Cirrhosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Sudarshana Datta, MD [2]

Overview

Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. The pathological hallmark of cirrhosis is the development of scar tissue which leads to replacement of normal liver parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function. When fibrosis of the liver reaches an advanced stage where distortion of the hepatic vasculature also occurs, it is termed as cirrhosis of the liver. The pathogenesis of cirrhosis involves inflammation, hepatic stellate cell activation, angiogenesis, and fibrogenesis. Kupffer cells are hepatic macrophages responsible for hepatic stellate cell activation during injury. Hepatic stellate cells (HSC) which are located in the subendothelial space of Disse, become activated in areas of liver injury and secrete transforming growth factor-beta 1 (TGF-β1), which leads to a fibrotic response and proliferation of connective tissue. Cirrhosis may also lead to hepatic microvascular changes including the formation of intra-hepatic shunts (due to angiogenesis and loss of parenchymal cells) and endothelial dysfunction. Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature, accompanied by regenerative nodule formation.

Pathophysiology

The pathogenesis of cirrhosis is as follows:[1][2][3][4][5][6]

Hepatic stellate cell activation

The role of hepatic stellate cells in the pathogenesis of cirrhosis is described below:

Microvascular changes

Cirrhosis leads to hepatic microvascular changes characterised by:[9]

Angiogenesis

Fibrosis

The role of fibrosis in the pathogenesis of cirrhosis is described below:

Pathogenesis of cirrhosis according to cause

Pathogenesis of cirrhosis based upon the underlying cause is as follows:

Pathophysiology of Cirrhosis due to Alcohol

Mechanisms of alcohol-induced liver damage include:[18][19][20][21]

Pathophysiology of Portal Hypertension due to Cirrhosis

Increased resistance

Hyperdynamic circulation in portal hypertension

Genetics

Gross Pathology

On gross examination, the liver may initially be enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm, and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis.

  • In the micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm.
  • In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm.
  • The mixed cirrhosis consists of a variety of nodules with different sizes.

On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension.

Cirrhosis

On gross pathology there are two types of cirrhosis:

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[41]
Macronodular cirrhosis[42]

Splenomegaly

On gross pathology, diffuse enlargement and congestion of the spleen are characteristic findings of splenomegaly.

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[43]

Esophageal Varices

On gross pathology, prominent, congested, and tortoise veins in the lower parts of esophagus are characteristic findings of esophageal varices.

Esophageal varices[44]

Images of gross pathology of cirrhosis

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Pathology

  • Microscopic pathology reveals the four stages of cirrhosis as it progresses:
    • Chronic nonsuppurative destructive cholangitis: inflammation and necrosis of portal tracts with lymphocyte infiltration leads to the destruction of the bile ducts
    • Development of biliary stasis and fibrosis
    • Periportal fibrosis progresses to bridging fibrosis
    • Increased proliferation of smaller bile ductules leads to regenerative nodule formation
  • Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa.
  • In these nodules, regenerating hepatocytes are present.
  • Portal tracts, central veins and the radial pattern of hepatocytes are absent.
  • Fibrous septa are present and inflammatory infiltrate composed of lymphocytes and macrophages) are also visible.
  • If the underlying cause is secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended leading to bile stasis.
  • Dilated ducts contain inspissated bile which appears as bile casts or bile thrombi (brown-green, amorphous).
  • Bile retention may be found also in the parenchyma and are referred to as "bile lakes".[45]

Microscopic pathology

The main microscopic histopathological findings in portal hypertension are related to cirrhosis, esophageal varices, hepatic amyloidosis, and congestive hepatopathy due to heart failure or Budd-Chiari syndrome.

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[46]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[47]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[48]

Hepatic amyloidosis

The main microscopic histopathological findings in hepatic amyloidosis is amorphous extracellular pink stuff on H&E staining.

Hepatic amyloidosis with amorphous amyloids (black arrow) and normal hepatocytes (blue arrow), via Librepathology.org[49]

Congestive hepatopathy

The main microscopic histopathological findings in congestive hepatopathy (due to heart failure or Budd-Chiari syndrome) are:

Congestive hepatopathy with central vein (yellow arrowhead), inflammatory cells, Councilman body (green arrowhead), and hepatocyte with mitotic figure (red arrowhead), via Librepathology.org[50]

Videos

References

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