Cirrhosis of the liver

Definition
Cirrhosis is a common chronic, progressive and diffusive liver disease, caused by one or several agents act repeatedly and persistently.
Histologically, cirrhosis is an irreversible alteration of the liver architecture, consisting of hepatic fibrosis and areas of nodular regeneration

Epidemiology

Worldwide major heath problem Over 500,000 deaths per year Over 20% were latent 2 ~ 10% in postmortem examination Common and death leading disease in China

Etiology and pathogenesis

Viral hepatitis Parasites (schistosomiasis) Alcoholic liver disease Cholestasis Hepatic-Venous outflow obstruction Toxicant and drugs Metabolic abnormality Malnutrition Cryptogenic cirrhosis

Viral hepatitis
HBV HCV HAV HEV

HBV + HDV

Viral hepatitis (HBV)

Global prevalence: >300 million carriers
5% world population

Varies widely High prevalence:

8% ~ 15%

Far East (southeast Asia China Philippines Indonesia) Middle East Africa parts of South America

Intermediate prevalence: 2% ~ 7%
Japan parts of south America eastern and southern Europe parts of central Asia

Low prevalence: <2%

US Canada northern Europe Australia

Viral hepatitis
Elimination of viral infected hepatocytes is dependent on
recognition of viral determinants in association with HLA proteins on the infected hepatocytes by cytotoxic T cells.

HLA protein display is modulated by exposure to

interferon and cytotoxic T cell, NK lytic processes.

During chronic HBV infection, infected liver cells failed to

induce IFN. Therefore, viral protein synthesis is not decreased, HLA protein display is not enhanced.

Parasites (Schistosomiasis)
Ova deposited in the portal zones Exciting a fibrous tissue reaction

Co-existence of malaria and cirrhosis reflects malnutrition, viral hepatitis and toxic factors

Alcoholic liver disease

1/3 cause of cirrhosis in Western country Most important factor: threshold dose: 600 Kg (men) 150~300 Kg (women) average daily consumption of alcohol > 40 ~ 80 g/D, over 10 ~ 15 years Liver: primary site of ethanol metabolism Ethanol can be oxidized by three enzymes systems ADH CYP2E1 catalase

Alcoholic liver disease

Mechanism
Direct effect by ethanol, or its first metabolite (acetaldehyde redox shift oxidant stress) Cell-mediated immune

Three histopathologic lesion:

fatty liver, alcoholic hepatitis, cirrhosis

Biliary cirrhosis
Primary Biliary Cirrhosis: Progressive destruction of small and intrahepatic bile ducts Prevalence: 40~150 cases/million Women >90 of cases 50y Abnormal immunoregulation Associated with HLA phenotyeps

Biliary cirrhosis
Secondary biliary cirrhosis: Obstruction of the biliary tree, further divided into two groups intra-hepatic and extra-hepatic obstruction

Hepatic-Venous outflow obstruction

Veno-occlusive disease
Budd-chiari syndrome Constrictive pericarditis Chronic congestive heart failure

Toxicant and drugs

Tetrachloride carbon

- methyldopa Tetracycline Phosphorus Arsenic

Metabolic abnormality
Iron storage disease (Hemochromatosis)

Copper storage disease (Wilsons disease)

Malnutrition
Chronic inflammatory bowel disease

Prolonged lack of dietary proteins and vitamins

Cryptogenic cirrhosis
Etiology is unknown

Viral infection are suscepted in some cases

Pathophysiology
Alcoholic cirrhosis accumulation of fat and scar formation in the liver cells Postnecrotic cirrhosis broad bands of scar tissue resulted from viral, toxic, or autoimmune hepatitis Biliary cirrhosis diffuse fibrosis with jaundice from chronic biliary obstruction Cardiac cirrhosis from long-standing right sided heart failure

Pathology and classification

Histopathological diagnosis: Excessive fibrous tissue Regenerating nodules Complete distortion of the normal relationship of hepatic venous outflow radicles and portal veins.

Anatomical types of regenerating nodules

Micronodular

Macronodular Mixed cirrhosis

Micronodular cirrhosis
Features: Thick regular septa Regenerating small nodules (<3mm) Involvement of every lobule

Alcoholism Malnutrition Biliary obstruction Hemochromatosis Venous outflow obstruction

Macronodular cirrhosis
Features: Septa Nodules of variable size (>3mm, even 1~ 3 cm) Normal lobules in the large nodules

Two subtypes: postnecrotic posthepatitic

Macronodular cirrhosis
Postnecrotic type: Coarsely scarred liver Large nodules surrounded by broad fibrous septa Clumping togathered numerous portal trials

Toxic cirrhosis Cryptogenic cirrhosis Multilobular cirrhosis

Macronodular cirrhosis
Posthepatitic type: Macronodules separated by slender fibrous strands Connect individual portal areas to each other Viral hepatitis Wilsons disease

Mixed cirrhosis
Features:
Presenting both micro- and macronodules

From micronodules to macronodules

Alcoholism Antitrypsin deficiency

Some aspects of pathology

The most useful morphologic classification: gross appearance of the liver The morphologic diagnosis of cirrhosis is more reliable than the histopathological diagnosis Schistosomiasis: incomplete septal cirrhosis coarse portal fibrosis Initially enlarged/subsequcetly shrinks

Clinical manifestation
Onset: Cryptical and slowly progressive Majority: 3~5 years or 10 years Minority: 3~6 months

Stages: Compensated Decompensated

Compensated stage
Fatigue Loss of appetite Anorexia Abdominal discomfort Abdominal pain
Hepatomegaly (slightly or moderately) Splenomegaly

Decompensated stage
Deterioration of liver function

Feature of portal hypertention

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Deterioration of liver function

General deterioration
Deterioration of heath, anorexia, weight loss, weakness, fatigue, Flatulent dyspepsia, abdominal distress, swelling of legs or abdomen, mild fever, loss of libido and hemorrhage.

Findings of physical examination Jaundice Dermatological and sexual signs Liver (enlarge or shrunken)

Jaundice

It always implies liver cell destruction exceeds the capacity for regeneration

Dermatologic and sexual signs

Skin pigmentation Clubbing fingers Spider angioma Liver palms (palmar erythema) Purpura Spontaneous bruising / epistaxes

Dermatologic and sexual signs

Feminization and hypogonadism
Gynecomastia testicular atrophy sparse body hair changes in hair distribution menstrual irregularities Mechanism: serum testosterone estrogens

Liver
Early stage Enlarged and palpable firm regular edge a fine to coarsely nodular surface Later stage Shrunk and impalpable

Features of portal hypertension

Portal-systemic collaterals Ascites

Splenomegaly

Anatomy and physiology of portal venous system

Begins in the capillaries of the intestines Terminates in the hepatic sinusoids Formed by the confluence of the superior and inferior mesenteric veins and splenic vein Liver receives 1500ml/min, 2/3 from portal vein Hepatic artery provides 50% oxygen The pressure within the sinusoids is low Lack of valves ***: Between the splanchnic venules and the heart

Portal-systemic collaterals
Esophageal and gastric varices

Dilation of the remnant of the umbilical vein

Dilation of abdominal veins Hemorrhoidial venous collaterals

Splenomegaly
Slightly or moderatory enlarged

Hypersplenism Leukopenia Thrombocytopenia Anemia

Ascites
Prominent feature of portal-hypertension
70% of patients are positive An early sign in presinusoidal portal hypertension relative late in intrahepatic portal hypertension Massive ascites: abdominal herniae
(

Complications
Upper gastrointestinal bleeding Hepatic encephalopathy Infection Hepatorenal syndrome Primary liver cancer Imbalance of electrolytes and acid-alkaline

Upper gastrointestinal bleeding

Major complication

Incredible high mortality Source of bleeding: esophageal varices 60%~80% gastric varices 7% congestive gastropathy 5%~20% (paptic ulcer, acute erosive gastritis etc)

Hepatic encephalopathy

The most severe and deadly complications

Infection
Increased risk for bacterial infection
pneumonia biliary infection E.coli infection and spontaneous bacterial peritonitis (SBP)

SBP
Pathogen of SBP: grams negative bacteria
Features of SBP:
fever, abdominal pain or tenderness

decreased bowel sounds

Suspected patients: sudden onset of HE or hypotension Diagnosis:

elevated ascites fluid white blood cells positive ascitic fluid culture

Hepatorenal syndrome
Decreased renal function due to severe liver disease Histologically normal kidney Involved factors Sympathetic nervous system Renin-angiotensin-aldosterone Prostaglandins Endotoxemia Others ( vasopressin , leukotriene etc)

Primary liver cancer

Suspected signs Hepatomegaly within short time Persistent abdominal pain Enlarged liver with uneven surface or mass Bloody ascites Serum -fetoprotein (-FP) 70%

Imbalance of electrolytes and acid-alkaline

Hyponatraemia Hypokalaemia

Metabolic alkalosis

Laboratory and other tests

Urine Serum Hematology Ultrasonograply Barium esophagogram Endoscopy Liver biopsy

Diagnosis
Patients with a history of viral hepatitis, prolonged alcohol overconsumption, schistosome infection, hemochromatosis Features of deterioration of liver function and portal hypertension Enlarged or shrunk liver with nodular surface Abnormal liver function tests Liver biopsy shows widespread fibrosis with nodular regeneration

Complete diagnosis

Etiology Morphology Hepatic function

Specific clinical clues to etiology of cirrhosis

Posthepatitic cirrhosis
Previous acute hepatitis, transfusion, illicit drugs
Multiorgan involment such as rash, arthritis, thyroiditis, colitis etc. Serum HBV or HCV positive Some markers of hepatitis, elevated gamma globulin or positive anti-nuclear antibodies.

Schistosomiasis
Contacting with fresh water contaminated with cercariae in epidemic area Splenomegaly being the earliest and most prominent sign Bleeding from esophageal varices may be the initial clinical presentation Liver function is relatively good

Alcoholic cirrhosis
Alcoholic beverage consumption >40~80 g for over 10 years Large parotid, myopathy, neuropathy, contraction of the palmar fascia sGOT > sGPT, sGOT/sGPT ratio>2 Polymorpho-nuclear leukocytosis

Primary biliary cirrhosis

Female (90%), middle age (40~60y), Pruritus before icterus Xanthomas Raynauds phenomen sclerodactyly telangiectasis skin hyperpigmentation Elevated AKP, IgM, antimitochondrial antibody

Wilsons disease
Family history of liver or neurologic disease Childhood onset Kayser-Fleischer corneal rings Grossly flapping tremor, spastic gait, other CNS disorder, osteochondritis Low serum ceruloplasmin

Hemochromatosis
Positive family history

Skin pigmentation, diabetes, pseudogout, cardiomyopathy, loss of body hair, testicular atrophy Elevated serum ferritin

Hepatic function (Child-Pugh score)

Index
Neuropathy

Range
None I, II III, IV None Mild Massive

Score
1 2 3 1 2 3

Ascite

Serum bilirubin
(mg / dl)

<2 2~3 >3

>3.5 2.8~3.5 <2.8 >50 30~50 <30

1 2 3
1 2 3 1 2 3

Serum albumin
(g / dl)

Ratio of prothrombin time activity

A: 5~8 scores;

B: 9~11 scores;

C: 12~15 scores

Differential diagnosis
Hepatomegaly
Ascites Complications Upper GI bleeding Hepatic encephalopathy Hepatorenal syndrome

Hepatomegaly
Chronic hepatitis
Primary liver cancer Parasitization Hemologic diseases (leukemia, lymphoma)

Metabolic diseases

Ascites
Tuberculous peritonitis Constrictive pericarditis

Chronic glumerulonephritis
Intraperitoneal tumors

Upper GI bleeding
Peptic ulcer, acute erosive gastritis, gastric cancer

and esophageal varices are four major sources of upper GI bleeding

In cirrhotic patients, bleeding are not entirely due

to varices

Hepatic encephalopathy
Hypoglycemia Uremia

Diabetic ketoacidosis Nonketonic hyperosmolar syndrome

Hepatorenal syndrome
Prerenal azotemia Acute tubular necrosis Drug nephrotoxicity Diagnosis is supported by avid urinary sodium retention Urine sodium concentration < 5 mmol / L unremarkable urinary sediment

Treatment
Supportive therapy Eliminating the specific causes Using antifibrotic drugs Management of ascites Management of complications Liver transplantation

Supportive therapy
Appropriate rest
1g protein/kg, 2000 Calories daily Vitamin(s), thiamine, vitamin K, iron and folic acid

Removal of exogenous aggravating agents

liver tonics, offending drugs control of infection and electrolyte

Correction of hypoalbuminemia and coagulation

fresh frozen plasma, platelet concentrates or prothrombin complex

Etiology and definitive treatment of cirrhosis

Etiology Virus hepatitis Schistosomiasis Alcohol Iron overload Copper overload 1 antitrypsin deficiency Tyrosinaemia Galactosaemia Cholestasis Budd-Chiari syndrome Immunological factors Toxins and drugs Cryptogenic Treatment ? Antivirals Praziquantel 60~80mg/kg for 2 days Abstention Vensection. Deferoxamine 0.5~1g/kg penicillamine 0.8~1.2 g/day ? Transplant Withdraw dietary tyrosine Withdraw milk and milk products Relieve biliary obstruction Relieve main venous block Prednison or predisolon 20~60 mg/day Identify and stop ---

Antifibrotic drugs
Penicillamine Primary biliary cirrhosis Wilsons disease Inhibiting the formation of cross-links of collagen
Colchicine

Inhibiting assembly of collagen Increasing collagenase production

Management of ascites
Ascites with severe, acute liver disease Improvement of liver function Ascites with stable or steadily worsening liver function Maximal reabsorption rate: 700~900 ml/day Goal of management:
weight loss < 1.0kg/day (ascites + peripheral edema) weight loss < 0.5kg/day (ascites)

Management of ascites
Sodium restriction Fluid restriction Diuresis Paracentesis Side-to-side portacaval shunt Peritoneovenous shunt Transjugular intrahepatic portosystemic shunts (TIPS)

Sodium restriction
1g sodium retaines 200 ml fluid > 0.75 g will result in ascites in cirrhotic patients < 0.5 g/d (22 mEg), restricted in patients without ascites

Strict bed rest improving renal clearance in the supine position

Fluid restriction

1000 ml/day

Diuresis
If sodium restriction are failed Diuretic for ascites
Urine loss loop diuretic Na++

K++

Furosemide Bumetamide Spironolactone Triamterene Amiloride

Distal diuretic Na+

Diuresis
Drugs of choice: Spironolactone Inhibiting aldosterone synthesis Causing natriuresis with sparing potassium 100mg~400mg/d may induce diuresis
Furosemide and/or thiazides

both natriuresis and potassium wasting Spironolactone(distal diuretic)+Furosemide(loop diuretic) sufficient to initial diuresis

Paracentesis
Paracentesis of 1~2 L of ascitic fluid

effective, less costly

Albumin or plasma infusion

expensive
Ascites reinfusion

inexpensive for refractory or massive ascites

Portal-systemic shunts
Side-to-side portacaval shunts

Peritoneovenous shunts (Le Veen shunt)

Transjugular intrahepatic portosystemic shunts (TIPS)

Management of complications
Variceal bleeding: General managements
maintain intravascular volum close monitoring blood pressure, urine output and mental status

Medical managements
use of vasoconstrictors (vasopression or somatostatin) sclerotherapy band ligation

Management of complications
Spontaneous bacterial peritonitis:
Empirical therapy with cefotoxanine or ampicillin

and an aminoglycoside Specific antibiotic therapy are selected 10~14 days duration Recurrent episodes are high

Management of complications

Hepatic encephalopathy Hepatorenal syndrome

Treatment is usually unsuccessful

Liver transplantation
Latest advance in management of cirrhosis

Frequently done in Western country

Summary
Definition fibrosis + nodular regeneration Viral hepatitis (China) alcohol (Western Country) Micro- , Macro- and mixed cirrhosis Decompensated stage: Deterioration of liver function Portal hypertension Complications Hepatic function: Child-Pugh score Sodium, fluid restriction, diuresis (Spirolactone)