Acute hepatitis is defined by active hepatocellular damage and necrosis, usually accompanied by a lobular inflammatory response, of short and often self-limited duration. This general picture can be produced by a wide variety of injurious agents and conditions, but, in practical terms, the designation is generally employed for cases caused by infectious organisms or drug reactions.

The paramount causes of acute hepatitis are the hepatitis viruses, and the term acute viral hepatitis is often reserved for this circumstance. By any measure, acute viral hepatitis represents one of the major diseases of the liver: Almost 60,000 cases are reported in the United States each year, but this figure clearly underestimates the frequency of the disease because of the large number of asymptomatic, subclinical, and unreported cases; the true prevalence may be three to ten times greater.^1-3

Other infectious organisms may also give rise to acute hepatitis on occasion, even though the liver is not their usual primary target. These organisms include several common human pathogens, prominently including members of the herpesvirus family such as the Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. In normal individuals, these agents typically give rise to a mild and clinically insignificant hepatitis that is overshadowed by other manifestations; only rarely does severe or clinically evident liver disease develop. In immunocompromised patients and newborn infants, on the other hand, these infections may be associated with serious liver involvement, and fulminant hepatic failure and death may be the result.

Acute hepatitis can adopt a variety of histologic patterns depending on the distribution of the hepatocyte necrosis and inflammation (Table 2-1). Recognition of these different patterns may help narrow the etiologic considerations, but the cause cannot be specifically identified except in the occasional instance when diagnostic viral inclusions are noted. Severe or massive hepatic necrosis can complicate any of these patterns, as discussed below, and therefore the extent of any underlying confluent necrosis should also be specified.

The diagnosis of acute hepatitis can usually be established by clinical, serologic, and virologic data. Liver biopsy plays a secondary diagnostic role, and the classic histologic appearances are therefore uncommonly encountered in general practice. Biopsies may be obtained, however, if acute hepatitis is not suspected clinically or if the clinical presentation or evolution of disease is atypical. In immunocompromised populations, histologic examination can also be useful in securing a rapid diagnosis of potentially treatable causes of acute hepatitis, such as cytomegalovirus or herpes simplex virus.

Other patterns of acute hepatocellular injury and inflammation can be recognized, but these have different implications and are generally distinguished from acute hepatitis. These include alcoholic hepatitis (Chapter 7), suppurative hepatitis (Chapter 8), and ischemic liver disease (Chapter 11). Giant cell hepatitis is a distinctive type of hepatocyte damage characterized by the formation of giant multinucleated hepatocytes. This is a typical pattern of hepatocellular cholestatic disorders in infants ("neonatal hepatitis"), but rare cases of acute giant cell hepatitis have also been noted in adults; these cases are not well characterized, but an association with paramyxoviruses has been proposed.^4,5

Traditionally, acute viral hepatitis was separated on epidemiologic grounds into an infectious type (hepatitis A) and a blood-borne serum type (hepatitis B). The responsible viruses were successfully isolated and characterized, and serologic tests for their specific identification were developed. Soon thereafter, the peculiar hepatitis D virus (or delta agent), was also recognized. However, it quickly became evident that many examples of assumed viral hepatitis could not be ascribed to any of these agents, and such cases were grouped under a descriptive label of non-A, non-B hepatitis. This was an imprecise diagnosis, based on the exclusion of other causes of liver damage, but it constituted a major, albeit heterogeneous, category of acute hepatitis. Non-A, non-B hepatitis gained importance as the dominant type of post-transfusion hepatitis with a high risk of progression to chronic hepatitis. After intensive investigation, unique applications of molecular biology techniques have recently led to the discovery of two viruses responsible for most cases of non-A, non-B hepatitis: the hepatitis C virus, the major cause of parenterally transmitted non-A, non-B hepatitis, and the hepatitis E virus, which causes an enterically transmitted form of non-A, non-B hepatitis. There are hints at still other hepatitis viruses, but, if they exist, they probably account for only a small percentage of cases.

Therefore, acute viral hepatitis is now known to be caused by at least five distinct viruses, designated by the letters A through E. Each has its own biology, serology, and natural history (Table 2-2). Specific tests for each virus are now (or soon will be) available, permitting a precise etiologic diagnosis in most instances. In practice, the typical case of acute viral hepatitis can be accurately diagnosed by clinical and biochemical features together with appropriate viral serology, and the indications for liver biopsy are few.⁶¹ The histology of acute viral hepatitis nevertheless remains a standard paradigm of hepatic pathology.

The pathogenesis of acute viral hepatitis is incompletely understood. The best studied circumstance is acute hepatitis B, where indirect evidence suggests that the liver damage results, not from a direct cytopathic effect of the virus, but rather through immunologic-mediated mechanisms.^7,73,75,76 The general concept is that the infected hepatocytes express viral antigens at the cell surface in conjunction with major histocompatibility complex products, and thereby become targets for immune attack. Natural killer and cytotoxic T lymphocytes then destroy the hepatocytes, in most instances eliminating the virus. In support of this hypothesis is the finding of circulating lymphocytes sensitized to hepatitis B viral antigens and the accumulation within the liver tissue of natural killer and T lymphocyte populations.^8,32,44,109 Although this is an attractive concept, many of the details are yet to be defined, and alternative mechanisms are possible. Hepatitis A and D have been considered to result from direct viral cytotoxicity, but this has been disputed, and an immunologic pathogenesis similar to that for hepatitis B has been suggested.^24,77,106

The hepatitis viruses produce a broad spectrum of clinical manifestations, ranging from an inapparent infection to a precipitous and fatal disease. Although there are some differences among the various agents, none is specific, and serologic tests remain the only means of establishing an exact etiologic diagnosis.

The incubation period varies from a few weeks to as long as six months. With hepatitis A and E, the mean period is approximately 30 to 40 days (range, 15-50 days), whereas the average with hepatitis B is 80 days (range, 15-160 days) and with hepatitis C, about 50 days (range, 14-160 days). The incubation period of hepatitis D is not clearly established, but it is probably similar to hepatitis B.⁷¹ In general, the time of peak infectivity occurs during the late stage of the incubation period and early after the onset of clinical disease.

Many cases of acute viral hepatitis are asymptomatic or accompanied only by minor, nonspecific symptoms such as mild fever, nausea and vomiting, or flu-like complaints. These mild cases are apt to remain undiagnosed; they may be detected by prospective biochemical monitoring in patients with a history of exposure to hepatitis, but are usually recognized only with retrospective serologic surveys that indicate past infection. Inapparent infections are especially frequent in infants and children, as symptomatic disease becomes more prevalent with advancing age, and are particularly noted with hepatitis A and post-transfusion hepatitis C.⁷¹

The classic attack of acute viral hepatitis is preceded by a prodrome that lasts from a few days to several weeks. This is characterized by malaise, anorexia, nausea and vomiting, abdominal discomfort, myalgias, and fever. A serum sickness-like syndrome with arthritis and rash may arise, particularly with hepatitis B, and is presumed to develop because of circulating immune complexes. These various prodromal symptoms herald the onset of jaundice, which is often preceded by darkening of the urine. Lightening of the stool color or mild pruritus may be noted by some patients. Once jaundice appears, the anorexia and malaise typically begin to wane, and, within a few weeks, the jaundice begins to disappear. Convalescence may be prolonged, but full recovery within six months is the rule.

Physical examination usually reveals few signs other than jaundice. The liver is typically enlarged and tender, and splenomegaly or minor lymphadenopathy is noted in some patients. The cardinal laboratory finding is an increase in the serum transaminases -- aspartate aminotransferase and alanine aminotransferase. These two cytoplasmic enzymes leak from damaged liver cells and are therefore key biochemical indicators of hepatic injury. In acute viral hepatitis, their serum levels are typically elevated five-fold or more, although the degree of increase does not correlate well with the extent of hepatocyte damage or the outcome of the hepatitis. Conjugated hyperbilirubinemia is variably present, and the alkaline phosphatase is usually only mildly elevated. The diagnosis can be confirmed and the exact etiology established by determination of specific viral antigens and antibodies (Table 2-2).

The severe end of the clinical spectrum is exemplified by fulminant hepatitis, defined by the rapid development of liver failure during the course of the hepatitis.^214,220 The dominant clinical features include encephalopathy and coagulopathy, and massive hepatic necrosis represents the usual underlying histologic picture, as discussed below. Fulminant hepatitis is an uncommon complication of acute viral hepatitis, seen in less than 1% of hepatitis A and B infections, but it carries a poor prognosis with a mortality rate that exceeds 50% in most series.

The usual case of acute viral hepatitis is self-limited, and supportive and symptomatic care is the only treatment required. A small percentage of patients may suffer a relapse of acute hepatitis before their recovery is complete; this is seen with hepatitis C, where multiple relapses may evolve into chronic hepatitis, but it also occurs with hepatitis A and usually resolves without sequelae.^55,99

A more serious problem is persistence of the virus and the development of a chronic infection, a complication that arises, with variable frequency, in patients with hepatitis B, hepatitis C, and hepatitis D superinfection, but does not occur in hepatitis A or E infections. Chronic infections are an important reservoir of further infections and, furthermore, may give rise to ongoing liver disease and chronic hepatitis. Hepatocellular carcinoma is an important complication of chronic hepatitis B, and probably hepatitis C, infections.

Hepatitis A.^45,65 The hepatitis A virus is a small enterovirus within the picornavirus family, which includes such pathogens as the polio virus, coxsackieviruses, and echoviruses. The virion is composed of a single-stranded RNA genome and a capsid that is fashioned from copies of four polypeptides. Only a single serotype is recognized.

Hepatitis A is transmitted primarily by the fecal-oral route, usually through the ingestion of contaminated water or food, and the infection can be acquired either sporadically or as part of a common-source outbreak or epidemic. Spread of the disease is encouraged by overcrowding or poor sanitation; infection rates are therefore higher in developing countries and in individuals in custodial institutions such as military facilities, prisons, and day care centers. Hepatitis A accounts for about half of the reported cases of viral hepatitis in the United States.²

Hepatitis A typically presents as a mild or inapparent illness of children and young adults; serious disease is infrequent and generally associated with increasing age. Occasional patients may suffer a prolonged clinical course, sometimes presenting a cholestatic picture that may be confused with biliary obstruction, but persistent infection and chronic hepatitis do not develop.^41,66,96 The serologic diagnosis is based on identifying IgM antibody to hepatitis A antigen (IgM anti-HAV), which appears early in the infection and declines in a few months in most patients. During convalescence, IgG antibody titers rise and persist, probable for lifetime; this antibody probably conveys immunity, and its presence serves as a marker of prior exposure.⁴⁸

Hepatitis B.^38,51 The hepatitis B virus is the prototype of the newly recognized hepadnavirus family, a unique group of hepatotrophic DNA viruses that infect a number of animal species. The intact virus, also known as the Dane particle, consists of a 28 nm central nucleocapsid core enclosed by an outer surface envelope. The core contains the DNA genome -- a compact, partially double-stranded circle of 3,200 base pairs -- an endogenous DNA-polymerase, and two antigens, hepatitis B core antigen (HBcAg) and the related e antigen (HBeAg).⁷⁴ These two antigens are the products of a single gene region; HBcAg remains within the hepatocyte while HBeAg, the soluble form, is exported into the serum during active viral replication. The viral envelope contains several protein components, the major one being the hepatitis B surface antigen (HBsAg). Large quantities of excess HBsAg circulate in the serum as spherical or tubular particles that lack viral DNA; the vast abundance of antigenic material, originally known as the Australian antigen, aided the discovery of the hepatitis B virus, and it facilitates the serologic diagnosis of hepatitis B infection.

The virus is spread primarily by parenteral routes, either from acutely infected patients or, more commonly, from chronic viral carriers. This latter group constitutes a reservoir estimated worldwide at 300 million people, most living in the Far East and sub-Saharan Africa, where up to 20% of the population may harbor the virus. In the United States, by contrast, chronic carriage of hepatitis B virus occurs in less than 2% of the general population.⁶⁸ Viral transmission classically occurs through percutaneous routes by means of contaminated whole blood and blood products or infected instruments. Since the virus is found in many body fluids, it can also be spread by intimate or sexual contact or from mother to infant during delivery. Maternal-neonatal transmission is largely responsible for perpetuating the disease in areas of high prevalence, as almost all perinatally infected infants develop a chronic infection and are capable of passing the virus on to their own infants. In low prevalence areas, on the other hand, the disease occurs primarily in young adults through intravenous drug abuse, sexual activity, or occupational exposure to blood products; post-transfusion hepatitis B has been almost eliminated by routine screening of blood donors.^3,56 In about a third of cases, however, these risk factors are absent and the patients have presumably acquired the virus in some unrecognized parenteral fashion.

The hepatitis B virus is an important cause of acute hepatitis, responsible for roughly 40% of cases reported in the United States, and tends to produce a disease of more insidious onset and prolonged course than hepatitis A.² Fulminant hepatitis is uncommon, but, overall, chronic infections develop in as many as to 10% of patients. Highly sensitive and specific tests for hepatitis B antigens and their corresponding antibodies provide the chief means for establishing the diagnosis, following the course, and assessing the prognosis. The key marker of active infection is HBsAg, which appears in the serum within weeks of exposure to the virus. This is quickly followed by the arrival of HBeAg, a marker of active viral replication and infectivity. In the usual self-limited infection, these antigens soon disappear, usually becoming undetectable by three or four months; their persistence after six months indicates chronic infection. Concomitantly, antibodies to HBcAg (anti-HBc), HBeAg (anti-HBe), and HBsAg (anti-HBs) emerge. IgM anti-HBc becomes detectable first, shortly before symptoms develop, and its presence therefore denotes recent acute infection. Anti-HBs does not appear until the acute disease is over and convalescence has begun, typically months after HBsAg has disappeared; it indicates recovery from infection and confers lifetime immunity. Given this serologic sequence, acute hepatitis B can be established by positive HBsAg and IgM anti-HBc. Tests for circulating hepatitis B DNA and DNA polymerase are available but are primarily research tools.⁴⁸

Hepatitis C.^37,49 The hepatitis C virus is the recently discovered cause of most non-A, non-B hepatitis, responsible for almost all post-transfusion cases and the bulk of sporadic instances.^23,62 Our understanding of this virus is rapidly evolving, and additional information from better diagnostic tests is increasingly available. The virus has not been entirely characterized, but it is an enveloped RNA virus that is related to the human flaviviruses, which include the yellow fever virus.

The epidemiology of hepatitis C is complicated by the relatively low sensitivity of the tests that were initially available. Nevertheless, the abundant data collected on non-A, non-B hepatitis can, for the most part, be translated to hepatitis C, although the two are not exactly synonymous. The chief means of transmission is parenteral; populations at risk therefore include intravenous drug users, recipients of blood transfusions, hemophiliacs, individuals with multiple sexual partners, renal dialysis patients, and health care workers.^10,34,98 Hepatitis C accounts for 75% to 95% of transfusion-associated hepatitis, and donor testing is expected to greatly decrease this complication. Perinatal transmission has also been documented.¹⁰³ Nonetheless, some 20% to 50% of hepatitis C infections are sporadic and unassociated with any obvious parenteral exposure. Since the virus does not appear to be spread effectively by nonparenteral routes, exactly how sporadic disease is acquired represents an unsolved mystery.^33,52 Overall, the prevalence of positivity for the hepatitis C antibody is about 1% in blood donors from several geographic areas.^37,101

Hepatitis C virus causes the same spectrum of disease as the hepatitis B virus, ranging from acute infection to chronic infection, and possibly including hepatocellular carcinoma.^46,57 The virus also likely produces fulminant hepatitis, but its exact role is not entirely established.¹¹⁴ The acute infection is often silent, with jaundice appearing in only a minority of patients. Aplastic anemia or transient agranulocytosis are uncommon but notorious complications, possibly resulting from direct marrow injury by the virus.¹¹⁵ A characteristic biochemical feature, seen in both acute and chronic disease, is the marked fluctuation in serum transaminase levels over time. Hepatitis C infections frequently progress to chronic hepatitis; this develops in about 50% to 70% of patients and eventuates in cirrhosis in approximately 10% of the total.⁹⁸

Diagnostic tests for hepatitis C are undergoing rapid change. The virus circulates in extremely low concentrations, below the limit of most conventional assays, and the predominant test has been the detection of an antibody to a recombinant hepatitis C polypeptide (anti-HCV). Anti-HCV appears in the serum between one and three months after the onset of acute infection, but it may be delayed up to a year.^9,48,70 The first-generation test for the antibody is not completely reliable; both false-negative and false-positive results are known to occur. Additional tests utilizing Western immunoblotting techniques are now available, but their specificity is not completely defined. The virus can also be detected by identifying circulating viral RNA by techniques such as the polymerase chain reaction; this represents a better marker of disease than the antibody test, but the methods are technically demanding.^35,48

Hepatitis D.^19,26,89 Also known as the delta agent, the hepatitis D virus is a peculiar, incomplete virus that requires the hepatitis B virus for its propagation and expression. The infection therefore only occurs in individuals with a concurrent acute or chronic hepatitis B infection. The virus is a small RNA virus that cannot be classified in any of the known animal virus groups, but it resembles certain plant pathogens, including viroids, satellite RNAs, and satellite viruses. The virion consists of an outer coat of hepatitis B surface antigen surrounding an inner core that contains the tiny RNA genome and two structural proteins representing the serologically defined hepatitis D antigen.

Hepatitis D infection is endemic among hepatitis B carriers in geographic areas such as the Mediterranean and Amazon Basins and the Middle East, but is inexplicably uncommon in similarly susceptible populations in China or southeast Asia.⁹⁰ The disease is infrequent in North American and northern Europe except among high-risk individuals -- intravenous drug addicts and those frequently exposed to blood and blood products such as hemophiliacs or hemodialysis patients. Epidemics of severe, fulminant disease are reported in isolated populations in northern South America and in groups of intravenous drug users.^21,67,85 The modes of transmission other than percutaneous routes are not well understood, but presumably are similar to hepatitis B.

The hepatitis D virus can cause both acute and chronic hepatitis and, on the average, yields more serious and severe disease than the other hepatitis viruses. Acute hepatitis D occurs either as a coinfection with acute hepatitis B, or as a superinfection imposed on the chronic hepatitis B carriage. These two circumstances exhibit different clinical courses and outcomes and should be distinguished. Coinfections generally resolve: most acute hepatitis B infections are self-limited, and hepatitis D cannot persist without continuing hepatitis B infection. These simultaneous infections cannot be distinguished on clinical grounds from uncomplicated acute hepatitis B, but some cases, particularly in intravenous drug users, exhibit a biphasic course with a greater risk of fulminant hepatitis and mortality.^22,26 Superinfection with hepatitis D may also cause fulminant hepatitis, but a more frequent sequel is the development of chronic hepatitis D. This may transform mild chronic hepatitis B disease into severe and progressive chronic active hepatitis and cirrhosis.^42,43,47

The serologic diagnosis of acute hepatitis D can be difficult. This is largely because the generally available assay -- an antibody to the hepatitis D virus (anti-HDV) -- appears late in the disease, often transiently and with low titers, so that both acute and convalescent sera need to be examined.^11,48 These difficulties may be solved by other, more sensitive tests currently under investigation, including assays for IgM anti-HDV, hepatitis D antigen, and hepatitis D nucleic acids. Coinfection with hepatitis B can be distinguished from superinfection by the presence of IgM anti-HBc.

Hepatitis E.^86,116 The recently identified hepatitis E virus is tentatively identified as the cause of enterically transmitted non-A, non-B hepatitis. It appears to be a small unenveloped virus, possibly a member of the calicivirus group, and its genome has been cloned. Additional information about the nature of this agent should be forthcoming.⁸⁸

The epidemiology of hepatitis E resembles that of hepatitis A. The virus is transmitted by the fecal-oral route, primarily through contaminated water, and is responsible for sporadic and epidemic hepatitis in the Indian subcontinent, Asia, the Soviet Union, northern Africa, and Central America.^87,108 Cases recognized in the developed world have been imported from these areas.²⁸ The infection favors young adults with a peak incidence of disease in the third and fourth decades. Pregnant women are particularly susceptible, often developing a severe infection with a mortality rate of up to 20%. The disease is self-limited, and neither a carrier state nor chronic infections have been identified.

Serologic tests for hepatitis E are not available for routine use, although immune electron microscopy and immunofluorescence have been employed to identify viral antigen or antibody. Until practical serologic tests are available, the diagnosis must be based on clinical setting and exclusion of other possibilities.⁴⁸

Pathologic Features^{17,53,54,81,84}

The hepatitis viruses all produce a similar morphologic picture characterized by diffuse hepatocyte injury and necrosis together with a predominantly mononuclear inflammatory response. As a consequence of these changes, the normal orderly arrangement of the liver cell plates is disturbed and the hepatocytes display irregularities in their size, shape, and staining characteristics. This all combines to produce a distinctive appearance of lobular chaos and cellularity seen at low power (Figure 2-1). Although these changes are found throughout the lobule to some degree, their extent and intensity vary widely, depending in part on the severity and course of the infection, the degree of host response, and the particular virus involved.

Most morphologic descriptions are of well-established hepatitis, and the pathology of very early or subclinical examples is not well established. The histologic changes appear to be particularly modest with only slight hepatocyte swelling, scattered foci of lobular necrosis, and prominent Kupffer cells. Scattered lobular neutrophils may be seen.

Hepatocyte injury and subsequent necrosis adopt two major forms in acute viral hepatitis. In one form, known as ballooning degeneration, the liver cells become swollen, rounded, and pale-staining (Figure 2-2). The cytoplasm is partially rarefied, particularly along the cellular periphery, and the cytoplasmic remnants clump around the nucleus; cell membranes are frequently indistinct. The nuclei are also often swollen and enlarged with prominent nucleoli and dense nuclear membranes. The degree of ballooning degeneration varies across the lobule, although classically the centrilobular region is most severely affected.

Ballooned hepatocytes undergo lytic necrosis: They disappear from the cell plates, leaving behind punctate foci of stromal collapse that are marked by small, poorly-defined collections of lymphocytes and Kupffer cells (Figure 2-3). Actual cytolysis of the hepatocytes is not usually visible, but its occurrence can be inferred from these inflammatory clusters.

Alternately, the hepatocytes may suffer acidophilic degeneration and death. In this type of injury, the cells acquire an intensely eosinophilic cytoplasm with pyknotic or fragmented nuclei (Figure 2-4). Some cells eventually develop into acidophilic bodies -- shrunken refractile masses, with or without nuclear remnants or accompanying inflammatory cells (Figure 2-5). These bodies may sit within the liver cell plates or be expelled into the sinusoids where they await phagocytosis by neighboring Kupffer cells. Some acidophilic bodies likely represent a manifestation of apoptosis, a general physiologic process of cellular self-destruction that occurs in normal livers but is a nonspecific finding in several pathologic conditions.^15,97 In apoptosis, cells become condensed and fragmented, producing numerous globules of various size; larger globules may appear as acidophilic bodies by light microscopy.

In the classic case of acute viral hepatitis, these two forms of hepatocellular necrosis affect individual or small adjacent groups of hepatocytes, leading to multiple, scattered interruptions in the continuity of the liver cell plates. This focal pattern of cell drop-out is referred to as spotty necrosis. In some instances, centrilobular accentuation of the hepatocyte injury results in confluent loss of liver cells around the central vein, but this has no great clinical or prognostic consequences (Figure 2-6).

Concomitant with the hepatocellular injury is the presence of hepatocyte regeneration. This is manifest by such features as mitoses, multinucleation, and crowding of the periportal cell plates by small, uniform, clear or basophilic hepatocytes (Figure 2-7).¹⁰⁵ Liver cell plates become irregularly thickened and occasional hepatocellular rosettes may appear.

The lobular inflammatory response in acute viral hepatitis consists primarily of lymphocytes and macrophages, sometimes with a few admixed plasma cells, neutrophils, or eosinophils (Figure 2-8).⁷² The infiltrate may involve the lobule diffusely, accumulating in areas of focal necrosis and sites of hepatocyte injury, but its intensity and degree vary considerably. In addition, Kupffer cells become hypertrophied and hyperplastic, often collecting a yellow-brown and PAS-positive pigment that represents phagocytosed lipofuscin, cellular debris, or (less often) bile. Endothelial cells become swollen and granular.¹⁴

Other lobular changes include fatty change and canalicular cholestasis. Fatty change of either macrovesicular or microvesicular type is a variable finding, most often noted with hepatitis C. Canalicular cholestasis is usually a minor component manifest only by scattered canalicular bile plugs. However, it may be a dominating feature in some cases, the so-called cholestatic viral hepatitis variant, and the pathologic and clinical features may both misleadingly simulate biliary obstruction. Histologically this variant is characterized by prominent bile plugs (often accompanied by cholestatic rosettes), conspicuous bile ductular proliferation, and neutrophil-rich portal inflammation (Figure 2-9). Affected patients may present with deep jaundice, pruritus, and elevated serum alkaline phosphatase levels. The clinical course is typically protracted with cholestasis persisting for up to eight months.^6,96,102

The portal tracts also acquire an inflammatory infiltrate composed of lymphocytes and macrophages with an occasional plasma cell, eosinophil, or neutrophil. Lymphoid aggregates, with or without germinal centers, are seen in some instances. The inflammatory infiltrate may be limited to the portal tract, but, at times, it trickles into the adjacent parenchyma and obscures the margin of the tract (Figure 2-10). This spillover of inflammatory cells can be mistaken for the piecemeal necrosis of chronic active hepatitis, but it can be distinguished because the periportal hepatocytes suffer little loss or necrosis. Nonetheless, in occasional cases, intense periportal inflammation with true piecemeal necrosis may occur.^13,107 The result may be the formation of necrotic zones joining one portal tract to another.

The interlobular bile ducts may demonstrate epithelial injury with irregularity of nuclear size and shape, cytoplasmic vacuolation, and intraepithelial inflammatory cells. Bile ductular proliferation, if present, is typically mild and accompanied by scattered neutrophils.

In the usual uncomplicated case, the histologic changes slowly resolve over weeks to months. The hepatocellular injury and necrosis gradually subside, and regenerative activity becomes prominent with variable liver cell pleomorphism, enlargement, mitoses, and binucleation. The inflammatory component regresses, first from the lobules and then from the portal tracts. Clusters of enlarged and PAS-positive Kupffer cells and other macrophages remain behind as indicators of prior cell death. These cells may also contain stainable iron, and finding both types of pigment is said to be almost diagnostic of resolving acute hepatitis.⁵⁴ Minor residual inflammatory changes may linger for months, yielding a picture of nonspecific reactive hepatitis or chronic persistent hepatitis, but they gradually disappear and the liver returns to normal.

The different hepatitis viruses produce minor and subtle differences within this basic histologic picture, although none of the changes is sufficiently specific to be diagnostic of the viral type.

Hepatitis A. Typical features of hepatitis A include a periportal predominance of hepatocellular injury and necrosis and a conspicuous portal and periportal inflammatory infiltrate that contains abundant plasma cells (Figure 2-11). These features can cause confusion with chronic active hepatitis, particular when centrilobular injury is relatively mild, but clinical and serologic features usually point to the correct diagnosis. In some cases, canalicular cholestasis is a dominant feature. When hepatocyte damage and necrosis are relatively minor, the histologic picture may suggest a primary cholestatic condition such as biliary obstruction.^{6,59,79,96,102}

Hepatitis B. Hepatitis B generally conforms best to the classic pattern of acute viral hepatitis with pronounced centrilobular hepatocyte damage and inflammation. Lobular lymphocytes are often closely apposed to normal and damaged hepatocytes and may even be found within their cytoplasm in some instances.^{6,30,50,59,79}

Hepatitis C. Several histologic clues have been described in hepatitis C, usually in the form of post-transfusion non-A, non-B hepatitis. The prevalence of these changes varies among studies, and none is a consistent finding. Fatty change is commonly found, usually mild in degree although sometimes in greater quantity; either large or small droplets may be present. Some cases are marked by prominent acidophilic degeneration that yields numerous, irregularly-shaped acidophilic bodies (Figure 2-12A). A distinctive pattern of sinusoidal inflammation is occasionally seen; this is characterized by prominent beading of lymphocytes along the sinusoids, similar to that seen in hepatitis due to Epstein-Barr virus (Figure 2-12B). The portal inflammatory infiltrate may be unusually dense and contain lymphoid aggregates with germinal centers. Bile duct injury is sometimes noted and resembles that seen in primary biliary cirrhosis, but does not result in destruction and loss of the duct (Chapter 5).^{12,30,60,92,95}

Hepatitis D. Many cases of hepatitis D show no special histologic clues: they demonstrate features of the concurrent hepatitis B infection, although the degree of hepatic injury tends to be more severe than with hepatitis B alone.²⁶ In some instances, microvesicular fatty change and prominent acidophilic degeneration have been noted, particularly in South American epidemics of hepatitis D, but also in examples in the United States (Figure 2-13).^21,64,85,110

Hepatitis E. Hepatitis E resembles hepatitis A in its histologic features, as well as in its clinical picture and epidemiology: canalicular cholestasis and dense portal and periportal inflammatory infiltrates are the predominant features.^28,29,87

Immunohistochemistry. Various hepatitis virus antigens can be detected in liver tissue by immunohistochemical techniques.^39,58,69 However, these viral markers are only transiently expressed during the incubation and early symptomatic periods of acute viral hepatitis and may not present during active disease, presumably because the virus is rapidly eliminated. Therefore, immunohistochemistry is not generally useful in the diagnosis of acute viral hepatitis, especially since reliable and noninvasive serologic tests are generally available. One exception, however, is acute hepatitis D, where, because of the limitations of the currently available serologic tests, demonstrating the presence of viral antigen may be diagnostically useful (Figure 2-14).¹⁹

Bridging Necrosis. Occasional examples of acute viral hepatitis are complicated by bridging necrosis in which groups of neighboring hepatocytes undergo confluent necrosis and form arcuate necrotic bands that stretch across the hepatic lobules and join vascular structures (Figure 2-15). Although noted in less than 10% of unselected acute hepatitis cases, bridging necrosis is noteworthy because it may be associated with a severe or protracted clinical course, particularly in older patients, and is a disputed predictor of chronicity.^20,40,82,83

The necrotic bands can connect one central vein to another, forming central-central necrotic bridges, or may join central veins to portal tracts and create central-portal necrotic bridges. The anatomic distribution of bridging necrosis is explained by the acinar architecture of the liver: central-central bridging arises from confluent necrosis affecting the periphery (zone 3) of the complex acinus, whereas central-portal bridging develops when the necrosis extends to the periphery of the simple acinus as well.^15,16 The central-portal bridges are often considered to be the most important, as they disrupt the normal microcirculation and permit shunting of blood from the portal to the systemic circulation; the term bridging necrosis is sometimes restricted to this type.

Although bridging necrosis can usually be accurately identified in biopsy specimens, its precise distribution may be difficult to define, particularly because the bridges may be irregularly dispersed across the liver. The subcapsular zone appears particularly susceptible and may be disproportionately affected as compared with the remainder of the liver. Sampling error can thereby become a considerable problem in biopsy interpretation, and the recommendation is that specimens should be at least 2 cm in length or contain a minimum of two or three necrotic bridges before a confident diagnosis of bridging necrosis be made.^20,25

Zones of confluent bridging necrosis can be mistaken for the fibrous septa of chronic active hepatitis or cirrhosis. The distinction can be made by examining the density of the connective tissue in the affected area: the thin, delicate appearance of the collapsed framework in bridging necrosis contrasts with the solid, wavy fibers of the fibrosis of chronic processes. Elastic tissue stains are also useful in this discrimination because elastic fibers are absent from zones of recent collapse but occur in mature fibrosis.^93,104

Several histologic features have been proffered as risk factors for progression to chronic hepatitis and cirrhosis.^17,15 Unfortunately, most of the proposed indicators are controversial, and there is great disparity among various studies, resulting partially from differences in patient selection, causative agents, and the timing of the biopsy. The infrequent use of liver biopsy in acute viral hepatitis has rendered much of the controversy moot.

Piecemeal necrosis with intense periportal inflammation is often cited as a prognostic factor. In one study, for example, a chronic course developed in 90% of patients with hepatitis B or non-A, non-B who exhibited piecemeal necrosis, and similar results have been reported by others.^31,80,107 However, different investigations, including several prospective studies, contradict this association.^36,50,94 Note also that piecemeal necrosis can be seen in hepatitis A, which does not progress to chronic disease.

Similar considerations apply to bridging necrosis as a predictive indicator. A number of studies indicate that patients with bridging necrosis are more apt to develop subsequent chronic hepatitis; the risk has ranged from 18% to 33%.^{20,78,100,113} This conclusion is not confirmed by other reports, again including prospective studies, suggesting that the prognostic importance of bridging necrosis has been overemphasized.^50,94,112

Therefore, neither of these indicators appears to be a robust indicator of prognosis, as they are often found in individuals with self-limited disease and an uncomplicated course. Nevertheless, in patients who do not eliminate the virus and suffer a persistent infection, these changes probably form the basis of continuing and progressive disease, facilitating the development of fibrous septa and, eventually, cirrhosis.

Additional commonly cited prognostic indicators such as portal lymphoid follicles and bile duct damage are now recognized to be common features of hepatitis C infection. Chronic infection is common with this virus, and this fact may explain these indicators' prognostic significance.

A variety of conditions may exhibit hepatocellular injury and lobular inflammation resembling that seen in acute viral hepatitis. Acute hepatitis resulting from other infectious agents can sometimes be distinguished by their distinctive histologic patterns, as outlined in Table 2-1, but clinical history and ancillary tests are often required for a secure diagnosis. Drug-induced acute hepatitis, discussed below, may be histologically indistinguishable from viral hepatitis; such features as eosinophils, granulomas, bile duct injury, fatty change, or well-defined zones of necrosis might point to a drug etiology, but, of course, they are not conclusive signs.

Canalicular cholestasis of any cause is often accompanied by mild lobular inflammation and liver cell damage, and therefore acute cholestatic disorders such as biliary obstruction enter the differential diagnosis. These lobular changes occur only in areas bearing canalicular bile plugs, in contrast to the more diffuse distribution in acute viral hepatitis, and focal interruptions of the liver cell plates are not prominent. Alcoholic hepatitis is another consideration, but it is distinguished by the neutrophilic character of the inflammation, the occurrence of Mallory bodies, and the presence of pericellular fibrosis.

Chronic hepatitis, especially when accompanied by a prominent lobular inflammatory component, can be mistaken for acute viral hepatitis. This is a notorious problem with chronic hepatitis C, but it may occur with any type of chronic hepatitis, including some cases with autoimmune serologic features.^27,63 In chronic hepatitis, the lobular component tends to show less centrilobular accentuation, and underlying features indicative of chronicity, such as fibrosis, may be a clue to the correct diagnosis. Nevertheless, the distinction may sometimes be impossible on histologic grounds, and close attention to the clinical setting, serologic data, and time course of the illness is necessary. Confusion may also arise when acute hepatitis is superimposed on preexisting chronic liver disease, either because of viral reactivation or superinfection with an additional agent.¹¹¹

Heatstroke may also give rise to hepatic alterations that resemble acute viral hepatitis, and the clinical history is obviously pertinent.^18,91 In addition, mild lobular inflammation, scattered focal necroses, and a patchy portal infiltrate can all be seen as a nonspecific reactive process ("nonspecific reactive hepatitis"); the distinction from minimal or resolving acute hepatitis may not be possible histologically.

Infection with the Epstein-Barr virus is usually asymptomatic in children, but, in adolescents and adults, it regularly presents as infectious mononucleosis. This is an acute, self-limited disorder characterized by fever, pharyngitis, malaise, generalized lymphadenopathy, and the appearance of the classic "atypical" lymphocytes in the peripheral blood.

The liver is affected in over 90% of cases of infectious mononucleosis. However, this is generally an mild or inapparent hepatitis that is recognized only by biochemical or histologic abnormalities and is eclipsed by the customary manifestations of mononucleosis.^125,126,131 Clinically evident liver involvement develops in only 5% to 10% of patients; occasional patients, particularly those over 40 years, may present with conspicuous jaundice and abdominal pain suggesting biliary obstruction.^117,122,124 The diagnosis is confirmed by serologic tests for heterophil antibodies or specific antibodies to viral antigens, but when the typical features of mononucleosis are missing, the correct diagnosis may not be suspected. Generally the illness resolves within four to six weeks, and death is a rare complication, seen with overwhelming infection in apparently normal individuals or in patients afflicted with immunodeficiency syndromes. Progression to chronic hepatitis or cirrhosis has not been convincingly demonstrated.

Epstein-Barr viral hepatitis may also develop after liver transplantation, either with primary infection or with the reactivation of latent virus.^128,130 The clinical illness, which may occur months to years after transplantation, resembles that of mononucleosis with adenopathy, fever, and pharyngitis, but atypical features such as arthralgias and joint effusions, encephalitis, pneumonitis, or ascites may also appear. A reduction of immunosuppression, sometimes with the addition of acyclovir therapy, leads to resolution in most instances, although occasional patients develop recurrences or progress to a viral-associated lymphoproliferative disorder.¹²¹

The histologic picture is characterized by dense mononuclear infiltrates that fill the portal tracts and spread along the sinusoids in a distinctive single-file array (Figure 2-16, 2-17). The mononuclear cells comprise lymphocytes -- including the large, atypical lymphocytes found in the peripheral blood -- with a few plasma cells. Kupffer cells are enlarged and numerous, sometimes forming small granulomatoid clusters, but true epithelioid granulomas are uncommon; lipogranulomas with fibrin rings may be seen in some instances.^123,129 Hepatocellular alterations are comparatively minor, comprising mild cell swelling and occasional focal necroses, but mitoses can be surprisingly prominent. Diffuse liver cell injury or massive necrosis is exceptional, and canalicular cholestasis or fatty change uncommon.^118-120,125

This pattern of sinusoidal inflammation must be distinguished from hepatic involvement by leukemia or lymphoma; the infiltrate of hepatitis is distinguished by its polymorphic character. Extramedullary hematopoiesis is also be included in the differential diagnosis, but the distinction is not difficult if close attention is paid to the cell types present.

In more severe Epstein-Barr viral hepatitis, as seen in liver transplant recipients, for example, the portal and periportal inflammatory infiltrate becomes increasingly prominent with numerous immunoblasts, plasmacytoid lymphocytes, and plasma cells (Figure 2-18). Mild bile duct damage or periportal confluent necrosis may be seen.^127,128,130 The appearances may be mistaken for malignant lymphoma, and may, in fact, progress to overt lymphoma. The virus can be detected within infiltrating lymphocytes by immunostains for viral nuclear-associated antigen on frozen tissue or by in situ hybridization for viral nucleic acid.¹³⁰

Cytomegalovirus is an ubiquitous human pathogen that gives rise to a diverse range of manifestations. Exposure to the virus is widespread: Roughly 50% of adults in the United States have serologic evidence of past infection, with the prevalence depending primarily on socioeconomic status and age.¹⁴⁰ Most of these infections are silent, however, and associated clinical disease is infrequent. Nonetheless, after active infection, the agent can persist in a latent state and is capable of being reactivated at a later time, particularly if normal immunity is lost. Significant cytomegalovirus infections therefore usually occur in the setting of immunosuppression, such as occurs with organ transplantation or the acquired immunodeficiency syndrome (AIDS), or congenital infection.

Although the liver is often affected in cytomegalovirus disease, this involvement is usually mild or asymptomatic. Only occasionally does it become a major manifestation or dominate the clinical picture. Cytomegalovirus hepatitis can be separated into three general clinicopathologic categories (Table 2-3).

In normal children and adults, cytomegalovirus can produce a mononucleosis-like illness that is clinically and pathologically similar to that seen with Epstein-Barr virus. ^138,160 Malaise, fever, and atypical lymphocytosis are the primary presenting features, lymphadenopathy and pharyngitis are infrequent, and, unlike typical mononucleosis, heterophil antibodies are not identified. Liver involvement is common, as manifest by mildly increased transaminase levels and minimal alkaline phosphatase or bilirubin elevations, but symptomatic liver disease is unusual. Exceptional cases presenting with cholestatic jaundice or fulminant hepatic failure have been reported.^152,154 The hepatitis usually resolves within several weeks, and chronic liver disease does not develop.

The histologic changes in this type of cytomegalovirus hepatitis are essentially the same as those seen with Epstein-Barr virus mononucleosis.^156,160 The portal tracts and sinusoids accrue a prominent mononuclear infiltrate composed principally of small and large atypical lymphocytes. In the sinusoids, these cells are dispersed in a characteristic string-of-beads arrangement and may be associated with small aggregates of Kupffer cells and occasional granulomas (Figure 2-19).^134,150 Fibrin-ring lipogranulomas have also been noted.¹⁴⁴ Hepatocellular damage is limited to scattered focal necroses and acidophilic bodies, except in rare cases with massive hepatocellular necrosis.¹⁵⁴ Viral inclusions are strikingly absent, and immunohistochemical studies generally of no use in establishing the diagnosis.^152,156,160

Cytomegalovirus is the single most important cause of opportunistic hepatitis in immunocompromised patients. Among the most prominently affected are recipients of organ allografts, including kidney, liver, heart, heart-lung, and bone marrow transplants.¹⁵⁷ The prevalence is greatest with liver transplantation, where up to 10% to 20% of patients develop cytomegalovirus hepatitis; whether this is because the allograft represent a primary target for viral injury or because of the extra surveillance given the liver in hepatic transplantation is not certain.^135,148 Other predisposing circumstances include the acquired immunodeficiency syndrome (AIDS), various malignancies including leukemias and lymphoma, cytotoxic therapy for a variety of disorders, and severe debilitation.^{139,141,143,153}

Liver involvement can appear alone -- particularly in liver transplant recipients -- but other manifestations of opportunistic cytomegalovirus disease may also be present, including pneumonitis, retinitis, or gastrointestinal ulceration; with dissemination, almost any organ may be affected. In general, primary infection is more apt to lead to more severe disease than is reactivation or superinfection with the virus; possible sources of exposure include the grafted organ, blood product transfusions, and sexual contact.^151,155 Among liver transplant recipients, the greatest risk occurs in patients who are seronegative and receive a liver from a seropositive donor, patients who have received antilymphocyte therapy (such as OKT3 monoclonal antibody), and patients who are undergoing retransplantation.^{135,147,155,158}

The clinical manifestations are variable and encompass fever, malaise, myalgias, arthralgias, nausea, and abdominal pain. In allograft recipients, these symptoms typically develop from two weeks to four months after transplantation. Laboratory abnormalities include leukopenia, an atypical lymphocytosis, and thrombocytopenia. Elevations in serum transaminases, alkaline phosphatase, and bilirubin levels are typical, and, at times, may suggest a cholestatic process. The diagnosis is established by detecting the virus within liver tissue, either by culture or histology, and thus liver biopsy plays an important diagnostic role. Mild hepatic involvement may resolve if the immunosuppression can be reduced, but more severe disease may require antiviral therapy with ganciclovir.¹⁵⁸ Various strategies for viral prophylaxis in this population are being actively explored.

The histologic hallmark is the presence of the distinctive cytopathic changes of cytomegalovirus. The affected cells are enlarged, often to three or four times the size of their uninfected counterparts, and characteristically harbor both intranuclear and cytoplasmic inclusions (Figure 2-20). The intranuclear inclusions appear as large, glassy masses within the nucleus, separated by a clear halo from the irregularly thickened nuclear membrane. The cytoplasmic inclusions are represented by basophilic or amphophilic granules of various size, but they are sometimes difficult to discern. These changes can affect any cell type including hepatocytes, biliary epithelium, endothelial cells, and Kupffer cells and other macrophages, and the number and distribution of affected cells varies greatly among cases. Inclusion-bearing cells are often unattended by inflammatory cells, but may be encircled by a cluster of neutrophils (Figure 2-21). Confluent foci of hepatocellular necrosis may occur, but massive necrosis is unusual.

In less intense disease, viral inclusions are fewer, and a variety of nonspecific alterations become more conspicuous. These comprise a mild lobular hepatitis with focal hepatocellular necroses and scattered acidophilic bodies together with patchy portal infiltration by mononuclear cells. Clues to the correct diagnosis include the presence of small neutrophil collections within the lobules or karyorrhexic debris in the portal tracts; these findings should prompt a diligent search, with additional sections from the block if necessary, to find the distinctive inclusions.^157,161

The typical cytopathic changes are diagnostic, but care should be taken to avoid confusing the intranuclear inclusions for large nucleoli or the inclusions of other viruses. In questionable cases, immunohistochemical techniques are useful in corroborating the presence of cytomegalovirus and, by employing monoclonal antibodies directed at early viral antigens, the virus can be detected even before inclusions appear.^148,149,160 In situ hybridization for viral DNA has also been employed, but the results have been variable and the sensitivity of the technique challenged.^{142,146,148,159,162}

Cytomegalovirus hepatitis may also occur with congenital and, to a lesser degree, perinatal infections. Most such infections are asymptomatic, but any of the wide range of clinical manifestations typically seen with intrauterine infections may also be produced: low birthweight and prematurity, anemia, pneumonitis, thrombocytopenia and purpura, and evidence of central nervous system damage such as microcephaly, cerebral calcification, mental retardation, and hearing loss.¹³² Liver involvement is another common feature of symptomatic disease, and most affected infants present with hepatomegaly, jaundice, and elevated serum transaminase and bilirubin levels.¹³⁸

The histologic features resemble those of opportunistic cytomegalovirus hepatitis with the distinctive cytopathic changes representing the key finding. Viral inclusions may reside in any of the liver's constituent cells and, among different cases, vary in number from sparse to plentiful. A variety of alterations are seen in the background liver. Some cases display a neonatal hepatitis-like pattern with canalicular cholestasis, focal hepatocellular injury and necrosis, and occasional giant multinucleated giant cells, while others demonstrate portal inflammation of variable intensity together with bile ductular proliferation and portal fibrosis, features that simulate biliary atresia (Figure 2-22).^133,145 Extramedullary hematopoiesis is a common and prominent accompaniment. The liver appears unaffected in some cases, with viral inclusions, particularly in biliary epithelium, constituting the only abnormality. At the other extreme, confluent hepatocellular necrosis is reported, although rarely.

In infants who survive, the hepatic changes generally subside and do not progress to chronic liver disease, although portal and periportal fibrosis sometimes persist. In exceptional cases, diffuse sinusoidal fibrosis develops, resulting in noncirrhotic portal hypertension and hepatic failure.^137,163 Viral-induced bile duct damage has been also associated with paucity of intrahepatic bile ducts and biliary atresia.¹³⁶

Hepatitis due to the herpes simplex virus usually occurs as a component of disseminated infection, and, although multiorgan involvement is thus the rule, in some instances the hepatic manifestations become unusually conspicuous and govern the clinical picture.¹⁶⁶ Typically affected are newborn infants, patients with immunologic compromise because of organ transplantation, malignancies, or immunosuppressive therapy, or individuals suffering malnutrition or debilitation.^{164,165,169,172} Occasional cases have also been noted in immunocompetent adults, many of them pregnant women.^167,168 Patients variably present with fever, abdominal tenderness, headache, myalgias, or pharyngitis, and mucocutaneous herpetic lesions are inconsistently identified. Serum transaminase levels are elevated, often markedly, and evidence of disseminated intravascular coagulation is frequently noted. A rapidly progressive clinical course is the rule with fulminant hepatic failure and death as the common outcome; consequentially, many cases are only recognized at autopsy. Antiviral agents such as acyclovir have been effective in some cases, and, in transplant recipients, prophylactic treatment appears useful in reducing subsequent infection.^168,169

The characteristic histology consists of circumscribed foci of coagulative necrosis randomly distributed throughout the lobule (Figure 2-23). These foci range from microscopic lesions, affecting only a few liver cells, to large, irregular geographic zones, and are recognized on gross examination as punctate yellow areas surrounded by hemorrhage. Associated inflammation is typically minimal with infiltration of the necrotic zones by neutrophils or mononuclear cells in some cases.^170,171 The diagnostic viral inclusions are found, in variable number, within surviving hepatocytes at the margins of the necrotic foci. These inclusions consist of two types (Figure 2-24): dense, eosinophilic masses that sit within the nucleus surrounded by a halo (Cowdry type A) or faintly basophilic homogeneous bodies that completely occupy the nucleus (Cowdry B type).

Because the morphology is characteristic, liver biopsy is a rapid, accurate diagnostic technique. Immunohistochemistry and in situ hybridization techniques can be used to specifically identify the virus, although these are not necessary to secure the diagnosis.^159,167,170

Acute hepatitis is a rare complication of adenovirus infections in immunocompromised patients, with pediatric liver transplant recipients accounting for most of the reported cases.^{175,185,186,191} Histologic features consist of irregular foci of hepatocellular necrosis, haphazardly arranged but varying in extent. In severe cases, the necrosis forms well-defined zones with little accompanying inflammation, and the histologic picture resembles herpes simplex virus hepatitis. Some cases seen in liver transplant recipients, however, demonstrate small necrotic zones together with granulomatoid lesions formed from circumscribed aggregates of macrophages with neutrophils.¹⁷⁷ The diagnosis can be suspected by finding the typical inclusions of adenovirus -- irregular and deeply basophilic "smudged" bodies that obliterate the nucleus. These may be difficult to identify with certainty and may be confused with poorly-preserved cytomegalovirus inclusions. Viral culture, serologic testing, electron microscopy, or immunostaining for viral antigens are confirmatory.

Varicella-zoster virus can cause a mild or subclinical hepatitis in infected children or adults, often in conjunction with varicella pneumonia, but clinically evident liver disease is rare. Severe and fatal hepatitis may occur with disseminated disease in either immunocompromised or normal individuals.^189,193 The histologic findings are identical to those of herpes simplex viral hepatitis.

Generalized infections by enteroviruses such as coxsackievirus A or B and echovirus can be accompanied by hepatitis, usually in newborns or immunocompromised patients, but also in normal adults.^183,187,190 Histologically, this is characterized by focal coagulative necrosis of groups of liver cells with a sparse neutrophil infiltrate, and the common result is massive hepatocellular necrosis. The picture suggests herpetic hepatitis, but viral inclusions are not seen.

Toxoplasmosis may be either an acquired or congential infection with differing implications. Acquired toxoplasmosis is a rare cause of acute hepatitis in normal or immunocompromised individuals. The clinical presentation is variable with fever, lymphadenopathy, fatigue, skin rash, and sometimes jaundice; acute viral hepatitis or infectious mononucleosis may be suspected.^196,198 Liver biopsy specimens display prominent sinusoidal and portal inflammation, hepatocellular injury with scattered focal necroses, and Kupffer cell clusters and occasional granulomas.^123,200

Congenital toxoplasmosis is clinically dominated by chorioretinitis, hydrocephalus or microcephalus, and cerebral calcifications, although hepatic manifestations are occasionally seen. The hepatic histology is not specific, ranging from nonspecific reactive alterations to variable hepatocyte necrosis with canalicular cholestasis, portal inflammation, bile ductular proliferation, and occasional fibrosis. Giant multinucleated hepatocytes may be present, and marked extramedullary hematopoiesis is common.¹⁷⁸ In either setting, the organism is rarely seen with routine stains, but can be demonstrated by immunohistochemical techniques.

Leptospirosis manifests with fever, chills, headache, myalgias, nausea and vomiting, and changes of meningeal irritation. With severe disease, evidence of hepatic and renal failure develop, and jaundice, hypotension, hemorrhage supervene and may result in death. The histologic features range from near normal liver to an acute viral hepatitis pattern with hepatocellular swelling, focal necrosis with acidophilic bodies, variable portal and lobular inflammation, and often prominent cholestasis.¹⁷⁶ Kupffer cells may display erythrophagocytosis. The responsible spirochetes are difficult to recognize with silver stains, but have been identified by immunohistochemical methods.¹⁸⁰

The so-called exotic viruses, including the yellow fever, Lassa, Marburg, and Ebola viruses, focus on the liver as a prime target.^182,184,202 Found principally in tropical regions, these organisms produce outbreaks of severe hepatitis with a considerable mortality rate. The clinical presentation includes fever and chills, headache, myalgias, vomiting, abdominal pain, and hemorrhagic manifestations, prompting the general designation of viral hemorrhagic fever for these infections. All produce a similar histologic pattern with widely scattered foci of acidophilic degeneration and necrosis involving single or small groups of hepatocytes in a checkerboard or "salt-and-pepper" pattern (Figure 2-25).^179,184,199 Small fat droplets may be seen in some degenerating cells, producing the classic Councilman body described in yellow fever.¹⁹⁷ Inflammation tends to be a minor component. The changes may be accentuated in the midzonal regions, but in severe cases, the necrosis become confluent and involves much of the lobule.

Other infectious causes of acute hepatitis are uncommon, and the accompanying pathologic features are not well defined. Rubella can cause a modest hepatitis in adults, although it is better known for the occasional cases of neonatal hepatitis that result from congenital infections.^192,201 Measles may similarly give rise to a modest hepatitis, particularly in severely ill adults; this injury may be potentiated by acetaminophen administration.^173,181 Moreover, immunocompromised hosts with disseminated measles infection may suffer massive hepatic necrosis.¹⁷⁴ The newly discovered herpesvirus, human herpesvirus-6, has been serologically correlated with acute, and even fulminant, hepatitis in recent reports.^188,194,195

Many drugs and toxins can cause acute hepatocellular injury and necrosis. The resulting hepatitis may be confused clinically with other forms of acute hepatitis, and the diagnosis depends heavily on careful clinicopathologic correlation since the histologic features are often not distinctive (Chapter 12).^207,208 In most instances, once the responsible agent is removed, the hepatitis resolves although with severe involvement, death may result; chronic disease is a rare outcome.¹⁰⁰

Drug-induced hepatitis gives rise to a spectrum of pathologic changes, including almost any of the histologic patterns of acute hepatitis. As a rule, there are no features that permit a exact diagnosis on histologic grounds alone, but certain findings should arouse suspicion of a drug reaction: abundant eosinophils, granulomas, fatty change, bile duct damage, well-defined zones of confluent necrosis, and an inflammatory response that is disproportionately weak for the degree of necrosis.^84,204 The absence of such findings does not exclude drugs from etiologic consideration.

The mildest alterations of drug-induced acute hepatitis constitute a nonspecific reactive hepatitis -- scattered acidophilic bodies and focal necroses with minimal, patchy inflammation. Because this histologic picture is seen in a broad range of clinical settings, a strict causal relationship with a particular drug may be difficult to establish, but aspirin and semisynthetic penicillin analogues such as oxacillin are among the drugs that have been incriminated.^205,212

More vigorous injury yields a classic viral hepatitis pattern -- generalized hepatocellular degeneration and necrosis with variable inflammatory infiltration of lobules and portal tracts. This pattern has been noted toxicity to many drugs including isoniazid, methyldopa, halothane, sulfonamides, and phenytoin.^203,207,211 Canalicular cholestasis is a variable and often minor feature that, when marked, generates a combined cholestatic and hepatitic appearance; although this occurs with cholestatic viral hepatitis, a drug-induced reaction should be strongly considered.

A mononucleosis-like hepatitis characterized by prominent beading of mononuclear cells along the sinusoids has been reported with phenytoin, paraminosalicylic acid, and dapsone.^206,211 The clinical presentation includes fever, lymphadenopathy, and atypical lymphocytosis, features that mimic infectious mononucleosis, but the pertinent serologic tests are negative.

Diverse drugs and toxins produce severe hepatic damage with confluent, bridging, and even massive necrosis. Many of the responsible agents are intrinsic hepatotoxins that, in sufficient dosage, cause necrosis with a zonal distribution; commonly the centrilobular region is involved, as with acetaminophen overdoses and Amanita mushroom poisoning, but periportal necrosis is also reported in ferrous sulfate and yellow phosphorus toxicity.^207,209 Furthermore, numerous drugs capable of producing idiosyncratic hepatocellular injury may, on occasion, give rise to severe necrosis. Notable offenders include halothane, isoniazid, methyldopa, ketoconazole, and iproniazid, among others.^203,207,210

These terms denote the severe and widespread destruction of liver parenchyma that represents the common pathologic counterpart of fulminant hepatic failure. They may complicate several types of acute hepatic injury, and infectious organisms, drugs and toxins, and ischemic disease constitute the most prevalent causes.^214,216,233 The terms massive and submassive have been defined in different ways with submassive generally implying that the loss of hepatic parenchyma is less than complete. This distinction is necessary arbitrary, however, since the degree of necrosis forms a continuous spectrum without clear-cut points of demarcation and, moreover, is unevenly distributed across the liver. The label of massive hepatic necrosis will therefore be used here as a convenient synonym for extensive confluent necrosis, irrespective of the presence of some residual hepatocytes.

The hepatitis viruses are the prime causes of massive necrosis, accounting for 60% to 75% of cases in most studies, and all five viral types -- hepatitis A through E -- have been implicated.^220,226,230 Hepatitis B and D are among the most frequent; many cases are also attributed to non-A, non-B hepatitis, but the extent to which hepatitis C is responsible remains to be clarified. Occasional examples of massive hepatic necrosis are reported with other viral organisms, particularly in immunocompromised patients; these agents include members of the herpesvirus family (Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and varicella-zoster virus), adenovirus, coxsackievirus, and echovirus. (However, other causes of massive necrosis have not been scrupulously excluded in some of these cases.) The so-called exotic viruses are well-known for producing severe necrosis, and although rarely seen in the developed world, they should be considered in travelers from endemic areas.

About 20% of cases of massive necrosis are ascribed to drugs and toxins. Since these agents are responsible for only some 5% of acute hepatitis, their relative risk for severe hepatocellular destruction is greater than that of acute viral hepatitis.²¹⁴ A long list of substances have been implicated, as noted above, including acetaminophen, halothane, isoniazid, methyldopa, selacryn, and dihydralazine.²⁰⁷

Extensive necrosis may occasionally develop as a result of ischemic liver disease. Any of a variety of conditions associated with severe hepatic hypoperfusion or hypoxia can be responsible, including circulatory collapse and shock, heat stroke, occlusion of the hepatic artery or portal vein, and venous outflow obstruction due to veno-occlusive disease or Budd-Chiari syndrome (Chapter 11).^{18,213,227,232}

Wilson's disease may also present with massive hepatic necrosis, although typically this develops within a background of preexisting cirrhosis (Chapter 9).^218,225 In pediatric patients, such metabolic derangements such as acute tyrosinemia, galactosemia, hereditary fructose intolerance, and neonatal hemochromatosis may also manifest with severe necrosis and collapse, but often fibrosis has evolved by the time of histologic examination.^217,237

Patients with massive hepatic necrosis present with severe clinical hepatitis with fulminant hepatic failure a common complication. This is defined by the rapid appearance of liver failure soon after the onset of clinical disease, usually specified as within eight weeks, although shorter time periods have also been proposed.^214,220,238 The chief manifestation of fulminant hepatitis is encephalopathy, beginning with mild behavioral changes and confusion and progressing to increasing somnolence and tremor and, in severe cases, coma. Coagulopathy is also frequently present, and the ensuing hemorrhage therefore a substantial problem. Adding to this may be a variety of additional complications, including cerebral edema, acute renal or respiratory failure, sepsis, hypoglycemia, and metabolic acidosis.

The mortality rate is accordingly high, averaging 60% to 70% overall, with survival the poorest among drug-induced and non-A, non-B hepatitis cases.^229,239 Those patients who survive generally recover completely, although chronic hepatitis and cirrhosis develop in some.^223,224 Treatment is largely supportive, and although numerous therapeutic measures have been tried, such as corticosteroids and other drugs, exchange transfusions, and artificial liver support, none has proven efficacy in improving survival. Liver transplantation has consequently become the treatment of choice for many patients. Survival rates of up to 75% are reported, but the precise indications and timing of transplantation need better definition.^{215,216,229,231}

Other patients with massive necrosis exhibit a more protracted clinical course with hepatic failure appearing from eight weeks to as long as 3 to 6 months after the onset of disease. These patients tend to be middle-aged or older and generally have lesser degrees of necrosis. Various names have been applied to this circumstance, reflecting different aspects of apparently the same basic syndrome; these include subfulminant hepatic failure, subacute hepatic necrosis, late onset hepatic failure, and impaired regeneration syndrome.^20,40,82 The mortality rate is considerable, ranging as high as 80%, and survivors appear to be at great risk of developing chronic hepatitis and cirrhosis. This conclusion is complicated, however, because the clinical and histologic features of these cases overlap with those of chronic hepatitis, and exact criteria for distinguishing the two are not clearly established.

Massive hepatic necrosis is characterized by extensive destruction of the hepatic parenchyma with confluent disappearance of the hepatocytes and eventual collapse of the reticulin framework (Figure 2-26). The necrotic zones contain a variable, but usually sparse, inflammatory infiltrate composed primarily of mononuclear cells, and pigment-laden Kupffer cells and other macrophages are often prominent. Lymphocytic endophlebitis of the central veins may be observed. Proliferated bile ductular structures with accompanying neutrophils are frequently conspicuous in and around the portal tracts (Figure 2-27); some of these structures appear to be composed of both hepatocytes and biliary epithelium and have been referred to as neocholangioles.⁸⁴ The combination of ductular proliferation, neutrophil infiltration and, in some instances, bile extravasates, can mimic biliary obstruction.²³⁵

Typically the necrosis involves entire hepatic lobules, but its extent varies from severe bridging necrosis, on one hand, to multilobular necrosis with extension into contiguous lobules, on the other. Lesions are irregularly dispersed within the liver, often with the left lobe most severely affected, and some areas may be relatively spared (Figure 2-28).^222,233

The surviving liver cells show a variety of alterations, reflecting in part the nature of the primary injury, but these may be minor in some cases. Evidence of hepatocellular regeneration with numerous mitoses and thickened cell plates is often pronounced, and poorly-defined parenchymal nodules may develop if the patient survives long enough. Regenerative changes may be absent in some cases, particularly in older patients. With adequate hepatocyte regeneration, the collapsed zones can be repopulated and the liver completely reconstituted. If, on the other hand, regeneration is deficient or the reticulin framework sufficiently disrupted, fibrous scarring can result with cirrhosis as a possible outcome.

The histologic features are generally not helpful in establishing an etiology, but occasionally the changes the residual liver can provide a clue. Most specifically, viral inclusions may be noted in cases due to herpes simplex virus, cytomegalovirus, adenovirus, or varicella-zoster virus, with immunohistochemical stains as a confirmatory aid. Wilson's disease is suggested by finding copper deposition, and Budd-Chiari syndrome or veno-occlusive disease by the presence of appropriate central vein lesions.²¹⁸

There is no strict correlation between the histologic changes and the clinical picture or outcome, but, in general, greater degrees of necrosis are associated with a poorer prognosis, with death commonly intervening when more than 65% to 80% of the hepatocytes are lost.^219,221,236 Note also that massive necrosis may occur as a focal process, frequently with a subcapsular distribution, in a wide variety of hepatic insults including liver transplantation.²³⁴ The ominous clinical implications of diffuse massive necrosis, of course, do not apply. Conversely, fulminant hepatic failure need not be associated with massive necrosis, as it may additionally result from severe but nonlethal hepatocellular dysfunction, as in Reye's syndrome, for instance.