Biliary Cirrhosis – Symptoms and Causes

Biliary Cirrhosis

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

1. Primary biliary cirrhosis in which the destructive process of unknown aetiology affects intrahepatic bile ducts.
2. Secondary biliary cirrhosis results from prolonged mechanical obstruction of the extrahepatic biliary passages.
3. Primary sclerosing cholangitis and autoimmune cholangiopathy causing biliary cirrhosis.

Biliary cirrhosis Etiology The aetiology of these forms of biliary cirrhosis is distinctive:

Read And Learn More: Systemic Pathology Notes

1. Primary biliary cirrhosis The aetiology of this type remains unknown. However, a few factors have been implicated:

1. The condition is predominant in middle-aged women (male: female ratio = 1:9) and has led to the suggestion of a possible endocrine origin.
2. Familial incidence has been observed which suggests the role of some genetic influence and certain HLA types.
3. There is an elevated cholesterol level with the appearance of xanthoma and xanthelasma. Hepatomegaly and chronic liver disease are late features of the disease.
4. However, presently the most widely accepted hypothesis is the autoimmune origin of the disease.

In support are the following observations:

1. increased incidence of associated autoimmune diseases (for example. scleroderma, Sjögren’s syndrome, CREST syndrome, and autoimmune thyroiditis),
2. circulating anti-mitochondrial antibody of IgG class detected in more than 90% of cases;
3. elevated levels of immunoglobulins, particularly of IgM;
4. increased levels of circulating immune complexes;
5. decreased the number of circulating T-cells; and
6. accumulation of T-cells around bile ducts.

2. Secondary biliary cirrhosis: Most cases of secondary biliary cirrhosis result from prolonged obstruction of extrahepatic biliary passages. These causes include the following:

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

3. Cirrhosis due to primary sclerosing cholangitis: Primary or idiopathic sclerosing cholangitis is a chronic cholestatic syndrome of unknown aetiology.

• It is characterised by progressive, inflammatory, sclerosing and obliterative processes affecting the entire biliary passages, both extrahepatic and intrahepatic ducts.
• Although aetiology remains unknown, various mechanisms have been postulated which include viral and bacterial infections, immunologic injury, toxins, and genetic predisposition.
• Morphologic Features: Grossly, in biliary cirrhosis of all types, the liver is initially enlarged and characteristically greenish in appearance, but later becomes smaller, firmer and coarsely micronodular In cirrhosis due to primary sclerosing cholangitis, there is characteristic beading of intra- and extrahepatic bile ducts due to irregular strictures and dilatation.

Microscopically, the features of intra and extrahepatic cholestasis correspond to primary and secondary biliary cirrhosis respectively discussed. The salient features of various forms of biliary cirrhosis are as under.

1. Primary biliary cirrhosis: The diagnostic histologic feature is chronic, non-suppurative, destructive cholangitis involving intrahepatic bile ducts. The disease evolves through the following 4 histologic states

• Stage 1 There are florid bile duct lesions confined to portal tracts. The changes in the affected area consist of the destruction of bile ducts, the presence of bile plugs, infiltration with acute and chronic inflammatory cells and sometimes the formation of granulomas and lymphoid follicles.
• Stage 2 There is ductular proliferation. The ductal involvement is quite widespread with very few normal bile ducts.
• The inflammatory infiltrate to extends beyond the portal tracts into the surrounding hepatic parenchyma. Periportal Mallory bodies may be present.
• Stage 3 This stage is characterised by fibrous scarring interconnecting the portal areas. There is diminished inflammatory infiltrate and a reduced number of bile ducts.
• Stage 4 Well-formed micronodular pattern of cirrhosis develops in a period of a few years.

2. Secondary biliary cirrhosis: Prolonged obstruction of extrahepatic bile ducts may produce the following histologic changes:

1. Bile stasis, degeneration and focal areas of centrilobular necrosis of hepatocytes.
2. Proliferation, dilatation and rupture of bile ductules in the portal area with the formation of bile lakes.
3. Cholangitis, sterile or pyogenic, with an accumulation of polymorphs around the bile ducts.
4. The progressive expansion of the portal tract by fibrosis and evolution into micronodular cirrhosis.

3. Cirrhosis due to primary sclerosing cholangitis Following changes are seen:

1. Fibrosing cholangitis with lymphocytic infiltrate around bile ducts with segmental involvement.
2. Periductal fibrosis with eventual obliteration of the lumen of affected bile ducts.
3. Intervening bile ducts are dilated, tortuous and inflamed.
4. Late cases show cholestasis and a full-blown picture of biliary cirrhosis.

Primary Sclerosing Cholangitis Clinical Features: Clinical features of the three types of biliary cirrhosis are variable

• Primary biliary cirrhosis may remain asymptomatic for months to years. Symptoms develop insidiously. Basically, it is a cholestatic disorder.
• The patients present with persistent pruritus, dark urine, pale stools, steatorrhoea, jaundice and skin pigmentation. The earliest laboratory finding is a markedly elevated serum alkaline phosphatase level.
• Elevation of serum lipids is accompanied by the appearance of periorbital xanthelasma and xanthomas over joints.
• Death usually results from hepatic failure, variceal bleeding, intercurrent infections and the concomitant development of cancers of the liver and breast.

• Diagnosis of secondary biliary cirrhosis is considered in patients with a previous history of gallstones, biliary tract surgery or clinical features of ascending cholangitis.
• Patients of primary sclerosing cholangitis may remain asymptomatic or may show features of cholestatic jaundice (raised alkaline phosphatase, pruritus, fatigue).
• Late cases show manifestations of chronic liver disease. The disease occurs in 3rd to 5th decade of life with twofold preponderance in males.
• Contrasting features of three main types of intrahepatic disorders leading to biliary cirrhosis
  are summarized in.

Pigment Cirrhosis in Haemochromatosis

• 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.
• The condition is characterised by a triad of features micronodular pigment cirrhosis, diabetes mellitus and skin pigmentation.
• On the basis of the last two features, the disease has also come to be termed ‘bronze diabetes’.
• Males predominate and manifest earlier since women have physiologic iron loss delaying the effects of excessive accumulation of iron. Haemochromatosis exists in 2 main forms
• Idiopathic (primary, genetic) haemochromatosis is an autosomal recessive disorder of excessive accumulation of iron.
  • It is associated with overexpression of the HFE gene located on chromosome 6 close to the HLA gene locus and normally regulates intestinal absorption of iron.
  • Mutated (overexpressed) HFE gene complexes with transferrin receptors on intestinal crypt epithelial cells and results in excessive absorption of dietary iron throughout life.
• 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.

Etiopathogenesis: A general discussion of iron metabolism and iron excess states is given on.

• Normally, the body’s iron content is 3-4 gm which is maintained in such a way that intestinal mucosal absorption of iron is equal to its loss. This amount is approximately 1 mg/day in men and 1.5 mg/day in menstruating women.
• In haemochromatosis, however, this amount goes up to 4 mg/day or more, as evidenced by elevated serum iron (normal about 125 mg/dl) and increased serum transferrin saturation (normal 30%).

In idiopathic or hereditary haemochromatosis, the primary mechanism of disease appears to be the genetic basis in which the defect may either lie at the intestinal mucosal level causing excessive iron absorption, or at the post-absorption excretion level leading to excessive accumulation of iron.

• The excess iron in primary haemochromatosis is deposited mainly in the cytoplasm of parenchymal cells of organs such as the liver, pancreas, spleen, heart and endocrine glands.
• Tissue injury results from iron-laden lysosomes of parenchymal cells and lipid peroxidation of cell organelles by excess iron.
• In secondary or acquired haemochromatosis, there is excessive accumulation of iron due to acquired causes like ineffective erythropoiesis, defective haemoglobin synthesis, multiple blood transfusions and enhanced absorption of iron due to alcohol consumption.
• The last-named phenomenon is called African iron overload in individuals of African descent who have a gene, ferroportin, that predisposes them for iron overload (earlier called Bantu siderosis affecting South African Bantu tribals who consume large quantities of home-brew prepared in iron vessels).
• Cases of secondary haemochromatosis have increased iron storage within the reticuloendothelial system and liver. However, the magnitude of the iron excess in secondary haemochromatosis is generally insufficient to cause tissue damage.

Morphologic Features: Excessive deposition of iron in organs and tissues is ferritin and haemosiderin, both of which appear as golden-yellow pigment granules in the cytoplasm of affected parenchymal cells and haemosiderin stains positively with Prussian blue reaction.

• The organs most frequently affected are the liver and pancreas, and to a lesser extent, the heart, endocrine glands, skin, synovium and testis.
• In the liver, excess pigment accumulates in the hepatocytes, and less often Kupffer cells and in bile duct epithelium.
• The deposits in the initial stage may be prominent in the periportal liver cells along with increased fibrosis in the portal zone. Eventually, micronodular cirrhosis develops.
• The deposits may produce a grossly chocolate-brown colour of the liver and nodular surface.
• In the pancreas, pigmentation is less intense and is found in the acinar and islet cells. The deposits in the pancreas produce diffuse interstitial fibrosis and atrophy of parenchymal cells leading to the occurrence of diabetes mellitus.

Clinical Features The major clinical manifestations of haemochromatosis include skin pigmentation, diabetes mellitus, hepatic and cardiac dysfunction, arthropathy and hypogonadism.

• Characteristic bronze pigmentation is the presenting feature in about 90% of cases.
• Demonstration of excessive parenchymal iron stores is possible by measurement of serum iron, determination of per cent saturation of transferrin, measurement of serum ferritin concentration, estimation of charitable iron stores using a chelating agent (for example desferrioxamine), and finally, by liver biopsy.
• The occurrence of hepatocellular carcinoma is a late complication of haemochromatosis-induced cirrhosis.

Cirrhosis in Wilson’s Disease

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

These accumulations lead to the triad of features:

1. Cirrhosis 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).

• • The disease manifests predominantly in children and young adults (5-30 years).
  • Initially, the clinical manifestations are referable to liver involvement such as jaundice and hepatomegaly (hepatic form) but later progressive neuropsychiatric changes and Kayser-Fleischer rings in the cornea appear.

Pathogenesis: The pathogenesis of Wilson’s disease is best understood when compared
with normal copper metabolism.

• Normally, dietary copper is more than the body’s requirement.
• Excess copper so absorbed through the stomach and duodenum is transported to the liver where it is incorporated into α2- globulin to form ceruloplasmin, which is excreted by the liver via bile normally.
• Most of the plasma copper circulates as ceruloplasmin. Only a minute amount of copper is excreted in the urine normally.
• In Wilson’s disease, the initial steps of dietary absorption and transport of copper to the liver are normal but copper accumulates in the liver rather than being excreted by the liver.
• The underlying defect in chromosome 13 is a mutation in the ATP7B gene, the normal hepatic copperexcreting gene.
• Eventually, the capacity of hepatocytes to store copper is exceeded and copper is released into circulation which then gets deposited in extrahepatic tissues such as the brain, eyes and others.
• However, increased copper in the kidney does not produce any serious renal dysfunction.

Biochemical abnormalities in Wilson’s disease include the following:

1. Decreased serum ceruloplasmin (due to impaired synthesis of apo ceruloplasmin in the damaged liver and defective mobilisation of copper from hepatocellular lysosomes).
2. Increased hepatic copper in liver biopsy (due to excessive accumulation of copper in the liver).
3. Increased urinary excretion of copper.
4. However, serum copper level estimation is of no diagnostic help and may vary from low-tonormal-to-high depending upon the stage of the disease.

Morphologic Features: The liver shows varying grades of changes that include fatty change, acute and chronic active hepatitis, submassive liver necrosis and macronodular cirrhosis. Mallory bodies are present in some cases.

• Copper is usually deposited in the periportal hepatocytes in the form of reddish granules in the cytoplasm or as reddish cytoplasmic colouration, 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, and in the kidney as fatty and hydropic change.

Cirrhosis in α-1-Antitrypsin Deficiency

• Alpha-1-antitrypsin deficiency is an autosomal codominant condition in which the homozygous state produces liver disease (cirrhosis), pulmonary disease (emphysema), or both.
• α-1-antitrypsin is a glycoprotein normally synthesised in the rough endoplasmic reticulum of the hepatocytes and is the most potent protease inhibitor (Pi).
• A single autosomal dominant gene coding for α-1-antitrypsin is located on the long arm of chromosome 14 that codes for immunoglobulin light chains too.
• 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.
• Other phenotypes in which liver disease occurs are PiSS and Pi-null in which serum α-1-antitrypsin value is nearly totally deficient.
• In intermediate phenotypes, PiMZ and PiSZ persons are predisposed to develop hepatocellular carcinoma.
• The patients may present with respiratory disease due to the development of emphysema or may develop liver dysfunction, or both.
• At birth or in neonates, the features of cholestatic jaundice of varying severity may appear. In adolescence, the condition may evolve into hepatitis or cirrhosis which is usually well compensated.

Morphologic Features: Pulmonary changes in α-1-antitrypsin deficiency in the form of emphysema are described. The hepatic changes vary according to the age at which the deficiency becomes apparent.

• At birth or in neonates, the histologic features consist of neonatal hepatitis that may be acute or ‘pure’ cholestasis.
• Micronodular or macronodular cirrhosis may appear in childhood or in adolescence in which the diagnostic feature is the presence of intracellular, acidophilic, PAS-positive globules in the periportal hepatocytes.
• Ultrastructurally, these globules consist of the dilated rough endoplasmic reticulum.

Cardiac Cirrhosis

• 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.
• The pressure in the right ventricle is elevated which is transmitted to the liver via the inferior vena cava and hepatic veins.
• The patients generally have enlarged and tender livers with mild liver dysfunction. Splenomegaly occurs due to simple passive congestion.

Morphologic Features: Grossly, the liver is enlarged and firm with stretched Glisson’s capsule.

• Histologically, in the 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.

Indian Childhood Cirrhosis

• 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.
• There is no role of viral infection in its aetiology. Instead, a combination of some common toxic effects and inherited abnormality of copper metabolism has been suggested. Death occurs due to hepatic failure within a year of diagnosis.

Morphologic Features Five histologic types of ICC have been distinguished of which type II is the most common. This form is characterised by the following features

1. Liver cell injury ranges from ballooning degeneration to significant damage to hepatocytes.
2. Prominent Mallory bodies in some hepatocytes without fatty change.
3. Neutrophilic and sometimes along with lymphocytic infiltrate.
4. Creeping pericellular fibrosis which may eventually lead to fine micro-macro-nodular cirrhosis.
5. There is significant deposition of copper and copper-associated proteins in hepatocytes, often more than what is seen in Wilson’s disease.

• • Thus, the picture resembles acute alcoholic hepatitis but without fatty change and with greatly impaired regeneration.
  • There is a marked increase in hepatic copper since the milk consumed by such infants is often boiled and stored in copper vessels in India. The condition has to be distinguished from Wilson’s disease.

Cirrhosis in Autoimmune Hepatitis

• 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 ranging from indolent to severe rapid course.
• This form of hepatitis has prominent autoimmune etiopathogenesis is supported by immunologic abnormalities and a few other characteristic diagnostic criteria as
  1. Female gender predisposition.
  2. Predominant elevation of aminotransferases (AST and ALT).
  3. Hyperglobulinaemia (elevated IgG and γ-globulin).
  4. High serum titres of serum autoantibodies: anti-nuclear (ANA), anti-smooth muscle (SMA) (directed against actin, vimentin, and skeletal), and liver-kidney microsomal (LKM1) autoantibodies, but absence of antimitochondrial antibodies.
  5. Concurrent presence of other autoimmune diseases.
  6. Presence of HLA-B1, -B8, -DR3 and -DR4 haplotypes.
  7. Lack of prominent elevation of alkaline phosphatase.
  8.  Exclusion of chronic hepatitis of other known etiologies (viral, toxic, genetic etc).
• Morphologic Features: Autoimmune hepatitis is morphologically indistinguishable from chronic hepatitis of viral aetiology. Patients who survive active disease develop cirrhosis.
• There are features of burnt-out chronic autoimmune hepatitis accompanied by cirrhosis.

Cirrhosis in Non-alcoholic Steatohepatitis

• Non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD) is a form of hepatitis resembling alcoholic liver disease but is seen in nondrinkers of alcohol.
• The condition is seen more commonly in affluent Western societies and has a strong association with obesity, dyslipidaemia and type 2 diabetes mellitus.
• It is seen in younger patients with equal gender prevalence. Patients are generally asymptomatic and are diagnosed by routine biochemical tests.
• Morphologic Features: Nafld is a form of chronic hepatitis after known causes have been excluded. About 10-30% of cases of NASH progress to increased fibrosis and develop cirrhosis.

Miscellaneous Forms of Cirrhosis

• In addition to the various types of cirrhosis just described, a few other uncommon types associated with different diseases are sometimes distinguished. These include the following:

Metabolic disorders examples in galactosaemia, hereditary fructose intolerance, and glycogen storage diseases.

Infectious diseases example brucellosis, schistosomiasis, syphilis (hepar lobatum) and toxoplasma infection.

Gastrointestinal disorders examples in inflammatory bowel disease, cystic fibrosis of the pancreas and intestinal bypass surgery for obesity.

Infiltrative diseases example in sarcoidosis.

Cryptogenic Cirrhosis

• Finally, when all the known etiologic types of cirrhosis have been excluded, there remain patients with cirrhosis in whom the cause is unknown.
• These cases are grouped under a wastebasket diagnosis of cryptogenic cirrhosis (crypto = concealed).