key: cord-027858-j8kioy8e
authors: Lefkowitch, Jay H.
title: Acute Viral Hepatitis
date: 2020-06-22
journal: Scheuer's Liver Biopsy Interpretation
DOI: 10.1016/b978-0-7020-3410-7.00012-5
sha: 
doc_id: 27858
cord_uid: j8kioy8e

nan

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 viruses [5] [6] [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 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 

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 

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] [19] [20] [21] [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.

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 78 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 prominent 25 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.

Sinusoidal and venular endothelial cells also take part in the hepatitic process. Sinusoidal endothelial cells become swollen and may contain dense iron-positive granules 26 ( Fig. 6.5 ). 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 ( 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. 

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 and periportal necrosis.

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 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 82 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.) P P 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 In a minority of patients with acute viral hepatitis confluent necrosis extends throughout entire lobules or acini (panlobular or panacinar necrosis) or several adjacent ones (multilobular or multiacinar necrosis). This is a common feature in patients with fulminant hepatitis. The term 'massive necrosis' is also sometimes used, but can be misleading in so far as a needle biopsy specimen may not be representative of the liver as a whole and can lead to over-or under-estimation of the true extent of liver damage. 29 This throws doubt on the usefulness of liver biopsy as a means of assessing prognosis in severe acute hepatitis. Sometimes multilobular necrosis involves only the subcapsular zone, and a small needle specimen may then give a falsely pessimistic picture (see Fig. 1.3) . In multilobular necrosis the parenchyma is replaced by collapsed stroma, inflammatory cells and activated macrophages (Fig. 6.11) . Around the surviving portal tracts, there are prominent duct-like structures, some of which probably represent proliferation of pluripotential progenitor cells 30-32 (see Fig. 4.6D) . Late-onset hepatic failure is a term used for patients developing encephalopathy between 8 and 24 weeks after onset of symptoms. 33 Study of liver biopsies and explanted livers from these patients has shown a consistent pattern of map-like necrosis together with areas of nodular regeneration.

Periportal necrosis rather than the more usual perivenular necrosis is a feature in some patients with hepatitis A (below).

There are more similarities than differences between hepatitis types A, B, C, D and E, but certain patterns are more common in one type than another and are described here. They do not allow the pathologist to identify the cause of the hepatitis on histological Portal tracts (P) can be identified but the parenchyma has been replaced by inflammatory cells, necrotic debris and duct-like structures. (Needle biopsy, H&E.) P P appearance alone. The picture may be confused by the presence of more than one virus, or by additional damage resulting from alcohol abuse.

Two main patterns are described, occurring separately or together. [34] [35] [36] One is a histological picture of perivenular cholestasis with little liver-cell damage or inflammation, easily mistaken for other causes of cholestasis ( Fig. 6.12) . The second is a hepatitis with periportal necrosis and a dense portal infiltrate which includes abundant, often aggregated plasma cells (Fig. 6.13 ). These two patterns may be related, the cholestasis resulting from interruption of bile flow by the periportal necrosis. 22 Other patterns of hepatitis as described above are also found, but fulminant hepatitis with multilobular necrosis is rare. Extensive microvesicular change of hepatocytes, previously described in hepatitis D infection, has been seen also in severe acute hepatitis A (Fig. 6.14) . Fibrin-ring granulomas have been reported. 37, 38 A chronic course 39 is very rare.

The histological appearances are broadly similar to those of other forms of viral hepatitis. Some of the differences reported in the literature may well reflect patient selection rather than features specific for hepatitis B virus (HBV) infection. However, lymphocytes and macrophages sometimes lie in close contact with hepatocytes (peripolesis) or even invaginate them deeply (emperipolesis), which probably reflects the immunological nature of the cell damage. In a comparative study, periportal inflammation tended to be more severe in acute hepatitis B than in hepatitis C. 40 Liver cells and their nuclei may show a moderate degree of pleomorphism. In most cases of acute hepatitis, the hepatitis B core and surface antigens (HBcAg and HBsAg) are either not demonstrable or very sparse, but in one study of livers infected with a HBV mutant, 41 HBsAg could be demonstrated by immunostaining Following clinical recovery of acute hepatitis B, occult infection and mild histological abnormalities including portal inflammation, focal necrosis, apoptosis and fibrosis may persist for at least a decade. 43 Reactivation of a previously occult or quiescent chronic hepatitis B infection may cause changes closely resembling acute hepatitis. In such instances the presence of (1) portal tract lymphoid aggregates, (2) significant lymphoplasmacytic interface hepatitis, (3) any evidence of fibrosis on connective tissue stains, and (4) substantial positivity of HBsAg in hepatocytes on immunostaining all point to the underlying chronicity of the process.

Usually the histological features of hepatitis C are those of any acute hepatitis, but two distinguishing features have been noted. First, there may be prominent infiltration of sinusoids by lymphocytes in the absence of severe liver-cell damage, 44 giving rise to a picture reminiscent of infectious mononucleosis (Fig. 6.15) . Second, lymphoid follicles and bile-duct damage, features also associated with chronic hepatitis, may be seen within a few weeks or months of onset. 45 There may be cholestasis. The common finding of steatosis in hepatitis C is discussed in Chapter 9. Fulminant hepatitis C is very rare in the Western world 3 but may be commoner in parts of Asia. 46

Co-infection or superinfection with the hepatitis D virus (HDV) alters the course of type B hepatitis. It encourages chronicity and enhances severity, 47-49 except after liver transplantation. The antigen, HDAg, can easily be demonstrated immunohistochemically in paraffin sections and is mainly found in hepatocyte nuclei (Fig. 6.16) . These may have finely granular eosinophilic centres (so-called 'sanded' nuclei 50 ). Cytoplasmic and membraneassociated staining is also sometimes seen. Severe acute hepatitis in a patient with markers of HBV infection may be due to superinfection by HDV of a chronic HBV carrier. 51 In an outbreak of HDV infection among Venezuelan Indians, notable features included early small-droplet fatty change, sparse lymphocytes and abundant macrophages in the parenchyma and substantial portal infiltration. 52 Later in the attack, there was extensive necrosis and collapse. Microvesicular fatty change and acidophilic necrosis of hepatocytes have been reported from Colombia 53 and North America. 54 In non-immunosuppressed patients with current HDV infection, liver biopsy is likely to show substantial necrosis and inflammation. However, there are HDVendemic regions where the virus produces little significant disease. 55 Following liver transplantation, on the other hand, HDV without HBV is sometimes demonstrable in the absence of hepatitic changes, indicating that HDV can survive in the absence of HBV. It does not then appear, however, to be capable of causing liver damage. 56

Hepatitis E is the result of enteric infection by an RNA virus with four genotypes. 57, 58 The disease has caused epidemics in Asia and has also been found in Africa, North and South America and Europe. In the Western world, it is most often seen in travellers (Fig. 6.17) but sporadic disease is sometimes due to local ingestion of virus-contaminated meat. 59 Infection does not appear to lead to chronic disease, but may cause severe decompensation of pre-existing chronic liver disease due to other causes. 60, 61 The possibility of posttransplantation chronic hepatitis and cirrhosis due to use of hepatitis E virus-infected donor organs (liver, kidney, pancreas) has been raised in several reports. [62] [63] [64] There is little detailed information on the pathological changes of hepatitis E virus infection in man. In a small number of patients studied, the appearances were like those of hepatitis A, with prominent cholestasis and a predominantly portal and periportal inflammatory infiltrate. 65 Portal lymphoid aggregates and periportal ductular reaction with neutrophilia at the edges of portal tracts are also described. 59 Histological cholestasis has been described in an elderly patient with a prolonged cholestatic clinical course. 66 The liver of a pregnant woman with fatal hepatitis E showed little portal inflammation, much cholestasis and prominent phlebitis, and virus particles were seen in bile ductules by electron microscopy. 67 

The distinction of acute hepatitis from bile-duct obstruction rests mainly on the finding of typical hepatitic changes in the parenchyma. The portal tract oedema of duct obstruction is absent. Drug-related hepatitis may be indistinguishable from viral hepatitis and should always be suspected if the cause of the hepatitis is in doubt. Features more common in drug-induced than in viral hepatitis include sharply defined perivenular necrosis, granulomas, bile-duct damage, abundant neutrophils or eosinophils and a poorly developed portal inflammatory reaction. Cholestasis may overshadow the hepatitic features. Autoimmune hepatitis may have a clinically acute onset, histologically indistinguishable from viral hepatitis or alternatively with histological features of chronic disease. This is discussed more fully in Chapter 9. In steatohepatitis there is usually conspicuous fatty change.

Mallory bodies may be present in ballooned hepatocytes and the infiltrate typically includes neutrophils. The key to the diagnosis is the presence of pericellular fibrosis in affected areas. The differentiation of acute from chronic hepatitis is briefly discussed under bridging necrosis in Chapter 4. While the parenchymal changes predominate in acute hepatitis, especially in perivenular areas, portal and periportal changes predominate in chronic disease. The distinction is sometimes difficult to make, especially when extensive lobular changes are found during an exacerbation of chronic hepatitis or in reactivated chronic hepatitis B as described earlier.

As far as can be deduced from the available evidence, most examples of hepatitis A, B and E are followed by complete or near-complete resolution and a return of the liver to normal. A chronic course is probably more common when hepatitis B is complicated by delta infection than otherwise, and in hepatitis C the risk of chronicity is high. Even in patients whose hepatitis resolves, some residual changes may persist for many months after clinical recovery (Figs 6.18, 6.19 ).

Localised collapse, scarring and regeneration following severe hepatitis with bridging or panlobular necrosis sometimes produce a histological picture indistinguishable from cirrhosis.

Necrosis is usually severe. Regenerative hyperplasia of surviving hepatocytes or progenitor cells may be seen.

Most individuals with hepatitis C virus infection develop chronic hepatitis. This has substantial impact on daily liver biopsy practice. Chronic hepatitis also develops in many patients with hepatitis B. 

Cirrhosis resulting from infection with a hepatitis virus almost always follows a period of chronic hepatitis, with repeated or continuous hepatocellular necrosis and regeneration. Occasionally it may follow directly after a single episode of severe acute hepatitis.

This may develop on the basis of cirrhosis in patients infected with HBV or HCV. Occasionally, however, hepatocellular carcinoma is found in the absence of cirrhosis, usually after a prolonged period of chronic liver disease. 68 

Fulminant non-A-G viral hepatitis leading to liver transplantation

Activation of hepatic stellate cells in liver tissue of patients with fulminant liver failure after treatment with bioartificial liver

Viral hepatitisrelated acute liver failure

Clinicopathologic spectrum of massive and submassive hepatic necrosis in infants and children

Herpes simplexinduced fulminant hepatitis in adults: a call for empiric therapy

Five cases of fulminant hepatitis due to herpes simplex virus in adults

Epstein-Barr virus (EBV)-induced liver failure in the absence of extensive liver-cell necrosis: a case for cytokine-induced liver dysfunction?

Fulminant adenovirus hepatitis following bone marrow transplantation. A case report and brief review of the literature

Acute liver failure in a renal transplant patient caused by adenoviral hepatitis superimposed on a fibrosing cholestatic hepatitis B

SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases

The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1: a review

Kupfer cell-dependent hepatitis occurs during influenza infection

Systemic viral infections and collateral damage in the liver

Apoptosis and viral hepatitis

The pathology of the liver in yellow fever

Syncytial giant-cell hepatitis. Sporadic hepatitis with distinctive pathological features, a severe clinical course and paramyxoviral features

A case of syncytial giant cell hepatitis with features of a paramyxoviral infection

Postinfantile giant-cell transformation in hepatitis

Syncytial giant-cell hepatitis -a specific disease entity?

Post-infantile giant cell hepatitis in patients with primary sclerosing cholangitis and autoimmune hepatitis

Syncytial giant-cell hepatitis due to autoimmune hepatitis type II (LKM1+) presenting as subfulminant hepatitis

Hepatic giant cells in hepatitis C virus (HCV) mono-infection and HCV/ HIV co-infection

Cholestatic features in hepatitis A

Memory T cells represent the predominant lymphocyte subset in acute and chronic liver inflammation

Immunoglobulin-containing plasma cells in acute hepatitis

Endothelial cell changes in acute hepatitis. A light and electron microscopic study

Hepatic fibrosis and collapse: histological distinction by orcein staining

The formation of elastic fibers in livers with massive hepatic necrosis

Histopathological heterogeneity in fulminant hepatic failure

Ductular reaction after submassive necrosis in humans. Special emphasis on analysis of ductular hepatocytes

Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man

The stem cell niche of human livers: symmetry between development and regeneration

Late-onset hepatic failure: clinical features, serology and outcome following transplantation

The pathology of hepatitis A in man

Light microscopic findings of liver biopsy specimens from patients with hepatitis type A and comparison with type B

Pathology of acute hepatitis A in humans. Comparison with acute hepatitis B

Hepatic fibrin-ring granulomas in a patient with hepatitis A

Fibrin ring granulomas in hepatitis A

Chronic hepatitis A with persistent viral replication

Comparison of clinical, virologic and pathologic features in patients with acute hepatitis B and C

Pathology of livers infected with 'silent' hepatitis B virus mutant

Talc liver

Long-term histologic and virologic outcomes of acute self-limited hepatitis B

Short incubation non-A, non-B hepatitis transmitted by factor VIII concentrates in patients with congenital coagulation disorders

Liver biopsy features of acute hepatitis C compared with hepatitis A, B and non-A, non-B, non-C

The role of hepatitis C virus in fulminant viral hepatitis in an area with endemic hepatitis A and B

Natural course of delta superinfection in chronic hepatitis B virusinfected patients: histopathologic study with multiple liver biopsies

A histological study of hepatitis delta virus liver disease

Natural course of patients with chronic type B hepatitis following acute hepatitis delta virus superinfection

Sanded nuclei in delta patients

Influence of delta infection on severity of hepatitis B

Histologic studies of severe delta agent infection in Venezuelan Indians

Specific histologic features of Santa Marta hepatitis: a severe form of hepatitis delta-virus infection in northern South America

Cytopathic liver injury in acute delta virus hepatitis

Hepatitis D: thirty years after

Evidence that hepatitis D virus needs hepatitis B virus to cause hepatocellular damage

An overview and recent advances in clinical and laboratory research

Hepatitis E: an emerging awareness of an old disease

The histology of acute autochthonous hepatitis E virus infection

Hepatitis E virus superinfection in patients with chronic liver disease

Hepatitis E superinfection produces severe decompensation in patients with chronic liver disease

Hepatitis E virus and chronic hepatitis in organ-transplant recipients

Hepatitis E virus-related cirrhosis in kidney-and kidney-pancreastransplant recipients

Hepatitis E: does it cause chronic hepatitis?

Hepatitis A-like non-A, non-B hepatitis: light and electron microscopic observations of three cases

Acute hepatitis E virus infection presenting as a prolonged cholestatic jaundice

Virus-like particles in the liver of a patient with fulminant hepatitis and antibody to hepatitis E virus

Hepatocellular carcinoma without cirrhosis in the West: epidemiological factors and histopathology of the non-tumorous liver. Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire

Hepatitis E. An overview and recent advances in clinical and laboratory research

Apoptosis and necrosis in liver disease

Hepatitis B virus epidemiology, disease burden, treatment and current and emerging prevention and control measures

Structural biology of hepatitis C virus

Hepatitis E: an emerging awareness of an old disease

History of viral hepatitis: a tale of dogmas and misinterpretations

Acute and chronic viral hepatitis