Friday 30 May 2003
The essential components of the acute phase of hepatitis are:
Hepatocellular damage range from minor degrees of cell swelling to cell death. They are accompanied by the inflammatory infiltration described below, reflecting the important role of cellular immunity in the pathogenesis of most forms of hepatitis.
Both hepatocellular damage and inflammation are usually most severe in perivenular areas, giving rise to a characteristic histological pattern. A periportal pattern of necrosis and inflammation, sometimes seen in hepatitis A, is less common.
The mildest and probably reversible change is cell swelling. The cytoplasm of affected cells is rarified, granular and sometimes finely vacuolated. The more severe degrees of cell swelling are called ballooning degeneration. This differs from the feathery degeneration of cholestasis, in which the cytoplasm has a reticular pattern.
Other hepatocytes undergo apoptosis, which is an important method of cell death in hepatitis. Shrinkage and increased staining of the cytoplasm, sometimes called acidophilic change or degeneration, is probably a precursor of apoptosis, in which the hepatocytes shrink further, become very dense and undergo fragmentation.
The apoptotic bodies seen lying free in the sinusoids represent the largest fragments or entire unfragmented apoptotic cells. They are also called "acidophil bodies" or "Councilman bodies" (Councilman having first described them in yellow fever). Apoptotic bodies sometimes contain pyknotic nuclear remnants and often appear to bulge beyond the plane of the section.
Another form of hepatocellular damage in acute hepatitis is focal necrosis (spotty necrosis), in which liver-cell plates are disrupted or replaced by small groups of lymphocytes and macrophages. Whether these mark a site of necrosis or of apoptosis is not clear; the damage to hepatocytes is deduced from their absence rather than seen.
Whatever its mechanism, loss of hepatocytes or liver-cell drop out, coupled with focal regeneration, leads to a characteristic irregularity of the liver-cell plates, which usually allows acute hepatitis to be distinguished from hepatocellular damage secondary to cholestasis. The loss of hepatocytes also leads to condensation of the extracellular matrix, best seen in reticulin preparations.
Hepatocyte nuclei show prominent nucleoli and increased variation in size and may be multiple.
When syncytial giant hepatocytes are very prominent, the term "giant-cell hepatitis" is appropriate. This is only rarely of proven viral origin and is also more characteristic of acute hepatitis in neonates.
In adults, autoimmune hepatitis and hepatitis C virus with or without human immunodeficiency virus co-infection are important associations.
Cholestasis in the form of bile thrombi in canaliculi is common in acute hepatitis but rare in chronic hepatitis, which is diagnostically helpful. It is a result of damage to the bile secretory apparatus of the hepatocytes, but may also result from interference with bile flow at the level of the portal tracts. The term "cholestatic hepatitis" is best kept as a clinical description of patients with a prolonged cholestatic course.
Mild hepatocellular siderosis or steatosis is occasionally seen.
In acute hepatitis, the most conspicuous inflammation is usually perivenular. The extent of portal inflammation is very variable and portal tracts may be either normal in size or expanded. The larger conducting tracts are often spared. The edges of small portal tracts may be well defined or blurred by outward extension of the infiltrate. This so-called "spillover" resembles the interface hepatitis of chronic hepatitis and may be difficult to distinguish from it. The parenchymal changes, clinical history and virological findings usually make the correct diagnosis clear.
While most of the infiltrating cells in acute hepatitis are small T lymphocytes, plasma cells may also be prominent and there are often a few neutrophils and eosinophils.
The plasma cells do not necessarily indicate "autoimmune hepatitis", nor do a few eosinophils prove a diagnosis of "drug hepatic injury".
Kupffer cells and other macrophages accumulate and enlarge, many of them forming discrete clumps together with lymphocytes. They may contain tan-brown ceroid pigment, staining with periodic acid–Schiff (PAS) agent after diastase digestion. They may also contain stainable iron, but this is less common.
Sinusoidal and venular endothelial cells also take part in the hepatitic process. Sinusoidal endothelial cells become swollen and may contain dense iron-positive granules. The terminal hepatic venules may show disruption of the endothelium and lymphocytic infiltration.
In contrast to chronic hepatitis, the parenchymal changes dominate the picture, but there is always some portal inflammation, affecting most or all of the small portal tracts. The density of the portal infiltrate varies.
Interlobular bile ducts may show abnormalities including irregularity of the biliary epithelium, crowding of the biliary epithelium and stratification of the biliary epithelium, cytoplasmic vacuolation of the biliary epithelium and infiltration of the biliary epithelium by lymphocytes. These changes, together with lymphoid follicle formation, are most often seen in hepatitis C. A bile duct loss (ductopenia) is very rare.
histological variants in acute hepatitis
The histological changes in acute hepatitis are infinitely variable, but a few patterns deserve special mention. These are:
- confluent necrosis
- bridging necrosis
- necrosis of entire lobules
- periportal necrosis.
infectious acute hepatitis
- viral acute hepatitis
drug-induced acute hepatitis
acute hepatitis in genetic metabolic hepatic diseases
- alpha-1-antitrypsin deficiency
- Wilson disease
- Niemann-Pick disease type C
- cerebrohepatorenal syndrome (Zellweger syndrome)
- ornithine transcarbamyl transferase deficiency (ornithine transcarbamylase deficiency)
- acute tyrosinemia
- indian childhood cirrhosis
acute hepatitis in cholestatic diseases
- familial intrahepatic cholestatic syndromes (FIHCs)
- bile acid synthesis anomalies
- cystic fibrosis
indian childhood cirrhosis
alcoholic acute hepatitis
classsic viral pattern of acute hepatitis (diffuse hepatocyte injury and necrosis)
- hepatitis viruses
- drugs (drug-induced hepatitis)
mononucleosis pattern of acute hepatitis (lobular inflammation with sinusoidal distribution)
- Epstein-Barr virus (EBV hepatitis)
- hepatitis C virus (hepatitis C)
- cytomegalovirus (CMV hepatitis)
- drugs (drug-induced hepatitis)
herpetic pattern of acute hepatitis (randomly scattered foci of necrosis)
- Herpes simplex virus (HSV hepatitis)
- adenovirus (adenoviral hepatitis)
- varicella-zoster virus (HZV hepatitis)
- enteroviruses (enteroviral hepatitis)
Nota bene: Acute hepatitis is not usually an indication for liver biopsy. There are, however, at least three reasons why pathologists sometimes receive liver biopsy samples from patients with acute hepatitis:
First, there may be doubt about the clinical diagnosis, or even a mistaken working diagnosis.
Second, a diagnosis of hepatitis may be well established but the clinician needs information on the stage of the disease or its severity.
Third, the patient may have received a liver transplant and the pathologist is being asked to help decide if symptoms or biochemical abnormalities are due to recurrent (or new) viral hepatitis or to some other cause such as rejection.
For all these reasons, a knowledge of the pathology of acute hepatitis is essential. There is a further reason, no less important than the others: without a knowledge of acute hepatitis, the pathologist cannot hope to understand chronic hepatitis and cirrhosis, together the cause of most liver disease in the world.
- chronic hepatitis
- active chronic hepatitis