technique is the preferred
imaging technique in patients with suspected or known PH.
EVALUATION AND DIAGNOSIS Presence of collaterals at the splenic hilum, around the portal
vein, in the gallbladder fossa can be seen, and it establishes,
Portal hypertension is nearly universal in cirrhosis and
the diagnosis of PH. Additional clues about the presence of PH
it defines NCPF/idiopathic portal hypertension as well
can come from a dilated portal vein, presence, direction, flow
as EHPVO. It is also the most significant determinant of
patterns (in patients with cirrhosis, biphasic or monophasic
clinical features in conditions, such as schistosomiasis and
waveforms have been observed, whereas triphasic waveforms
congenital hepatic fibrosis. In other conditions, it either
have been observed in healthy subjects), velocity of portal
contributes to the morbidity and therapy directed to it may
blood flow, ascites, or splenomegaly. Presence of cavernoma
not be necessary. Extent of evaluation will depend upon
around the portal vein is a classic feature of EHPVO. Color
the clinical situation and local expertise with the available
techniques. Doppler US is efficient in diagnosing EHPVO if no color
Varicesthe source of blood loss in patients with PH flow or Doppler signal within the extrahepatic portal vein,
esophageal varices are the most common type of varices hepatopetal signal within the cavernoma or varices at the
encountered in clinical practice. Varices are the markers of GB wall is demonstrated. In addition, a nodular liver surface,
advanced PH. GV bleed less commonly, but, such bleeding is irregular liver margins may provide clues to the presence of
associated with higher mortality. cirrhosis as the etiology.
Portal hypertensive gastropathy is a source of chronic
blood loss. Ectopic varices should be considered in patients Upper Gastrointestinal Endoscopy
of obscure gastrointestinal bleeding. Clinical situations where
evaluation for PH becomes specifically necessary include: Presence of esophageal and/or GV confirm the presence
Planning management of cirrhosis of any etiology of PH. These should always be sought for by gastroscopy
Upper gastrointestinal bleedingdetermining etiology in every patient suspected to have PH. The number, size
and guide management (small or large), appearance (presence of red color signs)
Evaluation of unexplained splenomegaly, anemia, throm and location (esophageal, gastric) are all useful information
bocytopenia in the management and should always be done on the first
Assessment of altered liver function test results: acute or gastroscopy. Repeat gastroscopy may be necessary at defined
chronic intervals according to designed protocols to document the
Etiological assessment of unexplained, fluctuant altered appearance of varices (no varices at baseline), evolution of
behavior varices (size and red color signs), for delivering endoscopic
therapy [endoscopic variceal ligation (EVL)/endoscopic treatment of variceal hemorrhage (5 day failure). Reduction
sclerotherapy (EST)] and its follow-up. Gastroscopy can also of greater than 20% of HVPG while on nonselective beta-
provide clue to the presence of PHGwhich when severe blocker therapy for secondary prophylaxis picks up a
may be clinically significant, producing acute or chronic subset of portal hypertensives who will derive maximum
blood loss. However, trivial endoscopic signs (mild portal benefits of prophylaxis (Hemodynamic responders), while
gastropathy, early varices) should be reconfirmed by repeat nonresponders may need escalation of dosage, additional or
gastroscopy in unclear clinical situations, instead of jumping alternative therapies. Thus HVPG is evolving as a useful tool in
to a diagnosis of PH at haste. assessment, prognostication as well as in monitoring impact
of therapy in cirrhotic PH. Despite the relative simplicity,
reproducibility and usefulness of HVPG, the procedure is
How Frequently to Look for Varices? not widely used, because of the necessity for an expertise
Varices develop at a rate of 7% per year in those without and infrastructure, which is not always availablemore so
varices at baseline. Every cirrhotic patient should be in the developing countries. Further, it is relatively invasive
endoscopically screened for varices at the time of diagnosis. and the protocols for its use in clinical care of PH are yet to be
In patients without varices on initial endoscopy, a second mature. HVPG remain normal in presinusoidal causes of PH
(follow-up) evaluation should be performed after 23 years. like EHPVO.
The transition from small (less than 5 mm) to large varices
(more than 5 mm) occurs at a rate 8% per year. In patients
with small varices and preserved liver function (child A)
Other Modalities
endoscopy should be repeated once every 2 years. In patients Several other modalities like videocapsule endoscopy, CT
with advanced cirrhosis and any size or varices of any size scan, CT angiography, MR angiography and TE have been
with red wale marks, a 1 year interval is recommended (high shown to be useful as supplements in evaluation of PH
risk). Large varices always need a one yearly endoscopic (Tables 5 and 6). The radiological techniques (CT and MRI
surveillance. angiography) are useful in documenting ectopic varices,
particularly those in the retroperitoneal area. These are not
necessary in clinical management decisions. Videocapsule
Portal Pressure Measurement: Hepatic endoscopy is promising, innocuous but costly. TE provides a
Venous Pressure Gradient as a Clinical measure of liver stiffness based on ultrasonic acquisition of
the velocity of propagation of a shear wave. Diffuse fibrosis
Tool increases this velocity, expressed in kilopascals, in a cirrhotic
Measurement of portal pressure provides the most definitive liver and this has been shown to correlate with HVPG
evidence of PH. The direct methods for portal pressure measurements. Although the potential for TE in PH arise from
recordings are invasive procedures and are rarely used the relationship of PH to liver fibrosis, the fact that TE provide
nowadays. These include percutaneous transhepatic, an objective measure for fibrosis that is easy, noninvasive and
transvenous (transjugular) or surgical catheterization, of can be used repetitivelymore information is needed before
the portal vein. Instead, indirect methods of measuring it can be used for this purpose in clinical settings.
sinusoidal pressures have proved to be of value in the clinical
management as well as in research. A balloon catheter is
introduced into the hepatic vein and the pressure measured TREATMENT
in the deflated position of the balloon initially. This gives the
FHVP and equates with the inferior vena caval pressure under Varices are the primary focus for the treatment of PH.
normal conditions. Subsequently, the balloon is inflated and Prevention of the first episode bleeding from varices (primary
is put to a wedged position, while pressure measurements
Table 5: Tools for evaluation of portal hypertension
are taken. This WHPV is a measure of sinusoidal pressure
and WHVP-FHVP is the HVPG that has shown to a clinically Clinical examination
useful measure of PH. Normally HVPG is 35 mm of Hg. In Imaging modalities: Doppler ultrasonography, CT angiography, MR
cirrhosis, CSPH is defined as HVPG above 10 mm of Hg. angiography
Probability of variceal bleed reduces once HVPG drops below Endoscopy: Video endoscopy, Wireless capsule endoscopy
12 mm of Hg. In the acute setting, HVPG value of 20 mm of
Venous catheterization: Hepatic venouns pressure gradient measurement
Hg, measured within 24 hours of a variceal bleed is indicative
Newer modalities: Transient elastography
of a high chance of mortality and failure of measures for the
Table 6: Comparison of methods for assessment of portal hypertension on the natural history. This should always be kept in mind and
PH in cirrhosis be treated primarily in a systemic approach
Method Advantage Drawback
with drugs together with the local measures like EVL that
Clinical assessment Easy, beside Sensitivity, specificity low adds on to the benefits. In contrast, the focus in noncirrhotic
USG/doppler Widely available, Diagnostic accuracy not 100% PH is local treatment of the varices, drugs providing ancillary
economic Interobserver variability benefits.
CT/MR + Angio Vascular anatomy Detect late changes
well delineated costly
UGIE Widely available Invasive, interobserver Agents Available
variability in small varices
Agents used in pharmacotherapy of PH act primarily through
Capsule endoscopy Noninvasive Unable to correctly assess vasoconstriction in the splanchnic vascular bed (acute:
varix size, gastric varix, PHG
vasopressin, terlipressin, somatostatin, octreotide; chronic:
HVPG Best for Invasive nonselective beta blockerpropranolol, nadolol, carvedilol)
measurement
portal pressure
reducing portal flow and thereby pressure. They also produce
vasoconstriction and reduced flow through the varices. In
Fibroscan Noninvasive Not widely available
measurement of
addition, vasodilation in the intrahepatic microvasculature
fibrosis (nitrates) and more chronically active steady state alterations
of the sodium and water handling (spironolactone, losartan)
Abbreviations: USG, ultrasonography; UGIE, upper gastrointestinal
can be potentially useful on occasions by altering the
endoscopy; HVPG, hepatic venous pressure gradient; PHG, portal
hypertensive gastropathy pathophysiology of PH. Terlipressin and somatostatin are
the most widely used agents in acute variceal hemorrhage
whereas propranolol has been the mainstay of chronic
prophylaxis), acute management of an episode of variceal therapyused in primary and secondary prophylaxis. Other
bleeding and prevention of recurrent variceal bleeding agents are considered only when the above agents cannot be
(secondary prophylaxis) are the cornerstones of therapy. freely used because of contraindications (obstructive lung
Vasoactive drugs, endoscopic techniques for obliteration of disease: propranolol). There is no evidence that adding one
varices, interventional radiological (TIPS) and surgical shunts pharmacological agent to another improves the outcome:
between portal and systemic venous systemalone or in both in acute hemorrhage as well as in prophylaxis.
combinationare used for this purpose. While the available The endoscopic local therapies target variceal obliteration
drugs try to attenuate the altered hemodynamics of the by ligation (EVL) or sclerosis by injection (EST). Other locally
splanchnic vascular bed, endoscopic techniques are locally active therapies include obturation of GV by glue injection,
active and shunts function by mechanically diverting flow argon plasma coagulation in severe congestive gastropathy.
away from the high pressure portal system, trying to protect These modalities have no hemodynamic components,
the varices from the high pressure and high flow. All these need to be repeated and, therefore, necessitate periodic
measures are less than perfect and the outcomes of treatment endoscopies to be fruitful. EVL is the most acceptable of all
can falter any time in progressive liver diseases necessitating these and is used both in acute variceal hemorrhage as well
tight vigilance on follow-up. However, regression of PH as in prophylaxis.
through effective treatment of fibrosis in chronic liver
diseases is the best form of therapy of PH. This etiological Another local therapy: esophageal tamponade by
management should always be attempted along with variceal Sengstaken-Blakemore tube with three lumens and GV by
management, as an improved long-term outcome is possible Linton-Nachlas tubecan be temporarily useful in acute
only by this, e.g. treatment of HCV/HBV cirrhosis by antivirals, hemorrhage, often functioning as a bridge to more definitive
autoimmune hepatitis by immune suppression, etc. salvage therapy like TIPS or surgical shunts. Shunts-TIPS and
Most information on management of PH has been derived surgical: provide decompression of the hypertensive portal
from studies in cirrhosis. The principles of prophylaxis and system. However, since they divert portal inflow, they are
treatment of varices are the same in cirrhotic and noncirrhotic frequently associated with deterioration of liver function and
causes of PH. However, cirrhosis presents a unique situation greater propensity to hepatic encephalopathy in cirrhosis.
where the systemic pathophysiological derangements are This is less problematic in noncirrhotic PH and extrahepatic
more pronounced, dysfunction multiple organs are often PH where they have very good long-term outcomes. Shunts
present as component of the entire spectrum and an episode are resorted to only when drugs and endoscopic therapies
of variceal hemorrhage can have a spiraling downhill impact fail to impact: either as salvage in acute hemorrhage or
as a planned procedure in noncirrhotic PH and EHPVO. bleeding. Bacterial infection, active bleeding at an emergency
Other surgical techniques like devascularization and endoscopy, Child-Pugh score, aspartate aminotransferase
splenectomy are often resorted to as emergency procedures levels, presence of PVT, and an HVPG greater than 20 mm Hg
in acute hemorrhage when more definitive shunts become measured shortly after admission are the predictors of risk for
technically difficult. initial failure to control bleeding, early rebleeding, and 5 day
risk for death.
Implementation of effective treatments (in terms of
CLINICAL SCENERIOS AND THE USE OF endoscopic and pharmacological therapies and TIPS), as well
as improved general medical care (i.e. antibiotic prophylaxis)
MODALITIES have reduced the mortality from variceal bleeding by more
The treatment of bleeding in PH includes the primary than 50% over 2 decades. In 1980s, it was ~40%, and in last
prophylaxis of variceal hemorrhage in patients who have decade, it was ~20%. In spite of above measures, immediate
never bled, the treatment of the acute bleeding episode, mortality from uncontrolled bleeding occurs in 48% of
and the secondary prophylaxis of bleeding in patients who patients of variceal bleeding of which around 3% of patients
have survived a bleeding episode from esophageal or GV of variceal bleed die before reaching hospital. For the
(Table 7). purpose of simplicity, the general consensus is that any death
occurring within 6 weeks from hospital admission for variceal
bleeding should be considered as a bleeding-related death.
Acute Variceal Bleeding Interestingly, only 40% of the deaths are directly related to
bleeding, while most are caused by liver failure, infections
Management Principles and hepatorenal syndrome.
Death risk indicators following variceal bleed are Child-
Ruptured esophageal varices accounts for ~ 70% of all upper
Pugh classification or its components, blood urea nitrogen or
gastrointestinal bleeding episodes in patients with PH.
serum creatinine, active bleeding on endoscopy, hypovolemic
Diagnosis of variceal bleeding is established at emergency
shock, and hepatocellular carcinoma. Prognostic indicators
endoscopy based on observing one of the following: (i) active
in the early follow-up include early rebleeding, bacterial
bleeding from a varix (observation of blood spurting or oozing
infection, and renal failure.
from the varix) (nearly 20% of patients), (ii) white nipple or
clot adherent to a varix, and (iii) presence of varices without
other potential sources of bleeding. Treatment
Spontaneous cessation of variceal bleeding occurs in 40
50% of patients and with active therapy, control of bleeding Since nearly as many patients die due to liver failure, infection
can be increased in up to ~80% of the patients. Rebleeding from and renal failure as directly because of hypovolemia,
varices is a problem area and incidence of early rebleeding shock and uncontrolled hemorrhagetreatment of acute
(first 6 weeks) ranges between 30% and 40%. Active treatment hemorrhage is much more than just stopping the bleed. Every
of variceal bleeding reduces this 6-week rebleeding rate to patient with an acute variceal bleeding should be managed in
2035%. The rebleeding risk peaks in the first 5 days, with 40% an intensive care setting.
of all rebleeding episodes occurring in this very early period. Initial resuscitation should follow the classic airway,
The rebleeding risk remains high during the first 2 week, and breathing, circulation scheme. Airway should be
then declines slowly in the next 4 weeks. After 6 weeks the immediately secured, especially in patients with
risk of further bleeding becomes almost equal to that before encephalopathy, for fear of aspirating gastric contents,
chance of which is increased by endoscopic therapy.
Endotracheal intubation may be done to secure airway.
Table 7: Therapeutic options in patients with portal hypertension Blood volume replacement should be initiated as soon as
possible with plasma expanders, with maintenance target
Prophylaxis Target Options for systolic blood pressure being 100 mm Hg. Prolonged
Pre-primary Prevention of varix Treatment for underlying hypotension must be avoided to prevent infection and
formation disease, no role for b blocker renal failure, which are associated with increased risk of
Primary Prevention of first bleed b blocker or EVL rebleeding and death. Blood transfusion should aim for
Secondary Prevention of second/ EVL + b blocker; + TIPS maintenance of the hematocrit at 0.210.24 (Hb 78 g/L),
further bleed except in patients with rapid ongoing bleeding or with
Abbreviation: EVL, endoscopic variceal ligation ischemic heart disease, as vigorous overtransfusion may
Table 8: Pharmacotherapy for portal pressure reduction
Drug Administration Dose Setting Period of administration

Vasopressin (VP) VP: i.v. infusion VP: 0.4 u/min Acute bleed 25 days
Terlipressin IV bolus 2 mg/4 hours for 24 48 hours then Acute bleed 25 days
1 mg/4 hours
Somatostatin i.v. bolus + infusion 250 mcg followed by 250-500 mcg/ Acute bleed 25 days
hours
Octreotide i.v. bolus + infusion 50 mcg followed by 50 mcg/hours Acute bleed 25 days
Propranolol (non-selective Oral 20 mg bid; increase upto the Primary and secondary long-term
BB) tolerated maximum (320 mg/day) prophylaxis
Nadolol (non-selective BB) Oral 40 mg bid; increase upto the Primary and secondary long-term
tolerated maximum (160 mg/day) prophylaxis
Carvedilol (non-selective BB Oral 6.25 mg bid; increase upto the Primary and secondary long-term
with alfa-blocker activity) tolerated maximum (50 mg/day) prophylaxis
Isosorbide mononitrate Oral 1020 mg bid; increase up to 2040 Secondary prophylaxis long-term
bid if tolerated
induce rebound increase in portal pressure and rebleeding

(Table 8). The role of platelet transfusion or fresh frozen
plasma administration in this setting is not established.
The studies for the use of recombinant activated factor
VII in this setting have produced conflicting results, and
it is therefore not used routinely. Infection is a prognostic
indicator for early mortality and failure of 5 day control
of acute variceal bleeding. The most frequent infections
are spontaneous bacterial peritonitis (50%), urinary tract
infections (25%), and pneumonia (25%). Prophylactic
antibiotics in patients with acute variceal bleeding have
been shown to reduce both the risk of rebleeding and
mortality (Fig. 4). Therefore, antibiotics should be given to
all patients of variceal bleed from the time of admission.
Quinolones are most frequently used, initially through
intravenous route that can subsequently be changed to
oral route (Norfloxacin 400 mg twice a day for 7 days). In
high-risk patients (hypovolemic shock, ascites, jaundice,
or malnutrition) intravenous ceftriaxone (1 g IV twice daily
for 7 days) has recently been shown to be superior to oral
norfloxacin. Variceal bleeding is a well-known precipitator
Fig. 4: Algorithm of the management of acute bleeding from ruptured
of hepatic encephalopathy. Though commonly used esophageal varices
in practice, however, there are no data to support the
Abbreviations: UGIE, upper gastrointestinal endoscopy; EBL,
prophylactic use of lactulose or lactitol in this setting. endoscopic band ligation
Specifics: Initial therapy for acute variceal bleeding is based
on the combination of vasoactive drugs with endoscopic
therapy. Balloon tamponade and portal-systemic shunts, Terlipressin is the first choice if available, since it is the only
either surgical or TIPS are second-line approach for control drug that has been shown to improve survival. Somatostatin,
of bleeding when the drugs and endoscopic therapy fail to octreotide, or vapreotide are the second choice. Terlipressin
achieve bleeding control. is long-acting triglycyl-lysine derivative of vasopressin.
Terlipressin may be initiated at suspicion of variceal bleeding On the other hand, endoscopic therapy also improves
at a dose of 2 g/4 hours for the first 48 hours, and it may the efficacy of vasoactive treatment when provided along
be maintained for up to 5 days at a dose of 1 g/4 hours to with it. These findings form the basis of current approach
prevent rebleeding. Most importantly, it has been shown to of combining these two modalities, with early initiation of
improve survival as well as control of bleeding. vasoactive drug therapy (ideally during the transfer to the
Efficacy of terlipressin in controlling acute variceal hospital, even if active bleeding is only suspected). EVL (or
bleeding at 48 hours is 7580%, and 67% at 5 days. The other injection sclerotherapy if band ligation is technically difficult)
advantage is that terlipressin is also useful in hepatorenal is performed after initial resuscitation when the patient is
syndrome. The most common side effect of this drug is stable and bleeding has ceased or slowed.
abdominal pain. Serious side effects, such as peripheral or
myocardial ischemia occur infrequently (less than 3% of the
patients). FAILURE OF INITIAL THERAPY AND
Somatostatin is commonly used as an initial bolus of 250
g followed by a 250 g/hour infusion that is maintained SALVAGE
until the achievement of a 24-hour bleed free period. Therapy In 1020% of patients, variceal bleeding is unresponsive to
may be further maintained for up to 5 days to prevent early initial endoscopic and/or pharmacologic treatment. Second
rebleeding. Higher doses (500 g /hour) may be given in the endoscopic therapy may be attempted in this situation provided
subset of patients with more difficult bleedings (those with patient is hemodynamically stable and bleeding is mild. In
active bleeding at emergency endoscopy). Somatostatin other cases, second-line management has to be explored.
significantly improves the rate of control of bleeding compared Balloon tamponade achieves hemostasis in 6090% of
with placebo or nonactive treatment. However, the beneficial variceal bleedings. Bleeding recurs after deflation in over half
effect on the control of bleeding has not been translated into of the cases. Therefore it should only be used in the case of a
mortality reduction as seen in clinical trial. Side effects, such massive bleeding and only as a temporal (less than 24 hours)
as nausea, vomiting, and hyperglycemia occur in up to 30% of bridge to more definite treatment.
the patients. Transjugular intrahepatic portosystemic stent and surgical
Octreotide is the analogue of somatostatin with longer shunts are extremely effective definitive treatment options for
half-life. It is usually given as an initial bolus of 50 g, followed control of variceal bleeding (control rate approaches 95%), at
by an infusion of 25 or 50 g/hour. Therapy can be maintained the cost of worsening of liver function and encephalopathy
for 5 days to prevent early rebleeding. Octreotide may improve and mortality. However, technical expertise limits their use in
the results of endoscopic therapy but when used alone, its such emergency setting in most circumstances.
role in outcome of variceal bleeding is not well-established.
Acute Bleeding from Gastric Varices

Endoscopic Therapy
Initial treatment of gastric variceal bleeding is similar to
Endoscopic variceal ligation of varices and EST are the two that of esophageal variceal bleeding. Efficacy of vasoactive
available options in control of esophageal variceal bleeding. drugs has not been studied specifically in this setting.
Meta-analysis shows that EVL is better than sclerotherapy Linton-Nachlas tube which has a larger balloon compared to
in the initial control of bleeding, and is associated with Sengstaken tube has been used for the tamponade effect in
fewer adverse events and improved mortality statistics. EVL this setting. Various modes of endoscopic therapies, such as
is endoscopic therapy of choice in acute variceal bleeding. sclerotherapy, variceal obturation with tissue adhesives (glue
Injection sclerotherapy is an acceptable method when band injection), thrombin, elastic band ligation, and ligation with
ligation is not available or is technically difficult. large detachable snares have been reported. Cyanoacrylate
injection is more effective and safer than band ligation in the
control of acute bleeding, and it is also associated with less
Combination Therapy rebleeding. TIPS is effective in the treatment of bleeding GV,
Several randomized controlled trials demonstrate that early when endoscopic therapies fail, with success rate of greater
administration of a vasoactive drug facilitates endoscopy than 90% for initial hemostasis and a low rebleeding rate. TIPS
and improves control of bleeding and 5 day rebleeding rate. is usually associated with the embolization of the collateral
Drug therapy has shown to improve the results of endoscopic vessels that feed the varices. Derivative and devascularization
treatment if started just after sclerotherapy or band surgery are the last resort, but they have limited applicability
ligation. in advanced cirrhosis.
Acute Bleeding from Portal Hypertensive Treatments for the Prevention of First
Gastropathy Bleeding
In acute bleeding, b-adrenergic blockers, somatostatin, Use of nonselective -adrenergic blockers (propranolol or
octreotide, vasopressin, terlipressin, and estrogens have been nadolol) for prevention of first variceal bleeding in patients
used, as they decrease gastric perfusion in this condition. with varices is associated with reduction of the risk of first
variceal bleeding (from 24% to 15% after a median follow-up
of 2 years). The same therapy, though, is not associated with
Acute bleeding from Ectopic Varices significant reduction in mortality. The search for an alternative
Vasoactive agents may be used in acute settings just like to this approach has been stimulated by the facts that, about
esophagogastric variceal hemorrhages. Endotherapy may 25% of cirrhotic patients with medium/large esophageal
be attempted when bleeding lesion is identified. Large size varices may have either contraindications for the nonselective
of duodenal varices exerts dilutional effect on the sclerosant -blockers or cannot tolerate these drugs, and the protection
and therefore its efficacy is variable. Tissue adhesives are also afforded (~40% relative risk reduction) is also not enough
effective in this setting. Bleeding stomal varices are easily considering the vast patient population. EVL has been found
managed with local compression if the site of bleeding is to be effective for prevention of the first variceal bleeding in
apparent by examining the stoma. If local therapy fails, then patients with medium to large varices. Meta-analysis of 16
transhepatic obliteration of the bleeding stomal varices or trials comparing EVL with -adrenergic blockers as a first-line
TIPS placement may be attempted. option for primary prophylaxis of variceal bleeding shows
advantage of EVL over -adrenergic blockers in terms of
prevention of first bleeding, without differences in mortality.
PROPHYLACTIC THERAPIES But the long-term safety and efficacy of EVL in this setting is
unknown and also the side effects of EBL are serious (inclusive
of bleeding) that require hospitalization. The combination of
Patients without Varices EVL and -adrenergic blockers appears to offer no benefit
Currently, there is no evidence for any advantage of the use in terms of prevention of first bleeding when compared
of pharmacological therapy (nonselective -adrenergic with EVL alone and therefore this approach is not practiced.
blockers) in prevention of appearance of varices. Therefore, Baveno IV consensus is of opinion that the nonselective
disease-specific therapy is undertaken to prevent or to -blockers should be considered as first-choice treatment to
retard the progression of cirrhosis and thereby development prevent first variceal bleeding, while EVL should be offered to
of varices (i.e. abstinence in alcoholics, antivirals in viral patients with medium/large varices and contraindications or
cirrhosis, lifestyle change in nonalcoholic steatohepatitis, intolerance to -blockers. The recent Baveno V committee, on
corticosteroids in autoimmune hepatitis, phlebotomies in the other hand, opined for individualized decision to be taken
hemochromatosis, copper chelators in Wilsons disease). by the patient and the physician based on their preferences,
expertise and contraindication.
Patients with Varices

As most of the studies evaluated the benefit of pharmacological
Secondary Prophylaxis
therapy in medium to large varices, prophylactic treatment of Survivors of the first episode of variceal bleeding have 60%
varices is considered mainly in medium and large varices. chance of recurrence of bleed within 1 year. Therefore, it is
Small varices with red signs or in Child-Pugh class C patients prudent to opt for secondary prophylaxis. -blockers have
have a bleeding risk similar to that of big varices. Therefore, shown a reduction in rebleeding rate from 63% in controls
Baveno consensus extended prophylactic treatment to to 42% in treated patients along with significant reduction
patients with small varices with red signs or Child-Pugh C42. in mortality and also mortality from bleeding. Combination
The recent Baveno consensus even included patients with of -blockers with isosorbide mononitrate (ISMN) has
small varices without signs of increased risk, for treatment not been found to be more effective than EVL. EVL is
with nonselective blocker to prevent progression of varices preferred to sclerotherapy as it has been proven superior to
and bleeding. sclerotherapy.
Combined endoscopic and pharmacological therapy: laser, or heater probe. TIPS may be considered as an alternative
Combined EVL and pharmacotherapy (either -blocker alone therapy if all the above measures fail. Most importantly, liver
or with ISMN) has the advantage of less variceal rebleeding transplantation is the ultimate cure for this as PHG reverses
and variceal recurrence compared to pharmacotherapy alone. after transplantation.
In accordance with the above findings it is the combination
of two modalities that are used in current practice for the
secondary prophylaxis of variceal bleed. Ectopic Varices
Beta blocker is administered in prevention of rebleed from
ectopic varices, though it is backed by scanty evidences.
Follow-up Endoscopy in Patient Treated Embolotherapy is the alternative approach when portal
with Endoscopic Variceal Ligation/-blocker venous system is patent. Control of bleeding is achieved
in most cases though there is high risk of rebleeding. TIPS
Endoscopy should be done in monthly interval along with
and portosystemic shunting with surgery are the options in
band ligation as necessary with the aim for eradication
refractory cases.
of varices following index bleeding episode. Follow-up
endoscopies should be performed every 6 months after
eradication and varices should be re-eradicated as recurrence
is observed. SHUNTS AND SURGERY IN VARICEAL
BLEEDING: TRANSJUGULAR
Role of Transjugular Intrahepatic INTRAHEPATIC PORTOSYSTEMIC STENT
Portosystemic Stent As an alternative to surgical shunts, TIPS was first introduced
Transjugular intrahepatic portosystemic stent is superior in the 1980s. It is usually reserved for patients who fail
to both endoscopic therapies and pharmacotherapies in pharmacologic and endoscopic management of both acute
reducing the rebleeding rate at the cost of increased events of and recurrent variceal bleeding. Placement of TIPS helps
hepatic encephalopathy. The overall mortality is not improved restoration of blood flow from portal to hepatic vein bypassing
with TIPS therapy. As TIPS is compared with surgical shunts, it the fibrosed liver. A catheter is placed in hepatic venous system
is noted that surgical shunts (portocaval or distal splenorenal (usually the right hepatic vein) through right internal jugular
shunt) are equally or more effective than TIPS in terms of vein. With the help of a needle, a tract to portal vein is made.
lower rebleeding rate, mortality. Disadvantages of TIPS such Thereafter, the transhepatic tract is dilated, and a flexible metal
as stent thrombosis and necessity of reintervention can be stent is placed. In 90% of cases of uncontrolled bleeding, TIPS
overcome by the use of coated stents in place of bare stents. is successful in stopping bleeding. Early complications of
TIPS include fever, infection, renal dysfunction, intrahepatic
or intraperitoneal hemorrhage, and liver failure. Long-term
Gastric Varices complications of TIPS placement are hepatic encephalopathy
Nonselective -blockers or the tissue adhesive isobutyl- and stent occlusion. Over 20% of patients with TIPS will either
2-cyanoacrylate are the first-line therapy for secondary develop or have worsening hepatic encephalopathy. Stent
prophylaxis. Polytetrafluoroethylene (PTFE)-TIPS or shunt occlusion occurs in 70% patients in 1 year and 90% patients
surgery is the available option in cases of failure to control in 2 years.
bleed.
Surgery
Portal Hypertensive Gastropathy Three surgical methods are used in the management of PH,
Nonselective -blockers are the choice for secondary namely: (i) decompressive shunts, (ii) devascularization
prophylaxis for bleeding from PHG, with same dosage as for procedures, and (iii) liver transplantation. Decompressive
treating esophageal varices. Adequate iron supplementation surgical shunts are of three types:
is useful to prevent or correct chronic iron-deficient anemia 1. Total portosystemic shunts decompress all PHthey are
in patients with severe PHG. Rare patients who have repeated 10 mm or more in diameter and include side-to-side
severe bleeding from PHG despite pharmacological therapy portacaval, mesocaval, and central splenorenal shunts.
may be treated with endoscopic ablation, either by argon They are effective in controlling variceal bleeding and
plasma coagulation, neodymium: yttrium-aluminum garnet ascites but deprive the liver of hepatopetal portal flow and
increase the risks of progressive liver failure and enceph blood flow to the liver and do not accelerate liver failure or
alopathy. precipitate encephalopathy. High rebleeding rate (2040%) is
2. Partial portosystemic shunts reduce PH to approximately the disadvantage of these procedures.
12 mm Hgside-to-side portosystemic shunt with
diameter of 8 mm. Portal flow is maintained in 80% of the
patients. They are associated with a lower incidence of Liver Transplantation
encephalopathy and liver failure. Variceal bleeding itself is not an indication for liver
3. Selective shunts decompress gastroesophageal varices transplantation, but, following transplantation control of
but maintain PH. Varices are selectively decompressed, bleeding can be achieved in the 95% patients in whom
usually by a distal splenorenal shunt through the short transplantation is performed for other indications.
gastric veins, spleen, and splenic vein to the left renal vein.
Splanchnic and portal venous system maintains prograde
portal flow to the liver. SUMMARY
Cirrhosis of liver is the most common cause of PH and is due to
Indications the altered sinusoidal fabric caused by liver fibrosis. An increased
Surgery is primarily indicated when endoscopic therapy intrahepatic vascular resistance due to vasoconstriction in the
fails to control bleeding. However, their role in overall hepatic microvasculature initiates while increased portal blood
management of cirrhotic PH is very limited and reserved for flow due to splanchnic vasodilation perpetuates and sustains PH.
an acutely bleeding child A cirrhotic who fails to endoscopic Although structural disorganization in cirrhosis is the dominant
and pharmacotherapy while facilities for TIPS is not available. factor for genesis of PH, the fact that functional factors, such as
They are more flexibly used in EHPVOwhere the indications dynamicity of stellate cell and sinusoidal endothelial cell behavior
also include symptomatic hypersplenism, growth retardation, contributes to up to 30% of the raised intrahepatic vascular
portal biliopathy, massive splenomegaly affecting the quality resistance and altered milieu of vasoactive and angiogenic
of life, rare blood group, and remote area of residence where molecules such as nitric oxide, endothelins, VEGF plays an
less invasive endoscopic therapy is unlikely to be available in important role in the pathophysiologypresent opportunity for
face of an acute bleeding episode. Rex shunt or mesoportal intervention and drug development. Variceal hemorrhage is the
bypass is new approach of shunt surgery employed in patients most important outcome of PH, although PH contributes to other
of EHPVO that restores mesenteric blood flow to the liver organ dysfunctions, ascites and encephalopathy in cirrhosis.
through the Rex venous recessus (portion of left portal vein HVPG correlates with outcomes of PH, with a HVPG more than
joining the umbilical vein). Patients own internal jugular vein 10 mm of Hg signifying the critical downhill marker. Variceal
is usually used as a conduit to bypass blood from superior development and bleed can be predicted with HVPG above 12
mesenteric vein to left branch of portal vein. In addition to mm of Hg and reduction of HVPG below 12 mm of Hg had
correction of PH, it also amends the systemic manifestations been shown to diminish probability of variceal bleed. Mortality
of EHPVO such as normalization of coagulation parameters, due to variceal bleed has significantly improved over the last 3
improvement of liver function, and linear growth (Table 9). decades with new drugs and endoscopic therapies as well as more
organized efforts in intensive care management. Sepsis, renal
Devascularization failure and liver failure are important causes of adverse outcome
and should always be looked for in management. Nonselective
Devascularization procedures include splenectomy, gastric Beta blockers are the mainstay of primary prophylaxis, while the
and esophageal devascularization, and in some cases, combination of EVL and betablockers may be useful in secondary
esophageal transection. These procedures maintain portal prophylaxis. Terlipressin and EVL are the most useful modalities
in acute management. Treatment of the cause of liver disease can
Table 9: Surgery in portal hypertension regress PH and should always be planned.
Decompressive shunts, devascularizarion procedure and liver
transplantation are the surgical options in patients with portal hypertension
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36
cHAPTER
Hepatorenal Syndrome
Ziauddin Ahmed
DEFINITION pressure and reductions in plasma renin activity and

norepinephrine concentration
The hepatorenal syndrome (HRS) is considered when acute Creation of portosystemic shunt in order to reduce portal
renal failure develops due to severe reductions in renal hypertension due to advanced liver disease improves
perfusion in patients with advanced liver disease. The liver renal function. The reduction of intrahepatic pressure was
disease can be due to cirrhosis, severe alcoholic hepatitis, or associated with lower incidence of HRS and ascites.
fulminant hepatic failure from any etiology. It is estimated It is not used as a treatment of HRS due to higher incidence
that at least 40% of patients with cirrhosis and ascites will of hepatic encephalopathy and no survival benefit.
develop HRS during the natural history of their disease.
ESTIMATION OF RENAL FUNCTION

PATHOGENESIS
Liver produces creatinine and urea. Advance liver disease
Hepatorenal syndrome develops when scarred liver causes diminishes their production and low muscle mass in cirrhosis
portal hypertension, which in turn, is responsible for selective make them unreliable to estimate the GFR. In advanced liver
splanchnic arterial vasodilation. Increased production or disease apparently normal plasma creatinine [11.3 mg/dL
activity of vasodilators, mainly endothelium-derived nitric (88.4115 mol/L)] is usually associated with an abnormally
oxide in the splanchnic circulation is considered the initial low GFR (ranges from as low as 2060 mL/minute).
event. Blood urea nitrogen (BUN) may be low due to less
As the liver disease progresses, the rise in cardiac output production but also may be disproportionately high
and fall in systemic vascular resistance (SVR) occur. Low SVR- seemingly due to adequate urea production in some times
induced hypotension activates the renin-angiotensin and and due to prerenal avidity of sodium and water reabsorption
sympathetic nervous systems resulting renal vasoconstriction. which induce passive reabsorption of urea in the proximal
Renal vasoconstriction occurs in the absence of reduced tubule.
cardiac output and blood volume, which is in contrast to Creatinine clearance can be used to estimate GFR since
most clinical conditions associated with renal hypoperfusion. the 24 hour urine collection will demonstrate any fall in
This process may be due to bacterial translocation from the creatinine production and its excretion. Caution should
intestine into the mesenteric lymph nodes. be taken since renal insufficiency will tend to overestimate
Renal ischemia causes decrease in glomerular filtration the true GFR by as much as 40% due to increased tubular
rate and renal sodium excretion. secretion of creatinine.
The role of splanchnic vasodilation in these changes can
be supported by the following:
Improvement of renal and hemodynamic activities by CLINICAL PRESENTATION
administration of ornipressin, a preferential splanchnic
vasoconstrictor and an analog of antidiuretic hormone. Most patients with cirrhosis who develop HRS may present
Improvement of clinical parameters include improvement with nonspecific symptoms of fatigue, malaise and sometimes
in renal blood flow, glomerular filtration rate, urinary with decreased urine output. Physical stigmata of chronic
sodium excretion, urinary volume and mean arterial liver disease are usually present.
Hepatorenal Syndrome 331
The HRS is characterized by progressive rise in the plasma albumin replacement can precipitate type 1 HRS in up to
creatinine concentration even though the increment can be 15% of patients. Diuretics can cause prerenal azotemia,
as little as 0.1 mg/dL (9 micromol/L) per day, with periods which improves with the cessation of therapy and fluid
of stabilization or even slight improvement. This is usually repletion. In comparison, in the HRS the progression of renal
associated with benign urine sediment, and very low urinary failure continues despite volume repletion and even after
sodium. Oliguria is not always a key component but marked diuretics is stopped. Despite the irreversibility the HRS is
decrease in urinary output occurs just prior to death. considered a severe form of prerenal disease, as the kidneys
Two forms of HRS have been described based upon the are histologically normal and have been used successfully for
rapidity of the onset of renal failure: renal transplantation.
Type I HRS may be defined as the creatinine clearance
reduced by at least 50% to a value of less than 20 mL/minute
in 2-week time or twofold increase in serum creatinine to DIAGNOSIS
more than 2.5 mg/dL.(221 mol/L). The patients can be both
oliguric and nonoliguric but most are nonoliguric at the time The following diagnostic criteria of HRS have been proposed
of diagnosis of HRS. It is more serious type and associated in patients with chronic or acute hepatic disease with
with significant mortality. advanced hepatic failure and portal hypertension.
Type II HRS is defined as less severe renal insufficiency. Progressive increase in plasma creatinine concentration is
It is principally characterized by ascites that is resistant to above 1.5 mg/dL (133 micromol/L) over days to weeks. Due
diuretics. to the marked reduction in creatinine production in cirrhosis
the rise in plasma creatinine can be very minimal.
Other causes of renal impairment including use of
INCIDENCE nephrotoxic drugs, ongoing shock or bacterial infection,
obstruction or renal parenchymal disease using an ultrasound
The incidence of HRS in one study of nonazotemic patients should be ruled out. Spontaneous bacterial peritonitis also
with cirrhosis and ascites were 18% in 1 year and to 39% in should be excluded because immediate treatment can
5 years. The highest risks for developing HRS are in patients improve acute renal failure in 3040% of patients.
with hyponatremia and a high plasma renin activity. Most Urinary protein excretion is less than 500 mg/day and less
likely it reflects the increase in neurohumoral activities due to than 50 urinary red blood cells per high power field.
severe decline in renal perfusion. Renal function failed to improve after holding the diuretics
Hepatorenal syndrome can also occur in patients with for 2 days and attempt of volume expansion with intravenous
acute hepatic failure (alcoholic hepatitis) without established albumin (1 g/kg of body weight up to 100 g of albumin) for at
cirrhosis of liver. least 2 days.
Patients with primary biliary cirrhosis appear to be
relatively protected. HRS occurs less often or as a late
manifestation in this condition. Sodium retention and ascites DIFFERENTIAL DIAGNOSIS
formation are also less common and presumably due to
natriuretic and renal vasodilator actions of retained bile salts Acute tubular necrosis (ATN), acute glomerulonephritis,
in these patients. acute interstitial nephritis and vasculitis all can occur in
patients with liver disease and should be suspected in
patients with appropriate history and active urine sediments.
PRECIPITANTS In most cases the differential diagnosis of the HRS includes
other reversible prerenal disease, and ATN. HRS is a diagnosis
The onset of renal failure is insidious, but can be precipitated of exclusion when other potential causes of acute renal failure
by an acute insult, such as gastrointestinal bleeding, volume have been ruled out.
depletion due to over diuresis, spontaneous bacterial
peritonitis, or other infection. Trigger is also more likely to
occur in patients with underlying chronic kidney diseases. Prerenal Disease
Diuretics do not cause HRS. However, it can occur if The decreased renal perfusion can also be induced by volume
fluid removal is overtly rapid in patients with ascites but depletion due to gastrointestinal fluid losses, or bleeding, or
no peripheral edema. Large-volume paracentesis without diuretic therapy. Use of nonsteroidal anti-inflammatory drug
which compromise renal perfusion by decreasing vasodilator In comparison, octreotide or midodrine alone does not
prostaglandins are also commonly seen in these patients. appear to be beneficial.
Thus, the lack of improvement in renal function following In two studies, treatment was associated with a significant
discontinuation of nephrotoxins and a trial of fluid repletion reduction in mortality and a significantly higher incidence of
suggest a diagnosis of HRS. a reduction in serum creatinine concentration to less than 1.5
Hepatorenal syndrome should be differentiated from other mg/dL (133 mol/L). Some patients survived to be discharged
reversible causes of acute kidney injury because of its poor to home.
prognosis. Without effective treatment or liver transplant The dose of midodrine between 7.5 mg and 15 mg by mouth
most patients of HRS will not survive within weeks of the TID and octreotide as 100200 g subcutaneously can be tried
onset of renal failure. Hepatic encephalopathy is a common along with intravenous albumin at approximately 1 g/kg per
occurrence and death is usually due to complication of liver day (100 g maximum) in divided doses. Both midodrine and
failure, such as gastrointestinal bleeding. octreotide are titrated to increase the mean arterial pressure
at least 15 mm of Hg.
Acute Tubular Necrosis

Treatment with nephrotoxic agents, including aminoglyco
Norepinephrine
side, cisplatin or use of intravenous radiocontrast dye or Treatment with norepinephrine plus albumin in patients with
development of sepsis or bleeding complications can result type I HRS in an uncontrolled study also reported a significant
in ATN. reduction in serum creatinine concentration. Treatment with
Distinguishing ATN from prerenal disease may not be norepinephrine also provides significant blood pressure
always helpful in the patient with hepatic disease. The support in patients with HRS who are mostly hypotensive.
fractional excretion of sodium instead of more than two
normally seen in ATN may remain below 1% in patients with
cirrhosis due to the persistent renal ischemia despite full Vasopressin Analogs
blown ATN. Presence of granular and epithelial cell casts in Vasopressin analogs ornipressin administration along with
urinalysis also may be seen due to marked hyperbilirubinemia effective circulating volume expansion with IV albumin
alone without ATN. achieved improvement of GFR. However, this regimen may
also induce significant renal ischemia.
Another vasopressin analog, terlipressin administration
TREATMENT along with IV albumin showed significantly improved
renal function (as assessed by creatinine clearance, serum
When liver disease progresses the GFR also falls progressively. creatinine levels, and urine output). Although promising, the
The best treatment of HRS is a successful liver survival is not affected. It is also not available in USA.
transplantation. Improvement in hepatic function is
sometimes also seen due to partial resolution of the primary
disease. Improvement in the underlying liver disease is Other Therapeutic Agents
most impressive in patients with alcoholic liver disease with Other agents that have been tried with conflicting evidence
abstinence. This shows significant improvement in both liver of benefit, or evidence of harm, include misoprostol and
and renal function. Successful treatment of hepatitis B virus N-acetylcysteine, and angiotensin converting enzyme
infection with lamivudine in patients with decompensated inhibitor. Despite initial enthusiasm these drugs cannot be
cirrhosis also improves renal function. recommended without further studies.
Midodrine and Octreotide and Albumin

SURGICAL PROCEDURES
The combination therapy with midodrine, which is a selective
alpha-1 adrenergic agonist, octreotide, a somatostatin analog
along with IV albumin seems safe and effective. Renal function
Transjugular Intrahepatic
and systemic hemodynamics improve when midodrine, which Portosystemic Shunt
causes systemic vasoconstriction, and octreotide, which inhibits
The transjugular intrahepatic portosystemic shunt (TIPS)
the release of endogenous vasodilator when both are given
has been used for refractory ascites but its use in HRS setting
together.
Hepatorenal Syndrome 333
showed mixed result in renal function. Given the risks bilirubin greater than 3 mg/dL (51.3 micromol/L) or a serum
associated with high incidence of encephalopathy, TIPS may creatinine greater than 1.2 mg/dL (106 micromol/L) or BUN
be considered only as a last resort to gain any short-term greater than 20 mg/dL or serum sodium less than 130 meq/L
benefit in patients who are not a candidate for or are awaiting and HRS and improved survival.
liver transplantation.
Peritoneovenous Shunt PROGNOSIS

Insertion of a peritoneovenous shunt also did not show any The mortality in HRS is worse in patients who have
survival benefit despite improvement in systemic hemodyn preexisting liver disease. The prognosis is strongly dependent
amics and modest improvement in renal function. on spontaneous or medical therapy-induced reversal of liver
failure or successful transplantation of liver. Recovery of renal
function may be affected by pretransplant renal function
Dialysis and differences over time in indications for dialysis and in
Dialysis can be used in patients with HRS who progress eligibility for liver transplantation. The rate of recovery of
to uremia and or develop intractable volume overload. kidney function following recovery of liver failure is uncertain
Hemodialysis or continuous venovenous hemofiltration but a significant number of dialysis-dependent patients with
(CVVH) are commonly used when patients are awaiting a HRS recover renal function over time.
liver transplant or when there is a possibility of improvement
in liver function. Initiation of dialysis also improves the
priority score for the liver transplant. Survival on dialysis BIBLIOGRAPHY
primarily depends on the severity of the liver disease, as well
1. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and
as concurrent respiratory failure. It is also helpful to buy time
clinical type predict prognosis in hepatorenal syndrome:
in patients with an acute and potentially reversible hepatic
relevance to liver transplantation. Hepatology. 2005;41(6):1282-9.
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Other hybrid dialysis techniques were also tried with the and albumin in patients with type I hepatorenal syndrome: a
general concept of reinfusing ascetic fluid either intravascularly pilot study. Hepatology. 2002;36(2):374-80.
or intraperitoneally in the patients, but lack of controlled data 4. Esrailian E, Pantangco ER, Kyulo NL, et al. Octreotide/Midodrine
on survival have discouraged its application. therapy significantly improves renal function and 30-day
survival in patients with type 1 hepatorenal syndrome. Dig Dis
Sci. 2007;52(3):742-8.
5. Fernndez J, Navasa M, Planas R, et al. Primary prophylaxis
PREVENTION of spontaneous bacterial peritonitis delays hepatorenal
syndrome and improves survival in cirrhosis. Gastroenterology.
In some case HRS can be prevented especially in early 2007;133(3):818-24.
management of spontaneous bacterial peritonitis and/or 6. Garcia-Tsao G, Parikh CR, Viola A, et al. Acute kidney injury in
severe alcoholic hepatitis. cirrhosis. Hepatology. 2008;48(6):2064-77.
In cirrhotic patients who are diagnosed with spontaneous 7. Gins P, Schrier RW. Renal failure in cirrhosis. N Engl J Med.
bacterial peritonitis, starting intravenous albumin (1.5 mg/ 2009;361(13):1279-90.
kg) at the time of diagnosis and also another dose (1.0 g/kg) 8. Gluud LL, Kjaer MS, Christensen E. Terlipressin for hepatorenal
syndrome. Cochrane Database Syst Rev. 2006;(4):CD005162.
later on day three of antibiotic treatment may decrease the
9. Iwakiri Y. The molecules: mechanisms of arterial vasodilation
incidence of renal failure and also mortality.
observed in the splanchnic and systemic circulation in portal
Oral norfloxacin at a dose of 400 mg/day is associated with hypertension. J Clin Gastroenterol. 2007;41 Suppl 3:S288-94.
significantly decreased incidence of spontaneous bacterial 10. Kalambokis G, Economou M, Fotopoulos A, et al. The effects
peritonitis and HRS and also improved survival if given to of chronic treatment with octreotide versus octreotide
the cirrhotic patients whose ascitic fluid protein is less than plus midodrine on systemic hemodynamics and renal
1.5 g/dL and who have also fulfilled either of the following two hemodynamics and function in nonazotemic cirrhotic
criteria: a Child-Pugh score greater than 9 points and serum patients with ascites. Am J Gastroenterol. 2005;100(4):879-85.
11. Marik PE, Wood K, Starzl TE. The course of type 1 hepato-renal 17. Veldt BJ, Lain F, Guillygomarch A, et al. Indication of liver
syndrome post liver transplantation. Nephrol Dial Transplant. transplantation in severe alcoholic liver cirrhosis: quantitative
2006;21(2):478-82. evaluation and optimal timing. J Hepatol. 2002;36(1):93-8.
12. Martn-Llah M, Ppin MN, Guevara M, et al. Terlipressin 18. Wadei HM, Mai ML, Ahsan N, et al. Hepatorenal syndrome:
and albumin vs albumin in patients with cirrhosis and pathophysiology and management. Clin J Am Soc Nephrol.
hepatorenal syndrome: a randomized study. Gastroenterology. 2006;1(5):1066-79.
2008;134(5):1352-9. 19. Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis.
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Hepatology. 2005;41(3):422-33.
renal failure with refractory ascites. Clin Nephrol. 2004;62(5):374-9.
20. Witzke O, Baumann M, Patschan D, et al. Which patients
14. Pomier-Layrargues G, Paquin SC, Hassoun Z, et al. Octreotide in
benefit from hemodialysis therapy in hepatorenal syndrome? J
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15. Salerno F, Gerbes A, Gins P, et al. Diagnosis, prevention 21. Wong LP, Blackley MP, Andreoni KA, et al. Survival of liver
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37
cHAPTER
Drug-induced Liver Injury
Saeed Hamid, Om Parkash
INTRODUCTION Evaluation and Research and the Pharmaceuticals Research

and Manufacturers of America.
Drug-induced liver injury (DILI) has been recognized as an Drug-induced liver injury presents clinically in three
important health problem and a cause of acute as well as different patterns, which are hepatocellular, cholestatic and
chronic liver disease (CLD). As the liver has a central role in mixed. In the hepatocellular pattern, there is predominantly
the metabolism of almost all drugs, there may be an increased an elevation of transaminases, while in the cholestatic
propensity to liver damage due to the toxic (dose related) or pattern, there is predominantly an elevation of ALP. However,
idiosyncratic (unpredictable) effects of many drugs. DILI if these two patterns present simultaneously, it is labeled as
also exerts many repercussions on healthcare providers, the mixed variety of DILI. It is important to determine the
regulatory agencies and pharmaceutical industry, and this clinical pattern of DILI since many of the drugs present a
is an important issue when new drugs are to be launched in typical pattern, e.g. acetaminophen and isoniazid (INH) as
the market. For example, DILI has been the most important a hepatocellular pattern, augmentin and erythromycin as
reason for failure of approval of drug or withdrawal from cholestatic, while amitriptyline and captopril present a mixed
the market once released, as well as black box warnings by pattern of liver injury.
the Food and Drug Administration (FDA). Global literature Elevations in liver enzymes (ALT, AST and ALP) indicate
suggests that more than 1,100 drugs, herbal remedies, natural liver injury while elevations in total bilirubin and conjugated
products, vitamins, minerals, dietary supplements, and bilirubin indicate overall liver function.
recreational and illicit drugs are responsible for DILI.
EPIDEMIOLOGY
DEFINITION
This aspect of DILI is poorly understood until now due to
Often, DILI is hard to define accurately in clinical practice as many reasons like poor or underreporting, poor surveillance
this tends to occur in a background of many complementary systems and a lack of a generally acceptable definition of DILI
situations. In 1989, a panel of European and American despite a consensus statement in 1989.
experts defined DILI as an increase of more than twice the For most drugs, hepatotoxicity is considered to be
upper limit of the normal range (ULN) (>2) in the levels extremely rare and the incidence estimates range between 1 in
of serum alanine aminotransferase (ALT) or conjugated 10,000 and 1 in 100,000 of those exposed to the drug. However,
bilirubin, or a combined increase in the levels of aspartate most studies are retrospective and therefore lack standard
aminotransferase (AST), alkaline phosphatase (ALP) and diagnostic criteria, along with the limitation of selection bias
total bilirubin provided that one of these should be greater because of reported mainly from tertiary referral centers.
than two times the ULN. European data from Sweden and United Kingdom had
However, later it was redefined as an ALT level of greater shown possible DILI in 6.6% and 8.1% patients presenting
than three times ULN and total bilirubin level of greater with liver disease respectively. Data from US liver transplant
than two times ULN that may be used as a combined test database of United Network for Organ Sharing (UNOS) from
to define clinically significant impairment on liver function 1990 to 2002 showed that 15.6% of patients underwent liver
tests, in a conference cosponsored by American Association transplant for drug-induced acute liver failure (ALF). Among
for the Study of Liver Disease (AASLD), FDA center for Drug the entire transplant recipient, acetaminophen constituted
46% while other drugs comprised of 51%, which caused ALF Chronic liver disease patients due to either viral
and remaining 3% had concomitant acetaminophen along etiology like Hepatitis B virus (HBV)-associated CLD or
with other drugs causing DILI-induced ALF. chronic hepatitis C (CHC)-associated CLD or nonviral
Now, there are a couple of prospective studies available causes like nonalcoholic steatohepatitis (NASH)/alcoholic
from France and USA. A French population-based study has steatohepatitis (ASH) are generally at increased risk for DILI.
shown an approximate incidence of 13.9 per 100,000 persons Contrary to normal persons if these CLD patients develop
exposed. However, ALF study group recently had reported DILI, they have a worse prognosis as compared to the normal
about 10 years experience, which had shown prevalence of population. For instance, these CLD patients are at increased
approximately 11.1% DILI-induced ALF. risk of DILI caused by ATDINH or rifampicin.
Medications that most commonly cause DILI in Europe and
North America include acetaminophen, while in this part of the
world the most common cause of DILI is nonacetaminophen TYPES OF DRUG-INDUCED LIVER
drugs, especially antituberculous drugs (ATD). Recently,
a study conducted on a retrospective database of DILI in INJURY
the Department of Gastroenterology, St. Johns Medical There are two types of DILI: one is predictable and other one
College Hospital, Bengaluru, Karnataka, India revealed that is unpredictable.
approximately 57.8% of DILI in their patients was caused
by ATD, followed by antiepileptic drugs in 11.2% of cases,
nonsteroidal anti-inflammatory drugs (NSAIDs) in 2.6% cases Predictable Type of DILI
and atorvastatin in 1.6% of cases. However, USA data from the
This type of injury is dose dependent, which can be reproduced
Drug-Induced Liver Injury Network (DILIN) has also reported
in animals and usually presents within hours to few days of
different culprit drugs like antibiotics and central nervous
exposure of the offending drug when its dose reaches beyond
system (CNS) drugs, which are responsible for 45.5% and 15%
its threshold of causing injury. Examples of predictable injury
cases respectively if acetaminophen is excluded from the list.
would include acetaminophen toxicity at a dose of 20 grams,
Susceptibility to DILI among different population
and some other chemical agents like carbon tetrachloride,
categories (females, young children, the elderly and patients
phosphorus and chloroform, and hence, these compounds
suffering from other comorbid conditions particularly CLD
are no more in clinical use. Drugs causing a predictable injury
or the role of genetic influence) had been studied and has
can easily be identified during initial workup.
shown influence of these factors on DILI occurrence in these
individuals. Despite this, on critical analysis of different
studies we had found that these studies had failed to show Unpredictable Type of DILI
any strong association of any drug to these factors for causing
DILI in these particular subgroups.
(Idiosyncratic Reactions/Injury)
For example, studies from India had shown a female These reactions are either dose dependent or dose
propensity for ALF; however, studies in the Western literature independent and can be reproduced in animal models. These
do not support this tendency. For the elderly people it has reactions occur without warning and have a variable latency
been hypothesized that because of increasing age, drug period, which can range from a few days to many months. This
pharmacokinetics, including drug absorption, distribution, idiosyncratic response is further subclassified as allergic and
metabolism and elimination is altered. Most of the elderly are on nonallergic reactions. Allergic reactions usually present as
polypharmacy that may also be a contributing factor for DILI. fever, rash, lymphadenopathy or eosinophilia. Idiosyncratic
Regarding children, it has been seen that the pediatric response occurs only in a small percentage, i.e. 0.011%
population does not generally seem to be susceptible to DILI; of patients who have taken the culprit drug; henceforth, it
however, they do have increased susceptibility to selected signifies the importance of distinctiveness of individuals
compounds. Unusual idiosyncrasy of children with viral response to a drug that is either genetic or environmental.
infection to aspirin, i.e. Reyes syndrome is well established and That is why idiosyncrasy can be defined as an unpredictable
there are other additional examples like increased frequency of response in an individual due to the presence of one unusual
DILI with valproic acid and macrolides especially erythromycin. or several factors, which lead to DILI in such subjects.
Drug-induced Liver Injury 337
PATHOGENESIS either the extrinsic immune system (e.g. cytotoxic T cells)

or intracellular stress. Metabolites have the capability to
Drug Metabolism and Liver go through or advance a variety of biochemical reactions,
including covalent binding, depletion of reduced glutathione,
Liver is the chemical factory of the body and a well-equipped oxidative stress with consequent effects on DNA, lipids and
principal organ for drug metabolism. There are three protein. As a consequence, these biochemical events lead to
pathways of drug metabolism named as phase I, II and III. damage of cellular organelles like mitochondria, cytoskeleton,
These pathways alter the parent drug by using either one or endoplasmic reticulum and nucleus. Ultimately, these steps
two or all the phases of metabolism for drug elimination from lead to either necrosis or apoptotic cell death. The immune-
the body. These phases take place with help of certain proteins mediated attack on hepatocytes is started by metabolites with
(membrane transporters or enzymes), which are expressed the help of cytotoxic T cells through an apoptotic process, i.e.
and located at cellular and subcellular levels. Because of these by haptenization. In this process of haptenization, altered
proteins, this drug metabolism is a very coordinated process. proteins are formed when metabolite gets bind with proteins
resulting in altered protein and serve as neoantigens for the
immune system. In this way, the whole immune system gets
Phases of Drug Metabolism activated by helper T cells causing cytokines release, which
Phase I metabolism: In this pathway, certain chemical activates cytotoxic T cells, natural killer cells and B cells
reactions like oxidation, reduction and hydrolytic reactions ultimately leading to the activation of humoral and cellular
take place and with the help of these reactions, drug immunity. However, according to the danger hypothesis,
metabolites get conjugated or become more water soluble in this haptenization-mediated process itself is incapable of
subsequent phases. Most phase I reactions are metabolized triggering the immune response. Hence, the immunologic
by cytochrome P-450 enzymes. This phase can generate toxic response essentially needs costimulatory danger signals, and
electrophilic chemicals and free radicals. these can be either concomitant infections or inflammatory
conditions, such as concomitant CLD or human immun
Phase II metabolism: In this phase, the parent drug or
odeficiency virus (HIV) infection. The other possible
metabolites are conjugated with glutathione (GSH), sulfate
immunologic mechanism of DILI leading to cellular damage
or glucuronide to produce water soluble compounds so that
is by immunologic dysregulation, which is also known as
these products can be eliminated from the body in the bile
drug-induced autoimmune hepatitis. This mechanism can
or urine. These reactions occur with the help of enzymes like
lead to drug-induced autoimmune antibodies, e.g. anti-
glucuronosyl (or glucuronyl) transferases, sulfotransferases,
LKM (liver kidney microsomal antibody) directed against
glutathione-S transferases, and acetyl and amino acid
microsomal enzymes, and examples include halothane
N-transferases. Conjugation reactions are rate-limiting
hepatitis. Autoimmune antibodies like antinuclear antibody
reactions due to cofactors like glucuronic acid or inorganic
(ANA) and smooth muscle antibody (SMA) can be detected in
sulfate, and the relatively little ability of these enzyme systems
patients with nitrofurantoin-, methyldopa- or minocycline-
restricts the efficacy of drug elimination when metabolite
induced DILI. This autoimmune mechanism may involve
concentrations surpass enzyme saturation.
genetic predisposition through immune tolerance anomaly.
Phase III metabolism: This phase occurs after the second Adaptation is an important concept in immune-mediated
phase when these metabolites are ready to be excreted from injury in DILI in which DILI reverses despite continuation
the body; this signals the start of phase III metabolism. In of the drug. This process is also regulated at all three
this phase, there are different transporters present in liver phases of drug metabolism by decreasing the exposure of
cell canalicular and sinusoidal membrane involved in the toxic metabolite to liver cell. Organelle damage can elicit
excretion of metabolites from the body. upregulation of chaperones and replacement of organelles,
Genetics polymorphisms and environmental factors also e.g. mitochondrial damage induces mitochondrial genesis
affect these three different phases of drug metabolism. and endoplasmic reticulum stress induces an adaptive
response to modulate stress.
Biochemistry and Immunology of Drug-
induced Liver Injury Cellular Demise in Drug-induced Liver
The whole cascade of biochemical and immunological Injury
events leading to cell damage and ultimately cell death are The ultimate outcome of either pathway (i.e. biochemical or
triggered by the toxic metabolites. The clinical appearance immunological) is cellular failure/death. This demise could
of hepatitis is then a consequence of cell death mediated by be due to apoptosis or necrosis and mode of death is selected
based on the severity of injury or depletion of ATP, i.e. more suggested by Uetrecht who had shown that incidence of DILI
severe injury to mitochondria leads to necrosis, while less is rare in those cases that were given less than 10 mg drug
severe injury leads to apoptosis. dose daily and conversely, idiosyncratic DILI occurrence
is very likely in those who were given 1 gram or more. This
concept was later confirmed in a systematic fashion in a study
RISK FACTORS FOR IDIOSYNCRATIC on two data bases from US and Spain.
VARIETY OF DRUG-INDUCED LIVER INJURY

Metabolic Factors
Risk factors for this type of DILI can be broadly divided into
two varieties, i.e. nongenetic and genetic variety. This can be a very important risk factor if more than 50% of
drug is metabolized in the liver and causing DILI without
jaundice. Studies had also shown that majority of those drugs,
Nongenetic Variety of Risk Factors which have no hepatic metabolism are unlikely to cause
DILI, e.g. alendronate, gabapentin, hydrochlorothiazide,
Age etc. Drugs with biliary excretion pathway had a tendency to
This is a risk factor for certain medications at certain ages cause jaundice as compared to those drugs that had no biliary
like in pediatric population Reyes syndrome associated with excretion.
aspirin use and for valproic acid. As age increases, the risk
of DILI increases from certain drugs like INH and also for Group/Class Effect and Cross Sensitization
amoxicillin/clavulanate. Cholestatic type of injury is more
common in elderly persons while hepatocellular type is more Class effect means DILI risk for agents with narrow
common in younger population. Exact cause for this age- therapeutic class and cross sensitization means the risk of
related difference in DILI is uncertain, and there are some hepatotoxicity for agents with close chemical class structure,
hypothetical theories like older people have reduced liver e.g. between phenytoin and carbamazepine. Overall impact
blood flow or reduced renal function or these people are of cross sensitization and class effect is not well established.
on polypharmacy due to different concomitant comorbids.
However, these comorbidities polypharmacy theories have
been denied in prospective studies.
Drug Interaction
There are greater than or equal to 20 varieties of cytochrome
P450 (CYP) in the CYP system family in the human liver.
Gender These enzymes are responsible for the formation of reactive
Previously, it was thought that female gender was at high risk intermediate metabolites by most phase I reactions and these
of developing DILI as compared to males based on published metabolites are more abundant in the centrilobular zone than
retrospective data. However, prospective studies had failed to in the periportal zone. Drug metabolizing enzymes might
show this gender predilection for DILI until few years back. mediate the pathogenesis of DILI by causing centrilobular
Now some of the studies have shown an association of female necrosis, the characteristic feature of DILI. Some of the
gender with hepatocellular pattern of DILI along with worse drugs can modify the DILI potential of other drugs by the
outcome, i.e. ALF. One of DILIN study has shown significantly mechanism of enzyme induction, which in turn, leads to the
greater number of female patients with hepatocellular formation of reactive metabolites, e.g. rifampicin, phenytoin,
DILI than men. Interestingly male and female patients had INH, smoking and ethanol.
different susceptibility for different drugs, e.g. female subjects
are more prone to develop DILI secondary to halothane,
flucloxacillin, INH, nitrofurantoin and chlorpromazine
Alcohol Consumption
whereas male patients have increased risk of azathioprine- Despite a very well established role of acute and chronic
induced DILI. alcoholism on acetaminophen-induced DILI, it is less clear
for idiosyncratic DILI. Alcohol consumption might cause DILI
in only a few instances, like methotrexate, INH or halothane.
Daily Dose For example the risk of methotrexate-induced DILI leading to
Traditional teaching is that idiosyncratic response is fibrosis or cirrhosis might be increased in chronic alcoholism.
independent of dose, but this concept may be wrong as Similarly, chronic alcoholism can also cause increased risk of
ATT-induced DILI, possibly from alcohol-mediated induction or ductular injury. The cholestatic pattern mimics biliary
of hepatic CYP2E1. obstruction or is sometimes associated with a benign course
of pruritus and jaundice.
Symptoms of hypersensitivity include rash, fever, mucositis,
Comorbidity facial edema, vasculitis, bone marrow suppression, renal
Literature regarding the risk of DILI in comorbid conditions failure, pneumonitis, pancreatitis and lymphadenopathy,
is controversial. Patients with underlying liver disease are at along with either eosinophilia or atypical lymphocytosis.
higher risk for complicated courses and bad outcomes from These reactions are also known as systemic manifestations
DILI. of DILI. These features constitute a part of the characteristic
syndrome, which may have a genetic component; hence,
it is likely that it is caused by the formation of toxic drug
Genetic Factors metabolites, which is responsible for reactive metabolic
Because of the idiosyncrasy and rarity, there is the possibility syndrome (RMS) caused by activation of immunologic
of an association of DILI with genetic risk factors. Hence, DILI reactions by the drug metabolite acting as haptens.
is likely a complex genetic disorder in which many genetic
variants along with environmental risk factors are responsible Reactive Metabolite Syndrome
for causing liver injury. Several global organizations or
networks like DILIN, drug-induced liver injury genetics Examples of drugs causing RMS include sulfonamide,
network (DILIGEN) or Spanish hepatotoxicity registry are aminopenicillins, fluoroquinolones, clozapine, anti convuls
collecting genomic DNA from patients with signatory DILI ants (phenytoin, lamotrigine, carbamazepine, etc.),
caused by particular drugs. Therefore, in near future, we will minocycline, some NSAIDs and certain herbal medicines.
see interesting findings from the studies being done based on Risk factors for RMS include family history, in the presence
these registries. of glucocorticoids or valproic acid, initiation of new drug,
presence of autoimmune conditions with associated
autoimmune dysregulation (systemic lupus erythematosus)
CLINICAL AND LABORATORY FEATURES and HIV/AIDS. Reactive metabolite syndrome usually begins
before 12 weeks from the start of culprit drug, usually between
Clinical spectrum of DILI is characterized by the pattern of 2 weeks and 4 weeks. The features include fever, pharyngitis,
liver injury in the individual; these patterns are hepatocellular, malaise, periorbital edema, headache or otalgia, rhinorrhea
cholestatic or mixed type. These patterns cause characteristic and mouth ulcers. A severe drug eruption is an important
clinical, laboratory, and histological features. feature and usual as well. These erythematous reactions
sometimes may progress to toxic epidermal necrolysis
or erythema multiforme, and if associated with mucous
Clinical Features (Symptomatology) involvement, leads to Stevens-Johnsons syndrome. The
The symptomatology of DILI is highly variable and can typical hematological features include neutrophilia, atypical
manifest as symptoms of acute hepatitis like fatigue, nausea, lymphocytosis and eosinophilia along with the elevation
loss of appetite, upper abdomen pain, low grade fever, dark of acute phase reactants. Some other manifestations also
color urine, jaundice and pruritus. The difference between include lymphadenopathy, nephritis, pneumonitis and more
hepatocellular and cholestatic injury can be made based on severe hematologic abnormalities. The syndrome involves
clinical grounds, e.g. itching occurs early in the cholestatic the liver in only 13% of cases and can manifests as cholestasis,
pattern of DILI and occurs late in hepatocellular type of DILI. acute hepatitis and sometimes granuloma formation.
The hepatitis pattern of DILI is most commonly complicated
by ALF, which can be defined as coagulopathy (international Laboratory Features
normalized ratio >1.5) and hepatic encephalopathy occurring
26 weeks after the onset of illness in a patient without pre- According to the Council for International Organization of
existing CLD or cirrhosis. Drug-induced liver injury with ALF Medical Sciences (CIOMS), DILI is classified on the basis of
has particularly a bad prognosis without liver transplantation. transaminases and alkaline phosphatase into acute hepatitis,
The cholestatic pattern of DILI may be due to canalicular cholestasis or mixed pattern, and this schema has recently
cholestasis (bland cholestasis, i.e. histologically normal) been revised as follows:
ALT histologic feature of DILI is hepatic granuloma formation. No

specific drug culprit has been recognized for steatohepatitis,
ULN 5
1. Acute hepatitis pattern: ALT 3 ULN and liver fibrosis or hepatic tumors; however, sex steroids are
ALT
known to increase the vascularity of liver tumors and are
ULN
ALT
associated with sinusoidal dilatation or peliosis hepatis.

2. Cholestatic pattern: ALP 2 ULN and
ULN
2

ALT
Classification
ULN
Apart from the usual clinical pattern (hepatocellular,
3. Mixed pattern: ALT > 3 ULN and ALP >2 ULN and [(ALT/ cholestatic or mixed pattern), rarely DILI can also manifest
ULN)/(ALP/ULN) >25]. as granulomatous DILI, fibrosis, neoplasm, steatohepatitis
and vascular lesions. Hence, these are classified as shown in
Histological Features Table1 based on clinical, laboratory and histological features.
Histological features are the more accurate indicators of

DILI as compared to clinical and laboratory features because
these two features underestimate DILI. There are certain
DIAGNOSIS
features that suggest DILI on a liver biopsy and these include To establish a diagnosis of DILI is the most difficult task for
zonal necrosis or microvesicular steatosis, accompanying a physician because of the lack of specific diagnostic tests.
mitochondrial injury and mixed histologic features of This problem is further aggravated by multiple confounding
hepatocellular necrosis and cholestasis. Another common factors like lack of physician awareness, underreporting of
Table 1: DILI pattern and examples
DILI pattern Examples

Hepatitis
Immune-mediated (allergic) Allopurinol, diclofenac, halothane, methyldopa, minocycline, phenytoin, propylthiouracil, etc.
Nonimmune-mediated (nonallergic) Acarbose, amiodarone, bosentan, diclofenac, flutamide, HAART, statins, isoniazid, ketoconazole, labetalol,
leflunomide, methotrexate, paracetamol, pyrazinamide, rifampicin, troglitazone, sodium valproate,
zafirlukast, etc.
Cholestasis
Immune-mediated (allergic) ACE inhibitors, amitriptyline, amoxicillin/clavulanic acid, carbamazepine, chlorpromazine, cotrimoxazole,
erythromycins, phenobarbital, sulfonamides, tricyclic antidepressants, etc.
Nonimmune-mediated (nonallergic) Anabolic steroids, azathioprine, cyclosporine, estrogens, oral contraceptives, terbinafine, etc.
Fibrosis/cirrhosis Methotrexate
Granulomas (allergic) Allopurinol, amoxicillin/clavulanic acid, carbamazepine, hydralazine, methyldopa, penicillamine,
phenylbutazone, phenytoin, procainamide, quinidine, sulfonamides
Microvesicular steatosis NRTIs, sodium valproate
Neoplasms
Adenomas Anabolic steroids, oral contraceptives
Angiosarcoma Anabolic steroids
Cholangiocarcinoma Anabolic steroids
Hepatocellular cancer Anabolic steroids, danazol
Nonalcoholic steatohepatitis Amiodarone, tamoxifen, antipsychotics (insulin resistance)
Phospholipidosis Amiodarone
Vascular lesions
Budd-Chiari Oral contraceptives
Peiliosis hepatis Anabolic steroids, azathioprine, oral contraceptives
Perisinusoidal fibrosis Retinol (vitamin A), methotrexate
Veno-occlusive disease Busulfan, cyclophosphamide
Abbreviations: DILI, drug-induced liver injury; HAART, highly active antiretroviral therapy; ACE, angiotensin-converting enzyme; NRTIs,
nucleoside reverse transcriptase inhibitors
DILI and potential drug interactions to name a few. Therefore, be delayed for up to 1 year. This may be because of the slower
DILI is a diagnosis of exclusion in most cases, which requires regeneration of cholangiocytes as compared to hepatocytes.
certain things like suspicion for DILI, a well-elicited drug Therefore, patients with either mixed pattern or cholestatic
history and careful consideration of the temporal relationship pattern are more prone to develop CLD as compared to those
of the onset of DILI to initiation of the suspected drug. For with a hepatitis pattern of DILI. Improvement following
the clinician, diagnosing possible, probable or definite DILI dechallenge is not a reliable indicator of causality because
is more important than determining which of the candidate DILI might have reached its maximum intensity when the
drugs is the cause. Therefore, the diagnosis of DILI depends medication was stopped.
on multiple diagnostic elements for confirmation. These
include the following:
Time to onset (latency period) Risk Factors
Clinical features To determine the diagnosis and prognosis of DILI, it is
Time and course of recovery important to identify the risk factors (genetic and nongenetic)
Specific risk factors in a person suspected to have DILI. There are certain risk
Exclusion of other diagnosis factors, which predispose to DILI as mentioned in the
Previous reports on hepatotoxicity of suspected drugs earlier section of risk factors like age, sex, alcohol, comorbid
Liver biopsy condition and concurrent use of other drug. For example,
Rechallenge (in some cases, though generally not appro old age appears to be a risk factor for INH-induced DILI.
priate). Similarly, children are at risk of developing DILI typically
Reyes syndrome following aspirin use and also at risk of
valproate-induced DILI.
Latency Period
This is very difficult to define because timing of starting the
drug is quite often uncertain, symptoms are uncertain and Exclusion of Other Diagnosis
vague and are poorly remembered, and also laboratory So far there is no standardized diagnostic workup for the
tests are done at odd times, may be days or weeks after the diagnosis of DILI; however, it is the rule to exclude other
actual onset of DILI. This period is typically measured from causes of liver injury like viral hepatitis, metabolic causes,
the first day on which the suspected drug was taken to biliary diseases and autoimmune causes. Hence, workup
the day of onset of symptoms, jaundice or laboratory test of a patient with suspected DILI includes viral serology for
abnormalities, whichever comes first. However, latency hepatitis A, B, C, D and E viruses, autoimmune serology
period determination is important in making a diagnosis and (ANA, anti-dsDNA), metabolic workup for Wilsons disease,
decision making regarding the identification of culprit drug alpha-antitrypsin deficiency, hemochromatosis, hepatic and
from several medications like allopathic, herbals or dietary biliary imaging for excluding pancreatobiliary disease and to
supplements. help in excluding nonalcoholic fatty liver disease (Fig. 1).
Clinical Features Previous Reports of DILI

As described above in detail that clinical features determine This is an important element in determining DILI if there is
the clinical pattern of DILI, hence helpful in establishing the available literature regarding the suspected drug for causing
cause of DILI. DILI and whether the pattern of reported DILI by the drug
is similar to the current episode of DILI. Nevertheless, this
information is less reliable and hardly accessible because of
Time and Course of Recovery many reasons, e.g. many drugs do not have a signature DILI
The clinical course after drug withdrawal (dechallenge) is often pattern and in cases of rarely used or newly marketed drugs,
variable. It is expected in most cases that abnormal features the pattern of DILI caused by them is unknown. Typical
of DILI will improve after dechallenge (drug withdrawal), but examples of this would be herbal medications or dietary
in some of the cases DILI worsens for some time before any supplements where less literature is available. Finally many
improvement is apparent. The overall cholestatic pattern of of DILI-related cases are poorly reported. Hence, DILI experts
DILI resolves slowly as compared to hepatocellular pattern (DILIN initiative) have classified drugs with respect to their
and complete recovery from a cholestatic pattern of DILI may likelihood of causing DILI as shown in Table 2.
Fig. 1: Diagnosis of DILI

Abbreviations: DILI, drug-induced liver injury; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV,
hepatitis E virus; ETOH, ethanol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; US, ultrasound; CT, computed tomography;
MRCP, magnetic resonance cholangiopancreatography imaging; ERCP, endoscopic retrograde cholangiopancreatography; ANA, antinuclear
antibody; Anti-SMA, anti-smooth muscle antibody, TIBC, total iron-binding capacity; A1AT, alpha-1-antitrypsin antibody
Table 2: Classification of agent by likelihood of causing drug-induced severe consequences, such as mortality or severe permanent
liver injury disability. Nevertheless re-challenge can be tried if the initial
DILI has not caused a hypersensitivity reaction and has not
Grade Description Definition
caused severe DILI or if the agent is considered essential.
A Known At least 50 cases are reported in the literature,
Hence, careful rechallenge can be done for chemotherapeutic
some in case series (e.g. phenytoin, isoniazid and
amiodarone) or antituberculosis agents. Very rarely, rechallenge does not
lead to recurrence of DILI and this may be because of possible
B Rare There are at least 10 but lesser than 50 cases
in the literature, some in small case series (e.g. differences in the dose, concomitant medications or host
celecoxib, doxycycline, and atorvastatin) and/or environmental risk factors at the time of rechallenge.
C Very rare Agent has been rarely implicated in causing
hepatotoxicity, with lesser than 10 but at least
three convincing cases in the literature (e.g. Liver Biopsy
metformin and metronidazole)
Liver biopsy has been considered an important tool in
D Unproven Agent has been implicated in isolated case the diagnosis of difficult DILI cases, especially when the
reports as causing liver injury, but there are lesser
temporal relationship between drug ingestion of suspected
than three convincing cases in the literature (e.g.
vancomycin and theophylline) drug to cause DILI and onset of DILI is unclear. In fact, some
histological features like presence of eosinophils, granulomas,
E Not Agent has not been convincingly implicated
implicated in cases of liver injury (e.g. folic acid and zonal or massive necrosis and cholestasis with hepatitis may
hydrochlorothiazide) increase the index of suspicion of DILI; however, there are no
X Insufficient Agent has not been available for long enough or unique histological features that clearly confirm the presence
information used in enough patients to judge its hepatotoxic of DILI. Henceforth, prospective studies for the determination
potential (e.g. febuxostat, etravirine, and of liver biopsy in DILI are required.
iloperidone)
DETERMINANTS OF PROGNOSIS IN
Rechallenge
DRUG-INDUCED LIVER INJURY
This may be defined as either intentional or unintentional re-
exposure to the drug, which is suspected to have caused DILI Majority of the patients with acute DILI have a good prognosis
currently or previously. However, in practice, rechallenge if the offending drug is withdrawn on suspicion. However,
is rarely practiced because re-exposure can lead to very patients with concomitant jaundice or a predominantly
cholestatic pattern of DILI have a worse prognosis in terms MANAGEMENT AND TREATMENT
of morbidity and mortality as compared to patients without
jaundice. Prognosis is poor in patients who develop ALF and There is a little effective treatment available for cases of
do not undergo liver transplantation. Nevertheless, prognosis DILI except in cases of acetaminophen-induced DILI where
is better for the patients who develop paracetamol-induced there is effective therapy available, i.e. n-acetylcysteine
ALF than idiosyncratic DILI-induced ALF. (NAC). However, the foremost thing in the management
The concept of Hys law is very important to understand of DILI is to stop the offending drug and start symptomatic
when dealing with potential DILI cases, as this is being used and supportive treatment. Drug-induced liver injury would
by FDA and other regulatory agencies for drug monitoring recover spontaneously in majority of the patients, but
and postmarketing trials. This law indicates that mortality recovery is variable in different patients. In some patients, it
is around 1050% if DILI is associated with clinical jaundice may have prolonged course like in cholestatic pattern of DILI
and the serum bilirubin is 2.5 mg/dL or greater. This means and in some patients, DILI might lead to ALF. Since there is no
that DILI cases fulfilling Hys law in clinical drug trials are specific therapy for DILI as alluded to above, people had tried
considered to predict serious consequences postmarketing steroids in idiosyncratic type of DILI and ursodeoxycholic
phase of that particular drug. This law has been validated in acid (UDCA) in cholestatic pattern of DILI and some of the
the US, Sweden, and Spain. antioxidants. Literature regarding the role of these therapies
is controversial.
Severity Assessment of Drug-induced

Liver Injury (Grades) Role of Steroids in Drug-induced Liver
Drug-induced liver injury cases can be categorized as mild,
Injury
moderate, moderate-severe, severe and fatal as shown in Role of steroids is highlighted in published literature, i.e. case
Table 3 along with their definitions. reports or retrospective studies of idiosyncratic type of allergic
DILI with autoimmune features or hypersensitivity reactions.
For example, the use of steroids in phenytoin-induced DILI
leads to rapid improvement. There are also other examples in
Table 3: Grades of severity of drug-induced liver injury which role of steroids has been highlighted like for diclofenac,
sulfa-containing drug, methyldopa and propylthiouracil.
Grade Definition This existent literature is based on either case reports or
A Mild There are elevations in serum ALT and/or ALP levels, case series and lacks randomized case control trials, and it is
but the total serum bilirubin level is < 2.5 mg/dL and clearly not possible to do randomized control trial because of
INR is <1.5.
low incidence of DILI.
B Moderate There are elevations in serum ALT and/or AlP levels, Based on the available literature, recommendations
and the serum bilirubin level is > 2.5 mg/dL or INR is
cannot be made for or against the use of steroids for the
>1.5.
treatment of DILI. However, some authors do suggest that
C Moderate- There are elevations in serum ALT, ALP, and bilirubin
steroids can be tried for a brief period of time in few of the
severe or INR levels, and hospitalization or ongoing
hospitalization is prolonged because of a DILI episode. cases who had allergic features and are not improving on 45
days of withdrawal of the culprit drug.
D Severe There are elevations in serum ALT and/or ALP levels,
and the total serum bilirubin level is 2.5 mg/dL, and
there is at least one of the following:
Hepatic failure (INR 1.5, ascites or encephalopathy) Role of Ursodeoxycholic Acid in
Other organ failure believed to be due to a DILI Drug-induced Liver Injury
event (i.e. renal or pulmonary)
E Fatal Death or liver transplantation from DILI episode
(Cholestatic Pattern)
Abbreviations: DILI, drug-induced liver injury; ALT, alanine Ursodeoxycholic acid is a naturally occurring dihydroxy bile
aminotransferase; ALP, alkaline phosphatase; INR, international acid, which also has antioxidant properties and has a good
normalized ratio safety profile even in long-term use. This drug has been
effective in the treatment of primary biliary cirrhosis (PBC) Serial Liver Function Tests Monitoring
and probably in primary sclerosing cholangitis (PSC), but its
role is not established in PSC. This is an important issue in which whether serial monitoring
The proposed mechanism of action of UDCA in cholestatic of liver function tests helps in early detection of DILI or helpful
DILI is not clearly understood but it assumed that UDCA may in preventing DILI. This strategy is better for the patients who
prevent cholestatic damage by replacing toxic with nontoxic are on long-term therapy and on drugs, which can cause
bile acids by decreasing the histocompatibility antigens dose-dependent DILI. This is not a suitable strategy for drugs
displayed by hepatocytes or cholangiocytes, or by direct causing idiosyncratic DILI.
cytoprotective effects. Despite this theoretical basis for its
use, good evidence is lacking for UDCA as a treatment for
DILI of the cholestatic variety. The dose that has been used CONCLUSION
for cholestatic DILI is 1315 mg/kg body weight. Hence, it is
clear that there is no effective therapy for DILI, so we are left Drug-induced liver injury has been recognized as the most
with the strategy of prevention and early detection of DILI important health problem nowadays, causing acute as well as
as well as instant withdrawal of the culprit drug. Therefore, chronic liver disease. This entity has got many implications
early detection is very important and all patients who are for patients as well as healthcare providers along with drug
taking potentially hepatotoxic drugs should be warned that manufacturers. Most of the time, DILI presents in three
they immediately report any unexplained nausea/vomiting, different ways, i.e. hepatocellular (predominant elevation
right upper abdomen pain, malaise, lethargy or febrile of transaminases), cholestatic [predominant elevation of
illness. bilirubin, gamma-glutamyl transpeptidase (GGT) and ALP]
and mixed pattern. Overall prevalence of DILI ranges from
8% to 15% globally in different studies. It is either predictable
PREVENTION or unpredictable (idiosyncratic). Pathophysiology of DILI
involves the both biochemical and immunological mechanism
This strategy can be applied at various levels starting from the in causing liver damage. Idiosyncratic type of DILI had certain
drug development up to the clinical level as postmarketing risk factors like age, gender, daily dose, metabolic factors, etc.
surveillance. It shows a variety of clinical features, which include fatigue,
nausea, loss of appetite, upper abdomen pain, low grade
fever, dark color urine, yellow discoloration of skin (jaundice)
Drug Development and pruritus. Histological features, such as zonal necrosis or
This is the first step in the process of prevention of DILI and microvesicular steatosis accompanying mitochondrial injury
and mixed histologic features of hepatocellular necrosis
this process is achieved in the preclinical studies, especially in
and cholestasis are more accurate indicators of DILI. The
animal studies. These animal studies are helpful in predicting
diagnosis of DILI depends on multiple diagnostic elements
dose-related DILI as compared to idiosyncratic DILI. Phase1
for DILI confirmation and these elements are: time to onset
studies give the first chance to detect DILI in humans. In
(latency period), clinical features, time and course of recovery,
these phase 1 studies, few subjects (1530 participants) are
specific risk factors, exclusion of other diagnosis, previous
enrolled and subjected to a brief exposure with lower doses
reports on the hepatotoxicity of the suspected drugs, liver
of the investigational drug. Then comes the Phases 2 and 3 biopsy, rechallenge (in some cases though not appropriate).
efficacy and safety trials in which relatively larger doses are Prognosis is better if DILI is suspected early and the offending
to be administered to a larger group of participants. The drug is withdrawn immediately. Prognosis is usually bad in
most common example of drug withdrawal in this phase is those who develop ALF and do not undergo transplant and
troglitazone. also in those who develop cholestatic pattern. Severity of DILI
is categorized as mild, moderate, moderate-severe, severe
Postmarketing Monitoring and fatal. There is a little effective treatment available for
the cases of DILI except in cases of acetaminophen-induced
The Food and Drug Administration has launched a program DILI where there is effective therapy, i.e. NAC is available.
known as FDA MedWatch to determine DILI after the drug is Prevention is better and can be applied at various levels like
approved. from drug development to postmarketing.
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38
cHAPTER
Acute Liver Failure
Shivaram Prasad Singh, Parimal Lawate
INTRODUCTION existing cirrhosis and with an illness of duration of less than

26 weeks.
Acute liver failure (ALF) is a rare but catastrophic disorder, By definition, the liver should be previously healthy for
which can kill up to 80% of patients who do not receive a diagnosing ALF. There are, however, certain instances where
liver transplant or appropriate treatment. The starting event there may be unrecognized, asymptomatic preexisting
is rapidly progressive liver cell death with development chronic liver disease. Examples include acute exacerbation
of encephalopathy, coagulopathy and jaundice, which of hepatitis B, fulminant presentation of Wilsons disease
evolves into a multisystem disease with multiorgan failure. and some cases of autoimmune hepatitis. In these situations,
The clinical syndrome remains the same irrespective of attention should also be drawn to the entity of acute on
the etiology. Management of ALF includes identification chronic liver failure (ACLF), which can present as ALF.
of treatable causes, multidisciplinary supportive care and In children, encephalopathy may develop late in the
identification of patients who would benefit from liver course of disease or may sometimes be absent. The definition
transplantation. Appropriate and timely referral of these of ALF in children does not include encephalopathy, but
patients to a transplant center is important. coagulopathy due to liver injury is an essential component.
DEFINITION SUBCLASSIFICATION OF ACUTE LIVER

The first definition of ALF was by Trey and Davidson who FAILURE
termed it as fulminant hepatic failure (FHF). They defined
FHF as potentially reversible condition, the consequence of It was recognized for long that the duration between the onset
severe liver injury, with an onset of encephalopathy within 8 of jaundice and encephalopathy had an important bearing on
weeks of the appearance of first symptoms and in the absence mortality and prognosis. Reviewing 538 patients seen at the
of pre-existing liver disease. The American Association Liver Failure Unit of Kings College, London, OGrady et al.
for the Study of Liver Disease (AASLD) guidelines (2005) proposed categorizing ALF into three categories as shown in
have defined ALF as evidence of coagulopathy [usually an Table 1.
international normalized ratio (INR) 1.5] and any degree of Various groups have proposed varying definitions of ALF,
mental alteration (encephalopathy) in a patient without pre- and these have been summarized in Table 2.
Table 1: Subcategories of acute liver failure based on the interval between onset of jaundice and encephalopathy
Category Definition (jaundice to encephalopathy interval) Mortality

Hyperacute Within 7 days 35
Acute Within 828 days 7
Subacute Interval >28 days 14
Acute Liver Failure 347
Table 2: Different definitions of ALF by various workers
Trey and Davidson FHF: Development of HE within 8 weeks of the onset of symptoms
England ALF (includes only patients with encephalopathy): Subclassified on the basis of jaundice-HE interval
Hyperacute liver failure: 07 days
ALF: 828 days
Subacute liver failure: 2972 days
Late-onset ALF: 56182 days
France Acute hepatic failure: A rapidly developing impairment of liver function
Severe acute hepatic failure: Prothrombin time or factor V concentration below 50% of normal with or without HE.
Subclassification:
FHF: HE within 2 weeks of the onset of jaundice
Subfulminant hepatic failure: HE within 312 weeks of the onset of jaundice
IASL ALF (HE within 4 weeks of the onset of symptoms)
Subclassification:
ALF-hyperacute within 10 days
ALF-fulminant 1030 days
ALF not otherwise specified
Subacute liver failure (development of ascites and/or HE from 5 to 24 weeks after the onset of symptoms)
Subclassification by etiology:
Hepatitis A to E
Other viruses
Other
Not known
Abbreviations: ALF, acute liver failure; HE, hepatic encephalopathy; FHF, fulminant hepatic failure; IASL, International Association for the Study
of the Liver
ETIOLOGY development of ALF in HAV but also increase the mortality.

Studies have also shown an increased risk in homosexuals
Acute liver failure is a heterogeneous disorder with marked and intravenous drug users (IVDU). Preexisting liver disease,
geographical variation in etiology. While paracetamol and in particular hepatitis C virus (HCV) infection increases the
drugs are common causes in the West, viral hepatitis is the risk. The diagnosis is made on the basis of a positive IgM anti-
dominant cause in Eastern countries. HAV serology. Acute liver failure is generally seen in the first
Table 3 shows the geographic variation in etiology of ALF week after the onset of acute hepatitis A, and 90% of those
as reported in many large studies. patients who develop ALF due to HAV do so by 4 weeks.
Various series from India have described the causes for ALF Hepatitis B virus (HBV) is the most common cause for ALF
with a predominance of viral hepatitis. These are summarized in many parts of the world. However, in absolute terms, the
in Table 4. risk of developing ALF during acute hepatitis B is low (around
1%). In many patients, it may be difficult to differentiate a flare
The first five alphabets of the English language
of chronic hepatitis B (presenting as ALF) from an episode of
comprehensively summarize the etiology of ALF as shown in
acute hepatitis B causing ALF. In various Indian series, the
Table 5.
prevalence of HBV as a cause for ALF varies from 11 to 27%.
In HBV-related ALF, the body mounts a vigorous immune
Hepatotropic Viruses response to clear the virus-infected hepatocytes and viral
markers may therefore be negative. If HBV is suspected as a
All commonly recognized hepatitis viruses are known to cause for ALF in patients who are hepatitis B surface antigen
cause ALF. The risk of developing ALF and the clinical course (HBsAg) negative, indirect evidence of acute infection,
may depend on several variables including the hepatitis virus, including IgM anti-HBC and HBV DNA (qualitative) can lead
viral subtype, age, comorbidities and concomitant alcohol to a diagnosis of HBV ALF. There are reports suggesting that
intake. the precore mutants of HBV, which have a point mutation
Hepatitis A virus (HAV) is a common cause of ALF in at nucleotide position 1896 in precore region that prevents
northwestern Europe, where up to 2031% patients with secretion of hepatitis Be-antigen (HBeAg) are associated with
ALF are positive for IgM anti-HAV. Associated alcohol intake ALF. Older patients and women are at an increased risk of
and increasing age (>40 years) not only increase the risk of developing ALF due to HBV.
Table 3: Worldwide distribution of causes of ALF based on large series
Country Year No. of patients HBV HAV Other viruses Acetaminophen Drugs/toxins Misc. Indeterminate Authors
Spain 1993 62 42 2 NR 0 8 6 44 Castells et al.
US 1994 459 22.9 6.1 1.5 4.6 10.6 NR 29.9 Detre et al.
1994 115 19 NR 34 NR 14 2 31 Dodson et al.
1994 148 (children) 4.1 10.1 NR 2 8 2 73.6 Detre et al.
UK 1994 1257 7.5 4.8 0.4 60.9 6.1 6.8 16 Williams and Wendon
US 1995 60 15 8 0 18 15 5 38 Hoofnagle et al.
UK 1996 342 24 24 NR 73 26 11.4 8.2 Williams
India 1996 423 28 1.7 13 0 45 0 53 Acharya et al.
US 1999 295 10 7 NR 20 12 NR 15 Schlodt et al.
Nordic 2002 315 8 2 2 17 12 17 43 Brandsaeter et al.
countries
Abbreviations: ALF, acute liver failure; HBV, hepatitis B virus; HAV, hepatitis A virus; NR, not reported
Table 4: Etiology of ALF in India
Center Year No. of patients Hepatitis viruses Drugs Others

Indore 1996 95 100% 0% NR
Kashmir 1997 119 99% 1% NR
Chandigarh 1998 204 91% 7.4% 1.5%
Delhi 2000 458 95% 4.6% 0.4%
Total 876 97% 2.5% 0.5%
Viral hepatitis causes death in greater than 90%; therefore, ALF patients are an etiologically homogenous population
Abbreviations: ALF, acute liver failure; NR, not reported
Table 5: The first five alphabets of the English language summarizing parts of Africa. However, HDV is an extremely unusual
the etiology of acute liver failure (ALF) cause for ALF in eastern countries. In areas with a high HDV
prevalence, both types of HDV infection, namely coinfection
Alphabet Etiology
and superinfection can cause ALF. The risk is much higher in
A Hepatitis A, autoimmune patients who have a superinfection. The mortality in these
B Hepatitis B, Budd-Chiari, blood supply related patients can be very high (up to 20%). The risk is also higher
C Hepatitis C, childbirth related, cryptogenic in IVDU patients with HDV.
D Hepatitis D, drugs
Hepatitis E virus (HEV) is the most common viral cause for
ALF in India where it accounts for 2341% of patients with ALF.
E Hepatitis E, errors of metabolism
It is also the most common cause for ALF in Pakistan, China,
Southeast Asia, and Bangladesh. Unlike HAV, there is no
increase in the risk associated with increasing age. Hepatitis
Hepatitis C virus is an unusual cause for ALF in most parts E virus genotype 1, which is the most common genotype in
of the world. However, in Japan and Taiwan, HCV positivity endemic areas, appears to be more pathogenic in humans.
is found in up to 60% of patients with ALF. There are reports Genotypes 3 and 4 cause ALF less frequently while genotype
from Los Angeles on Hispanics from low socioeconomic 2 is not known to cause ALF. There is recent evidence of an
status in which 60% of patients with ALF may have HCV as the increasing prevalence of hepatitis E-related ALF in the West.
cause. There is an increased risk of ALF in hepatitis C infected This could be related to porcine exposure and international
patients who have coinfection with human immunodeficiency travel from endemic areas. It has very recently been shown
virus (HIV). that in the United States, some patients diagnosed as drug-
Hepatitis D virus (HDV) is the most common cause of induced ALF may in fact have HEV-related ALF when tested
ALF in Mediterranean, Middle East countries and some for HEV.
Pregnancy appears to increase the case fatality rate in Nonviral Tropical Infections
HEV, although the reasons for this are not clear. Alterations
in humoral and immune factors may contribute to this. The Dengue, Plasmodium falciparum, leptospirosis, rickettsial
increased severity of HEV in pregnancy has been reported fever and typhoid fever in their complicated form can present
from India but is not found in other geographical areas, such as ALF. Up to 90% of patients with dengue can have mild
as Egypt. Differences in strain virulence could contribute to alterations in transaminases with higher levels of aspartate
this variation. There is ongoing controversy about the reported aminotransferase (AST). Cases of dengue-associated ALF
increase in mortality from HEV-associated ALF in pregnancy have been described from Latin America, Thailand, India
in India. A recent series has suggested that pregnancy might and Pacific islands. Dengue virus can lead to liver damage
not adversely affect the outcome of liver failure in HEV. It is due to replication in liver cells with hepatocyte damage and
likely that the high mortality projected earlier was related to development of councilman bodies.
increased infection rates in pregnant women. In pregnant
females with HEV-related ALF, there is up to 40% chance
of transmitting the disease to neonates. Hepatitis E virus
Pregnancy-related Acute Liver Failure
infection is commonly transmitted from mother to fetus. This There are five liver diseases, which are specific for pregnancy.
results in high neonatal mortality. In the surviving neonates, Two of these, intrahepatic cholestasis and hyperemesis
HEV infection is self-limiting with short-lasting viremia. The gravidarium are not associated with preeclampsia. Three of
presence of IgM anti-HEV confirms the diagnosis of HEV ALF. them are associated with preeclampsia: (i) HELLP (hemolysis,
Non-AE hepatitis (NANE) is a condition where all viral elevated liver enzymes, and low platelets), (ii) eclampsia, and
markers for hepatitis are negative. In India, 1547% of ALF (iii) acute fatty liver of pregnancy (AFLP).
cases come under the category NANE ALF, and the viruses Acute fatty liver of pregnancy begins in the third trimester
implicated in this group of patients were GB virus Chepatitis and is more common in primigravidae, twin pregnancies and
G virus (globally distributed RNA flavivirus), torque teno virus those with male fetuses. Even in pregnancy, it is an unusual
(TTV; parenterally transmitted circovirus) and SEN virus cause for ALF. In a recent study from India, 249 pregnant
(found in IVDU patients with human immunodeficiency). women with ALF were studied over a period of 20 years and
However, current evidence suggests that these viruses are not the causes were as follows: HAV (0.8%), acute HBV (2.9%),
responsible for ALF. The cause for ALF in NANE hepatitis ALF HEV (59.4%), dual acute: two viral markers positive (1.6%),
remains unknown. Inadequate etiologic assessment and false only chronic markers (4.9%), drugs and toxins (2.5%), while
negative tests (depending on the assay used) could contribute 27.9% had a negative etiologic evaluation. Thus, HEV accounts
to some of the presumed NANE hepatitis cases. Table 6 for more than half of ALF as compared to nonpregnant
summarizes various features of ALF caused by hepatotropic females, and men and boys. In this series, pregnant patients
viruses. were younger than nonpregnant patients with ALF.
Table 6: Characteristics of ALF in hepatotropic viral hepatitis
Feature HAV HBV HCV HDV HEV

Risk of ALF Up to 0.1% 1% Rare Coinfection: 110% Up to 20% in pregnancy
Superinfection: 520%
Clincal Hyperacute Hyperacute or acute ? Subacute Acute Acute
course
Risk factors Age > 40 Females Coinfection Chronic HBV Pregnancy
IVDU Older age HBV
Alcohol Immune suppression
Spontaneous survival 4060% 1539% ? 3145% Up to 80%
Diagnostic tests IgM anti-HAV IgM anti-HBc HCV RNA IgM HDV IgM anti-HEV
HBsAg Anti-HCV IgM anti- HBC
HBV DNA
Abbreviations: ALF, acute liver failure; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis
E virus; IVDU, intravenous drug users; HBc, hepatitis B core antigen; HBsAg, hepatitis B surface antigen
Metabolic Disorders imine (NAPQI). At the usual therapeutic dose, up to 90%

acetaminophen is metabolized in the liver to glucuronide
Wilsons disease is an uncommon cause for ALF (23%) in and sulfate conjugates, which are excreted in the urine. The
the US, and is even less common in Eastern series. Acute liver remainder drug is either excreted unchanged in the urine or
failure due to Wilsons disease is considered uniformly fatal converted via cytochrome P450 pathway into a hepatotoxic
without transplantation. Although labeled as ALF, almost all metabolite, NAPQI. The small amount of NAPQI that is
patients with Wilsons disease ALF actually have underlying produced at therapeutic doses is conjugated with glutathione
cirrhosis, which may explain the uniformly high mortality. and excreted in the urine. In toxic doses of acetaminophen,
Diagnosis of Wilsons disease in the setting of ALF is difficult. the sulfation and glucuronidation pathways are overwhelmed
Pointers toward Wilsons disease are young age, evidence of and more of the drug is metabolized by the cytochrome P450
hemolysis and low serum ceruloplasmin (about 15% may pathway to NAPQI.
have a normal ceruloplasmin). High urinary and serum Increased formation of NAPQI can occur in conditions
copper may confirm the diagnosis. If facilities are available, inducing cytochrome P450 (chronic alcohol ingestion,
a transjugular liver biopsy showing a high liver copper may antiepileptic therapy, isoniazid), those depleting glutathione
be an option for confirming the diagnosis. Another indicator (fasting, malnutrition, chronic alcohol ingestion) or those
may be a high bilirubin (mg/dL) to alkaline phosphatase competing with glucuronidation pathways (zidovudine).
(IU/L) ratio (> 2.0). After ingestion of toxic doses of paracetamol, ALF develops
within 1272 hours. Initial symptoms can be nonspecific.
Biochemistry reveals extremely high transaminases and
Drug-induced Acute Liver Failure mildly elevated bilirubin at presentation.
Drugs are the common causes for ALF. The spectrum of drugs
varies between countries and also within a country. Herbal
hepatotoxicity is being increasingly recognized as a cause for Antitubercular treatment-induced Acute
ALF. The use of these drugs might not be reported by patients Liver Failure
unless specifically questioned, and no systemic evaluation
reports on toxicity of these drugs are generally available. Antitubercular treatment-induced acute liver failure (ATT-
A recent review of drug-induced ALF from the US reviewed ALF) is the most common cause for drug-induced ALF in
a total of 1,198 subjects with ALF from 23 sites in the US. Of the east. In a recent large series of 1,223 consecutive patients
these, 11.1% were considered to have drug-induced ALF. It with ALF reported from India, 5.7% patients had ATT as the
was more common in women, and antimicrobials were the sole cause for ALF, while in 1.2% there was simultaneous viral
most common cause. hepatitis. There can be variations within a country. A series
Drugs can cause ALF in a dose-dependent fashion or as of drug-induced hepatitis from Southern India reported
an idiosyncratic reaction. The former is generally hyperacute ALF due to many drugs other than ATT. Most patients had a
and has better chances of nontransplant survival. The latter hyperacute presentation with an average of 30 days duration of
presents in a subacute form and has a very poor nontransplant ATT prior to onset of ALF. Of the first line ATT drugs, isoniazid,
outcome. Paracetamol is the most common cause of ALF in rifampicin and pyrazinamide have well documented
the West. On the contrary, in the East, antitubercular drugs hepatotoxicity ranging from a mild asymptomatic elevation of
are the most common causes of drug-induced ALF. transaminases to ALF. Patients with ALF often show relatively
modest elevations of transaminases. Several factors increase
the risk of ATT hepatotoxicity. These include increasing age,
Paracetamol-induced Liver injury female sex, alcohol intake and malnutrition. Decompensated
Paracetamol (acetaminophen) causes injury in a dose- liver disease also increases the risk of ATT hepatotoxicity.
dependent manner. The toxic dose is high and injury is likely An important step in isoniazid metabolism is acetylation.
to occur when amounts ingested are greater than 250 mg/ Acetylator status divides patients into fast or slow acetylators.
kg in children and over 12 grams in 24 hours in adults. The There has been controversy whether fast or slow acetylators
percentage of patients who develop acute liver toxicity after are at a greater risk of hepatotoxicity. It is now accepted that
ingestion of a toxic dose is probably about 5%. The use of in slow acetylators, isoniazid metabolism is shifted to the
therapeutic doses of paracetamol in patients with chronic harmful pathway that favors production of hydrazine and its
liver disease is not associated with the risk of hepatotoxicity. toxic metabolites. About 20% of Asians and more than 50%
Paracetamol itself is not toxic and the cellular injury is black people are slow acetylators and are at an increased risk.
caused by an unstable metabolite N-acetyl-p-benzoquinone Preexisting HBV but not HCV infection may increase the risk.
Cardiovascular Causes of Acute liver failure leads to several metabolic alterations

including propensity for hypoglycemia due to depleted
Acute Liver Failure hepatic glycogen stores and failure of gluconeogenesis. A
Severe hypotension can lead to ischemic hepatopathy catabolic state results in protein breakdown and relative
with transaminases in the range of 10,000 IU/L with the decrease in branched chain amino acid (BCAA) levels. Free
AST more than alanine transaminase (ALT); however, fatty acid levels are increased due to decreased lipogenesis
presentation as ALF is rare despite the striking elevations in and increased peripheral lipolysis.
transaminases. Extensive metastatic malignancy in the liver
and lymphomatous involvement can also present as ALF. The
clinical picture and imaging findings are diagnostic in these CLINICAL FEATURES AND EVALUATION
patients.
All patients with ALF should be evaluated with a detailed
history taking and careful clinical examination. Laboratory
PATHOPHYSIOLOGY tests are done to assess for coagulopathy, to ascertain the
cause for ALF and for prognostication. In many patients,
Failure of liver function leads to important consequences as the initial clinical features may be nonspecific and include
shown in Figure 1. Failure of hepatobiliary excretory function anorexia, fatigue, abdominal pain, fever, and jaundice.
causes hyperbilirubinemia. This is more marked in patients History should include careful review of possible exposure
with Wilsons disease (with hemolysis) and in those with to infections, toxins and drugs. Family history of liver disease,
associated glucose-6-phosphate dehydrogenase (G6PD) past history to suggest liver disease, travel to endemic areas
deficiency. and history of epidemics of liver disease in the patients
Failure to metabolize ammonia leads to hepatic residential area should be specifically asked for. In the
encephalopathy, while alterations in xenobiotic metabolism recently returned traveler from the tropics, tropical infections
lead to alterations in drug metabolism. In some patients, should be borne in mind (these include HEV, malaria, dengue,
associated renal failure can add to the toxicity of drugs. leptospira and yellow fever). Drug history can be particularly
Failure of synthetic function results in coagulopathy. difficult to obtain. Quite often patients may not mention
Factors V and VII have the shortest half lives and are the drugs taken by them including over the counter medicines
earliest to be affected. and herbal medicines taken for the jaundice itself or for some
other illness. Review of prescriptions can be helpful in these
situations. Herbal preparations are generally considered
safe by patients, and history of having consumed these is
particularly difficult to obtain.
Physical examination should be carried out to assess for the
presence of jaundice, to assess mental status and to look for
evident signs of coagulopathy. Liver size should be assessed
by percussion. An enlarged liver is uncommon in ALF, but a
slightly enlarged liver may be seen in the initial stages of acute
viral hepatitis. A significantly enlarged liver may point toward
congestive hepatomegaly from a cardiac cause, Budd-Chiari
syndrome or an infiltrative disorder.
Systemic evaluation helps in assessing involvement of
other organ systems in ALF. A thorough evaluation should be
done to elicit signs of chronic liver disease. Features of chronic
liver disease will lead to a diagnosis of acute on chronic liver
disease and not ALF. The prognostic criteria described for
ALF will not apply to this group of patients.
Signs of hepatic encephalopathy should be sought for. The
West Haven grading is commonly used for assessing patients.
Not only the presence of hepatic encephalopathy is the sine
qua non for the diagnosis of ALF, but planning for transfer to
a transplant center should begin in patients with Grade I or II
Fig. 1: Pathophysiology of acute liver failure encephalopathy as they may worsen rapidly. Increasing grades
Table 7: West Haven grading of hepatic encephalopathy
Grade Mental status Neurologic signs EEG GCS

I Lack of awareness, euphoria, anxiety, shortened attention span, Slight tremor, apraxia, incoordination Normal 15
impaired addition/subtraction
II Lethargy, apathy, disorientation for time, inappropriate behavior, Asterexis, dysarthria, ataxia Generalized slowing 1115
personality change
III Somnolence, semistuporose, gross disorientation, responsive to stimuli Asterexis, ataxia Abnormal 811
IV Coma Decerebration Abnormal <8
Abbreviations: EEG, electroencephalogram; GCS, Glasgow coma scale
of encephalopathy are associated with worse outcomes. The Nutritional management is aimed at prevention of
standard classification of hepatic encephalopathy is shown in hypoglycemia and providing adequate calories as ALF is a
Table 7. catabolic state. Nasogastric feeding is recommended. About
2530 cal/kg/day and 11.5 gm/kg proteins are recommended.
Vegetable proteins do not exacerbate encephalopathy.
DIAGNOSTIC EVALULATION IN ACUTE Branched chain amino acid supplementation is recommended
but the evidence for this is limited. These can be administered
LIVER FAILURE intravenously in the form of an 8% solution, which contains
Diagnostic evaluation in ALF is done with various aims in greater than 40% BCAA. Branched chain amino acid enriched
mind: to find the etiology, to look for complications related enteral feeds or sachets with BCAA could be used through
to ALF, to prognosticate, to assess possible contraindications nasogastric tube. Excessive glutamine supplementation
to transplantation (e.g. ALF related to rapidly progressive should be avoided. Hypoglycemia is common in patients
metastatic malignancy in the liver). It is important to with ALF. Glucose can be given by infusion (1.52.0 g/kg/day)
determine the etiology of ALF as this helps in removing the in patients who develop hypoglycemia. Close monitoring
inciting agent and giving specific treatment when possible. It (finger-stick evaluation of glucose every 12 hours) is
also helps in assessing prognosis as prognosis varies with the necessary to keep glucose levels between 80 mg/dL and
etiology of ALF. 150 mg/dL. Diabetics with ALF should be supplemented
with appropriate doses of insulin generally by syringe pump
infusion.
Agitation can exacerbate intracranial pressure (ICP).
MANAGEMENT Adequate and judicious sedation is required for such patients
Patients with features of ALF should be admitted to an as well as those who are intubated and have multiple lines.
intensive care unit (ICU). In peripheral centers, it may be There is no guideline available for the choice of agents.
important to ensure that the ICU residents and staff are Propofol and benzodiazepines can both be used but can
familiar with management issues related to ICU care of the worsen hepatic encephalopathy by increasing the gamma
ALF patient. ICU care involves monitoring of the patient, aminobutyric acid neurotransmission. Propofol may be
treatment and prevention of complications, supportive preferred due to its shorter half life and ability to decrease
care, early identification and treatment of treatable causes cerebral blood flow (CBF) and ICP. The dose should not
of ALF and identification of patients who require liver exceed 5 mg/kg/hour to prevent development of propofol
transplantation. Other than medical and paramedical infusion syndrome. Opiates, especially morphine and
personnel, a nutritionist, social worker and transplant meperidine should be avoided. Fentanyl could be considered
coordinator should also be involved. due to shorter half life. Flumazenil if available can be used
to reverse the action of benzodiazepines. Particular care
should be taken in patients with renal failure because these
General Supportive Care patients can have accumulation of metabolites of these drugs
Supportive care includes nursing, nutritional management and decreased threshold for seizures. Sedation can make
and strict asepsis during procedures. neurologic assessment difficult. Shorter-acting agents are
therefore preferred. Agitated patients should preferably be and cyclic guanosine monophosphate (cGMP) are increased in the
intubated, sedated as required and mechanically ventilated. later stages of the disease, these have not been implicated as the
initiating trigger in these patients. Relative adrenal insufficiency
can be a contributor in some patients (hepatoadrenal syndrome). A
Management of Sepsis rapid adrenocorticotropic hormone (ACTH) stimulation test may
Almost 80% of patients with ALF develop infections during be considered in patients with large volume requirements or those
the course of their illness. Importantly, the presence of with resistant hypotension. Although insufficient evidence exists,
infections may preclude transplant in up to one-fourth of such such patients can be considered for treatment with corticosteroids.
patients and cause death in up to 40% patients. Clinically, A complicating factor in these patients is the loss of CBF
they present as bacteremia, pneumonia and urinary tract autoregulation. In normal individuals, the CBF is maintained
infections. Factors that cause sepsis are iatrogenic factors in a narrow range despite wide fluctuation (upwards or
and a state of immune paralysis, which is supposed to occur downwards) in the systemic blood pressure. Treating
in ALF. Iatrogenic factors include multiple intravascular hypotension in these patients can therefore be tricky,
lines, urinary catheterization and use of acid suppressive and overenthusiastic efforts at normalizing the systemic
therapy. Deranged immune function has been documented blood pressure can lead to a potential increase in CBF and
due, in part, to Kupffer cell dysfunction and Kupffer cell consequent increase in ICP. Cerebral perfusion pressure
loss in ALF. Translocation of bacteria from the gut has been (CPP) is defined as the difference between MAP and ICP. A
postulated. Besides, neutrophil function is also impaired in CPP greater than 60 is considered important to maintain
ALF. Organisms commonly found are gram-negative enteric normal neurologic functioning. In fact, at a few centers, a CPP
bacilli, Streptococcus and Staphylococcus. Fungal infections less than 40 for over 2 hours is considered as a contraindication
especially Candida are found in up to one-third patients. for transplantation.
Aspergillus infections have also been reported. Fungal
infections manifest later during the course and present as
fever and leukocytosis, unresponsive to antibiotics.
Monitoring
The parameters to be monitored in patients with ALF include
blood pressure, central venous pressure (CVP) and oxygen
Antibiotics with Broad Coverage, such as saturation and urine output. If facilities are available, pulse
Third Generation contour analysis can be used for hemodynamic monitoring.
It is desirable to maintain a MAP of 65 mm Hg, a cardiac index
Cephalosporins or piperacillin and tazobactam should be
of over 3.5 L/min/m2.
used. The role of routine prophylactic antibiotics is uncertain.
The spectrum of organisms and antibiotic policies vary
in individual centers and the antibiotic choice should be Fluids
dictated by local sensitivity patterns. Culture reports can help
in guiding changes in antibiotic choices. In the absence of There is no controlled data on the type of fluid used but a
positive cultures, antibiotics are generally recommended in all combination of crystalloids and colloids is generally used.
patients with ALF. Antifungal treatment may be considered in Use of 5% dextrose alone can aggravate hyponatremia.
patients with renal failure, prior antibiotic treatment, features
of progressive worsening clinical status due to ongoing sepsis, Vasopressors
especially later in the course of illness.
Although there are no controlled data on the choice of
vasopressors, noradrenaline is generally considered the
Hemodynamic Monitoring and preferred vasodilator. Vasopressin, which is used for severe
Treatment sepsis, is a powerful vasoconstrictor that acts through
V1 (which mediates vasoconstriction and are present in
Acute liver failure is characterized by multiorgan failure and a the systemic circulation) and V2 receptors (which are
hyperdynamic circulation. There is generalized vasodilatation present in the cerebral vascular bed and mediate cerebral
(unlike predominantly splanchnic vasodilatation in cirrhosis), vasodilatation). The analog of vasopressin, terlipressin, has
hypotension and low mean arterial pressure (MAP). Hypovolemia been used in a pilot study of ALF but was found to increase
is common in these patients due to poor oral intake and vomiting. the CBF and ICP possibly through its action on V2 receptors.
The cause for these changes is multifactorial. The exact However, this drug should be used with extreme caution in
mechanisms have not been elucidated, and although nitric oxide patients with ALF.
Pathogenesis and Treatment of Hepatic signs appear late in the course. Computed tomography (CT)
scanning and magnetic resonance imaging (MRI) are not very
Encephalopathy reliable for diagnosing increased ICP as they can only detect
The metabolism of ammonia is complex and involves mainly cerebral edema. The most accurate method of diagnosis is
four organs. These organs: gut, liver, kidney and muscle are ICP monitoring. This however remains controversial as the
important in the metabolism of ammonia. Forty percent of advantages of monitoring ICP have not been documented
ammonia is generated by the intestine from nitrogenous in a randomized controlled trial, the treatment goals have
substances caused by the action of bacterial urease and not been well defined and there is risk of hemorrhage and
amino acid oxidases, and the other 60% is derived from the infection. There are studies which show that prolonged high
metabolism of glutamine and transamination of other amino ICP (25 mm Hg) along with low CPP (<50 mm Hg) for over 2
acids. hours may preclude neurologic recovery and some of these
patients may therefore do badly despite liver transplantation.
The goal of treatment of cerebral edema is to reduce
Intracranial Hypertension in the brain volume or CBF. Treatment measures include
Acute Liver Failure nonpharmacologic and pharmacologic measures. Nonph
armacologic interventions are elevating the head end to up
The normal ICP is 510 mm Hg. An ICP exceeding 20 mm to 30, appropriated sedation especially in agitated patients,
Hg ICP is clinically significant. This rise in ICP occurs as a nursing the patient in a quiet area and avoiding unnecessary
consequence of increase in the intracranial volume. The stimulation. Hyperventilation can cause a transient restoration
three components that contribute to the intracranial volume of CBF autoregulation by lowering the paCO2. Its prolonged use
are brain, cerebrospinal fluid (CSF) and blood volume. An is not advocated. Hypothermia has been shown to be effective
increase in the volume of any of these leads to increased ICP. in some studies.
Of the three components, increased brain volume as a result Pharmacologic measures include use of mannitol and/or
of astrocyte swelling is a major contributor to increased ICP. hypertonic saline. These agents increase the blood osmolality
Astrocytes occupy about one-third of the cortex and have and thereby draw water from the swollen astrocytes into the
a role in water regulation in the brain as well as ammonia intravascular space. Mannitol is given in doses of 1g/kg body
detoxification. The latter is achieved by conversion of weight and is generally effective in reducing ICP in patients
ammonia to glutamine by amidation of glutamate by with mild to moderate increase in ICP.
glutamine synthetase (which is an astrocytic enzyme).
Glutamine is the most important organic osmolyte and its
buildup in the astrocyte leads to astrocyte swelling. It is also Respiratory Complications
believed to alter the mitochondrial membrane function
Respiratory complications include fluid overload, acute
causing dysfunction of membrane ion pumps.
lung injury progressing to adult respiratory distress
Increased cerebral blood flow as a consequence of
syndrome and infections related to ventilation. Mechanical
impaired vascular autoregulation is the other important
ventilation is required in all patients with grade III and IV
contributor to increased ICP. The cause for increased CBF
encephalopathy, those with hypoxia and hypercapnia.
is not clear. Nitric oxide and toxic products from the acutely
Transient propofol administration during endotracheal
necrotic liver (leading to vasodilatation) are postulated
intubation should be considered to prevent increased
mechanisms.
ICP, which occurs during these procedures. There are no
Risk factors correlated with the development of cerebral
guidelines on the mode of mechanical ventilation to be
edema include hyperacute liver failure, high serum ammonia
used. Low tidal volumes (6 mL/kg) should be used and
concentrations, need for vasopressor, renal support and the
the lowest levels of positive end-expiratory pressure which
development of sepsis.
attains adequate oxygenation should be used. Hypercapnia
causes increase in ICP and should be maintained at around
Diagnosis of Intracranial Hypertension in 35 mm Hg. If an ICP monitor is used, hyperventilation can be
used to titrate the pCO2 and ICP. Neuromuscular blockade
Acute Liver Failure with nondepolarizing agent, cis-atracurium, should be
Intracranial hypertension can be suspected clinically in considered as its metabolism is independent of hepatic and
patients with ALF by the presence of bradycardia, pupillary renal function. Succinylcholine, a polarizing neuromuscular
signs, signs of decerebration or sustained (>160 mm Hg) or blocking agent, should be avoided as it can cause muscular
paroxysmal (>200 mm Hg) hypertension. However, these contraction and increase ICP.
Renal Failure Clinically evident bleeding manifests as gastrointestinal

bleeding, bleed from the nasopharynx and sometimes as
Renal failure occurs in over half of the patients with ALF. intracranial bleed especially in patients who are undergoing
Some etiologic agents including drugs, such as paracetamol, ICP monitoring. Bleeding can occur spontaneously, during
halothane and sulfonamides, toxins, such as amanita, and invasive procedures or during or after liver transplantation.
certain infections such as dengue and leptospirosis are by Laboratory monitoring is done with hemoglobin, platelet
themselves associated with renal failure. counts, prothrombin time and INR. Factor V has the
About half to three-fourths of patients with paracetamol- shortest half life amongst clotting factors synthesized by
induced ALF develop renal failure. The degree of paracetamol- the liver. Monitoring levels of factor V has been suggested
induced renal injury may or may not correlate with liver as an indicator for liver transplant by the Clichy criteria. A
injury. It is probably derived from liver-derived reactive recent study classified coagulopathy on the basis of INR into
metabolites of paracetamol. Pathologically, it is associated moderate in 81% (INR 1.55), severe in 14% (INR 510) and
with acute tubular necrosis. It is not clear whether renal injury very severe in 5% (INR > 10). It is most severe in patients with
gets treated with n-acetyl cysteine (NAC). hepatitis B, acetaminophen poisoning and paradoxically
Leptospirosis and dengue should be suspected in the in patients with Budd-Chiari syndrome. The number of
appropriate setting. Conjunctival hemorrhages can be seen transfusions of fresh frozen plasma increased with increasing
in leptospirosis while petechial hemorrhages are seen in INR and need for ICP monitoring.
dengue. Treatment is with adequate hydration and renal Routine correction of coagulopathy on the basis of
replacement therapy as indicated. abnormal laboratory values is not indicated. It may hamper
Prerenal azotemia is common in patients with ALF and is decisions related to transplantation. Patients who require
treated with hydration (described above). invasive procedures such as insertion of central lines,
A syndrome similar to hepatorenal syndrome is seen in hemodialysis catheters and ICP monitoring should have
patients with ALF. The degree of splanchnic pooling of blood infusions of fresh frozen plasma. Cryoprecipitate should be
is less in these patients. Functional renal failure should be considered in patients with hypofibrinogenemia (100 mg/dL).
suspected in patients who have no other evident cause for Platelet count of less than 30,000/mm3 will require platelet
renal failure and who have a normal urine sediment and transfusions. Prophylactic platelet transfusions should be used
low urinary sodium. Unlike in cirrhosis the role of albumin, in patients with platelet counts less than 10,000/mm3. The role
terlipressin is not established in ALF. The potential risk of of prophylactic platelet transfusions for patients with platelet
using terlipressin is described above. counts between 10,000/mm3 and 30,000/mm3 is controversial
Renal replacement therapy with continuous renal and should be individualized. Low platelet counts are often
replacement is preferred. The indication for renal replacement associated with the development of DIC. Volume overload
is often fluid overload rather than the severity of renal failure invariably occurs during correction and can be an issue
and azotemia itself. in patients who have renal failure and oliguria. Exchange
plasmapheresis to reduce the risk of fluid overload has been
used routinely in some Asian centers. Recombinant factor
Coagulopathy VIIa can be another option in these patients. Early and limited
Coagulopathy is one of the two diagnostic criteria for experience suggests that it can be used 15 minutes to 2 hours
diagnosis of ALF and is therefore present in all patients with prior to insertion of ICP monitors in patients who are likely
ALF. It is also an important determinant for consideration to bleed. The dose used should be around 4060 g/kg body
of patients for liver transplantation. All coagulation factors weight and is thought to be more effective when used along
other than factor VIII are produced by the liver. Despite with FFP. The use of recombinant factor VIIa in this situation
severe coagulopathy, significant spontaneous hemorrhage is is an off label use. Vitamin K administration 10 mg parenterally
unusual in ALF. This may be related to underproduction of should be considered in all patients as this contributes to
coagulopathy in about one-fourths of patients with ALF.
anticoagulant proteins (protein C, protein S and antithrombin
III.) Also, there is upregulation of factor VIII production at
extrahepatic sites. Thrombocytopenia is also frequently seen Role of N-acetyl cysteine in
in patients with ALF. The pathogenesis is not clear as levels
of thrombopoietin (the liver derived stimulator of platelet Nonacetaminophen Acute Liver Failure
production) do not correlate with platelet counts. In some The American ALF study group recently conducted a trial of
patients, disseminated intravascular coagulation (DIC) may NAC in the management of ALF not caused by paracetamol.
be a contributory factor. The results are shown in Table 8.
Table 8: N-acetyl cysteine in nonacetaminophen ALF prognosis than those with indolent development of hepatic
encephalopathy.
Grade of Spontaneous Spontaneous p value
encephalopathy at survival in placebo survival in NAC
A number of prognostic models have been proposed to aid
admission group group in decision making in patients with ALFto decide who should
12 17/56 (30%) 30/58 (52%) 0.021
be treated medically, and who needs liver transplantation.
These include the well known Kings College Hospital criteria,
34 8/36 (22%) 2/23 (9%) 0.177
Clichy criteria and the Model end-stage liver disease (MELD)
Total 25/92 (27%) 32/81 (45%) 0.09 score. Besides these, a number of single variable prognostic
models have been proposed to improve prognostication but
these are all at a nascent stage and need further assessment
The role of NAC in nonparacetamol ALF has also been and validation before they can be used in practice.
studied in a recent trial of 173 patients. There was no difference Although these models are considerably helpful in
in the primary endpoint of the study, i.e. the overall survival decision making, one has to keep in mind that despite wide
at 21 days from starting NAC. The secondary endpoints use, these are far from satisfactory. Major methodological
namely transplant free survival and number of patients who flaws exist with the studies, which validate these criteria.
underwent orthotopic liver transplantation (OLT) at 1 year The studies have often been unblinded and retrospective,
was improved with NAC and the group, which benefited most and since ALF is not very common, most case series involve
was patients with grade 1 and 2 encephalopathy in whom small numbers spanning long periods of time during which
NAC was used. changing supporting medical therapies could potentially
influence survival. Besides, many authors have equated liver
transplantation with death resulting in false elevation of the
ASSESSMENT OF PROGNOSIS AND positive predictive value of the systems.
GUIDANCE FOR LIVER TRANSPLANT

LISTING The Clichy Criteria
These criteria were the first to be described by Bernau et al.
Early and accurate prognostic assessment of patients with ALF from Clichy. These criteria were derived from an analysis of
is of critical importance for optimum management of these 115 patients, all of whom had fulminant HBV infection, which
patients. Prognostication is critically important since the only were managed in the pretransplant era between 1972 and
proven beneficial therapeutic intervention in advanced ALF 1982. The criteria have been outlined in Table 9.
is transplantation, making the timing of transplantation and The criteria were shown to carry a positive predictive
selection of patients crucial. A false-negative selection can value and negative predictive value for death of 82% and 98%
lead to preventable death, and unnecessary transplantation respectively. Although these criteria have been used widely
carries not only needless risks of surgery, but also commits in Europe, they have significant limitations. Besides the fact
the patient to avoidable life-long immunosuppression and that there are only limited facility of factor V measurement/
waste of precious graft. assay, since the Clichy criteria were derived from hepatitis
Important predictors of outcome in ALF patients include: B-related ALF, when applied to ALF of other etiologies
Etiology of ALF especially acetaminophen (APAP)-related FHF, the criteria
Ultimate grade of hepatic encephalopathy has a substantial lower ability to identify patients who will
Speed of development of hepatic encephalopathy. survive without transplant. Besides, there is also absence of
The cause of ALF is one of the most important predictors good prognostic validation for Clichy criteria.
of outcome. Lower mortality rates are seen in ALF due to
acetaminophen toxicity (~30%) and HAV infection (~50%). Kings College Hospital Criteria
In contrast, in the remaining etiologies, the mortality rate is
very high (80100%). Mortality is also related to the ultimate The Kings College Hospital (KCH) criteria (Table 10) are
grade of hepatic encephalopathy in ALF patients. Patients currently extensively used by the transplant centers across
who develop grades 2, 3, and 4 hepatic encephalopathy have
Table 9: Clichy criteria for listing for liver transplantation proposed by
a mortality of 30, 50 and over 80%, respectively. Besides,
Bernau et al. (1986)
the speed of development of hepatic encephalopathy
also has a bearing on the outcome in ALF. Patients with Age <30 years Confusion or coma + factor V level <20%
faster development of hepatic encephalopathy have better Age >30 years Confusion or coma + factor V level <30%
Table 10: Kings College Hospital criteria for liver transplantation in improvising MELD, and this has resulted in different variants
acute liver failure of MELD including the following.
Paracetamol (acetaminophen) overdose
pH <7.3 (irrespective of encephalopathy)
Acharyas Criteria for the Tropics
Or all of the following:
Grade IIIIV encephalopathy Acharyas study from India showed that the rapidity of onset
Creatinine >300 mol/L of encephalopathy and cause of FHF did not influence the
Prothrombin time >100 seconds (INR >6.5) outcome. Coxs proportional hazard regression showed that
Nonparacetamol etiology age greater than or equal to 40 years, presence of cerebral
Prothrombin time >100 seconds
edema, serum bilirubin greater than or equal to 15 mg/dL,
Or any three of the following: and prothrombin time prolongation of 25 seconds or more
Age <10 years or >40 years
over controls were independent predictors of outcome.
Prothrombin time >50 seconds
Bilirubin >300 mol/L Ninety-three percent of the patients with three or more of the
Time from jaundice to encephalopathy >2 days above prognostic markers died. The sensitivity, specificity,
Non-A, non-B hepatitis, halothane or drug-induced ALF positive predictive value, and the negative predictive value of
the presence of three or more of these prognostic factors for
the globe. These criteria take into account the cause of the mortality was 93%, 80%, 86%, and 89.5%, respectively with a
ALF too. A meta-analysis for APAP-induced ALF has shown diagnostic accuracy of 87.3%. Thus, the criteria appear quite
that the KCH criteria had good specificity (92%), implying alluring, but surprisingly despite liver transplantation taking
that the patients who fulfill the KCH criteria are more likely to off in a big way, there has been no attempt from India or other
die without transplantation, but sensitivity was lower (69%). developing countries to validate or assess the utility of these
This implies that a proportion of patients would die without criteria.
fulfilling the criteria. When KCH criteria is compared with
the Clichy criteria for APAP-related ALF, it proved better
with a higher positive predictive value (92% versus 49%) and Acute Liver Failure Early Dynamic Model
predictive accuracy (83% versus 56%). For non-APAP patients Recently, Acharyas team at New Delhi investigated whether
too, the KCH criteria proved better than the Clichy criteria. early changes in the levels of dynamic variables could predict
the outcome better than models based on static baseline
Modified Kings College Hospital Criteria variables in patients with ALF. A total of 380 patients with
ALF (derivation cohort n = 244, validation cohort n = 136)
For the purpose of improving the diagnostic accuracy, the participated in the prospective observational study. The
KCH criteria have been modified to include other indices, derivation cohort was used to identify predictors of mortality.
such as blood lactate and serum phosphate. However, the The acute liver failure early dynamic (ALFED) model was
outcome of use of these modifications is far from satisfactory,
constructed based on whether the levels of predictive variables
and needs further assessment in larger patient population.
remained persistently high or increased over 3 days above the
discriminatory cut-off values identified in this study. Their
Model End-stage Liver Disease Score model used four variables: (i) arterial ammonia, (ii) serum
bilirubin, (iii) INR and, (iv) hepatic encephalopathy greater
The MELD score has been shown to be highly predictive of
than grade II. The ALFED model demonstrated excellent
3-month mortality for a variety of cohorts of patients with
discrimination with an area under the receiver operator
liver diseases waiting for liver transplantation. This score is
characteristic curve of 0.91 in the derivation cohort and of
calculated by the formula:
MELD score = (9.57 loge creatinine mg/dL + 3.78 loge 0.92 in the validation cohort. The investigators concluded that
bilirubin mg/dl + 11.20 loge INR + 6.43) performance of the ALFED model was superior to the KCH
This model has received wide acceptance globally and criteria and the MELD score, even when their 3-day serial
is used by a large number of centers all over the world for values were taken into consideration. An ALFED score of
deciding on the need for liver transplant and allocating greater than or equal to 4 had a high positive predictive value
priority for liver transplantation. The MELD score is very (85%) and negative predictive value (87%) in the validation
popular since this provides an easily measurable objective tool cohort. The ALFED model accurately predicted outcome
for selecting liver transplant candidates. However, because of in patients with ALF, and could after further studies be very
low sensitivity and specificity, there are constant attempts at useful in clinical decision making.
LIVER TRANSPLANTATION FOR ACUTE BIBLIOGRAPHY

LIVER FAILURE 1. Acharya SK, Batra Y, Hazari S, et al. Etiopathogenesis of acute
hepatic failure: Eastern versus Western countries. J Gastroenterol
A lot of progresses have been made in critical care of the
Hepatol. 2002;17 [Suppl 3]:S268-73.
ALF patient resulting in improved survival from 10 to 20% to
2. Acharya SK, Panda SK, Saxena A, et al. Acute hepatic failure in
around 40%. However, liver transplantation is considered the India: a perspective from the East. J Gastroenterol Hepatol.
primary curative treatment for ALF patients who are unlikely 2000;15:473-9.
to recover. Candidacy for transplantation must however be 3. Bhatia V, Singhal A, Panda SK, et al. A 20-year single-center
determined quickly for optimal benefit. Overall, the 1-year experience with acute liver failure during pregnancy: is the
survival following OLT for ALF is less (6080%) than that prognosis really worse? Hepatology. 2008;48:1577-85.
seen in chronic liver failure (8090%). Most of the deaths 4. Bhatia V, Singh R, Acharya SK. Predictive value of arterial
following liver transplantation occur in the first 23 months ammonia for complications and outcome in acute liver failure.
usually as a result of sepsis and neurological complications. Gut. 2006;55:98-104.
This is probably caused by sepsis and multiorgan failure. 5. Dhiman RK, Seth AK, Jain S, et al. Prognostic evaluation of early
Both deceased donor liver transplantation (DDLT) and living indicators in fulminant hepatic failure by multivariate analysis.
donor liver transplantation (LDLT) have been used to treat Dig Dis Sci. 1998;43:1311-6.
ALF. The latter has mainly been reported from the East. 6. Jaiswal SB, Chitnis DS, Asolkar MV, et al. Aetiology and prognostic
factors in hepatic failure in Central India. Trop Gastroenterol.
1996;17:217-20.
7. Khuroo MS. Acute liver failure in India. Hepatology. 1997;26:
CONCLUSION 244-6.
8. Khuroo MS, Kamili S. Clinical course and duration of viremia
Acute liver failure is a rapidly fatal emergency leading to
invertically transmitted hepatitis E virus (HEV) infection in
coagulopathy, hepatic encephalopathy and multisystem
babies born to HEV-infected mothers. J Viral Hepat. 2009;
organ failure. Early recognition of signs and symptoms of 16:519-23.
ALF are essential despite availability of optimal available 9. Larson MA. Acute liver failure In: Schiff ER, Maddrey WC, Sorrell
management resources. It is very important to quickly and MF (Eds). Schiffs Diseases of the Liver, 11th edition. Oxford:
accurately identify the ALF patients who are most likely Wiley-Blackwell; 2012. pp. 445-72.
to benefit from liver transplantation. For this, there is a 10. OGrady JG, Williams R. Classification of acute liver failure. Lancet.
need for a reliable predictive model of survival and need 1993;342:743.
for liver transplantation. The heterogeneous nature of ALF, 11. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group.
the wide variability in survival of these patients and the Drug-induced acute liver failure: results of a U.S. multicenter,
unpredictability of the course of ALF makes it very difficult prospective study. Hepatology. 2010;52:2065-76.
to predict as to who will survive without liver transplantation. 12. Sanyal AJ, Stravitz RT. Acute liver failure In: Zakim T, Boyer TD
It is unfortunate that due to the problems in the predictive (Eds). Hepatology: A Textbook of Liver Diseases, 5th edition.
models and the ubiquitous resource constraints especially Philadelphia, PA: Saunders Elsevier; 2006. pp. 383-415.
in developing countries, the majority of patients die without 13. Vaquero J, Blei AT. Etiology and management of fulminant
liver transplantation. hepatic failure. Curr Gastroenterol Rep. 2003;5:39-47.
39
cHAPTER
Biliary Atresia
Voranush Chongsrisawat, Sittisak Honsawek, Paisarn Vejchapipat, Yong Poovorawan
INTRODUCTION at different levels. In some cases, the common bile duct, cystic
duct and gall bladder are patent but the common hepatic
Biliary atresia (BA) is a progressive, idiopathic, necroinflam duct is atretic. Other cases of type 2 may have atresia of the
matory process resulting in obliteration of the extrahepatic common bile duct, cystic duct together with a portion of
biliary tree. It is a rare disease, with the reported prevalence common hepatic duct. Type 3 (>7590% of cases) has atresia
ranging from 1 in 5,000 to 1 in 19,000 live births. It is the of the entire extrahepatic biliary tract, including the gall-
most common cause of neonatal jaundice for which surgery bladder.
is indicated and also the most common indication for liver The obstruction of bile flow in BA results in worsening
transplantation in children. The pathogenesis of BA has cholestasis, liver fibrosis and cirrhosis, which lead to portal
remained a mystery. Most of the causal theories include hypertension and eventually liver failure. Early diagnosis and
defects resulting from a viral infection or toxin exposure, timely Kasai portoenterostomy to restore bile flow can help
defects in morphogenesis, genetic predisposition, defects in avoid the need of liver transplantation during childhood in a
prenatal circulation and immune dysregulation. number of patients.
Biliary atresia occurs in two distinct clinical forms: (i)
embryonic (or syndromic) and (ii) perinatal (or acquired). It
has been hypothesized that the process of inflammation and
obliteration of the extrahepatic bile ducts begins during the
embryonic and perinatal period, respectively. Approximately,
1020% of all cases exhibit the embryonic form, which is
associated with other congenital abnormalities. The most
common abnormality is biliary atresia splenic malformation
syndrome, including polysplenia, asplenia, situs inversus,
and vascular anomalies as for instance, absence of an inferior
vena cava and a preduodenal portal vein. The embryonic form
may be also associated with intestinal malrotation, cardiac
anomalies, such as ventricular septal defect, atrial septal
defect, and hypoplastic left heart. The perinatal form, which
is not associated with other congenital anomalies, accounts
for the remaining 8090% of cases.
Biliary atresia can be anatomically classified into three
types according to the level of the most proximal biliary
obstruction (Fig. 1). Type 1 (about 5% of cases) has an atretic
common bile duct with a patent common hepatic duct and
cystic duct. This type is often associated with a cystic change
of patent proximal bile duct, so called cystic biliary atresia,
which can be confused with choledochal cyst. Type 2 (less
than 20% of cases) shows atresia of the common hepatic duct Fig. 1: Types of biliary atresia
PATHOGENESIS to be linked to the pathogenesis of BA. Vascular endothelial

growth factor +936 C/T gene polymorphism, particularly
Despite a number of extensive clinical research studies on BA, the C allele, was associated with BA, possibly conferring
the etiology and pathogenesis of BA are largely unknown. Early increased susceptibility to the disease. In addition, there
studies postulated a congenital malformation of the biliary was no association between K469E intercellular adhesion
ductular system. Problems of hepatobiliary ontogenesis are molecule-1 polymorphism and the status of jaundice in BA
suggested by the embryonic form of atresia that is associated patients after Kasai operation. Connective tissue growth
with other congenital anomalies. However, the more common factor polymorphism at -447 G/C was not associated with BA
perinatal type is characterized by a progressive inflammatory and the jaundice status of the postoperative BA patients.
lesion, which suggests a role for infectious and/or toxic
agents causing bile duct obliteration. Identification of active
and progressive inflammation and destruction of the biliary Defects in Prenatal Circulation
system suggests that BA likely represents an acquired lesion. Bile ducts receive their blood supply exclusively from the
However, no single etiologic factor has been identified. hepatic arterial circulation. Interruptions of this flow account
Potential mechanisms involved in the pathogenesis of BA for bile duct damage in liver transplantation, as well as in a
have been proposed as follows. fetal sheep model. Impaired blood flow through hepatic
artery, which supplies the intra- and extrahepatic biliary
system in early development has been proposed to be an
Viral Infection/Toxin Exposure initiating factor for duct injury in BA.
The isolation of different viruses in livers of infants with
BA points to a potential role as an initiating factor in the
pathogenesis of disease. Numerous studies exploring a viral Immune or Autoimmune Dysregulation
etiology have focused on reovirus, rotavirus, cytomegalovirus Animal models of the condition support the role of
and other hepatotropic viruses. None has been fully autoimmunity. Autoreactive T cells specific to bile duct
substantiated. The argument for involvement of reovirus epithelia are sufficient to produce bile duct inflammation in
type 3 is the most compelling based on human antibody mice, causing a similar phenotype. Adoptive transfer of liver T
studies, immunohistochemistry, electron microscopy of viral cells from a mouse model of the disease can induce bile duct-
particles and the similarities with a mouse weanling model. specific disease in immunodeficient mice. These concepts are
Nevertheless, among these viruses, reovirus type 3 and being explored in human tissue.
rotavirus type C continue to emerge as potential triggering As the biliary tract cannot transport bile to the intestine,
agents for BA. bile is retained in the liver resulting in liver cirrhosis.
Proliferation of the small bile ductules occurs, and peribiliary
fibroblasts become activated. These reactive biliary epithelial
Defects in Morphogenesis cells in cholestasis, unlike the normal condition, produce
These are potentially caused by a toxin at a critical time in and secrete various cytokines, such as tumor necrosis factor
embryological development. The strongest evidence for this (TNF), interleukin-6 (IL-6), transforming growth factor
comes from children with the embryonic form of the disease. (TGF)-, endothelin and nitric oxide. Among these, TGF- is
Jaundice develops soon after birth, frequently with associated the most important profibrogenic cytokine that can be seen in
congenital abnormalities. liver fibrosis in chronic cholestasis.
Recently, various inflammatory cytokines and growth
factors have received increasing attention as possible
Genetic Predisposition roles in the pathophysiology of hepatic fibrosis in BA. The
The condition is unlikely to be inherited by Mendelian conclusive findings pertaining to the role of growth factors
genetics but genetic factors likely contribute. The increased in BA have demonstrated that macrophage migration
association with histocompatibility antigen HLA-B12 inhibitory factor, TGF--1, epidermal growth factor, insulin-
(haplotypes A9-B5 and A28-B35) and its early onset suggests like growth factor-1 and hepatocyte growth factor could play
a genetic susceptibility to an acquired insult. Reports of the a potential role in the pathophysiology of postoperative BA
combined occurrence of BA and neonatal hepatitis within patients. Furthermore, the significant increase of serum
families support the possibility of shared etiological features, bone morphogenetic protein 7, basic fibroblast growth factor,
where the outcome is modulated by the timing and severity of stem cell factor, tissue inhibitors of metalloproteinase-1
the insult. Genetic polymorphisms have already been shown was associated with a deterioration of hepatic function and
Biliary Atresia 361
the development of portal hypertension in BA patients after Alagille syndrome

Kasai procedure. It has been previously shown that various Nonsyndromic ductal paucity
inflammatory cytokines may also play important roles in the Hepatocellular cholestasis
pathophysiological process of BA. The high levels of serum Hepatitis (hepatitis A, hepatitis B, hepatitis C, TORCH)
IL-8, endothelin-1 and procollagen-III-peptide were related Alpha1-antitrypsin deficiency
to the severity of esophageal varices in children with BA after Inborn errors of bile acid synthesis
Kasai operation. Moreover, elevated serum adiponectin, Drug-induced cholestasis
osteopontin, matrix metalloproteinase-3, nitric oxide and Total parenteral nutrition (TPN)-associated cholestasis
hyaluronan levels were associated with poor outcome in BA. Progressive familial intrahepatic cholestasis
Additionally, serum 25-hydroxyvitamin D level was decreased Metabolic disorders (tyrosinemia, galactosemia, fruc
in BA patients with low bone mineral density (BMD). Also, tosemia)
circulating leptin and osteoprotegerin levels are correlated Neonatal intrahepatic cholestasis caused by citrin
with BMD and the presence of jaundice in BA, suggesting that deficiency (NICCD)
leptin and osteoprotegerin may play a physiological role in Idiopathic neonatal hepatitis.
maintaining bone mass of BA patients.
In an effort to identify genes involved in hepatobiliary
development associated with disease, patients with BA have SCREENING FOR BILIARY ATRESIA
been investigated. Genome wide association studies have
identified genes potentially important in the etiology of BA and Because of the importance of early diagnosis and management,
revealed that rs17095355 on 10q24, downstream of XPNPEP1 researchers have attempted to develop screening tests for
was involved in the metabolism of inflammatory mediators. BA. Unfortunately, development of methods to identify
Furthermore, -68 C/T XPNPEP1 gene polymorphism and conjugated bilirubin in dry blood spots for large-scale
particularly the T allele were found to be associated with neonatal screening has not yet been accomplished. Some
BA, possibly providing increased susceptibility to BA. countries such as Taiwan and Japan have implemented infant
Moreover, there was an association between +276 G/T stool color cards to help parents recognize the abnormally
adiponectin polymorphism and BA. In addition, eight pairs of pale stool, which is a consequence of biliary obstruction (Figs
discordant twins in a series of 143 postoperative BA patients 2A and B). This method is a simple, efficient and applicable
were reported. One pair was dizygotic twins based on sex mass screening method for early diagnosis and management
discrimination. Six were identical ABO blood groups and two of BA.
were also the same minor blood groups. The last two sets were
monozygotic twins based on common DNA polymorphisms
short tandem repeat loci. The identification of hypothetical CLINICAL MANIFESTATIONS
BA susceptibility genes resulted in a better understanding of
the mechanisms underlying BA and provided new evidence Patients with the embryonic form usually present with
for the development of preventive and curative approaches. jaundice within the first 2 weeks of life while those with
Delineation of the pathological mechanisms underlying bile the perinatal form have a short jaundice-free interval after
duct injury in BA will be necessary for the development of birth and develop jaundice at the age of around 28 weeks.
new potentially therapeutic agents for this serious pediatric Typically, BA presents with persistent jaundice, pale stools,
disorder. and dark urine in term infants with normal birth weights.
All term infants who remain jaundiced after 14 days (and
preterm infants after 21 days) should be investigated for
DIAGNOSIS liver disease. Splenomegaly is not generally a characteristic
unless presentation is delayed and it is thus a sign of portal
Causes of neonatal/infantile cholestasis include: hypertension.
Obstructive cholestasis
Biliary atresia
Congenital bile duct anomalies (choledochal cyst) INVESTIGATIONS
Cholelithiasis
Primary sclerosing cholangitis Early diagnosis is critical, and thus investigation of infants
Cholangitis associated with Langerhans cell histio with conjugated hyperbilirubinemia is designed to identify
cytosis BA and to exclude other causes. Biliary atresia is frequently
Figs 2A to B: (A) Pale yellow stool; (B) Acholic stool
Fig. 3: Suggested algorithm for investigation of infants with conjugated jaundice and pale stool
Abbreviations: DISIDA, diisopropyl iminodiacetic acid; IOC, intraoperative cholangiography; BA, biliary atresia; Liver Tx, liver transplantation
misdiagnosed as breast-milk jaundice, which leads to Blood Test

late referral for Kasai portoenterostomy. Figure 3 shows a
suggested algorithm for investigation of a neonate/infant Simple measurement of the conjugated fraction of bilirubin
with persistence conjugated jaundice and pale stool. is an appropriate initial test in neonates and infants with
Biliary Atresia 363
prolonged jaundice. Those with breast-milk jaundice have Hepatic Scintigraphy

increased serum concentrations of unconjugated bilirubin,
while conjugated bilirubin is raised in jaundice secondary to N-tert-butyliminodiacetic acid (TEBIDA) or diisopropyl
liver diseases. iminodiacetic acid (DISIDA) scan after pretreatment with
Patients with BA typically have cholestatic liver function phenobarbital 5 mg/kg/day for 35 days can be performed in
tests, including conjugated hyperbilirubinemia, raised equivocal cases. Uptake of the isotope by the liver followed by
gamma-glutamyltransferase, and modest elevation of nonexcretion into the intestine within 24 hours is suggestive
transaminases. Hepatic synthetic function is usually normal of BA (Figs 5A and B). Unfortunately, nonexcretion of the
at the early stage. Liver function tests alone are not sufficient isotope is not specific for BA and can also be seen in children
to distinguish BA from conditions causing intrahepatic with severe intrahepatic cholestasis.
cholestasis. In patients with equivocal pale stools, other
medical causes of conjugated hyperbilirubinemia should be
excluded.
Duodenal Tube Test
This test is frequently applied in Japan and China. It is
performed by placing a nasoduodenal tube in the third part of
Abdominal Ultrasonography the duodenum to facilitate continuous aspiration to identify
In BA, an abdominal ultrasonogram after a 4-hour fast bile. Demonstration of bile avoids the need for surgery, while
typically shows an enlarged liver with increased echogenicity, clear and non-bile stained duodenal secretions over 24 hours
absence of biliary dilation, and an absent or contracted gall- are strongly suggestive of BA.
bladder. Nonetheless, 20% of cases might have a normal gall-
bladder. Identification of hyperechogenic liver hilum, known
as the triangular cord sign, is a specific finding in almost
Liver Biopsy
all cases, but is operator dependent and can be difficult to Liver biopsy, usually performed percutaneously, is the usual
arrive at, with reported sensitivities varying from 50% to 70% diagnostic method in infants with prolonged jaundice. Typical
(Fig. 4). Ultrasonography can also identify features of the histological features of BA are evidence of extrahepatic biliary
splenic malformation syndrome. obstruction including ductal proliferation, cholestasis with
the appearance of bile plugs and varying degrees of portal
tract fibrosis (Fig. 6). Nonetheless, evidence of giant cell
transformation might be present in BA, making differentiation
from intrahepatic cholestasis difficult. The other drawback of
liver biopsy in BA is that the samples taken before 6 weeks
of age might not have typical histological features, and serial
biopsy samples might be required for diagnosis.
Endoscopic Retrograde
Cholangiopancreatography
and Magnetic Resonance
Cholangiopancreatography
These tests are available in some large centers. They are able
to demonstrate luminal patency of the bile duct but they are
technically difficult in small infants. As a result, at present
they still play a small role in the diagnostic workup for infants
with cholestasis.
Fig. 4: Sagittal sonogram in an infant with biliary atresia shows

triangular cord sign (as indicated by calipers) superior to portal vein
Operative Cholangiography
(arrow) It is regarded as the gold standard and definitive
Image courtesy: Panruethai Trinavarat, MD, Chulalongkorn University investigation in the diagnosis of BA. It can be undertaken
and Hospital either laparoscopically or surgically opened before Kasai
A B
Figs 5A and B: DISIDA scintigraphy showing (A) no radiotracer activity in the intestine in biliary atresia and (B) presence of radiotracer activity
in the intestine in neonatal hepatitis
Image courtesy: Supatporn Tepmongkol, MD, Chulalongkorn University and Hospital
Intraoperative cholangiogram can be performed by

injecting contrast into the gallbladder if it is present. It is
unnecessary to carry out a cholangiogram in patients with
atretic gallbladder and extrahepatic bile duct. In such cases,
visual assessment alone is sufficient to diagnose BA. In type
2 BA, a well-formed gallbladder is noted and contrast can
be demonstrated in the gut but no contrast is seen in the
intrahepatic ducts.
MANAGEMENT
At present, surgery is the only option available in the
confirmation of diagnosis (intraoperative cholangiography)
and therapeutic management (hepatic portoenterostomy or
Kasai operation) of BA. Once the diagnosis of BA is confirmed
Fig. 6: Liver histology in an infant with biliary atresia showing bile by intraoperative cholangiography, Kasai operation should
plugs, ductal proliferation and portal tract edema with fibrosis be carried out promptly. Sometimes, intraoperative diagnosis
Image courtesy: Naruemon Wisedopas, MD, Chulalongkorn of BA can be difficult due to various anatomical varieties
University and Hospital such as extrahepatic cystic BA. Hence, surgeons experience
is also vital in the surgical management. Kasai operation is
undertaken in an attempt to restore bile flow from the liver to
portoenterostomy. The open technique is more preferable the small intestine. In order to achieve this goal, a long roux-
since it allows proximal dissection of the hilar plate and the en-Y loop of bowel is created and directly anastomosed to the
ability to proceed with the Kasai portoenterostomy once the hilum of the liver, following excision of the biliary remnant
diagnosis of BA is ascertained. and portal fibrous plate.
Biliary Atresia 365
During the operation, the fibrotic biliary tract remnant is fossa on the right border. Studies have shown that extension
identified, and the patency of the biliary system is assessed of the portal dissection beyond the portal vein bifurcation
(Fig. 7). Kasai operation consists of a full liver mobilization may improve the probability of achieving bile drainage. Then,
out of the abdominal cavity to allow clear exposure of the a long retrocolic Roux loop (4045 cm) with an end-to-side
porta hepatis and a meticulous dissection of the porta hepatis anastomosis between the raw surface of the excised portal
area (Fig. 8). For full liver mobilization, only the left coronary fibrous plate and the jejunum end completes Kasai operation.
ligaments and falciform ligament need to be separated from The standard Kasai operation is still performed in an open
the diaphragm and anterior abdominal wall. manner. Although laparoscopic approach has been reported,
For dissection of the porta hepatis area, the dissection itself it was limited to few small series due to the rarity of the
must be carefully performed. The extent of dissection along disease. Its efficacy regarding the outcome and complications
the left and right branches of the portal vein should be wide, is yet to be evaluated.
from the round ligament on the left border to the gallbladder Postoperatively, patients are given oxygen, intravenous
fluids and broad-spectrum antibiotics. In our centers
protocol, steroids at 2 mg/kg/day at alternating days are
orally prescribed on the seventh day postoperatively for
at least 1 month but not more than 3 months. Steroids are
used both for their choleretic effects and to decrease fibrosis
at the anastomosis. Common complications following
Kasai operation include ascending cholangitis (3050%),
portal hypertension with its consequences (varices, ascites,
splenomegaly), and growth retardation.
If Kasai operation is successful, bile will drain into the roux
limb through very small patent bile canaliculi on the surface
of the excised portal fibrous plate and jaundice will start to
resolve within weeks following surgery. If jaundice persists
for more than 6 months after operation, liver transplantation
may be inevitable in the near future. The predictors for good
outcome following Kasai operation are age at operation of
less than 60 days, the presence of portal hypertension at the
time of Kasai operation and the experience of the care team
Fig. 7: Gross appearance of the porta hepatis area in biliary atresia including pediatric hepatologists and surgeons. After Kasai
type III operation, approximately 60% of patients will have their
jaundice resolved within 3 months. However, the remaining
patients will develop signs and symptoms of chronic liver
disease due to progressive biliary cirrhosis and will require
liver transplantation early in their lives. In the long-term, half
of the jaundice-free patients after surgery will deteriorate due
to progressive biliary cirrhosis and develop jaundice again.
Therefore, more than half of all patients undergoing Kasai
operation will eventually require liver transplantation (Fig. 9).
The primary indications for liver transplantation for patients
with BA include progressive jaundice, recurrent intractable
ascending cholangitis, poorly controlled portal hypertension,
intractable ascites, markedly decreased hepatic synthetic
function and significant growth retardation.
Late Complications of Biliary Atresia:

Post-Kasai Operation
Patients with BA even after successful Kasai portoenterostomy
Fig. 8: Full mobilization of the liver during Kasai portoenterostomy may suffer from complications, such as portal hypertension.
Fig. 9: The fate of patients with biliary atresia undergoing Kasai operation
Those with unsuccessful Kasai operation ultimately progress clubbing. Diagnosis is confirmed by contrast-enhanced
to biliary cirrhosis. echocardiography or pulmonary scintigraphy. This condition
regresses after liver transplantation.
Pulmonary hypertension is rarely encountered and
Portal Hypertension manifests with malaise, dyspnea and sudden death. The
Portal hypertension and subsequent complications diagnosis is suggested by echocardiography and cardiac
including ruptured esophageal and/or gastric varices (EV/ catheterization. Liver transplantation can reverse pulmonary
GV), splenomegaly and ascites arise in at least two-thirds hypertension at its early stage.
of the children after portoenterostomy, even in those with
complete restoration of the bile flow. It has been reported
that more than 50% of children with BA below the age of
Intrahepatic Bile Lakes
2 years developed EVs. Variceal sclerotherapy or band Intrahepatic bile lakes may develop several months to years
ligation is effective to prevent bleeding from ruptured EVs. after portoenterostomy, even in patients with complete
Transjugular intrahepatic portosystemic shunts (TIPS) or clearance of jaundice. These lakes may become infected and
surgical portosystemic shunts are rarely indicated in children, can be a cause of frequent cholangitis. Liver transplantation is
but may be necessary in those with life-threatening varices. the treatment of choice for recurrent infections.
Severe hypersplenism may require splenic artery
embolization. Ascites can be managed with salt restriction
and diuretics. Therapeutic abdominal paracentesis is required Malignancy
in patients with tense ascites compromising pulmonary Hepatocellular carcinoma and cholangiocarcinoma have
function. been reported in long-term survivors of portoenterostomy
with cirrhosis. Screening for malignancy should be performed
regularly in the follow-up of patients with successful Kasai
Hepatopulmonary Syndrome and portoenterostomy.
Pulmonary Hypertension
These two conditions may arise even after successful Biliary Cirrhosis and End-stage Liver Disease
portoenterostomy. Lack of clearance of gut-derived
vasoactive compounds due to portosystemic shunt leads Patients with unsuccessful Kasai operation usually develop
to hepatopulmonary syndrome with development of biliary cirrhosis with progressive jaundice and poor synthetic
intrapulmonary vascular shunts resulting in hypoxemia function (hypoalbuminemia, malnutrition and coagulopathy)
and orthodeoxia. Clinical features of hepatopulmonary during infancy. Biliary cirrhosis may occur in patients initially
syndrome include hypoxia, cyanosis, dyspnea and digital jaundice-free after Kasai operation. Liver transplantation
Biliary Atresia 367
is indicated in case of deteriorating liver function. In Ensure complete childhood vaccinations. Children
experienced centers, the 10-year survival rate following liver with end-stage liver disease are vulnerable to infection.
transplantation for BA has become as high as 90%. As a result, careful attention should be paid to ensure
The aims of treatment of biliary cirrhosis and end-stage that all patients receive all of the recommended
liver disease are as follows: routine childhood vaccinations. Patients listed for liver
Optimize nutritional status by providing adequate protein/ transplantation must receive attenuated live virus vac
caloric and fat-soluble vitamin intake cines such as mumps/measles/rubella and varicella
Children with cirrhosis and end-stage liver disease is at prior to the transplantation.
risk for developing nutritional compromise, which will
lead to significant short-term and long-term morbidities.
Patients with end-stage liver disease require increased CONCLUSION
caloric intake of up to 120150% of their estimated daily
requirements. Formulas containing medium-chain Biliary atresia remains a challenging disease. Ongoing
triglycerides are required to maximize fat absorption. research to elucidate the pathogenesis of the disease will
In addition, daily supplements of fat-soluble vitamins facilitate an improved understanding of the disease process,
must be provided. Fat-soluble vitamin supplementation which may lead to the development of novel intervention
should include vitamin A 5,00015,000 IU per day, in reducing hepatic fibrosis and cirrhosis. In the meantime,
vitamin D (alfacalcidol) 50 ng/kg/day, vitamin E 50200 early diagnosis and referral to experienced centers and long-
mg per day and vitamin K 2.55 mg per day. Supplemental term specialist care are still the key to successful treatment of
nasogastric tube feedings may be needed in case of severe this disease.
malnutrition
Prevent and control complication of portal hypertension
such as bleeding from ruptured EV/GV and ascites as BIBLIOGRAPHY
previously described
Get rid of infections, such as cholangitis, spontaneous 1. Baker A, Stevenson R, Dhawan A, et al. Guidelines for nutritional
bacterial peritonitis and septicemia. The common care for infants with cholestatic liver disease before liver
causative organisms include Streptococcus pneumoniae transplantation. Pediatr Transplant. 2007;11:825-34.
and gram-negative enteric bacteria. Treatment should be 2. Chongsrisawat V, Vejapipat P, Siripon N, et al. Transient
elastography for predicting esophageal/gastric varices in
with broad-spectrum antibiotics until specic culture and
children with biliary atresia. BMC Gastroenterol. 2011;11(1):41.
sensitivity results are available 3. Chuang JH, Chou MH, Wu CL, et al. Implication of innate
Control hepatic encephalopathy. Hepatic encephalopathy immunity in the pathogenesis of biliary atresia. Chang Gung
can develop in pediatric patients with end-stage liver Med J. 2006;29:240-50.
disease. The development of hepatic encephalopathy can 4. Cowles RA, Lobritto SJ, Ventura KA, et al. Timing of liver
be difcult to assess. Symptoms of early grades of hepatic transplantation in biliary atresiaresults in 71 children managed
encephalopathy, for instance irritability, inconsolable by a multidisciplinary team. J Pediatr Surg. 2008;43:1605-9.
crying and inattention to task are rather nonspecic 5. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet.
ndings with sick infants and children. Children with 2009;374:1704-13.
6. Humphrey TM, Stringer MD. Biliary atresia: US diagnosis.
end-stage liver disease should receive protein intake
Radiology. 2007;244:845-51.
around 23 g/kg/day. Such an amount of protein is 7. Khalil BA, Perera MT, Mirza DF. Clinical practice: management of
adequate for growth and would not cause excessive biliary atresia. Eur J Pediatr. 2010;169:395-402.
ammonia production. In children with advanced 8. Leonis MA, Balistreri WF. Evaluation and management of end-
cirrhosis and malnutrition, supplemental feeding with stage liver disease in children. Gastroenterology. 2008;134:
branched-chain amino acids leads to improvement of 1741-51.
the nutritional status without causing encephalopathy. 9. Lykavieris P, Chardot C, Sokhn M, et al. Outcome in adulthood
Lactulose can be used to decrease serum ammonia of biliary atresia: a study of 63 patients who survived for over 20
years with their native liver. Hepatology. 2005;41:366-71.
levels in pediatric patients with hepatic encephalopathy.
10. Mack CL, Sokol RJ. Unraveling the pathogenesis and etiology of
However, there have not been any studies evaluating the biliary atresia. Pediatr Res. 2005;57:87R-94R.
effectiveness of lactulose or neomycin for the prevention 11. Muraji T, Suskind DL, Irie N. Biliary atresia: a new immunological
of hepatic encephalopathy in infants and children with insight into etiopathogenesis. Expert Rev Gastroenterol Hepatol.
cirrhosis 2009;3:599-606.
12. Santos JL, Carvalho E, Bezerra JA. Advances in biliary atresia: from 15. Ure BM, Kuebler JF, Schukfeh N, et al. Survival with the native liver
patient care to research. Braz J Med Biol Res. 2010;43:522-7. after laparoscopic versus conventional Kasai portoenterostomy
13. Sookpotarom P, Vejchapipat P. Non-correctable biliary atresia in infants with biliary atresia: a prospective trial. Ann Surg. 2011;
with large extrahepatic cyst: a report of two cases. Eur J Pediatr 253:826-30.
Surg. 2007;17:295-7.
14. Sookpotarom P, Vejchapipat P, Chittmittrapap S, et al. Short-term 16. Vejchapipat P, Passakonnirin R, Sookpotarom P, et al. High-dose
results of Kasai operation for biliary atresia: experience from one steroids do not improve early outcome in biliary atresia. J Pediatr
institution. Asian J Surg. 2006;29:188-92. Surg. 2007;42:2102-5.
40
cHAPTER
Liver Diseases in Pregnancy
Shelley Haynes, Mandish K Dhanjal
INTRODUCTION Table 1: Normal values of liver function in pregnancy

Nonpregnant 1st Trimester 2nd 3rd
Liver disorders in pregnancy can be due to diseases unique Trimester Trimester
to pregnancy or diseases unrelated to pregnancy. Specific AST iu/L 740 1028 1129 1130
pregnancy disorders typically resolve postpartum and ALT iu/L 040 632 632 632
include obstetric cholestasis (OC), hemolysis, elevated liver GT iu/L 1150 537 543 341
and low platelets (HELLP) syndrome and acute fatty liver of Bilirubin mol/L 017 416 313 314
pregnancy (AFLP). Liver disease may be preexisting or arise de
Abbreviations: AST, aspartate transaminase; ALT, alanine transaminase;
novo in pregnancy. Asymptomatic preexisting liver disorders, GT, -glutamyl transpeptidase.
such as gallstones and hepatitis C, may become symptomatic
due to the significant physiological and metabolic changes of
pregnancy. Preexisting hepatitis B may be identified for the lower than the nonpregnant state (Table 1). Albumin levels
first time in pregnancy in countries where antenatal screening fall by about 2040% with a lower limit of normal in pregnancy
is routine. of 28 g/L. Alkaline phosphatase rises due to the production
Physiological demands in pregnancy are significant with of a heat-stable placental isoenzyme and levels in the third
marked metabolic change. Clinicians must be aware of trimester can be four times the nonpregnant state. Protein
these changes in order to appropriately assess and treat the synthesis increases in pregnancy giving rise to an increase in
pregnant woman. In particular, reference ranges for many clotting factors (VII, VIII, X and fibrinogen) which contributes
tests are often different to the nonpregnant state and can to the prothrombotic state of pregnancy. Fibrinogen levels are
change with gestation. almost doubled; therefore values which would be considered
normal outside pregnancy may be seen in the presence of
disseminated intravascular coagulation in pregnancy.
PHYSIOLOGICAL CHANGES IN
PREGNANCY
HEPATIC DISORDERS SPECIFIC TO
During pregnancy the liver is pushed superiorly and PREGNANCY
posteriorly by the gravid uterus. There is no increase in the
size or blood flow to the liver. Some markers of chronic liver
disease including palmar erythema, spider nevi, edema and a
Obstetric Cholestasis
low albumin are seen in normal pregnancy due to an increased Obstetric cholestasis, also known as intrahepatic cholestasis of
circulating volume, vasodilation and a low venous pressure. pregnancy, is a condition unique to pregnancy characterized
Hemodilution in pregnancy secondary to an increased plasma by pruritus, abnormal liver function and raised bile acids,
volume causes a physiological anemia and lowers the normal in the absence of a skin rash or other explanation. It usually
values for tests, such as those for liver function test (LFT). occurs in the third trimester of pregnancy and resolves
Aspartate transaminase (AST), alanine transaminase (ALT), postpartum. It is the most common pregnancy-related liver
-glutamyl transpeptidase (GT) and bilirubin levels all fall in disorder and is associated with fetal risks such as preterm
normal pregnancy with the upper limits of normal about 25% delivery and stillbirth.
Pathogenesis Table 2: Differential diagnosis of obstetric cholestasis
Obstetric cholestasis affects between 0.1% and 1.5% Condition Investigation

of pregnant women in Europe with a higher incidence Preeclampsia/HELLP Blood pressure, quantitative analysis of
among Scandinavian (2%) and South American women, syndrome proteinuria, if present (24-hour collection or
protein: creatinine ratio), FBC, U&E, creatinine,
particularly among the Araucanos Indians of Chile (5%). urate
OC is a multifactorial disease where genetic, endocrine and
Viral hepatitis Hepatitis A, B, C, CMV IgM and IgG, EBV IgM and
environmental factors all play a part, although the exact cause IgG
is unknown. There is an increased risk of OC among sisters
Primary biliary cirrhosis Antimitochondrial antibodies
and daughters of affected individuals and those affected
have a 90% recurrence risk in future pregnancies. Mutations Chronic active hepatitis Antismooth muscle antibodies
of the MDR3 gene have been identified in some women with Gallstones Ultrasound liver and gallbladder
OC. Both estrogens and progesterones are implicated in Abbreviations: HELLP, hemolysis, elevated liver enzymes, and low
the development of OC which tends to present in the third platelets; FBC, full blood count; U&E, urea and electrolytes; CMV,
trimester when these hormones are at their highest titers. An cytomegalovirus; EBV, Epstein-Barr virus.
increased incidence in OC is seen in multiple pregnancies
where hormone levels are higher than with singleton
pregnancies. Furthermore, women who are susceptible to
Maternal Risks
the development of OC can develop a similar cholestatic Pruritus can be intense and cause significant morbidity and
condition with exogenous estrogens and progesterones sleep deprivation. Excoriations are often seen and skin can
such as the contraceptive pill and in the luteal phase of the be scarred if scratching is vigorous. Fat malabsorption can
menstrual cycle. The incidence of OC in Scandinavia and lead to steatorrhea and subsequent vitamin K deficiency. This
Chile has been noted to be higher in the winter months. could potentially lead to a prolonged prothrombin time with
an increased risk of postpartum hemorrhage, although there
is little evidence for this. Both gallstones and hepatitis C are
Diagnosis seen more frequently in women with OC.
Itching, particularly of the abdomen, is a common symptom
of pregnancy, which in many is benign and resolves
spontaneously. In OC, most women present with pruritus
Fetal Risks
in the second or third trimester, although there have been Obstetric cholestasis is associated with an increased risk
reports of women presenting in early pregnancy. Pruritus of spontaneous and iatrogenic preterm delivery (425%).
is often intense, worse at night and can cause significant Animal studies have shown an increase in uterine contractility
maternal morbidity. The itch is typically generalized and and preterm delivery following treatment with bile acids. The
will often be worse on the palms of the hands and the soles raised bile acids in humans with OC may have an effect on
of the feet. However, the abdomen alone can just be affected uterine contractility increasing the incidence of spontaneous
and all women complaining of new onset itching in the third preterm labor.
trimester should be investigated for OC. Other fetal risks include meconium staining of liquor, fetal
A detailed history should be taken including personal and distress and intrauterine death (IUD, 3.5%) which usually
family history of OC, distribution of itch, drug history, use of occurs after 37 weeks gestation. Adverse events (asphyxia,
over-the-counter medicines, recent viral illness, antibiotic spontaneous preterm delivery and meconium liquor) appear
use, foreign travel and alcohol use. The skin should be to be related to the level of bile acids with a 12% increased
inspected for any evidence of a rash, which should be absent, risk of adverse events for every 1 mol/L of bile acid above 40
and jaundice which occurs in 1015%. Liver function tests mol/L.
and bile acids should be checked. In OC, ALT and AST are The mechanism of stillbirth is uncertain but the cause of
usually raised, with ALT being a more sensitive marker. GT death is usually acute anoxia rather than chronic placental
will be raised in 30% of cases and bilirubin in only 10%. Raised insufficiency. There is an indirect evidence of the mechanisms
bile acids are diagnostic of OC. Other causes of abnormal by which high bile acid levels may exert their harmful effects.
transaminases should be excluded (Table 2). Meconium contains high levels of bile acids in OC and has
If the itching persists but transaminases and bile acids are been shown to cause vasoconstriction of placental and
normal, repeat testing every 12 weeks should be performed umbilical cord vessels. Cultured rat cardiomyocytes treated
as pruritus in OC can precede biochemical abnormalities by with the bile acid taurocholic acid, have been shown to have a
several weeks. decrease in activity and a loss of ability to beat synchronously,
Liver Diseases in Pregnancy 371
supporting the hypothesis that raised bile acids within the often unfavorable as it can involve twice daily intravenous
fetal circulation could lead to sudden cardiac death. administration.
Early delivery by 3738 weeks to prevent IUD is often Water soluble vitamin K (10 mg daily) should be
practiced, although there is no strong evidence that this prescribed for women with OC after 36 weeks, particularly in
intervention improves outcome. Early delivery can be the presence of jaundice or steatorrhea or if there is abnormal
associated with risks such as failed induction of labor and clotting, to ensure adequate levels and to prevent a prolonged
subsequent cesarean section, and with neonatal respiratory prothrombin time which could be associated with postpartum
distress syndrome. Many women opt for early delivery as the hemorrhage.
small risk of stillbirth is unacceptable to them and outweighs Although there are no studies on rifampicin for the
the risks of early delivery. treatment of OC, it has been used in women who are resistant
to UCDA with some improvement in symptoms. Further
evaluation is needed before it can be recommended as a
Treatment treatment.
Topical preparations, such as calamine lotion or aqueous Liver function tests and bile acids should be checked
cream with menthol can help to alleviate itch and are safe to weekly once the diagnosis of OC has been made to monitor
use in pregnancy. The latter is more effective via its cooling treatment and disease severity, particularly as outcomes are
action. Antihistamines, such as chlorpheniramine (4 mg 6 worse with higher bile acid levels.
hourly), are safe to use in pregnancy, may help pruritus and
provide night sedation. Neither of these treatments have any
effect on fetal outcomes.
Postpartum Follow-up
Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid Women should be followed up postpartum to ensure pruritus
which replaces the pool of harmful bile acids and is well- resolves and biochemical changes return to normal. Itch
tolerated by women with OC when used in doses of 500 usually resolves within 48 hours and transaminases and bile
mg to 1 gm bd. It has been shown to improve pruritus and acids usually normalize within 28 weeks. If LFTs do not
biochemical abnormalities in women with OC, although resolve, then other causes should be sought. Women should
there is currently no evidence that it improves clinical be advised of the risk of recurrence in future pregnancy (90%)
outcomes. Its use is considered to be safe in pregnancy and it and with hormonal contraception.
is widely used in the treatment of OC, although larger studies
are needed to confirm safety. A randomized controlled trial
of 130 women with OC has compared treatment with either Hemolysis, Elevated Liver, and Low
UDCA (1g/day for 3 weeks), dexamethasone (12 mg/day for 1 Platelet Syndrome
week and placebo for 2 weeks), and placebo for 3 weeks. This
Preeclampsia is hypertension in pregnancy (BP 140/90)
study showed a significant reduction in ALT and bilirubin
in the UDCA-treated group. In a subgroup analysis of 34 presenting after 20 weeks gestation with significant
women with high serum bile acids of over 40 mol/L, there proteinuria (urinary protein: creatinine ratio 30 mg/mmol
was a significant reduction in pruritus by 75%, bile acids by or 24 hour urine collection 300 mg protein) and affects 10%
79%, ALT by 80%, and bilirubin by 50% in the UCDA group. of pregnancies. HELLP syndrome is a form of severe pre-
The study was too small to show a reduction in fetal adverse eclampsia associated with both significant maternal and fetal
events (spontaneous preterm delivery, asphyxial events and morbidity and mortality. In a recent review, HELLP syndrome
meconium). Larger studies are needed to assess further the occurred in 0.50.9% of all pregnancies and in 1020% of
effect of UCDA on fetal outcomes. women with severe preeclampsia.
Both dexamethasone and S adenosylmethionine
(SAMe) have been used for the treatment of OC with varied
improvement of symptoms and biochemistry. In the
Risk Factors
randomized-controlled trial discussed above, there was Risk factors for pre-eclampsia include first pregnancy, age
no improvement in pruritus or ALT levels in women taking over 40 years, previous preeclampsia, previous HELLP
dexamethasone, and it was less effective than UDCA in syndrome, family history of preeclampsia, obesity, chronic
reducing bile acids. Concerns regarding fetal neurological hypertension, diabetes, smoking, renal disease, multiple
effects with repeated maternal high dose dexamethasone pregnancy, antiphospholipid syndrome and inherited
limit its use in clinical practice. Treatment with SAMe is thrombophilias.
Pathogenesis Table 4: Investigations into hemolysis, elevated liver, and low platelet
syndrome and acute fatty liver of pregnancy
Preeclampsia is a multisystem disease where the exact
Liver function tests Amylase
etiology is unknown. Poor placentation is probably the initial
factor. In normal pregnancy, extravillous trophoblast invades FBC (including blood film) Blood pressure and quantitative analysis of
proteinuria if present (24hour collection or
the uterine spiral arteries to convert them from thick-walled
protein: creatinine ratio)
muscular vessels to high flow, low-resistance thin-walled
U&Es, creatinine Arterial blood gas
vessels. This process is usually complete by 2024 weeks. In
preeclampsia, there is a failure of this process resulting in Urate Lactate
placental under perfusion, hypoxia and the release of factors Clotting (check fibrin Exclude other causes raised LFTs
into the maternal circulation causing widespread endothelial degradation products if (Hepatitis A, B, C, CMV IgM/IgG, EBV
evidence of coagulopathy) IgM/IgG, antismooth muscle antibodies,
damage, intravascular platelet activation and consumption,
antimitochondrial antibodies, bile acids)
and vasospasm. In HELLP syndrome, endothelial damage can
Glucose Liver ultrasound
result in microangiopathic hemolysis and thrombocytopenia.
There is intravascular fibrin deposition and sinusoidal LDH Fetal ultrasound and cardiotocograph
obstruction within the liver causing raised transaminases, Abbreviations: LFT, liver function tests; FBC, full blood count;
periportal hemorrhage and infarction. In severe cases U&Es, urea and electrolytes; LDH, lactate dehydrogenase; CMV,
intrahepatic hemorrhage, subcapsular hematoma and liver cytomegalovirus; EBV, Epstein-Barr virus.
rupture can develop.
Along with AFLP, HELLP syndrome has been associated 109/L, +/- hemolysis) has also been described. Raised
with long chain 3-hydroxyacetyl coenzyme-A dehydrogenase transaminases are seen in preeclampsia but are usually lower
(LCHAD) deficiency (see acute fatty liver). than in HELLP syndrome. There is considerable cross over
between HELLP syndrome and AFLP and it can be difficult to
differentiate between the two disorders. Women with HELLP
Diagnosis syndrome are more likely to have preeclampsia (hypertension
Hemolysis, elevated liver and low platelet syndrome can and proteinuria), epigastric pain and thrombocytopenia
develop on a background of preeclampsia or can arise compared to those with AFLP.
suddenly with no preceding illness. Most cases present
antenatally in the third trimester, although nearly a
third present postnatally. Symptoms can be nonspecific
Maternal Risks
(summarized in Table 3) demanding a high index of suspicion. As HELLP syndrome is a form of severe preeclampsia, all
Symptoms may be insidious or develop rapidly into severe of the risks of preeclampsia can affect women with HELLP.
disease. The maternal mortality rate for HELLP syndrome is 1%.
Investigations are summarized in Table 4. HELLP syndrome Eclampsia, intracranial hemorrhage (single most common
is diagnosed in the presence of hemolysis (fragmented red cause of death from preeclampsia), abruption, renal failure,
cells on blood film, lactate dehydrogenase >600 iu/L or raised pulmonary edema, adult respiratory distress syndrome,
unconjugated bilirubin), elevated transaminases greater disseminated intravascular coagulation, acute liver failure,
than 70 iu/L and low platelets less than 100 109/L. Partial subcapsular liver hematoma, hepatic infarction, liver rupture
HELLP syndrome (transaminases >40 iu/L, platelets <150 and sepsis can all complicate HELLP syndrome.
Table 3: Symptoms of hemolysis, elevated liver and low platelet Fetal Risks
syndrome
Fetal mortality rates are 760% and will be dependent on
Generalized malaise (90%)
gestation at birth and level of care available. Intrauterine
Headache (50%) growth restriction secondary to placental insufficiency, fetal
Visual disturbance (blurring) distress, placental abruption and preterm birth (prolonged
Right upper quadrant pain/epigastric pain (6590%) stay in neonatal intensive care, respiratory distress syndrome,
Nausea/vomiting (3584%) necrotizing enterocolitis) are all complications of HELLP
syndrome. Preeclampsia is the most common cause of
Sudden swelling of hands, feet or face
iatrogenic preterm delivery.
Treatment In addition to corticosteroids for fetal reasons,

dexamethasone and betamethasone have been used for
Any woman with severe preeclampsia or HELLP should maternal treatment of HELLP syndrome. However, a recent
be managed by a multidisciplinary team consisting of Cochrane review looking at eleven random controlled trials
obstetricians, anesthetists, neonatologists and hematologists. (550 women) comparing corticosteroids with placebo found
In the presence of significant liver dysfunction, hepatologists that there was no difference in the risk of maternal death,
should be involved. severe maternal morbidity or perinatal/infant death. The
The mother should be stabilized, and it is essential that only clear effect of treatment on individual outcomes was
hypertension is controlled to reduce the risk of hemorrhagic improved platelet count. They concluded that there was
stroke and placental abruption. Labetalol (oral or insufficient evidence of benefits to support the routine use of
intravenous), intravenous hydralazine or oral nifedipine can steroids for the management of HELLP.
all be safely used for the management of acute hypertension Mode of delivery will depend on the fetomaternal
in pregnancy and postpartum when breast feeding women. condition, parity, gestation and cervical assessment (degree
Blood pressure should be maintained at 130150/80100 of dilatation and effacement). In early disease there may be
mm Hg with a mean arterial pressure less than 125 mm Hg. time to induce labor. This is more likely to be successful in
If treated too aggressively (BP <130/80 mm Hg) placental multiparous women and those near term. However, at early
hypoperfusion can cause fetal distress. As women with pre- gestations and in severe disease when delivery needs to be
eclampsia already have low intravascular volumes, diuretics expedited, delivery will need to be by cesarean section. Prior
should not be used to control blood pressure. It is important to delivery, platelet transfusion should be administered if the
to be aware that automated BP machines can underestimate platelet count is less than 20 109/L (<50 109/L if delivery
BP and validated manual sphygmomanometers should be is by cesarean section due to risk of hemorrhage) and any
used. Strict fluid balance should be maintained with hourly coagulopathy should be treated with fresh frozen plasma
input and output recordings. The total amount of fluid input and hematological input sought. Regional anesthesia is
should be restricted to 80 mL/hour to reduce the risk of fluid contraindicated when platelet counts are less than 80 109/L.
overload and pulmonary edema. Invasive monitoring (central Worsening epigastric or right upper quadrant pain could
venous pressure, arterial lines) may be required, particularly signify subcapsular liver hematoma formation. Imaging and
in the presence of oliguria or hemorrhage. Correctly fitting input from the surgical team is essential due to the risks of
graduated elastic compression stockings should be worn rupture and uncontrolled bleeding.
due to the increased risk of thrombosis. Cardiotocograph
monitoring is required while stabilizing the mother and an
ultrasound for fetal growth, liquor volume and Dopplers Postpartum
should be performed, if possible.
Regular monitoring within a high dependency unit setting
Magnesium sulfate should be commenced in those with
is essential as there can be further deterioration in the first
severe fulminating preeclampsia, particularly, if delivery is
48 hours following delivery. Those with severe disease may
planned within 24 hours, or if the woman has had an eclamptic
require intensive care support. Often there is continued
fit. This should be administered in a critical care setting with
oliguria in the first 24 hours, which is followed by a diuresis.
appropriate monitoring (continuous electrocardiograph,
oxygen saturation, respiratory rate, hourly reflexes and urine Fluid restriction should continue during the oliguric phase
output). A loading dose of 4 gm should be given intravenously due to the risk of fluid overload and pulmonary edema. Fluid
over 15 minutes, followed by an infusion of 1 g/hour main balance is more complicated in the presence of hemorrhage,
tained for 24 hours. If there are recurrent seizures, two further therefore invasive monitoring may be required. If the woman
boluses of 2 g can be given each over 15 minutes. is on magnesium sulfate, this should continue 24 hours
The only treatment for HELLP is to deliver the baby (if after delivery or 24 hours after the last fit, whichever is the
diagnosed antenatally). This should be done soon after the longest. As preeclampsia and HELLP syndrome increase the
maternal condition has been stabilized. If less than 34 weeks risk of thrombosis, graduated elastic compression stockings
gestation corticosteroids (betamethasone or dexamethasone and mechanical calf compression devices should be used.
12 mg intramuscularly for two doses 24 hours apart) should Thromboprophylaxis with low-molecular weight heparin can
be administered to improve fetal lung maturation. If the be started once the risk of hemorrhage is reduced and there
maternal condition deteriorates rapidly, there may not be is no coagulopathy.
adequate time for maximum beneficial effect of steroids Blood tests should be repeated at least 12 hourly until
which occurs 24 hours after the last dose. there is biochemical and hematological improvement.
Once women recover from the multisystem complications oxidation of mitochondrial fatty acids. Long chain fatty
of HELLP, they tend to make a good recovery. Hypertension acids are incorporated into triglycerides within hepatocytes
should be treated with oral agents which may be needed causing microvesicular steatosis. Subsequent impairment of
long term. Beta blockers, calcium channel antagonists and mitochondrial function results in hepatocyte synthetic failure
angiotensin converting enzyme inhibitors are all safe to use leading to hypoglycemia, prolonged prothrombin time and
in breastfeeding women. low albumin. LCHAD deficiency is an autosomal recessive
Any woman with HELLP syndrome should have a 6week condition and both AFLP and HELLP syndrome have been
hospital postnatal appointment where she should be seen in women who are heterozygous. It is hypothesized
examined for ongoing hypertension and proteinuria. Her that in the presence of a homozygous fetus that is unable to
liver and renal function should be tested to ensure they have oxidize long chain fatty acids, unmetabolized fatty acids enter
recovered. She should be counseled that the risk of recurrence the maternal circulation causing liver damage. The incidence
of pre-eclampsia in future pregnancy can be as high as 42% of severe liver disorders, such as AFLP and HELLP, has been
and the recurrence risk of HELLP syndrome is lower at 35%. observed more frequently in pregnancies where the fetus was
She should be recommended to take aspirin 75 mg daily from subsequently diagnosed with LCHAD deficiency. However,
the time of a positive pregnancy test in any future pregnancy not all women who carry fetuses with the abnormal genotype
as prophylaxis against pre-eclampsia. Due to the association will develop liver disease and LCHAD deficiency does not
with LCHAD deficiency, consideration should be given to the account for all cases of AFLP.
testing the fetus.
Diagnosis
Acute Fatty Liver of Pregnancy Acute fatty liver of pregnancy most commonly presents
Acute fatty liver of pregnancy is a rare and potentially lethal antenatally in the third trimester with one in four women
condition affecting 1:20,000 pregnancies. AFLP is a reversible presenting postpartum (usually within 4 days). There is
peripartum liver and renal impairment, which usually typically a prolonged prodromal phase of nonspecific
occurs in the third trimester of pregnancy, associated with symptoms, commonly nausea and vomiting, followed by
microvesicular fatty infiltration of the liver. It is considered to jaundice and then worsening hepatic function which can
be on the same spectrum of disorders as preeclampsia. It is lead to fulminant hepatic failure if left untreated (Table 5).
associated with a defect in fatty acid -oxidation. It is essential that clinicians have a high index of suspicion
Acute fatty liver of pregnancy is associated with a high in women presenting with common pregnancy symptoms.
incidence of maternal and perinatal mortality with reports Progression to severe disease can be rapid. The incidence
of 1218% and 758%, respectively. The largest prospective of infection is high and some women will have signs and
population-based study on AFLP in the UK conducted symptoms of sepsis.
through UK Obstetric Surveillance System (UKOSS) has The diagnosis of AFLP is difficult as there is not a clearly
recently shown a lower maternal rate and perinatal mortality established clinical definition. Furthermore, many features
rates of 1.8% and 7%, respectively, which probably reflects
improved diagnosis and management of these high-risk
cases. Table 5: Presenting symptoms and signs of acute fatty liver of
pregnancy
Characteristics Nausea and vomiting (70%)

Right upper-quadrant and epigastric pain (5080%)
Sixty-one percent of women with AFLP are in their first
Generalized malaise
pregnancy, with 18% having preeclampsia and 18% having a
Anorexia
multiple pregnancy. Women with AFLP are also more likely
to be carrying a male fetus. In the recent UKOSS study, 20% of Jaundice
women with AFLP had a body mass index less than 20, which Polyuria/polydipsia
is the first time this association has been seen. Infection/pyrexia
Hypertension and proteinuria
Pathogenesis Pancreatitis
Fulminant liver failure with hepatic encephalopathy
The exact pathophysiology is unknown but AFLP is
Upper gastrointestinal hemorrhage
associated with LCHAD deficiency which leads to abnormal
Table 6: Swansea criteria: greater than or equal to 6 of the following Table 7: Diagnostic features of women with acute fatty liver of
in the absence of another explanation pregnancy
Vomiting Leukocytosis > 11 x 109/L No. of women with value Median highest* or lowest
outside of normal range/n value (range)
Abdominal pain Ascites or bright liver on ultrasound scan
(%)
Polydipsia/polyuria Elevated transaminases (ALT or AST >42
Bilirubin 57/57 (100) 101 mol/L* (17677)
iu/L)
Glucose 43/55 (78) 3.1 mmol/L (1.08.2)
Encephalopathy Elevated ammonia >47 mol/L
Urate 43/49 (88) 510 mol* (49830)
Elevated bilirubin >14 mol/L Renal impairment Cr >150 mol/L
WCC 56/57 (98) 20.7 x 109* (8.546.5)
Hypoglycemia <4 mmol/L Coagulopathy (PT >14 seconds or APTT
>34 seconds) Platelet 37/57 (65) 122 x 1012 (14436)
Elevated urate >340 mol/L Microvesicular steatosis on liver biopsy Transaminases 57/57 (100) AST 310 iu/L* (373,198)
ALT 300 iu/L* (211,156)
Abbreviations: AST, aspartate transaminase; ALT, alanine
transaminase; PT, prothrombin time; APTT, activated partial Ammonia 2/4 (50) 43 mol* (1371)
thromboplastin time. Creatinine 33/57 (58) 169 mol/L* (64395)
Coagulopathy 40/46 (87) PT 22 s* (13315)
are similar to HELLP syndrome. Women with AFLP tend to APTT 49 s* (18108)
have lower glucose levels, a higher urate level, higher white Abbreviations: WCC, white sell count; AST, aspartate transaminase;
cell count and higher transaminases than those with HELLP ALT, alanine transaminase; PT, prothrombin time; APTT, activated
syndrome. Those with AFLP are also more likely to vomit, partial thromboplastin time.
have a coagulopathy and acidosis. Criteria for diagnosing
AFLP proposed by Chng et al. (Table 6) were tested in the
hemorrhage and pancreatitis are complications of AFLP
UKOSS study which found substantial agreement between
and need to be managed appropriately. Admission to an
the clinical diagnosis of cases and criteria. They suggested
intensive care unit or specialist liver unit (65%) occurs in the
that these criteria should be adopted for future studies to
majority of women. Pancreatitis in women with AFLP is a
ensure diagnostic consistency and comparability.
poor prognostic sign.
Once AFLP is suspected a full assessment should
A retrospective review of 54 pregnant women with severe
be made and investigations, as summarized in Table 4
liver disease (AFLP = 18, hypertension-related liver disease =
should be performed. Table 7 shows the ranges for results
for the 57 women in the UKOSS study. All women had 32, other causes = 4) admitted to a specialist liver unit found
raised transaminases and bilirubin, with the majority that admission lactate of greater than 2.8 mg/dL following a
having a leukocytosis, raised urate, abnormal clotting and period of resuscitation had a sensitivity and specificity of 73%
hypoglycemia. However, results can vary markedly making and 78%, respectively in predicting liver transplantation or
diagnosis difficult. death. In combination with encephalopathy, the sensitivity
Hypoglycemia, coagulopathy and a falling albumin level and specificity increased to 90% and 86%. None of the six
are all markers of disease severity in AFLP. The degree of the women in this study listed for transplantation fulfilled the
transaminitis is not prognostic. Kings College criteria which identifies those with acute liver
Microvesicular steatosis is the most characteristic feature failure at high risk of death who may benefit from a liver
of AFLP on liver biopsy. However, liver biopsy is rarely transplant. They concluded that standard criteria used for
indicated for diagnosis due to the risk of hemorrhage in the listing patients for liver transplant may not be appropriate for
presence of abnormal clotting. women with pregnancy-associated liver disease.
Maternal Risks Fetal Risks

Maternal mortality still poses a significant risk to women with The perinatal mortality is high with reports of death in up to
AFLP particularly in the developing world. Maternal mortality 66% of cases although this is likely to be an overestimate. The
rates have decreased recently probably due to prompt recent UKOSS study identified six stillbirths and one neonatal
diagnosis and women receiving the appropriate intensive death out of the 67 infants delivered giving a perinatal
care support. Fulminant liver failure, liver transplantation mortality rate 104 per 1,000 births. Fetal distress is common,
(1.8%), renal failure (14%), sepsis, gastrointestinal especially in the presence of maternal acidosis.
Treatment DISORDERS NOT SPECIFIC TO

Prompt diagnosis, supportive management and delivery in PREGNANCY
antenatal cases are the most important aspects of managing
AFLP. A multidisciplinary team approach is essential involving Gallstones
obstetricians, anesthetists, hepatologists, hematologists and
Gallstones are seen in 312% of pregnant women. The
neonatologists. Treatment is supportive with one to one care.
incidence is increased in pregnancy due to decreased
Hypoglycemia and coagulopathy should be aggressively
treated with dextrose and blood products as advised by the gallbladder motility and delayed emptying. Increased
hematologists. Broad-spectrum intravenous antibiotics bile cholesterol, lower bile acids and increased ratio of
should be commenced and any specific source of infection cholic acid to chenodeoxycholic acid also contribute to the
treated. Strict fluid balance is necessary due to the risk of stone formation. Most remain asymptomatic with acute
pulmonary edema and renal failure and invasive monitoring cholecystitis occurring in 0.1% of pregnancies.
with central venous pressure and arterial lines is often needed. Symptoms, signs, diagnosis and management will be
Hypertension should be treated as in HELLP syndrome. the same as the nonpregnant state. Seventy-five percent of
Hourly neurological observations should be performed to women will respond to conservative management by keeping
assess for encephalopathy. Dialysis may be required in the the patient nil by mouth, administering intravenous fluids,
presence of renal failure. Correctly fitting graduated elastic antibiotics and analgesia. Surgical treatment should be
compression stockings should be worn. Fetal viability should performed postpartum unless conservative treatment fails,
be confirmed and continuous cardiotocography monitoring recurrent attacks occur, there is suspected perforation of the
commenced if the fetus is still alive. If possible, a fetal gallbladder or an empyema develops. This is best performed
ultrasound should be performed. in the second trimester when the risk of miscarriage is low
Once the maternal condition has been stabilized, delivery and the uterus is not too large that it obstructs the operating
should be expedited. The mode of delivery is dependent on field. Laparoscopic cholecystectomy can be performed in
the fetomaternal clinical condition, gestation and cervical pregnancy. Risks of surgery include miscarriage and preterm
assessment. If the fetus is less than 34 weeks gestation, labor.
corticosteroids should be administered for fetal lung
maturation if there is time. However, if the maternal condition
is deteriorating delivery needs to be expedited, an urgent Hepatitis
cesarean section should be performed with blood product
support if necessary. In the presence of mild disease, there
Hepatitis A Virus
may be time to induce labor which is associated with less Hepatitis A is almost always a self-limiting illness with no
blood loss. Anesthetic input is essential as regional anesthesia increased risks in pregnancy. If women are travelling to
is contraindicated in the presence of a coagulopathy and at risk areas, hepatitis A vaccine can be administered in
general anesthetic can worsen encephalopathy. Nonsteroidal pregnancy as it is an inactivated-virus vaccine. There are no
anti-inflammatory drugs should be avoided postpartum. known fetal effects of an acute infection in the mother. If an
unvaccinated pregnant woman has had exposure to hepatitis
A, immunoglobulin can be administered. If the baby is born
Postpartum Follow-up within 2 weeks of a maternal infection, immunoglobulin
Postnatal recovery may be prolonged, particularly in the should be given to the neonate.
presence of multiorgan failure. Liver function tests should be
monitored regularly until they normalize. There have been
case reports of women developing chronic pancreatitis in
Hepatitis B Virus
the long-term. Consideration should be given to testing the Hepatitis B affects 280 million people worldwide. Between
neonate for LCHAD deficiency due to the association with 5% and 10% of infected individuals become chronic carriers
AFLP. and 2530% of the carriers die from long-term complications
Due to the rarity of the condition, the risk of recurrence is (primary hepatocellular carcinoma and cirrhosis). In
not known. In the UKOSS study, there was one woman who endemic areas, infection during the neonatal period and
had previously had AFLP. If the diagnosis of LCHAD deficiency childhood is significant. In developed countries, screening
has been made in the neonate then the risks of recurrent AFLP programs for hepatitis surface antigen (HBsAg) among
will be higher. Early review in future pregnancy is essential. pregnant women help identify those who need specific
follow-up, allow vaccination of seronegative household of a very high viral load or other infections such as HIV, it
members and vaccination and follow-up of the baby. Women may be advantageous. Invasive procedures including fetal
found to be positive for hepatitis B virus (HBV) should be blood sampling, fetal scalp electrode, and ventouse delivery
checked for hepatitis C virus (HCV) and HIV as this will should be avoided. Breast feeding is not contraindicated in
influence management and mode of delivery. Liver function maternal HCV infection but should be avoided if the nipples
tests should be monitored throughout pregnancy. are cracked or bleeding or if the patient is also HIV positive.
Acute HBV infection in pregnancy has the same symptoms, Treatment with ribavirin is contraindicated in pregnancy as it
signs and investigations as the nonpregnant state. Vertical is highly teratogenic and should be stopped 6 months prior to
transmission with infection in the first trimester is 10%, but conception.
rises dramatically to 90% with infection in the third trimester.
Treatment is supportive, as in the nonpregnant state with
avoidance of liver-metabolized drugs. For hepatitis B carriers, Hepatitis D Virus
the fetus is usually infected at the time of delivery, although Hepatitis D virus is only found in women with HBV infection.
intrauterine infection can occur. Transmission is greater Transmission to the fetus is rare and reduced by the same
among those who are HBV e antigen positive (HBeAg, 90%) preventative measure as for HBV, including vaccination of the
compared with those who are HBsAg positive and HBeAg newborn with the HBV vaccine.
negative (10%). Intrauterine infection is more likely during an
acute infection in pregnancy or with high maternal HBV DNA
levels. A high viral load is associated with failed immunization Hepatitis E Virus
in the neonate and these women may benefit from treatment Hepatitis E virus (HEV) is a self-limiting infection in the
with lamivudine. nonpregnant population, however, it is associated with
Cesarean section does not confer fetal protection so it significant maternal and fetal morbidity and mortality in
is not indicated for HBV infection alone. In the presence of pregnancy. Infection is more common in pregnancy and the
concomitant HIV or HCV infection, cesarean section can severity and progression of symptoms are worse. Fulminant
reduce transmission of the viruses to the fetus. In a woman liver failure occurs in 3269% with an associated maternal
with hepatitis B, fetal blood sampling, fetal scalp electrodes, mortality of 41%. Mortality rates increase with advancing
and operative vaginal delivery (particularly ventouse) can gestation. The vertical transmission rate is one-third. Two-
increase fetal transfer, so they should be avoided. thirds of the affected women will deliver preterm and the fetal
The neonate should receive hepatitis B immunoglobulin loss rate is 3062%. Women with suspected or proven HEV
(HBIG) immediately postpartum along with the hepatitis B should be managed in a specialist liver unit. There is currently
vaccination at birth, 1 month and 6 months. This combined no vaccination available.
approach, increases efficacy to over 90%. It is safe for mothers
to breastfeed as long as the baby has received HBIG and the
HBV vaccination.
BIBLIOGRAPHY
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Hepatitis C Virus myometral contractility of the isolated pregnant uterus]. Rev
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109(1):99-104
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10. Hirvioja ML, Tuimala R, Vuori J. The treatment of intrahepatic
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41
cHAPTER
Liver Transplantation
Ravi Mohanka, Punit Singla, AS Soin
HISTORY AND EVALUATION lifesaving LT to all those who need it and in time to benefit
from it.
Liver transplantation (LT) is a procedure of replacing a Fulfilling the large gap between demand for LT and
severely damaged, injured or dysfunctional liver with a availability of organs is crucial in reducing waiting list
functionally normal one. Liver being a deep seated and very mortality. In the past, waiting list mortality was particularly
vascular organ, initial attempts at transplantation were met very high in children, because pediatric donors were scarce
with profound technical difficulties, severe bleeding, high and the whole liver from an adult donor was often too big
complication rates and mortality. Liver transplantation was for them; thus putting children waiting for a transplant at a
first attempted and subsequently successfully performed by disadvantage. Efforts to overcome this gap have been directed
Dr Thomas Starzl. Since then, it has evolved to address various at increasing donation rates, expanding the donor pool and
initial problems associated with it into a safe operation. It optimizing the use of available organs. Thus, reduced size
is currently the standard of care for the treatment of end- liver transplant was described, where the liver graft was
stage liver disease (ESLD). During its evolution, not only the reduced in size to fit into the small abdomen, and rest of the
feasibility of various complex surgical techniques have been liver was discarded. The technique was improvised to obtain
demonstrated and need for various types of liver grafts better two lobes useful for two transplants, i.e. split liver transplant
defined, but its indications in various diseases and outcomes (SLTx), the split commonly being performed on the bench,
have been better understood. The last few decades has i.e. ex situ. Soon, techniques for in situ split in the donor were
witnessed an increase in number of centers and transplants developed to reduce cold ischemic time (CIT). In traditional
all over the world. Several incremental developments have SLTx [adult-child split liver (ACSL)], the liver is split along
contributed to its success, such as better understanding the umbilical fissure resulting in a right extended lobe and
of liver anatomy, transplant immunology, availability of left lateral segment for use in an adult and child respectively.
better immunosuppressive drugs, antimicrobials, organ In adult-adult split liver (AASL), the liver is split along the
preservation solutions, surgical instruments, innovations Cantlies line into right and left lobes suitable for two adults.
in surgical techniques and advancements in anesthetic and Another innovation in AASL ex situ SLTx technique is the full
critical care. The Western world took the lead in defining the right-left split, where inferior vena cava (IVC) and middle
legal framework, logistic support and infrastructure required hepatic vein (MHV) are divided down their vertical axis
for retrieval of solid organs from brain dead (deceased) and shared between both lobes to optimize their outflow.
donors and transplantation. As a result, allocation of this Reduced grafts contribute 0.9% and 4% of transplants in
scarce resource is now more objective, transparent and fair. USA and Europe, respectively, while corresponding figures
Soon, the demand for LT outstripped the availability of donor for SLTx are 4.4% and about 5%. Emboldened by adequacy,
organs resulting in significant mortality while waiting. There safety, technical feasibility and experience with partial liver
also was, and still is, large variation in organ donation rates grafts and demonstration of liver regeneration, partial liver
between various countries, ranging from 30 donations per grafts were harvested from living donors and successfully
million population (pmp) in some European countries to as used first in children and then in adults. Necessitated by
low as 0.02 pmp in some Asian countries, probably because poor deceased donation rates, Asian centers developed
of difference in sociocultural beliefs, healthcare economic techniques of living donor liver transplantation (LDLT),
structure and availability of expertise in that part of the world. pioneered several surgical techniques and gained a large
Despite significantly improved survival after LT, shortage of experience. Adult to adult LDLT generally entails right
donor organs remains the major limiting factor to provide lobe donation which being a major procedure, concerns of
donor safety and its ethical appropriateness continues to Table 1: Common etiologies of liver failure needing liver
be widely debated. Latest techniques in laparoscopic and transplantation
robotic surgery are increasingly being used in donor surgery
Adults Children
to reduce donor morbidity. Currently, while in most North
Chronic liver disease (CLD) Chronic liver failure
and South American and European countries, deceased
Chronic hepatitis Cholestatic disorders
donor liver transplantation (DDLT) is predominant, most Viral (hepatitis B or C)* BA (most common)
LT in Asian countries are LDLT. In the USA in 2010, 6,291 Alcoholic* Alagilles syndrome
LT were performed, out of which 6,009 were DDLT and 282 Cryptogenic* Nonsyndromic biliary hypoplasia
were LDLT, while the waiting list consisted of nearly 16,000 Autoimmune hepatitis (AIH) Familial intrahepatic cholestasis
Drug-induced liver injury (DILI) Chronic hepatitis
patients. In Europe, about 4,000 transplants are performed
Cholestatic disorders AIH
each year, with 668 DDLT and 21 LDLT performed in the UK Primary biliary cirrhosis (PBC) Viral (hepatitis B, C, other)
in 2010. In Brazil, little more than 1,000 transplants were done Primary sclerosing cholangitis Cryptogenic
in 2010, only 7% of them being LDLT. It is estimated that in (PSC)
India, about 20,000 LT are required, while in 2010, the best Cystic fibrosis
Biliary atresia (BA)
year so far, only about 700 LT were performed, most being
LDLT. Acute liver failure (ALF) ALF
Fulminant subacute viral Autoimmune
While all types of LT described above involve complete
hepatitis (A, B or E)* Toxin (halothane/paracetamol)
removal of native liver and replacement with a new liver Toxin-drugs (paracetamol)* Viral hepatitis (A*, B, C, E* or
graft at the same location in abdomen, i.e. orthotopic LT, Pregnancy related NA-G)
modifications may be required in rare situations. The native Amanita poisoning Indeterminate
liver may be left behind and the new liver graft implanted in Wilsons disease
Indeterminate
iliac fossa, i.e. heterotopic auxiliary liver transplant (HALT) or
the native liver may be partially removed and the new graft Liver tumors Liver tumors (selected cases)
Hepatocellular carcinoma (HCC) Hepatoblastoma
implanted in its place, i.e. auxiliary partial orthotopic liver
Benign tumors (rarely) Benign tumors (rarely)
transplant (APOLT). Another complex technique is dual Other tumors (metastatic Other tumors (HCC)
lobe transplant, where partial livers from two living donors neuroendocrine tumors)
are transplanted into one patient to increase the hepatocyte Metabolic diseases Metabolic disorders
mass. When patients with metabolic enzyme defect undergo 1-antitrypsin deciency (A1A) 1-antitrypsin deciency
LT, their native livers may be used for another LT called as a Hemochromatosis CF
dominotransplant. Wilsons disease Glycogen storage disease (type
Nonalcoholic steatohepatitis IV)
(NASH)/nonalcoholic fatty liver Tyrosinemia (type I)
disease (NAFLD)* Wilsons disease*
INDICATIONS for liver Crigler-Najjar (type I)
Familial hypercholesterolemia
transplantation Fatty acid oxidation defects
Primary oxalosis
Etiologies of liver diseases and Indications for LT are different Organic acidemia
in adults and children, but they can be broadly grouped into Urea cycle defects
decompensated chronic liver disease (CLD)/ESLD, fulminant Uncommon Uncommon
hepatic failure/acute liver failure (FHF/ALF), liver tumors Budd-Chiari syndrome Fibropolycystic liver disease
and metabolic liver diseases (Table 1). Polycystic liver disease
Amyloidosis
Hepatitis C virus (HCV) is the most common indication for Noncirrhotic portal fibrosis
LT and constitutes about 40% of transplants in USA, 15% in
* common
Europe, 34% in Asia and 30% at our center. Hepatitis B virus
(HBV) generally constitutes about 67% of transplants but
almost 80% in South Korea and 15% at our center. Alcoholic
liver disease constitutes 1218% of transplants in USA and
Europe, about 3% in Asia and 22% at our center. cholangiocarcinoma, hepatoblastoma, embryonal sarcomas
Hepatocellular carcinoma (HCC) constitutes about and hemangioendotheliomas is rare.
1025% of transplants. At our center, 23% of the transplant Cholestatic liver diseases [primary sclerosing cholangitis
recipients had HCC (most with underlying cirrhosis). (PSC), primary biliary cirrhosis (PBC) and secondary biliary
Liver transplantation for other liver tumors, such as cirrhosis] constitute about 825% of transplants. Nonalcoholic
Liver Transplantation 381
steatohepatitis (NASH) and nonalcoholic fatty liver disease the liver but leading to injury to other organ systems, such
(NAFLD) are increasing indications for LT. Metabolic diseases as the urea cycle disorders, Crigler-Najjar syndrome and
like Wilsons disease and hemochromatosis constitute hyperoxaluria. While hepatoblastoma is the most common
about 36% of transplants. If the cause of ESLD is obscure pediatric liver tumor requiring LT, HCC is commonly found in
despite extensive preoperative testing, they are labeled as children with tyrosinemia.
cryptogenic, which constitutes about 210% of transplants,
although some of these might have underlying NAFLD not
diagnosed preoperatively.
Indications for Liver

Acute liver failure constitutes about 39% of transplants. The
etiology of ALF differs amongst age groups and geographically transplantation, selection,
across the world. The most common etiology of ALF among and PRIORITIZATION for organ
adults in the US and most of Europe is viral hepatitis (hepatitis
A, B, E) while that in the UK is drug-induced liver injury
allocation
(DILI) mostly related to acetaminophen overdose. Metabolic
diseases, such as congenital hemochromatosis, galactosemia, Indications in Chronic Liver Disease/
tyrosinemia and mitochondrial cytopathies present early in End-stage Liver Disease
children, while Wilsons disease generally presents later in
childhood. In India, major causes of ALF are viral hepatitis In CLD, the need to transplant is estimated based on the
(90%, Hepatitis E > A > B) and DILI (antituberculosis drugs severity of liver disease, which is graded and prognosticated
and herbal preparations). About 1520% cases are due to by scoring systems, such as the Child-Turcotte-Pugh (CTP)
indeterminate cause, which in children may be up to 50%. and model for end-stage liver disease (MELD) scores
Approximately 520% LT (9% at our center) is performed (Tables 2A and 2B). While in USA, MELD score is used for
in children, biliary atresia being the most common indication prioritization and organ allocation, in Europe, allocation in
followed by metabolic diseases. Liver-specific metabolic various geographical areas is governed by different organ
diseases can be divided into: (i) those that lead to liver injury, exchange organizations and protocols, e.g. United Kingdom
with or without other organ involvement, such as alpha- Transplant (UKT), Eurotransplant, Scandiatransplant and
1-antitrypsin deficiency, Wilsons disease, tyrosinemia, others. Disease-specific scores are good at prognostication
familial cholestasis and cystic fibrosis, and (ii) diseases due but find limited application for comparison or prioritization
to a metabolic defect expressed solely or predominantly in among large cohorts (Table 2C).
Table 2A: Severity assessment for chronic liver disease
CriteriaChild-Turcotte-Pugh (CTP) Points

score 1 2 3
Serum total bilirubin [mol/L (mg/dL)] <34 (<2) 3450 (23) >50 (> 3)
Serum albumin (g/L) >35 2835 <28
Prothrombin time (INR) <1.7 1.712.2 >2.2
Ascites None Controlled with diuretics Refractory
Hepatic encephalopathy None Grade III Grade IIIIV
MELD and its variations
MELD score (for patients >12 years of age) = 9.57 x Log [serum creatinine (mg/dL)] + 3.78 x Log [serum bilirubin (mg/dL)] + 11.2 x Log (INR) + 6.43 Values
range (640)
MELD-sodium = 9.57 x Loge [serum creatinine (mg/dL)] + 3.78 x Loge [serum bilirubin (mg/dL)] + 11.2 x Loge (INR) + 6.43 + 1.59 x [135 serum sodium
(mg/dL)]
UKELD = 1.485 x Loge [serum creatinine (mol/L)]) + 3.13 x Loge [serum bilirubin (mol/L)] + 5.395 x Loge (INR) + 81.565 x Loge [serum sodium (mmol/L)]
+ 435
PELD scoring system
PELD score (patients up to 12 years) = 0.480 x Loge [serum bilirubin (mg/dL)] + 1.857 x Loge (INR)- 0.687 x Loge [serum albumin (g/dL)] + 0.436 (if the patient
is <1 year old) + 0.667 [if the patient has growth failure (2 standard deviation)]
Abbreviations: INR, international normalized ratio; MELD, model for end-stage liver disease; UKELD, United Kingdom model for end-stage liver
disease; PELD, pediatric end-stage liver disease
Table 2B: Prognostic implications of MELD/CTP systems in CLD Indications in Hepatocellular Carcinoma
Prognostic implications of CTP score Liver transplantation is the best option for patients with
Class Score Survival CLD and HCC, because not only it offers complete resection
A 56 90% at 5 years with the widest surgical margin (total hepatectomy), it also
B 79 80% at 5 years eliminates the potentially tumorogenic environment of
cirrhotic liver. Until the 1990s, patients with advanced HCC
C 1015 60% at 1 year
underwent LT resulting in very high recurrence rates and
Prognostic implications of MELD score
poor survival. However, when LT was restricted to patients
Score Survival with limited HCC, very good outcomes were achieved. A
3 months 1 year large majority of patients with HCC do not have very severe
09 98% 90% CLD, thus allocation scores based on CLD severity put them
1019 94% 80% at a disadvantage, they had very long waiting times and
progression of tumor. In 2002, in USA, the Milan criteria were
2029 81% 66%
accepted to upgrade MELD score and prioritization on the
3039 48% 33%
waiting list for patients with limited HCC. With improved
>35 29% imaging, multimodality treatment [including transarterial
Abbreviations: MELD, model for end-stage liver disease; CTP, Child- chemoembolization (TACE), radiofrequency ablation (RFA),
Turcotte-Pugh; CLD, chronic liver disease ethanol injection and cryosurgery], excellent outcomes have
been achieved lately. At about the same time, LDLT also
Table 2C: Etiology-specific scoring systems in chronic liver disease
gained popularity, thus practically eliminating waiting time.
Alcoholic liver disease Soon it was felt that the Milan criteria were too restrictive
Maddrey (modified) DF calculated as = 4.6 (prolongation of prothrombin and excluded patients with reasonable survival. Many liberal
time in seconds) + serum bilirubin (mg/dL). A modified DF score >32 in criteria have been described and used since then, especially
the presence of hepatic encephalopathy predicts >50% mortality within 28 in LDLT, some incorporating in addition to morphological
days in patients with alcoholic hepatitis criteria, pathological and molecular markers (Table 3).
GAHS (2005): GAHS is a composite scoring system based on age, serum
bilirubin, blood urea nitrogen, prothrombin time and the peripheral Table 3: Various criteria for liver transplantation in HCC
leukocyte count. GAHS 9 is a predictor of mortality and is more accurate
than DF in predicting both 28- and 84-day mortality Criteria Single Multiple lesions Non-size criteria
Lille model incorporates age, renal insufficiency, albumin, prothrombin lesion (cm) No. Size (cm)
time, bilirubin and the evolution of bilirubin on day 7 to predict 6-month Milan 5 3 3
mortality in patients with severe alcoholic hepatitis who have received UCSF 6.5 3 4.5 Sum of all
corticosteroid therapy diameters 8.5 cm
PSC Pittsburgh criteria Modified TNM staging
Mayo PSC risk score: R = 0.03 x (age in years) + 0.54 x log (bilirubin in mg/ Barcelona <7 3 <5
dL) + 0.54 x log (AST in IU/L) + 1.24 x (history of variceal bleeding) - 0.84 x 5 <3
(albumin in g/dL) Kyoto 10 5 PIVKA 100 mAU/mL
Primary biliary cirrhosis Tokyo (5-5 rule) 5 <5
Mayo risk score (R): 0.871 x loge (bilirubin in mg/dL) - 2.53 x loge (albumin Bologna (Italy) 5-6 2 5
in g/dL) + 0.039 x (age in years) + loge x (prothrombin time in seconds) + criteria
6 4 (sum
0:859 (if edema is present) 12)
Nazer score (Wilsons disease) Hangzhou criteria 8 cm or >8 cm, with grade I or II/AFP 400
Based on serum bilirubin, AST and prothrombin time (each parameter New Milan (up to 7) Sum of number of tumors + diameter of largest
graded on a 04 scale); cutoff >7 tumor 7
New Wilsonss index (revised Wilsons disease prediction index) Edmonton Total tumor volume 115 mL, AFP 400 ng/mL
Asan criteria 6 5 No gross vascular
Based on a combination of AST, albumin, bilirubin, INR and white cell count
invasion
(each parameter was graded on a 04 scale); cutoff >11
Abbreviations: UCSF, University of California, San Francisco; TNM,
Abbreviations: DF, discriminant function; GAHS, Glasgow alcoholic
tumor node metastasis; PIVKA, proteins induced by vitamin k
hepatitis score; PSC, primary sclerosing cholangitis; AST, aspartate
antagonists; AFP, alpha fetoprotein
aminotransferase; INR, international normalized ratio
Indications in Fulminant Hepatic Failure/ Indications in Children

Acute Liver Failure Liver transplantation is indicated when liver disease in
In ALF, Kings college criteria (KCC) (Table 4A) are widely used children is either progressive, decompensated, significantly
to predict outcome and determine the need for transplant. impacts growth and development, quality of life or causes
Other criteria (Table 4B) like Villejuif-Clichy criteria, Acute recurrent cholangitis and sepsis. Pediatric end-stage liver
Physiology and Chronic Health Evaluation II (APACHE II) disease (PELD) score takes into account severity of liver
score and MELD score have also been shown to be useful for dysfunction and growth failure and is used for wait listing
prognostication in ALF. Evidence of hepatocyte necrosis on (> 25) and organ allocation in USA (Table 2A). Indications and
liver biopsy, fall in transaminases and reducing liver size on timing of LT for metabolic disorders is commonly dictated
imaging are indicators of poor response to supportive care. by its systemic manifestations rather than measures of liver
dysfunction. Similarly, in children with hepatoblastoma,
Table 4A: Kings college criteria (KCC) optimal timing for LT depends on chemoradiation schedule.
It is therefore common for pediatric transplant programs to
Acetaminophen-induced liver failure
offer LDLT or request prioritization as exception to PELD
Arterial blood pH <7.30 (irrespective of grade of encephalopathy) score.
Or all of the following:
Prothrombin time >100 seconds (INR >6.5)
Serum creatinine >300 mol/L
Grade III/IV hepatic encephalopathy Contraindications for Liver
Nonacetaminophen acute liver failure transplantation
Prothrombin time >100 seconds (INR >6.5) irrespective of grade of
encephalopathy In patients with CLD, contraindications for LT are malignancy
Or with extrahepatic or macrovascular involvement, active,
any three of the following (irrespective of grade of encephalopathy) extrahepatic uncontrolled or refractory infection, severe
Age <10 or >40 years cardiopulmonary or other comorbid conditions, active
Etiology: non-A/non-B hepatitis, drug-induced psychiatric illness or lack of psychosocial support, active
Duration of jaundice to encephalopathy >7 days
Prothrombin time >50 seconds (INR >3.5)
alcohol or other substance abuse, or anticipated major
Serum bilirubin >300 mol/L technical difficulty, e.g. portal vein thrombosis (PVT) or
dense adhesions.
In patients with ALF, absolute contraindications are
Table 4B: Prognostic criteria for acute liver failure intracranial pressure (ICP) greater than 35 mm Hg, cerebral
perfusion pressure (CPP) less than 40 mm Hg for more than
Prognostic Etiology Predictor of poor prognostic
variable outcome 2 hours, fixed and dilated pupils, poor transcranial Doppler
KCC All signal, features of brain death, established systemic sepsis
Clichy criteria All HE + factor V <20% (age <30 or septic shock, severe acute lung injury or severe multi-
years) or <30% (age >30 years) organ system failure. Relative contraindications are repeated
Factor V; factor Acetaminophen Factor VIIIV ratio >30 suicide attempts or psychological instability.
VIII/V ratio Factor V <10%
APACHE II All APACHE II >19
Gc-globulin All Gc-globulin <100 mg/L
recipient evaluation and
Lactate Acetaminophen Admission arterial lactate >3.5
or >3.0 mmol/L after fluid preparation
resuscitation
AFP Acetaminophen AFP <3.9 mcg/L 24 hours post- Patients undergo comprehensive evaluation by a
peak ALT multidisciplinary team to establish the etiology and severity
MELD Acetaminophen MELD >33 at onset of HE of liver disease and patients suitability for LT. Once deemed
Nonacetaminophen MELD >32 suitable for LT, patients are waitlisted, proactively monitored
Abbreviations: KCC, Kings college criteria; HE, hepatic enceph and managed to prevent deterioration because the waiting
alopathy; APACHE II, acute physiology and chronic health evaluation period might be long and risk of mortality is high.
II; AFP, AFP, alpha fetoprotein; ALT, alanine transaminase; MELD, Evaluation includes a detailed history and physical
model for end-stage liver disease examination. History of alcohol abuse or past blood
transfusion might indicate the etiology. History of previous While Na less than 120 mmol/L is a contraindication for LT
abdominal surgery, especially upper gastrointestinal/ unless corrected. It should be corrected gradually with strict
hepatobiliary (HPB) surgery and corresponding abdominal fluid restriction, stopping diuretics and giving albumin to
scar should be examined to better plan a technically avoid central pontine myelinolysis.
challenging LT. Serologic markers may help determine etiology and plan
Ascites should be graded and patients with grade 1 or long-term antiviral therapy. Hepatitis B patients should
2 ascites should be managed with fluid and salt restriction, be treated with antiviral medications and a negative viral
diuretics, prophylactic antibiotics for spontaneous bacterial load preferably achieved before transplant. They may need
peritonitis (SBP) and periodic monitoring for renal function perioperative hepatitis B immunoglobulin and postoperative
and electrolyte imbalance. Patients with moderate or tense antiviral medications. Patient having HBcAb positive
ascites may need diagnostic or therapeutic paracentesis and but HBV DNA negative requirts antiviral therapy alone.
plasma expanders such as albumin. Spontaneous bacterial Cytomegalovirus (CMV) IgG negative patients are at a high
peritonitis (positive culture and/or cell count >250 cells/ risk of postoperative CMV infection and should be given
mm3) should be treated with intravenous antibiotics. antiviral prophylaxis. Microbiologic screen is done to rule
Although minimal encephalopathy, i.e. subtle changes out active infections. Autoimmune antibody screen, iron
in mental function detectable on neurophysical tests can be and copper profile is done to determine etiology. Endocrine
seen in 3070% of patients, but about 30% patients develop abnormalities (thyroid and lipid), if any, should be corrected
overt clinical hepatic encephalopathy (HE), which is before LT.
graded using semiquantitative West Haven criteria. Hepatic Detailed cardiorespiratory risk analysis and evaluation
encephalopathy may be precipitated by constipation, with electrocardiogram (ECG), stress echocardiography
gastrointestinal bleeding, infection, sedatives, renal and (ECHO), pulmonary function tests (PFT), arterial blood
electrolyte abnormalities, excessive dietary protein intake, gas (ABG), and coronary or pulmonary imaging if required
severe decompensation (e.g. PVT), transjugular intrahepatic is done and expert opinion sought. Patients found to have
portosystemic shunt (TIPS) or any surgical procedure. portopulmonary hypertension (PPHTN) are at significantly
It is managed with nonabsorbable disaccharides, such higher perioperative and long-term risk. If pulmonary artery
as lactulose, restricted protein diet (minimum 30 g/day) systolic pressures (PASP) are elevated on ECHO, right heart
and luminal antibiotics, such as neomycin or rifaximin to pressure measurements should be done. Pulmonary vascular
minimize endogenous ammonia production. Patients with resistance (PVR) greater than 240 dynes/cm2 and pulmonary
grade III HE should be considered for elective intubation for wedge pressure less than 15 mm Hg are suggestive of PPHTN.
airway protection. Mild or moderate pulmonary arterial hypertension (PAH/
Patients undergo detailed laboratory testing including PPHTN) should be treated with pulmonary vasodilators
complete hemogram, coagulation profile, and liver and (prostacyclin, bosentan or sildenafil) and normal pressures
renal function tests. Assessment of degree of hypersplenism documented (PASP to <3540 mm Hg and PVR <400 dynes/
and coagulopathy enables appropriate provision of blood cm2) before surgery.
products for surgery. Renal vasoconstriction associated with Hypoxemia (PaO2 <70 mm Hg on ABG or alveolar to
advanced liver disease leads to severe renal vasoconstriction arterial (Aa) oxygen gradient >20 mm Hg) suggestive of
and functional renal insufficiency called as hepatorenal hepatopulmonary syndrome (HPS) may be found in 1520%
syndrome (HRS). In patients with renal dysfunction, the cause patients. It should be confirmed with bubble ECHO and shunt
should be investigated and in suspected HRS, combination fraction quantified with Tc 99 macroaggregated albumin
of vasoconstrictor drugs (noradrenaline, midodrine or scan. Patients with severe HPS (PaO2 <60 mm Hg) have a high
vasopressin analogs such as terlipressin or octreotide) and risk of mortality, although they may not have a high disease
plasma volume expansion with albumin could be tried to severity score (CTP/MELD). Because HPS is potentially
reverse HRS. Nonsteroidal anti-inflammatory drugs (NSAIDs), reversible with LT, they qualify for MELD exception in USA.
which inhibit prostaglandin synthesis and hemodialysis may Preoperative PaO2 less than 50 mm Hg and shunt fraction
further decrease renal blood flow and should be avoided. greater than 20% are contraindications for LT.
Patients with glomerular filtration rate (GFR) less than 30 mL/ Liver imaging in the form of ultrasound abdomen with
min, significant proteinuria or need for prolonged dialysis Doppler, triphasic computed tomography (CT) scan or magnetic
should be considered for simultaneous liver kidney (SLK) resonance imaging (MRI) should be done to evaluate for liver
transplant. Hyponatremia (Na <130 mmol/L) is commonly mass and outline the anatomy and patency of liver vessels, i.e.
found and has been incorporated in MELD-Na and UKELD hepatic artery (HA), portal vein (PV) and hepatic veins (HVs).
scores to improve their prognostication value (Table 2A). Patients with HCC should undergo tumor evaluation in the
Table 5: Donors for deceased donor liver transplantation

Ideal donor ECD Donation after cardiac death
50 years or younger Steatosis (>30%), necrosis, fibrosis Maastricht classification
Type 1: Brought dead
No hepatobiliary disease Old age (>65 years) Type 2: Unsuccessful resuscitation
Normal LFTs Prolonged CIT (>10 hours) Type 3: Awaiting cardiac arrest
No severe abdominal trauma/systemic High LFTs (bilirubin >2 mg%, AST/ALT Type 4: Cardiac arrest after brainstem death
infection/cancer > four times normal)
Hemodynamic and respiratory stability (systolic Reactive serology (HBsAg, HCVab, HBcAb)
blood pressure > 100 mm Hg, CVP >5 cm H2O)
None or low vasopressor support (dopamine < Donor BMI (>35)
10 g/kg/min)
Urine output >50 mL/hr and normal creatinine High vasopressor support
ICU stay (>5 days)
High serum sodium (>160)
Active infection: positive blood cultures with
MDR organism
Malignancy (low grade brain or skin)
Abbreviations: ECD, extended criteria donor; LFTs, liver function tests; CVP, central venous pressure; CIT, cold ischemia time; AST, aspartate
aminotransferase; ALT, alanine transaminase; HBsAg, hepatitis B surface antigen; HCVab, hepatitis C virus antibody; HBcAb, hepatitis B core
antibody; BMI, body mass index; MDR, multidrug resistant
form of tumor markers [alpha fetoprotein (AFP)], positron transplant community to extend the criteria and accept
emission tomography (PET) and bone scan to evaluate extent of marginal livers for transplantation. Although a consensus
its spread. Female patients should undergo mammogram and definition remains elusive, a marginal or extended criteria
PAP smear to rule out common malignancies. donor (ECD) (Table 5) has risk factors for suboptimal graft
Upper and lower gastrointestinal endoscopy is done function. The decision to retrieve and use such an organ
to evaluate portal hypertension (PHT) and rule out depends on the judgment of the transplant team and informed
malignancies. Patients with small varices should undergo consent of the intended recipient. If two or more ECD criteria
periodic surveillance endoscopy if the waiting period is long. are met, the liver might be at too high risk to use. An ageing
Patients with history of severe variceal hemorrhage in the past, population has led to increase in average donor age. While
active bleeding at the time of endoscopy, stigmata of recent livers from older donors are smaller and tend to be more
hemorrhage, large varices, severe liver disease or impaired fibrotic, this does not seem to influence recipient outcome.
renal function should be considered for noncardioselective Steatotic livers have higher susceptibility to ischemia,
beta-blockers such as propranolol or nadolol. preservation and reperfusion injury and are graded based
All patients should be evaluated by a psychiatrist, dentist, on macrovesicular steatosis into mild (<30%), moderate
anesthetist, hepatologist, cardiologist and pulmonologist for (3060%) or severe (>60%). While risk of graft dysfunction
surgical fitness. with microvesicular steatosis or mild macrosteatosis is
minimal and with severe macrosteatosis unacceptable, the
risk with moderate steatosis remains unclear. Prolonged
CIT increases the risk of primary nonfunction (PNF) and is
donor Evaluation and an independent risk factor for hepatic ischemiareperfusion
preparation injury, intrahepatic biliary stricture as well as early rejection.
While CIT less than 1216 hours is well tolerated, it is
Donor Selection for Deceased Donor essential that CIT should be minimized. Hepatitis B virus
Liver Transplantation positive donor livers can be safely used in HBV recipients or
those with immunity (vaccinated) against HBV. The HBcAb
In 1980s, LT was relatively new, and deceased donors were positive donor livers can be used too with a small risk of de
very carefully selected; however, over time the large demand- novo HBV infection. Hepatitis C virus positive donor livers
supply gap and high wait list, mortality has prompted the with no evidence of hepatitis or fibrosis on biopsy have been
used for HCV patients without adversely impacting HCV graft volume may be managed by graft inflow modulation or
recurrence, and graft or patient survival. Donor Na greater use of dual lobes in the recipient, both of which do not increase
than 155 meq/L significantly increases risk of PNF, but not the donor risk. Donor steatosis may be reduced by following
if corrected before organ retrieval. Livers from donors with a dedicated exercise and weight loss regimen. However,
non-melanoma skin cancers, in situ cancers or noncerebellar potential donors with inadequate estimated remnant or
low-grade brain tumors not treated with ventriculoperitoneal significant medical risks should not be accepted for donation.
shunts carry an acceptable risk of transmission (0.02%). With increasing experience, many centers, including ours
Donation after cardiac death (DCD), i.e. non-heart beating seldom reject donors for anatomical variations.
donors (NHBD) have severe brain injury incompatible with
recovery but do not meet the Harvard criteria for brainstem
death. Donation after cardiac death can be stratified into four
categories (Table 5) and two groups: uncontrolled (categories Surgical technique
1 and 2) and controlled (categories 3 and 4). Uncontrolled
donation may necessitate additional measures like Donor Operation
placement of femoral or peritoneal cannulae for precooling
or cardiopulmonary bypass. These interventions may lead to Liver Recovery from Deceased Donor (Fig. 1)
several social and ethical concerns about withdrawal of care;
The liver may be recovered in isolation or as part of a
therefore, some centers only accept organs from controlled
multiorgan harvesting. Broadly the procedure consists of
donors, even though retrieval protocols vary in different
warm dissection, in situ cold perfusion of abdominal organs
centers. The risks of PNF and ischemic type intrahepatic biliary
strictures (IHBS) are major concerns in use of these grafts. with preservative solution followed by cold dissection,
harvesting and packing. Abdomen and chest are opened
with a midline incision and sternotomy. Round, falciform
Donor Evaluation and Preparation for and left triangular ligaments are divided. Extended Balfour
Living Donor Liver Transplantation and sternal retractors are placed. A rapid exploration of the
abdominal cavity is done to rule out tumors.
The spirit of living donation mandates that the decision to
donate should be free, voluntary and informed. A detailed and
thorough evaluation is an important multistep process, with
more intensive and invasive tests reserved till later in the process
to minimize the risk of surgery and optimize donor safety.
Potential donors prescreened for blood group are
counseled about the evaluation process and their willingness
is confirmed. A detailed history and physical examination
are undertaken, especially history of previous HPB surgery.
Hematological, biochemical and serological workup includes
hemogram, liver and renal function tests and viral marker.
Next step is to evaluate for steatosis, which is generally done by
using liver attenuation index (LAI = L - S) or liver/spleen (L/S)
ratio on plain CT scan; alternatively MRI may be used. If their
verdict is equivocal, a liver biopsy should be done. The next
step is a triphasic liver CT scan for volumetry with calculation
of graft to recipient weight ratio (GRWR) and estimation
of future donor remnant volume. It also gives a roadmap of
hepatic vasculature for surgical planning. This is followed
by magnetic resonance cholangiopancreatography (MRCP)
to outline biliary anatomy. Cardiorespiratory evaluation is
done by ECG, ECHO and PFT and risk analysis by cardiologist
and pulmonologist. Invasive coronary or pulmonary imaging
and carotid Doppler may be indicated in older donors with
other risk factors. The donor also undergoes gynecology,
hepatology, psychiatrist and anesthesia evaluation. Fig. 1: Deceased donor liver recovery
Inadequate volume, steatosis and medical risks remain Abbreviations: HTK, histidine tryptophan ketoglutarate preservative solution;
important reasons for rejection of donors. The problem of low IVC, inferior vena cava; SMV, superior mesenteric vein
Warm dissection: Liver is grossly accessed for color, cannulation and perfusion are performed followed by warm
consistency, edges and character, biopsies are taken if blood venting. Rest of the dissection is done in cold dissection
needed, porta hepatis and gastrohepatic ligaments are phase.
inspected and palpated to identify any variations in anatomy,
in particular, accessory or replaced HA branches. Medial
visceral rotation is performed to expose infrarenal aorta and Recovery for In-situ Split Liver Transplant
IVC; aorta is isolated and looped. Inferior mesenteric vein When a donor is planned for in situ split, availability of all
(IMV) is isolated near the ligament of Trietz, unless pancreas equipment, personnel and coordination with other recovery
is also being harvested, when only aortic flush is done. Aorta teams is crucial as the warm dissection phase is prolonged
is isolated and encircled either in supraceliac or thoracic area. by 1.52 hours. After the standard steps of warm dissection
The gallbladder is incised and flushed with saline. If thoracic as above, porta hepatis is dissected to identify and isolate the
organs are simultaneously being retrieved, the cardiac team common, right and left hepatic arteries, PV and bile ducts. A
prepares the heart for cardioplegia. cholangiogram is performed to identify biliary anatomy. If
Cold perfusion: After heparinization with 20,000 IU, both ACSL is planned, the liver is split along the umbilical fissure.
infrarenal aorta and IMV are cannulated proximally and If AASL is planned, HA and PV of either right or left side are
ligated distally. All abdominal viscera are rapidly perfused with temporarily occluded to identify the ischemic plane and split
cold perfusion solution [histidine-tryptophan-ketoglutarate along the same. Parenchymal transection may be performed
(HTK)] at 4C through both cannulae. Supraceliac (or using a cavitronic ultrasonic surgical aspirator (CUSA) or
thoracic) aorta is cross clamped (coordinating with the any other method. Once the transection is complete, cold
cardioplegia) and the IVC is incised at cavoatrial junction (or perfusion is started. In cold dissection phase, hilar structures
infrarenal area) to vent the warm blood away from abdominal are divided; conventionally, the main PV and common bile
organs. Sterile ice slush is packed perihepatically and poured duct stay with the right lobe graft while the common HA stays
in abdominal cavity for surface cooling of organs. Generally, with the left lobe. The remaining retrieval is performed in the
810 L and 2L of HTK is flushed through the aortic and IMV standard fashion. The two lobes are packed separately.
cannulae respectively, or until the effluent is clear.
Cold dissection: The common bile duct is divided and Bench Preparation for Deceased
flushed. Once perfusion is completed, splenic artery and
gastroduodenal artery (GDA) are identified, divided and
Donor Liver Graft
tagged, and common HA is dissected back to the celiac On the bench, liver is inspected for gross appearance,
axis. Any accessory or replaced right or left hepatic arteries uniformity of perfusion, procurement injuries and vascular
are dissected back to the superior mesenteric artery (SMA) anatomy. Remaining diaphragm is dissected off, IVC is
or left gastric artery (LGA), respectively. The PV is divided separated from surrounding tissues and all its tributaries,
as low as possible in the retropancreatic region, unless the including phrenic and adrenal veins are ligated. Portal vein
pancreas is also being harvested, in which case, it is divided is dissected clean from the surrounding tissue. Superior
few millimeters above the pancreas. Division of cavoatrial mesenteric artery and LGA are examined for accessory
junction is completed leaving a cuff of thoracic IVC. The IVC hepatic vessels. Arterial dissection is done from celiac trunk
is transected above the renal veins after careful identification. toward the liver, preserving all hepatic arterial supply and
Aorta is transected below the SMA but above the renal arteries long lengths of splenic artery and GDA. All branches from
after careful identification. Aorta is divided in the supraceliac PV and HA are carefully ligated. Arterial reconstruction is
or thoracic area. The diaphragm is divided on both sides of performed, if required, such that the whole graft is supplied
the liver. Finally, the liver is dissected off the retroperitoneum by a common feeder artery, preferably fashioned into a Carrel
behind the IVC and aorta free from its attachments. Liver is patch. Infrahepatic IVC is closed with a ligature or a vascular
delivered out, stored in an air-tight bag with HTK and packed stapler. Cholecystectomy is performed. Liver is repacked in
in layers of sterile ice on inside and ice cooler on outside. cold preservation solution until implantation.
Liver Recovery after Cardiac Death (Donation Ex-situ Split on the Bench
after Cardiac Death/Nonheart Beating Donors) When ex-situ split is planned, the whole liver is immersed
in cold preservation solution surrounded by ice. Hilar
The steps of recovery are as above with the goal of establishing structures are identified and isolated. The liver is split along
cold perfusion promptly. A quick laparotomy, rapid aortic the umbilical fissure or along Cantalies line depending on
the type of split planned using the Kelly clamp technique.

All fibrous structures identified in the transection plane
are ligated on both sides and divided. The IVC is preserved
with the right lobe. As in in situ SLTx, conventionally, the
main PV and common bile duct stay with the right lobe graft
while the common HA stays with the left lobe. If full left-right
split is planned, the MHV is divided longitudinally with the
parenchyma. Once the split is complete, the IVC is divided
along its longitudinal axis so that each lobe gets half of it. The
IVC and roof of MHV are reconstructed using vein grafts.
Living Donor Hepatectomy

While left lateral segment donation is generally required for
pediatric LDLT and right lobe for adult-to-adult living donor Fig. 2: Living donor hepatectomy
Abbreviations: RHV, right hepatic vein; MHV, middle hepatic vein
liver transplantation (AALDLT), the left lobe may be used for
an adolescent or small adult.
cessation of outflow may lead to reversal of flow in anterior
The abdomen is opened by Mercedez Benz, Inverted
segments, resulting in loss of functional volume and diversion
J (hockey stick) or midline incision. Liver is mobilized by
of excess portal flow into posterior segments subjecting them
dividing the round, falciform and ipsilateral triangular
to hyperperfusion and damage.
ligaments. For right lobe donation, short HV between the right
lobe and IVC are isolated and divided, preserving any veins Modified right lobe graft: The right lobe is retrieved without the
larger than 5 mm and the right HV is isolated. For left lobe or MHV; however, major segment V and VIII veins are preserved
left lateral segment donation, left and middle HV are isolated. and reconstructed using an extension graft for anastomosis
Cholecystectomy is performed and a cholangiogram may be with the IVC. Some studies have demonstrated lack of
done. The common HA, bile duct and PV are identified and adequate outflow using this technique because of limited
ipsilateral HA, PV and hepatic ducts are isolated. Lobar HA and number of tributaries drained and inconsistent patency of
PV branches are occluded temporarily with a vascular clamp long narrow conduits and narrow anastomoses.
and interlobar ischemic plane is marked. Liver parenchyma Extended right lobe/right lobe with MHV: In extended right
is transected along the ischemic line using CUSA, ligating lobe, the entire MHV was preserved with the right lobe by
and dividing any fibrous structures encountered along the moving the transection plane 1 cm to the left of ischemic line
transaction line. The lobar hepatic duct is divided. Liver is (Fig. 2). This technique has been modified by most centers
removed by dividing ipsilateral PV, HA and HV and quickly to include the MHV with right lobe without moving the
perfused with preservative solution. transection plane. While subtotal length of MHV is retrieved
The vascular inflow is exclusive to each lobe and therefore to protect LHV-MHV common outflow in the donor, MHV is
can be conveniently divided. However, because there are cored out to preserve overlying parenchyma with the donor.
three HVs, and the MHV drains parts of both lobes, the side In the modified right lobe grafts and extended right lobe
without MHV is at a risk of congestion. The left lateral segment grafts, anterior sector venous outflow can be extended using
is generally drained by the left hepatic vein (LHV) and left lobe various vascular conduits, which can be retrieved from vessels
by both LHV and MHV and they are retrieved with these veins of recipient or donor, or can use recanalized umbilical vein or
respectively. However, the need of including MHV with the cryopreserved vascular grafts.
right lobe graft is not clear, and therefore various techniques Those in favor of MHV retrieval with right lobe express
for right lobe retrieval have been described. concerns of suboptimal functional graft volume, while
Standard right lobe graft: In this type of graft, the right lobe is advocates of right lobe retrieval without MHV cite concerns
retrieved without the MHV and its tributaries ligated. Anterior of donor safety, although the risk has not borne out in the
sector congestion was often noted and disregarded based experience so far. Some centers follow a flexible or algorithmic
on the assumption that intrahepatic venovenous collaterals approach depending on the donor age, recipient status,
would compensate for the cessation of outflow. Subsequently, volume of left lobe remnant, presence or absence of steatosis
it was realized that pre-existing intrahepatic collaterals are and anatomy of segmental veins for inclusion or exclusion of
variable, new ones might take a few weeks to form and abrupt MHV in right-lobe living donor liver transplantation (RLDLT).
Bench Preparation for Living Short HV (inferior veins) are divided between ligatures,
larger ones are securely sutured, especially in patients with
Donor Liver Graft caudate hypertrophy. Right HV, MHV and LHV are clamped
Hepatic artery and PV are examined, and if required, and divided leaving long stumps. Thus, the native liver is
lengthened using extension grafts. For right lobe grafts, explanted without clamping the IVC (Fig. 3).
segmental HV or MHV may be extended using vein grafts. Conventional technique of recipient native hepatectomy:
Initial steps are as described above. After division of the hilar
structures, the IVC is mobilized off the retroperitoneum and
Minimal Access Donor Hepatectomy right adrenal vein divided between ligatures. Suprahepatic
(Laparoscopic/Robotic) and infrahepatic (suprarenal) IVC are mobilized, looped and
vascular clamps applied. Inferior vena cava is then divided
Currently, very few centers perform laparoscopic or robotic between the two clamps and liver is explanted along with the
donor hepatectomy for less pain, better cosmetic scar, less intrahepatic portion of IVC (Fig. 4).
wound complications, early recovery and discharge from the Anhepatic phase: Anhepatic phase is characterized by profound
hospital. However, because of limited experience with this physiologic and hemodynamic changes due to absence of the
evolving field, presently minimal access donor hepatectomy liver and occlusion of PV and IVC (conventional technique).
can only be justified in very selected cases with favorable Absence of the liver leads to loss of homeostasis, hypoglycemia,
vascular anatomy by a team with a large experience in open
and laparoscopic liver surgery.
Recipient Operation
The recipient operation can be broadly divided into the initial
phase of recipient native hepatectomy leading to anhepatic
phase and implantation of the liver graft resulting in the
neohepatic phase.
Recipient Native Hepatectomy

Recipient native hepatectomy is a critical phase of the
operation because of risk of bleeding and may be technically
demanding in patients with previous upper abdominal
surgery or SBP. It may be performed using the conventional Fig. 3: Piggyback technique of recipient hepatectomy
or piggyback technique, the latter lately having found favor
worldwide. While the conventional technique involves
resection of native liver together with the retrohepatic IVC
attached, the piggyback technique consists of dissection of the
caudate and right lobe off the retrohepatic IVC to preserve it
in the recipient. Therefore, while the conventional technique
allows quicker hepatectomy, piggyback technique maintains
hemodynamic stability and preserves renal venous outflow.
Piggyback technique for recipient native hepatectomy: A
Mercedes Benz incision is made; costal margins are retracted
upwards and outwards. Falciform, left triangular and
gastrohepatic ligaments are divided in succession, ligating
collaterals and accessory left HA if present. Porta hepatis
is dissected to isolate and divide HA branches, common
bile duct and the PV, preserving long stumps. The liver is
mobilized by dividing the right triangular ligament until
the IVC is identified. Inferior vena cava is dissected off the Fig. 4: Classical technique of recipient hepatectomy
retroperitoneum and adrenal vein divided between ligatures. Abbreviation: IVC, inferior vena cava
hypothermia, coagulopathy and acidosis. These can be performed leaving a growth factor. Some centers flush out the
avoided by keeping a close watch on blood sugars, ABG, TEG, HTK at this stage with albumin or lactated Ringers solution.
etc. and correction with dextrose, plasma infusion, bicarbonate The graft is reperfused with recipient portal blood. Reperfusion
infusion, inotropes, etc. Portal vein occlusion leads to may cause hemodynamic instability because of hyperkalemia,
mesenteric hypertension and bowel congestion. A portocaval tissue factors release and loss of systemic resistance. In patients
shunt may be done if the anhepatic phase is expected to be with preoperative PVT, thrombectomy and extension graft from
long or significant bowel congestion is observed. Although the recipient PV or SMV may be required before anastomosis.
uncommon, a venovenous bypass (VVB) may be used to This is followed by hepatic arterial anastomosis with recipient
reduce the adverse effects of IVC and PV occlusion, especially HA. Rarely, a supraceliac or infrarenal aortic inflow graft may
in patients with renal or cardiac dysfunction. be required. Some centers prefer simultaneous reperfusion
with both portal and arterial blood.
Venovenous bypass: In case VVB is planned, PV is cannulated
Partial graft implantation using piggyback technique: A partial
before its division, and femoral and internal jugular veins
graft may be obtained from a living donor or split from a deceased
(IJV) are cannulated percutaneously. Alternatively, femoral
donor. While partial grafts from living donors come with no IVC
and axillary veins are cannulated by open technique. The
and short stumps of HV and ipsilateral portal structures, split
bypass circuit redirects blood from PV and IVC (via the grafts from deceased donors may come with or without IVC and
femoral vein) into superior vena cava (SVC) via IJV, aided may have either a short stump of ipsilateral portal structures
by a pump during anhepatic phase, thereby decongesting or with long lengths of common trunks. Thus, although most
mesenteric and caudal systemic areas, decreasing bleeding commonly split grafts are implanted in piggyback fashion, they
and maintaining hemodynamic stability. With increasing use may be implanted using the classical technique.
of piggyback technique, its utility is limited. For right lobe implantation, a wide anastomosis is made
between the donor RHV and recipient RHV extended on
to the IVC. Any significant inferior HV (>5 mm) preserved
Liver Allograft Implantation during graft retrieval is anastomosed end-to-side to a
separate cavotomy. Graft anterior sector outflow extension
Implantation of the new liver consists of vascular anastomosis, is anastomosed end-to-side to a new cavotomy (Fig. 6) This
reperfusion and biliary reconstruction. The graft could be is followed by graft right portal vein (RPV) anastomosis with
implanted using the conventional or the piggyback technique, recipient main portal vein (MPV) followed by reperfusion.
the latter being more commonly used. Graft HA is anastomosed end-to-end with recipient HA or
Whole graft implantation using piggyback technique: In another arterial branch. Donor bile duct is anastomosed end-
this technique, stumps of all three recipient HVs are joined to-end with recipient bile duct, except in children and patients
together to form a common cloaca, which is then anastomosed with PSC, where a Roux-en-Y choledochojejunostomy is
to suprahepatic graft IVC (Fig. 5). Alternatively, side-to-side preferred. Biliary stents and T-tubes are used according to the
cavoplasty may be done. End-to-end PV anastomosis is center policy, but both are increasingly going out of favor.
Fig. 5: Piggyback technique of liver graft implantation Fig. 6: Living donor right lobe graft implantation
Abbreviation: IVC, inferior vena cava Abbreviations: RHV, right hepatic vein; MHV, middle hepatic vein; IVC,
inferior vena cava
For left lobe or left lateral segment (LLS) implantation using a Carrel patch and biliary reconstruction is performed
recipients LHV-MHV is used for outflow anastomosis and in standard fashion as described above.
remaining anastomoses are performed in standard manner Neohepatic phase: Inferior vena cava clamps are released
described above (Fig. 7). These grafts should be fixed to the just before portal reperfusion leading to neohepatic phase,
falciform ligament to avoid twisting and outflow occlusion. which causes release of potassium and cytokines into
Children may benefit by delayed primary abdominal wall circulation and may cause significant hemodynamic changes
closure to avoid compartment syndrome. due to hyperkalemia, cardiac arrhythmias, hypotension and
Classical technique of liver graft implantation: In this pulmonary edema. These changes may be more dramatic in
technique, the donor and recipient suprahepatic IVC are steatotic or DCD livers.
anastomosed end-to-end followed by infrahepatic IVC
(Fig. 8). If VVB is used, it is discontinued at this point, PV is
trimmed to appropriate length, graft PV is anastomosed end- innovative strategies in Liver
to-end with recipient PV leaving a growth factor and it is
reperfused. Arterial reconstruction is preferably performed transplantation
Auxiliary Liver Transplantation
Some patients with ALF who meet the criteria for LT may
have adequate potential for regeneration, and functional and
morphological recovery. Auxiliary liver transplantation (ALTx)
supports the liver function till the native liver recovers and
subsequently immunosuppression can be withdrawn allowing
graft atrophy. Initially, graft was placed in heterotopic position
(HALT); however, constraints of space, portal flow and venous
outflow limited its usefulness. Auxiliary partial orthotopic liver
transplant involves removal of one-half of native liver enabling
placement of an auxiliary partial graft orthotopically in its place.
Auxiliary liver transplantation is restricted to hemodynamically
stable patients less than 40 years without evidence of
CLD. In adults, 71% 1-year survival and 30% freedom from
immunosuppression has been reported, whereas in children,
Fig. 7: Left Lateral segment living donor graft implantation corresponding figures are 85% and 65%, respectively.
Abbreviations: LHV, left hepatic vein; RHV, right hepatic vein; IVC, inferior vena
cava
Dual-lobe Living Donor Liver
Transplantation
Living donors are commonly rejected for inadequate
estimated graft volume. Dual lobe LDLT allows two donors
to donate one lobe each to provide adequate liver mass for
one recipient. This is a technically demanding procedure,
commonly involves implantation of one right and left lobe or
two left lobes. It should be used very selectively and only in
most experienced centers.
ABO Incompatible Liver Transplant

ABO incompatible liver transplant (ABOi) grafts have
conventionally been considered a contraindication for LT
because of high risk of humoral rejection. Early attempts were
Fig. 8: Classical technique of liver graft implantation successful in children, probably because of low antibody titers
Abbreviation: IVC, inferior vena cava and an immature complement system in infants and young
children. The regimen of perioperative plasmapheresis, intensivists, nurses, technicians, coordinators and specialists
intrahepatic arterial or portal infusion (using prostaglandin from many allied specialties.
E1, steroids or gabexate mesylate), splenectomy, and triple or Postoperatively, patients are extubated in transplant
quadruple drug therapy containing of calcineurin inhibitors intensive care unit (ICU) (although suitable patients may
(CNI), steroids, cyclophosphamide and azathioprine, or be extubated in the operation theater), closely monitored
mycophenolate mofetil (MMF) has been successful in there followed by routine recovery in the ward and are
preventing humoral rejection and improving outcomes of discharged when clinically appropriate for life-long follow-
ABOi LT. Living donor liver transplantation is especially up. In view of immunosuppressive medications including
suitable for ABOi as it allows time for preparation and high-dose steroids, patients receive prophylactic antibiotics,
antibody reducing strategies to be employed and monitored. antifungal and antiviral medications, Pneumocystis carinii
prophylaxis with sulphamethoxazole/trimethoprim, ulcer
prophylaxis with a proton pump inhibitor and antiplatelet
Domino Liver Transplantation prophylaxis with low-dose aspirin. They also receive
Domino LT is an innovative procedure in which liver removed mineral and vitamin supplements and drugs for preexisting
from a patient with metabolic disease can be used in another comorbidities. Routine follow-up involves monitoring vital
patient with liver failure because it is structurally and functionally parameters, routine laboratory parameters, graft function
normal apart from production of abnormal protein. Patients with and immunosuppressive drug levels. Children are also
familial amyloid polyneuropathy (FAPN) are the most common monitored for growth and development. Patients should
domino liver donors, but other conditions such as maple adhere to strict hygienic practices and take prophylactic
syrup urine disease (MSUD), primary hyperoxaluria, protein antibiotics for inadvertent contact with people with serious
C deficiency, homozygous familial hypercholesterolemia and viral infections, such as varicella. Common illnesses, such
citrullinemia have also been domino donors. The riskbenefit as upper respiratory infection, fever, vomiting and diarrhea
ratio has to be individualized and these livers should be used in should be treated on their merits, but generally always
elderly patients with lifeexpectancy less than the time needed requires medical consultation. Regular dental care should be
to develop clinical symptoms from the domino graft, those with done and prophylactic antibiotics should be used for invasive
malignancy or those whose condition precludes a long time on procedures. Skin conditions, such as eczema, warts and
waiting list. However, it poses surgical challenges and needs cancer are common; these should be minimized by active
technical innovations for safe recovery of the domino liver and life-long solar prophylaxis and managed by a specialist.
successful implantation. While early (first 3 months) complications are generally
due to technical aspects of the operation (i.e. vascular and
biliary complications), graft quality and infections (Table6),
Paired Donor Exchange in Living Donor those in intermediate period (312 months) are due to
Liver Transplantation rejection and opportunistic infections and late ones (after 12
months) because of long-term drug toxicity, biliary stricture,
Another strategy to overcome the hurdle of ABO recurrent disease, malignancy [skin cancers, post-transplant
incompatibility in LDLT is paired donor exchange, where lymphoproliferative disease (PTLD), etc.], cardiorespiratory,
one ABO incompatible donor-recipient pair is matched cerebrovascular and chronic rejection. Complications
with another complementary ABO pair with compatibility significantly impact graft loss, mortality and may significantly
across the pair. It does not impose any additional risk on increase perioperative and long-term costs.
individual donors or recipients, although it is logistically
more demanding.
Primary Graft Nonfunction
Primary nonfunction is uncommon (DDLT: 4.69%, LDLT:
Postoperative management, 0.3%), but potentially life-threatening without urgent
complications, and Outcomes retransplantation. It is characterized by encephalopathy,
minimal bile production, hyperbilirubinemia, coagulopathy,
Post-transplant care involves monitoring of hemodynamic, rapidly rising liver enzymes, increasing serum lactate level,
clinical and laboratory parameters, timely detection and histologic evidence of hepatocyte necrosis in the absence of any
management of complications and balanced immuno vascular complication and may progress to multisystem failure.
suppression to prevent graft rejection and avoid infection. Various donor risk factors, such as advanced age, moderate to
It is generally delivered by a multidisciplinary team of severe steatosis, prolonged ischemic time, high serum sodium
dedicated transplant surgeons, physicians, anesthesiologists, and DCD have been implicated as causative factors.
Table 6: Post-transplant complications
Early (<3 months) Intermediate (312 months) Late (>12 months)

Bleeding CMV infection PTLD
Vascular complications Biliary strictures Late biliary strictures
Primary graft nonfunction Hepatic vein stenosis Renal dysfunction
Infections/bacterial sepsis Rejection Hypertension
Small-for-size syndrome EBV infection, PTLD Noncompliance with medications
Biliary leak Hypertension NODM
Rejection Poor growth Recurrence (HCV, HBV, HCC)
Perforated viscus Unusual infections
Surgical site infections Cancer
Growth failure
Osteopenia
Hernia (incisional and others)
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post-transplant lymphoproliferative disease; NODM, new-onset diabetes
mellitus; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma
Small-for-size Syndrome Vascular Complications

Small-for-size syndrome (SFSS) is a multifactorial
Hepatic Arterial Complications
pathophysiological entity seen in partial grafts originally
described in patients who received grafts with inadequate Hepatic artery thrombosis (HAT) is seen in children (68%)
hepatocyte mass or functional volume for their metabolic and in LDLT more than adults (4%) and DDLT, although very
needs. However, causes of SFSS, such as small graft size low rates (1%) have been reported and is more common in
[graft to recipient body weight ratio (GRWR) <0.8 or standard grafts with multiple arterial anastomoses.
liver volume (SLV) <35%], poor graft quality (moderate to Hepatic artery thrombosis may present with dramatic
severe steatosis, fibrosis), portal hyperperfusion leading to increase in liver function tests (LFTs), bile duct necrosis or
sinusoidal congestion, hemorrhagic necrosis of perisinusoidal may be diagnosed on protocol Doppler ultrasonography
hepatocytes, relative hypoxia because of HA buffer response, (DUS). A resistive index of less than 0.5, focal increase in
outflow obstruction leading to selective reversal of portal flow velocity, systolic acceleration time greater than 150 ms and
in some segments and consequent hyperperfusion injury in parvus tardus waveform on color Doppler are predictive
remaining segments are better understood. factors for HAT. It may need a CT or conventional angiogram
Clinical spectrum of SFSS consists of coagulopathy, ascites, for confirmation and/or management. If diagnosed early,
prolonged cholestasis and encephalopathy often associated an emergency thrombolysis or surgical revision may
with pulmonary and renal failure and frequently culminating be graft saving. If these fail or if diagnosis is delayed, a
in death of the recipient without retransplantation. Small retransplantation may be life saving. Late HAT (>3 weeks)
for size syndrome is established after exclusion of technical may present with biliary complications and is best managed
(arterial/portal thrombosis, venous congestion or biliary), by radiological interventions with significant success rates.
septic and immunological injury, and currently lacks a On rare occasion, a chronic HAT may remain undiagnosed
consensus definition. because of collateralization through vascularized adhesions
Strategies to prevent or treat SFSS include prevention via the phrenic artery or mesenteric vessels of a roux loop of
of portal hyperperfusion, either pharmacologically using jejunum.
vasoactive drugs (somatostatin or vasopressin analogs) or Hepatic artery stenosis (>50% reduction in caliber on
surgical methods of reduce portal flow, such as splenectomy, angiography) may be encountered in about 5% patients.
splenic artery ligation, mesocaval shunt or hemiportocaval They may be clinically silent or present with multiple biliary
shunt with a goal of maintaining portal flow less than 400 strictures and intermittent bacteremia and may need
mL/100 g of graft or portal pressure less than 20 mm Hg. radiological stenting.
Portal Vein Complications more commonly in LDLT as compared to DDLT, and can be
focal at the anastomotic or nonanastomotic sites, or diffuse.
Portal vein thrombosis is seen in 37% patients, more in Anastomotic strictures usually develop within the first year
children. Portal vein complications can be due to technical of transplant and are best managed with endoscopic balloon
issues such as kinking or redundancy of PV, poor mesenteric dilatation and stenting or percutaneous transhepatic dilatation
flow due to steal syndrome, stenosis, anastomotic stricture and stenting (in patients with Roux-en-Y anastomosis). Very
or twist. In early post-transplant period, PVT can manifest as early strictures or those with failed attempts at interventional
rapid graft dysfunction and massive ascites, and is diagnosed techniques may need surgical revision or conversion to Roux-
on DUS or CT angiography. Early PVT is best treated by en-Y biliary anastomosis. Diffuse intrahepatic strictures
immediate surgical thrombectomy, revascularization, may be due to severe preservation injury, ischemic insult
correction of technical problem, ligation of large collaterals or hepatic arterial insufficiency. In such cases, although an
and if necessary, bypass grafting from SMV. Portal vein extrahepatic dominant stricture can be managed by stenting,
thrombosis later than the first week may be amenable to a retransplant may be eventually necessary. After stenting,
percutaneous transhepatic radiological interventions or long-term surveillance and periodic stent exchange is
retransplantation. Portal vein stenosis is usually diagnosed required until stricture remodeling, after which they can be
by Doppler ultrasound by turbulent flow, confirmed by removed.
transanastomotic PV pressure gradient and can be treated by
PV stenting. Late PVT may not threaten graft survival but can
lead to troublesome PHT; percutaneous transhepatic stenting Immunosuppression and Rejection
may be effective in treatment.
Allograft Rejection
Hepatic Venous Complications Donor human leukocyte antigens (HLA) expressed in the graft
hepatocytes or those processed by antigen presenting cells
Hepatic venous outflow obstruction (HVOO) is relatively (APCs) evoke cell-mediated and humoral immune responses
uncommon and may be due to a narrow anastomosis, twist against the graft and is termed as rejection. Liver tends to be
or thrombosis of HV. In early post-transplant period, they relatively resilient to rejection, especially antibody mediated
can manifest as graft dysfunction and massive ascites. Failure as compared to other organs, probably because of large
to recognize and treat it in time can result in graft failure, size of allograft, minimal class I HLA antigen expression on
graft rupture or bleeding. Doppler ultrasonography and CT hepatocytes, production of soluble major histocompatibility
angiography are usually diagnostic. Early HVOO is corrected complex (MHC)-I molecules or transfer of the passenger
by immediate surgical thrombectomy, while late HVOO may donor cells with the graft to the recipient establishing
be amenable to transjugular angioplasty and stenting. Side- microchimerism. Thus, the need for pharmacological
to-side cavocavostomy with an endovascular stapler may be immunosuppression in LT is less as compared to other organs.
useful for severe HV and/or IVC outflow obstruction after Acute cellular rejection (ACR) may be encountered in as
piggyback implantation. many as 2040% patients within the first 36 months and may
be as high as 5070% in children. The episodes are generally
early, mild and may not cause clinically significant symptoms
Biliary Complications or histological architectural sequelae; their risk decreases
Patients may have bile leak (1234%) early (<4 weeks) or with time and they generally do not adversely affect the
late. An early bile leak is commonly anastomotic or from patient or graft outcomes. With current immunosuppression
the cut surface in partial grafts, whereas late ones may occur protocols, graft loss secondary to rejection is uncommon.
after T-tube removal. They are most commonly diagnosed Acute cellular rejection may present with fever, jaundice,
by bilious drain output or postoperative collection or by abdominal pain or raised transaminases, but neither the
a hepatobiliary iminodiacetic acid (HIDA) scan. It may biochemical parameters nor physical signs are specific for
either stop spontaneously or be managed with endoscopic rejection and need histological confirmation. Lymphocytic
sphincterotomy and biliary stenting. Although LDLT infiltration in portal triads, venous endothelial inflammation
was associated with higher bile leak in the past, with and bile duct damage are seen on histology, graded using
improved techniques and experience, results comparable rejection activity index (RAI) and used to guide therapy.
to DDLT are common. For a large early leak, conversion to Variations in surveillance transaminases without any evidence
hepaticojejunostomy may be required. of biliary or vascular problems, or intercurrent illness may be
Biliary strictures are seen in 416% of the transplants, presumptive for ACR without biopsy and treated as such.
Chronic rejection is uncommon (25%) and may occur antiproliferative agents, mammalian target of rapamycin
following multiple episodes of refractory acute rejection or (mTOR) inhibitors and steroids (Table 7). The selection of
de novo mostly due to poor compliance. It is characterized agents is based on an individuals medical history as well as
by slowly progressive clinical and biochemical signs of on institutional experience and preference.
cholestasis, bile duct paucity (ductopenia) on histopathology Calcineurin inhibitors have a narrow therapeutic window
and may require retransplantation. and wide interaction profile necessitating periodic monitoring
for renal function, glycemic status, blood pressure and drug
levels for dose adjustments. Tacrolimus is generally preferred
Immunosuppressive Drugs and believed to be important in preventing chronic rejection.
Rejection can be prevented or treated by drugs, which target Steroids form the backbone of most immunosuppressive
various sites in T cell activation or proliferation cascade to regimens and antirejection treatment. Antiproliferative
inactivate or deplete immune reactive T cells (Fig. 9). There agents (nucleoside inhibitors) should be used cautiously or
is no single drug that reliably prevents rejection at a safe discontinued in infants, pregnant women and leukopenic
dose or one that induces donor-specific immune tolerance; patients. mTOR inhibitors are not nephrotoxic and have
therefore, combination of drugs is commonly used. The potent in vitro antineoplastic activity but cause proteinuria
immunosuppression regimen and protocols used all over and hyperlipidemia. The IL-2R blockers (daclizumab and
the world are not uniform and continue to evolve with basiliximab) are effective as induction agents in pediatric
availability of newer drugs. The goal is to provide effective population in steroid minimization or CNI minimization
immunosuppression against allograft rejection while protocols. T and B cell receptor antibodies such as
preserving immunologic control of infection and neoplasms. muromonab-CD3 (OKT3), antilymphocyte antibodies
However, prolonged use of these medications can lead to (thymoglobulin) and alemtuzumab (campath 1H, anti-CD52)
severe and significant adverse effects and toxicities. are not routinely used in LT, but may have an important role
Classically, immunosuppression regimen consists of an in CNI or steroid sparing regimens and for the treatment
induction phase followed by life-long maintenance phase. of steroid-resistant rejection, but should not be used in
Induction is generally done with a bolus dose of steroids HCV patients. Other molecules that are yet to find clinical
or rarely using one of the interleukin-2 receptor (IL-2R) applicability in therapeutic immunosuppression are FK778
or T cell depleting antibodies followed by maintenance (interferes with pyrimidine metabolism and DNA synthesis),
with combination of two or more drugs, including CNIs, janus kinase (JAK 3 inhibitors), FTY720 (inhibits T cell
Fig. 9: Mechanism of action of various immunosuppressive agents

Table 7: Immunosuppressive drugs
Group Name (preparations) Mechanism of action Side effects Doses/target levels
Calcineurin Cyclosporine (cyclosporin A, Suppresses activation of T Hypertension 1015 mg/kg/day in two

inhibitors microemulsified Neoral) lymphocytes by blocking Renal dysfunction doses
(CNI) production of interleukin-2 (IL- Hirsutism Target 250350 ng/mL
2) and other lymphokines via Neurological complications
cyclophilin Gum hyperplasia
Tacrolimus (sustained-release Suppresses activation of T Tremor 0.150.3 mg/kg/day
Advagraf) lymphocytes by blocking Hyperglycemia Target 810 ng/mL
production of IL-2 and other Hyperkalemia
lymphokines by binding to T cell Hypertension
FK binding protein (FKBP 12) Headache
Renal dysfunction
Corticosteroids Methylprednisolone Causes emigration of T cells Hyperglycemia 2501,000 mg at the time of
Wysolone from intravascular to lymphoid Cardiovascular problems transplant as induction dose
tissues Fluid retention and then 1mg/kg/day as
Blocks activation of T cells and Myopathy maintenance and tapering of
antigen presenting cells (APCs) Peptic ulcer dose thereafter
by inactivating nuclear factor Impaired wound healing
Inhibits cytokine transcription Ocular problems (cataract/
by APC glaucoma)
Nucleoside Azathioprine Inhibits purine synthesis and Cytopenia (bone marrow 35 mg/kg orally or IV once
inhibitor differentiation and proliferation suppression) a day
of T and B lymphocytes Gastrointestinal disturbance
Mycophenolate mofetil (MMF) 150600 mg/m2/dose
(less with enteric-coated
MMF potassium - Cellcept
mycophenolate)
MMF Sodium - Myfortic
mTOR Sirolimus Binds to FKBP12 which inhibits Early hepatic artery 6 mg followed by a
inhibitors activation of mammalian thrombosis (HAT) maintenance dose of 2 mg
target of rapamycin (mTOR) Dyslipidemia given once daily
regulatory kinase Proteinuria Target 512 ng/mL
Inhibits T lymphocyte Cytopenia
Everolimus 1.52 mg in divided doses
activation and proliferation by Target 38 ng/mL
IL-2, IL-4 and IL-5
T and B cell Basiliximab (chimeric) IL-2 receptor antagonist by Acne 20 mg on the day of surgery
receptor binding with high affinity to Gastrointestinal disturbance and 20 mg after 4 days
antibodies alpha chain of IL-2 receptors Tremor
complex and inhibit IL-2
Daclizumab (humanized) Back pain 1 mg/kg every 14 days (total
binding Gastrointestinal disturbance five doses)
Competitive antagonism of IL- Impaired wound healing
2-induced T cell proliferation Pedal edema
Thymoglobulin (ATG) Antibodies against multiple Cytokine release syndrome 1.55 mg/kg as a single
thymocyte surface antigens. First-dose effect (ranges infusion usually over 46
Depletes circulating T from flu-like symptoms to hours for 35 days
lymphocytes, modulates pulmonary edema
their activation, homing and
cytotoxicity
OKT3 (Muromonab-CD3) Directed against CD3 complex, 5 mg intravenously daily for
inactivates and depletes T 1014 days
lymphocytes
Alemtuzumab Directed against CD52, depletes Flu-like symptoms 30 mg perioperatively
lymphocytes, natural killer cells
and monocytes
migration to venule endothelial cells in secondary lymphoid Weaning Immunosuppression and

tissue), betalacept (CTLA-4 homolog competing with CD28
for CD80/86 binding and inhibiting T cell costimulation), Tolerance
efalizumab (nondepleting mAb inhibiting LFA-1 functions) Immune responses specific to the allograft can be held
and protein kinase C inhibitors. in check by suppressive mechanisms, hence the term
operational or prope tolerance. It has been observed that
with appropriately designed weaning protocols starting 25
Immunosuppressive Strategies years after the transplant, about 20% of the LT recipients
Triple immunosuppression is very commonly used and can be maintained without or with very low doses of
consists of steroid bolus for induction followed by a CNI, immunosuppression. The key to advancing the tolerance
MMF and steroid for maintenance. Steroids are tapered off concept is being able to recognize it, so patients can be
over 3 months to 1 year to avoid long-term side effects and accurately selected for immunosuppression weaning or
MMF over 12 years. In patients with renal dysfunction, minimization.
induction with an IL-2R antibody allows CNI sparing in early
postoperative period. Patients with autoimmune hepatitis
(AIH) need higher drug levels and life-long low-dose steroids Infections and Antimicrobials
to prevent rejection and disease recurrence. Patients with Patients receive prophylactic antibiotics and antifungals
HCC may benefit from sirolimus-based regimens combined whereas prophylactic antiviral medications are used in high-
with steroid minimization. Patients with HCV infection risk patients. Children should be immunized for their age
might benefit from antiviral properties of cyclosporine over before transplant because live vaccines are contraindicated
tacrolimus, slow steroid taper and avoidance of IL-R or T
after LT. Infectious complications (2956%) are the most
cell depleting antibodies to prevent rapid recurrence and
common causes of morbidity and mortality after transplant;
progression of HCV. Pediatric patients benefit from IL-2R
therefore, close surveillance, early evaluation and timely
antibody induction and need rapid tapering of steroids to
empiric therapy should be instituted, especially because
avoid adverse influence on growth. Elderly patients have low
immunosuppression may mask common signs of infection,
risk of rejection and high risk of neurological complications;
therefore, low CNI levels should be maintained. promote rapid progression and predispose to atypical
Missed immunosuppressant medications should not be infections. Serious bacterial infections may occur in about
double dosed, but simply resumed at normal doses as soon one-third of patients, mostly in the first 3 months. The
as possible. Lapses in compliance should be suspected if cornerstone of treatment for serious infections is temporary
there are wide unexplained variations in transaminases or reduction or cessation of immunosuppression along with
drug levels. Reminders using mobile phone, text messages, appropriate antimicrobial therapy. Empirical antibiotics
daily diary and close monitoring have been shown to improve must be changed to sensitivity-specific ones and stopped
compliance. Gastroenteritis often results in spuriously after adequate therapy to avoid super-added infections and
elevated CNI levels and mild elevations of liver transaminases. Clostridium difficile colitis.
Rejection episodes are diagnosed with a liver biopsy and
treated in a step-wise fashion, starting with steroid boluses,
followed by tapering doses, failing which it may be labeled as
Early Infections (<1 Month)
steroid resistant, which may be treated with antithymocyte Surgical site infections are common despite universal
globulin or IL-2R antibodies. use of prophylactic antibiotics. Nosocomial infections
There is a trend toward minimizing immunosuppression in abdomen and chest with Staphylococcus, Klebsiella,
because of risk of long-term morbidity, such as drug toxicity,
Psuedomonas, Enterococcus and Candida may be seen
infections, malignancy, metabolic, cardiorespiratory and
because of lines, catheters, drains or mechanical ventilation.
cerebrovascular complications and growth failure. Indeed,
Infections associated with operative complications,
there is significantly more post-transplant morbidity and
mortality from infection than from rejection, particularly i.e. bile leak, obstruction or vascular thrombosis may
in infants. There is also evidence that some lymphocytic require radiological or surgical interventions such as
population of the graft may facilitate graft tolerance and is not drainage of collections, stenting or revision in addition to
necessarily always harmful. pharmacotherapy.
Intermediate (Opportunistic) Infections (16 Metabolic syndrome is common after LT and increases
risks of cardiovascular disease, cardiovascular death, liver
Months) disease-related death and overall mortality. Immuno
Cytomegalovirus infection is common, especially in patients suppressive drugs may cause hyperlipidemia, diabetes and
without natural immunity (CMV IgG negative) who receive an hypertension. Judicious use and selection of steroids, CNIs
organ from a donor with previous infection (CMV IgG positive). and mToR inhibitors might help reduce long-term morbidity
It may manifest with fever, malaise, arthralgia, leukopenia, after LT.
thrombocytopenia, pneumonia, gastroenteritis, hepatitis or Hypercholesterolemia is seen in 1545% and hyper
retinitis. Antiviral prophylaxis or preemptive therapy with triglyceridemia in 40% of recipients due to corticosteroid-
valganciclovir is widely used in high-risk patients. It also induced rise in low-density lipoprotein (LDL) production,
has immunomodulatory effects associated with higher risk use of cyclosporine and sirolimus. It is managed with low
of bacterial, fungal or HCV infection. Prolonged subclinical fat diet, alcohol avoidance and 3-hydroxy-3-methylglutaryl-
CMV infection is associated with an increased risk of chronic coenzyme A (HMG-CoA) reductase inhibitors. While statins
rejection. are hepatotoxic, gemfibrozil carries a risk of myositis and
Herpes simplex viral (HSV) infection causes painful bile acid binding resins like cholestyramine may reduce CNI
orogenital blisters. Reactivation of varicella zoster viral (VZV) absorption.
infection causes painful blisters in unilateral dermatomal Obesity can be seen in 1742% of patients and is mainly
distribution. Prophylaxis with acyclovir is recommended for attributed to high-dose steroids. Risk modification remains
patients not on CMV prophylaxis. the main preventive strategy. Sibutramine and orlistat reduce
Pneumocystis carinii pneumonia is now uncommon CNI absorption and are not recommended.
because of universal cotrimoxazole prophylaxis. Prophylaxis New onset post-transplant diabetes mellitus (NODM,
with clotrimazole drops is effective in reducing candidal PTDM) is seen in 1330% of recipients and its prevalence
infections, such as oral candidiasis, esophagitis or vaginitis, decreases with time from 26% at 1 year to 1% at 3 years.
although systemic antifungal prophylaxis with oral flucon Steroid-induced insulin resistance and CNI related B cell
azole is commonly used. toxicity seem to be primary mechanisms and PTDM is
Opportunistic infection with atypical organisms such as associated with more infections, renal dysfunction and
Aspergillus, Nocardia, Listeria, Cryptococcus, Mycobacterium accelerated fibrosis progression in HCV patients.
tuberculosis, respiratory syncytial virus (RSV), human herpes Hypertension occurs in 6570% of the patients after LT
virus 6 (HHV-6), influenza, adenovirus and Epstein Barr virus and can be managed by diet modification, weight reduction,
(EBV) infections may be increasing because of universal salt restriction, regular exercise, calcium channel blockers,
prophylaxis. EBV infection is particularly concerning because steroid taper and reducing CNI use. New-onset coronary
of its causative association with PTLD. artery disease (CAD) is seen in about 4.9% of patients.
Hyperuricemia is seen in about 40% recipients but
clinical gout occurs in about 625% of them, especially with
Late Infections (>6 Months) cyclosporine use. Allopurinol can be used for prophylaxis,
Community-acquired and opportunistic infections are seen and NSAIDs or steroids are used for acute gout as colchicine
more commonly, as prophylaxis is discontinued, patients is poorly tolerated.
recover from surgery and go back to the community. Bone diseases in form of osteopenia, osteoporosis or
Pneumonia, urinary infection, Legionella, Listeriosis, Crypto both can be seen in up to 1060% of the cases. Osteoporosis
coccus, Histoplasma, Coccidioides and Blastomyces are seen affecting spine and hip is common, especially in patients
occasionally. with cholestatic liver disease. It might be due to steroids,
secondary hyperparathyroidism, hypogonadism and vitamin
D deficiency. Management includes vitamin D and calcium
Long-term Complications supplementation and antiresorptive agents like calcitonin,
etidronate, calcium and sodium fluoride and bisphosphonates.
In the long-term, metabolic and cardiovascular complications,
Renal dysfunction occurs in 49% of the LT recipients
drug toxicity and recurrence of disease are the major causes
mainly related to the use of CNI, presence of pretransplant
of morbidity and mortality. While patients might have risk
renal dysfunction and other renal diseases. Management
factors for some of these conditions, toxicity due to long-term
includes avoiding CNI and strict control of risk factors like
usage of immunosuppression has additive effect; therefore,
hypertension and diabetes.
steroid or CNI sparing regimens may reduce their incidence.
Skin and lymphoid malignancies (PTLD) are common after such as entecavir and tenofovir. With effective antiviral
LT with reported incidence up to 40% and 10% respectively. medications, HBV recurrence is rare.
Post-transplant lymphoproliferative disease has a strong Recurrence of autoimmune diseases, such as PSC, PBC
association with EBV infection causing immune failure and AIH may be as high as 15% at 3 years to 30% at 10 years.
of control of EBV-infected B cell proliferation. Presenting Life-long low-dose steroid prophylaxis is used in patients
features are variable, and may include mononucleosis- with AIH and recurrence typically responds to increased
like symptoms (fatigue, fevers and lymphadenopathy), immunosuppression.
localized or disseminated lymphoproliferation with tumors In recipients with NASH/NAFLD, steatosis can be seen in up
of the lymph nodes, liver, lung, kidney, bone marrow, to 60% of cases at 1 year and fibrosis in up to 2040% of cases after
central nervous system or small intestine. Tissue biopsy 5 years. Prevention and treatment is centered around weight
showing plasma cell hyperplasia, B cell hyperplasia, B cell loss, diet modification, exercise, ursodeoxycholic acid (UDCA),
lymphoma or immunoblastic lymphoma is diagnostic and clofibrate, gemfibriozil, vitamin E, and n-acetylcysteine.
immunostaining reveals its clonality. Treatment involves Active alcohol abuse and concerns of recidivism or
cessation or reduction of immunosuppression, surgical compliance are common reasons for denial of transplant
removal of local lymphoproliferative lesions, ganciclovir, listing. About 820% patients resume drinking after transplant
anti-CD20 monoclonal-antibody rituximab and systemic and have poor long-term survival.
cytotoxic chemotherapy. Hepatocellular carcinoma tumor-free survival rates of
8590%, 7075% and greater than 60% at 1, 3 and 5 years have
been reported, with no significant influence of DDLT versus
Disease Recurrence LDLT. Preoperative treatments, AFP greater than 30 ng/mL,
Hepatitis C virus graft reinfection after transplant is neutrophil-to-lymphocyte ratio greater than 5, exceeding
universal and may show histological changes as early as Milan criteria at final histology, poor tumor differentiation
first postoperative week. Acute lobular hepatitis develops in and presence of microvascular invasion predicted a lower
about 75% of HCV recipients with progression to cirrhosis recurrence free survival.
in 2530% at 5 years. Risk factors for recurrence are older
donors, graft steatosis, prolonged ischemia time, genotype
1B, high pre- and post-transplant viral loads, CMV infection,
Outcomes
use of T cell depleting therapies or bolus steroids. Recurrent Overall 1-, 5-, 10- and 15-year patient survival after DDLT
HCV infection is best diagnosed by high HCV viral load is 7987%, 6773%, 5768% and 5064%, respectively and
and protocol liver biopsy; however, it might be difficult to corresponding graft survival is 7382%, 6467%, 5759% and
differentiate from ACR. Treatment with recurrent HCV with 5055%. The 2- and 5-year patient survival rates after SLTx
pegylated interferon and ribavirin has improved virologic and whole LT were 86.3% and 82.6%, and 78.4% and 75.6%
and histologic response, although optimal timing of starting respectively. In SLTx recipients, large and experienced (> 30
therapy is still unclear. Early concern about faster recurrence procedures) centers have reported comparable survival as
in LDLT has not been seen in recent series. Very rarely, whole liver LT. In AASL, patient survival at 1 year is 75% and
patients may develop very early and rapidly progressive HCV 87% for the right and left lobe respectively. Overall patient
recurrence called as fibrosing cholestatic hepatitis (FCH), the survival at 1 year and 3 years is less with DCD (80% and 68%
outcome of which is very poor. respectively) than with brain dead donors (91% and 84%
In 1980s, LT for HBV was associated with universal graft respectively) but have similar rates of PNF, although DCD
reinfection, rapidly progressive disease recurrence and livers have higher biliary complications and retransplantation
patient survival of less than 10%. Hepatitis B immunoglobulin rate for ischemic cholangiopathy.
(HBIg) and effective antiviral agents, i.e. lamivudine, adefovir
In LDLT, 1- and 5-year patient survival is 7893.5% and
and entecavir have reduced graft reinfection rates to less than 7683.2%, respectively. Donor complications varies from 15%
5% and even allowed transplantation of HBcAb +ve livers into to more than 75% depending upon the definition of morbidity
low-risk patients. used and experience of the center and estimated mortality
All potential LT recipients should be screened for hepatitis risk of 0.2%. Pediatric LT is one of the most successful solid
B surface antibody (HBsAb) titers and be vaccinated if organ transplants with 1- and 5-year survival close to 90% and
inadequate. Prophylaxis for HBV recurrence consists of HBIg 85% respectively. Neonates have lower survival than older
during anhepatic phase and postoperatively to keep anti children. Split liver transplant and LDLT have dramatically
HBsAb titers greater than 500 IU/L for first 6 months and reduced waiting times virtually eliminating elective waiting
thereafter greater than 250 IU/L and antiviral medications, list mortality. Very good outcomes can be expected in HCC
patients because they are generally not very sick at LT except 7. Bozorgzadeh A, Orloff M, Abt P, et al. Survival outcomes in liver
for the risk of recurrence. Overall survival rates of 9095%, transplantation for hepatocellular carcinoma, comparing impact
8085%, and greater than 75% at 1, 3 and 5 years have been of hepatitis C versus other etiology of cirrhosis. Liver Transpl.
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phenomenon in auxiliary partial orthotopic liver transplantation
commonly reported in ALF patients Five- and 10-year survival
by modulation of the venous outflow of the native liver. Liver
rates vary between 60% and 70%.
Transpl. 2005;11(9):1140-3.
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or metabolic disease, expectation of long-term survival and results in full-right full-left splitting of the deceased donor liver.
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but are able to resume work in a few months. Pregnancy is safe outcomes of 3200 liver transplantations over two decades: a
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42
cHAPTER
Gallstone Disease
A Kadir Dokmeci, Mustafa Yakut
INTRODUCTION weight loss, delayed small intestine transit time, cirrhosis of

the liver, hemolytic anemia, hypertriglyceridemia, terminal
Cholelithiasis is one of the most common diseases of the ileal resection, delayed small intestine transit time, metabolic
digestive system. It is a frequent, high-cost disease that syndrome, some medications (for example, estrogens and
requires hospitalization. Gallstones are present in about oral contraceptives, octreotide, clofibrate, and ceftriaxone)
1015 of the adult population in western populations. It is and reduced physical activity. Abnormal gallbladder motility
estimated that about 2025 million people in the US suffer also has a role in gallstone formation.
from gallstones. In an ultrasound screening in Italy on Cholesterol stones are typically seen in adults. It is very
29,000 people between the ages 30 years and 69 years, the rare to observe cholesterol stones in children or adolescents.
gallstone prevalence was established as 18.8% and 9.5% Prevalence of gallstones increases in a linear pattern with age
in women and men, respectively. Although most show an in both sexes. Over half of the women over 70 have gallstones.
asymptomatic course, about one-third may lead to symptoms The potential of women to develop gallstones across all age
and complications. Annual gallstone-related treatment cost groups is about twofold compared to men. Human and animal
exceeds 6 billion dollars based on US data. studies demonstrated that estrogen increased the secretion of
About 7585% of the cases in western populations are biliary cholesterol in the liver and the cholesterol saturation
caused by cholesterol-rich gallstones. Pigment stones in the bile in consequence. As a result, it increases the risk
are more common in Asian populations versus western of cholesterol stone formation. Many studies indicate that
populations. Cholesterol stones contain monohydrate crystals the use of oral contraceptive and conjugated estrogen in the
and amorphous calcium bilirubinate calculus, and mostly premenopausal period increases the incidence of gallstone
this crystalline concretion also include calcium carbonate formation by twofold. A comparison of postmenopausal
and calcium phosphate. Cholesterol is classified as pure or estrogen use in women and estrogen use for prostate cancer
mixed cholesterol stones. Mixed stones contain at least 50% in men demonstrated that gallstone formation in both groups
cholesterol. Pigment stones are most of calcium bilirubinate is comparable. Hepatic estrogen-receptor alpha increases
and are classified in two subgroups: black pigment stones the synthesis of stimulating sterol-regulatory element
(about 20%) and brown pigment stones (about 4.5%). binding protein-2 molecule and regulates the cholesterol
Although rare, calcium carbonate stones and fatty acid biosynthesis by negative feedback. These stimulants increase
calcium stones have also been observed. Gallstones can also the new cholesterol synthesis and the bile is supersaturated.
be categorized as intrahepatic stones, gallbladder stones, and These events cause the cholesterol to precipitate and lead
choledocholithiasis (common bile duct) stones. Intrahepatic to gallstone formation. Decrease in estrogen-induced
stones are mostly brown pigment stones. Gallbladder stones low-density lipoprotein level also contributes to the stone
are typically cholesterol stones and common bile duct stones development. Moreover, high estrogen levels reduce the
are typically mixed stones. gallbladder motility and induce gallstone hypomotility.
Pregnancy is also a risk factor for sludge and stone
formation. Increased level of estrogen in pregnancy leads
RISK FACTORS IN GALLSTONE to the increased cholesterol synthesis and causes the bile to
FORMATION be supersaturated. Also, gallbladder motility decreases and
consequently gallbladder volume increases and biliary stasis
Major risk factors in gallstone formation include age, female develop. These series of events result in bladder sludge and
gender, genetic polymorphisms, pregnancy, obesity, rapid bladder stone formation(s). Gallstone risk is further increased
Gallstone Disease 405
in the third trimester. Increased parity is another risk factor United States and Europe (20%), only 5% of the population
for gallstone formation in women. is affected in Africa. Similarly, gallstone prevalence is about
A diet rich in calories, cholesterol, saturated fatty acids, 510% in Asia. These regional differences indicate the effect
refined carbohydrates, proteins and salt and poor in fiber of genetics on gallstone formation. It has been demonstrated
heightens the incidence of cholesterol stone formation(s). that gallstones are more common among immediate family
Rapid weight loss is another of risk factors responsible for compared to others and that it is threefold in pair of twins.
gallstone formation. A comprehensive study where 43,141 twins were assessed
Total parenteral nutrition (TPN) causes cholelitiasis and demonstrated that genetic factors are greater in monozygotic
acalculus cholelithiasis. Gallbladder sludge starts to form twins versus dizygotic twins. Another study conducted on 232
due to the prolonged hunger in the third week at the earliest Mexican-American subjects indicated that the cholesterol
during the TPN use. Consequently, gallstones formation is 7-hydroxylase (CYP7A1) gene is associated with gallstone
observed in about 43% of the adults and in 45% of children formation in men. Changes in the ABC proteins that are
about 3 months later. the transporters in the canalicular membrane change
Since gallbladder sludge facilitates the crystallization of the bile structure and contribute to the formation of the
cholesterol crystals and nucleation, it plays a critical role both gallstones. ABC transporter B4 (ABCB4) gene, encodes the
in the cholesterol stones and pigment stones pathogenesis. phosphatidylcholine transfer protein in the canalicular
It also helps the precipitation of calcium bilirubinate. It membrane of hepatocytes. Particularly in Asia, as a result
inevitably leads to the macroscopic stone formation at the of the mutation in this gene, the phosphatidylcholine level
end. in the bile lowers and causes the formation of gallstones. It
The effect of many medications on the gallstone formation was shown that CYP7A1 activity is reduced and HMG-CoA
has been demonstrated. Lipid lowering medications affect reductase activity is increased in patients with gallstones
the gallstone formation by regulating the key pathways of the versus control. Gallbladder hypomotility is an effective
metabolism of bile salt and cholesterol. Clofibrate increases factor in gallstone formation. Cholecystokinin (CCK) and
the cholesterol supersaturation of the bile, by reducing 7 alpha- CCK1 receptor genes have a regulator role in the gallbladder
hydroxylase enzyme activities. Somatostatin analog octreotide motility. Mutations in CCK and CCKR-1 genes are associated
increases gallstone formation. Octreotide reduces gallbladder with gallstone risk. Polymorphisms in the apolipoprotein
motility, causes reduced intestinal movement and increases (APO) E, APOB genes related to cholesterol transport in
deoxycholic production and absorption in the colon and plasma are associated with gallstone formation.
increases the formation of cholesterol stones. It is believed that Polygenetic disorders can also have a role in gallstone
the third generation cephalosporin ceftriaxone, which is an formation. Various pathogenetic events differing from
antibiotic often preferred in the daily practice aggregates with population to population play a part in gallstone formation.
calcium to produce insoluble bile salt and this in return causes It is shown that variations in the SLC10A2 gene affecting the
biliary sludge. apical sodium-dependent bile acid transporter play a role in
Systemic diseases, such as lipid disorders, diabetes the gallstone formation in German population. A cholesterol-
mellitus and obesity are associated with increased gallstone rich diet plays a part in cholesterol stone formation by
risk. Cholesterol stone formation risk reduces with high HDL increasing the biliary cholesterol secretion and reducing
cholesterol. However, cholesterol stone formation increases bile salt pool. Increase of intestinal cholesterol intake and
in hypertriglyceridemia cases. Rate of gallstone development esterification of sterol may be playing an important part in
in body mass index (>45 kg/m2) patients is sevenfold versus gallstone formation(r). Some studies demonstrated that
nonobese women. Gallbladder motility is typically damaged cholesterol uptake proteins Niemann Pick C1 like protein 1
in patients with diabetes mellitus. Nevertheless, it is hard to and acyl coenzyme A-cholesterol acyl transferase enzyme
say that diabetes mellitus is an independent risk factor in (involved in cholesterol esterification) increased jejunum.
gallstone formation. Terminal ileal diseases and spinal cord Moreover, studies on mice demonstrated that inhibition
injuries are also reported to increase the gallstone formation of intestinal cholesterol absorption by Ezetimibe therapy
risk. regresse cholesterol crystallization in the gallbladder. ABCG5/
G8 gene increases the cholesterol secretion from hepatocyte
canalicular membrane to the bile duct and the variants of
GENETIC FACTORS IN GALLSTONE that gene are associated with the increased rate of gallstone
FORMATION formation in various studies. It is reported in studies on mice
that insulin resistance increases gallstone formation. Benign
Many genetic mutations are associated with gallstone recurrent cholestasis type 2 created by the ABCB11 gene
formation. In contrast to the high gallstone prevalence in the mutation is a reason of increased gallstone risk due to the
insufficient bile salt. Multidrug resistance 3 P-glycoprotein Bile salts dissolve in aqueous solutions, since they have
ensures phospholipid secretion in the canalicular membrane. both hydrophilic and hydrophobic parts, they are amphiphilic.
Mutation in this gene causes low phospholipid-associated This characteristic of bile salts is both particular characteristic
cholelithiasis. Farnesoid X receptor (FXR: NR1H4) is a of the aqueous solution and to the character of the hydroxyl
member of the nuclear receptor superfamily and plays a groups in the bile salts. Once the bile salt concentration
part in the cholesterol and bile-salt regulation. It adjusts the exceeds micelle concentration, bile salt monomers precipitate
solubility of the bile salts and phospholipids. They cause spontaneously and create simple micelles. Simple micelles are
gallstone formation in the mutations in this gene. small, disk-shaped and thermodynamically stable precipitates.
Mucin secretion and regulation in the gallbladder are These change cholesterol into a soluble form. Simple micelles
regulated by some genes. These genes include MUC1 and also dissolve phospholipids to create mixed micelles and add
MUC5AC. Incidence of cholesterol stone formation is found to them into their own structure. Mixed micelles have the ability
be lower in cases of MUC1 gene impairments in mice studies. to dissolve at least three times more cholesterol compared
MUC1 gene also creates a susceptibility to cholelithogenesis to simple micelles. Dimensions of mixed micelles may vary
by increasing cholesterol absorption in the gallbladder and depending on the bile salt rate and phospholipids. Mixed
impairs the gallbladder motility. micelles have a bilayered structure consisting of hydrophobic
groups and phospholipids. Phospholipid structure of the
outer layer consists of an interface with the aqueous bile,
BILE LIPIDS AND CHOLESTEROL while the hydrophobic groups are in the inner layer. Therefore,
cholesterol molecules become soluble on the inside of this
GALLSTONE PATHOGENESIS bilayered structure, away from the aqueous areas. Soluble
cholesterol amount depends on the proportion of the bile salts
Cholesterol, phospholipids, and bile salts are the major lipids
to the phospholipids. When the proportion of the phospholipid
of the gallbladder; biliary pigments are on the other hand
to the bile salts is 0.20.3, solubility of the cholesterol reaches
minor solutions. Cholesterol comprises 95% of the sterol
maximum. Another structure enabling the solubility of the
compounds in the bile and gallstones. The remnant 5% sterols
cholesterol in the bile beside the micelles is vesicles. Biliary
are the cholesterol precursors taken by the diet. The level of
vesicles are single lamella, sphere-shaped structures. They
cholesterol esters in the bile is negligible in the gallstones.
contain phospholipids, cholesterol and very small quantities
The major phospholipid lecithin (phosphatidylcholine)
of bile salts.
composes over 95% of the total phospholipids. Phospholipids
Vesicles are relatively static. However, they are affected by
form 1025% of all lipids in the bile salts, typically contain
many factors, particularly biliary lipid concentrations and the
steroid nucleus and that nucleus has four hydrocarbon rings.
proportions of the cholesterol, phospholipid and bile salts to
The rings have hydroxyl functions. This chain is conjugated
each other. Vesicles are relatively more stable when the bile salt
with taurine or glycine with bound. In the gallbladders, over
concentration is relatively lower and only some vesicles turn
95% of the bile salts are of steroid structure, and they are into micelles. On the other hand, vesicles turn completely into
found conjugated with taurine or glycine with amid bound. mixed micelles when the bile salt concentration increases.
Hydrophilic parts of the bile salts consist of hydroxyl groups Because phospholipids are transported to mixed micelles
and glycine or chains conjugated with taurine. Hydrophobic from the vesicles that are relatively more than phospholipids,
parts on the other hand comprise the steroidal nucleus. residual vesicles are restructured again. This structuring
Bile salts have both hydrophilic and hydrophobic sides and makes the vesicles rich in cholesterol. Thus, the cholesterol
therefore, they are highly soluble, amphiphilic molecules amount in the vesicle relatively exceeds the phospholipid
similar to detergent. amount. In case the cholesterol-phospholipid rate in the
Primary bile salts are hepatic catabolic products of remaining vesicles is relatively low (<1), these are relatively
cholesterol and consist of cholate (trihydroxy bile salt) and stable. However, if the cholesterol-phospholipid rate is greater
chenodeoxycholate (dihydroxy bile salt). Secondary bile than 1, then vesicles become unstable. These cholesterol-rich
salts consist of deoxylate, ursodeoxycholate and lithocholate. vesicles may turn into low cholesterol vesicles or micelles or
Secondary bile salts are formed by the metabolizing of the may form greater (about 500 nm) multilamellar vesicles by
primary bile salts by the bacteria in the ileum and colon. precipitating or aggregating. Liquid crystals are structurally
These salts do not accrete in the bile, but metabolized through unstable and form cholesterol monohydrate crystals in a
hepatic and bacterial reduction. Hence, tertiary bile salts solid plaque form; this process ends with the formation of
chenodeoxycholate (hepatic reduction) or its 7-beta epimere the cholesterol nucleus. Vesicles provide the main cholesterol
ursodeoxycholate (bacterial reduction) are formed. source for the formation of cholesterol nucleus.
In typical physiologic conditions, bile turns into a Cholesterol nucleation and crystallization have a major
concentrate gradually in the biliary track and consequently part in the formation of cholesterol stones. However, the
bile salt concentration reaches critical levels in the micelles. fact that some patients who have cholesterol crystals but
When this occurs, bile salts start to modify the structure not cholesterol stones, give rise to the thought that the
of the vesicles rich in phospholipid secreted to the bile by presence of cholesterol crystals in the bile does not always
the hepatocytes. These interactions indicate the beginning result in crystallization. Delayed gallbladder emptying
of molecular regulations that result in simple and mixed might be the required second critical phase for gallstone
micelles. formation. Impairment of the postprandial gallbladder
Cholesterol solubility in aqueous solution is quite low. emptying function, prolongs the time period that the bile
It is not sufficient to solubilize the cholesterol inside the stays in the gallbladder and accelerates the nucleation of
micelles when cholesterol rate in the bile is increased and cholesterol crystals which consequently has an effect on
bile salt and phosphatidylcholine rate in bile is decreased. macroscopic stone formation. Gallbladder wall inflammation
Supersaturation and cholesterol crystal formation are is a considerable factor in gallstone formation. Unesterified
observed in the early stage of the gallstones. Cholesterol cholesterol, detergent bile salts and bacteria cause
accumulates the surplus in the vesicles. Vesicles are bile inflammation. It is demonstrated in some studies that H. pylori
spheres consisting of cholesterol and phospholipids. Vesicles infection plays a part in bile wall inflammation and gallstone
are formed when the phospholipids rate exceeds the bile formation; however, this effect is not clear yet. The amorphous
salt rate. When the cholesterol/phospholipids rate is higher material at the center of the stones contains together with a
than 1, cholesterol nucleation occurs. Rate of nucleation of draft formed by cholesterol nucleation and crystallization,
cholesterol crystals in the supersaturated vesicles is higher bilirubin, bile salt, mucin glycoprotein, calcium carbonate,
versus the supersaturated micelles. phosphate, copper and sulfur. The development of the draft
The balance between the bile salt, phospholipid and in a stone and the remaining parts of the gallstone depend
cholesterol is the basis for the gallstone formation. This balance on the biliary proteins, mucins and cholesterol saturation
is illustrated with a triangle-shaped diagram. One phase zone in the bile. Cholesterol stones contain cholesterol crystals
(only micelles), and there are micelle and cholesterol crystal placed radially or horizontally in an organic matrix, because,
formation in other two phases. There are micelles, vesicles cholesterol crystals typically precipitate randomly in
and cholesterol crystals in the third phase. The cholesterol amorphous crystals and radially and concentrically forms a
intensity relatively increases from the bottom to the top of this layer. Cholesterol crystals settle perpendicularly to the surface
diagram and cholesterol crystallization formation rate rises. on the outer side of the stones. Mucin provides a convenient
From left to right on the diagram, phospholipid rate increases matrix for gallstone formation during the gallstone formation
relatively compared to the bile salts and solubilization of process. Moreover, concentric pigmented rings segment the
the cholesterol in the vesicles rises. Despite the peaked cholesterol crystals with different axial origins. Chemical
cholesterol rate at the bottom of this triangle, phospholipid/ composition of these rings are typically similar to the center
phospholipid + bile salt rate is maintained at the same rate of the gallstone and these rings reflect other calcium salts
with the bottom. There are also additional factors that affect and mucin glycoproteins structure.
the bile salt-phospholipid-cholesterol triangular structure
which is the basis of gallstone formation. Unsaturated acyl
chains amount contained in the phospholipids and bile PIGMENT STONES
salt hydrophobicity is also a significant factor in gallstone
formation. Transfer throughout bile ducts and storage of bile Brown and black pigment stones are created by pigmentation
in the gallbladder for a long time result in the absorption of with bilirubin precipitation and bilirubin metabolism
the water. Later on, because of the progressive increase in the anomaly. Pigment stones consist of bile pigment and mucin
bile salt rate micelle formation occurs with the mixed bile salt- glycoproteins. While black pigment stones contain insoluble
phospholipid-cholesterol structure. When the cholesterol/ polymeric calcium bilirubinate, brown pigment stones
phospholipid rate is higher than 1, micelle supersaturates contain monomeric calcium bilirubinate.
with micelle and crystal nucleation occurs. Increased Black pigment stones are typically observed in patients
hydrophobic bile acid (deoxycholate) rate accelerates with chronic hemolytic anemia and liver cirrhosis. Elevated
cholesterol crystallization. It is demonstrated on selected indirect bilirubin precipitates in the bilirubinate and
cases that hydrophilic bile salt ursodeoxycholate desaturates forms calculus. The major factor in the formation of black
the bile and eliminates the stone. Other experimental studies pigment stones is the hypersecretion of bilirubin conjugates
indicated that phospholipid acyl chain composition is to the bile. And it increases in hemolysis cases. Calcium
effective on cholesterol crystallization. salts of indirect bilirubin are formed by the aggregation
of the mucin, glycoprotein, phospholipid, and residues. It various positions to show the mobility of the stone and the
develops secondary to the infection caused by the stasis in sludge (left posterior oblique, left lateral decubitus, prone,
the gallbladder or biliary tract. E. coli is particularly blamed supine, etc.). Gallstones are echogenic, mobile intraluminal
for that. They are secondary to parasite infections in Asiatic formations creating an acoustic shadow in posteriors.
populations. Creation of an acoustic shadow largely depends on the size of
the stone. Therefore, stones smaller than 3 mm may not have
a shadow. At high frequencies, sound absorption increases
DIAGNOSIS AND FOLLOW-UP IN and therefore, it is possible to see the shadows of the stones
without a shadow by using higher frequency transducer. In
GALLSTONE-RELATED DISEASES the presence of numerous smaller stones, the patient should
Observation and follow-up is usually sufficient in be given a position to make the stones come closer to see the
asymptomatic gallstones except for special cases. Elevated acoustic shadow.
complication risk in patients may require exclusive If the gallbladder is completely full with stones, it is
approaches. It is recommended to perform prophylactic confused with gas-filled intestine loop. Typically, the stones
cholecystectomy for some diseases of the bile tree (choledoch have clean shadow; gases have a dirty shadows. Another way
cyst, Caroli disease, pancreatic duct draining anomalies, of differentiating the gas-filled bladder from the gas-filled
large bile adenomas, porcelain gallbladder) and increased intestine is the characteristic image called wall-echo shadow
cholangiocarcinoma and gallbladder carcinoma risk of some sign. This symptom consists of two arch-shaped lines and
ethnic groups. shadows. The first outer line is hyperechogenic, the lower
Pigment stones are common and mostly asymptomatic second line consist of the bright echogenicity of the stone
in patients with sickle cell anemia. If these patients are to and the shadows of the following stones. If the intensity of the
undergo abdominal surgery for other reasons, incidental gallbladder is high, stones may float in the sac.
cholecystectomy is recommended. Similarly, morbidly obese Polyp and sludge concretion may also be of help in
patients who will undergo bariatric surgery have a high risk of differentiating and diagnosing gallstones. However, polyps
gallstone complications. Cholecystectomy is recommended are immobile, echogene formations without shadow adhered
for these patients. to the sac wall. Sludge concretion is always mobile; however,
they do not cast a shadow and are larger than stones without a
shadow. Bile sludge consists of calcium bilirubinate granules
Imaging Methods and cholesterol crystals. Bile sludge may be hyperechogene
Modalities other than ultrasonography (USG) should not or hypoechogene. It may fill the sac completely. However,
be used routinely in patients suspected to have gallstones; typically, they form at the dependent part of the sac and build
diagnostic assessment must be made based on the clinical up a bile-sludge level.
conditions step-by-step later on. Fifty percent of the pigment Sonographic findings of the acute cholecystitis includes
stones and 20% of the cholesterol stones contain calcium at presence of stones in the gallbladder, increased gallbladder
a detectable level in abdominal graphy. Therefore, the use of wall (>3 mm), increased gallbladder size, presence of
direct graphy in diagnosis is limited and this method is not pericholecystic liquid, stones stuck in the neck or ductus
used for diagnostic purposes in clinical practice. Abdominal cysticus of the gallbladder and pain when the gallbladder
graphy is beneficial in cases of gallstone complications, such lodge is pressed with a probe.
as cholecystitis, coloenteric fistula and gallstone ileus or for
porcelain sac screening.
Endoscopic Ultrasonography
Ultrasonography It has a high accuracy rate particularly in the diagnosis
of choledocholithiasis. It is very expensive and invasive
The patients are required to fast at least 68 hours before compared to USG. Endoscopic ultrasonography (EUS) is
the gallbladder examination. Examination must be made more advantageous than transabdominal USG, in that it can
at supine position, with 35 MHz sector probe, through scan the biliary duct from inside the gastrointestinal lumen;
the intercostal and subcostal space. Low-level echos are these advantages include its closeness to the bile duct, its
frequently caused by reverberation artefact in gallbladder higher resolution, intestinal gas superposition and absence of
lumen. To eliminate that, the approach must be performed abdominal wall layers. Some studies reported 98% negative
through the intercostal space from superior, and the larger predictive and 99% positive predictive value for EUS and
part of the liver must be used as a window. Patients must take 97% success rate in diagnosis of bile duct stones compared
to endoscopic retrograde cholangiopancreatography (ERCP). sac wall, chronic inflammatory cell infiltration and intact
EUS is also superior to magnetic resonance cholangi mucus.
opancreatography (MRCP) in scanning of the bile duct
stones. The major benefit of EUS is that it allows avoiding
unnecessary ERCP and sphincterotomy in patients suspected Clinical Findings and Diagnosis
of choledocholithiasis. Biliary pain is not well-localized since it is visceral. Patients
often describe an upper abdomen pain that is localized in the
upper right quadrant and epigastric area. Eating may aggravate
Endoscopic Retrograde the pain. Onset of the pain often coincides with the beginning
Cholangiopancreatography of weight gaining episodes and during the distinct physical
inactivity conditions. Pain gradually aggravates between
It is one of the most effective modalities in choledocholithiasis
the fifteenth minute to first hour and then demonstrates a
scanning. Stones in the bile duct appear as the filling defect
plateau for about 12 hours before slowly relieving. Acute
(95% sensitive, 95% specificity). Therapeutic application
cholecystitis must be considered instead of simple biliary
of ERCP is limited to choledocholithiasis and other bile
pain if it lasts more than 6 hours. About 30% of the patients
duct diseases. Because ERCP is an invasive method
with conventional biliary pain do not suffer from an additional
and has potential complications such as pancreatitis,
pain attack until month 24. Therefore, cholecystectomy
postsphincterotomy bleeding. With the increase in the use
may be recommended for patients experiencing recurrent
of EUS and magnetic resonance imaging (MRI), the use of
biliary pain. The probability of developing complications that
ERCP for diagnostic use has very much decreased. It is only
requires urgent surgical intervention in patients with biliary
preferred today if required for therapeutic intervention. EUS
pain history is about 12% per year. Laboratory parameters
and MRCP show equivalent accuracy in choledocholithiasis
of patients with uncomplicated biliary pain are normal.
diagnosis.
Typically and frequently, USG is recommended as an imaging
method for patients with no other symptom than biliary pain.
Computerized Tomography and Magnetic Recurring uncomplicated, biliary pain with stones and sac is
typically treated by elective laparoscopic cholecystectomy.
Resonance Imaging
Computerized tomography (CT) is used in patients with
cholelithiasis or choledocholithiasis to image complications Acute Cholecystitis
of acute cholecystitis pericholecystitic liquid, sac-wall gas, Gallbladder inflammation is accompanied with abdominal
gallbladder-wall perforation and abscess. MRCP offers pain, upper right quadrant sensitivity, fever and leukocytosis.
high benefits in bile duct imaging and stone scanning. This It is caused by the obstruction of gallbladder neck, Hartmanns
modality is particularly beneficial in imaging the anomalies sack or cystic duct by stones. In about 10%, cholecystitis
of the most distal extrahepatic part of the bile duct even if may develop without the presence of stones (acalculous
the ductus is not enlarged. MRCP monitors bile duct with cholecystitis?). Acute cholecystitis with stones are typically
three dimensions and at high sensitivity. Sensitivity of MRCP observed in young and healthy patients and its prognosis
versus ERCP in choledocholithiasis scanning is 93% and its is good, whereas acalculous cholecystitis develops in older
specificity is 94%. CT and MRI are noninvasive, but they do patients and is accompanied with high rates of mortality
not have any therapeutic applications. and morbidity. Histological changes include from edema to
necrosis and sac-wall perforation.
GALLSTONE DISEASES Clinical Findings, Diagnosis, and Treatment

Biliary Pain and Chronic Cholecystitis Approximately two-third of the patients with acute
cholecystitis defined pain before attack. If biliary pain persists
The most common symptom of cholelithiasis is biliary pain. more than 6 hours, acute cholecystitis should be considered.
Biliary pain (biliary colic) is caused by the obstruction of the If the inflammation on the sac wall progresses, then visceral
cystic duct by one or more than one stones intermittently. pain not localized well turns into serious parietal pain localized
Biliary colic may not be necessarily accompanied by in the right-side upper quadrant. Nausea and vomiting are
gallbladder inflammation. Most common histological change among the characteristic symptoms of cholecystitis, but are
in patients suffering from biliary pain is mild fibrosis on the not as serious as intestinal obstruction or acute pancreatitis.
While acute cholecystitis symptoms are nonspecific in some the standard method for diagnosis and treatment of bile duct
patients, some of them may come up with toxic findings, such stones. Specificity and precision of ERCP is 95%.
as fever and rebounding serious pain. The Murphy finding
is specific. It is cessation of the pain and inhalation during
hand-contact of the examiner to the inflamed gallbladder Cholangitis
when the examiner palpates the right subcostal area and The most fatal and serious cholangitis is acute bacterial
when the patient takes a deep breath. Leukocytosis, serum cholangitis. Suppuration accumulates under pressure in bile
aminotransfrase and alkaline phosphatase (ALP) levels are ducts. This causes fast diffusion to the bloodstream from the
increased. Serum bilirubin levels may also increase. USG liver, which results in septicemia. In approximately 85% of the
is the only beneficial method in patients with acute right cases, cholangitis occurs due to bile stasis secondary to bile
upper quadrant pain and sensitivity. Existing sonographic duct stones.
Murphy sign should have predictive value higher than 90%
for diagnosing acute cholecystitis. The biggest advantage of
CT for patients with acute cholecystitis is that it shows the Clinical Findings, Diagnosis, and Treatment
complications. Upper quadrant pain with Charcots triad, and jaundice and
Patients with suspicion of acute cholecystitis are fever are the clinical findings. Complete triad is seen in 70% of
hospitalized. They should be given liquid and electrolytes. the patients. The pain can be slight and temporary, however,
Antibiotics are not necessary for cases not complicated. If accompanied by chill and shivering. Mental confusion,
the patient looks toxic or if complications are suspected, lethargy and delirium can occur in elderly patients. During
antibiotics effective on gram-negative bacteria should be physical examinations, fever is seen in 95% of the patients,
given. The definitive treatment is cholecystectomy. and right upper quadrant sensitivity is seen in 90% of the
patients. However, jaundice is clinically defined in 80% of the
Choledocholithiasis patients. Laboratory finding is useful for revealing that the
cause of sepsis is the biliary tree. Serum bilirubin value is high
Stones in the bile duct may remain asymptomatic for years in 80% of the patients. ERCP is the standard test for diagnosis
just like gallbladder stones, and the bile duct stones may drop of bile duct stones and cholangitis. Antibiotics and draining
into the duodenum discreetly. Benign episodes of the stones with ERCP are the basis of the treatment.
in the bile duct that cause recurrent biliary pain are more
evident clinically, and have life-threatening complications.
They may cause serious complications, such as cholangitis BIBLIOGRAPHY
and acute pancreatitis.
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43
cHAPTER
Cholangiocarcinoma
Christopher A Wadsworth, Simon D Taylor-Robinson, Shahid A Khan
INTRODUCTION of CC is short, with median survival of 36 months in

patients receiving palliative care. Overall, median survival in
Cholangiocarcinoma (CC) is a cancer that arises in developed countries is less than 2 years.
the epithelial cells of the bile ducts and has features of
cholangiocyte differentiation. Max Durand-Fardel, a French
physician, was the first author to describe CC. In 1840, he RISK FACTORS
reported a series of four postmortem examinations of patients
with jaundice who had rapidly succumbed to their disease. Inflammatory Risk Factors
In three cases, examination revealed tumors of the pancreas
obstructing the bile duct. In the final case, he reported a Known risk factors for CC include PSC, chronic secondary
soft, whitish, cancerous material, enveloping and completely cholangitis and chronic cholelithiasis. PSC is the most
filling the bile duct but that did not extend beyond the wall common known cause of CC in the west but still only
of the duct. He concluded that this represented a primary accounts for 20% of cases. The majority of CC cases in the west
cancer of the extrahepatic bile duct. are sporadic, with no known predisposing cause. Worldwide,
chronic infestation of the biliary tree with the parasitic liver
fluke Opisthorchis viverrini (OV) is a major risk factor for CC.
EPIDEMIOLOGY AND PROGNOSIS In Northern Thailand a 5- to 15-fold increased risk of CC is
described in OV-infested individuals.
Cholangiocarcinoma is the most common cause of death Congenital anatomical anomalies in the biliary tree such
from primary liver cancer in the UK, causing over 1,000 deaths as Carolis syndrome and choledochal cyst carry a lifetime
per year. Globally, incidence varies with both geography risk CC of around 15%. These conditions cause structural
and ethnicity independently. The population of northern abnormalities including dilation and cystic irregularity of the
Thailand has a very high rate that has been clearly associated bile ducts. They are thought to cause biliary stasis and flux of
with endemic liver fluke infestation. Chile also has a very pancreatic juice into the bile duct causing chronic epithelial
high incidence while Australia has a very low incidence inflammation.
with no clear variation in known risk factors for CC between The viral hepatitides have been investigated as potential
the two countries. Studies of the US population have shown risk factors for CC. Hepatitis C infection has been examined in
wide variation between different ethnic groups with rates of several case-control studies and found to confer a lifetime risk
1.22/100,000 in Hispanic Americans and 0.170.5/100,000 in of CC of around 4%, well above the background population
African Americans. risk. Hepatitis B and HIV infection have also been implicated,
Since 1968, there has been a 15-fold increase in mortality but less strongly. Cirrhosis of any cause increases the risk
from CC in the UK, with a similar global trend across of CC. Causative mechanisms have not been elucidated for
industrialized countries. The mortality rate of CC is equal to these risk factors, but chronic inflammation of the liver and
its incidence. Mortality from CC is so high as most patients DNA disruption are features in common.
present too late for complete surgical resection, the only cure,
and the cancer is resistant to chemotherapy and radiotherapy.
The median age at diagnosis of CC is 65 years and it rarely
Toxic Risk Factors
presents before the fifth decade, except in patients with Studies have implicated a variety of toxins and occupational
primary sclerosing cholangitis (PSC) or uncommon genetic risks with CC, with varying strength of evidence. Thorotrast,
diseases of the biliary transporter proteins. The prognosis an a particle emitting radiological contrast containing
Cholangiocarcinoma 413
thorium oxide, was used and subsequently proscribed in the biliary pathology. The sequence of genetic changes and their
middle of the last century. Thorium oxide has a long half- role in initiation and progression of CC in not clear. Stepwise
life and is concentrated in the reticuloendothelial system. cholangiocyte gene mutations are likely related to exposure to
It has been incontrovertibly linked with CC and a number endogenous mutagens or exogenous toxins.
of other malignancies, with a latency period of 2035 years. The common features of the disease risk factors for CC
Thorotrast exposure increases the risk of CC to 300 times are chronic cholestasis and inflammation of the biliary tree.
that of the general population. Epidemiological studies Such inflammation increases cell turnover, overwhelms local
have implicated tobacco smoking and alcohol use, although tissue repair pathways, and is intrinsically pro-oncogenic.
conflicting evidence also exists. Occupational exposure to Inflammatory cytokines, growth factors and bile acids
the manufacture of rubber, petrochemicals and varnishes is contribute to these molecular changes. Inducible nitric
an independent risk factor for CC. These associations have oxide synthase (iNOS) is overexpressed in PSC and CC, and
been ascribed to exposure to chemical byproducts, including is induced by cytokines. iNOS upregulation causes increased
dioxins and nitrosamines. Promutagenic DNA adducts have levels of reactive nitrogen oxide species causing DNA
been identified in CC-adjacent human tissue, indicating breakage, gene and protein mutation and suppression of DNA
exposure to DNA damaging exogenous toxins. A proposed repair enzymes. Ongoing damage to the biliary epithelium
common pathway of these environmental risks is exposure may enhance cholangiocyte exposure to endogenous
of the biliary epithelium to oncogenic substances, causing mutagens, such as hydrophobic bile acids and oxygen free
a sequence of genetic mutations thought to initiate and radical species, as well as exogenous carcinogens that are
promote neoplasia. concentrated and excreted in the bile.
Genetic Risk Factors HISTOPATHOLOGICAL

Lynch syndrome (hereditary nonpolyposis colorectal
cancer) and biliary papillomatosis, which are both genetic
CLASSIFICATION
conditions, increase risk of CC. Biliary papillomatosis carries
a huge (85%) risk of conversion to CC. These inborn genetic Histological Classification
mutations appear to offer an epithelial substrate that is highly More than 90% of CCs are adenocarcinomas, and the
vulnerable to subsequent oncogenic factors. remainder is squamous cell carcinomas. CC can be classified
Genetic defects leading to congenital abnormalities in bile as well, moderately or poorly differentiated. All subtypes have
salt transporter proteins such as bile salt exporter pump, FIC1 a propensity for local invasion, indolent growth, perineural
and multidrug resistant protein 3 cause cholestatic disease spread and mucin production. Three distinct histological
in infants. These defects result in unstable bile content and subtypes of CC have been describedsclerosing, nodular
deconjugation of xenobiotics, previously conjugated in the and papillary. A substantial majority are of the sclerosing
liver. Very early onset hepatocellular carcinoma (HCC) and type, characterized by an intense desmoplastic reaction.
CC have been reported in this group. Invasion along and through the bile duct wall is an early
feature. Presentation is generally at a late stage and prognosis
is particularly poor. Sclerosing CC has a radiological
PATHOGENESIS appearance similar to that of benign strictures of the bile
duct, complicating diagnosis and management further.
Cholangiocarcinoma results from malignant transformation
of cholangiocytes, although transformation of biliary and
hepatic stem cells may also lead to CC development. In
Anatomical Classification
comparison to other gastrointestinal tract malignancies, the The anatomical site of any CC is of critical importance as
pathogenesis of CC is poorly understood. Molecular studies this determines resectability, the nature of any surgery and
of dysplastic biliary and CC tissues have demonstrated the likelihood of its success. About 65% are hilar or perihilar
cumulative genetic mutations in the epithelium. (Klatskin tumors), 25% in the distal bile duct (defined as
Dysregulation of oncogenes (K-Ras, c-myc, c-neu, c-erbB-2, beyond the point at which the bile duct passes posterior to the
c-met, CCND1) and tumor suppressor genes (p53, DPC4/ duodenum) and 10% are within the peripheral liver. Perihilar
Smad4, CDKN2A, ABC, p16INK4a) has been demonstrated. and distal lesions are classified as extrahepatic while lesions
However, the frequency of such mutations varies widely peripheral to the hilum are classified as intrahepatic. In
with ethnicity, tumor stage, tumor location and preexisting planning surgery, further detailed anatomical classification
diagnosis is fraught with variability in technique, for both

endoscopist and cytopathologist.
In the studies considered here, gold-standard technique
and expert operators were used. Real-world performance is
likely to be substantially worse.
Fig. 1: Bismuth-Corlette classification of hilar cholangiocarcinoma,

Cytopathological Markers
based on ductal extent of the lesion Immunohistochemistry has been unhelpful in the
differentiation of CC from other malignancies, as no
specific markers have been identified. However, the use of
of perihilar CC is made into Bismuth-Corlette categories DNA proliferation measures shows promise. Cytokeratin,
(Fig. 1). CC, cancer of the gallbladder and cancer of the carcinoembryonic antigen (CEA) and mucin staining
ampulla of Vater are considered to be separate entities. of biopsy tissue are suggestive of the diagnosis, but are
nonspecific. Testing of K-Ras and p53 mutation in cells
collected for cytology has been investigated in clinical studies
PATHOLOGICAL DIAGNOSIS and shown not to improve sensitivity or specificity.
Diagnostic Histology Digital Image Analysis and Fluorescent

The fibrotic, paucicellular nature of CC, makes successful In Situ Hybridization
sampling for histology or cytology very difficult. In small
Digital image analysis (DIA) measures the quantity of nuclear
or early lesions, percutaneous biopsy often reveals normal
DNA in cells whilst FISH labels DNA with a fluorescent marker,
or fibrotic tissue only. The intimate relation of most CCs
permitting visualization of chromosomal abnormalities. The
to large bile ducts, and their adjacent blood vessels, means
use of DIA or FISH can improve the sensitivity and specificity
that percutaneous or laparoscopic biopsy carry significant
of biliary stricture cytology in patients with and without PSC.
risk of damaging critical structures. Very large or peripheral
In one study, DIA offered sensitivity and specificity of 39%
lesions may be highly amenable to percutaneous biopsy.
and 77% compared with 18% and 98% with standard cytology.
Seeding of malignant cells from a CC through a biopsy track
In patients with PSC DIA has sensitivity of 43% and specificity
is a theoretical possibility and has been demonstrated in
of 87%. FISH has sensitivity of 47% and specificity of 100% in
studies of HCC. It is therefore avoided in cases where curative
such patients.
resection is thought possible.
Diagnostic Cytopathology Cytopathology in Primary Sclerosing

Collection of cytology samples from extrahepatic biliary
Cholangitis
strictures is possible, using a brush or biopsy forceps at False positivity of cytopathological analysis is more common
endoscopic retrograde cholangiopancreatography (ERCP). in patients with PSC and, in combination with the confounding
The desmoplastic nature of most CCs means that these radiological findings in PSC, can lead to incorrect diagnosis
techniques offer a low yield of material for analysis. The and therapy.
cellular inflammatory response in conditions such as PSC
complicates analysis further as atypical cells are seen in
both conditions. In clinical studies, the sensitivity of these CLINICAL FEATURES
techniques (or combinations of them) ranges from 40% to
64% and specificity from 90 to 100%. These studies included Cholangiocarcinoma runs a long, latent course before
patients with a mixture of diseases, including metastatic and symptoms trigger presentation. Symptoms of icterus and
pancreatic cancers compressing the bile duct. Subgroup pruritus are common, but occur only once bile outflow is
analyses suggest that cytological sampling is more likely to almost completely obstructed. A minority of patients report
yield the diagnosis in lesions that originate in the bile duct, a dull right upper abdominal pain. Nonspecific features
i.e. CC. Differential sensitivities for CC and pancreatic cancer include lethargy, weight loss and low-grade pyrexia. The long
of 80% and 35%, respectively have been shown. Cytological latency before presentation is thought to contribute to the
advanced stage at diagnosis and, therefore, poor prognosis. CA19-9 but this has not been validated in prospective clinical
Physical signs of CC include jaundice, right upper abdominal studies.
mass or hepatomegaly and only occur when the lesion is
extensive enough to cause palpable mass effect or substantial
biliary obstruction. Where the patient suffers from preexisting Imaging in the Diagnosis and Staging of
benign biliary disease such as PSC, progressive jaundice, Cholangiocarcinoma
weight loss and malaise may accompany deterioration of that
A variety of imaging techniques is used in the assessment of
underlying disease or herald the development of CC. It is also
biliary strictures. Imaging is the mainstay of diagnosis and
impossible to clinically distinguish the presenting symptoms
staging of CC and in western healthcare systems most patients
and signs of CC from those of HCC, pancreatic cancer or
undergo three or more imaging techniques before their lesion
metastatic cancer of the liver.
is considered fully characterized. Recent advances include
detection of perfusion characteristics of benign and malignant
lesions, liver-specific contrast agents and enhanced signal
LABORATORY TESTS and imaging detector technology. Standard imaging techniques can reliably
distinguish malignant from some common benign causes of
Serum Biochemistry biliary obstruction, such as choledocholithiasis. However,
Standard liver function tests including bilirubin, alkaline discrimination between benign and malignant strictures of
phosphatase (ALP) and transaminases are usually elevated the bile ducts is more difficult. Cholangiography is the most
at the time of diagnosis. Peripheral CC often causes no accurate way to delineate the site and intraductal extent of
elevation in bilirubin, as the volume of liver obstructed by the any stricture. This can be obtained via ERCP, percutaneous
lesion does not affect the total excretory capacity of the liver transhepatic cholangiogram (PTC) or magnetic resonance
significantly. Elevated bilirubin and ALP are associated with cholangiopancreatography (MRCP) with equal accuracy.
all benign and malignant cholestatic diseases. Progressive In a 6-year prospective study of 230 patients with PSC, 10%
deterioration of these indices in patients with PSC may were diagnosed with CC. The use of Ca19-9 alone was less
indicate an evolving CC. sensitive than a combination of Ca19-9 and cross-sectional
imaging. However, the addition of imaging did not improve
specificity, positive predictive value (PPV) or negative
Tumor Markers predictive value. The addition of cholangiography (as MRCP
or ERCP) did improve specificity and PPV. Approximately
Carbohydrate antigen 19-9 (CA19-9) is the most widely
70% of patients with PSC have cholangiographic evidence of
used tumor marker in the diagnosis of CC. The defining
both intra and extrahepatic ductal involvementincluding
antibody reacts with mucin glycoproteins that are coated
stricturing and dilation. New, malignant strictures may be
with sialylated blood-group epitopes, such as sialyl Lewisa.
superimposed on these strictures, making accurate detection
Large studies have demonstrated sensitivity and specificity
of up to 75% and 85%, respectively. However, specificity is difficult. This is a major problemin one study of 125 PSC
greatly reduced in the presence of cholestasis or cholangitis. patients who were followed up for 10 years, 45% developed a
In studies of PSC cohorts, sensitivity and specificity have dominant stricture at some point.
ranged hugely; 3880% and 5098%, respectively. The Even with the full range of imaging technologies discussed
selection criteria of cases studied and the CA19-9 cutoff in the following sections, correct diagnosis and staging of CC
value used account for the huge variation. Most importantly, is often impossible.
the elevation of CA19-9 has been shown to occur late in the
development of CC. In a longitudinal study of PSC patients Ultrasound
undergoing screening for CC with CA19-9, only 2/14 patients
who developed CC were candidates for curative treatment. Transabdominal B-mode ultrasound: Transabdominal
CA19-9 is also elevated in gastric cancer, pancreatic cancer, ultrasound is a quick, widely-available and safe test.
primary biliary cirrhosis and individuals who smoke. Around Transabdominal B-mode US is highly sensitive for the
7% of the population are Lewis-negative and are unable to detection of bile duct dilation and, in this context and skilled
express CA19-9 at all. hands, delineating the site of any obstruction. However, US
Carcinoembryonic antigen has been investigated is operator-dependent and has low sensitivity and specificity
extensively but is only positive in about 30% of patients with for CC detection and is inaccurate in estimating local tumor
CC. Some studies have suggested that CEA can enhance extent. Sensitivity for detection of hepatic masses of any type
sensitivity and specificity when used in conjunction with ranges from 37 to 87%.
Contrast-enhanced ultrasound: Improvements to ultrasound

technology, and the development of associated contrast
agents, have led to major recent advances. The contrast
agents have a microbubble structure, consisting of bubbles
of inert gas with a stabilizing shell. The bubbles are 35
mm in diameter and remain intact in the circulation for
some minutes. When exposed to US energy, these bubbles
generate specific signals that allow precise assessment of
vascular perfusion of lesions in different phases. The ability
to characterize lesions, including intrahepatic CC, is thereby
improved. On contrast-enhanced ultrasound (CEUS)
examination intrahepatic CCs are typically hypovascular
in the delayed phase after contrast administration. This
characteristic is shared with metastatic liver cancers, but
may discriminate CC mass from HCC or benign vascular
lesions. Unfortunately, CEUS is of less utility in detecting the
commonest extrahepatic, infiltrating form of CC, especially
in patients with PSC. Fig. 2: Multidetector computed tomography with contrast image. A
hilar mass (arrow) is causing a stricture at the liver hilum and dilation
of right and left hepatic ducts
Computed Tomography
New multidetector computed tomography (MDCT) has
reduced the time required to image the whole liver by a factor disease. In one study CC PET/CT had sensitivity of 93%
of three, imaging the whole body in less than 1 minute. This and specificity of 80% for intrahepatic lesions. For the
permits repeated imaging through different vascular phases, more common extrahepatic CC this fell to 55% and 33%,
improving lesion characterization. Small hilar lesions are respectively. Sensitivity and specificity for regional lymph
often not detected on computed tomography (CT) due to node metastases were 12% and 96%. Another study found
their fibrotic, infiltrating nature and isoattenuation with sensitivity of 85% for nodular forms of CC but a dismal
normal liver tissue. When seen, these lesions tend to be 18% for the commoner infiltrating type. Sensitivity for
hypoattenuating with delayed enhancement sometimes seen previously undetected extrahepatic metastases was 65%.
due to contrast retention within the fibrous tumor tissue. CT PET/CT was found to alter management significantly in the
is highly sensitive for biliary dilation and identification of the majority of patients in a study of non-PSC CC cohort. One
site of biliary obstruction. Multiphase imaging permits 3D study demonstrated utility of PET/CT in characterizing
reconstructions of the hepatic arterial and venous systems, lesions in PSC but false positivity is common in patients
which can improve assessment of vascular invasion. Older with inflammatory biliary diseases. Despite disappointing
studies have suggested that CT has low sensitivity and performance of PET/CT in the clinical management of CC,
specificity for CC, is inaccurate at estimating local tumor it maintains a limited role. Its PPV in regional nodal disease
extent and predicts resectability with accuracy of only 60%. of non-PSC patients being staged prior to curative resection
MDCT may have improved these disappointing results (or transplantation) may avoid inappropriate surgery for
substantially. A CT image of a CC and the associated biliary incurable lesions.
dilation is provided in Figure 2.
Multidetector CT is the modality of choice for detection of
chest, and distant abdominal, metastatic CC. Its main role is Magnetic Resonance Imaging and Magnetic
in the detection of vascular invasion and metastatic disease. Resonance Cholangiopancreatography
Magnetic resonance imaging (MRI) can provide contrast-
Positron Emission Tomography and enhanced images of the liver parenchyma, as well as
cholangiographic images, noninvasively. This permits
Computed Tomography assessment of intra- and extrahepatic lesions and the ductal
Several studies have considered the use of P-(18F)-2- and periductal extent of any tumor. Liver MRI normally
deoxyglucose positron emission tomography (PET)/CT utilizes a T1-weighted in-phase/out-of phase spoiled gradient
to resolve indeterminate cases as benign or malignant echo sequence and at least one T2-weighted sequence.
Addition of a fat-saturated spoiled gradient echo sequences Magnetic Resonance

with intravenous contrast allows assessment of tumor
enhancement patterns. Diffusion-weighted MRI utilizes the Cholangiopancreatography
motion of water protons to improve conspicuity of tumors. Magnetic resonance cholangiopancreatography provides
Magnetic resonance imaging-contrast agents include high-resolution cholangiography and is noninvasive. It
nonspecific extracellular contrast agents, such as gadolinium requires no contrast and utilizes MR imaging data accrued
chelate and liver-specific agents. Liver-specific agents may with heavily T2-weighted sequences. The high water
be hepatocyte selective, reticuloendothelial system specific content of bile acts as an endogenous contrast medium.
or have combined properties. Administration of gadolinium Cholangiocarcinomas are seen as shouldered stenotic
allows assessment of vascularity in lesions through different or sclerosing ductal lesions. Subtle duct wall thickening,
phases. The timing of enhancement and contrast washout nodular or papillary filling defects may be seen. MRCP is
often permits clear characterization of a lesion. highly sensitive for biliary obstruction and its localization. It
The combination of cholangiography and extraductal is slightly less accurate than ERCP for differentiating benign
information provided by a MRI/MRCP study make it the and malignant biliary strictures. Detection of intraductal
investigation of choice for diagnosis and local staging of CC. abnormalities on MRCP depends upon visualization of
defects within the high signal bile. In nonobstructed,
nondilated biliary systems, sensitivity and specificity fall off
Magnetic Resonance Imaging substantially. Spatial resolution is also reduced when MRI
The enhancement of CC on MRI is nonspecific. It typically data is reconstructed into the MRCP. Although MRCP can
appears hypointense on T1-weighted scans and hyperintense detect proximal ductal extent more accurately than ERCP
on T2-weighted scans. MR is sensitive for satellite intrahepatic it can underestimate the extent of hilar and distal ductal
liver metastases. After administration of gadolinium, lesions. An MRCP biliary reconstruction image is provided
extrahepatic CCs show slow homogeneous enhancement in Figure4, showing a tight hilar stricture with filling defects
into the late phase. Intrahepatic lesions tend to enhance extending into both right and left main hepatic ducts.
peripherally initially, with prolonged retention of contrast in
the late phase. Using intravenous gadolinium or specific MR
liver-contrast agents, such as ferumoxide can enhance the Endoscopic Techniques in the Diagnosis and
sensitivity of MRI studies for CC. Contrast MRI assessment of Staging of Cholangiocarcinoma
vascular invasion is comparable to traditional angiography.
Endoscopic retrograde cholangiopancreatography: It is still
An example of MRI image of a CC, with associated intrahepatic
considered the gold standard for imaging the biliary tree
biliary dilation is provided in Figure 3.
Fig. 3: Magnetic resonance image of hilar cholangiocarcinoma. There is Fig. 4: Magnetic resonance cholangiopancreatography image. A hilar
a visible mass at the liver hilum, with bilateral intraheptic duct dilation stricture (arrow) is causing intrahepatic duct dilation
and is widely available in the West and many developing Choledochoscopy (e.g. SpyGlassTM system): Recent techno
countries. The bile duct is cannulated and contrast is instilled logical advances have reignited interest in this technique. The
under endoscopic and fluoroscopic control. High-resolution procedure requires insertion of a small, fiberoptic endoscope
cholangiograms are obtained in which biliary strictures can through the biopsy channel of a standard duodenoscope
be reliably detected and differentiated from other obstructing (or a percutaneous system) into the bile duct. First, second
pathologies, such as cholelithiasis. Differentiation of benign and third order bile ducts can be accessed and visualized.
(owing to PSC or pancreatitis) and malignant strictures can be Modern systems permit biopsy of biliary lesions under direct
problematic. Features that favor malignancy include stricture endoscopic vision. Mucosal appearances that are suggestive
length of greater than 10 mm, a ragged contour, abrupt of malignancy include nodularity, papillomatosis and
transition (shouldering) or fixed filling defect. Strictures at ulceration. These systems can facilitate stent insertion and
the hilum are highly suspicious and warrant particularly targeted biopsy of specific strictures.
aggressive investigation for malignancy. Figure 5 shows a A number of case series have been reported that examine
radiographic image acquired during early filling of the duct the use of choledochoscopy to assess strictures. A recent
at ERCP and demonstrates a tight common hepatic duct prospective study examined 76 patients with indeterminate
stricture. Figure 6 shows a larger, more exophytic hilar tumor biliary strictures after noninvasive imaging. 22/38 (58%) of
with an extensive intraluminal filling defect. malignant strictures were correctly characterized by ERCP
Tissue sampling can be undertaken at ERCP using a alone. The addition of choledochoscopy with targeted biopsy
variety of techniques including cytology brushings, biopsy increased the sensitivity for malignancy to 38/38 (100%).
forceps and bile aspiration for cytology. Therapy, such as Seven of the thirty-eight benign strictures were the result
stent insertion, can be delivered. However, ERCP provides of PSC, and one of these cases was falsely categorized as
only two-dimensional imaging of the bile duct and gives no malignant after choledochoscopy and biopsy. A further case
extraductal information. ERCP carries a significant risk of series of 255 indeterminate strictures claimed that relevant
serious morbidity, particularly pancreatitis. information was garnered by choledochoscopy and biopsy
Fig. 5: Endoscopic retrograde cholangiopancreatography radiographic Fig. 6: Endoscopic retrograde cholangiopancreatography radiographic
image during early filling with contrast. A tight common hepatic duct image of hilar cholangiocarcinoma. Note the extensive mass visible
stricture is seen (arrow) as a filling defect within the common hepatic duct, left and right main
ducts (arrow)
in 68% of cases, changing the diagnosis in 10%. However, Intraductal Ultrasound

malignancy was only demonstrated by choledochoscopy and
biopsy in 10% of the lesions that were subsequently proven Intraductal ultrasound (IDUS) requires the passage of a
to be cancerous at excision. In a study of 53 patients with catheter-mounted US probe into the bile duct through an
PSC and indeterminate dominant stricture, sensitivity and endoscope or percutaneous biliary drain. This allows radial
specificity for CC both exceeded 90%. imaging of the biliary tree. Various characteristics correlate
Some centers have employed confocal microscopy, which is with malignancy, particularly IDUS evidence of bile duct wall
established in the endoscopic assessment of gastric and colonic disruption. A small (n = 30) retrospective study demonstrated
neoplasms, to assess biliary strictures at choledochoscopy. sensitivity and specificity of 92% in categorizing strictures
Fluorescein solution is instilled into the bile duct through the as benign or malignantsuperior to ERCP in this particular
channel of choledochoscope. This is followed by a catheter- study. Use of IDUS to enhance cytology yield, in combination
based microscope that allows visualization of the pattern of with ERCP or ERCP and tissue sampling may improve overall
cells and vessels in the stricture. Lesions are classified using accuracy to greater than 90%. Some centers are now using
criteria similar to those used in the confocal microscopic contrast-enhancement techniques with IDUS. However,
assessment of other GI lesions. In a group of patients with these studies on indeterminate biliary strictures have been
previously indeterminate lesions, sensitivity for malignancy on a heterogeneous group, with only small numbers of PSC
of ERCP alone, with the addition of choledochoscopy or with patients included.
the addition of choledochoscopy and confocal microscopy Current IDUS technology has only limited ability to
were 56%, 59%, and 83%, respectively. Other groups have evaluate the layers of the bile duct and infiltration of
examined biliary strictures experimentally using narrow-band surrounding structures, such as lymph nodes. IDUS is only
imaging technology. These techniques of in vivo pathological available in a very limited number of centers.
classification show some promise but remain experimental at
present.
Modern choledochoscopy appears very promising but SCREENING FOR CHOLANGIOCARCINOMA
has several disadvantages. The double scope systems are
expensive and expertise is currently limited to a few highly Even though the PSC patient cohort can be readily identified
specialist centers. Choledochoscopy is invasive and gathers as at high-risk of CC, there is currently no proven benefit
no information beyond the lumen of the bile duct and so does in screening for CC in this group. A number of longitudinal
not contribute to staging of the disease. studies of formal screening protocols have utilized CA19-
9, ultrasound, MRCP and ERCP with cytology. Although
Endoscopic ultrasound: It requires a modified endoscope, some protocols have achieved respectable sensitivity and
with an ultrasound probe built into its tip. The bile specificity, outcomes remain unaltered. In the UK, diagnosis
duct can be imaged reliably to the bifurcation of right of CC contraindicates liver transplant in patients with PSC.
and left hepatic ducts, through the wall of the stomach Such patients are also highly unlikely to be candidates
or duodenum. Endoscopic ultrasound (EUS) permits for curative liver resection. Criteria for an effective formal
sampling of suspected CC by fine-needle aspiration (FNA). screening program were published by Wilson and Junger in
The two largest case series examining EUS + FNA reported 1968and are retained by the WHO today. Two of these are
sensitivities of 86% and 89% for CC. However, this strategy not currently met in the case of CC in PSC: (i) that there should
is avoided in the assessment of potentially resectable hilar be an accepted and effective treatment available for patients
lesions, as there is a risk of tumor seeding. EUS is highly with the disease, and (ii) that the screening test detects
sensitive for local nodal disease and this has been studied disease at an earlier stage, when treatment is more effective.
in trials of highly selected liver transplantation for CC. Of 47 Until refined diagnostic tools permit earlier diagnosis, or new
patients, 17% were found to have local lymph node disease treatments that improve outcome, become available, formal
on EUS and FNA, precluding transplant. The exclusion screening programs for CC in those with PSC are unlikely to
of such patients from inappropriate transplantation has lead to improved survival.
contributed to hugely improved outcomes in transplantation
for irresectable CC.
Endoscopic ultrasound is hampered by limited range so is STAGING OF CHOLANGIOCARCINOMA
unhelpful in imaging lesions extending proximal to the hilum
and intrahepatic lesions. It is highly operator dependent and Staging of CC is currently poor. Even in cases where curative
requires very costly systems. resection is attempted, survival rates are low. CC is a
highly invasive tumor with early vascular and perineural survival benefit. Contraindications to surgery include proven
invasion. Imaging is the mainstay of preoperative staging, distant metastases, malignant ascites, bilateral vascular or
supplemented with staging laparoscopy in indeterminate biliary involvement, advanced cirrhosis or PSC. In a large
cases. Perihilar lesions are particularly difficult to stage case series, resection was feasible in distal, intrahepatic and
correctly and often resectability can only be determined at perihilar lesions in 91%, 60%, and 56% of cases, respectively.
surgery. Survival after diagnosis with CC is dependent on Monofocal intrahepatic CC can be resected in a segmental
complete surgical resection, with clear margins. fashion with 5 year survival rates of 2244%. Surgery for
A number of staging systems have been used, based on perihilar lesions is determined by Bismuth-Corlette criteria.
tumor-node metastases (TNM) criteria, the American Joint Patients with Bismuth I and II lesions undergo en bloc
Committee on Cancer, TNM criteria being the most widely resection of the extrahepatic bile ducts, gall bladder and hilar
used. Such systems are based on pathological parameters lymph nodes with the formation of a hepatojejunostomy. Type
and require an excised lesion for precise classification, III and IV lesions require lobectomy or hemihepatectomy
although imaging and biopsy findings are used to define a of the corresponding liver. Distal lesions are resected with
provisional stage preoperatively. Intrahepatic CC is accurately a pylorus preserving pancreaticoduodenectomy (Whipple
staged according to the same criteria as HCC. This system procedure).
is not appropriate for staging of extrahepatic CC, as it does R0 resection of perihilar CC carries a 5-year survival of
not take account of features of extrahepatic CC that inform 1141% and for distal CC 2737%. Overall 5-year survival for
management, such as precise ductal distribution of hilar CC, R0 resections remains less than 50%. It is likely that some of
hepatic function, hepatic atrophy and vascular invasion. The these studies underestimate current outcomes as survival
Memorial Sloan-Kettering system adds biliary extent, vascular rates after CC resection have improved in the last decade
encasement and liver atrophy to the TNM criteria. Correlation most likely due to improved staging and patient selection.
with R0 resection, nodal spread and survival is somewhat When surgery is planned, preoperative relief of any
improved using this system. A very recent study examined biliary obstruction is usually attempted. It is generally
147 cases of distal bile duct CC in detail. On multivariate accepted that the poor nutrition, coagulopathy, renal
analyses, tumor invasion depth through the bile duct wall was impairment and potential for sepsis associated with biliary
the factor most associated with negative outcome. Invasion obstruction increase the risks of surgery. However, a recent
of 512 mm or greater than 12 mm had more than a threefold major randomized controlled trial (RCT) of preoperative
or sixfold increased risk of death respectively, compared with relief of biliary obstruction in pancreatic head cancer
patients who had a lesion invading less than 5 mm (512 versus proceeding to primary surgery have cast doubt on
mm, HR = 3.8; >12 mm, HR = 6.7 p <0.05). Depth of invasion these assumptions. Most experts still maintain that, unless
is not included in current staging systems. Expert groups are definitive surgery can be undertaken very rapidly (which is
currently refining and validating systems that include factors often precluded by patient, surgeon and healthcare system
such as depth of invasion, jaundice and performance status. factors), preoperative relief of obstruction remains critical.
Even when staged as operable, clear margins are achieved In CC surgery, where a significant proportion of the liver
in only 2050% of patients undergoing curative resection for may be resected, it is essential that the hepatic remnant is
CC. In those patients with clear margins, the 5 year survival functioning optimally, mandating relief of the profound
rate is 1947%. Those undergoing resection with positive hepatic effects of severe cholestasis. It is important that the
margins have 5 year survival of 012%. This indicates that liver is as fully drained as possible, avoiding the persistence
even with high quality expert imaging, current staging is poor of undrained, infected liver segments. Methods for relieving
and does not predict resectability of CC or survival well. biliary obstruction are considered below.
TREATMENT Surgery for Primary Sclerosing Cholangitis

Patients with Cholangiocarcinoma
Surgery Resection of CC in patients with PSC has higher associated
Surgery is the only therapy that can cure CC. Survival morbidity and mortality. The underlying liver function may be
correlates strongly with negative margins (R0 resection), inadequate to withstand resection of the required volume of
absence of vascular invasion and absence of lymph node liver. Resection for extrahepatic lesions requires the formation
involvement. Resection is usually only attempted with of a biliary-enteric anastomosis, which can exacerbate the
curative intent, as palliative or debulking resections confer no ongoing cholangitis, and is an additional risk factor for CC.
Finally, PSC patients with CC are likely to have multifocal neoplasms showed no benefit of chemoradiotherapy in the CC
CC, or at least multifocal biliary dysplasia, that makes subgroup. In patients with positive margins at surgery, there is
early recurrence or development of a new lesion common. stronger evidence in support of adjuvant chemoradiotherapy.
Outcomes for patients with PSC who develop intrahepatic or Small retrospective series have demonstrated improved
perihilar CC and undergo resection are dismal. 5-year survival (34% versus 14%) and median survival (21
months versus 8 months). Postoperative chemoradiotherapy
is therefore generally recommended to patients with positive
Orthoptic Liver Transplantation resection margins.
Historically, orthoptic liver transplantation (OLT) for
unresectable CC has achieved appalling outcomes. Early
tumor recurrence and very poor survival rates were the rule.
Palliative Therapy
In the last decade, a number of centers have attempted liver Given that 5090% of CC patients have unresectable disease
transplantation in highly selected patients. Protocols include at diagnosis, palliative therapy is the mainstay. With full
exhaustive preoperative assessment, including a staging palliative treatment, median survival of 6 months is achieved,
laparotomy, with preoperative chemotherapy and intraductal versus 2 months with expectant care. The major morbidity
brachytherapy. Patients with irresectable disease confined to is related to biliary obstruction. The resultant jaundice is
the liver, and who tolerate the neoadjuvant regime, undergo debilitating and obstruction rapidly leads to deterioration of
transplantation. In the largest published series, the cohort that liver function and death.
actually underwent transplantation had 1, 3, and 5 years survival
after OLT of 90%, 80%, and 71%. These figures are comparable to
those achieved with OLT for other indications. Even in centers Endoscopic Palliation
where it available, only a small proportion of patients with Endoscopic insertion of biliary stents is the principal palliative
CC is considered candidates for OLT. The excellent survival therapy for CC. Plastic or metal stents can be deployed
figures are a result of the meticulous selection of appropriate through strictures at ERCP and can reliably decompress the
cases. The strict exclusion criteria, the cost of protocols and the biliary tree. The choice of metal or plastic stent depends on the
small donor pool mean that OLT is likely to remain of limited security of the malignant diagnosis, the predicted prognosis
utility in the treatment of CC. For now, CC remains an absolute and local resources. Although they are less prone to blockage
contraindication to OLT in most countries worldwide. and migration, metal stents do not improve survival when
compared to plastic. Plastic stents have an average patency
Neoadjuvant Therapy of 4 months, with metal stents lasting up to a year. Uncovered
metal stents are very difficult to remove once placed, so are
Neoadjuvant chemoradiotherapy is rarely feasible as CC only used when unresectable CC has been proven. Partially
patients are often jaundiced with poor performance status at and fully covered metal biliary stents are now available and
presentation. Small series of patients have been studied with are easily removed endoscopically or at surgery if necessary.
complete responses in 2030% and partial responses in the In some centers, these are used in preference to plastic stents
remainder. Cases of irresectable CC being downstaged and where the final diagnosis and potential for surgery are not yet
then resected successfully have been reported. However, determined and reliable interim biliary drainage is desired.
prospective clinical studies are required and neoadjuvant Sometimes, multiple metal stents are required to relieve
therapy remains feasible in only a minority of patients. sepsis associated with biliary stasis (Fig. 7).
Photodynamic therapy (PDT) has shown some promise in
Adjuvant Therapy the palliative management of CC. A hematoporphyrin such as
PhotofrinTM (Axcan Pharma Inc., Mont-St.-Hilaire, Canada) is
Adjuvant chemotherapy, in conjunction with R0 resection of administered systemically to the patient as a photosensitizing
CC, has not been proven to improve recurrence or survival agent. Light is then delivered to the CC stricture using an
rates. Many centers offer 5-fluorouracil or gemcitabine-based endoscopically introduced catheter. The protocols in current
adjuvant chemotherapy and this is the subject on ongoing use lead to tissue damage to a depth of 46 mm. Side effects,
clinical trials. Routine adjuvant chemoradiotherapy has such as cutaneous photosensitivity, and the limited depth of
been studied in small retrospective case series, which have tumor destruction, are limitations. However, PDT is currently
suggested a modest survival benefit. However, a prospective one of the limited numbers of therapeutic options available to
RCT of a mixed group of biliary, ampullary and pancreatic the patients with CC.
Fig. 7: Endoscopic retrograde cholangiopancreatography radio Fig. 8: Endoscopic retrograde cholangiopancreatography radiographic
graphic image. In a complex hilar stricture with tumor extension into image after insertion of an internal/external drain into the right liver
multiple segmental ducts, four metal stents have been required to at percutaneous transhepatic cholangiogram (arrow) and endoscopic
achieve palliative drainage and resolution of sepsis. Intra-arterial placement of a plastic stent into the left liver
coils can also be seen, which have been placed during previous
tumor embolization
Radiofrequency ablation (RFA) of CC tissue is possible, Oncological palliation: Chemotherapy with gemcitabine
using a RF coil mounted on a biliary catheter. This catheter is and cisplatin has utility in patients with unresectable CC,
then introduced at ERCP and RF energy delivered directly to with prolongation in median survival from 8 to 26 weeks.
the stricturing lesion. This technique is able to quickly deliver The benefit of the combination of gemcitabine and cisplatin
large amounts of energy to the CC tissue without the need for has recently been confirmed by a major RCT. Studies
sensitizing agents. The technique has shown promise in early have incorporated all types of CC, gallbladder cancer and
studies and larger scale clinical trials are awaited. Given the
ampullary cancer. This is a flaw, and expert groups have
success of RFA in the treatment of other solid malignancies,
advocated separate clinical studies in each of these cancers.
such as HCC, this approach may prove of benefit.
Where ERC with placement of endobiliary prostheses is However, the rarity of these cancers, and the difficulty in
not available, or proves technically impossible, a PTC may be establishing such high quality RCTs, mean that these studies
performed. This permits the insertion of internal or external are not imminent.
biliary drainage systems and endobiliary stents. Figure 8 Palliative external beam radiotherapy, with or without
illustrates a case in which both an internal/external drain chemotherapy, may reduce biliary obstruction and pain but
inserted at PTC, and a plastic stent inserted at ERCP, have does not confer any survival benefit. Small studies of high-
been required. dose radiotherapy with chemotherapy, including intraductal
Surgical palliation: There is no role for surgical debulking. brachytherapy, have shown increased 2-year survival (48%
Laparoscopic biliary bypass surgery is sometimes required for versus 0%). However, prospective studies have not been
palliative relief of jaundice. However, endoscopic decompression performed and complication rates with high intensity
is generally preferred as the associated morbidity is lower. chemoradiotherapy are higher.
PUBLISHED GUIDELINES pathologists, radiologists, endoscopists and oncologists

to collaborate as a multidisciplinary team. Unfortunately,
Detailed guidelines for the diagnosis and management of CC until better therapeutic options emerge or earlier diagnosis
were first published by the British Society of Gastroenterology becomes the norm, the mortality of this disease is unlikely to
(BSG) in 2002. A summary of the diagnostic criteria for CC improveeven in well-funded healthcare systems. Until such
included in this guideline is provided in Table 1. An updated time, the priority must be to accurately identify the minority
version of these guidelines will be published in 2011/12. The of patients who will benefit from resection and to optimize
use of such guidelines is helpful but clearly local policies, the palliative care of the majority who will not.
patient needs and healthcare economics must be considered
in their interpretation.
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44
cHAPTER
Acute Pancreatitis
Mahesh Gupta, Uday C Ghoshal
INTRODUCTION ETIOLOGY
Acute pancreatitis (AP) is disease occurring due to multiple In adults, the most important risk factors for AP are gallstones
causes affecting all age groups. It is associated with varying (38%) and alcohol (36%). In the remaining 2030%, the
degrees of acute inflammation and parenchymal injury to the disease is caused by trauma, drugs, heredity, infection and
gland. The incidence of AP ranges from 5 to 73 per 100,000 toxins. In a subset of patients, no etiology can be identified
populations per year. The exact incidence is difficult to (idiopathic). The incidence of gallstone pancreatitis is more
estimate as mild disease may go unnoticed and severe disease in white women, age above 60 years and small stones or
may lead to mortality in 1025% of patients and may occur microlithiasis. The causes of AP have been enumerated in
before diagnosis is made. It is a potentially serious illness Table 1.
with overall mortality about 5% despite recent advances in
diagnosis and management. Table 1: Causes of acute pancreatitis
Interstitial pancreatitis and necrotizing pancreatitis occur
in 85% and up to 15% of AP. Approximately 1% of patients with Gallstone disease
interstitial pancreatitis experience organ failure and a very Alcohol
low mortality of about 3% compared to 17% in necrotizing Metabolic
pancreatitis. The mortality in patients of AP without organ Hyperlipidemia
failure, with single organ failure and with multisystem organ Hypercalcemia
failure is nil, 3% (range 08%), and 47% (range 2869%), Trauma
respectively. External
Surgical
Early diagnosis, adequate severity assessment and
Endoscopic retrograde cholangiopancreatography (ERCP)
early recognition of complication are key factors for better
Ischemia
outcome; on the above issues, recommendations from
Hypoperfusion
various authorities, classification systems, and methods for Atheroembolic
severity assessment have been described in the literature. Vasculitis
Pancreatic duct obstruction
Pancreatic tumors
DEFINITIONS Parasites
Pancreas divisum
Ampullary and duodenal lesions
According to the Atlanta criteria, AP is defined as an
Sphincter of Oddi dysfunction
acute inflammatory process of the pancreas with variable
Infections
involvement of other regional tissues or remote organ
Viruses
systems. Diagnosis of AP is based on the following criteria: Bacteria
epigastric pain consistent with the disease, elevation of Parasites
pancreatic enzymes in serum (amylase or lipase) greater than Hereditary
three times the upper limit of normal and morphological
Venom
evidence of the disease on imaging [(computed tomography
Drugs
(CT) or magnetic resonance imaging, (MRI)]. Any two of the
above three should be present to diagnose AP. Idiopathic
Acute Pancreatitis 427
Bile Duct Stone (Choledocholithiasis) contradicts this hypothesis. Despite all these controversies,
gallstones remain an important etiologic factor in AP. Acosta
Choledocholithiasis is the most common biliary abnormality et al. showed that gallstones were present in feces of 34 of
associated with AP, although AP can be associated with 36 patients with biliary pancreatitis compared to only 3 of
acalculous biliary disease. The cause and effect relationship 36 controls who had gallstones without pancreatitis. These
has been established by prevention of recurrence of observations suggest a definite link between gallstone
pancreatitis after clearing the bile duct of stones and passage and development of pancreatitis. Eventually, whether
cholecystectomy. duration of stone impaction influence development of
Opie in 1901 performed autopsy on a patient who died of pancreatitis was studied; it was shown that impaction of stone
pancreatitis and found impacted stone at lower end of bile in ampulla lasting longer than 48 hours caused significant and
duct. He proposed the common-channel theory stating that often lethal damage to the pancreas. Increased intrapancreatic
gallstone migration into the common bile duct was the main ductal pressure resulting from ongoing exocrine secretion
cause of AP due to blockage below the junction of the biliary into an obstructed pancreatic duct is another mechanism of
and pancreatic ducts. It was hypothesized that obstruction pancreatitis due to causes that impede the flow of pancreatic
caused bile to reflux into the pancreatic duct, thus damaging juice. Increase in intraductal pressure causes rupture of
pancreatic parenchyma by the detergent action of bile salts the smaller ductules and leakage of pancreatic juice into
and activation of pancreatic enzymes within the organ the parenchyma, activating inflammatory process. The
(Fig. 1). But in subsequent years, investigators failed to find mechanism by which ductal hypertension initiates pancreatic
a stone impaction in common bile duct and a common injury is still under investigation.
channel in up to one-third of patients who died of AP. Also, it Biliary sludge and microlithiasis, which are formed
was found that pressure was higher in pancreas than biliary after prolonged fasting or total parenteral nutrition, or
tract raising controversy in this theory. In animal studies, the from mechanical stasis as in distal bile duct obstruction
flow of normal bile through an unobstructed pancreatic duct are common causes of AP in a subset of patients in whom
did not result in AP. it was commonly thought to be idiopathic in the past. Lee
Another proposed mechanism is that after the passage et al. detected biliary sludge in 67% of patients with idiopathic
of gallstone, the sphincter of Oddi remains incompetent pancreatitis. In uncontrolled studies, biliary sludge was found
temporarily, permitting the duodenal juice to reflux into to cause pancreatitis, and its recurrence has been prevented
the pancreatic ductal system, which can activate pancreatic by cholecystectomy, papillotomy or ursodeoxycholic acid
enzymes. However, lack of predisposition to AP in spite of therapy. Presence of dilated common bile duct on imaging
Sphincter of Oddi incompetence caused by sphincterotomy study suggests biliary etiology of AP. Acute pancreatitis is
reported after formation of biliary sludge associated with the
use of ceftriaxone.
Alcohol
Though frequency of alcoholism as a cause of AP will vary from
country to country, it is implicated in 35% of patients in some
series. The risk of developing pancreatitis increases with both
amount and duration of alcohol intake. Alcoholic pancreatitis
generally occurs in persons having more than eight alcoholic
drinks/day (>100 g/day) for more than 5 years. Only 510%
of the alcoholics develop pancreatitis. This low rate argues
that genetic or environmental cofactors are important in the
development of alcoholic pancreatitis. Smoking is one of the
important cofactor. In a patient with first attack of pancreatitis,
alcohol is considered as the causative agent if other possible
causative factors are absent. The disease can become
recurrent with continued alcohol intake. Recurrent acute
attacks can also ultimately leads to chronic pancreatitis. In a
study, about 70% of patients developed chronic pancreatitis
Fig. 1: Common channel theory of biliary pancreatitis after 10 years of initial acute alcoholic pancreatitis episode.
Several mechanisms are proposed by which alcohol can hypotension, drugs (calcium chloride preoperatively) and
induce pancreatitis: pancreatic trauma are factors implicated in development of
Direct metabolic toxicity to pancreatic acinar cells, where pancreatitis in these patients.
it can interfere with enzyme synthesis and secretion. The Endoscopic retrograde cholangiopancreatography (ERCP)
effect of ethanol is initial brief secretory increase followed results in pancreatitis in 210% patients, although in some
by inhibition series frequency as high as 40% has been reported. Direct
Spasm of the sphincter of Oddi leading to increased injury to the organ and intraductal hypertension during the
pressure in the pancreatic duct procedure are the mechanisms of post-ERCP pancreatitis.
Intracellular calcium release from both the endoplasmic Pancreatitis is usually mild in these patients and has favorable
reticulum and acid stores and acute trypsin activation outcome.
Increases in ductal permeability causing leakage of
pancreatic enzymes out of the pancreatic duct into the
surrounding tissue causing tissue damage Definition of Post-ERCP Pancreatitis
Transient decreases in pancreatic blood flow leading to As per consensus published in 1991, post-ERCP pancreatitis
ischemic injury to the gland. is defined as a clinical syndrome consistent with AP with
The inappropriate activation of trypsin by ethanol has been a serum amylase level at least three times upper limit of
demonstrated in vitro. Ethanol can alter lipid metabolism, normal persisting for more than 24 hours after the procedure
and a transient hyperlipidemic state is sometimes seen during requiring more than one night hospitalization. Depending
an attack of alcoholic pancreatitis, although the etiologic upon the duration and complications, it is classified as:
significance of this observation remains uncertain. Mild: Post-ERCP pancreatitis requiring admission or
prolongation of planned admission to 23 days
Moderate: Pancreatitis requiring hospital stay of 410 days
Tumors Severe: Hospital stay of more than 10 days or complications
Tumor should be considered in elderly nonalcoholic patients like pseudocyst; need for drainage of collection.
with AP without gallstones. Pancreatic carcinoma is present in
approximately 12% of patients with AP. Intraductal papillary
mucinous neoplasm (IPMN) is the most common pancreatic Pathophysiology of Post-ERCP Pancreatitis
tumor that causes AP possibly resulting from blockage of The proposed mechanisms are as follows:
pancreatic duct. Acute pancreatitis can be the first clinical Mechanical obstruction: Obstruction to the pancreatic
manifestation of a periampullary tumor. flow by:
Trauma to the pancreatic sphincter or proximal
pancreatic duct
Trauma Edema of the pancreatic sphincter secondary to
Blunt abdominal trauma and penetrating injuries are sphincterotomy or thermal damage
implicated as a cause of AP in about 0.2% and 1% of cases Prolonged spasm of the pancreatic sphincter in patients
respectively. Pancreatitis should be suspected in patients with sphincter hypertension
with abdominal pain or fluid collections associated with Increase in hydrostatic pressure in the pancreatic duct:
hyperamylasemia following abdominal trauma. Clinically, This may be related to:
pancreatitis may vary from mild to severe. The main Contrast medium injection into the pancreatic duct
pancreatic duct may get disrupted due to trauma. Ductal Pancreatic manometry without distal aspiration
disruption may cause enzymes leakage and parenchymal Distal obstruction.
injury, fluid collection and pancreatic ascites. Various factors as discussed above lead to premature
intracellular activation of pancreatic enzymes causing
autodigestion, and release of inflammatory cytokines
Iatrogenic Pancreatitis that produce both local and systemic effects. A proper
Postprocedure pancreatitis is known to occur after understanding of the patient and procedure-related risk
percutaneous pancreatic biopsy, biliary duct surgery, renal factors can guide careful selection of patients for ERCP and
lithotripsy, distal gastrectomy, splenectomy, cardiopulmonary need for prophylactic pancreatic stenting or medication to
bypass and cardiac transplantation. Transient intraoperative prevent occurrence or severity of post-ERCP pancreatitis.
Patient-related Risk Factors for Post-ERCP Table 2: Drugs known to cause acute pancreatitis
Pancreatitis Sphincter of Oddi spasm

Opiates
Young age
Drug-related hypersensitivity reaction
Female gender
Suspected sphincter of Oddi dysfunction 5-aminosalicylic acid/sulfasalazine
Past history of post-ERCP pancreatitis Azathioprine
Normal bilirubin 6-mercaptopurine
Absence of stone in common bile duct. Metronidazole
Tetracycline
Procedure-related Risk Factors for Toxic effect on pancreatic parenchyma
Post-ERCP Pancreatitis Pentamidine

Furosemide
Contrast injection into the pancreatic duct
Valproic acid
Difficult cannulation
Precut sphincterotomy Didanosine
Pancreatic sphincterotomy Drug-induced hypertriglyceridemia
Balloon dilatation of biliary sphincter Thiazides
Isoretinoin
Operator/Technique-related Risk Factors Tamoxifen

Overdose reaction
Trainee (fellow) participation
Acetaminophen
Cannulation without using wire to guide it
No placement of pancreatic duct stent in high-risk
procedures.
Pancreatic stent placement in after predisposing Tuberculosis of the pancreas is rare even in countries where
procedures can reduce risk of post-ERCP pancreatitis and is the disease is endemic. Diagnosis can be made by histological
widely performed at many centers. examination after laparoscopy or fine needle aspiration. Other
reliable methods for detecting Mycobacterium are tissue
culture or polymerase chain reaction. Acute pancreatitis
Drugs has been detected in 422% of patients with AIDS. The exact
Acute pancreatitis in 2% patients have been reported to be pathophysiological mechanism in AIDS patients is not clear
caused by drugs, although in some series frequency was as but proposed etiological factors include drugs, opportunistic
low as 0.3% and in others as high as 5.3%. A list of drugs known infections and neoplasms associated with AIDS.
to cause AP and the possible mechanism of its occurrence has
been summarized in Table 2.
Hypercalcemia
Hypercalcemia and primary hyperparathyroidism are
Infections associated with AP. Primary hyperparathyroidism causes
Infections as a cause of AP are rare and account for less less than 0.5% of all cases of pancreatitis. In a retrospective
than 1% of cases. Mumps, coxsackievirus, cytomegalovirus, review of 1,435 patients with primary hyperparathyroidism,
hepatitis B, herpes simplex, varicella zoster and Mycoplasma 40 patients (3.2%) had pancreatitis without any other cause
pneumoniae are thought to infect pancreas and cause for pancreatitis. Proposed mechanisms include calcium
AP. These agents have not been isolated from a diseased deposition within the pancreatic duct or trypsinogen
pancreas. Hepatitis E virus has been found to be associated activation. Rapid calcium infusion in rats has led to AP in a
with pancreatitis in India. dose-dependent fashion.
In a prospective study from India, Ascaris was found to be
an important cause of AP in 59 of 256 (23%) patients. Possible
mechanisms considered are obstruction of pancreatic duct
Hyperlipidemia
caused by the worm after migration from duodenum and Hypertriglyceridemia causes about 2% of cases of AP. A serum
jejunum. triglyceride level greater than 1,000 mg/dL is suggestive
and a level greater than 2,000 mg/dL is diagnostic for fibrosis, is also associated with increased risk of pancreatitis
hypertriglyceridemia as etiology in a patient with clinical but it is usually chronic.
diagnosis of AP. The presence of pancreas divisum has been considered
Alcoholic pancreatitis is sometimes associated with an to be associated with pancreatitis. Azotemia, vasculitis,
elevated serum triglyceride level, but is rarely higher than sphincter of Oddi dysfunction, venom of Trinidadian
1,000 mg/dL. The triglyceride level tends to decline during scorpion Tityus trinitatis are among the other causes for AP.
hospitalization due to altered feeding habit, drugs or fluid Finally, no apparent cause can be ascribed in some cases of
therapy; therefore, it should be measured at first contact AP, and these constitute the group referred to as idiopathic
with patient with no other obvious etiology. It has been pancreatitis.
suggested that lipase can liberate large amounts of toxic fatty
acids into the pancreatic microcirculation. This could lead to
endothelial injury, clogging of blood vessels and consequent PATHOPHYSIOLOGY
ischemic states. Mechanism proposed is production of free
fatty acids by lipase action on triglyceride, which are toxic Pancreas synthesizes a large amount of digestive enzymes
to acinar cells and capillary endothelium. Pancreatitis from in physiologic state. These enzymes are potentially injurious
hypertriglyceridemia mainly occurs in type I and type V to pancreatic parenchyma by autodigestion of the gland if
hyperlipidemia. The clinical presentation and severity of AP is activated inappropriately within pancreas; to prevent such
similar to other causes, and treatment consists primarily the autodigestion, these enzymes are intracellularly assembled
lowering of lipid level along with supportive treatment of AP. as inactive precursors called proenzymes or zymogens. These
are enclosed within membrane-bound organelles, referred
to as zymogen granules. Zymogens are then transported
Autoimmune Pancreatitis and secreted outside of the gland into the ducts. Another
Autoimmune pancreatitis tends to cause chronic pancreatitis level of protection is provided by the presence of trypsin
rather than AP and presents with characteristic clinical, inhibitors, which are transported and stored along with the
pathologic and radiologic findings such as young age, male digestive enzyme zymogens. These inhibit small amounts of
gender, bulky sausage-shaped pancreas with nondilated prematurely activated trypsinogen within pancreatic acinar
duct. They have mild abdominal pain and mildly elevated cells. Activation from trypsinogen to trypsin occurs later
serum amylase and lipase levels. These patients often present in the duodenum by the action of brush-border enzyme
with jaundice, IgG4-containing lymphoplasmocytic infiltrate enteropeptidase (or enterokinase). Trypsin further activates
or a focal mass in the pancreatic head on CT confusing with other zymogens to active digestive enzymes.
tumor, and irregular narrowing of the proximal pancreatic The pathophysiology of AP is considered in three phases:
duct on ERCP. Patients characteristically have elevated serum 1. Premature activation of trypsin within acinar cells.
IgG4 levels in the serum. Corticosteroids generally produce 2. Pancreatic inflammation and tissue digestion by various
rapid improvement in symptoms, normalize the laboratory mechanisms and pathways.
parameters, reverse the inflammatory process and resolve the 3. Extension of local inflammation to systemic, leading to
radiographic abnormalities. systemic inflammatory response syndrome (SIRS) or acute
respiratory distress syndrome (ARDS).
The event starts with premature intrapancreatic activation
Miscellaneous Causes of trypsinogen to trypsin, which further activates other
Various other etiological factors are also implicated and enzymes to cause pancreatic tissue digestion, which results
constitute less than 5% of AP. Hereditary and genetic in an inflammatory response. The hypothesis is supported by
causes are usually associated with chronic pancreatitis but the fact that activated digestive enzymes are found within the
sometimes can present as AP also. Mutations in cationic pancreas during pancreatitis, and the histology of pancreatitis
trypsinogen gene PRSS1, which is responsible for premature is suggestive of a coagulative necrosis caused by enzymatic
conversion of trypsinogen to trypsin, can cause pancreatitis digestion. Also, there is lack of active trypsin inhibition.
at a very young age, with development of chronic pancreatitis However, the mechanism(s) of erroneous activation are
later. Mutations in SPINK1 gene that encodes for a pancreatic not fully understood. The activated proteases (trypsin and
trypsin inhibitor are associated with acute and chronic elastase) and lipase break down tissue and cell membranes,
pancreatitis. This mutation results in impaired ability to causing edema, vascular damage, hemorrhage and necrosis.
counteract the effects of activated trypsin within pancreatic It is generally believed that pancreatitis begins with the
acinar cells. Mutations in the CFTR gene, which cause cystic activation of digestive zymogens inside acinar cells, which
FACTORS DETERMINING
THE SEVERITY OF PANCREATITIS
The severity of AP varies from mild form of self-limiting
disease to a more severe and sometimes lethal attack. The
determinants of severity are multifactorial. Identification
of these factors is of therapeutic importance, as their
manipulation may alter the process of pancreatic injury
and hence improves the morbidity and mortality. The
inflammatory process starting with enzyme activation and
acinal cell injury intracellularly occurs by the activation of
transcription factors, such as nuclear factor-kappa B (NF-B)
and activator protein 1. An approach to prevent or reduce
the severity of pancreatitis is to inhibit the early events
in pancreatitis, intrapancreatic trypsinogen and NF-B
activation.
The production of proinflammatory factors leads to further
acinar cell necrosis, SIRS, and other organ dysfunction,
including lung injury manifesting as ARDS. The ultimate
severity of AP depends on the extent of systemic inflammatory
response, as well as several cytokines and chemokines
Fig. 2: Autoactivation theory for pathogenesis of acute pancreatitis that play a critical role in the activation and migration of
inflammatory cells to the affected site. The pancreatic acinar
cells are also a source of inflammatory mediators during
pancreatitis. The factors associated with pancreatitis and
cause acinar cell injury. Studies suggest that the subsequent systemic inflammation are given in Table 3.
events consist of accumulation and activation of inflammatory The ultimate outcome of pancreatic injury and systemic
cells, and release of cytokines and other chemical mediators response depends on the balance between the pro- and
of inflammation leading to variable severity. The severity anti-inflammatory factors. Treatment of AP is to target
of AP depends on the amount of tissue damage, which can
progress to a SIRS, multiorgan failure or death (Fig. 2).
Table 3: Factors associated with pancreatitis and systemic
Steer and Saluja have provided colocalization theory as
inflammation
the cellular mechanism of AP. In the normal pancreas, the
inactive digestive zymogens and the lysosomal hydrolases Proinflammatory mediators Anti-inflammatory mediators
are present separately in discrete organelles within the Tumor necrosis factor (TNF)- IL-10
cytoplasm. However, as the duct gets obstructed, zymogens Interleukin (IL)-1 Complement component C5a
and hydrolases become improperly colocalized in presence
IL-6 soluble TNF receptors (sTNFR)
of calcium in a vacuolar structure in the pancreatic acinar cell.
Platelet activating factor (PAF) IL-1 receptor antagonist (IL-1ra)
After this, cathepsin B activates trypsinogen to trypsin, which
further mediates the permeability of colocalized organelles Intercellular adhesion molecule-1 Neutral endopeptidase (NEP)
(ICAM-1) and selectins
releasing cathepsin B and other contents of these colocalized
organelles into the cytosol. Now, cathepsin B in cytosol IL-8
activates apoptosis by causing cytochrome C to be released Monocyte chemoattractant
from the mitochondria by activation of the B-cell lymphoma protein-1 (MCP-1), Mob1
2 (Bcl-2) family of proteins. Trypsin, once activated, activates Substance P
the other pancreatic enzymes. These active digestive enzymes Granulocyte-macrophage colony-
then begin autodigestion within the pancreatic acinar cells stimulating factor
leading to pancreatitis. Further support for this hypothesis Macrophage migration inhibitory
is provided by findings that inhibition of cathepsin B activity factor
by the highly specific inhibitor, CA-074me, protects against Cyclooxygenase-2 (COX-2), prost
intra-acinar cell trypsinogen activation and pancreatitis in aglandin E1, nitric oxide, and
two different models of experimental pancreatitis. reactive oxygen species
inflammatory mediators to decrease the inflammatory Atlanta Criteria for Severe Acute
response; various agents used are anti-tumor necrosis factor
(TNF) alpha antibody, interleukin (IL)-1 receptor antagonist, Pancreatitis
anti-intercellular adhesion molecule-1 (anti-ICAM-1) and These were adopted in 1992 by the International Symposium
anti-CD3 antibodies, IL-10, recombinant platelet activating on AP. Presence of any of the following five main categories of
factor (PAF) acetyl hydrolase and the calcineurin antagonist parameters indicates severe AP.
FK506. Toll-like receptor 4 (TLR4) is significant in determining 1. Organ failure
the severity of AP. The TLR4 initiates a complex signaling Shock: Systolic blood pressure less than 90 mm Hg
pathway when it interacts with lipopolysaccharides that Pulmonary insufficiency: PaO2 less than or equal to 60
result in a proinflammatory response. It is likely that TLR4 mm Hg
antagonists would be a good therapy against pancreatitis. Renal failure: Serum creatinine greater than 2 mg/dL
Gastrointestinal bleeding: Greater than 500 mL/24 hours
2. Local complications
SEVERITY ASSESSMENT Pancreatic necrosis
Pancreatic abscess
Severity of AP varies, the determinants are multifactorial. It Pancreatic pseudocyst
is defined by various scoring systems based on the presence 3. Systemic complicationsdisseminated intravascular
of organ failure, local complications or both. It is important coagulation
to know that the severity of disease, since the patients Platelet count of less than or equal to 100,000/mm3
with severe disease require close monitoring and possible Fibrinogen level of less than 1 g/L
intervention. Specific laboratory values that measure the Fibrin-split products level of greater than 80 g/mL
systemic inflammatory response such as C-reactive protein Metabolic disturbance: Calcium level of less than or
(CRP), scoring systems that assess inflammation or organ equal to 7.5 mg/dL
failure [Ransons and acute physiology and chronic health 4. APACHE-II points (Table 4)
evaluation (APACHE) scores], and imaging studies are 5. Ransons signs (Table 5)
useful in predicting both complications and death. Bedside
evaluation of patient for several clinical findings including
thirst, oliguria, progressive tachycardia, tachypnea, agitation, APACHE II Score
confusion or symptoms not improving within the first 2 days This is based on initial values of 12 routine physiological
are warning signs of impending severe disease. The various measurements, age and previous health status. Score greater
scoring systems used are as follows. than or equal to 8 defines severe pancreatitis (Table 4).
Table 4: APACHE II score

APACHE II score = Acute physiology score + Age points + Chronic health points
+4 +3 +2 +1 0 +1 +2 +3 +4
0
1 Rectal temperature ( C) >41 3940.9 3838.9 3638.4 3435.9 3233.9 3031.9 <29.9
2 Mean arterial pressure (mmHg) >160 130159 110129 70109 5069 <49
3 Heart rate (bpm) >180 140179 110139 70109 5569 4054 <39
4 Respiratory rate (bpm) >50 3549 2534 1224 1011 69 <5
5 Oxygen delivery (mL/min) >500 350499 200349 <200
6 PO2 (mm Hg) >70 6170 5560 <55
7 Arterial pH >7.7 7.67.69 7.57.59 7.37.49 7.257.3 7.157.2 <7.15
8 Serum sodium (mmol/L) >180 160179 155159 150154 130149 120129 111119 <110
9 Serum potassium (mmol/L) >7 66.9 5.55.9 3.55.4 33.4 2.52.9 <2.5
10 Serum creatinine (mg/dL) >3.5 23.4 1.51.9 0.61.4 <0.6
11 Hematocrit (%) >60 5059.9 4649.9 3045.9 2029.9 <20
12 White cell count (103/mL) >40 2039.9 1519.9 314.9 12.9 <1
Contd...
Contd...
+4 +3 +2 +1 0 +1 +2 +3 +4
Age points
<45 0
4554 2
5564 3
6574 5
>75 6
Chronic health points
History of severe organ insufficiency Points

Nonoperative patients 5
Emergency postoperative patients 5
Elective postoperative patients 2
Table 5: Ransons prognostic criteria Table 6: BISAP score
Parameters Non-gallstone Gallstone 1.Blood urea nitrogen >25 mg/dL

pancreatitis pancreatitis 2.Impaired mental status
At admission 3.Systemic inflammatory response syndrome (SIRS)
Age >55 years >70 years 4.Age >60 years
White blood cells >16,000/mm3 >18,000/mm3 5.Pleural effusion
Blood glucose >200 mg/dL >220 mg/dL
*Score >3 is associated with 712 times risk of developing organ failure.
Serum lactate dehydrogenase >350 IU/L >400 IU/L
Serum aspartate >250 IU/L >250 IU/L
aminotransferase Table 7: Systemic inflammatory response syndrome (SIRS)
During initial 48 hours
1.Temperature >38C or <36C
Hematocrit decrease >10% >10%
2.Heart rate >90 beats/min
Blood urea nitrogen increase >5 mg/dL >2 mg/dL
3.Respiratory rate >20 breaths/min or arterial PCO2 <32 mm Hg
Serum calcium <8 mg/dL <8 mg/dL
4.WBC count >12,000 or <4,000 cells/mm3
Arterial pO2 <60 mmHg NA
SIRS is present if two or more of the four criteria are present.
Serum base deficit >4 mEq/L >5 mEq/L
Fluid sequestration >6 L >4 L
The presence of the SIRS is an early predictor of multiorgan
Note: 1 point for each positive factor
dysfunction syndrome and mortality from AP, particularly
if SIRS persists beyond 48 hours. Systemic inflammatory
Ransons Criteria response syndrome is defined by the clinical parameter as
given in Table 7 and can be easily assessed at bedside for
Score greater than or equal to 3 defines severe pancreatitis patients with AP. In a study, the mortality rate was 0.7% in
(Table 5). patients without SIRS, 8% in patients with transient SIRS and
25% in those with persistent SIRS beyond 48 hours.
BISAP Scoring (Bedside Index for

Severity in Acute Pancreatitis) Sequential Organ Failure Assessment
It was derived from data collected from approximately 3,700
Score
patients with AP and has been validated by comparing its Sequential organ failure assessment (SOFA) score helps the
predictive accuracy with that of APACHE II (Table 6). Its treating physician to assess organ injury and dysfunction.
predictive accuracy is similar to the more complex APACHE It includes assessment of central nervous system, liver,
II score.
Table 8: Sequential organ failure assessment (SOFA) score assessment
Score 0 1 2 3 4
Respiration: PaO2/FIO2 (mm of >400 <400 <300 <200 without respiratory <200 with respiratory
Hg) support support
Coagulation: Platelets (x 103/L) >150 <150 <100 <50 <20
Liver: Bilirubin (mol/L) <20 2032 33101 102204 >204
Kidney: Creatinine (mol/L) or <110 110170 171299 300440 or <500 mL/day >440 or <200 mL/day
urine output
Central nervous system: Glassgow 15 1314 1012 69 <6
coma score
Cardiovascular: Hypotension None MAP >70 Dopamine <5 g/kg/ Dopamine >5 g/kg/min Dopamine >15 g/kg/
mmHg min or dobutamine (any or noradrenaline <0.1 min or noradrenaline
dose) g/min >0.1 g/min
Abbreviation: MAP, mean arterial pressure
Table 9: Computed tomography severity index (CTSI)

cardiovascular, respiratory, coagulation and renal functions
(Table 8). End-organ injury is usually mild during AP but CT grade Points
can contribute to the systemic inflammatory response and Normal pancreas (grade A) 0
sometimes may lead to severe episode. Focal or diffuse enlargement (grade B) 1
Intrinsic change and peripancreatic fat stranding (grade C) 2
C-reactive Protein Single, ill-defined collection of fluid (grade D) 3
Acute pancreatitis may be associated with raised serum Multiple collections of fluid or gas in or adjacent to pancreas 4
(grade E)
CRP, an acute-phase reactant. It has been used as a marker
of severe pancreatitis. The sensitivity ranges from 60 to 100% Necrosis score
and the specificity is 75100% using the cutoffs of 100210 No pancreatic necrosis 0
mg/L. The accuracy of using CRP for measurement of severity Necrosis of one-third of pancreas 2
is similar to Ransons scoring system but the test is not helpful Necrosis of one-third to one-half of pancreas 4
at admission in assessing severity as the peak is generally 36 Necrosis of >50% of pancreas 6
72 hours after admission.
Table 10: Prediction of mortality and complication according to

Computed Tomography Severity Index Balthazar computed tomography severity index (CTSI)
The computed tomography severity index (CTSI) is a Severity index Mortality Complications
combination of the sum of the necrosis score and points 01 0% 0%
assigned to five grades of findings on CT (Table 9). The index
23 3% 8%
ranges from 0 to 10, with higher scores indicating a greater
46 6% 35%
severity of illness (Figs 3A to D and Table 10).
710 17% 92%
COMPLICATIONS OF ACUTE
Walled of pancreatic necrosis
PANCREATITIS Acute fluid collection
Pancreatic abscess
Local Pancreatic pseudocyst: Pain, infection, rupture,
Pancreatic and peripancreatic necrosis hemorrhage, intestinal or biliary obstruction
Sterile Hemorrhagic pancreatitis
Infected
A B
C D
Figs 3A to D: Computed tomography scans with intravenous and oral contrast. (A) There is a pseudocyst (black arrow) in tail region of
pancreas with some pancreatic parenchyma seen posteriorly (white arrows). Area of necrosis are present in head and tail region; (B) CT grade
E. Multiple fluid collection associated with liquefied necrosis greater than 50% (large arrows). The part of body and tail of the pancreas are still
enhancing (small straight arrows). N = liquefied gland necrosis, S = spleen, L = liver; (C) The head and part of the body are still enhancing (white
arrows). Area of necrosis are present in head and tail region (black arrows); (D) There is a pseudocyst (black arrow) in tail region of pancreas
with some pancreatic parenchyma seen posteriorly (white arrows). Area of necrosis is present in head and tail region.
Source: Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology. 2002;223:603-13
Pancreatic ascites Systemic

Disruption of pancreatic duct
Pseudocyst rupture Pulmonary
Vascular involvement Pleural effusion
Pseudoaneurysm: splenic or gastroduodenal vessel Atelectesis
involvement Pneumonia
Thrombosis of portal or splenic veins ARDS
Bowel infarction Cardiovascular
Hypotension
Arrhythmia intensity, and may persist for several hours. Band-like back
Pericardial effusion radiation may occur in half of the patients. Pain may be
Sudden death absent in 510% of pancreatitis attacks. Altered mentation
Renal may occur in AP due to complications developing in severe
Oliguria pancreatitis like hypovolemia, hypoxemia, dyselectrolytemia,
Azotemia azotemia, fever and toxic effect of pancreatic enzymes on
Renal artery or vein thrombosis central nervous system.
Acute tubular necrosis Other upper abdominal conditions like peptic ulcer
Hematological disease with or without perforation, small bowel obstruction,
Disseminated intravascular coagulation bowel perforation and acute cholecystitis can be confused
Gastrointestinal with AP. Pain of AP is sometimes relieved by the patient
Erosive gastritits leaning forward, not by vomiting and is noncolicky in contrast
Peptic ulcer disease to pain of bowel obstruction.
Portal venous thrombosis Differential diagnosis of acute pancreatitis:
Metabolic Peptic ulcer disease
Hyperglycemia Perforarted peptic ulcer
Hypertriglyceridemia Acute cholecystitis
Hypocalcemia Biliary pain
Encephalopathy Mesenteric ischemia or infarction
Neurological Small intestinal obstruction
Fat embolism Left side basal pneumonia with pleurisy
Psychosis. Inferior wall myocardial infarction
Pancreatic and peripancreatic necrosis consists of focal Dissecting aortic aneurysm.
or diffuse nonviable pancreatic parenchyma and usually Examination findings vary according to the severity
peripancreatic fat necrosis. of disease; the patient may have tachycardia, tachypnea,
Hemorrhagic pancreatitis should also be used with hypotension and fever. Hypotension may occur as a result
caution, and this term is not a synonym for necrotizing of hypovolemia due to fluid sequestration in pancreatic bed.
pancreatitis. If the fluid loss is marked, renal complication like oliguria
leading to prerenal azotemia with elevated blood urea
nitrogen and creatinine levels may occur. Fever may occur due
MANAGEMENT to inflammatory mediators from peripancreatic inflammation
rather than infection. Abdominal tenderness also increases
Early diagnosis, adequate severity assessment and prompt with disease severity. Severe disease may present with
initiation of treatment in a patient with pancreatitis improves marked abdominal tenderness and guarding the epigastric
outcome and can prevent organ failure. Though the initial region. However, since pancreas is a retroperitoneal organ,
treatment is largely supportive, the etiological factors need symptoms may be more than the abdominal signs. The bowel
to be dealt with, if feasible. Severe episode must be identified sounds are decreased or absent as inflammation of pancreas
early as intensive care in such patients improves outcome. and surrounding tissue leads to paralytic ileus. Localized
inflammation adjacent to small intestine produces a sentinel
loop and localized inflammation adjacent to the transverse
DIAGNOSIS colon produces a colon cutoff sign. With progression of
disease, abdomen may be distended with intraperitoneal fluid
and peripancreatic inflammation. Patient may develop left-
Clinical sided pleural effusion due to subdiaphragmatic inflammation
The clinical diagnosis of pancreatitis starts with high index leading to respiratory compromise. In some patients,
of suspicion in a patient with typical upper abdominal pain. ecchymosis may occur in the flanks, called Gray-Turners
Pain may occur in epigastrium, right upper quadrant or left sign and in the periumbilical region, called Cullens sign
upper quadrant. Pain is usually acute in onset, generally after due to hemorrhage from hemorrhagic pancreatitis. Presences
a meal, continuous deep boring type and may be associated of jaundice along with raised transaminases occur in biliary
with nausea, retching and vomiting, moderate to severe in pancreatitis.
Laboratory Tests Serum amylase levels in alcoholic pancreatitis are not very
high. Urinary excretion of pancreatic enzymes increases
Complete hemogram including hematocrit, liver chemistries, during pancreatitis; therefore, urinary levels may be more
calcium, and triglycerides, amylase, lipase, imaging studies sensitive than serum amylase levels for AP. Urinary amylase
for pancreas should be tested within the first 24 hours in levels usually remain elevated for several days even after
patients clinically suspected to have AP. normalization of serum amylase level has taken place. Level
The systemic inflammatory response occurring in of urinary trypsinogen activation peptide (TAP) has good
pancreatitis commonly leads to leukocytosis and there may correlation with severity of pancreatitis. It is 57 amino acid
be mild hyperglycemia because of reduced insulin secretion peptide released from the N-terminus of trypsinogen during
and increased glucagon levels. Hemoconcentration may its activation.
occur due to fluid loss and hypovolemia. Hemoconcentration Raised serum lipase more than three times normal has
is a predictor of severe necrotizing pancreatitis and the sensitivity of 100% and specificity of 99%. Moreover, the lipase
absence of hemoconcentration at admission or during the level remains elevated for longer duration; therefore, serum
first 24 hours suggests that patient is unlikely to have severe lipase is a better indicator of probability of the disease. Other
pancreatitis. Raised serum aspartate aminotransferase (AST) pancreatic enzymes like trypsinogen, elastase, carboxylester,
and alanine aminotransferase (ALT) may occur in both biliary colipase, ribonuclease and carboxypeptidase A may also leak
and alcoholic pancreatitis but levels are much higher (>3 into serum and get elevated but none of these is superior
times of normal) in biliary etiology. in diagnosing AP. Other serum protein detectable only in
pancreatitis is pancreatitis-associated protein (PAP) or
pancreatic-specific protein (PSP), a heat shock protein with
Serum Markers accuracy of detecting pancreatitis similar to serum amylase
Pancreas synthesizes and secretes multiple digestive enzymes test.
including amylase, lipase, trypsinogen and elastase; the levels
of these enzymes are elevated in serum of most patients
with AP. The diagnosis of AP is based on at least a threefold Imaging Studies
elevation of amylase or lipase in the serum. Radiography of abdomen in standing position is important
For diagnosis of AP, serum amylase levels are measured especially to rule out other etiologies simulating AP like bowel
usually and concentration increases immediately after the perforation and bowel obstruction. Abdominal ultrasound,
onset of disease on first day and level decreases after second CT or MRI can identify gallstones or a tumor (an infrequent
day. Repeated or frequent measurement of serum enzymes cause of pancreatitis), as well as local complications. Magnetic
is not needed. The sensitivity of amylase to diagnose AP resonance imaging may also identify early duct disruption
ranges from 81 to 96% while specificity is 85% when cutoff that is not seen on CT. Transabdominal ultrasonography
value above normal is used. When cut-off value more than is more sensitive than either CT or MRI for identifying
three times is used, the specificity is nearly 100%. Smith et al. gallstones and sludge, and for detecting bile-duct dilatation,
showed that the sensitivity and specificity of amylase were but it is insensitive for detecting stones in the distal bile duct.
69% and 96%, respectively. The magnitude of rise does not Endoscopic ultrasonography (EUS) may be the most accurate
reflect the severity; higher levels of serum amylase may occur test for diagnosing or ruling out biliary causes of AP and may
in milder AP as compared to more severe AP. In patients guide the emergency use of ERCP.
with severe necrotic or fatal pancreatitis, pancreas may
not release large amounts of enzymes into the circulation,
and hence, the amylase level may be normal or only mildly
Abdominal and Chest Radiography
raised. Hyperamylasemia is a sensitive indicator of AP but Patient with unexplained severe abdominal pain should
may also occur in many other conditions not involving undergo supine and upright chest and abdominal
pancreatitis, including macroamylasemia, renal failure, post- radiographs. Abdominal radiographs are performed mainly
ERCP, esophageal perforation, duodenal perforation, small to exclude alternative abdominal diseases but may indicate
bowel obstruction and pregnancy. Total serum amylase also findings suggestive of pancreatitis. Intestinal loops may be
includes salivary amylase; therefore, measuring pancreatic- dilated from a generalized ileus. A severe ileus may produce
specific amylase (p-amylase) is more specific. multiple air-fluid levels. When a bowel loop overlies the
Lipids interfere with measurement of serum amylase, so inflamed pancreas, the spasm of distal bowel causes focal
values may be normal in patients of AP with hyperlipidemia. In dilatation of proximal bowel loop called sentinel loop.
such cases, serial dilutions help in appropriate measurement. Similarly, peripancreatic inflammation at splenic flexure
leads to focally dilated mid-transverse colon known as colon Magnetic resonance imaging has limited application for
cut-off sign. Edema and inflammation of the pancreatic head diagnostic imaging of AP because it is less available, more
is manifested as widened C-loop. Occasionally, gallbladder cumbersome and more expensive than CT. It has advantages
may show calculi when these are calcified, suggesting in selected patients like those with renal dysfunction,
gallstone pancreatitis. The chest radiograph may show pregnancy, and are allergic to contrast. Magnetic resonance
pleural effusion commonly on left side, elevation of the left cholangiopancreatography (MRCP) is better than CT for
hemidiaphragm, basal atelectasis and pulmonary infiltrates. biliary and pancreatic ducts abnormality and has a higher
Presence of pleural effusion early in the course of AP may sensitivity in detecting choledocholithiasis. In a recent meta-
indicate a severe disease. analysis, MRCP had 90% sensitivity and 95% specificity for
detecting choledocholithiasis. MRI may also be superior to
CT in the characterization of pancreatic fluid collections.
Ultrasound MRCP is used currently to detect choledocholithiasis before
Abdominal ultrasound examination is a cheap and safe therapeutic ERCP.
modality to diagnose AP and identify etiology like gallstones
in suspected biliary pancreatitis especially in presence of
jaundice and complications. Abdominal ultrasound is about
Endoscopic Ultrasound
95% sensitive for detection of cholelithiasis and about 50% Endoscopic ultrasound is somewhat more sensitive than
sensitive for detection of choledocholithiasis. It can also MRCP in detecting choledocholithiasis. It is useful in
detect extrapancreatic fluid collections, ductal dilations patients who are pregnant because of its relative safety
and pancreatic edema. Inflamed pancreas is recognized as during pregnancy and in patients who cannot undergo
hypoechoic and enlarged because of parenchymal edema. MRCP, such as patients who have internal metallic devices.
Dilation of the common bile duct alone is neither sensitive ERCP with sphincterotomy is essential for the diagnosis and
nor specific for the detection of common bile duct stones. therapy of symptomatic choledocholithiasis and is valuable
However, in about 2030% of patients, it may not provide for determining the cause of recurrent AP of unknown
satisfactory results because of the presence of bowel gas, origin. Cholescintigraphy is highly useful to diagnose acute
which obscure sonographic imaging of the pancreas. cholecystitis, where it is the test of choice, but it provides
Abdominal ultrasound is less accurate than CT for detecting limited information about the bile ducts and is not indicated
peripancreatic inflammation and intrapancreatic necrosis but in the evaluation of suspected choledocholithiasis.
it has the advantages of low cost, availability and portability
for bedside evaluation of patients.
TREATMENT
Computed Tomography and Magnetic Patients with AP especially with symptoms and signs indicating
Resonance Imaging severe pancreatitis should be hospitalized and therapy should
be started for optimal management even before etiology or
A CT scan of the pancreas is better than ultrasound to
complication are identified. Patients exhibiting early signs
diagnose pancreatitis, and detect severity and complications.
of organ failure should be provided intensive care for early
It is used to distinguish milder forms of the disease from
recognition and aggressive treatment of complications. The
more severe necrotizing or infected pancreatitis in patients
treatment for AP is aimed at general supportive therapy,
whose clinical presentation raises the suspicion of advanced
recognition and prevention of complications and therapy for
disease. Patients who present with severe pancreatitis
specific etiology like gallstones.
or are not improving with treatment after several days of
supportive therapy should undergo abdominal CT with
both intravenous and oral contrast. Pancreatic inflammation Supportive Therapy
and complications are recognized reliably as enlargement
In case of milder episode, supportive treatment with volume
of pancreas, heterogeneous or poorly enhancing pancreas
replacement using intravenous fluids, analgesics and bowel
of less than 50 Hounsfield units and necrotic areas within
rest in case of paralytic ileus is sufficient. In patients with
the gland. Peripancreatic inflammation is visualized as
respiratory distress, oxygen administration may be needed.
peripancreatic fat stranding. Peripancreatic fluid collection,
Milder episode may not require invasive monitoring for
ascites or vessels involvement is also detected on abdominal
fluid therapy as in case of severe episode where central
CT with contrast.
venous catheter and Foleys catheter may be required for mortality rate rather it enhances proinflammatory response
optimal monitoring of fluid balance. During initial few days and leads to multiple complications. Enteral nutrition can
of treatment, antiemetics and decompression by continuous be provided by nasogastric or nasojejunal feeding tube and
nasogastric tube aspiration help in relieving vomiting, helps in preventing infectious complications and surgical
abdominal distension and discomfort due to ileus. interventions. Tube feeding prevents pancreatic stimulation,
Severe episodes of AP need team approach, including which occurs by presence of food in gastric or duodenal
gastroenterologist, intensivist, interventional radiologist and lumen. A randomized study comparing nasogastric and
also referral help from nephrologist, pulmonologist, and nasojejunal feeding in severe AP suggested no significant
surgeons. For these patients, along with supportive treatment, clinical difference between the two. The amount of calories
close monitoring, nutritional support, intensive care support and type of nutrient through the enteral feeding tube may
and timely intervention are required. Still, the mortality in vary but should be started as early as feasible according to the
severe episode remains high. clinical status of patient. The diet is increased slowly starting
Patients with AP are fluid depleted because of fluid loss in with liquids to semisolids and then solids to minimize the risk
abdomen and inflamed pancreas, which may lead to impaired of postprandial pain and recurrent pancreatitis.
pancreatic perfusion. Decreased pancreatic perfusion can Among patients with necrotizing pancreatitis, infection is
further increase pancreatic necrosis and complications of AP seen in up to 33% of patients. Infection of pancreatic necrosis
like azotemia due to acute tubular necrosis. Fluid replacement leads to complication and increase in morbidity and mortality,
improves hemoconcentration by dilution and improving but prevention of infection by prophylactic use of antibiotics
pancreatic perfusion. Since hematocrit more than 47% and for severe pancreatitis is debated. A double-blind, placebo-
failure to decrease in 24 hours is associated with necrotizing controlled, randomized trial suggested no improvement in
pancreatitis, and fluids sequestration of more than 6 L terms of infected pancreatic necrosis or mortality in severe
during the first 2 days is predictor of severe disease, the fluid pancreatitis when compared with specific use of antibiotic
replacement and resultant hemodilution help in preventing when local infections or sepsis occurred. The meta-analysis
severe disease as shown in studies with intravenous dextran. of eight controlled trials showed significantly lower mortality
Hyperglycemia may occur due to altered insulin secretion in patients receiving prophylactic antibiotics compared to
in AP, and insulin may be needed for the management of untreated controls in total 814 patients (6.6% versus 13.3%; P
hyperglycemia but insulin should be used with caution as = 0.016). The American College of Gastroenterology does not
glucose levels are fluctuating and also the glucagon response recommend prophylactic use of antibiotic to prevent infection
to hypoglycemia is blunted in AP. Hypocalcemia which occurs in AP, but according to the American Gastroenterology
in AP due to systemic endotoxin release should be looked for Association guidelines, prophylactic antibiotics should be
and treated with intravenous calcium. administered when the pancreatic necrosis is 30% or greater on
Pain relief is important in the management of AP and abdominal CT scan. The antibiotics should be broad spectrum
opiates have good potency for analgesia. Analgesics should including imipenem, third-generation cephalosporins and
be given in adequate doses along with monitoring to avoid piperacillin. Prolonged use of broad-spectrum antibiotics is
excessive sedation, which can be associated with opiates. associated with high risk of intra-abdominal Candida infection
Morphine is known to increase the sphincter pressure; and increased mortality. Therefore, antibiotics should be used
therefore, meperidine is a better choice for this purpose judiciously when suspected infection of pancreatic necrosis or
which does not raise the sphincter of Oddi pressure. The other infective complications are present. Studies have shown
metabolites of meperidine can cause agitation and seizures a beneficial effect with prophylactic antibiotics use in such
if used for longer duration, and when long-term analgesia is cases.
needed, fentanyl is a better alternative.
Patients with AP are advised not to take orally when pain,
vomiting or ileus is present. Nasogastric aspiration should
Therapy for Complications
be reserved for patients with significant ileus, abdominal Acute pancreatitis is associated with local as well as systemic
distension or persistent vomiting. Suppression of exocrine complications, and these should be identified early and
pancreatic function by bowel rest and parenteral nutrition treated specifically. Disseminated fat necrosis and sterile
has been advocated, but studies have shown that bowel rest pancreatic necrosis need only supportive treatment. Local
is associated with intestinal mucosal atrophy and increased complication like infected necrosis needs antibiotics, or if
bacterial translocation from lumen causing infectious resistant to antibiotics, may require CT or ultrasonography-
complications. Total parenteral nutrition does not improve guided aspiration or surgical intervention for debridement and
necrosectomy. Antibiotics should be given according to the dilated common bile duct. Patients with biliary pancreatitis
culture and sensitivity report. For respiratory complications, should be evaluated for the presence of common bile duct
current guidelines recommend that the supplemental oxygen stones. It is important to recognize gallstones because one-
should be provided initially by nasal cannula; endotracheal third to two-thirds of these patients have recurrent episodes of
intubation and assisted ventilation are required when AP in next 3 months if gallstones are not dealt with. Endoscopic
nasal oxygen fails to correct hypoxemia. Severe dyspnea retrograde cholangiopancreatography is indicated in those
and progressive hypoxemia despite supplemental oxygen with severe pancreatitis with cholangitis for clearance of bile
indicates occurrence of ARDS, the most serious respiratory duct stones when patient is not amenable to cholecystectomy
complication of AP. If ARDS occurs, early ventillatory support either due to poor physical fitness or postcholecystectomy
should be provided to prevent respiratory muscle fatigue and status. ERCP should be performed primarily in patients with
further hypoxemia. high suspicion of bile duct stones and should be avoided in
The presence of renal complications requires intensive patients with low suspicion of retained bile duct stones, who
fluid balance monitoring, use of diuretics and dialysis if are planned to have cholecystectomy. Further, it should be
metabolic acidosis and other complications occur. Patients considered that bile duct stone has already passed off the
developing hypotension need vasopressor support with duct by the time cholangiography is considered in most of
dopamine or noradrenaline. Electrolytes including sodium, the patients with mild biliary pancreatitis, and routine ERCP
potassium, calcium and magnesium should be monitored prior to cholecystectomy in such cases is not needed and
and corrected accordingly. Pancreatic pseudocyst formed by only adds to complications. Persistent biliary obstruction
leakage of pancreatic secretions and liquefaction of necrotic and obstruction of pancreatic duct is associated with more
pancreatic tissue with a pseudocapsule near the pancreas severe disease by causing ascending cholangitis leading
or within pancreatic parenchyma should be monitored by to organ failure. Trials have shown a significant benefit for
serial imagings for size and for any evidence of infection. early sphincterotomy and stone extraction, primarily in
Pain, fever, biliary obstruction or gastric outlet obstruction patients with severe AP with ascending cholangitis. If patient
due to compression of stomach may occur due to pseudocyst. with biliary pancreatitis has progressive increase in serum
Symptomatic, infected or increasing size of pseudocyst needs bilirubin and other liver function tests, and imagings show
internal drainage. Drainage can be done via endoscopic persistent dilatation of the common bile duct, common bile
duct obstruction by gallstones should be strongly suspected.
cystogastrostomy or transpapillary pancreatic duct stent for
In such circumstance, it is reasonable to proceed directly to
a communicating pseudocyst, which bridge the leak when
ERCP, or if the patient is candidate for cholecystectomy with
the main pancreatic duct is in continuity. Surgical drainage
cholangiogram in the near future, imaging studies with EUS or
is required for those not amenable to management by above
MRCP can be done prior to ERCP to look for bile duct stones
methods. Pancreatic ascites formed from pancreatic duct
and to decide need for ERCP. Endoscopic ultrasonography is
disruption, inflammation or leakage of secretions may get
generally considered to be the more accurate method than
infected; needs antibiotics, aggressive paracentesis and
MRCP as later can miss smaller stones or stones impacted
octreotide injections to decrease pancreatic secretions.
at lower end. A meta-analysis concluded that endoscopic
Splenic vein thrombosis due to vascular compression or sphincterotomy significantly reduces complications in severe
inflammation may lead to formation of varices especially but not in mild gallstone-associated pancreatitis, but there
gastric, which in turn require management if bleeds. was no reduction in mortality.
Splenectomy for isolated bleeding gastric varices may be an
option in some cases. A pancreatic abscess formed by infected
peripancreatic pseudocyst or from pancreatic necrosis usually
occurs after 5 weeks of AP. Appropriate treatments including
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45
cHAPTER
Chronic Pancreatitis
Muhammad Umar, Hamama-tul-Bushra Khaar
INTRODUCTION of chronic pancreatitis (acute pancreatitisrecurrent acute

pancreatitischronic pancreatitis) has been postulated by a
Chronic pancreatitis is the chronic inflammation of pancreas number of studies.
characterized by irreversible structural changes due to The expression of a disease in an individual is influenced
parenchymal destruction and fibrosis of the gland resulting by multiple genetic and environmental cofactors. In terms
in loss of exocrine and endocrine function with hallmark of gene susceptibility, PRSS1 (protease serine 1) was the first
features of abdominal pain, malabsorption, malnutrition gene to be discovered for pancreatitis. A cationic trypsinogen
and diabetes mellitus. Abnormalities of pancreatic structure is encoded by mutation in PRSS1, which leads to premature
might include pancreatic parenchymal atrophy or pancreatic and persistent activation of trypsinogen inside the acinar
enlargement, pancreatic ductal dilatation, irregularities, cells. The resultant trypsin formation also activates other
strictures or pancreatic calcification may be present. pancreatic enzymes and consequently this cascade of
pancreatic injury is repeated again and again in genetically
predisposed individuals.
PATHOGENESIS
It is important to review the basic structure and function of Trypsin Regulation by Calcium
the normal pancreas before understanding the pathogenic Trypsinogen is stored in the apical areas of acinar cells and
process leading to chronic pancreatitis. The pancreas is both hypercalcemia inside the cells in this region has profound
an exocrine and endocrine gland that has an important role effects on enzymatic activity. A high level of calcium in
in digestion and energy balance. acinar cells not only promotes the activation of trypsinogen
The exocrine pancreas consists of acinar and ductal via trypsin but also stabilizes and prevents trypsin autolysis
cells. The pancreatic secretions consist of inactive digestive thus ensuring prolonged intracellular trypsin survival. These
enzymes produced by the acinar cells. The pH of these
pathological mechanisms occur when normal protective
secretions is basic owing to presence of sodium bicarbonate
mechanisms of acinar cells (e.g. opening up of calcium
component added by the ductal cells. The pancreatic enzymes
channels in apical membrane) are overcome by toxic stimuli
are normally activated in the lumen of small intestine.
like alcohol or bile acid reflux, etc. or though other means of
Inappropriate activation of these digestive enzymes inside
neurohormonal hyperstimulation.
pancreatic tissue, by numerous pathologic mechanisms,
can cause serious damage to pancreatic architecture. These
processes when repeated can result in chronic and permanent Pancreatic Secretory Trypsin Inhibitors
pancreatic damage.
Initially, acute pancreatitis was considered a self-limiting Pancreatic secretory trypsin inhibitor (PSTI), also known
and reversible process, but now it is considered as an initiating as serine protease inhibitor Kazal type 1 (SPINK1) inhibits
mechanism for chronic pancreatitis. the prematurely activated trypsinogen. Its importance was
Recurrent attacks of acute pancreatitis may occur due realized when patients with mutated SPINK1 developed
to partial blockage of pancreatic duct by strictures or recurrent acute and chronic pancreatitis.
pseudocysts as a result of scarring from initial attack of acute Pancreatitis associated with SPINK1 gene mutation is
pancreatitis. There is progressive destruction and fibrosis of mostly seen in children and in cases of familial and tropical
both exocrine and endocrine acinar cells. The natural history pancreatitis.
Chronic Pancreatitis 443
A B
Fig. 1: (A) Acinar cellphotomicrograph (top) and line diagram (bottom); (B) Duct cellphotomicrograph (top) and line diagram (bottom)
Role of Cystic Fibrosis Transmembrane with loss of bicarbonate secretion weakens the protection from
trypsin activation. CFTR mutation was also being demonstrated
Conductance Regulator in idiopathic and alcoholic pancreatitis (Fig. 1).
The cells in the pancreatic duct are important in protecting the
pancreas from acute and chronic inflammation by secretion
of fluid, which quickly sweeps the zymogens out of pancreas.
Theories of Pathogenesis
The key molecule in the pancreatic duct is cystic fibrosis
transmembrane conductance regulator (CFTR) located at the
Oxidative Stress Theory
apical (luminal) surface of the duct cells. Mutation in CFTR It was proposed by Braganza et al. that hepatic mixed function
gene results in cystic fibrosis. The morphological features of oxidases are the main factor contributing to pathogenesis
pancreas in cystic fibrosis resemble chronic pancreatitis with of pancreatic diseases. These hepatic enzymes are mainly
scattered dilatation of ducts that are filled with protein rich responsible for detoxification of harmful blood-borne
material, and cannot be flushed out of the ducts. substances, such as fats or alcohol. The by-products of these
The CFTR gene is responsible for both bicarbonate and substances are capable of producing oxidative damage and
chloride secretion, but is independently regulated by different frequently come in contact with pancreas either via systemic
intracellular second messenger system; therefore, some CFTR circulation or through the reflux of bile into the pancreatic
mutations specifically disrupt chloride secretion but not duct. Persistent oxidant stress leads to pancreatic tissue injury
bicarbonate secretion These mutations lead to cystic fibrosis and resultant fibrosis. This hypothesis is being criticized by
with pancreatic sparing, while other CFTR mutations associated researchers who found oxidized products in the alcohol fed
rats in the absence of inflammatory changes in pancreatic Glycoprotein 2

tissue. The exact pathologic role of oxidative stress as an
initiator or a consequent of pancreatic inflammatory damage This is another acinar cell protein, which is a major component
is still to be defined. of the zymogen granule cell membranes. Although, this
protein is found in pancreatic stones, it remains unclear
whether glycoprotein-2 (GP-2) represents an initiating factor
Toxic Metabolism Theory of stone formation.
According to Bordalo et al. there are two main pathways
for alcohol metabolism, i.e. oxidative and nonoxidative Necrosis Fibrosis Theory
pathways. Alcohol is a precursor of lipid accumulation
in cytoplasm of acinar cells. The key factor leading to The necrosis fibrosis theory emphasizes that acute and
pancreatic damage is attributed to a byproduct of pancreatic chronic pancreatitis represents a spectrum of same disease.
ethanol metabolism in the form of fatty acid ethyl esters. The The natural history of the diseases starts with an episode of
resultant pathologic changes ranges from fatty degeneration acute pancreatitis, which produces inflammation, necrosis
(steatopancreatitis) to necrosis at cellular level with end and scarring in the periductal area. Secondarily, stone
result of a widespread pancreatic fibrosis. The definite formation occurs due to resultant obstruction and stasis
proof of steatopancreatitis as a true precursor of pancreatic and the process if repeated and becomes prolonged leads to
fibrosis is still lacking and its presence might be a chance wide spread atrophy and fibrosis within the ductal system.
finding of an unrelated or even a reversible pathological Histopathological findings reflect severity of disease with
finding related to alcohol. acute pancreatitis (especially its resolving form) manifesting
as mild fibrosis in perilobular region to more widespread
fibrosis (with ductal distortion) as seen in chronic pancreatitis.
Stone and Ductal Obstruction Theory
Stone and duct obstruction theory proposes the initiation of Primary Duct Hypothesis
chronic pancreatitis in pancreatic ductules due to repeated
contact of stones and ductal epithelial cells leading to ulcer Cavallins et al. proposed that inflammation, scarring, and
and scar formation in main pancreatic ducts. The resultant consequent destruction of ductal architecture is caused by an
obstruction and stasis cause further stone formation and immunologic attack on the duct epithelium.
eventually results in atrophy and fibrosis of the whole The target of this attack may be some specific genetic or
ductal system. According to this theory concurrent alcohol acquired antigens on the duct epithelium. In this way, chronic
consumption, if present, merely alters the composition of pancreatitis is an autoimmune duct destroying disease
pancreatic juice in favor of further stone formation. Specific similar to primary sclerosing cholangitis both histologically
proteins, in addition to alcohol are also involved in pancreatic and in radiographic ductal appearance.
stone formation as evident by the structure of a pancreatic
stone, which is made up of a gel matrix formed by multiple
fibrillar proteins and polysaccharides which contains the
Sentinel Acute Pancreatitis Event Hypothesis
crystalline calcium carbonate lattice. In this hypothesis, the first (or sentinel) episode of acute
pancreatitis activates the immune cells and stellate cells that
are crucial for the development of chronic inflammation and
Pancreatic Stone Protein fibrosis; thus, the sentinel acute pancreatitis event (SAPE)
Pancreatic stone protein (PSP) is also known as lithostatin. hypothesis identifies point in time when various risk factors
It is a phosphoprotein synthesized in pancreatic acinar (e.g. alcohol and smoking) become etiologic factors, and
cells. In vitro, it prevents precipitation of calcium carbonate initiate the process that ends in chronic pancreatitis.
in pancreatic fluid supersaturated with calcium. It was also
supported by a clinical study that primary event in stone Role of Pancreatic Stellate Cells
formation was decreased in PSP, and PSP concentration in
the pancreatic fluid of patients with chronic pancreatitis was FibrosisChronic Pancreatitis
decreased compared to healthy normal subjects. This theory Pancreatic stellate cells have a central role in pathogenesis
has long been abandoned due to lack of evidence in support of pancreatic fibrosis as evident from similar observation
by follow-up studies. in pancreas of rats. These cells are triangular in shape
Table 1: TIGAR-O classification system of etiologies for chronic

pancreatitis
Toxic-metabolic Alcoholic
Tobacco smoking
Hypercalcemia (hyperparathyroidism)
Hyperlipidemia
Chronic renal failure
Medication (phenacetin abuse possibly from
chronic renal insufficiency)
Toxins [organotin compounds, (e.g. di-N-butyltin
dichloride; DBTC)]
Idiopathic Early onset
Late onset
Tropical (tropical calcific pancreatitis, fibrocalculous
pancreatic diabetes)
Other
Genetic Hereditary pancreatitis (cationic trypsinogen
mutation)
Fig. 2: Pathogenesis of chronic pancreatitis Autosomal dominant [PRSS1 mutations (e.g.
Arg122His)]
Autosomal recessive (cystic fibrosis
and store vitamin A. In inactive stage, they are located in transmembrane conductance regulator (CFTR)
perivascular region of pancreases and contain a lipid droplet. mutations, serine protease inhibitor Kazal type 1
(SPINK1) mutations, -1 antitrypsin deficiency)
The pancreatic stellate cells transform into fibroblasts upon Complex/modifiers
activation in the panacianr region. Other features of activation
Autoimmune Isolated autoimmune episodes
are the lose of lipid droplet and synthesis of collagen types I Syndromic autoimmune disorders (Sjgrens
and III, and fibronectin (Fig. 2). syndrome, inflammatory bowel disease, primary
Several factors have been identified that trigger the biliary cirrhosis)
transformation of stellate cells into their activated form. Recurrent and Post-necrotic (severe acute pancreatitis)
Alcohol and its metabolite acetaldehyde have been found severe acute Recurrent acute pancreatitis
to activate the rat pancreatic stellate cells. Oxidative stress is pancreatitis Vascular diseases/ischemia
another factor, which has been shown in a number of studies Postirradiation
to activate pancreatic and hepatic stellate cells. Pancreatic Obstructive Pancreatic divisum
stellate cells are stimulated by different types of cytokines Sphincter of Oddi disorders (controversial)
Duct obstruction (e.g. tumor)
such as platelet-derived growth factor (PDGF), transforming Preampullary duodenal wall cysts
growth factor beta (TGF-), interleukin (IL)-1, IL-6 and Post-traumatic pancreatic duct scars
tumor necrosis factor (TNF)-, which are released during
the inflammatory phase of acute pancreatitis. Transforming
Chronic obstructive pancreatitis
growth factor-a has an important role in pancreatic fibrosis
Chronic inflammatory pancreatitis.
and also plays a major role in fibrogenesis in other organs,
Recently, the TIGAR-O classification of chronic pancreatitis
including the lung, liver and kidney.
has replaced the previous Marseilles classification system.
TIGAR-O classification system categorizes risk factors for
chronic pancreatitis according to mechanisms and etiologies
CLASSIFICATION OF PANCREATITIS (Table 1). Multiple and interacting risk factors can be
Pancreatitis has been classified in different ways based on identified for each individual (Fig. 3).
clinical presentation, radiographic features, and etiology.
Merseilles, Rome system classified pancreatitis into acute and Toxic and Metabolic Factors
chronic forms with further subdivision of chronic pancreatitis
according to morphologic and radiological characteristics.
Marseilles Rome classification of pancreatitis is as follows:
Alcohol
Acute pancreatitis Alcohol is a major risk factor for pancreatitis especially in
Chronic calcifying pancreatitis western countries with chronic pancreatitis occurring after
Fig. 3: Pathogenic pathways proposed to explain each etiology of chronic pancreatitis enumerated in the TIGAR-O classification. It is likely that
different pathophysiologic mechanisms may explain the diverse etiologies of chronic pancreatitis.
Abbreviations: HP, hereditary pancreatitis; CFTR, cystic fibrosis transmembrane conductance regulator; SPINK1, serine protease inhibitor
Kazal type 1; SAPE, sentinel acute pancreatitis event
repeated attacks of acute pancreatitis. The initial acute attack Other mechanisms are induction of oxidative stress and
of alcoholic pancreatitis is preceded by a prolong alcohol enhanced pancreatic calcifications.
abuse for 510 years. The risk of developing pancreatitis
increases with the amount of alcohol consumed. A daily
intake of 150 g/day or more is required. The type of alcoholic Hypercalcemia
beverage does not appear to be relevant. Pancreatitis due to hypercalcemia occurs via trypsin
The pathogenesis of alcoholic pancreatitis is multifactorial activation. This theory is supported by the increased incidence
with oxidative stress form alcohol metabolism inside pancreas of chronic pancreatitis in patients with hyperparathyroidism.
being an important contributor. Another key factor is the
destabilization of intracellular membranes via increased
pancreatic enzyme synthesis predisposing the gland to auto- Chronic Renal Insufficiency
digestion. Despite these facts, only 1020% of alcoholics develop Renal failure patients are at risk for developing acute and
pancreatitis suggesting the role of some unknown genetic and chronic pancreatitis. The suggested mechanism includes
environmental factors triggering the events in predisposed uremic toxicity to the parenchyma, decreased pancreatic
individuals. Despite a controversial role in the natural history blood flow due to hypovolemia during dialysis, secondary
of alcoholic pancreatitis, the frequency of attacks and severity hyperparathyroidism and hypercalcemia.
of disease are decreased by alcohol abstinence.
Idiopathic
Tobacco Smoking Despite the inability to find a specific risk factor in 1030% of
Smoking is another risk factor for development of chronic patients, the term idiopathic variety of chronic pancreatitis is
pancreatitis with adverse affects on the composition and gradually becoming obscure due to understanding of genetic,
quantity of pancreatic juice. The basic pH of pancreatic immunological, and environmental factors for developing
secretions is altered by effects on bicarbonate component this disease. Idiopathic chronic pancreatitis is divided into
and the amount is decreased via affecting synthetic pathways. early and late onset subgroups. The early-onset idiopathic
chronic pancreatitis presents usually within first two decade multisystem involvement and steroid responsiveness. Other
of life with features of severe abdominal pain, morphological autoimmune disease like primary biliary cirrhosis, sclerosing
changes in pancreas, and exocrine pancreatic insufficiency cholangitis, Sjgrens syndrome and inflammatory bowel
only, with pancreatic calcification occurring much later in the disease etc can also be a part of disease manifestation (Fig. 4).
course of diseases. In contrast, the late onset variety presents in Retroperitoneal fibrosis and lung nodules are also sometimes
4th5th decades with little or absent abdominal pain, features associated with AIP. According to primary duct hypothesis,
of pancreatic insufficiency, and evidence of pancreatic AIP is thought to represent an immunological phenomenon
calcification. Both exocrine and endocrine abnormalities against the pancreatic ductal cells, which is supported by a
are evident in late-onset idiopathic chronic pancreatitis. histopathological evidence of a lymphocytic and plasma cell
Unidentified alcohol abuse and undiagnosed genetic defects infiltration mostly around pancreatic duct, along with wide
are thought to be potential underlying mechanisms. spread fibrotic changes.
An AIP most often presents with a mild abdominal
pain (severe pain is unusual), jaundice, and weight loss.
Tropical Pancreatitis In adult male patients (>50 years of age), pancreatic mass
Tropical pancreatitis is endemic in certain developing mimicking a pancreatic ductal adenocarcinoma is a common
regions within 30 of equator, including India, Indonesia, presentation. Extrahepatic diffuse biliary stricture, which can
Thailand, Bangladesh, Srilanka, Uganda, Nigeria, Zaire, be monomorphic or long segmental (without calcification
and Brazil. Abdominal pain begins in childhood and is or cysts) is responsible for features of obstructive jaundice.
followed by rapid progression to endocrine and exocrine The revised Japan Pancreas Society criteria and the Mayo
insufficiency. The child or adult presents with signs of Clinic HISORT (histology, imaging, serology, other organ
malnutrition, high blood sugar and dilated ducts with involvement, and response to steroid therapy) criteria are
pancreatic calculi. The etiology of tropical pancreas mainly used to diagnose AIP criteria.
remains unknown; malnutrition was suspected as a major
causative factor and hence the disease was even described
as nutritional pancreatitis. Although protein malnutrition
is thought to play an important role, the deficiency of
micronutrient, including vitamin C and minerals (e.g. zinc,
copper and magnesium) may have some role. The cassava is
important food ingredient in these areas containing cyanide
alkaloids injurious to the pancreas.
Hereditary Pancreatitis
The postulated mechanism of this theory is the transformation
of repeated painful episodes of childhood pancreatitis into
adult onset chronic pancreatitis and pancreatic cancer.
pancreatic manifestation
The genetic defects associated with hereditary pancreatitis
include mutation of CFTR gene or SPINK1 mutation.
Autoimmune Pancreatitis
Autoimmune pancreatitis (AIP) was first described by
Yoshida et al. as a form of chronic pancreatitis associated with Fig. 4: Overview of other organ involvement and management of
autoimmune manifestations. The usual age of presentation is in autoimmune pancreatitis.
the 5th and 6th decades, although an earlier or late presentation Abbreviations: AIP, autoimmune pancreatitis; CSS, chronic sclerosing
is also not uncommon. Recently, AIP is recognized as part of sialadenitis; IAC, IgG4-associated cholangitis; IAN, IgG4-associated
spectrum of diseases associated with Immunoglobulin G4 nephritis; IgG4, immunoglobulin G4; IRPF, IgG4-associated retroperito
(IgG4), which is an inflammatory disorder characterized by neal fibrosis
Exocrine and Endocrine Insufficiency in Sphincter of Oddi Dysfunction

Autoimmune Pancreatitis The mechanism for sphincter of Oddi dysfunction is either
organic (stenosis) or functional (dysmotility) obstruction. The
Diabetes has been reported in 70% of patient in AIP in some
resultant bile reflux into pancreatic duct leads to recurrent
studies. It has also been demonstrated that 92% of patients
attacks of pancreatitis. Manometry reveals a hypertensive
with AIP had decreased pancreatic fluid volume or amylase
sphincter of Oddi with >40 mm Hg pressures. The ablation
output in response to secretin and 4.1% of patients with AIP
of common channel by endoscopic biliary sphincterotomy
have decreased bicarbonate secretion. leads to symptom improvement in around 80% of cases.
Immunoglobulin-associated Pancreas Divisum

Systemic Disease Pancreas divisum is the most common pancreatic congenital
IgG4-associated cholangitis: It is predominantly present malformation.
in men (85%) with a mean age of 62 years in a series of 53 Normally, the pancreas is drained via ventral duct
patients. Ninety-two percent had associated AIP, 77% had of wirsung through common route in major papilla. In
pancreatic divisum, drainage occurs via the dorsal duct of
obstructive jaundice, 74% had increased serum IgG4 levels
santorini through minor papilla. Pancreatitis can occur due
and 88% had large number of IgG4 cells in bile duct biopsy.
to a stenosed minor papilla (obstruction theory). Therapeutic
Evidence from liver biopsies of AIP patients has demonstrated
options include stenting of pancreatic duct in the short-
portal inflammation/ or sclerosis, interface/ or lobular
term with sphincterotomy of minor papilla as the definitive
hepatitis, and canalicular cholestasis. Plasma cells with IgG4
treatment.
are prominently seen in liver and kidney biopsy specimen
(the later presenting as a renal mass and tubulointerstitial
nephritis) and also in inflammatory abdominal aortic Anatomical Abnormalities
aneurysm. Anatomic variation or malformations like periampullary
diverticula, duodenal duplication cysts, choledochocele,
anomalous pancreaticobiliary junction in annular pancreas
Obstructive Pancreatitis may lead to recurrent acute pancreatitis. Occasionally,
According to stone and duct obstruction theory, pancreatic recurrent pancreatitis may be the presentation in patients
duct obstruction promotes stagnation of pancreatic juice thus with pancreaticobiliary tumors.
making it more lithogenic, whereas necrosisfibrosis theory
proposes periductular fibrosis due to recurrent attacks of acute
pancreatitis as causative agent. Hypertension within ductal SYMPTOMS AND SIGNS
system and interstitium resulting from stones and strictures
leads to glandular damage and impairs the postprandial Pain
augmentation of blood flow resulting in mismatch of oxygen
A dull and boring epigastric pain, which radiates to back, is
supply and demand.
present in about 5080% cases. The pain is typically worsened
after eating and associated with nausea and vomiting. There
Microlithiasis and Biliary Sludges are two patterns of pain: (i) type A pain has features of shorter
duration pain episodes with frequent relapses and each
Microlithiasis refers to <2 mm stones are made up of either attack last for days to weeks along with pain free intervals in
cholesterol monohydrate or calcium-based complexes between the attacks; (ii) type B pain is characterized by severe
containing bilirubinate or carbonate. Sludge is referred to pain of longer duration. Pancreatic enzymes are not typically
a suspension complex containing crystals, glycoproteins, raised significantly in this type of pain exacerbations.
mucin or cellular debris. In certain cases, over years, pancreatic pain gradually
Microlithiasis leads to pancreatitis either by transiently diminishes due to pancreatic burnout secondary to pancreatic
impacting in the papilla leading to the pancreatic duct calcifications, and exocrine and endocrine insufficiency.
obstruction or repeated obstruction produce papillary However, in a small subset of patients (5.820%), chronic
stenosis and sphincter of Oddi dysfunction (SOD). pancreatitis may have a painless course.
The pathophysiology of pain in chronic pancreatitis is diabetes requires insulin and is typically brittle because of
poorly understood. Multiple factors have been suspected. concomitant glucagon deficiency.
These include inflammation, nerves entrapment in fibrosis,
and duct obstruction leading to high back pressure and
Pancreatic Malabsorption
parenchymal ischemia. Complications like pseudocyst can
also be responsible for pain. Mechanism of pain in chronic It was established that human pancreas has 9095% more
pancreatitis has been explained in Table 2 and Figure 5. lipolytic activity than necessary for fat absorption; therefore,
steatorrhea in chronic pancreatitis occurs only when lipase
Increase in intraductal and interstitial pressure may cause
output falls below 510% of normal. It was supported by
changes in parenchymal blood flow and pH resulting in tissue
a subsequent study in which 10% of the normal lipolytic
ischemia and pain. The relation between intraductal pressure
activity was administered directly in the duodenum and
and pain was evidenced by a pressure of 16 mm Hg and 18 steatorrhea was abolished. In severe steatorrhea, the patient
mm Hg in normal pancreas and 1848 mm Hg in patients may pass oily and greasy stools three to four times per day.
with chronic pancreatitis and ductal dilatation. The beneficial Severe vitamin deficiency is rarely present as most of the
effects of surgical or endoscopic procedure to overcome undigested fat is in the form of triglycerides, which do not
outflow obstruction are further evidence in favor of pain due bind fat-soluble vitamins. Furthermore, the bile secretion
to obstructive theory. and absorptive surface of small intestine is normal; therefore,
vitamin deficiencies rarely occur.
Diabetes Mellitus
Signs in Chronic Pancreatitis
Pancreatic diabetes occurs only when 80% of the gland has
been destroyed; therefore, it usually occurs late in disease. In mild chronic pancreatitis, patient may appear well nourished
Diabetes occurs in 5070% of chronic pancreatitis and up and healthy except for some upper abdominal tenderness;
to 90% of calcific chronic pancreatitis patients. Pancreatic however, in advanced chronic pancreatitis and steatorrhea,
severe malnutrition and weight loss may be present.
Jaundice may be present if biliary drainage is obstructed
Table 2: Mechanisms of pain in chronic pancreatitis by stricture stone or pancreatic mass. Splenic vein thrombosis
leads to splenomegaly.
Acute inflammation during an acute relapse; with cytokines stimulate
stellate cells leading to microvascular ischemia
Increased intraductal pressure in the face of ductal obstruction caused by
strictures and intraductal stones COMPLICATIONS OF CHRONIC
Increased pancreatic pressure because of pseudocyst PANCREATITIS
Intrapancreatic neural inflammation
Pancreatic pseudocysts may result due to pancreatic duct
Peripancreatic inflammation involving duodenum and retroperitoneum
obstruction. It is a benign cyst resulting from upstream
Fig. 5: Mechanism of pain in chronic pancreatitis

dilatation and cyst formation, which communicates with Table 4: Chronic pancreatitis complications by incidence
the main pancreatic duct. Pancreatic fistula, ascites and
Complication Incidence (%)
pleural effusion result due to communication of pseudocyst
with adjacent cavities. It is characterized by epigastric mass, Acute pancreatitis Recurrent
tenderness and elevated serum amylase and lipase levels. Chronic pain 8090
Biliary and cystic outlet obstruction may occur due Diabetes mellitus > 40
to duodenal obstruction by severe fibrosis. Pancreatic Weight loss > 40
adenocarcinoma develops in 9% of patients with long- Pancreatic cancer 1540
standing chronic pancreatitis. Splenic vein thrombosis is
Pseudocyst 2530
common and usually asymptomatic; however, recurrent
bleeding from secondary gastric varices may develop in some Malabsorption and steatorrhea 1015
patients (Tables 3 and 4). Bile duct, duodenal, or gastric obstruction 510
Pancreatic ascites or pleural effusion <10
DIAGNOSIS Splenic or portal vein thrombosis <1

Pseudoaneurysm, especially of splenic artery <1
The diagnosis of chronic pancreatitis is not straightforward Vitamin deficiency (A, D*, E, K and B12) Rare
in all patients. It is easy in patients with long-standing * Vitamin D deficiency has recently been reported more often with
pancreatic exocrine dysfunction
Table 3: Complications of chronic pancreatitis
Complication Signs and Treatment
symptoms chronic pancreatitis with identifiable abnormalities of the
Pseudocysts Increased pain Drainage for large or structure and function of the gland; however, the diagnosis
symptomatic pseudocysts is very challenging in patients with chronic abdominal
Endoscopic drainage pain syndrome in whom computed tomography (CT)
(transmural or transpapillary)
and magnetic resonance imaging/magnetic resonance
Surgical drainage (cyst
gastrostomy or cyst cholangiopancreatography (MRI/MRCP) results are
jejunostomy) normal. These patients who do not have easily identifiable
Vomiting abnormalities of pancreatic structure or function might be
Mild elevations in amylase and lipase levels having early chronic pancreatitis.
Biliary obstruction Jaundice Drainage of obstructing
pseudocyst
Endoscopic decompression Basic Laboratory Test
Surgical decompression All patients should undergo the routine laboratory and
Gastric outlet Abdominal pain Drainage of pseudocyst imaging studies including complete blood count, serum
obstruction
amylase, lipase, liver function test and blood glucose (Table 5).
Early satiety Surgical gastrojejunostomy
Nausea and
vomiting Pancreatic Function Tests
Pancreatic Increased pain Consider surgical resection
adenocarcinoma Pancreatic function tests (PFTs) are used to evaluate
Weight loss Palliation steatorrhea and exocrine insufficiency. A gastroduodenal
Pancreatic ascites Increased Endoscopic stent placement tube with double lumen is used to directly measure pancreatic
abdominal girth functions with preprocedural intravenous cholecystokinin
High-amylase Total parenteral (CCK) or secretin for stimulation of pancreatic secretions.
ascites nutrition The enzymatic and base content of the pancreatic fluid are
Pleural effusion Shortness of Therapeutic thoracentesis analyzed. These direct tests are highly sensitive to diagnose
breath
initial stages of chronic pancreatitis and detect early decline
High-amylase Endoscopic stent placement
in pancreatic function before clinical manifestations like
pleural fluid
steatorrhea have developed thus have high sensitivity.
Total parenteral nutrition
Indirect PFTs are noninvasive tests that include fecal fat
Splenic vein Bleeding from
thrombosis gastric varices
analysis, fecal chymotrypsin, and fecal elastase assays.
Table 5: Laboratory tests used in the evaluation of the patient with Endoscopic retrograde cholangiopancreatography (ERCP)
suspected chronic pancreatitis has been compared with endoscopic-based pancreatic
function test in 35 patients. The results of ERCP and
Tests Comments
endoscopic pancreatic function test were in agreement in 60%
Complete blood count Elevated with infection, abscess
of the patients. The sensitivity of ERCP was 71% and specificity
Serum amylase and lipase Nonspecific for chronic pancreatitis was 90%; for the endoscopic pancreatic function test, the
Total bilirubin, alkaline Elevated in biliary pancreatitis and ductal corresponding values were 96% and 37%, respectively.
phosphatase and hepatic obstruction by strictures or mass Mostly when ERCP is abnormal, secretin pancreozymin
transaminase
test is abnormal. However, rarely the abnormal secretin
Fasting serum glucose Elevation suggests pancreatic diabetes pancreozymin test is the only abnormality indicative of chronic
Pancreatic function tests Sometimes useful in early chronic pancreatitis.
pancreatitis with normal computed
tomography or magnetic resonance
imaging Indirect Pancreatic Function Tests
Fecal fat estimation >7 g fat/day is abnormal; quantitative;
requires 72 hours; should be on a diet of Serum total amylase, lipase and trypsin levels are normal in
100 g fat/day chronic pancreatitis. Fecal chymotrypsin levels are usually
Fecal elastase <200 g/g (0.20 g/kg) of stool is abnormal; normal in chronic pancreatitis, but may be abnormal in the
noninvasive; exogenous pancreatic presence of steatorrhea.
supplementation will not alter results; Fat malabsorption can be accessed by radioactive-labeled
requires only 20 g of stool triglyceride tests. The triolein 14C breath test shows a strong
Secretin stimulation Peak bicarbonate concentration <80 mEq/L correlation of the peak radioactive excretion with the presence
(80 mmol/L) in duodenal secretion; best or absence of steatorrhea. The triolein 14C breath test cannot
test for diagnosing pancreatic exocrine
be used to differentiate fat malabsorption due to pancreatic
insufficiency
insufficiency from that due to any other cause.
Serum trypsinogen <20 ng/mL (0.83 nmol/L) is abnormal
At present the triolein 14C breath test appears to be as
Lipid panel Significantly elevated triglycerides are a sensitive and specific as the measurement of stool fat in the
rare cause of chronic pancreatitis
diagnosis of fat malabsorption.
Calcium Hyperparathyroidism is a rare cause of
chronic pancreatitis
NBTPABA test: The bentiromide (N-benzoyl-1-tryosyl para-
aminobenzoic acid) is the combination of para-aminobenzoic
Immunoglobulin G4 serum Abnormality may indicate autoimmune
antibody, antinuclear pancreatitis acid (PABA) and a chymotrypsin sensitive dipeptide. When
antibody, rheumatoid factor, bentiromide enters the duodenum, the dipeptide is separated
erythrocyte sedimentation from PABA by pancreatic chymotrypsin. The free PABA is
rate
readily absorbed and transported to the liver where it is
Note: the tests are listed in order from most to least commonly conjugated and excreted into the urine and can be easily
performed measured by a simple colorimetric technique. This test is
80% sensitive and 90% specific for detecting pancreatic
Direct Pancreatic Function Tests insufficiency.
The direct pancreatic function tests are becoming accessible Pancreatic schilling test: The pancreatic schilling test is based
by using endoscopes to collect pancreatic juice instead of the on the requirement for pancreatic enzyme in the absorption
traditional oroduodenal tubes. of cobalamine. The test is carried out by simultaneously
In endoscopic-based pancreatic function tests, either giving the patient 57Co-cobalamine intrinsic factor (IF),
secretin or CCK (or both) can be administered to stimulate
58
Co-cobalamine-F-protein, cobinamide and IF by mouth.
pancreatic secretion. If secretin is given, a bicarbonate rich The patient also receives 1,000 g of unlabeled cobalamine
ductal fluid is produced and bicarbonate concentration in intravenously as in the standard schilling test. The excretion
sequential samples can be measured. If CCK is given, an ratio of 58Co to 57Co is less than 1.0 in pancreatic insufficiency.
enzyme-rich fluid is obtained and levels of enzyme activity,
usually lipase, can be measured. After administration of
either of these secretagogues, it may take up to 60 minutes
Imaging Studies
for peak output to occur; therefore, pancreatic secretion are Various imaging and endoscopic studies for the diagnosis of
collected and analyzed over 3060 minutes. chronic pancreatitis are given in Table 6 and are as follows.
Table 6: Imaging and endoscopic studies for the diagnosis of chronic echotexture, variation in size and shape of the gland and
pancreatitis presence of pseudocysts. The sensitivity of ultrasonography
Test Sensitivity Specificity Comment is 5070% with a specificity of 8090%. New ultrasound
(%) (%) technique, contrast-enhanced ultrasound, which utilizes
Plain abdominal NA NA Not routinely recommended; the combination of microbubbles of gas that enhance the
radiography calcifications may be visible echogenicity of blood flow and tissue harmonic imaging
Ultrasonography NA NA Rarely diagnostic; may be improve the assessment of vascularity of lesion. It has been
useful for ultrasonography-
reported that pancreatic tissue vascularity on contrast-
guided aspiration of cyst
Contrast- 7590 85 Initial radiologic test of choice
enhanced ultrasound correlates with the pathologic grade
enhanced for evaluation of suspected of inflammation and inversely with the grade of fibrosis.
computed chronic pancreatitis; can These findings would be helpful in diagnosing autoimmune
tomography visualize calcifications, pancreatitis and monitor the clinical response to steroid
pseudocysts, thrombosis,
pseudoaneurysms, necrosis
treatment.
and atrophy
Endoscopic
retrograde cho
7595 90 Reference standard in many
studies; invasive and associated
Contrast-enhanced Computed Tomography
langiopancreato- with complications; mainly used The CT can detect structural abnormalities, including focal
graphy in diagnosis of early chronic
pancreatitis with normal or diffuse pancreatic enlargement, glandular atrophy,
computed tomography and calcification, pancreatic duct enlargement and pseudocyst.
pancreatic function tests It can also detect the splenic and portal vein thrombosis, and
Magnetic reso- 85 100 Noninvasive and nonion- duodenal and biliary obstruction. The sensitivity of CT in
nance imaging or izing radiation or contrast
establishing the diagnosis of chronic pancreatitis is 7590%
magnetic reso- media; less sensitive than
nance cholangio- endoscopic retrograde with a specificity of 85%. Recently, the multidetector flow
pancreatography cholangiopancreatography for computed tomography (MDCT) which allows faster image
evaluation of side branches; acquisition and improved resolution, further helps in the
can be combined with secretin
diagnosis of chronic pancreatitis. Cambridge grading system
test
for chronic pancreatitis is shown in Table 7. Figure 6 to 8
Endoscopic 97 60 Useful in evaluation of early
ultrasonography chronic pancreatitis, pancreatic depict different conditions in chronic pancreatitis.
mass and cystic lesions; can
be combined with fine-needle
aspiration biopsy Table 7: Cambridge grading of chronic pancreatitis by ultrasound and
Abbreviation: NA, not available computed tomography
Normal Good quality study visualizing the entire gland without

abnormality
Plain Abdominal Radiography Equivocal One abnormal sign:
It is not routinely recommended; however, pancreatic Main pancreatic duct 24 mm
Gland one- to twofold normal
calcifications may be present in 2560% of chronic alcoholic
pancreatitis and 3580% of tropical, hereditary, or idiopathic Mild/ One abnormal sign plus one or more of the following:
moderate Cavities >10 mm
pancreatitis.
Duct irregularity
These calcifications represent intraductal stones rather Focal acute pancreatitis
parenchymal calcification. The visualization of pancreatic Parenchymal heterogeneity
calcification is sensitive and specific predictor of chronic Increased echogenicity of duct wall
pancreatitis; however, only 5060% of these patients have Contour irregularity of head/body
diabetes or steatorrhea. Marked Mild/moderate plus one or more of the following:
Cavities >10 mm
Intraductal filling defects
Abdominal Ultrasonography Calculi/pancreatic calcifications
Duct obstruction (stricture)
Abdominal ultrasonography reveals pancreatic calcification, Severe duct dilatation of irregularity
dilatation of the main pancreatic duct, changes in pancreatic Contiguous organ invasion
Fig. 8: Chronic pancreatitis: an axial CT scan showing an enlarged

pancreas
Fig. 6: Chronic pancreatitis: an axial nonenhanced CT scan showing of chronic pancreatitis. Pancreatic duct calculi are seen as
pancreatic calcification
round filling defects. Gadolinium enhancement is decreased
in pancreatic fibrosis due to decreased vascularity.
In addition to evaluation of pancreatic exocrine function,
secretin stimulated magnetic resonance cholangiopancreato
gram (S-MRCP) is the best modality for identification of
diseased pancreatic ducts, especially in the absence of any
abnormality in normal physiologic state. It is also an excellent
tool to describe the anatomic relationship of pancreatic duct
with pseudocysts.
Endoscopic Ultrasound
Endoscopic ultrasound (EUS) has been studied extensively
in diagnosing chronic pancreatitis. It is more sensitive in
showing the changes at an earlier stage of disease. The
EUS findings usually seen in chronic pancreatitis are
hyperechoic foci or strandings and lobularity in gland
Fig. 7: Chronic pancreatitis: an axial CT scan showing pancreatic margins. In addition stones, calcification and cysts are also
calcification in association with a pseudocyst frequently seen. Other abnormalities often seen are the
dilatation, irregularities, and atrophy of ductal system with
a heterogenous echo pattern. Three to five ultrasonographic
Magnetic Resonance Imaging/Magnetic above mentioned findings are sufficient to make a diagnosis
for chronic pancreatitis (Table 8).
Resonance Cholangiopancreatography The specifity and negative predictive value of a EUS score
Magnetic resonance imaging technology with gadalonium 5 is 100% for diagnosis of chronic pancreatitis. Despite
enhancement is an excellent tool for assessing pancreatic having a good sensitivity value, elastography with endoscopic
parenchymal and ductal structure. In addition, pancreatic ultrasound is limited in distinguishing chronic pancreatitis
function can be evaluated by quantifying pancreatic fluid from pancreatic tumors due to a similar fibrous stroma in
output after injection of a secretagogue. both diseases.
Magnetic resonance cholangiopancreatographic appear The sensitivity of endoscopic ultrasound is equal or better
ance of characteritistic beading in pancreatic duct is hallmark than other tests for detecting sludge and microlithiasis.
Fig. 9: Diagnosis of chronic pancreatitis

Abbreviations: CT, computed tomography; MRCP, magnetic resonance cholangiopancreatography; EUS, endoscopic ultrasound; FNAB, fine-
needle aspiration biopsy
Table 8: Endoscopic ultrasound features of chronic pancreatitis branches of main pancreatic duct which shows dilatation
with or without stenosis. Deposition of protein plug or calculi
Parenchymal features
with lumen of duct leads to radiological findings of mucosal
Gland atrophy
irregularities and filling defects (Fig. 10). The number of
Hyperechoic foci
Hyperechoic stranding opacified side branches may be reduced in a focal or diffuse
Cysts manner because of ductal occlusion. Similar changes are
Lobularity seen in the main pancreatic duct later in the course of disease.
Ductal features Alternating stenosis and dilatation of the pancreatic
Narrowing duct leads to appearance of beading or string of pearls.
Dilatation Well delineated or irregular cavities are seen in pancreatic
Irregularity parenchyma which are small (12 cm) in size and have different
Calculi shapes (round or oval). Occasionally contrast material may
Side branch dilatation
fill large pseudocyst via fistulous communications. Prolonged
Hyperechoic walls
emptying of contrast material may be observed. An accessory
duct has been found in chronic pancreatitis where the dorsal
duct joined the main duct near its first inferior branch in the
Secretin EUS is used to diagnose Sphincter of Oddi
form of a short type of insertion of the accessory pancreatic
dysfunction by showing persistent pancreatic duct dilatation
duct into the main duct. It is also noted that the diameter
after secretin stimulation (Fig. 9).
of the terminal portion of the accessory duct is frequently
greater than 2 mm.
Endoscopic Retrograde In chronic pancreatitis, changes are also seen in common
bile duct, which are mosr often due to periductal fibrosis.
Cholangiopancreatography The most common radiological appearance is a smooth and
This is the most sensitive and specific modality for extensive narrowing of the duct along with gradual tapering of
evaluating chronic pancreatitis. Endoscopic retrograde the distal duct. Another finding is an hour-glass appearance
cholangiopancreatography is an invasive procedure and itself due to alternating stenosis and dilatation.
has the potential complication of causing acute pancreatitis The MRCP is a noninvasive technique, which offers several
and ascending cholangitis. The earliest findings are in side advantages over ERCP due to absence of procedure-related
in diffuse fibrosis variety due to a reduction in the number

of intrapancreatic arteries. The major vessels encircling the
pancreas may also be involved and sleeve-like narrowing
of splenic artery may occur. Splenic vein occlusion occurs
in 2050% of patients. Pancreatic angiography is usually
reserved for patients in whom vascular complications are
suspected.
TREATMENT
Management options for chronic pancreatitis include
medical, endoscopic and surgical.
Medical Treatment
The goals of medical treatment are to modify disease-
exacerbating behavior to enable the pancreas to heal itself, to
alleviate the pain and to restore digestion and absorption.
Behavior Modification
Fig. 10: Chronic pancreatitis: endoscopic retrograde cholangio
pancreatogram showing a dilated common bile duct (CBD) with The mainstay of behavior modification is on cessation of
a stricture at lower end. Pancreatic duct is ectatic and tortuous alcohol and smoking. It should be noted however that relief
pancreatic duct of pain from chronic pancreatitis after alcohol abstinence
occurs only in early stages and there is little evidence for
complications and avoidance of exposure to high doses of pain improvement in advanced stages of alcohol-induced
x-rays. Despite these facts, ERCP in addition to its therapeutic chronic pancreatitis. Still the data suggest that the death
potential, is still useful for grossly examining the ampulla, rates for patients who continue to abuse alcohol are doubled
brush or biopsy sampling of tissues, bile aspiration, and as comparison to those who abstain. Also the number of
performing sphincter of Oddi manometery (SOM). episodes of recurrent acute pancreatitis is reduced in patients
with alcohol abstinence probably due to the necrosis fibrosis
hypothesis.
Fluorodeoxyglucose Positron Therefore standardized counseling approaches for
abstinence from alcohol are valuable for reduction,
Emission Tomography prevention and delay in development of chronic pancreatitis.
According to preliminary studies, fluorodeoxyglucose positron Tobacco smoking is also considered as a risk factor for
emission tomography (FDG-PET) can detect carcinoma chronic alcoholic pancreatitis and further accelerates the
complicating chronic pancreatitis and can cause intense FDG progression of disease. Lungs and stomach malignancies and
uptake in autoimmune pancreatitis. increased cardiovascular diseases associated with smoking
further increases the morbidity and mortality in patients with
chronic pancreatitis.
Angiography
The duration and severity of pancreatitis is the main
determinant of findings observed during pancreatic
Antioxidant Therapy
angiography. Inside pancreatic tissue, the major pancreatic Oxidative stress has some role in the pathogenesis of chronic
arteries and their branches have a beaded appearance pancreatitis, antioxidant treatment with methionine,
especially in long-standing disease. Chronic pancreatitis betacarotene, and vitamin C and E may have a beneficial clinical
with patchy fibrosis in pancreatic parenchyma results in effect in patient with chronic pancreatitis, most probably by
prolonged contrast enhancement, while the reverse happens inhibiting the release of oxygen-derived free radicals.
Pain Relief Analgesics

Pain is the most distressing and challenging symptom of Non-narcotic analgesics (e.g. nonsteroidal anti-inflammatory
chronic pancreatitis. A number of factors contribute to the drugs, acetaminophen, tramadol) should be used as first
pain, so diagnostic tests are necessary to identify the cause of step in the management of pain. If pain persists, low doses of
pain. If no structural abnormality is found, medical therapy mild narcotics may be added, while in severe pain stronger
can be attempted. opiates can be used in selected cases. Addiction is a common
An evidence-based technical review on pain management consequence and should be closely monitored.
in chronic pancreatitis has been published by the American
Gastroenterological Association (AGA).
The following algorithm based on the available data is Pancreatic Enzymes
proposed by AGA (Fig. 11). It is presumed that stimulation of pancreas by food causes
pain due to CCK release from the duodenum by both digestive
products of the food and CCK-releasing factor. Cholecystokinin
acts directly on pancreatic cells and indirectly through neural
pathways, stimulate pancreas, which causes pain. The exogenous
pancreatic enzyme when taken with meal suppresses CCK
release. This decreases pancreatic stimulation and pain.
Differential Nerve Blockade

A differential nerve blockade (DNB) is indicated for any
patient with pancreatic pain that does not respond to non-
narcotic analgesics and enzymes.
A significant short-term pain relief may be obtained by CT-
guided or EUS-guided celiac plexus block or steroid injection
in the celiac plexus.
Treatment of Pancreatic Malabsorption

Medium chronic triglycerides are directly absorbed by the
small intestine without any requirement for digestion by
lipase or micellar solubilization.
Pancreatic enzymes are used for the treatment of
maldigestion in chronic pancreatitis. Lipase is the most
important component of the exogenous pancreatic enzymes
preparations that determines its effectiveness. A minimum of
30,000 U lipase per meal is adequate for intraluminal digestion
of fat and protein in most patients. The dose may be titrated to
as much as 60,00080,000 U. Enzymes are taken at the onset
of each meal, or half may be taken at the start of meal and the
other half approximately 15 minutes into the meal. Uncoated
preparations are preferable to coated preparations. A proton-
pump inhibitor or histamine receptor antagonist is required to
suppress gastric acid as it can denature the uncoated enzyme
preparations (Fig. 12).
Fig. 11: Guidelines for the treatment of pain in chronic pancreatitis

Treatment of Autoimmune Pancreatitis
Abbreviations: CT, computed tomography; ERCP, endoscopic The natural history and optimal treatment protocols of
retrograde cholangiopancreatography; EUS, endoscopic ultrasound autoimmune pancreatitis have not been established. However,
Fig. 13: Insertion of a metal stent in the main pancreatic duct
Fig. 12: Treatment of pancreatic malabsorption stricture can be dilated by balloon dilatation alone, while
complex fibrotic strictures may require one or more stent
placement after balloon dilatation for a satisfactory and long-
autoimmune pancreatitis is exquisitely steroid responsive and
term response (Fig. 13).
relapse rate among patients who receive steroid is lower than
A relapse rate of 30% was reported within 2 years, and
those who are not treated with steroid. Relapses do respond
pain relief in 65% of patients with ductal outflow obstruction
to steroid, and long-term, low-dose steroid treatment is an
treated with stent placement.
option recommended by Japanese Consensus guidelines.
Pancreatic Duct Stone Removal

Endoscopic Treatment
Pancreatic stones obstructing the pancreatic duct may
The aim of endoscopic therapy is to relieve pancreatic duct
cause pain and recurrent pancreatitis; however, only 10
obstruction due to stricture or stone, thereby decreasing
35% of stones present in the main duct can be removed
the duct pressure, to drain fluid collections or to divert
by balloon or basket, while stones in side branches are
flow away from the fistula/leak. Endoscopic retrograde
difficult to remove. Larger stones may require lithotripsy
cholangiopancreatography is used to treat pancreatic strictures,
via extracorporeal shockwave lithotripsy (ESWL) followed
pancreatic ductal stones, pseudocysts, pancreatic duct fistulas
by balloon or basket sweep. Patients frequently require
and bile duct strictures.
several ESWL sessions to achieve stone clearance from the
duct. Intraductal lithotripsy guided by pancreatoscopy has
Pancreatic Sphincterotomy also been used to fragment pancreatic duct stones. The
pain relief was reported in 7080% of patients after stone
Pancreatic sphincterotomy is used to treat SOD. However,
removal and the pain relapse rate was approximately 30%
pancreatic sphincterotomy is also performed for the
over 2 years.
management of pancreatic stone, stricture or combined
pancreatobiliary sphincterotomy for SOD. The early
complications include pancreatitis (27%), bleeding (3%), Pancreatic Pseudocysts
perforation (<1%), and sphincter stenosis (10%).
A pancreatic pseudocyst communicating with pancreatic
duct can be treated with transpapillary stents (Fig. 14), while
Pancreatic Duct Stricture Dilatation/ noncommunicating pseudocysts that bulge in stomach or
Stenting duodenum are treated by transduodenal or transgastric
cystostomy when the distance between the gut wall and the
Pancreatic duct stricture due to chronic pancreatitis may be pseuodocyst is less than 1 cm with no intervening major
focal head/body stricture or often are densely fibrotic. Focal vascular structure (Figs 15A to F).
Pancreatic Duct Leaks

Pancreatic duct leaks are treated with endoscopic placement of
transpapillary stents with a success rate of approximately 60%.
Treatment of Chronic Pancreatitis due to

Pancreas Divisum
Sphincterotomy of minor papilla with stent placement has
reported 75% improvement in recurrent pancreatitis and
improvement of pain in approximately 50% of patients.
Common Bile Duct Obstruction in Chronic

Fig. 14: A pancreatogram of patient with chronic pancreatitis with Pancreatitis
recurrent abdominal pain. A pseudocyst is shown to be communicating
The anatomical relation of common bile duct with head of
with main pancreatic duct. Endoscopically, a transpapillary stent was
placed into the pancreatic duct pancreas is an important factor leading to distal common
A B C
D E F
Figs 15A to F: Gastric or duodenal luminal bulge treatment with an endoscopic approach. (A) A pseudocyst seen bulging into stomach; (B)
A cystotome used to puncture cyst causing free drainage of pus; (C) Transmural dilatation with a 10 mm balloon; (D) A single (7 Fr) double
pigtail stent was placed; (E) Subsequently two double (7 Fr) pigtail stents were placed into the cyst as clearly shown in (F) fluoroscopic view
bile duct stricture in about 30% of patients with chronic 9. Apte MV, Phillips PA, Fahmy RG, et al. Does alcohol directly
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46
cHAPTER
Carcinoma Pancreas
Sanjay Govil
INTRODUCTION Pancreatic adenocarcinoma is known to develop in a

series of steps from benign ductal epithelium to invasive
Despite the progress made in early detection and treatment of malignancy rather like the adenoma-carcinoma sequence of
other cancers, pancreatic cancer continues to have a dismal colonic cancer. The ductal epithelium transforms to cuboidal
story. Surgical resection remains the only effective treatment or columnar epithelium in peripheral (less than 5 mm) ducts
for this disease, but is suitable for less than 20% of patients. and goes through the stages of PanIN 1A (flat, low-grade),
The 5-year survival among the fortunate few who undergo PanIN 1B (papillary, low-grade), PanIN 2 (intermediate grade)
successful resection is 1520%, but it is below 5% for all and PanIN 3 (high-grade or carcinoma in situ) to invasive
comers, and has not changed over the last 50 years. carcinoma. These changes are microscopic and are associated
Research into the pathogenesis of pancreatic cancer has with a number of gene mutations (Fig. 1). With the completion
identified precursors of the disease that may help in early of the pancreatic cancer genome project more than 1,500
diagnosis, prevention and screening. The recognition that somatic mutations have been identified in association with
pancreatic cancer goes through a sequence of molecular pancreatic cancer, of which the four most frequent are k-RAS
and genetic events to progress from normal duct epithelium, (95%), p53 (80%), p16/CDKN2A (7580%) and SMAD4/
through pancreatic intraepithelial neoplasia (PanIN) to DPC4 (60%). The first two have been used to diagnose early
invasive malignancy, and that these changes are associated pancreatic cancers from an analysis of pancreatic juice at
with subtle morphological changes potentially detectable on endoscopic retrograde cholangiopancreatography (ERCP).
imaging has raised hopes of early diagnosis amongst high- So far these diagnostic techniques are cumbersome and not
risk patients. useful in clinical practice. The identification of molecular
Better imaging allows for more accurate diagnosis and changes in PanIN lesions provides potential targets for
staging and helps select patients for appropriate therapy. therapeutic intervention. Cox-2 pathway, Sonic Hedgehog
Surgery, particularly in large volume centers, is considerably pathway and methylthioadenosine phosphorylase gene
safer than before and is increasingly being performed inactivation are potentially the most useful targets.
laparoscopically. The scope of surgery has widened to include Recently PanIN, so far a microscopic entity, has been
patients with locally advanced disease, particularly those that associated with adjacent focal lobular atrophy. Lobular
respond to neoadjuvant chemoradiotherapy. Unfortunately, atrophy is detectable on magnetic resonance imaging (MRI),
most patients with this dreaded disease are diagnosed too late and as a hypoechoic lesion on endoscopic ultrasound (EUS).
for potential cure; treatment is largely aimed at prolonging It is not seen with all PanIN lesions but it does hold out hope
life and palliating symptoms. as a marker for malignancy similar to microcalcification seen
on mammography.
The other precursors of pancreatic cancer, although
PATHOGENESIS macroscopic, are much less frequent. They are mucinous
cystic neoplasms (MCN) and intraductal papillary mucinous
Considerable progress has been made in understanding neoplasms (IPMN). MCN are cystic neoplasms lined by mucin
the pathogenesis of pancreatic cancer over the last couple producing cells associated with an ovarian stroma. The cells
of decades. Unfortunately this has not yet translated into lining the neoplasm are associated with a spectrum of dysplasia
effective screening or earlier diagnosis. However, there is and one-third has invasive malignancy. When detected on
hope on the horizon. imaging they may be resected in order to prevent cancer.
Carcinoma Pancreas 467
Fig. 1: A PanINgram depicting some of the morphological and genetic changes taking place in the pathogenesis of pancreatic adenocarcinoma
Intraductal papillary mucinous neoplasms are papillary Table 1: Inherited syndromes associated with increased risk of
mucin producing tumors that line pancreatic ducts. They too pancreatic cancer
are associated with a spectrum of morphological changes
Syndrome Gene Gene function Lifetime
from dysplasia to invasive malignancy. IPMN involving risk (%)
the main pancreatic duct are more likely to be associated
Hereditary PRS S1 Cationic trypsinogen 2540
with cancer while side branch IPMNs are usually benign. pancreatitis
Surgical resection is considered appropriate for main duct
Familial atypical CDKN2A/p16 Tumor suppressor 1017
or combined IPMN, whereas side branch IPMN may be multiple mole
followed. melanoma
Inherited syndromes associated with an increased risk of Hereditary breast BRCA 2 Tumor suppressor 5
pancreatic cancer are listed in Table 1. These form only a very ovarian cancer BRCA1 Tumor suppressor 3.6
small minority of patients with pancreatic cancer. Familial syndrome
pancreatic cancer has been used to describe families with two Peutz-Jeghers STK11/LKB1 Tumor suppressor, 1136
or more first degree relatives with pancreatic cancer without syndrome serine threonine kinase
a known genetic defect. Those with three first degree relatives Lynch syndrome MLH1, MSH2, Mismatch repair 3.7
diagnosed with pancreatic cancer have a thirty-twofold risk of MSH6, PMS2
developing this disease compared to the general population
and a 40% risk of cancer over their lifetime.
Currently, despite the overall poor results of screening, tomography (CT) and/or FNAC. Patients with focal lesions
any person with a greater than tenfold risk of developing of doubt for malignant potential are offered laparoscopic
pancreatic cancer is advised screening (Table 2). Screening is distal pancreatectomy or total pancreatectomy. Although
recommended from the age of 30 years in patients with Peutz- no deaths have been reported from amongst the published
Jeghers syndrome and 4045 years in all other conditionsor screening programs, they have obvious limitations. The
10 years before the onset of cancer in the youngest affected screening protocol is invasive and has a distinct possibility
family member. EUS is the most commonly used screening of complications; 3040% of those resected had either PanIN
tool, but the interval between screening evaluations is 2 or benign IPMN and there is no evidence that those that
not defined. Most studies have performed screening underwent distal pancreatectomy have any reduced risk
examinations annually. When EUS shows any suspicious focal of developing premalignant lesions or carcinoma in the
lesion, these are further evaluated using ERCP, computed remaining pancreas.
Table 2: Potential candidates for screening for pancreatic cancer Table 3: Tumor markers in pancreatic cancer
An affected individual with Peutz-Jeghers syndrome Serum marker Sensitivity Specificity

An affected individual with hereditary pancreatitis CA 19-9 7090 90
CEA 1692 4993
Three or more first, second or third degree relatives with pancreatic cancer
and one or more first degree relatives with pancreatic cancer CA 50 6590 5873
CA 242 5783 7990
A known mutation carrier of BRCA1, BRCA2, p16, MLH1, MSH2, MSH6 or
PMS2 and one or more first or second degree relatives with pancreatic CA 125 4560 7686
cancer CA 195 89 73
Tissue polypeptide-specific antigen 5098 2297
Tissue inhibitor metalloproteinase 1 6099 6099
Span 1 5087 5090
TUMOR MARKERS
The most commonly used tumor marker for pancreatic cancer nodal and vascular involvement. The greatest limitation of
is CA 19-9 despite the fact that there is considerable overlap EUS is the long learning curve and the fact that it is operator
between pancreatic cancer and other benign conditions, dependent. It is an excellent complementary tool to CT in
especially jaundice, pancreatitis and cholangitis. A number of experienced hands. One of the greatest advantages of EUS
markers (Table 3) have been identified but none individually is the ability to perform transduodenal biopsy of pancreatic
is accurate enough to be used as a diagnostic or screening lesions with greater accuracy and fewer complications than
tool. A multicytokine panel of markers has recently been the percutaneous route. Although preoperative histology is
tested and found to be more accurate than any individually. usually unnecessary, it has a role in patients with borderline
The principal role of CA 19-9 is in following up response resectable lesions that require neoadjuvant therapy or
to therapy in those patients who have elevated levels at sometimes in high-risk patients. EUS may also help in difficult
diagnosis. cannulations of the obstructed common bile duct during
ERCP and for celiac blocks to palliate chronic pain.
Magnetic resonance imaging is generally considered less
IMAGING/STAGING accurate than multidetector CT in evaluating pancreatic
cancer. Its role is largely limited to patients with renal
Pancreas protocol multidetector CT imaging is the mainstay dysfunction who are unsuitable for contrast CT. The contrast
of evaluation of the pancreas. The pancreas protocol requires between the normal pancreatic parenchyma and tumor is
a dual phase scan with contrast bolus tracking and 5 mm slices greater in MRI so that it may be easier to detect lesions that
through the pancreas. The addition of 3D reconstruction adds are isodense on CT scan or when there is surrounding chronic
greatly to assessment of tumor morphology and vascular pancreatitis. The additional information from MRCP adds to
involvement. Most pancreatic adenocarcinoma is hypodense the value of cross-sectional imaging in certain situations.
on CT but approximately 1015% can be isodense and may The role of fluorodeoxyglucose-positron emission
be missed unless suspected due to secondary effects such as tomography (FDG-PET) scan in the diagnosis and staging of
pancreatic, bile duct or vascular obstruction. Hypervascular pancreatic cancer is still evolving but it appears to have an
masses are usually neuroendocrine tumors. The sensitivity of important role in detection of distant metastases in particular.
CT drops for masses below 15 mm diameter and is poor for FDG-PET detected metastatic disease that was not identified
assessment of lymph node or peritoneal disease. However, CT on CT or MRI in one quarter of patients with pancreatic cancer
is accurate in the assessment of larger masses, detecting liver in a recent study by Kauhanen et al. It is also useful in detecting
metastases and vascular involvement. Contiguity between the small lesions obstructing the bile duct or on a background of
mass and the vessels greater than 50% of the circumference chronic pancreatitis when the PET image is superimposed on
(180 of contact) of the vessel is highly indicative of vascular CT. One of the limitations of PET is its inability to differentiate
involvement. Stents within the bile duct create star artefacts tumor from inflammation. It may grossly overstage the tumor
on CT which significantly interfere with the ability to assess in a setting of acute pancreatitis or cholangitis. It is therefore
the mass. CT should therefore always be performed before best done before any form of endoscopic intervention.
biliary stenting. Side-viewing endoscopy is very useful for biopsy of
Endoscopic ultrasound is an excellent modality for ampullary carcinoma or pancreatic cancer with duodenal
assessment and detection of pancreatic masses smaller than infiltration. ERCP is used mainly to relieve biliary obstruction.
1520 mm diameter. It can detect lesions as small as 23 However, it is important to remember that endoscopic biliary
mm diameter and is equivalent to CT in evaluating lymph drainage is unnecessary and indeed potentially harmful for
patients who are candidates for resection unless the patient Tumors of the Head and Uncinate Process
has acute cholangitis, hypoalbuminemia or an expected
delay prior to operation. Patients should therefore complete Tumors of the head and uncinate process of the pancreas
their clinical evaluation and staging prior to consideration for are treated by pancreaticoduodenectomy (PD). Uncinate
ERCP and stenting. When ERCP is planned brush cytology process tumors are less likely to have bile duct obstruction
from the stricture may yield diagnostic material in about and more likely to have vascular involvement. PD has
3040% of patients. The yield from this may be increased by become considerably safer over the years with most large
staining for k-Ras mutation. volume centers reporting operative mortalities of 13%.
Diagnostic laparoscopy helps detect disease metastatic to Unfortunately the morbidity of this operation remains high
the liver or peritoneum that may be missed on radiological (about 30%)particularly due to pancreatic leak and delayed
imaging. The yield from laparoscopy has reduced over the gastric emptying. A number of comparative trials between
past 20 years with the advent of better quality CT scans; the standard and pylorus-preserving PD have shown them to
however, it still plays an important role in 515% of patients. be equivalent in terms of radicality, functional outcome and
Some centers feel this is too infrequent to warrant routine risk of delayed gastric emptying. Four randomized trials have
laparoscopy and perform it only in high-risk patients with confirmed that extended lymphadenectomy of N2 lymph
low-volume ascites, tumors larger than 3 cm in diameter, nodes do not provide any survival advantage and may cause
tumors of the body and tail and high CA19-9 levels (above 100
troublesome postoperative diarrhea.
U/mL). Laparoscopy is also warranted in patients with locally
Portal or superior mesenteric vein involvement by tumor
advanced tumors being considered for neoadjuvant therapy.
is no longer considered a contraindication for resection
Laparoscopy is not warranted for ampullary tumors.
as long as the superior mesenteric or common hepatic
arteries are uninvolved. Segments of up to 3 cm of the vein
may be repaired primarily after mobilizing the small bowel
TREATMENT mesentery, however, longer lengths may require interposition
graftsmost commonly the left renal vein or a Gore-tex graft.
Surgery The procedure usually requires 2030 minutes of portal
Surgery is the most effective treatment for pancreatic cancer. vein occlusion and is safe even in jaundiced patients. True
Unfortunately only 1020% of patients are candidates for histological infiltration of the wall is noted in about two-
resection after staging procedures described above. The thirds of resected veins; in the remainder the adhesion is due
cancers of pancreas may be classified into those that are to desmoplasia.
clearly resectable and those that are locally advanced (Table One of the deficiencies of PD, particularly when
4). The latter may be considered for neoadjuvant treatment considering vein resections is that superior mesenteric
and re-evaluated for surgery. artery (SMA) involvement is only detected with surety
at the very last step of the resection because the SMA is
Table 4: Definition of resectable and borderline resectable pancreatic the posterior most structure in the dissection. Recently
cancer modifications of technique have allowed artery-first
dissections in which the SMA is approached superior to
Resectable Borderline resectable
the left renal vein after mobilization of the duodenum
No distant metastases No distant metastases
early in the operation. This technique permits early
No radiographic evidence of Venous involvement of the SMV/PV determination of resectability prior to any irreversible step
SMV or portal vein abutment, without encasement of the nearby arteries
distortion, venous thrombus Short segment occlusion of the SMV/PV
in the operation, reduces blood loss due to early ligation
or encasement with suitable vessel proximal and distal to of the pancreaticoduodenal arteries from the SMA, makes
it, allowing safe reconstruction vein resection easier when necessary and permits a more
Clear fat planes around the Gastroduodenal artery encasement up to complete uncinate process dissection in order to obtain
SMA, celiac axis and hepatic the hepatic artery involving up to 90 of clear surgical margins.
artery the circumference of the hepatic artery
Recently, there has been a resurgence of interest in arterial
without involvement of the celiac axis
Tumor abutment of the SMA not to involve reconstructions in high-volume centers. The high morbidity
more than 180 of the circumference associated with arterial reconstructions has been minimized
Abbreviations: SMV, superior mesenteric vein; PV, portal vein; SMA, but the benefits in terms of survival, if any, are still to be
superior mesenteric artery. evaluated.
Tumors of the Body and Tail Table 5: Outcome of pancreatic resection
These tumors are often bulky and/or metastatic at diagnosis Perioperative mortality 05%
since they do not produce symptoms until late in the disease. Complications
Whenever possible, resection prolongs survival. Today, the Overall 3540%
standard of care is laparoscopic distal pancreatectomy. One Pancreatic fistula 515% (2040% for distal resections)
of the modifications of distal pancreatectomy is the Radical
Delayed gastric function 515%
Antegrade Modular Pancreaticosplenectomy procedure in which
Survival (Poorer for distal tumors)
pancreatic parenchymal division is the first step of the procedure.
Dissection then proceeds toward the spleen, incorporating the 2 years 4050%
Gerotas fascia and the adrenal gland if required. This procedure 5 years 1525%
permits a greater degree of circumferential tumor clearance 10 years 510%
than a standard distal pancreatectomy. Once again, whether this
translates to better survival is unclear.
Table 6: Role of adjuvant chemotherapy in pancreatic cancer:
Another technique under evaluation is resection of the important clinical trials
celiac axis en-bloc with tumors of the body of pancreas. Hepatic
artery flow to the liver is maintained either by reconstructing Study N Treatment 5-year Median P value
the hepatic artery origin or by embolizing the origin of the survival survival
hepatic artery to promote collateral flow from the SMA via the GITSG 49 Chemoradiation 21 versus 0.035
gastroduodenal artery, 37 days prior to planned surgery. (1985) versus observation 10.9 mon
ESPAC 1 289 Chemotherapy 21 versus 20 versus 0.009
(2004) versus 8 mon 15.5 mon
R0/R1 Resection no chemotherapy 0.05
Chemoradiation 15.9 versus
Most series evaluating PD for carcinoma head of the pancreas versus 17.9 mon
demonstrate R1 resections in 3040% of cases. The margins no chemoradiation
most frequently involved are the posterior and medial margins. EORTC 120 Chemoradiation 15.6 0.165
These studies do not demonstrate any difference in median (2007) versus observation versus12.0
survival between those who have undergone an R0 or R1 mon
resection. Verbeke and Menon demonstrated a much higher CONKO 368 Gemcitabine 22 versus 22.1 versus 0.06
proportion of R1 (defined as less than 1 mm circumferential (2007) versus observation 9 mo 20.1 mon
margin) resections utilizing a standard protocol for specimen RTOG 380 Gemcitabine + 20.5 versus 0.05
evaluationin the range of 7580%. This technique of color (2008) 5FU/EBRT versus 16.9 mon
5FU + 5FU/EBRT
coding the surfaces of the specimen and slicing the specimen in
the axial plane is simple, effective and recommended. The high ESPAC 3 1088 5FU + folinic 23 versus 0.39
(2010) acid versus 23.6 mon
rate of R1 resections detected after the use of this standardized
gemcitabine
protocol correlates better with the known fact that 60% of
patients develop local recurrence after resection. The artery
first technique of dissection may help provide a greater chance tumor downstaging prior to resection, higher rate of R0
of R0 resection, although this has not yet been proven (Table 5). resections and better patient selection. This comes at the
expense of the possibility of tumor progression or metastasis,
Chemotherapy/Radiation Therapy and the need for invasive procedures to obtain biopsy. No
randomized trials are available to determine the benefit
The role of chemotherapy and radiation therapy for pancreatic of neoadjuvant chemotherapy. A review of neoadjuvant
cancer must be evaluated in three settings: neoadjuvant, chemotherapy for primarily resectable lesions was equivalent
adjuvant and as primary treatment for advanced disease (in terms of median survival) to surgery with adjuvant
(Table 6). therapy but was achieved at the expense of a higher operative
morbidity and mortality. However, neoadjuvant therapy for
initially unresectable lesions permitted exploration in 46.9%
Neoadjuvant Therapy patients evaluated, of which 69.9% were resected, 79.2% with
The potential benefits of neoadjuvant chemotherapy include R0 resection. This treatment must be considered for patients
shorter treatment duration, higher completion rate and with locally advanced disease who constitute 3040% of
all patients with pancreatic cancer. The median survival of resections. The toxicity of radiotherapy is minimized by the
these patients was equivalent to those who were primarily use of image-guided systems (IGRT).
resectable.
The most commonly used chemotherapeutic agents were
5FU (fluorouracil) or gemcitabine. Multidrug combinations Treatment for Unresectable or
using these two drugs, sometimes in combination Metastatic Disease
with cisplatinum or erlotinib were more effective than
Gemcitabine or 5FU-based chemotherapy is used to
monotherapy (CR 2.2% versus 5.3%; PR 25.8% versus 34.7%).
Most trials used radiotherapy [image-guided radiation prolong median survival in patients with unresectable
therapy (IGRT)] in doses of 4550 Gy. or metastatic pancreatic cancer. Despite initial promise,
bevacizumab and cetuximab have not been useful in this
setting. Trials using erlotinib or interferon provide hope for
Adjuvant Therapy the future. Radiotherapy is useful in selected patients with
The role of adjuvant chemotherapy for pancreatic cancer is good performance status. Stereotactic body radiotherapy
well-established (Table 6). The European Study for Pancreatic either on its own or as a boost to supplement IGRT provides
Cancer 1 (ESPAC-1), CONKO-001 and ESPAC-3 trials all excellent local control rates in preliminary studies. Surgery or
showed benefit for adjuvant chemotherapy. Gemcitabine endoscopic stenting is useful to palliate biliary and duodenal
and 5FU with leucovorin were found to be equivalent but obstruction. Coeliac nerve blocks are helpful in controlling
gemcitabine had a better safety profile and was more effective pain.
in patients with node positive disease or R1 resection.
The addition of radiotherapy to chemotherapy is more
controversial even though local failure rates after resection CONCLUSION
are in the region of 6080%. The Gastrointestinal Tumor Study
Group and Radiation Therapy Oncology Group trials favored Pancreatic cancer remains one of the most lethal of all
chemoradiotherapy while the ESPAC-1 and European malignancies (Fig. 2). The challenge is in identifying the
Organization for Research and Treatment of Cancer trials did disease early, identifying patients with favorable tumors
not find any benefit from radiotherapyindeed there may for aggressive management, using neoadjuvant therapies
be a harmful effect related to toxicity. Chemoradiotherapy to increase the proportion of patients suitable for surgical
is preferred over chemotherapy alone in patients who resection, making surgical resection safer and finding newer
are younger, have good performance status and have R1 and more effective modalities to treat this dreaded disease.
Fig. 2: Outcomes of treatment for pancreatic cancer

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Index
Page numbers followed by f and t indicate figures and tables, respectively.
A Acute fatty liver of pregnancy, 374 prognosis, 215

Acute hepatitis B, 165166 risk factors, 214
Abdominal computed tomography Acute icteric hepatitis, 194 Allograft rejection, 394
scan, 50 Acute liver failure (ALF), 166 Amebic liver abscess
Abdominal discomfort, 95 clinical features, 351 clinical presentation, 248
Abdominal lymph nodes, 70 definition, 346 diagnosis, 249
Abdominal pain and global symptoms, 98 diagnostic evalulation in, 352 long-term follow-up, 250
Abdominal tuberculosis etiology, 347 medical therapy, 249
clinical features, 71 evaluation, 351 pathology, 248
colonic tuberculosis, 69f liver transplantation for, 358 prognostic marker, 250
diagnosis of, 72, 75 management, 352 American Joint Committee on Cancer
gastrointestinal tract, 68 pathophysiology of, 351, 351f (AJCC), 19t
investigations, 72 renal failure, 355 5-Aminosalicylates, 8687, 92
barium studies, 7273 respiratory complications, 354 Amylase, 284
computed tomography (CT), 73, subclassification of, 346347 Anemia, 19
73f74f Acute pancreatitis (AP) Anorexia, 19
histopathology, 72 chronic pancreatitis, 458 Anticytokine therapy, 217
interferon-gamma release assays, 72 classification of, 445 Antidepressants, 40
microbiology, 72 complications of, 434, 439440 Anti-helicobacter pylori therapy, 60
sonography, 73 definitions, 426 Antioxidants, 211
tuberculin skin test, 72 diagnosis, 436, 450 Antispasmodics, 98
X-ray, 72 etiology, 426 Antitumor necrosis factor (TNF), 128
laparoscopic findings of, 69f imaging studies, 451 Antiviral drug resistance, 171
management, 7576 management, 436 Apoptosis, 205206
pathogenesis, 68 pathophysiology, 430 Argon plasma coagulation (APC), 22
risk factors, 68 severity assessment, 432 Ascites, 275
sites of involvement, 68 surgical treatment of, 459 causes of, 280t
Abdominal ultrasonography, 363, 452 symptoms and signs, 448450 etiology, 280
ABO incompatible liver transplant, 391 treatment, 438, 455 evaluation and diagnosis, 282
Acetaldehyde, 215 Acute tubular necrosis (ATN), 331332 noncirrhotic, 281
Acholic stool, 362f Adaptive immune response, 177 pathogenesis, 280281
Acute cholecystitis, 409410 Adefovir dipivoxil, 170 physical examination, 282
Acute diarrheal diseases Adjuvant chemotherapy, 421 prognosis, 295
definition, 138 Aflatoxin, 303 refractory, 293295
epidemiology, 138 Alcohol, 28, 427 treatment of, 288
etiology, 138139 Alcoholic liver disease (ALD), 214, Ascitic fluid analysis, 75
management, 142143 216217 Atrophic gastritis, 45
mechanisms, 139140 disease spectrum, 214 Autoimmune hepatitis
medications, 143 history and physical examination, 215 classification, 239
prevention, 142 pathogenesis, 215 clinical features, 242
differential diagnosis, 243 laboratory tests and imaging, 415 molecular genetics of sporadic, 108
epidemiology, 239 pathogenesis, 413 mortality rates estimation, 102t
immunopathogenesis, 240 pathological diagnosis, 414 obesity, 110
pathogenic pathways, 240 published guidelines, 423 pathophysiology of, 104
treatment, 243 risk factors, 412 position of, 103
Autoimmune pancreatitis, 430, 447 screening for, 419 preventive measures, 113
Auxiliary liver transplantation, 391 staging of, 419420 reproductive factors, 111
Azathioprine, 87 treatment, 420 risk factors, 109t
tumor markers, 415 screening, 113
B Cholangiopancreatography, 409 treatment, 115116
Cholangitis, 410 Colorectal polypoid, 103
Bacteria, 140 bacterial cholangitis, 225 Computed tomography scan, 208
Bacterial cholangitis, 224 drug-related, 227 Contrast-enhanced Computed
Ballooning degeneration, 209f histiocytosis x, 227 Tomography, 452
Barretts esophagus, 4, 18f immunodeficiency-related, 226 Corticosteroids, 87, 92, 217
B-cell lymphoma, 125 secondary sclerosing, 225 C-reactive protein, 434
Best supportive care (BSC), 55 vascular cholangitis, 225 CriglerNajjar syndrome, 154
Beta-catenin mutation, 47 Cholecystitis, Acute, Crohns disease, 69, 80, 86
Bifidobacterium infantis, 98 Choledocholithiasis, 410 management of, 90
Bile duct stone (Choledocholithiasis), 427 Cholelithiasis, 404 perianal, 91
Biliary atresia (BA), 359 Chronic hepatitis B, 167 treatment guidelines for, 90t
clinical manifestations, 361 Chronic pancreatitis Crohns disease activity index (CDAI), 84t
diagnosis, 361 pathogenesis, 442 Cyclooxygenase-1 (COX-1), 27
disida scintigraphy, 364f Chronic inflammation, 112 Cyclooxygenase-2 (COX-2) inhibitors, 31
investigations, 361 Chylous ascites, 285 Cyclosporine, 87
management, 364365 Cirrhosis, 304
pathogenesis, 360
types of, 359f
clinical presentation, 269
D
complications of, 273274
Biliary complications, 394 diagnosis, 269 Dendritic cells, role of, 147
Biliary lymphomas, 128 etiology of, 267t Diabetes Mellitus, 304
Bilirubin, 285 Kupffer cells, 269 Diagnostic cytopathology, 414
Bilirubin metabolism pathogenesis of, 268f Diarrhea, 98
hyperbilirubinemia, 153 treatment of, 272273 Dientamoeba fragilis, 142
Blastocystis hominis, 142 Clean water index (CWI), 32 Diet, 28
Burkitt lymphoma (BL), 127 Coagulopathy, 355 Diffuse gastric cancer (HDGC), 47
Colonic tuberculosis, 69f Diuretics, 289
C Colonoscopy, 74, 82, 83f DNA hypermethylation, 105
Colorectal cancer, 112 Domino liver transplantation, 392
Carcinoma pancreas Colorectal carcinoma (CRC) Donor hepatectomy, 388
adjuvant therapy, 471 age-standardized rates estimation, Drug-induced liver injury (DILI), 335
metastatic disease, 471 102t clinical features, 339
paningram, 467f chemoprevention, 115 definition, 335
pathogenesis, 466 clinical features, 112113 diagnosis, 340
treatment, 469 diagnosis, 112113 epidemiology, 335
tumor markers, 468469 dietary factors, 110 laboratory features, 339
Central nervous system (CNS), 37 distribution, 102 management and treatment, 343
Cerebrospinal fluid study, 264 drugs, 111112 pathogenesis, 337
Chemotherapy, 22 epidemiological trends, 101 prevention, 344
Chlamydia, 85 health education, 115 risk factors for, 338
Cholangiocarcinoma (CCA), 224 high fatty diet, 110 types, 336
clinical features, 414415 incidence of, 101102 Duodenal carcinoma, 29
epidemiology and prognosis, 412 inherited susceptibility, 106 Duodenal tube test, 363
histopathological classification, 413 management, 113 D-xylose breath test, 64
Index 475
Dyspepsia prognostic factors, 19 mortality, 55

acid suppression, 39 radiographic endoscopic, 19 occupation, 44
approach, 39f risk factors, 1718, 17t palliative surgery, 54
criteria for, 36t self-expanding metallic stents, 23f pathology and molecular
differential diagnosis of, 38t signs and symptoms of, 18t pathogenesis of, 4546
drug-induced, 28 treatment, 2122 peptic ulcer disease, 60
epidemiology, 36 Esophageal dilation, 22 physical activity, 44
etiologic factors associated, 38 Esophageal dysmotility, 4 preoperative evaluation, 4950
functional, 28 Exogenous hormones, 303 smoking, 44
management, 38 TNM staging for, 49t
neutralization, 39
F treatment, 5152
pathogenetic mechanisms for, 37 Gastric carcinoma, 28
pathophysiologic mechanisms of, 36 Familial adenomatous polyposis (FAP), Gastric MALT lymphomas, 124
pathophysiological tests for, 39t 106 Gastric mantle cell lymphoma, 125f
physiological dysfunctions in, 36 Familial adenomatous polyposis, 107 Gastric ulcer, 26
quality of life, 41 Familial colorectal carcinoma, 108 Gastric varices, 319
Rome criteria, 35 Fatty liver, CT scan of, 208f Gastroesophageal reflux disease (GERD)
symptoms and pathophysiological Fecal occult blood tests (FOBT), 101 definition, 1
mechanism, 3738 Fibrosis, 206 diagnosis, 58, 6f
treatment options for, 39t Functional gastrointestinal disorders epidemiology, 1, 2f3f
Dysphagia, 18, 224 (FGID), 35 goals of therapy, 8
management, 811
E G pathogenesis, 45
pathophysiology, 4, 4f
Elastography, 270271 Gallbladder, 70 role of H. pylori, 5
Endogenous hormones, 303 Gallstone disease role of surgery, 11
Endoscopic biopsy, 7, 7f bile lipids, 406407 spectrum, 2, 3f
Endoscopic mucosal resection, 22 cholesterol, 406407 standard vs double dose, 9f
Endoscopic retrograde diagnosis, 408 symptoms, 2, 3t
cholangiopancreatography, 418f genetic factors in, 405 Gastrointestinal bleeding, 19
Endoscopic submucosal dissection pigment stones, 407 Gastrointestinal lymphomas
risk factors in, 404 clinical features, 121122
(ESD), 5960
Gastric acid hypersecretion, 26 diagnostic evaluation, 122
End-stage renal disease, 194
Gastric cancer histology, 121
Entamoeba histolytica, 141
anthropometry, 44 pathology, 122123
Entecavir, 170
classification, 58 pretreatment evaluation, 123
Enteral nutrition, 23
clinical features, 4748 staging, 123
Enteric nervous system (ENS), 37
diagnosis, 4849 treatment, 123124
Enteropathy-type intestinal T-cell
dietary factors, 4344 Gastrointestinal stromal tumor
lymphoma (EATL), 126
diffuse type, 46 clinical features, 132133
Erythrocyte sedimentation rate (ESR), 96
early, 5758 cytogenetics, 133134
Esophageal acid hypersensitivity, 4
endoscopic appearances, 5859 epidemiology, 132
Esophageal carcinoma epidemiology, 58 histogenesis, 132
Barretts esophagus, 18f etiology, 43 histology, 133
biology and genetics, 18 extent of gastric resection, 52 imaging, 133
clinical presentation, 18 further research, 57 immunohistochemistry, 133
clinical stage, 19 helicobacter pylori, 43 KIT-negative gists, 134
complications, 19 histologic appearance, 46 prognostic value of, 134135
decreased risk for, 18 histological interpretation, 58 risk stratification, 135
epidemiology, 17 intestinal vs.diffuse types, 45 treatment of, 135
incidence of, 17 invasive surgery, 54 Gastrointestinal follicular lymphoma,
investigations, 2021 medical conditions, 44 125126
prognosis, 23 molecular markers, 60 Giardia, 141
Gilberts syndrome, 154 pregnancy and, 172 Hepatosplenic T-cell lymphoma, 128
clinical and genetic characteristics of, reactivation of, 167168 Hepatotropic viruses, hepatitis A virus
155t vaccination, 173 (HAV), 199
Granulomatous diseases, 28 Hepatitis B virus (HBV) infection, 176 Hereditary diffuse gastric cancer
chronic infection, 179 (HDGC), 47
implications for, 181
H Hepatitis C virus, 202203
Hereditary nonpolyposis colorectal
cancer (HNPCC), 105, 108
Hamartomatous polyposis syndromes, challenges, 195 Hiatus hernia, 4
107 clinical characteristics and, 189 Hilar cholangiocarcinoma, magnetic
Hartnups disease, 62 diagnostic workup, 190 resonance image of, 417f
HBeAg, 179 discovery of, 184 Hydatid cyst disease
HBsAg, 180 economic burden of, 191 complications, 258
HBX protein, 179 global burden of hepatitis, 184 diagnosis, 258
HCV genotypes, 193 incidence, 186 epidemiology, 257
Health-related quality of life (HRQL), 2 risk factors for, 187 prevention, 261
Helicobacter pylori, 26, 32, 38, 40 strategies to prevent, 195 transmission, 258
Hemochromatosis, 304 treatment, 119193 treatment, 259
Hemolysis, 153 Hepatitis E virus, 200201 Hypercalcemia, 429
Hepatic bilirubin clearance, 154 clinical features, 162 Hypertriglyceridemia, 429
Hepatic bilirubin conjugation, 154 epidemiology, 161 Hypertrophic cecal TB, 68
Hepatic encephalopathy (HE), 274, 297 genome organization, 160, 161f
clinical signs, 297 laboratory detection, 161
diagnosis, 298 prevention, 162 I
importance, 297 viral life cycle, 161 Iatrogenic pancreatitis, 428
pathogenesis, 299 Hepatocellular carcinoma (HCC), 176, IgG4-associated cholangitis, 223
treatment, 300 277, 302, 304, 310 Ileocecal valve, Involvement of, 74f
Hepatic hydrothorax, 287 clinical manifestations, 305 Ileocolonic disease, 81
Hepatic injury, 168 demographic factors, 302 Imatinib-resistant gastrointestinal
diagnosis and staging, 306
Hepatic scintigraphy, 363 stromal tumors, 135136
environmental risk factors, 302
Hepatitis Immune system, 79
epidemiology, 302
hepatitis A virus, 376 Immunoproliferative small intestinal
hepatitis b virus, 302
hepatitis B virus, 376 disease (IPSID), 127
hepatitis c virus, 303
hepatitis C virus, 377 Immunosuppressive drugs, 395
host factors, 304
hepatitis D virus, 377 Impaired gastric accommodation, 37
natural history of, 304
hepatitis E virus, 377 Increased visceral hypersensitivity, 37
prevention, 310311
Hepatitis A Virus Infiltrative diseases, 28
resection, 308
changing epidemiology, 200 Inflammatory bowel disease (IBD), 77
surveillance, 305
epidemiology, 158159 assessment for, 85
transplantation, 308
genome organization, 157, 157f assessment of activity of, 84
treatment, 307
pathogenesis, 159 breastfeeding, 92
Hepatocyte injury, 205
physical properties, 157 Hepatopulmonary syndrome, 366 diagnostic criteria, 8182
prevention, 159 Hepatorenal syndrome (HRS), 276, 330 differential diagnosis, 85
Hepatitis B virus, 201 clinical presentation, 330331 environmental factors, 79
antibodies, 165 diagnosis, 331 epidemiology, 77
antigens, 165 differential diagnosis, 331 evaluation of patients, 82
disease manifestations of, 165 estimation of, 330 extraintestinal manifestation of, 81, 82t
extrahepatic manifestations of, 173 incidence, 331 fertility and pregnancy, 9192
genomic structure of, 164f pathogenesis, 330 genetic factors, 7879
genotypes of, 165 precipitants, 331 histologic evaluation, 83
hepatocellular carcinoma, 172173 prevention, 333 history, 86
modes of transmission, 165 prognosis, 333 investigations for, 8283
molecular biology of, 164165 surgical procedures, 332 management, 86
postexposure prophylaxis, 173174 treatment, 332 nutrition in, 92
Index 477
pathogenesis, 77 Liver immunology Minimal hepatic encephalopathy,

photomicrographs of, 83f and potentialities for, 148 298299
ulcerative colitis vs. Crohns disease, biology of, 147 Mismatch repair (MMR) system, 105
78t cellular types related, 145 Mucosal barrier, role of, 79
Infliximab, 91, 217 hepatic sinusoidal and apcs, 146f MutY-homolog (MYH)-associated
Insulin-lowering agents, 211 immunoprivileged status of, 150151 polyposis (MAP), 106
Interferon-gamma release assays, 72 toll-like receptors, 149 Mycobacteria, 72
Intestinal bacterial overgrowth (SIBO), 95 Liver transplantation (LT)
Intestinal tuberculosis, 85 contraindications for, 383
N
Intraperitoneal chemotherapy, 57 disease recurrence, 399
Irritable bowel syndrome (IBS), 94 donor evaluation, 385 Narrow band imaging (NBI), 7, 59
clinical manifestations, 95 evaluation, 379 National Comprehensive Cancer Network
diagnostic testing, 9697 history, 379 (NCCN), 51
differential diagnosis, 97 indications for, 380 Natural killer cells, 148
enteric infection, 95 infections and antimicrobials, 397 Natural killer of T-cell type (NKT)
management, 97 long-term complications, 398399 lymphoma, 127
pathophysiology, 94 outcomes, 399400 Necrosis fibrosis theory, 444
physical findings, 96 post-transplant complications, 393t Nonalcoholic fatty liver disease (NAFLD)
stress, 94 preparation, 384385 epidemiology, 204
Irritable bowel syndrome with diarrhea preparation, 385 pathogenesis of fatty liver, 205
(IBS-D), 94 recipient evaluation, 384385 Nonatrophic gastritis, 45
Isoniazid, 75 surgical technique, 386 Nonpolypoid adenoma, 103
Isospora belli, 141 Lower esophageal sphincter (LES), 4 Nonsteroidal anti-inflammatory drugs
Lymphadenectomy, 53 (NSAIDs), 2627, 31
Norepinephrine, 332
K Lymphoproliferative disorders, 129
Kupffer cells, 146147

M O
Obesity, 45, 304
L Macrovesicular steatosis., 209f
Occult gastrointestinal bleeding, 4748
Magnetic resonance imaging, 208, 417
Lamivudine, 169 Malabsorption disorders Odynophagia, 19
Laparoscopy, 74 approach, 63 Oncological palliation, 422
staging, 51 bile acid, 65 Orthotopic liver transplantation (OLT),
Leptospirosis clinical features, 6263 356
clinical and laboratory profile of, 263f diagnostic workup, 63 Oxidative stress theory, 443
clinical manifestations, 262 differential diagnoses, 63
differential diagnosis, 264 endoscopic assessment, 66 P
epidemiology, 262 epidemiology, 61
laboratory diagnosis, 264 management plan, 6667 Pale yellow stool, 362f
microbiology, 262 pathophysiology, 61 Palliation therapy, 22
pathogenesis, 262 radiological tests, 66 Palliative external beam radiotherapy,
prevention, 265266 tests for carbohydrate, 64 422
prognosis, 265 tests for fat, 64 Palliative therapy, 421
risk factors for, 262 tests for protein, 6566 Pancreas, 70, 128
treatment, 265 Malt lymphoma of B-cell type (MLB), 127 Pancreatic insufficiency, 65
Linitis plastica, 53 Mantle zone cell lymphoma, 125 Pancreatic stone protein (PSP), 444
Liver, 70 6-mercaptopurine, 87 Paraneoplastic manifestations, 48
allograft implantation, 390 Mesalamine, 90 Parasites
biopsy, 191, 209, 271, 363 Metabolic diseases, 304 blastocystis hominis, 142
disorders, 369 Metabolic disorders, 350 dientamoeba fragilis
function tests, 270 Metastatic disease, therapy for, 56 entamoeba histolytica, 141
lymphoma, 129 Metformin, 211 giardia, 141
sinusoidal endothelial cells, 146 Microsporidia, 141 isospora belli, 141
microsporidia, 141 etiology, 230 gastrointestinal follicular lymphoma,1

Peptic ulcer disease imaging, 234 25126
clinical features, 25 pathophysiology, 230 mantle zone cell lymphoma (MZL),
clinical signs, 26 patient management, 234 125
diagnosis of, 29 Primary graft nonfunction, 392 Sonography, 7374
differential diagnosis, 28 Primary sclerosing cholangitis (PSC), 220 Spontaneous bacterial peritonitis (SBP),
etiology, 26 clinical features, 222 276
familial aggregation, 27 diagnosis, 222223 Squamous cell carcinoma (SCC), 17
genetic factors, 27 epidemiology, 220221 Sulphasalazine, 90
in Asia, 32 etiology and pathogenesis, 221
in East, 32 hepatic transplantation, 225
infections, 29 management of, 223 T
management of, 3233 medical treatment, 225 Telbivudine, 170
mechanism of, 25 prognosis, 225
Tenofovir, 170
prevalence, 31 Protein malabsorption, 6566
Thiazolidinediones, 211
psychologic factors, 28 Proton pump inhibitors (PPIs), 7
Thyroid stimulating hormone (TSH), 96
racial and regional differences, 32 Purified protein derivative (PPD), 72
Pyogenic liver abscess Toll-like receptors (TLRs), 149
risk factors, 3132
clinical manifestations, 252 Transarterial chemoembolization, 309
treatment, 2930
complications, 255 Transarterial radioembolization (TARE),
Pericellular fibrosis, 210f
differential diagnosis, 253 309
Peritoneum, 69
epidemiology, 251 Transjugular intrahepatic portosystemic
Peritonitis, 286
microbiology, 252 stent, 327
PeutzJeghers syndrome, 107
Plain abdominal radiography, 452 mortality, 255 Trauma, 428
pathogenesis, 251 Tricyclic antidepressants (TCA), 40
Platelet syndrome, 371
treatment, 253254 Tropical pancreatitis, 447
Portal hypertensive gastropathy, 327, 366
causes of, 315t Tuberculin skin test, 72
clinical sequelae of, 317 R Tumors, 428
etiology, 314
Radiation therapy, 22
evaluation and diagnosis, 320
Radiofrequency ablation (RFA), 422 U
indications, 328
Radiological tests, 66 Ulcerative colitis, 80, 86
pathophysiology of, 3163178
Ransons criteria, 433 management of, 88
prophylactic therapies, 326327
Reactive oxygen species (ROS), 215 probiotics in, 88
scenerios, 323
Recipient native hepatectomy, 389
treatment, 321 surgery for, 89
Recurrent abdominal pain/discomfort, 95
ultrasonography, 320 truelove and Witts criteria for, 84t
Reflux esophagitis (RE), 1
Portosystemic shunt, 291 Ulcerative colitis disease activity index
Retroperitoneum, 128
Positron emission tomography (PET), 51, Rifaximin, 98 (UCDAI), 84t
416 Rome process, 35 Ultrasonography, 408
Pregnancy, 369 endoscopic, 408
acute fatty liver of, 374 Upper gastrointestinal bleeding (UGIB),
diagnosis, 370 S 31
disorders not specific to, 376 Selective serotonin reuptake inhibitors Ursodeoxycholic acid, 343
hepatic disorders specific, 369 (SSRI), 40
obstetric cholestasis, 369
physiological changes in, 369
Serologic markers, 51 V
Serologic testing, Interpretation of, 167t
treatment, 371 Serum markers, 437 Vaccine, 115
Prerenal disease, 331 Shigellosis, 140 Vasopressin analogs, 332
Primary biliary cirrhosis (PBC), 229, 232 Small bowel lymphoma, 127128 Virion structure, 157
biliary cirrhosis, 232 Small-for-size syndrome (SFSS), 393 Virus, 141
clinical manifestations, 231 Small intestinal lymphomas Visceral hypersensitivity, 94
diagnosis, 233 enteropathy-type intestinal t-cell Vitamin B12 (cobalamin) malabsorption,
epidemiology, 229 lymphoma (EATL), 126 65

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Textbook of

Mahmud Hasan Sheikh Mohammad Fazle Akbar

The Health Sciences Publishers

2015, Jaypee Brothers Medical Publishers

Inquiries for bulk sales may be solicited at: jaypee@jaypeebrothers.com

First Edition: 2015

Bangabandhu Sheikh Mujibur Rahman

A Kadir Dokmeci Anil Arora

Abhijit Chowdhury Arun J Sanyal

Ajay Duseja Ashish Kumar

Ajesh Goyal AS Soin

Amna Subhan Butt Axel Hsu

Andrew Vaillant Cassiano Ribeiro Pires

Christopher A Wadsworth Gourdas Choudhuri

Cihan Yurdaydin Govind K Makharia

Cristiane Alves Villela-Nogueira Hamama-tul-Bushra Khaar

Debashis Misra Hamizah Razlan

Fazal Karim Izazul Haque

Furqan Ahmed Javed Yakoob

GK Dhali Julio Cesar Aguilar

Kaushal Kishor Prasad Mandish K Dhanjal

Khin Maung Win Mazhar Haque

Kshaunish Das Md Delwar Hossain

Mahesh Gupta Md Rabiul Hossain

Mamun-Al-Mahtab Mian Mashhud Ahmad

Man-Fung Yuen Moiss Copelman

Monjur Ahmed Om Parkash

Muhammad Umar Paisarn Vejchapipat

Murat Saru Parimal Lawate

Mustafa Yakut P Karayiannis

Narendra Choudhary Premashis Kar

Natalia Balbi Flores Punit Singla

Nurdan Tzn Rakesh Kochhar

Ramazan Idilman Sachin Gupta

Ravi Mohanka Saeed Hamid

Roger W Chapman Salimur Rahman

Rosmawati Mohamed Sanjay Govil

SM Wasim Jafri Saroj Kant Sinha

Sabyasachi Ray Shahab Abid

Shahid A Khan Taranjeet S Jolly

Sheikh Mohammad Fazle Akbar Uday C Ghoshal

Shelley Haynes Vikas Singla

Shivaram Prasad Singh Voranush Chongsrisawat

Sittisak Honsawek Yong Poovorawan

Sony Sebastian Thazhath Zaigham Abbas

Sujay Ray Ziauddin Ahmed

Parveen J Kumar cbe

Chapter 1: Gastroesophageal Reflux Disease 1

Chapter 2: Carcinoma of Esophagus 17

Chapter 3: Peptic Ulcer Disease 25

Chapter 4: Peptic Ulcer Disease in AsiaPacific 31

Chapter 5: Functional Dyspepsia 35

Chapter 6: Gastric Cancer 43

Chapter 7: Malabsorption Disorders 61

Chapter 8: Abdominal Tuberculosis 68

Chapter 9: Inflammatory Bowel Disease 77

Chapter 10: Irritable Bowel Syndrome 94

Chapter 11: Colorectal Carcinoma 101

Chapter 12: Gastrointestinal Lymphomas 121

Chapter 13: Gastrointestinal Stromal Tumor 132

Histogenesis132; Epidemiology132; Clinical Features132; Imaging133;

Chapter 14: Acute Diarrheal Diseases 138

Chapter 15: Liver Immunology 145