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

HAV

HCV

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

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

connection.lww.com/ Products/morton/Ch41.asp

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

Range

Neuropathy

None
I, II
III, IV

1
2
3

Ascite

None
Mild
Massive

1
2
3

Serum bilirubin

<2
2~3
>3

1
2
3

>3.5
2.8~3.5
<2.8

1
2
3

(mg / dl)

Serum albumin
(g / dl)

Ratio of prothrombin time activity

A: 5~8 scores;

Score

>50
30~50
<30

B: 9~11 scores;

1
2
3

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++

Distal diuretic
Na+

Furosemide
Bumetamide
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

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)