Dietary Interventions in Liver Disease: Foods, Nutrients, and Dietary Supplements

Dietary Interventions in Liver Disease

Foods, Nutrients, and Dietary Supplements

Editors

Ronald Ross Watson

Victor R. Preedy

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Acknowledgments

Section I. Overview of Liver Health

Chapter 1. Genome-Based Nutrition in Chronic Liver Disease

1. Introduction

2. Genome-Based Nutrition: A Regionalized and Personalized Diet

3. Genes, Microbiota, and Regionalized Diet

4. Nutritional Intervention in Chronic Liver Disease

5. Concluding Remarks

List of Abbreviations

Glossary

Chapter 2. Current Therapeutic Strategies for Alcoholic Liver Disease

1. Introduction

2. Pathogenesis of Alcoholic Liver Disease

3. Current Therapies for Alcoholic Liver Disease

Endnotes

Chapter 3. Features of Hepatic Encephalopathy

1. Introduction

2. Pathogenesis

3. Clinical Features of Hepatic Encephalopathy

4. Laboratory Irregularities in Hepatic Encephalopathy

5. Regular Precipitants of Hepatic Encephalopathy

6. Distinguishable Diagnosis for Hepatic Encephalopathy

7. Controlling of Hepatic Encephalopathy

8. Insignificant Hepatic Encephalopathy

Chapter 4. The Liver Before and After Bariatric Surgery

1. Introduction: The Liver of the Obese Patient

2. The Liver After the Bariatric Surgery

3. Final Discussion

4. Conclusion

Chapter 5. Oxidative Stress and Dysfunction of the Intracellular Proteolytic Machinery: A Pathological Hallmark of Nonalcoholic Fatty Liver Disease

1. Introduction

2. Intracellular Proteolysis

3. ROS and Intracellular Proteolysis

4. The Interconnection of ROS, Intracellular Proteolysis, and NAFLD

5. Conclusion Remarks

Section II. Fruits Improve Liver Health

Chapter 6. Polyphenols in the Management of Chronic Liver Diseases Including Hepatocellular Carcinoma

1. Introduction

2. Dietary Polyphenols in the Prevention of Chronic Liver Diseases

3. Effect on Non–alcoholic Fatty Liver Diseases

4. Effect on Nonalcoholic Steatohepatitis

5. Effect of Polyphenols on Alcoholic Liver Diseases

6. Control of Hepatitis B Virus Infection

7. Control of Hepatitis C Virus Infection

8. Management of Hepatocellular Carcinoma

9. Conclusions

List of Abbreviations

Glossary

Chapter 7. Phytochemicals in the Prevention of Ethanol-Induced Hepatotoxicity: A Revisit

1. Introduction

2. Phytochemicals in the Protection of Alcohol-Induced Hepatotoxicity

3. Mechanisms

4. Conclusions

List of Abbreviations

Chapter 8. Protective Actions of Polyphenols in the Development of Nonalcoholic Fatty Liver Disease

1. Introduction

2. Pathogenesis and Progression of NAFLD

3. Polyphenols in Foods and Natural Products

4. Protective Action of Polyphenols Against NAFLD Progression

5. Conclusion

Chapter 9. Phytotherapy for the Liver

1. Introduction

2. Liver Disease Treatment

3. Plant-Derived Compounds With Liver Beneficial Properties

4. Curcuma longa

5. Silybum marianum

6. Quercetin

7. Naringenin

8. Coffee

9. Stevia

10. Resveratrol

11. l-Theanine

12. Hesperidin

13. Colchicine

14. Rosemary

15. Glycyrrhizin (Glycyrrhizic Acid)

16. Other Plant-Derived Compounds

17. Conclusions and Perspectives

Section III. Herbs and Plants for Treating Liver Disease

Chapter 10. Curcuma longa, the Polyphenolic Curcumin Compound and Pharmacological Effects on Liver

1. Introduction of Curcuma longa

2. The Polyphenolic Curcumin Compound

3. Curcumin and Liver Disease

4. Conclusions

List of Abbreviations

Chapter 11. Nymphaea alba and Liver Protection

1. Introduction

2. Traditional Uses

3. Phytoconstituents

4. Validated Studies

5. Phenolics of N. alba and Liver Protection

6. Conclusion

List of Abbreviations

Chapter 12. The Flavone Baicalein and Its Use in Gastrointestinal Disease

1. Introduction

2. Extraction and Purification

3. Metabolism and Conversion

4. Use of Baicalein in Gastrointestinal Disease

5. Mechanism of Action of Baicalein

6. Conclusion

Chapter 13. Pyrroloquinoline Quinone: Its Profile, Effects on the Liver and Implications for Health and Disease Prevention

1. Introduction: Pyrroloquinoline Quinone

2. Factors Contributing to the Development of NAFLD/NASH

3. Systemic Effects of PQQ on NAFLD/NASH

4. Human Studies and Implications for Health

5. Conclusions

Chapter 14. Herbal Weight Loss Supplements: From Dubious Efficacy to Direct Toxicity

1. Introduction

2. The Surge of Herbal Product Use Within Complementary and Alternative Medicine

3. The Internet as a Source of Information About Herbal Weight Loss Supplements

4. Herbal Supplement Identity, Efficacy, and Safety: Bedlam in the Cyber Marketplace

5. Mexican Hawthorn Root

6. Toxicity of Thevetia spp.

7. Candlenut Tree Seed

8. Botanical Characteristics

9. Use of the Candlenut Tree in Asian Traditional Medicine

10. Weight Loss and Other Health Claims Made on the Internet for Candlenut Tree Seeds

11. International Health Agencies Ban Candlenut Seed Due to Its Toxicity

12. Conclusions

Chapter 15. Tea (Camellia sinensis L. Kuntze) as Hepatoprotective Agent: A Revisit

1. Introduction

2. Phytochemistry of Tea

3. Validated Uses

4. Tea Protects Against the Alcohol-Induced Hepatotoxicity

5. Tea Protects Against Carbon Tetrachloride–Induced Hepatotoxicity

6. Effect of Tea on N-Acetaminophen-Induced Hepatotoxicity

7. Tea Is Effective in Viral Hepatitis

8. Effect of Tea on Ischemia-Reperfusion Injury

9. Effect of Tea on Fatty Liver Disease

10. Effect of Tea on Hepatotoxicity of Lead

11. Effect of Tea on Hepatotoxicity of Arsenic

12. Effect of Tea on Phenobarbitol-Induced Liver Damage

13. Effect of Tea on Hepatotoxicity of Microcystin

14. Effect of Tea on Hepatotoxicity of Aflatoxins

15. Effect of Tea on Hepatotoxicity of Azathioprine

16. Effect of Tea on Galactosamine- and Lipopolysaccharide-Induced Liver Damage

17. Effect of Tea on Hepatotoxicity of Insecticides

18. Effect of Tea on Hepatocarcinogenesis

19. Conclusions

List of Abbreviations

Chapter 16. Hepatoprotective Effects of the Indian Gooseberry (Emblica officinalis Gaertn): A Revisit

1. Introduction

2. Phytochemicals

3. Traditional Uses

4. Scientifically Validated Studies

5. Effect of Amla on Hepatotoxicity of Ethanol

6. Effect of Amla on Hepatotoxicity of Heavy Metals Arsenic and Cadmium

7. Effect of Amla on Hepatotoxicity of Iron Overload

8. Effect of Amla on Hepatotoxicity of Ochratoxin

9. Effect of Amla on Hepatotoxicity of Antitubercular Drugs

10. Effect of Amla on Hepatotoxicity of Hexachlorocyclohexane

11. Effect of Amla on Hepatotoxicity of Carbon Tetrachloride

12. Effect of Amla on Hepatotoxicity of Paracetamol

13. Effect of Amla Phytochemicals on Galactosamine- and Lipopolysaccharide-Induced Liver Damage

14. Effect of Amla Phytochemicals on Hepatotoxicity of Microcystin

15. Effect of Amla on Hepatocarcinogenesis

16. Effect of Amla on Hepatic Lipid Metabolism and Metabolic Syndrome

17. Effect of Amla on NonAlcoholic Fatty Liver Disease

18. Mechanism of Action(s) Responsible for the Hepatoprotective Effects

19. Conclusions

List of Abbreviations

Section IV. Dietary Macronutrients and Micronutrients for Healthy Liver Function

Chapter 17. Major Dietary Interventions for the Management of Liver Disease

1. Introduction

2. Liver as an Organ

3. Liver Failure

4. Causes of Hepatic Injury

5. NonAlcoholic Fatty Liver Disease

6. Alcoholic Liver Disease

7. Chronic Hepatitis B and Chronic Hepatitis C

8. Hepatocellular Carcinoma

9. Dietary Interventions in the Management of Liver Diseases

10. Diet Types

11. Fat

12. Protein

13. Carbohydrates

14. Glycemic Index

15. Antioxidants

16. Bile Acids and Fiber

17. Prebiotics and Probiotics

18. The Mediterranean and Other Diets

19. Zinc

20. Niacin (Nicotinic Acid)

21. Astaxanthin

22. Curcumin

23. Conclusion

Chapter 18. The Effects of Dietary Advanced Glycation End Products (AGEs) on Liver Disorders

1. Advanced Glycation End Products

2. Circulating AGEs and Liver Disorders

3. The AGEs–RAGE System in Liver Disorders

4. The Effects of Dietary AGEs on Liver Disorders

5. Dietary Interventions to Reduce the AGEs

6. Summary

List of Abbreviations

Chapter 19. Molecular Mechanisms of the Protective Role of Wheat Germ Oil Against Oxidative Stress–Induced Liver Disease

1. Introduction

2. Reactive Oxygen Species and Liver Diseases

3. Wheat Germ Oil and Liver Diseases

Chapter 20. Critical Role of Hepatic Fatty-Acyl Phospholipid Remodeling in Obese and Nonobese Fatty Liver Mouse Models

1. Introduction

2. Phospholipids in NAFLD and NASH

3. Phospholipid-Metabolizing Genes in Obesity and NAFLD

4. Summarized Findings and Proposed Mechanisms

5. Perspectives

6. Conclusions

List of Abbreviations

Chapter 21. Vitamin D3 and Liver Protection

1. Introduction

2. Materials and Methods

3. Results

4. Discussion

Chapter 22. The Role of Carbohydrate Response Element–Binding Protein in the Development of Liver Diseases

1. Introduction

2. ChREBP, a Glucose-Activated Transcription Factor That Regulates Glucose and Lipid Metabolism

3. Dietary Composition and ChREBP

4. ChREBP and Liver Diseases

5. Supplement and ChREBP

6. Conclusion

Chapter 23. Trans fatty acid in the liver and central nervous system

1. Introduction

2. Hydrogenation Process

3. Biochemical Metabolism

4. Trans Fatty Acids and Liver Damage

5. Trans Fatty Acids and the Central Nervous System

6. Final Considerations

Chapter 24. Fish Oil Supplements During Perinatal Life: Impact on the Liver of Offspring

1. Introduction

2. Role of Fatty Acids in Fetal Development

3. Fatty Acids and Epigenetics

4. Fish Oil Supplements During Pregnancy

5. Prevalence and Pathogenic Aspects of Nonalcoholic Fatty Liver Disease

6. Fetal Programming Origins of NAFLD

7. Potential Protective Role of Fish Oil in the NAFLD Development

Chapter 25. Purple Rice Bran Improves Hepatic Insulin Signaling via Activation of Akt and Stabilization of IGF in Diabetic Rats

1. Introduction

2. Methods

3. Results

4. Discussion and Conclusion

Section V. Toxic Dietary Materials Including Alcohol-Induced Liver Dysfunction: Treatment

Chapter 26. Heavy Metals and Low-Oxygen Microenvironment—Its Impact on Liver Metabolism and Dietary Supplementation

1. Introduction

2. Heavy Metals and Its Interactions

3. Hypoxia Pathophysiology

4. Heavy Metals in Liver Diseases

5. Hypoxia and Liver Diseases

6. Heavy Metals (Nickel and Lead), Hypoxia, and Liver Functions—Role of Dietary Supplementations

7. Conclusion

Chapter 27. Cadmium and Fullerenes in Liver Diseases

1. Introduction

2. Liver and Oxidative Stress

3. Cadmium as the Model of Hepatotoxicity

4. Fullerenes and Liver Protection

Chapter 28. Beneficial Effects of Natural Compounds on Heavy Metal–Induced Hepatotoxicity

1. Introduction

2. Arsenic Hepatotoxicity

3. Cadmium Hepatotoxicity

4. Chromium Hepatotoxicity

5. Copper Hepatotoxicity

6. Lead Hepatotoxicity

7. Mercury Hepatotoxicity

8. Effects of Natural Products on Heavy Metal–Induced Hepatotoxicity

Chapter 29. Nutritional and Dietary Interventions for Nonalcoholic Fatty Liver Disease

1. Introduction

2. Epidemiology

3. Risk Factors

4. Pathogenesis

5. Clinical Manifestations

6. Histopathology

7. Diagnosis

8. Natural Course and Outcomes

9. Treatment

10. Conclusions

Chapter 30. Dietary Management of Nonalcoholic Fatty Liver Disease (NAFLD) by n-3 Polyunsaturated Fatty Acid (PUFA) Supplementation: A Perspective on the Role of n-3 PUFA-Derived Lipid Mediators

1. Background

2. NAFLD—Worldwide Burden

3. Dietary Carbohydrates: A Glance at Fructose

4. Hepatic Fructose Metabolism

5. Fructose, the Common Etiological Factor of NAFLD

6. Management of NAFLD

7. Pharmacotherapy

8. Lifestyle Intervention

9. Dietary Fat

10. Metabolic Fate of n-3 Long-Chain PUFA: Bioactive Lipid Mediators

11. Eicosapentaenoic Acid (EPA; C20:5n-3)–Derived Lipid Mediators

12. Docosahexaenoic Acid (DHA; C22:6n-3)–Derived Lipid Mediators

13. n-3 PUFA and NAFLD

14. Lipid Mediators of n-3 PUFA and NAFLD

15. Conclusion

Index

Copyright

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List of Contributors

Soniya Abraham,     Undergraduate student, Father Muller Medical College, Mangalore, India

Fahimeh Agh,     Department of Nutrition, School of Health, Iran University of Medical sciences, Tehran, Iran

Idris Adewale Ahmed,     Department of Biotechnology, Faculty of Science, Lincoln University College Malaysia, Petaling Jaya, Malaysia

El-Sayed Akool,     Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

Malath Azeez Al-Saadi,     Basic Science\Pharmacology-Dentistry College, University of Babylon, Al-hilla, Babil, Iraq

Mohamed M. Amin,     Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt

Encarnación Amusquivar,     Department of Biochemistry and Chemistry, University San Pablo CEU, Madrid, Spain

Riham O. Bakr,     Pharmacognosy Department, Faculty of Pharmacy, October University for Modern Sciences and Arts, Giza, Egypt

Manjeshwar Shrinath Baliga,     Department of Research, Mangalore Institute of Oncology, Mangalore, India

M.P. Baliga-Rao,     Department of Research, Mangalore Institute of Oncology, Mangalore, India

Ganesh Bhandari,     Undergraduate student, Father Muller Medical College, Mangalore, India

Harshith P. Bhat,     Mangalore Institute of Oncology, Mangalore, India

M.S. Biradar,     Department of Medicine, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India

Flavio A. Cadegiani

Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil

Corpometria Institute, Centro Clínico Advance, Brasília, Brazil

Cindy X. Cai,     Division of Gastroenterology and Hepatology, Department of Internal Medicine, VA Loma Linda Healthcare System, Loma Linda University, Loma Linda, CA, United States

Stella Carlos,     Department of Nutrition Services, VA Loma Linda Healthcare System, Loma Linda, CA, United States

Shobha Castelino-Prabhu,     Department of Pathology, VA Loma Linda Healthcare System, Loma Linda, CA, United States

Walee Chamulitrat,     Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany

Marshal David Colin,     Undergraduate student, Father Muller Medical College, Mangalore, India

Kusal K. Das,     Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India

Swastika Das,     Department of Chemistry, BLDE Association’s, Dr. P.G. Halakatti College of Engineering and Technology, Vijayapur, India

Sinisa Djurasevic,     University of Belgrade Faculty of Biology, Belgrade, Serbia

Alaa El-Din El-Sayed El-Sisi,     Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt

Abbasali Emamjomeh,     Computational Biotechnology Lab (CBB), Department of Plant Breeding and Biotechnology (PBB), University of Zabol, Zabol, Iran

Junichi Fujii,     Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata, Japan

Thomas George,     Undergraduate student, Father Muller Medical College, Mangalore, India

Armando E. González-Stuart,     School of Pharmacy-University of Texas at El Paso, El Paso, TX, United States

Nguyen Thanh Hai,     School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam

Parisa Hasanein,     Department of Biology, School of Basic Sciences, University of Zabol, Zabol, Iran

Emilio Herrera,     Department of Biochemistry and Chemistry, University San Pablo CEU, Madrid, Spain

Ei Ei Hlaing

Department of Biochemistry, Chiang Mai University, Chiang Mai, Thailand

Department of Biochemistry, University of Medicine, Mandalay, Myanmar

Takujiro Homma,     Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata, Japan

Rajesh Honnutagi,     Department of Medicine, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India

Katsumi Iizuka

Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu, Japan

Gifu University Hospital Center for Nutritional Support and Infection Control, Gifu, Japan

SM Jeyakumar,     Division of Lipid Biochemistry, National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India

Karen R. Jonscher,     Department of Anesthesiology, University of Colorado Denver, Aurora, CO, United States

Rui Kang,     Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States

Vijay Kumar,     Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India

Narissara Lailerd,     Department of Physiology, Chiang Mai University, Chiang Mai, Thailand

Ji-Young Lee,     Department of Nutritional Sciences, University of Connecticut, Storrs, CT, United States

Yoojin Lee,     Department of Nutritional Sciences, University of Connecticut, Storrs, CT, United States

Gerhard Liebisch,     Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany

Rafael Longhi,     Department of Basic Health Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil

Dewan Syed Abdul Majid,     Department of Physiology, School of Medicine, Tulane University, New Orleans, LA, United States

Dina Zakaria Mohamed,     Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt

Lata Mullur,     Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India

Pablo Muriel,     Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico

Dong Thi Nham,     School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam

Claudia Ojeda-Granados

Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Mexico

Health Sciences Center, University of Guadalajara, Guadalajara, Mexico

Princy Louis Palatty,     Department of Pharmacology, Amrita Institute of Medical Sciences, Kochi, India

Arturo Panduro

Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Mexico

Health Sciences Center, University of Guadalajara, Guadalajara, Mexico

Anita Pathil,     Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany

Sladjan Pavlovic,     University of Belgrade Institute for Biological Research Sinisa Stankovic, Belgrade, Serbia

Snezana Pejic,     University of Belgrade Vinca Institute of Nuclear Sciences, Belgrade, Serbia

Pichapat Piamrojanaphat,     Department of Biochemistry, Chiang Mai University, Chiang Mai, Thailand

Arnadi Ramachandrayya Shivashankara,     Undergraduate student, Father Muller Medical College, Mangalore, India

Erika Ramos-Tovar,     Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico

Suresh Rao,     Mangalore Institute of Oncology, Mangalore, India

R. Chandramouli Reddy,     Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India

Ingrid Rivera-Iñiguez

Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Mexico

Health Sciences Center, University of Guadalajara, Guadalajara, Mexico

José O. Rivera,     School of Pharmacy-University of Texas at El Paso, El Paso, TX, United States

Sonia Roman

Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Mexico

Health Sciences Center, University of Guadalajara, Guadalajara, Mexico

Sittiruk Roytrakul,     National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand

Robert B. Rucker,     Department of Nutrition, University of California, Davis, CA, United States

Supicha Rungcharoenarrichit,     Department of Biochemistry, Chiang Mai University, Chiang Mai, Thailand

Samia Salim Sokar,     Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt

Maricruz Sepulveda-Villegas

Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Mexico

Health Sciences Center, University of Guadalajara, Guadalajara, Mexico

Farzad Shidfar,     Department of Nutrition, School of Health, Iran University of Medical sciences, Tehran, Iran

Surendra Kumar Shukla,     Eppley Cancer Institute, University of Nebraska Medical Centre, Omaha, NE, United States

Pejman Solaimani,     Division of Gastroenterology and Hepatology, Department of Internal Medicine, VA Loma Linda Healthcare System, Loma Linda University, Loma Linda, CA, United States

Wolfgang Stremmel,     Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany

Daolin Tang

The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, People’s Republic of China

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States

K.R. Thilakchand,     Department of Research, Mangalore Institute of Oncology, Mangalore, India

Dang Kim Thu,     School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam

Zoran Todorovic,     University of Belgrade Faculty of Medicine, University Medical Center Bezanijska kosa, Belgrade, Serbia

Chuong Tran,     Division of Gastroenterology and Hepatology, Department of Internal Medicine, VA Loma Linda Healthcare System, Loma Linda University, Loma Linda, CA, United States

Bansari J. Trivedi,     Department of Nutrition Services, VA Loma Linda Healthcare System, Loma Linda, CA, United States

Bui Thanh Tung,     School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam

A Vajreswari,     Division of Lipid Biochemistry, National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India

Sunitha Venkatesh,     Mangalore Institute of Oncology, Mangalore, India

Yangchun Xie

Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States

Acknowledgments

The work of Dr. Watson’s editorial assistant, Bethany L. Steven, in communicating with authors, editors, and working on the manuscripts was critical to the successful completion of the book. It is very much appreciated. Support for Ms. Stevens’ and Dr. Watson’s editing was graciously provided by Southwest Scientific Editing & Consulting, LLC. Direction and guidance from Elsevier staff was critical. Finally, the work of the librarian at the Arizona Health Science Library, Mari Stoddard, was vital and very helpful in identifying key researchers who participated in the book.

Section I

Overview of Liver Health

Outline

Chapter 1. Genome-Based Nutrition in Chronic Liver Disease

Chapter 2. Current Therapeutic Strategies for Alcoholic Liver Disease

Chapter 3. Features of Hepatic Encephalopathy

Chapter 4. The Liver Before and After Bariatric Surgery

Chapter 5. Oxidative Stress and Dysfunction of the Intracellular Proteolytic Machinery: A Pathological Hallmark of Nonalcoholic Fatty Liver Disease

Chapter 1

Genome-Based Nutrition in Chronic Liver Disease

Sonia Roman¹,², Ingrid Rivera-Iñiguez¹,², Claudia Ojeda-Granados¹,², Maricruz Sepulveda-Villegas¹,², and Arturo Panduro¹,²     ¹Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Mexico     ²Health Sciences Center, University of Guadalajara, Guadalajara, Mexico

Abstract

Chronic liver disease is mainly caused by alcohol abuse, viral hepatitis, and obesity-related nonalcoholic steatohepatitis (NASH). These hepatopathogenic agents activate physiopathological processes that lead to inflammation, fibrosis, cirrhosis, and in some cases liver cancer. As genes and lifestyle factors such as diet, physical activity, and emotional state are involved, each population may have differential genetic susceptibility and specific risk factor interactions. Hence, genome-based nutritional strategies are aimed to tailor the correct diet based on the population's genetic background and regional food culture to avoid or reverse liver damage caused by nutrition-related processes. Once the correct diet has been established, specific modifications can be introduced for patients with NASH, alcoholic liver disease, or hepatitis C infection. This chapter provides examples of genome-based nutritional strategies to provide a healthier diet for liver-diseased patients. Herein, we highlight the involvement of genes and regional foods with anti-inflammatory, antioxidant, and antifibrogenic properties that may aid to counteract the negative impact of the current hepatopathogenic diet.

Keywords

Alcoholic liver disease; Food culture; Genome-based nutrition; Hepatitis C infection; Hepatopathogenic diet; Microbiota; Nonalcoholic steatohepatitis; Nutrigenetics; Nutrigenomics; Nutrition transition

1. Introduction

1.1. Chronic Liver Disease

Liver cirrhosis is a chronic disease that initiates by an inflammatory process with or without accumulation of fat, followed by fibrosis. The degree of fibrosis (F) can be staged F1 (initial), F2 (intermediate), F3 (advanced), and F4 (cirrhosis). Once clinical cirrhosis becomes manifest, the patient may die due to systemic complications of liver cirrhosis or progress to hepatocellular carcinoma.

The main etiological agents that lead to liver cirrhosis are alcoholism, viral hepatitis B and C, and most recently, obesity in subjects that are susceptible to develop nonalcoholic steatohepatitis (NASH). The progression of each disease may last from 25 to 30  years due to differential interactions between genes and key environmental lifestyle factors such as diet, physical activity, and emotional state. Therefore, this time span may be shorter or longer. Furthermore, with the use of noninvasive techniques such as transient elastography or serum markers, liver damage may be detected in early stages (F1–F3) before cirrhosis is present so that an appropriate medical-nutritional therapy can be implemented. The best strategy would be to eliminate the etiological agent to prevent or reverse liver damage. In regard to this point, there has been considerable enthusiasm worldwide for the efficacy of the new antiviral agents for hepatitis B and C,¹ whereas alcoholism has diminished in some developing countries.² However, the obesity epidemic is a new threat that compromises the health of liver-diseased patients regardless of the etiology in both wealthy and impoverished countries. Therefore, each nation needs to evaluate the impact of these illnesses to implement nutritional strategies for liver-diseased patients aimed to avoid or reverse the progression of chronic liver diseases and nutrition-related comorbidities.

This obesity epidemic is driven by a global wave of nutritional transition where populations waive their traditional diet and lifestyle. This transition has created an imbalance between the ancestral genes respective to the current lifestyle which has been associated with an increased risk of developing some of the highly prevalent nutrition-related chronic diseases (NRCDs) of today. For example, in the last 50  years, the Mexican population underwent a nutrition transition from a traditional dietary pattern, passing through undernutrition, and currently overnutrition. Excess weight is prevalent in 72.1% of the adult population affecting all socioeconomic statuses but mostly those with low income that comprises more than 50% of the population. Furthermore, the leading causes of mortality are type 2 diabetes, cardiovascular disease, and liver cirrhosis.³ The leading causes of liver cirrhosis are the excessive consumption of alcohol, followed by hepatitis B and C virus (HCV), and an increasing rate of NASH.⁴,⁵ Furthermore, the main dyslipidemias in Mexico are hypercholesterolemia, hypertriglyceridemia, and hypoalphalipoproteinemia.⁶ All three types have been associated with genetic susceptibility combined with a particular dietary pattern described as a hepatopathogenic diet that places individuals at risk for NRCDs as aforementioned.⁶,⁷

1.2. Hepatopathogenic Diet and Its Variations by Liver Disease Etiology

Among the Mexican population, the characteristics of a hepatopathogenic diet have been defined.⁷ This dietary pattern is characterized by an excessive energy intake, an imbalance of macronutrients, as well as a low content of fiber and micronutrients with antioxidant and anti-inflammatory properties such as vitamins A and E, folates, magnesium, selenium, and zinc. Notably, this diet contains a disproportionate amount of simple sugars (>10%), saturated fats (>10%), more than 200  mg of dietary cholesterol, and an increased ratio of n-6: n-3 polyunsaturated fatty acids (PUFAs) (12:1)⁸. Overall, this unhealthy diet has been associated with the increase in the consumption of industrial food containing high-fructose corn syrup such as sweetened beverages, together with overfried foods cooked in oil or lard, red meat, high-fat dairy products, and confectionery foods. Furthermore, an increase in the number of sedentary activities is common, leading to less calorie expenditure. This dietary pattern has been identified in both lean and excess weight patients, as well as those with chronic liver disease.⁷,⁸ However, the dietary composition of the hepatopathogenic diet may have differential features according to the etiology of liver disease and related lifestyle. For example, it has been documented that patients who are normal weight consume a hepatopathogenic diet containing high amounts of animal fat (saturated fat) obtained from red meat, cold cuts, and processed foods and less amount of fruits, vegetables, legumes, and selenium. However, those with excess weight eat the same diet but consume a lower amount of monounsaturated fats and fish meat. These dietary patterns have been associated with dyslipidemias such as hypercholesterolemia and hypertriglyceridemia, respectively. On the other hand, alcoholic patients present hypertriglyceridemia and consume excess calories through the consumption of carbohydrates (cereals, alcoholic beverages, soft drinks), high cholesterol levels (red meat), and high sodium due to salty snacks.⁷ In contrast, patients with HCV manifest metabolic alterations such as hypoalphalipoproteinemia, insulin resistance, and high levels of liver enzymes. These alterations may be related to the metabolic dynamics between circulating lipids and the viral particle. However, despite the fact that they tend to consume a healthier diet compared with the other groups of patients, most of them are overweight and obese, suggesting the influence of the hepatopathogenic diet.⁷ In conclusion, an adequate dietary intervention should be oriented to reverse the hepatopathogenic effect of this diet based on the identification of food group responsible for the excess calories, nutrient imbalance, and metabolic dysfunction in each etiology of liver disease.

2. Genome-Based Nutrition: A Regionalized and Personalized Diet

Genomic medicine provides a new approach to how health professionals prevent, manage, and treat many types of diseases. Regardless that they may be infectious or noncommunicable, the onset and progression will depend on the presence of genetic and environmental risk factors.⁹ In the field of nutritional genomics, genome-based nutrition refers to a strategy that considers the population’s or individual’s genetic background and lifestyle to set tailored nutritional recommendations or interventions. Most modern-day NRCDs may be considered as an imbalance between several ancestral polymorphic genes generated by gene-culture coevolutionary processes and the current-day lifestyle.¹⁰ Therefore, restoring this balance should be the main target of a nutritional genomic therapy in which the correct diet that should be recommended to healthy individuals would take into account ethnicity, genetics, and cultural, social, and environmental factors of the population they belong to.¹¹ The morbidity and mortality due to NRCDs have been tackled in some countries by promoting the consumption of traditional diets or integrating regional foods, as in the case of the Mediterranean-type diet.¹² However, each region provides its biodiversity with differences in genotype frequencies, food products, and food culture.

As an example, genome-based nutrition strategies in Mexico would include the knowledge of the Mexican genome and the food cultural history of the population. First, the Mexican population is an admixture of the ancestral Amerindian population with Caucasian and African lineages.¹¹ However, this admixture is heterogeneous throughout the country.¹³ Therefore, it is expected that the proportion of the ancestral Amerindian genes vary from 50% to 100% based on the geographic location and demographic history of the population. Second, the Mesoamerican diet is the basis of the Mexican food culture.¹⁴ However, this traditional diet is widely diverse in regional food ingredients as the result of the miscegenation between the Old and New World cultural food patterns. However, these regional diets have evolved toward the westernized and hepatopathogenic diet that currently has a negative impact on the population’s health. Given these antecedents, studies have been carried out to evaluate the prevalence profile of some diet-related adaptive gene polymorphisms to determine the dietary features to which the Mexican population is genetically adapted. These studies have shown that diet-related gene polymorphisms have a heterogeneous distribution in which the ethnic groups (Amerindians) revealed the highest frequencies of adaptive alleles such as MTHFR 677T, ABCA1 230C, and APOE ε4 followed by mestizos, while the mean of AMY1 diploid copy number was 6.82  ±  3.3 copies.¹⁵ Nonetheless, the frequency of the European-related LCT-13910T adaptive allele was highest in mestizos with high European ancestry but extremely low in Amerindians.¹⁶ The abovementioned diet-related genes are involved in folate (MTHFR) and lipid (ABCA1 and APOE) metabolism, as well as in dairy (LCT) and starch (AMY1) digestion. Being carriers of adaptive alleles may require nutritional specifications related to traditional dietary practices to avoid the risk of disease to which they have currently been associated. For example, the highly prevalent MTHFR 677T may demand an adequate folate intake or even higher than the Recommended Daily Allowances for the general population. The high frequency of ABCA1 230C and APOE ε4 suggests a genetic adaptation to low-saturated fat/cholesterol diet, so the excess in the consumption of these nutrients should be discouraged. Furthermore, a mean AMY1 gene copy number of ≥6 copies is consistent with agricultural societies capable of digesting high-starch foods, and the low prevalence of the European LCT-13910T allele indicates that this population is not genetically adapted to digest dairy in adulthood. Therefore, the consumption of milk and dairy products as essentials of the diet should not be recommended. Furthermore, the association of the risk alleles of some taste receptor genes such as TAS1R2, TAS2R38, and CD36 with dyslipidemia and liver damage should not be neglected.¹⁷–²⁰

Thus, to modify the current hepatopathogenic dietary pattern, genome-based nutritional advice should be tailored in a regionalized or individualized manner according to the genetic background, regional foods, and traditional food culture of each population. Once the correct diet has been established, specific modifications can be made as required for each liver disease, for example, a correct diet plus antioxidant foods for NASH or a correct diet plus anti-HCV nutrients for patients with chronic HCV infection. This action may be worth replicating in other populations around the world to achieve sustainable and healthier lifestyles.

3. Genes, Microbiota, and Regionalized Diet

Beneficial bacteria from the intestine confer numerous health benefits to the host, including metabolism regulation, energy homeostasis, intestinal motility, immune system control, and host behavior regulation.²¹ However, gut microbiota alterations facilitate the progression of chronic diseases such as obesity, cardiovascular diseases, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), as well as altered emotions and eating behaviors.²²,²³ Factors such as the type of birth, diet, alcohol consumption, viral infections, stress, age, body weight, exercise, use of antibiotics, genetics, and geography modify gut microbiota composition.²⁴ The study of gene polymorphisms and environment interactions with gut bacteria is the main focus of research to understand the development of chronic diseases and negative emotions.²⁵

The central nervous system maintains bidirectional communication with the intestine. Moreover, in the presence of energy balance/brain reward system alterations, negative emotions and stress promote the release of cortisol. Cortisol results in dysbiosis, allowing pathogens and toxins to permeate the gut barrier and activate inflammation.²⁶ Cytokines such as TNFα and IL-1β facilitate abnormalities in lipid metabolism, signal insulin, promote apoptosis, impair lipid oxidation, and promote fibrogenesis.²⁷ In an excess energy intake from a westernized type of diet, the input and type of short-chain fatty acids (SCFAs) are associated with a higher energy source, lipid accumulation, and liver damage.²⁸,²⁹ Concretely, acetate and propionate are involved in hepatic lipogenesis and gluconeogenesis.²⁸ Probiotics, prebiotics, functional nutrients, and different dietary strategies are used to restore the balance in gut microbiota community. Emerging evidence shows that probiotics improve liver metabolism. One way of doing so is by preventing intestinal fat absorption, reducing fasting, and postprandial nonesterified fatty acids levels as showed when Lactobacillus gasseri SBT2055 in fermented milk was administered.³⁰ Other probiotics contribute to SCFA production such as MIYAIRI 588 strain of C. butyricum which produces butyrate and in this way, prevents hepatic lipid accumulation, improves gut barrier permeability, and suppresses hepatic oxidative stress.³¹ Regarding prebiotics, dietary interventions provide prebiotics such as inulin and galacto-oligosaccharides, guar gum, hemicellulose, glutamine, pectin, and other oligosaccharides.³² These prebiotics produce SCFAs that contribute to increases in beneficial microorganisms such as Bifidobacteria and Lactobacilli, which are involved in protection against obesity as they inhibit the adhesion of pathogenic microorganisms to intestinal mucosa that could alter permeability.³³ Also, intestinal fermentation of fructans increases incretin production such as GLP-1 and GLP2 secreted by intestinal lumen cells, which regulate insulin secretion by pancreatic B cells, promoting satiety.³⁴ Dietary strategies based on a more regionalized concept such as the Mediterranean diet have proved to restore gut microbiota in obese patients.³⁵ This diet improves gastrointestinal symptoms and increases adherence to dietary treatment.³⁶ These promising results relate to the antioxidant, anti-inflammatory, and prebiotic capacity of Mediterranean foods such as tea, fermented milk products, vegetables, wheat bread, rice, chocolate, coffee, and many others.³⁷ However, efficient response to foods is influenced by genetic adaptations to the environment.¹¹,¹⁵ Recently, in Mexico, regional prebiotic foods (maize, beans, tomato, prickly pear, and chia and pumpkin seeds) based on the components of the Mesoamerican diet showed increments of beneficial bacteria that promote reductions in metabolic parameters, body composition, adipocyte size; decrease oxidative stress markers; and improve cognitive parameters in an experimental model.³⁸ Both of these regional dietary strategies prevent chronic disease development and increase the level of treatment compliance by restoring the gut bacteria community, meaning that emotions and modulation of behavior by the gut microbiota need to be considered in the management of obesity and gastrointestinal and chronic liver diseases.²⁵

4. Nutritional Intervention in Chronic Liver Disease

Management of chronic liver disease requires that patients are provided with a comprehensive medical and nutritional intervention. In the case of NAFLD/NASH, reversing the metabolic abnormalities induced by obesity is a primary goal, whereas halting the consumption of alcohol in patients with alcoholic liver disease (ALD) or fighting HCV with antivirals would be the ideal strategy. Commonly, these diseases are detected at advanced stages, in which the number of associated comorbidities is high and therapy becomes complex. How genome-based nutritional strategies are set up to prevent or reverse the deleterious effect on liver health will depend on the population’s genetic susceptibility to develop liver disease, the stage of fibrosis, and the specific composition of the regional hepatopathogenic diet. In this next section, examples of genome-based nutritional strategies to provide a healthier diet for liver-diseased patients are provided.

4.1. Nonalcoholic Fatty Liver Disease—Nonalcoholic Steatohepatitis

NAFLD refers to the accumulation of ≥5% of fat in liver cells and is considered a risk factor for an aggressive form known as NASH. NAFLD and NASH have become a global trend parallel to the uprising rate of obesity in both children and adults in populations that have acquired a Westernized lifestyle.³⁹ Physiopathologically, NASH is a stage of oxidative stress and hepatocyte inflammation activated by excess liver triglycerides (either dietary, driven by insulin resistance, or by de novo lipogenesis) which can eventually cause fibrosis, cirrhosis, and in some cases, hepatocellular carcinoma.⁴⁰ However, genetic and environmental risk factors are involved in the progression of NAFLD/NASH. Two gene variations have been related to the differences in the prevalence of NAFLD worldwide: TMSF2 Glu167Lys variant which reduces protein function, and PNPLA3 Ile148 Met which limits hepatic triglyceride hydrolysis, both of which have been associated with severe steatosis.³⁹,⁴¹,⁴² On the other hand, poor dietary habits and sedentary lifestyle are recognized as risk factors for progression.³⁹ Therefore, considering these factors, tailoring the international recommendations by a genome-based nutritional strategy is required to provide a specific NAFLD/NASH treatment for different populations. For example, in patients with risk of NASH in Mexico, nutritional interventions should consider a correct genome-based regionalized diet as explained earlier with modifications given the high rate of obesity rate, the consumption of a hepatopathogenic diet, and low physical activity that affects the population. In the following subsections, these considerations are detailed.

4.1.1. Weight Loss Goals and Energy Restriction

Losing weight through diet and exercise is the primary strategy. It is essential to consider realistic goals to promote a sustained and healthy weight loss. Considering that most NAFLD/NASH patients are overweight or obese, a weight loss strategy ranging from 5% to 10% of the initial weight in 6  months is desirable.⁴³ According to different therapeutic guidelines for NAFLD/NASH (Table 1.1), a weight reduction of 3%–10% is expected. Improvements in simple steatosis are observed with a 3%–5% of body weight loss, whereas a 7%–10% is associated with improvements in the histopathological features of NASH.⁴⁰ However, a weight loss ≥10% is needed for resolution of NASH and fibrosis regression.⁴⁴ Energy restriction through diet is required to achieve weight loss. Therefore, it is recommended that energy be reduced from 500  kcal/day to 1000  kcal/day or 30% less of the total energy requirement. The energy intake recommended for women is 1200–1500  kcal/day and 1500–1800  kcal/day for men (considering physical activity and personal requirements). This aim intends to promote a healthy weight loss which comprises around 0.5–1  kg per week.⁴³ In contrast, a dramatic weight loss of >1.6  kg/week should be avoided as this may worsen NASH and promote the development of gallstones.⁴⁵

Table 1.1

AASLD, American Association for the Study of Liver Diseases; AISF, Italian Association for the Study of the Liver; APWP, Asia-Pacific Working Party; CSE, Chinese Society of Endocrinology; EASL, EASD, EASO, European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Association for the Study of Obesity; PUFAs, polyunsaturated fatty acids; SFA, saturated fatty acid; WGO, World Gastroenterology Organization.

a EASL-EASD-EASO. Clinical Practice Guidelines for the management of nonalcoholic fatty liver disease. J Hepatol 2016;64(6):1388–402.

b Loria P, Adinolfi LE, Bellentani S, et al. Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. Dig Liver Dis 2010;42(4):272–82.

c Chitturi S, Farrell GC, Hashimoto E, Saibara T, Lau GKK, Sollano JD. Nonalcoholic fatty liver disease in the Asia-Pacific region: definitions and overview of proposed guidelines. J Gastroenterol Hepatol 2007;22(6):778–87.

Adapted from Roman S, Ojeda-Granados C, Ramos-Lopez O, Panduro A. Genome-based nutrition: an intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis. World J Gastroenterol 2015;21(12):3449–61.

4.1.2. Macronutrient Distribution

Carbohydrates: Very restrictive diets or diets with abnormal macronutrient distribution can decrease long-term adherence. Carbohydrate distribution is relevant in nutritional therapy due to its metabolic effect on de novo lipogenesis. For NAFLD patients, a moderate carbohydrate restriction is recommended (40%–50%) in order to improve the hepatic and metabolic profile. A similar effect has been documented with low-carbohydrate diets (<40%). However, these diets have in the long term, low palatability or poor adherence. On the other hand, high-carbohydate diets (50%–65%) are associated with worsening of the NAFLD/NASH spectrum.⁴⁶ Also, carbohydrate quality matters; the most recommended are complex carbohydrates which have low glycemic index, high fiber, and starch present in vegetables, fruits, seeds, and whole grains.⁴³ Also, it is important to take care of the glycemic load.¹⁵ Simple carbohydrates must be restricted to <10% of the total energy requirements. High intake of added sugar (not natural sources as fruits or vegetables), specially fructose (present in industrialized products, soft drinks, bakery products and fast foods), must be restricted in NAFLD patients because the excessive consumption of these food products induces lipogenesis, intrahepatic lipid accumulations, and insulin resistance.⁴⁷,⁴⁸

Lipids: The dietary lipid recommendation for the general population is <30% of the total energy requirements. Adequate consumption of monounsaturated fatty acids (MUFAs) and PUFAs have an essential contribution to the lipid and anti-inflammatory profile. MUFAs and PUFAs each must be consumed in >10% of the total energy.⁴⁹ For PUFAs, an optimal n-6: n-3 ratio of 5:1 has shown beneficial outcomes.⁵⁰ Saturated fatty acids (SFAs) are recommended in >7% to <10% of the total energy intake to diminish the risk of dyslipidemia. Also, it is essential to avoid trans-fatty acids mainly present in processed and fast food.⁴⁸,⁵¹

Protein: Although currently there is a lack of evidence related with the quality and requirements of protein for NAFLD patients, it is known that protein deficiency causes steatosis and that protein excess can be associated with side health effects. Therefore, the protein intake of 15%–20% can be considered as recommendable.⁴⁸,⁵¹ Vegetable protein sources should be promoted to avoid SFAs through animal sources.

4.1.3. Microbiota and NASH

As mentioned earlier, the hepatopathogenic diet is a Westernized type of diet which has also been associated with gut dysbiosis and disease progression. The consumption of diets rich in proteins and saturated fats from animal products increment the abundance of Bacteroides, while simple carbohydrates contribute to the abundance of Prevotella, conferring a proinflammatory potential.⁵²

High-fat diets contribute to choline metabolism shift to methylamine production and consequent accumulation of hepatic triglycerides in insulin-resistant mice.⁵³ In germ-free mice, an administration of a high-fat diet induced NASH by increasing Streptococcaceae, weight, liver inflammation, and liver damage markers.⁵⁴ Simple sugars such as fructose in combination with a high-fat dietinduced increments in Enterobacteria and consequently liver disease.⁵⁵ Also, fructose alone promotes the progression of hepatic lipid accumulation, impairments in fatty acids oxidation, inflammation, and alterations in microbiota.⁵⁶–⁵⁸ Dramatic consumption of fructose beverages facilitates the increase of endotoxins in adolescents with NAFLD when compared with healthy controls.⁵⁹ A combination of blueberry juice and Bifidobacterium lactis, Lactobacillus bulgaricus, and Streptococcus thermophiles achieve to prevent NASH progression by improving hepatic and lipid biomarkers due to downregulation of lipogenic genes.⁶⁰

4.1.4. Genome-Based Nutritional Strategy

The hepatopathogenic diet promotes obesity and a dysbiosis that aggravates the hepatic and metabolic profile of the NAFLD/NASH spectrum. Restoration of health as proposed by international guidelines requires that each country elaborate local recommendations based on a genome-based regionalized diet that could supply the dietary components necessary to counteract the physiopathological processes of NAFLD/NASH. Many food compounds have a hepatoprotective effect. Although the source can change according to geographic location, the active ingredient may be similar.¹⁵ MUFAs, PUFAs, and micronutrients such as vitamins C and E with antioxidant and antifibrogenic activity, as well as choline, folic acids, vitamin D, and magnesium, have been identified as beneficial compounds from the diet to treat NAFLD/NASH.¹¹ Several food ingredients identified in the Mexican food culture have been included in a genome-based nutritional strategy because these ingredients have anti-inflammatory and antioxidant capacity and antifibrogenic properties and improve insulin sensitivity and lipid profile (Table 1.2).¹¹ Furthermore, several of these ingredients also have an impact on the restoration of gut microbiota. Other natural sources of Old World origin such as garlic, ginger, turmeric, cinnamon, cumin, grapes, broccoli, and onions can also be considered based on their availability and local preferences.⁶¹

Table 1.2

CHs, carbohydrates; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids.

a Tejuino: Fermented maize beverage.

b Pulque: fermented agave plant beverage.

c Tepache: fermented fruit (pineapple) beverage. Quelites: leafy green vegetables.

Adapted from Roman S, Ojeda-Granados C, Ramos-Lopez O, Panduro A. Genome-based nutrition: an intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis. World J Gastroenterol 2015;21(12):3449–61.

4.2. Alcoholic Liver Disease

Alcohol use is an important and primary cause of ALD worldwide.⁶² Decades ago, ALD was detected in advanced stages of liver decompensation and focused mainly on the acute symptoms and the clinical complications related to cirrhosis.⁶³ At this stage of disease it was advised to rest as much as possible and to cease the intake of protein, water, and salt.⁶⁴,⁶⁵ Recently, diagnosed ALD patients are advised to withdraw the consumption of alcohol and to consume a balanced diet, specifically with a proper intake of protein. Nutrition management for the hospitalized patient focuses on electrolyte repletion and prevents catabolism. In general, malnutrition was a prevalent complication in ALD patients in advanced stages of the disease that led to high mortality rates. Standard clinical guidelines are aimed to assess the nutritional status of ALD and provide adequate nutrition via oral route or nasojejunal route when necessary. Enteral feeding strategies have considered a goal of protein intake of 1.2–1.5  g/kg and a caloric intake of 35–40  Kcal/kg of ideal body weight. Furthermore, nutritional supplementation to achieve adequate caloric intake and to remedy micronutrient deficiencies is usually suggested. Micronutrient supplementation could include zinc, thiamine, folic acid, and B complex vitamins.⁶²,⁶⁶ However, there are no guidelines for the adequate supplementation doses of micronutrients in ALD patients.

4.2.1. Genome-Based Nutritional Strategy

It may seem obvious that the risk of ALD increases with the amount that is consumed, alcoholic people being the most prone to develop steatosis and even evolve to cirrhosis. However, various genetic and environmental factors are involved that influence the risk of addiction and ALD.⁶⁷ Genetic polymorphisms are biological modulators of the degree in which alcohol can cause liver damage that varies by ethnicity.² On the other hand, alcoholic patients consuming a hepatopathogenic diet, as in the case of the Mexican population, have a high calorie intake due to simple carbohydrates contained in alcoholic beverages, added soft drinks, and salty snacks that elicits the brain reward system. In consequence, alcoholics are at high risk of being overweight or obese. This dietary pattern has been associated with hypertriglyceridemia and early onset of liver cirrhosis in carriers of the FABP2 Thr54 variant⁶⁸ and the APOE ε2 allele,⁶⁹ an allele that is highly prevalent among the Mexican mestizos with Caucasian ancestry. A genome-based nutritional strategy would then consider a more integrative and preventive approach in which the early detection of liver damage is imperative. In general, patients at risk for ALD should follow a diet reduced in saturated fat and simple carbohydrates, rich in antioxidants and fiber, and with sufficient protein intake in agreement with the gene–environment interaction like the proposed regionalized diet as alcohol intake facilitates the progression to cirrhosis associated with changes in gut microbiota composition that positively regulate alcohol metabolic enzymes.⁷⁰ Alcohol abstinence combined with a balanced regionalized diet could provide hepatoprotection and restoration of the gut microbiota as well. Additionally, registering not only the amount of alcohol and the calories derived from alcoholic beverages but also the pattern of consumption including the type of alcoholic beverage would aid to define the regional differences among populations that lead to liver damage. Therefore, each region needs to characterize the population’s genetic and social-cultural background regarding alcohol consumption and its effect on liver health.

4.3. Hepatitis C Virus Infection

Chronic infection with HCV remains one of the leading causes of chronic liver disease globally despite the increasing progress and improvement of direct-acting antiviral drugs (DAAs).⁷¹ The study of the HCV life cycle has revealed that its viral persistence and pathogenesis relies on its ability to interact with a growing number of host factors primarily involved in lipid metabolism and innate immunity. Some of the molecular mechanisms by which HCV interferes and modulates the host lipid metabolism have been described. For example, HCV hijacks the lipoproteins rich in cholesteryl esters and triglycerides (VLDL/LDL) to circulate throughout the bloodstream as a complex named lipoviroparticle (LPV). The apolipoproteins present in these lipoproteins are apoE, apoB, and apoC, their cell receptors (mainly LDLR, CD81, SR-B1, CLDN1, and OCLN), coreceptors, and other cell-binding factors that the LPV co-opts to enter the hepatocyte. Also, the lipid composition of hepatocyte membranes, lipid droplets, and cell transcriptional factors, as well as the enzymes involved in fatty acids and cholesterol biosynthesis (LXR, SREBPs, PPAR-α, FAS, HMG-CoA, DGAT1) has been described. Furthermore, VLDL assembly and secretion pathway is closely associated with the formation and secretion of its virions.⁷²,⁷³ HCV affects the lipid metabolism by enhancing lipogenesis, downregulating fatty acid degradation, and impairing VLDL lipoprotein secretion with a resulting decreased export of cholesterol and beta-lipoproteins. Therefore, HCV favors a lipid-rich intracellular but a lipid-decreased extrahepatic environment to ameliorate its life cycle.⁷⁴ The outcome of the interaction between the virus and the lipid metabolism is observed in the metabolic profile frequently displayed in HCV chronically-infected patients. This profile is characterized by hypocholesterolemia, hypobetalipoproteinemia, and in some cases liver steatosis, insulin resistance, or type 2 diabetes. The development of this metabolic profile is also influenced by host genetic factors (e.g., PNPLA3 rs738409, IL28B rs12980275, and MTTP rs1800803 polymorphism) and viral genetics (genotype 3) favoring the intrahepatic lipid accumulation.⁷⁵,⁷⁶

4.3.1. Genome-Based Nutritional Strategy

Diet is another factor that can directly influence lipid metabolism and even modulate the lipid content of both lipid droplets and cell membranes including hepatocytes. The features of the hepatopathogenic dietary pattern (i.e., the excess of energy intake, high consumption of SFAs, cholesterol, simple carbohydrates such as fructose, and an increased ratio of n-6: n-3 PUFAs) have been associated with insulin resistance, abnormal intrahepatic lipid accumulation, inflammation, fibrosis, and thus the onset and progression of liver.⁷,⁸,⁷⁷,⁷⁸

As these dietary components are capable of interacting and regulating the expression of lipogenic genes, they consequently favor the intrahepatic lipid-rich environment for virus efficient replication. Furthermore, in the context of HCV infection, several studies have found specific dietary elements to enhance RNA replication and have described the plausible mechanisms (Table 1.3). Conversely, some foods or nutrients denoted as anti-HCV nutrients have been identified that interfere with these replication mechanisms, among which are dietary PUFAs (linoleic, arachidonic, docosahexaenoic, and eicosapentaenoic acids), β-carotene, vitamin D2, and gallic acid (Table 1.3).

Hence, a dietary assessment in these groups of patients is crucial to correct the dietary features that stimulate both HCV replication and liver damage. A genome-based nutritional strategy should be endorsed to integrate anti-HCV nutrients according to each population’s genetics, food culture, and available regional foods. Performing an adequate nutritional intervention adjunctive to the antiviral therapy is essential to achieve sustained virological response. Likewise, patients not having access to pharmacological treatment due to the high cost, particularly in low- and middle-income countries,¹ can also benefit from this nutritional genomic therapy at least to prevent or attenuate the liver disease progression.

Table 1.3

CHs, carbohydrates; FAS, fatty acid synthase; IFN, interferon; LXR, liver X receptor; MUFAs, monounsaturated fatty acids; PPAR-α, peroxisome proliferator–activated receptor; RBV, ribavirin; SFAs, saturated fatty acids; SREBP, sterol regulatory element–binding protein; TGs, triglycerides; VLDL, very low–density lipoprotein.

a Strable MS, Ntambi JM. Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit Rev Biochem Mol Biol 2010;45(3):199–214.

b Kapadia SB, Chisari FV. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA 2005;102(7):2561–66.

c Basciano H, Federico K, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab (Lond) 2005;2(1):5.

d Yano M, Ikeda M, Abe K, et al. Comprehensive analysis of the effects of ordinary nutrients on hepatitis C virus RNA replication in cell culture. Antimicrob Agents Chemother 2007;51(6):2016–27.

e Nakamura M, Saito H, Ikeda M, et al. An antioxidant resveratrol significantly enhanced replication of hepatitis C. World J Gastroenterol 2010;16(2):184–92.

f Miyoshi H, Moriya K, Tsutsumi T, et al. Pathogenesis of lipid metabolism disorder in hepatitis C: polyunsaturated fatty acids counteract lipid alterations induced by the core protein. J Hepatol 2011;54(3):432–8.

g Shibata C, Ohno M, Otsuka M, et al. The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels. Virology 2014;462–463:42–8.

h Govea-Salas M, Rivas-Estilla M, Rodríguez-Herrera R, et al. Gallic acid decreases hepatitis C virus expression through its antioxidant capacity. Exp Ther Med 2016;11(2):619–24.

5. Concluding Remarks

• Chronic liver diseases need to be attended by comprehensive medical nutritional therapies.

• Genome-based nutritional strategies are aimed to restore the balance between the ancestral genes and current lifestyle, preferentially as prevention and at early stages of the disease.

• Gene polymorphisms and dietary pattern interactions differ by population, so the correct diet should be tailored accordingly and by etiology of liver disease.

• Dietary interventions for liver-diseased patients should contain regional food ingredients with antioxidant, anti-inflammatory, and antifibrogenic properties.

• The formulation of the specific strategy will depend on the stage of progression of liver disease.

List of Abbreviations

ABCA1   ATP-binding cassette transporter A1

ALD   Alcoholic liver disease

AMY1   Salivary amylase 1 gene

APOE   Apolipoprotein E

CD36   Scavenger receptor class B, member 3

CD81   Cluster of differentiation 81

CHs   Carbohydrates

CLDN1   Claudin-1 receptor

DAAs   Direct-acting antiviral drugs

DGAT1   Diacylglycerol acyltransferase 1

F   Fibrosis

FAS   Fatty acid synthase

GLP-1   Glucose-like peptide 1

GLP-2   Glucose-like peptide 2

GOS   Galacto-oligosaccharides

HCV   Hepatitis C virus

HMG-CoA   3-hydroxy-3-methyl-glutaryl-coenzyme A reductase

IL-1β   Interleukin 1β

IL28B   Interleukin 28B

LCT   Lactase gene

LDL   Low-density lipoprotein

LDLR   Low-density lipoprotein receptor

LVP   Lipoviroparticle

LXR   Liver X receptor

MTHFR   Methylenetetrahydrofolate reductase

MTTP   Microsomal triglyceride transfer protein

MUFAs   Monounsaturated fatty acids

NAFLD   Nonalcoholic fatty liver disease

NASH   Nonalcoholic steatohepatitis

NRCDs   Nutrition-related chronic diseases

OCLN   Occludin receptor

PNPLA3   Patatin-like phospholipase domain containing 3

PPAR-α   Peroxisome proliferator–activated receptor alpha

PUFAs   Polyunsaturated fatty acids

RNA   Ribonucleic acid

SCFAs   Short-chain fatty acids

SFAs   Saturated fatty acids

SR-B1   Scavenger receptor class B type 1

SREBP   Sterol regulatory element–binding protein

TAS1R2   Taste 1 receptor member 2

TAS2R38   Taste 2 receptor member 38

TM6SF2   Transmembrane 6 superfamily member 2

TNFα   Tumor necrosis factor alpha

VLDL   Very low–density lipoprotein

Glossary

Gene–culture coevolution   Gene evolution as a result of cultural evolutionary processes.

Diet-related adaptive gene polymorphisms   Refers to signatures of genetic adaptations related to particular environments or dietary components to which individuals were exposed for thousands of years, namely, as consequence of their gene–culture coevolutionary processes.

Nutrition transition   Changes in the dietary pattern of a population in a short period.

Mestizo(s)   In Mexico, it refers to the population who have inherited Amerindian, European, and African lineages in distinct proportions.

Prebiotics   Include primarily nondigestible fibers, which are selectively fermented by intestinal bacteria, promoting changes in gut bacteria composition and activity.

Probiotics   Live microorganisms that when administered in adequate amounts confer beneficial effects on the host.

Quelites   The endemic leafy green vegetables of Mesoamerica (now Mexico).

References

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