Hepatitis pathophysiology

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Overview

Pathophysiology

The liver, like all organs, responds to injury in a limited number of ways and a number of patterns have been identified. Liver biopsies are rarely performed for acute hepatitis and because of this the histology of chronic hepatitis is better known than that of acute hepatitis.

Acute

In acute hepatitis the lesions (areas of abnormal tissue) predominantly contain diffuse sinusoidal and portal mononuclear infiltrates (lymphocytes, plasma cells, Kupffer cells) and swollen hepatocytes. Acidophilic cells (Councilman bodies) are common. Hepatocyte regeneration and cholestasis (canalicular bile plugs) typically are present. Bridging hepatic necrosis (areas of necrosis connecting two or more portal tracts) may also occur. There may be some lobular disarray. Although aggregates of lymphocytes in portal zones may occur these are usually neither common nor prominent. The normal architecture is preserved. There is no evidence of fibrosis or cirrhosis (fibrosis plus regenerative nodules). In severe cases prominent hepatocellular necrosis around the central vein (zone 3) may be seen.

In submassive necrosis – a rare presentation of acute hepatitis – there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts. The degree of parenchymal inflammation is variable and is proportional to duration of disease. Two distinct patterns of necrosis have been recognized: (1) zonal coagulative necrosis or (2) panlobular (nonzonal) necrosis. Numerous macrophages and lymphocytes are present. Necrosis and inflammation of the biliary tree occurs. Hyperplasia of the surviving biliary tract cells may be present. Stromal hemorrhage is common.

The histology may show some correlation with the cause:

• Zone 1 (periportal) occurs in phosphorus poisoning or eclampsia.
• Zone 2 (midzonal) – rare – is seen in yellow fever.
• Zone 3 (centrilobular) occurs with ischemic injury, toxic effects, carbon tetrachloride exposure or chloroform ingestion. Drugs such as acetaminophen may be metabolized in zone 1 to toxic compounds that cause necrosis in zone 3.

Where patients have recovered from this condition, biopsies commonly show multiacinar regenerative nodules (previously known as adenomatous hyperplasia).

Massive hepatic necrosis is also known and is usually rapidly fatal. The pathology resembles that of submassive necrosis but is more markered in both degree and extent.

Chronic

Chronic hepatitis has been better studied and several conditions have been described.

Chronic active hepatitis was the term used to described cases of hepatitis for more than 6 months with portal based inflammation, fibrosis, disruption of the terminal plate and piecemeal necrosis. This term has now been replaced by the diagnosis of 'chronic hepatitis with piecemeal (periportal) necrosis (or interface hepatitis) with or without fibrosis.'

Chronic persistent hepatitis was the term used to describe chronic hepatitis with no significant periportal necrosis or regeneration with a fairly dense mononuclear portal infiltrate. Councilman bodies are frequently seen within the lobule. This condition is now referred to as 'chronic hepatitis without piecemeal necrosis (or interface hepatitis).'

Chronic lobular hepatitis was the term used to describe chronic hepatitis with persistent parenchymal focal hepatocyte necrosis (apoptosis) with mononuclear sinusoidal infiltrates. This is now referred to as 'chronic hepatitis without piecemeal necrosis (or interface hepatitis).'

These terms have since been deprecated. This was done because it was realized that these conditions could alter over time and what might have been regarded as a relatively benign lesion could still progress to cirrhosis. The simpler term 'chronic hepatitis' is now preferred in association with the causative agent (when known) and a grade based on the degree of inflammation, piecemeal or bridging necrosis (interface hepatitis) and the stage of fibrosis. Several grading systems have been proposed but none have been adopted universally.

Cirrhosis is a diffuse process characterized by regenerative nodules that are separated from one another by bands of fibrosis. It is the end stage for many chronic liver diseases. The pathophysiological process that results in cirrhosis is as follows: hepatocytes are lost through a gradual process of hepatocellular injury and inflammation. This injury stimulates a regenerative response in the remaining hepatocytes. The fibrotic scars limit the extent to which the normal architecture can be reestablished as the scars isolate groups of hepatocytes. This results in the formation of nodules. Angiogenesis (new vessel formation) accompanies scar production which results in the formation of abnormal channels between the central hepatic veins and the portal vessels. This in turn causes shunting of blood around the regenerating parenchyma. Normal vascular structures including the sinusoidal channels may be obliterated by fibrotic tissue leading to portal hypertension. The overall reduction in hepatocyte mass, in conjunction with the portal blood shunting, prevents the liver from accomplishing its usual functions – the filtering of blood from the gastrointestinal tract and serum protein production. These changes give rise to the clinical manifestations of cirrhosis.

Specific Cases

Most of the causes of hepatitis cannot be distinguished on the basis of the pathology but some do have particular features that are suggestive of a particular diagnosis.

The presence of micronodular cirrhosis, Mallory bodies and fatty change within a single biopsy are highly suggestive of alcoholic injury. Perivenular, pericellular fibrosis (known as 'chicken wire fibrosis' because of its appearance on trichrome or van Gieson stains) with partial or complete obliteration of the central vein is also very suggestive of alcohol abuse.

Cardiac, ischemic and venous outflow obstruction all cause similar patterns. The sinusoids are often dilated and filled with erythrocytes. The liver cell plates may be compressed. Coagulative necrosis of the hepatocytes can occur around the central vein. Hemosiderin and lipochrome laden macrophages and inflammatory cells may be found. At the edge of the fibrotic zone cholestasis may be present. The portal tracts are rarely significantly involved until late in the course.

Biliary tract disease including primary biliary cirrhosis, sclerosing cholangitis, inflammatory changes associated with idiopathic inflammatory bowel disease and duct obstruction have similar histology in their early stages. Although these diseases tend to primarily involve the biliary tract they may also be associated with chronic inflammation within the liver and difficult to distinguish on histological grounds alone. The fibrotic changes associated with these disease principally involve the portal tracts with cholangiole proliferation, portal tract inflammation with neutrophils surrounding the cholangioles, disruption of the terminal plate by mononuclear inflammatory cells and occasional hepatocyte necrosis. The central veins are either not involved in the fibrotic process or become involved only late in the course of the disease. Consequently the central–portal relationships are minimally distorted. Where cirrhosis is present it tends to be in the form of a portal–portal bridging fibrosis.

Hepatitis E causes different histological patterns that depend on the host's background. In immunocompetent patients the typical pattern is of severe intralobular necrosis and acute cholangitis in the portal tract with numerous neutrophils. This normally resolves without sequelae. Disease is more severe in those with preexisting liver disease such as cirrhosis. In the immunocompromised patients chronic infection may result with rapid progression to cirrhosis. The histology is similar to that found in hepatitis C virus with dense lymphocytic portal infiltrate, constant peacemeal necrosis and fibrosis.

Microscopic Pathology

Alcoholic hepatitis evident by fatty change, cell necrosis, Mallory bodies

References