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

• HBV + HDV

• HAV

• HEV

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 parts of central Asia eastern and southern Europe

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 (Wilson’s 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

• Wilson’s 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 (腹疝）

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: gram’s 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 α-fetoprotein (α-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 Raynaud’s phenomen

sclerodactyly telangiectasis

skin hyperpigmentation

• Elevated AKP, IgM, antimitochondrial antibody

Wilson’s 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 Range ScoreNeuropathy None 1

I, II 2 III, IV 3

Ascite None 1

Mild 2 Massive 3

Serum bilirubin <2 1

(mg / dl) 2~3 2 >3 3

Serum albumin >3.5 1

(g / dl) 2.8~3.5 2 <2.8 3

Ratio of prothrombin time activity >50 1

30~50 2 <30 3

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 Treatment

Virus hepatitis ? Antivirals

Schistosomiasis Praziquantel 60~80mg/kg for 2 days

Alcohol Abstention

Iron overload Vensection. Deferoxamine 0.5~1g/kg

Copper overload penicillamine 0.8~1.2 g/day

α1 antitrypsin deficiency ? Transplant

Tyrosinaemia Withdraw dietary tyrosine

Galactosaemia Withdraw milk and milk products

Cholestasis Relieve biliary obstruction

Budd-Chiari syndrome Relieve main venous block

Immunological factors Prednison or predisolon 20~60 mg/day

Toxins and drugs Identify and stop

Cryptogenic ---

Antifibrotic drugs

• Penicillamine

Primary biliary cirrhosis

Wilson’s 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

Distal diuretic

Na+ K Spironolactone

Triamterene

Amiloride

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

beta-adrenergic blockade

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)