CHAPTER 6 Acute Viral Hepatitis
Introduction
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. This chapter describes acute viral hepatitis and its immediate sequelae in the immunocompetent patient. The specific problems of diagnosing hepatitis in an immunosuppressed patient after transplantation are reviewed in Chapter 16.
The hepatitis viruses are listed in Table 6.1. While several other candidates have been extensively investigated in recent years, none has so far been established as a definite cause of viral hepatitis and most episodes of acute and chronic hepatitis can be attributed to one of the viruses listed, to autoimmune hepatitis (Ch. 9) or to a hepatotoxic agent (Ch. 8). An exception to this statement is fulminant hepatitis, the cause of which cannot currently be established in a substantial minority of patients,1–3 including children.4 Occasionally, a virus more often associated with infection of other organs, such as one of the herpes viruses5–7 or an adenovirus,8,9 gives rise to a severe hepatitis. These agents are further discussed in Chapter 15. Mild acute hepatitis has been reported in patients infected with the SARS virus (severe acute respiratory syndrome-associated coronavirus).10,11
Table 6.1 The hepatitis viruses
| Virus | Type | Spread and disease |
|---|---|---|
| Hepatitis A (HAV) | RNA hepatovirus | Faecal–oral, acute |
| Hepatitis B (HBV) | DNA hepadnavirus | Parenteral, acute or chronic |
| Hepatitis C (HCV) | RNA hepacivirus | Parenteral or sporadic; acute, more often chronic |
| Hepatitis D (HDV) | RNA deltavirus, defective | Pathogenic when combined with HBV |
| Hepatitis E (HEV) | RNA virus | Faecal–oral, epidemic or sporadic acute disease |
Occasionally, mild serum liver test abnormalities and mild histological hepatitis (‘bystander hepatitis’) with apoptotic bodies, focal necrosis and lymphocytic inflammation are seen in systemic, non-hepatic viral infections such as pulmonary influenza and result from migration to the liver of and collateral damage by CD8 T-lymphocytes.12,13
Pathological features
Hepatocellular damage
Changes seen under the light microscope 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 (Fig. 6.1). 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 (Fig. 6.2). This differs from the feathery degeneration of cholestasis, in which the cytoplasm has a reticular pattern (see Fig. 5.3). Other hepatocytes undergo apoptosis, which is an important method of cell death in hepatitis.14 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 (Fig. 6.2). They are also called acidophil bodies or Councilman bodies, Councilman having first described them in yellow fever.15 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 (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 (Fig. 6.3).
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.16,17 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.18–22
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.23 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.
The inflammatory infiltrate
Unlike classic acute inflammation, viral hepatitis is characterised by a mainly lymphocytic infiltrate within the parenchyma and portal tracts. 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 (Ch. 9) 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,24 plasma cells may also be prominent25 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 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 (Fig. 6.4). They may also contain stainable iron (Fig. 6.5), but this is less common.
Figure 6.4 Acute viral hepatitis.
Macrophages contain diastase PAS-positive material. (Needle biopsy, diastase-PAS.)
Sinusoidal and venular endothelial cells also take part in the hepatitic process. Sinusoidal endothelial cells become swollen and may contain dense iron-positive granules26 (Fig. 6.5). Terminal hepatic venules may show disruption of the endothelium and lymphocytic infiltration.
Portal changes
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 (Fig. 6.6). The density of the infiltrate varies. Interlobular bile ducts may show abnormalities including irregularity, crowding and stratification of the epithelium, cytoplasmic vacuolation and infiltration by lymphocytes (Fig. 6.7). These changes, together with lymphoid follicle formation, are most often seen in hepatitis C. Bile-duct loss (ductopenia) is very rare.
Histological variants
Confluent necrosis signifies death of a substantial area of the parenchyma. Focal as opposed to zonal areas of confluent necrosis haphazardly distributed in relation to lobular zones are more likely to be due to causes other than acute viral hepatitis; possibilities to be considered include opportunistic infections with herpes simplex or zoster viruses and lymphoma. Bridging necrosis (Figs 6.8, 6.9, and Fig. 4.2) is the term given to confluent necrosis linking terminal venules to portal tracts. A possible explanation for this location is that it represents the entire zone 3 of an acinus, a view supported by the curved shape of many bridges. Bridging necrosis is a manifestation of severe acute hepatitis but its distribution even within a single biopsy may be irregular. Necrosis and inflammation linking adjacent portal tracts without involvement of terminal venules should not strictly be called bridging because it almost certainly has different pathogenetic significance; it results from widening of portal tracts, with or without periportal necrosis.
Bridges of confluent necrosis with subsequent collapse may be mistaken for the septa of chronic liver disease. In making the important distinction between them, the pathologist is often helped by stains for elastic tissue. Unlike stains for collagens, these normally give negative results in the parenchyma, but elastic tissue accumulates as septa age.27 Recent collapse is therefore negative (Fig. 6.10), whereas old septa are positive. Substantial amounts of elastic tissue take months or years to accumulate, but small amounts can be detected by sensitive methods such as Victoria blue as early as 1 or 2 months after onset of hepatitis.28
Figure 6.10 Acute hepatitis: bridging necrosis.
The field is the same as that shown in Fig. 6.9. A stain for elastic fibres is positive in two portal tracts (P) but not in the intervening area of collapse. A necrotic bridge (arrow) is also negative. Inset: This contrasts with an elastic fibre-rich septum in chronic liver disease. (Needle biopsy, orcein.)
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