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Pathology and Pathophysiology of Cirrhosis

Updated on July 27, 2013

Cirrhosis is defined as diffuse involvement of the whole liver with slowly progressive necrosis of liver cells (hepatocytes) leading to liver failure. The pathogenesis of cirrhosis is a complex process and is described in this article with the objective of improving the knowledge of the professionals and medical students rather than the general public. The pathological changes of cirrhosis are also included in the article as a part of the series of articles written by the author on cirrhosis. A simplified article on the disease is linked with further links on complications of the disease for readers who are interested.

Pathogenesis of cirrhosis is complex. The liver cells are injured by a chronic disease process, which then undergo inflammatory changes leading to cell death (necrosis) and fibrosis. Fibrosis is initiated by activation of stellate cells, which are induced by cytokines, active oxygen intermediates, autocrine signals and paracrine signals implemented by hepatocytes & Kupffer cells. Stellate cells initiate fibrosis by swelling, losing retinoids and up regulating receptors for prolliferative cytokines (PDGF, TGF-β1 [most potent fibrogenic factor]). 

Stellate cell activation in chronic liver disease also leads to expression of α-actin, which is a contractile protein. The contractions are induced by endothelin, nitrousoxide and prostaglandins. Normal matrix in spaces of Disse in the liver are replaced by Collagen 1,3 and fibronectin. Subendothelial fibrosis leads to the loss of endothelial fenestrations resulting in the impairment of liver functions. Tissue inhibitors of metaloproteinases increase and inhibit matrix metaloproteinases (degrade excessive matrix collagen). Evidence is present regarding reversibility of liver fibrosis through alterations in these pathways, though not applicable to clinical practice at the moment. Fibrosis of portal tracts result in abnormal venous flow pattern through liver leading to an increased resistance to portal blood flow precipitating portal hypertention (high blood pressure in portal venous circulation).

The pathological changes seen in cirrhosis are important in the diagnosis of the disease as well as for aetiological diagnosis. They include fibrosis involving both central veins & peripheral areas, formation of regenerative nodules due to the hyperplasia of surviving liver cells and distortion of normal architecture of the liver. Two macroscopic (appearance of the liver as seen by the naked eye) types of cirrhosis have been described. However, a mixed pattern may also be seen.

a) Micronodular cirrhosis (<3mm nodules) – where the liver is usually enlarged with small nodules of uniform size. This is associated with alcohol (yellow colour due to steatosis), haemochromatosis (dark reddish brown due to iron), drugs, chronic venous obstruction, chronic hepatitis and chronic biliary disease (greenish colour)

b) Macronodualr cirrhosis (>3mm nodules) – where the liver is almost always shrunken with large bulging nodules. This is the common form seen in chronic viral hepatitis, chronic autoimmune hepatitis, Wilson’s disease and after fusion of micronodules in alcoholic liver disease and haemochromatosis.

Microscopically the nodules are composed of hyperplastic hepatocytes separated by fibrous tissue. The liver cells are enlarged and the vasculature distorted due to the fibrosis involving portal triads. Fistulous communications may be formed between portal veins & hepatic arterioles.


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