Cirrhosis

Question 1

Cirrhosis is characterized by?

Answer 1

1. It involves the entire liver.
2. The normal lobular architecture of hepatic parenchyma is disorganised.
3. There is formation of nodules separated from one another by irregular bands of fibrosis.
4. It occurs following hepatocellular necrosis of varying etiology so that there are alternate areas of necrosis and regenerative nodules.

Question 2

Cirrhosis; Pathogenesis

Answer 2

Initiated by hepatocellular necrosis.

Fibrogenesis

• Fibrosis in the liver lobules may be portal-central, portal-portal, or both.
• The mechanism of fibrosis is by increased synthesis of all types of collagen and increase in the number of collagen-producing cells.
• In cirrhosis, there is proliferation of fat-storing cells underlying the sinusoidal epithelium which become transformed into myofibroblasts and fibrocytes.

Regenerative Nodule

• Possibly, growth factors, chalones and hormonal imbalance, play a role in regeneration.

Question 3

Cirrhosis; Classsification

Answer 3

1. Micronodular cirrhosis. In micronodular cirrhosis, the nodules are usually regular and small, less than 3 mm in diameter.
2. Macronodular cirrhosis. In this type, the nodules are of variable size and are generally larger than 3 mm in diameter. The pattern of involvement is more irregular than in micronodular cirrhosis.
3. Mixed cirrhosis. In mixed type, some parts of the liver show micronodular appearance while other parts show macronodular pattern.

Question 4

Sequential stages in Alcohol liver disease.

Answer 4

1. Alcoholic Steatosis (fatty liver)
2. Alcoholic hepatitis
3. Alcoholic cirrhosis

Question 5

Ethanol Metabolism

Answer 5

First step:

Ethanol is catabolised to acetaldehyde in the liver by the following three pathways, one major and two minor:

1. In the cytosol, by the major rate-limiting pathway of alcohol dehydrogenase (ADH).
2. In the smooth endoplasmic reticulum, via microsomal P-450 oxidases (also called microsomal ethanol oxidising system, MEOS), where only part of ethanol is metabolised.
3. In the peroxisomes, minor pathway via catalase such as H2O2.
4. Acetaldehyde is toxic and may cause membrane damage and cell necrosis.

Second step:

The second step occurs in the mitochondria where acetaldehyde is converted to acetate with ALDH acting as a co-enzyme. Simultaneously, the same cofactor, NAD, is reduced to NADH resulting in increased NADH: NAD redox ratio which is the basic biochemical alteration occurring during ethanol metabolism.

Question 6

Hepatotoxicity by ethanol metabolites.

Answer 6

1. Production of protein-aldehyde adducts
2. Formation of malon-di-aldehyde-acetaldehyde (MAA) adducts

Question 7

Alcoholic Steatosis (fatty liver)

Answer 7

• The liver is enlarged, yellow, greasy and firm with a smooth and glistening capsule.
• The features consist of initial microvesicular droplets of fat in the hepatocyte cytoplasm followed by more common and pronounced feature of macrovesicular large droplets of fat displacing the nucleus to the periphery.
• Fat cysts may develop due to coalescence and rupture of fat-containing hepatocytes.
• Less often, lipogranulomas consisting of collection of lymphocytes, macrophages and some multinucleate giant cells may be found.

Question 8

Alcoholic Hepatitis

Answer 8

Alcoholic hepatitis develops acutely, usually following a bout of heavy drinking.

M/E:

1. Hepatocellular necrosis
2. Mallory bodies or alcoholic hyalin
3. Inflammatory response
4. Fibrosis

Question 9

Alcoholic Cirrhosis

Answer 9

Alcoholic cirrhosis is the most common form of lesion, constituting 60-70% of all cases of cirrhosis.

Alcoholic cirrhosis classically begins as micronodular cirrhosis (nodules less than 3 mm diameter), the liver being large, fatty and weighing usually above 2 kg.

Eventually over a span of years, the liver shrinks to less than 1 kg in weight, becomes non-fatty, having macronodular cirrhosis (nodules larger than 3 mm in diameter), resembling post-necrotic cirrhosis.

On cut section, spheroidal or angular nodules of fibrous septa are seen.

Question 10

Alcoholic Cirrhosis; Morphology

Answer 10

• Nodular pattern
• Fibrous septa
• Hepatic parenchyma
• Necrosis, inflammation and bile duct proliferation

Question 11

Liver Cirrhosis; lab diagnosis

Answer 11

1. Elevated transaminases: increase in SGOT (AST) is more than that of SGPT (ALT).
2. Rise in serum γ-glutamyl transpeptidase (γ-GT).
3. Elevation in serum alkaline phosphatase.
4. Hyperbilirubinaemia.
5. Hypoproteinaemia with reversal of albumin-globulin ratio.
6. Prolonged prothrombin time and partial thromboplastin time.
7. Anaemia.
8. Neutrophilic leucocytosis in alcoholic hepatitis and in secondary infections.

Question 12

Post-necrotic Cirrhosis

Answer 12

Post-necrotic cirrhosis, also termed post-hepatitic cirrhosis, macronodular cirrhosis and coarsely nodular cirrhosis, is characterised by large and irregular nodules with broad bands of connective tissue and occurring most commonly after previous viral hepatitis.

Question 13

Post-necrotic Cirrhosis; G/A

Answer 13

The liver is usually small, weighing less than 1 kg, having distorted shape with irregular and coarse scars and nodules of varying size.

Sectioned surface shows scars and nodules varying in diameter from 3 mm to a few centimeters.

Question 14

Post-necrotic Cirrhosis; Clinical features

Answer 14

Splenomegaly and hypersplenism are other prominent features.

The results of haematologic and liver function test are similar to those of alcoholic cirrhosis.

Out of the various types of cirrhosis, post-necrotic cirrhosis, especially when related to hepatitis B and C virus infection in early life, is more frequently associated with hepatocellular carcinoma.

Question 15

Biliary Cirrhosis

Answer 15

Biliary cirrhosis is defined as a chronic disorder characterised by clinical, biochemical and morphological features of long-continued cholestasis of intrahepatic or extrahepatic origin.

G/A: In biliary cirrhosis of all types, the liver is initially enlarged and characteristically greenish in appearance, but later becomes smaller, firmer and coarsely micronodular

Question 16

Primary biliary cirrhosis; Etiology

Answer 16

1. Endocrine origin
2. Familial incidence
3. Elevated cholestrol
4. Autoimmune origin

Question 17

Secondary biliary cirrhosis; Etiology

Answer 17

1. Extrahepatic cholelithiasis, most common
2. Biliary atresia
3. Cancer of biliary tree and of head of pancreas
4. Postoperative strictures with superimposed ascending cholangitis.

Question 18

Pigment Cirrhosis in Haemochromatosis

Answer 18

1. Haemochromatosis is an iron-storage disorder in which there is excessive accumulation of iron in parenchymal cells with eventual tissue damage and functional insufficiency of organs such as the liver, pancreas, heart and pituitary gland.
2. The condition is characterised by a triad of features— micronodular pigment cirrhosis, diabetes mellitus and skin pigmentation.
3. On the basis of the last two features, the disease has also come to be termed as ‘bronze diabetes’.

Question 19

Haemochromatosis exists in 2 main forms:

Answer 19

1. Idiopathic (primary, genetic) haemochromatosis is an autosomal recessive disorder of excessive accumulation of iron. It is associated with overexpression of HFE gene located on chromosome 6 close to the HLA gene locus, and normally regulates intestinal absorption of iron.
2. Secondary (acquired) haemochromatosis is gross iron overload with tissue injury arising secondary to other diseases such as thalassaemia, sideroblastic anaemias, alcoholic cirrhosis or multiple transfusions.

Question 20

Cirrhosis in Wilson’s Disease

Answer 20

Wilson’s disease, also termed by a more descriptive designation of hepatolenticular degeneration, is an autosomal recessive inherited disease of copper metabolism, characterised by toxic accumulation of copper in many tissues, chiefly the liver, brain and eye.

These accumulations lead to the triad of features:

1. Cirhosis of the liver.
2. Bilateral degeneration of the basal ganglia of the brain.
3. Greenish-brown pigmented rings in the periphery of the cornea (Kayser-Fleischer rings).

Question 21

The underlying defect in chromosome 13 is a mutation in ATP7B gene, the normal hepatic copper-excreting gene.

Biochemical abnormalities in Wilson’s disease include the following:

Answer 21

1. Decreased serum ceruloplasmin
2. Increased hepatic copper
3. Increased urinary excretion of copper.
4. However, serum copper levels are of no diagnostic help and may vary from low-to-normal-to-high depending upon the stage of disease.

Question 22

Cirrhosis in Wilson’s disease; Morphology

Answer 22

Copper is usually deposited in the periportal hepatocytes in the form of reddish granules in the cytoplasm or as reddish cytoplasmic coloration, stainable by rubeanic acid or rhodamine stains for copper.

Involvement of basal ganglia in the brain is seen in the form of toxic injury to neurons.

In the cornea as greenish-brown deposits of copper in Descemet’s membrane.

In the kidney as fatty and hydropic change.

Question 23

Cirrhosis in α-1-Antitrypsin Deficiency

Answer 23

• Alpha-1-antitrypsin deficiency is an autosomal codominant condition in which the homozygous state produces liver disease (cirrhosis), pulmonary disease (emphysema), or both.
• Out of 24 different alleles labelled alphabetically, PiMM is the most common normal phenotype, while the most frequent abnormal phenotype in α-1-antitrypsin deficiency leading to liver and/or lung disease is PiZZ in homozygote form.

Question 24

Cardiac Cirrhosis

Answer 24

Cardiac cirrhosis is an uncommon complication of severe right-sided congestive heart failure of long-standing duration. The common causes culminating in cardiac cirrhosis are cor pulmonale, tricuspid insufficiency or constrictive pericarditis.

G/A The liver is enlarged and firm with stretched Glisson’s capsule.

M/E In acute stage, the hepatic sinusoids are dilated and congested with haemorrhagic necrosis of centrilobular hepatocytes (central haemorrhagic necrosis). Severe and more prolonged heart failure results in delicate fibrous strands radiating from the central veins. These fibrous strands may form interconnections leading to cardiac cirrhosis and regenerative nodules.

Question 25

Indian Childhood Cirrhosis

Answer 25

Indian childhood cirrhosis (ICC) is an unusual form of cirrhosis seen in children between the age of 6 months and 3 years in rural, middle class, Hindus in India and in parts of South-East Asia and in the Middle-East.

Type II is the most common

There is significant deposition of copper and copper-associated proteins in hepatocytes, often more than what is seen in Wilson’s disease.

Question 26

Cirrhosis in Autoimmune Hepatitis

Answer 26

Autoimmune hepatitis (also called lupoid hepatitis) is a form of chronic hepatitis characterised by continued hepatocellular injury, inflammation and fibrosis which may progress to cirrhosis. The condition may run a variable natural history rangingfrom indolent to severe rapid course.

Question 27

Cirrhosis in Non-alcoholic Steatohepatitis

Answer 27

Non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD) is a from of hepatitis resembling alcoholic liver disease but seen in nondrinkers of alcohol.

The condition is seen more commonly in affluent western socieities, has a strong association with obesity, dyslipidaemia and type 2 diabetes mellitus.

It is seen in youger patients with equal gender prevalence.

Question 28

Non-cirrhotic portal fibrosis (NCPF)

Answer 28

Non-cirrhotic portal fibrosis (NCPF) is a group of congenital and acquired diseases in which there is localised or generalised hepatic fibrosis without nodular regenerative activity and there is absence of clinical and functional evidence of cirrhosis.

One of the types associated with increased portal fibrosis without definite cirrhosis is seen in idiopathic (primary) portal hypertension with splenomegaly, reported from India and Japan.

The type common in India, particularly in young males, is related to chronic arsenic ingestion in drinking water and intake of orthodox medicines.

M/E; The features are:

• Standing out of portal tracts due to their increased amount of fibrous tissue in triad without significant inflammation.
• Obliterative sclerosis of portal vein branches in the portal tracts (obliterative portovenopathy).