The surrounding liver may show a variety of alterations, including those changes suggesting an adjacent mass lesion such as bile ductular proliferation with accompanying portal inflammation and sinusoidal dilatation, as well as the nonspecific finding of cholestasis or fatty change.^56,63

Histoplasmosis. Perhaps the most common of the systemic mycosis, histoplasmosis is found throughout the world, but is especially prevalent in highly endemic areas such as the Mississippi and Ohio River valleys of the central United States. The disease is contracted through inhalation of airborne spores of the soil fungus Histoplasma capsulatum and basically represents an acute respiratory infection that, in most patients, is asymptomatic and self-limited.⁴⁵ During this initial infection, the organism may transiently migrate by lymphohematogenous routes and covertly seed other organs, the liver among them, and the healed remnants of these foci may be discovered later. These lesions are usually located in and around the hepatic capsule and comprise dense fibrotic nodules, often calcified, with residual granulomatous inflammation; distorted organisms can occasionally be demonstrated by special stains. Other than indicating past exposure to the fungus, the nodules are of no great consequence and usually represent an incidental finding.⁷⁶

More dramatic hepatic involvement is associated with disseminated histoplasmosis. This rare, progressive form of the disease occurs primarily in individual predisposed by the extremes of age or immunocompromise; it represents one of the defining infection of AIDS.^293,318 Characterized by widespread infection of the mononuclear phagocyte system, disseminated histoplasmosis consequently affects a wide variety of sites including the spleen, lymph nodes, bone marrow, adrenal glands, gastrointestinal tract, and oropharynx, as well as the lungs and liver. The clinical spectrum is correspondingly broad, ranging from a severe, fulminant illness dominated by constitutional symptoms to an indolent, low-grade condition with localized manifestations and a more prolonged course.^46,87,92

Liver involvement is noted in 60% to over 90% of cases; often a prominent feature, it constitutes the major clinical manifestation in some instances.^61,92 Such involvement is typically manifest by hepatomegaly, sometimes marked and accompanied by splenomegaly, variable elevations of serum alkaline phosphatase and aminotransferase levels, and, less often, jaundice or hyperbilirubinemia. The diagnosis is best established by identifying the organism through culture or pathologic examination; liver biopsy is occasionally helpful in this regard.^46,107

The histologic changes of disseminated histoplasmosis encompass granulomatous inflammatory reactions of variable intensity and extent. At one end of the spectrum are well-formed epithelioid granulomas, which vary in size and are irregularly scattered within the parenchyma (Figure 8-11). Caseous necrosis is an inconsistent accompaniment, and multinucleated giant cells only occasionally seen; in some cases, the granulomas become large and confluent and may exhibit peripheral fibrosis. Considered in isolation, such lesions may be difficult to distinguish from the healing residua of preexisting primary infections noted above. Overall, epithelioid granulomas are reported in approximately 15% to 60% of disseminated cases, but tend to be associated with the mild, indolent form of the disease.^45,86,92,107

Less developed granulomatous reactions are characterized by loose aggregates of Kupffer cells and macrophages with occasional lymphocytes or other cells. These lesions often exhibit a central zone of necrosis, which is sometimes more conspicuous than the cellular reaction, and sparse multinucleated giant cells may be seen. These alterations are attended by nonspecific reactive changes including mild portal inflammation and scattered acidophilic bodies. In severe fulminant disease, the granulomatous response tends to be feeble, and the histologic picture distinguished by prominent accumulations of enlarged, fungal-laden Kupffer cells and other macrophages. These cells collect within the sinusoids, sometimes clustering in the periportal region, and may involve the walls of small blood vessels. There is little associated inflammatory reaction.^45,86

Coccidioidomycosis. This disease is caused by Coccidioides immitis, a dimorphic fungus endemic in arid regions of the southwestern United States, northern Mexico, and Central and South America. The primary manifestation is a benign, self-limited, and asymptomatic pulmonary infection. Progression to chronic lung disease is unusual, and dissemination to extrapulmonary sites -- most often the skin, musculoskeletal system, or meninges -- is even more uncommon, occurring in fewer than 1% of cases.²³ Groups susceptible to dissemination include pregnant women, certain racial and ethnic populations (blacks, Filipinos, and Hispanics) and immunocompromised hosts, including patients treated with immunosuppressive chemotherapy, recipients of organ transplants, and individuals with AIDS.^23,39,47

Liver involvement is noted at autopsy in roughly half of the disseminated cases, but this rarely gives rise to clinical manifestations. Some patients present with a hepatitis-like picture that includes jaundice, nausea and vomiting, abdominal tenderness, hepatomegaly, or fever. The serum aminotransferase levels may be moderately increased, and minor elevations of serum alkaline phosphatase and bilirubin values occasionally noted.⁵³

Other Fungal Infections. The liver may also be affected in disseminated infections with cryptococcosis, blastomycosis, paracoccidioidomycosis, or trichosporonosis.^10,35,59 For the most part, hepatic involvement is a minor feature identified at autopsy in fatal cases, although in rare instances, it represents a more prominent clinical manifestation. The histologic features comprise granulomas that are variably complicated by necrosis, suppuration, or eosinophilia, and the diagnosis is established by identifying the particular organism.⁸⁹

Schistosomiasis. Liver involvement is a major complication of schistosomal infections, particularly with Schistosoma mansoni, S. japonicum, and S. mekongi. Since these parasites are endemic in parts of Asia, Africa, the Middle East, and Central and South America, hepatic schistosomiasis may well be the world's leading cause of chronic liver disease.^36,40 Like other trematodes, the schistosomes have a complex life cycle: The eggs hatch in fresh water and, within the intermediate snail host, develop into the infective cercariae; these larval forms then penetrate human skin, migrate through the circulation, and eventually mature into adult worms that inhabit the mesenteric venous system. The mature females release large numbers of ova, some of which are carried by the portal veins and introduced into the liver. This egg deposition and the ensuing host response are primarily responsible for the hepatic consequences of schistosomal infection.^36,74

In the early acute stages, an active inflammatory response may be provoked. The portal tracts acquire an inflammatory infiltrate replete with eosinophils, sometimes resulting in eosinophilic abscesses, and focal hepatocyte necrosis and Kupffer cell hyperplasia are noted, but the inciting ova are only occasionally seen.^10,24

Of greater consequence is the development of chronic disease, the severity of which depends upon the intensity and duration of ova deposition.³⁶ The histologic hallmarks are granulomatous inflammation and fibrosis together with schistosome eggs in varying numbers. Epithelioid granulomas with occasional multinucleated giant cells are noted in portal tracts and are accompanied by scattered lymphocytes, plasma cells, and eosinophils (Figure 8-13). Fibrosis progressively surrounds and replaces the granulomas, and the portal tracts become enlarged and sclerotic (Figure 8-14); in time, fibrous septa link adjacent portal regions.²⁵ On occasion, sinusoidal fibrosis may also develop within the space of Disse.

Granulomatous inflammation and fibrosis may also involve the portal vein branches, variously producing endophlebitis, thrombosis, or sclerotic narrowing or obliteration. The result is extensive obstruction and destruction of the intrahepatic portal veins, particularly in the periphery of the liver, with intimal thickening of the larger vessels. In response, the hepatic arterial branches may proliferate, and irregular thin-walled collateral vessels, known as angiomatoids, can appear within the portal tracts.^10,24 In the absence of granulomas or ova, the distinction from hepatoportal sclerosis can be difficult. The intrahepatic bile ducts may also display evidence of epithelial damage or hyperplasia.¹⁰⁴

The extensive portal fibrosis seen in the severe forms of the disease represents the classic morphologic pattern of chronic schistosomiasis. This pattern has been eponymously designated as Symmers' fibrosis, but is more colorfully known as "pipestem" fibrosis because the dense sclerotic cords seen at gross examination resemble the stems of white clay pipes.⁶⁸ Despite the considerable fibrosis, the hepatic parenchyma remains largely unaffected, and, since nodular hyperplasia does not supervene, there is no progression to cirrhosis.

Nevertheless, the major consequence of chronic schistosomiasis is portal hypertension, which is produced by the blockage of the portal vein radicles and accordingly classified on a physiologic basis as presinusoidal. The affected patients, who comprise only a minority of those infected, thus present with esophageal varices and hepatosplenomegaly, with variceal bleeding a leading cause of death. In contrast to cirrhosis, however, hepatic function is generally well-preserved, and features of liver decompensation such as encephalopathy or jaundice develop only in endstage or complicated disease.^36,74

Visceral Leishmaniasis. This systemic infection, also known as kala-azar, is caused by Leishmania donovani, a protozoan parasite widely dispersed among tropical and subtropic regions including the Mediterranean basin and areas of South America, Africa, and Asia. The organism, which is transmitted to humans through the bite of the sandfly vector, infects and disseminates within cells of the mononuclear phagocytic system. The clinical manifestations therefore often include hepatosplenomegaly and generalized lymphadenopathy in addition to low-grade fever, pancytopenia, and nonspecific constitutional symptoms. More striking evidence of hepatic dysfunction is an uncommon feature.⁷⁵

Visceral Larva Migrans. The larval forms of certain helminths can aberrantly travel through human tissues, invading such as organs as the liver, lungs, brain, eyes, and heart. The clinical manifestations, collectively known as visceral larva migrans, are accordingly varied: Most patients are asymptomatic, but others exhibit fever, hepatomegaly, cough, or wheezing, and, in more serious cases, focal neurologic deficits or convulsions may occur. Peripheral eosinophilia is an almost universal feature.

The most common culprit is Toxocara canis, a common intestinal nematode of dogs. Humans acquire the organism by ingesting soil contaminated with egg-bearing fecal material, and children under six years are therefore most commonly infected. Other reported cases are associated with infections by Toxocara catis, Capillaria hepatica, Strongyloides stercoralis, and several Ascaris and Ancylostoma species.^10,67,82

The histologic findings comprise eosinophilic abscesses that are variably surrounded by a zone of granulomatous inflammation with epithelioid macrophages and multinucleated giant cells (Figure 8-16). The central necrotic zone may display Charcot-Leyden crystals, and, in rare instances, larval remnants are identified. The lesions heal with fibrosis and eventually produce focal white scars that may be seen upon gross examination.⁶⁷

Other Helminthic Infections. Several adult worms that reside in the portal venous drainage are capable of shedding ova into the liver and producing egg granulomas similar to those seen in schistosomiasis. Such lesions have been noted in infections with Capillaria hepatica (a rodent parasite rarely found in humans), Ascaris lumbricoides, and the several biliary trematodes, including Fasciola hepatica and Clonorchis sinensis.^10,28

Adult worms within the liver do not typically incite a granulomatous reaction, although one reported exception is ectopic Enterobius vermicularis.⁷⁰

Numerous additional pathogens spanning the microbial spectrum have been associated with hepatic granulomas. Although a conspicuous histologic feature in some of these infections, the granulomas are more often an inconsistent manifestation, sporadically reported and sometimes superimposed upon other histologic patterns.

Among the implicated viruses are cytomegalovirus and Epstein-Barr virus; a microgranulomatous response is commonly noted, but granulomas may also rarely develop, usually in the setting of mononucleosis and a prominent sinusoidal inflammatory pattern.³⁰ Poorly-defined granulomas and microgranulomas have been described in infections with Rickettsia conorii (boutonneuse fever), chlamydial diseases such as disseminated lymphogranuloma venereum and psittacosis, and occasional cases of syphilis.^10,49

Hepatic involvement in cat scratch disease is distinguished by granulomas, often with central necrosis or suppuration, just as in affected lymph nodes, and the pleomorphic cat scratch bacillus, now designated Afipia felis, may be demonstrated by the Warthin-Starry technique. Large confluent granulomas may detected radiographically or seen at time of laparotomy.^37,62,85 In Whipple's disease, noncaseating epithelioid granulomas may be noted in the portal tracts or parenchyma, but they lack the PAS-positive bacillary inclusions characteristic of the disease, which are instead found within Kupffer cells and other macrophages.^44,69

In other disseminated bacterial infections, a granulomatous response may be variably combined with suppurative inflammation and microabscesses; most often, the granulomatous component takes the form of microgranulomas, but true granulomas may also evolve. This combination is seen with such diseases as listeriosis, melioidosis, tularemia, and actinomycosis.^10,187,196 A similar picture may occur in systemic mycoses, particularly candidiasis, as noted above.

Isolated reports describe granulomas in such protozoan infections as acquired toxoplasmosis and giardiasis.^79,84,106

Sarcoidosis

Sarcoidosis is an idiopathic granulomatous disorder that may involve almost any organ, and among the sites most favored is the liver. Hepatic involvement is noted in approximately two-thirds of cases, with a range in various surveys from 20% to over 90%.^12,123 Most affected patients, however, are asymptomatic and exhibit no clinical or laboratory evidence of liver disease. As many as 30% of patients exhibit hepatomegaly or mild liver enzyme abnormalities, most commonly elevated alkaline phosphatase levels, but serious liver dysfunction manifest by jaundice, hepatic failure, or portal hypertension is a rare complication.^131,154

The classic histologic picture is characterized by well-formed noncaseating epithelioid granulomas. These prototypic lesions consist of sharply defined, compact aggregates of epithelioid cells with a scattering of multinucleated giant cells (Figure 8-17). The giant cells may be adorned by such captivating but nonspecific cytoplasmic inclusions as asteroid bodies, Schaumann bodies, or calcium oxalate crystals. An accompanying component of inflammatory cells including lymphocytes, macrophages, plasma cells, and eosinophils is commonly noted; these cells form a thin enveloping cuff in developed granulomas, but may be intermingled among the epithelioid cells in early, active lesions. Some granulomas may also demonstrate a small central focus of fibrinoid necrosis, distinguished by its granular or fibrillar appearance, but caseous necrosis is not seen. Granulomas may occur singly, in clusters, or in coalescent masses, and, although preferring the portal and periportal areas, they may be found anywhere in the lobule.^6,123

In mature and senescent granulomas, fibrosis becomes increasingly prominent, both within and around the lesions (Figure 8-18). Strands of connective tissue infiltrate into and dissect the granulomas, in time cleaving them into multinodular masses. In addition, the margin of the granuloma develops a pronounced mantle of concentric fibrous tissue. The eventual outcome is a dense, nodular scar, often hyalinized, which may contain a few residual giant cells. Although the histologic alterations are, by themselves, not diagnostic of sarcoidosis, the finding of multiple granulomas clustered within a fibrotic focus is strongly suggestive, particularly when potentially confounding conditions are excluded.

The granulomas in hepatic sarcoidosis may be joined by a variety of additional lesions, sometimes with particular clinical implications. Nonspecific reactive changes are occasionally found and comprise variable degrees of focal lobular necrosis and inflammation, portal infiltration by mononuclear cells, and Kupffer cell hyperplasia. When conspicuous, such changes may be mistaken for acute or chronic hepatitis. In general, these alterations tend to be more pronounced in patients with active clinical disease evinced by fever, arthralgia, or erythema nodosum.^123,131

The interlobular bile ducts are the focus of other alterations, including epithelial injury, granulomatous cholangitis, concentric periductal fibrosis simulating

primary sclerosing cholangitis, or, most notably, destruction and loss of the ducts.^{118,135,142,143} The disappearance of interlobular ducts leads to chronic cholestasis, characterized histologically by periportal hepatocyte swelling, copper accumulation, and occasionally Mallory bodies, and may ultimately give rise to biliary cirrhosis (Chapter 5). Clinically these patients experience a syndrome of protracted cholestasis with pruritus, jaundice, and markedly increased alkaline phosphatase levels; hepatic decompensation, portal hypertension, and death may follow. These cases share certain histologic and clinical features with primary biliary cirrhosis, but they generally can be distinguished by the presence of pulmonary involvement and absence of antimitochondrial antibodies. In singular cases, both disorders are reported to coexist, and the possibility of common pathogenetic factors has been raised.^126,130

Advanced disease, characterized by extensive fibrosis and even cirrhosis, develops in a small fraction of cases. The fibrosis can be attributed to healing of granulomas or, in occasional instances, to chronic cholestasis, although some scarring is unrelated to these lesions and additional pathologic mechanisms may also be responsible. The clinical consequences of these changes include portal hypertension with its accompanying manifestations. On occasion, however, portal hypertension occurs in the absence of significant fibrosis, and injury and compression of small portal vein branches by granulomas is presumably responsible.^151,154 Sarcoidosis has also been complicated in singular cases by the Budd-Chiari syndrome, developing because of granulomatous involvement of the hepatic veins.^140,144

Drug-Induced Granulomas ^124,132

Granulomas represent an important manifestation of drug-related hepatotoxicity, and several dozen agents have been implicated, including allopurinol, sulfonamide, phenylbutazone, hydralazine, carbamazepine, and diltiazem.^{117,119,129,153} The prevalence of drug-induced granulomas is difficult to define precisely, as many reports describe only isolated cases, but, in various series, drugs are held responsible for approximately 5% to 29% of hepatic granulomas.^1,9,132 The discrepancy reflects, in part, the problems involved in clearly establishing that a particular agent is the cause of the granulomas, especially when patients receive multiple medications and are affected by coexisting conditions.

The clinical and laboratory features are varied and nonspecific. Some patients are asymptomatic, while others present with fever and hepatomegaly. Features suggesting systemic hypersensitivity such as cutaneous rashes, lymphadenopathy, peripheral eosinophilia, hypergammaglobulinemia, and circulating autoantibodies are sometimes present. The serum aminotransferase and alkaline phosphatase levels are increased to varying degrees and may be strikingly elevated in some instances; hyperbilirubinemia may also be noted. The diagnosis, as with any drug-related injury, requires a high level of suspicion and a conscientious drug history and is based on a careful temporal correlation between drug administration and subsequent evidence of hepatic disease. Because the changes resolve rapidly once the drug is stopped, the diagnosis should be strongly considered in any case of unexplained hepatic granulomas.

Drug-induced granulomas consist of noncaseating granulomas of varying number and size. They range from compact sarcoidal masses to loose epithelioid aggregates and are distributed both in portal tracts and within the lobules (Figure 8-19). Multinucleated giant cells are often present, and the granulomas are variably infiltrated by lymphocytes, plasma cells, and, most notably, eosinophils. There are no histologic features that specifically indicate a drug etiology, but prominent infiltration by eosinophils provides a strong diagnostic clue; fungal, parasitic, and paraneoplastic granulomas are, however, included in the differential diagnosis. Fibrin-ring granulomas have been described in allopurinol toxicity, but they are an uncommon feature.^148,155

Granulomas can be the sole histologic abnormality, but they may be accompanied by a variety of further alterations. The lobules may exhibit minor reactive inflammation, fatty change, abundant microgranulomas, or, in more dramatic cases, canalicular cholestasis or active hepatocyte injury with cytoplasmic ballooning and acidophilic bodies.^119,134 Portal granulomas may be accompanied by bile duct injury, and associated acute cholangitis with ductal infiltration by neutrophils has been described.^129,136,149 Other reports indicate the presence of a vasculitis involving the hepatic artery or portal vein branches.^122,134 With cessation of drug therapy, the inflammation component wanes and normal histology is restored; fibrosis or progressive liver disease does not develop.

Other Associated Conditions

Roughly 50% of cases of primary biliary cirrhosis demonstrate granulomas. These range from poorly-demarcated aggregates of macrophages, usually in a periductal location, to discrete, well-organized granulomas that may be found in lobules as well as portal tracts (Figure 8-20). At their most distinctive, the granulomas develop in close proximity to damaged bile ducts and help form the classic florid duct lesion of primary biliary cirrhosis. The diagnosis is suggested by the presence of bile duct loss and chronic cholestasis, but granulomas can help separate primary biliary cirrhosis from potentially confounding conditions such as chronic active hepatitis (Chapter 5).^128,137 Granulomas have also been described in many other forms of liver disease, but generally as a nonspecific reaction rather than an integral feature of the condition; they may be seen, for example, in biliary obstruction in response to bile extravasation.

A wide range of extrahepatic inflammatory and autoimmune diseases may be accompanied by hepatic granulomas. The best example is Crohn's disease, but other disorders, including ulcerative colitis, rheumatoid arthritis, temporal arteritis, polymyalgia rheumatica, and Wegener's granulomatosis, have also been sporadically implicated. Chronic granulomatous disease of childhood is principally characterized by granular lipofuscin-like pigment within portal macrophages and Kupffer cells, but necrotizing and suppurative granulomas may also develop.^139,150 Many extrinsic substances can also incite hepatic granulomas, including aluminum, barium, beryllium, silica, starch, and talc.^10,127,133

Hepatic granulomas may additionally occur as a paraneoplastic phenomenon. Hodgkin's disease is the most frequently described association; epithelioid granulomas, rarely with caseation or with fibrin rings, are noted in as many as 12% of patients (Figure 8-21).^14,125,145 The finding of granulomas may antedate the diagnosis of Hodgkin's disease, and, in some studies, has been identified as a favorable prognostic sign, although this has not been confirmed in series with longer follow-up.^115,116,141 Other cases have involved non-Hodkgin's lymphomas, hairy cell leukemia, renal cell carcinoma, thymoma, and primary hepatic neoplasms.^{1,116,120,146}

Despite a proper diagnostic investigation, the cause of hepatic granulomas not infrequently remains obscure; this is true of up to 40% of cases in published series. In some instances, the cause becomes evident with further follow-up, and, in other cases, the granulomas are an incidental histologic finding, likely reflecting a nonspecific hepatic response that is without long-term consequences.^1,3,116 Therefore, once the major causes are excluded by appropriate studies, an exhaustive etiologic search is not usually justified.

Another group of cases without a defined cause are associated with a poorly-understood chronic syndrome with systemic manifestations termed idiopathic granulomatous hepatitis. These patients present clinically with fever and chills, malaise, weight loss, myalgias, arthralgias, or abdominal pain. Pertinent laboratory findings include an elevated erythrocyte sedimentation rate, anemia, and hypergammaglobulinemia, in addition to increased serum aminotransferase or alkaline phosphatase levels. In rare cases, the granulomas primarily involve the small portal and hepatic veins and may give rise to portal hypertension or the Budd-Chiari syndrome.^138,156 Granulomas may also be identified in such commonly biopsied extrahepatic sites as lymph nodes, bone marrow, or kidney, but pulmonary involvement is uncommon. The natural history of this syndrome is not well defined: the condition spontaneously resolves in some instances, but many patients require corticosteroid therapy for control of their disease. The nosologic status of the entity is debated, particularly because alterative diagnoses sometimes become apparent later, and the relationship with sarcoidosis is a point of contention.^{121,147,152,157}

This pattern of inflammation, as in other organs, is characterized by pronounced neutrophilic infiltration and active parenchymal necrosis. The lesions may take the form of grossly identifiable abscesses or be represented by small microabscesses, and the predominant cause is, of course, bacterial infections, but other agents may also provoke such a response.

Suppurative reactions may be confused with so-called surgical hepatitis, the small clusters of neutrophils that occur as artifactual lesions in surgical biopsy specimens. These clusters are distinguished by their distribution predominantly in subcapsular, sinusoidal, and centrilobular locations.^164,175,178 Steatohepatitis is also characterized by a neutrophil-rich lobular infiltrate, but is differentiated by its accompanying findings, including Mallory bodies, fatty change, and fibrosis.

Pyogenic liver abscesses are a dramatic but uncommon lesion, found in less than 1.5% of autopsied patients, and are rarely a consideration in biopsy interpretation. They develop, for the most part, as secondary suppurative foci carried from infections elsewhere by biliary or hematogenous routes. Although the incidence has been stable over several decades, the relative frequency of the primary infections has changed with improvements in diagnosis and treatment.^{162,168,169,173,179}

A frequent cause, accounting for up to 60% of cases, is bacterial cholangitis with ascension into the liver to form cholangitic abscesses. Bacterial cholangitis can complicate biliary obstruction of any origin, including gallstones, strictures, neoplasms, or parasites, and may follow endoscopic or surgical manipulation of the bile ducts. It is also associated with the enigmatic condition known as recurrent pyogenic cholangitis (Chapter 5). Many other intraabdominal inflammatory processes may also be responsible for hepatic abscesses, although they are a less common source than in the past. Included are acute appendicitis, diverticulitis, inflammatory bowel disease (particularly Crohn's disease), peptic ulcer disease, and gastrointestinal malignancies, all of which presumably lead to portal vein bacteremia and pylephlebitis.^165,182 Infrequent cases reflect systemic bacteremia associated with distant localized infections such as osteomyelitis, endocarditis, or pneumonia or with generalized septicemia. Bacteria may also be directly introduced into the liver, either by extension from a contiguous infection or by blunt or penetrating trauma, which includes liver biopsy and surgical procedures.¹⁷⁷ Furthermore, various preexisting cysts, malignancies, or infarcts may be secondarily infected. In 20% to 35% of cases, however, no cause is identified.^{159,162,168,179}

The infections are frequently polymicrobial, and their bacteriology reflects the diversity of primary sources. The enteric Gram-negative bacilli such as E. coli or Klebsiella are commonly isolated, but enterococci or, less often, staphylococcal or streptococcal species may be found; on rare occasions, Yersinia, Salmonella, or Hemophilus species have been identified.¹⁹³ Anaerobic organisms are present in up to 50% of cases, particularly those originating from gastrointestinal sources, and probably account for many of the "sterile" abscesses noted in early series. Implicated organisms include Bacteroides species, Fusobacterium species, and the anaerobic and microaerophilic streptococci.^159,162,174

The typical patient, given the common underlying causes, is middle-aged or older, although the age range is broad; the peak prevalence is in the sixth decade, and the sex ratio is roughly equal, although some studies show a slight male predominance. Predisposing factors include malignant neoplasms, diabetes mellitus, immunosuppressive therapy, other conditions associated with impaired host defenses, and, in children and newborns, chronic granulomatous disease, sickle cell anemia, and umbilical vein catheterization.^139,173,184 Most patients complain of fever, abdominal pain, and nonspecific constitutional symptoms, and hepatomegaly and abdominal tenderness are often noted. These symptoms are of short duration in many cases, but with more indolent disease, the clinical findings may be few and insidious in onset. Such patients, who often have idiopathic abscesses, may then present with fever of unknown origin or an unexplained hepatic mass.^{162,169,170,173,179}

Laboratory abnormalities include leukocytosis and elevated serum alkaline phosphatase and bilirubin levels, especially in cholangitis-associated cases, and minor increases in serum aminotransferases may be seen. Radiographic imaging studies such as ultrasonography, computerized tomography, and scintigraphy are highly sensitive, although nonspecific, techniques for detecting abscesses and are also useful in guiding percutaneous aspiration both for diagnostic and therapeutic purposes. The diagnosis can be suggested by appropriate radiologic studies and confirmed by positive bacterial cultures from blood or aspirated material.^{162,170,179,181}

Treatment involves appropriate broad-spectrum antibiotic coverage combined, in most cases, with drainage through either percutaneous or surgical means. The overall mortality rate is about 25%, but the outcome depends upon the timeliness of the diagnosis and the underlying illness; multiple small abscesses, delayed diagnosis, and advanced age are associated with a poorer prognosis.^{162,170,174,188}

Hepatic abscesses, similar to abscesses anywhere, appear grossly as destructive cavities filled with purulent, necrotic debris and are almost evenly divided between solitary and multiple types (Figure 8-22). As a rule, cryptogenic and traumatic abscesses tend to be single, while the cholangitic and bacteremic variants are commonly multiple. The right lobe is commonly favored, presumably because of its greater volume and preferential reception of superior mesenteric blood.¹⁷³ The size of the abscesses varies greatly, ranging from microscopic to several cm in diameter and exceeding 8 to 10 cm in approximately 20% of cases.^170,188

The histologic features entail intense neutrophil infiltration and necrosis with a variable zone of surrounding organization and fibrosis (Figure 8-23). On occasion, the responsible organism can be identified by Gram stains; this will help exclude nonbacterial causes of hepatic abscesses. The surrounding liver may show a variety of accompanying lesions: cholestasis, portal tract changes evincing bacterial cholangitis and biliary obstruction such as acute cholangitis, ductular proliferation, and neutrophil infiltration, and portal vein inflammation or thrombosis suggesting a pylephlebitic origin.

Hepatic involvement is common feature of neonatal listeriosis, particularly in the early-onset form associated with transplacental transmission.^167,176,192 Adult listerial infections are uncommon and usually opportunistic in nature; the clinical manifestation in most instances is meningoencephalitis, but the liver may be involved in disseminated cases, and an acute hepatitis-like clinical picture produced.^166,196 The histologic features comprise scattered microabscesses, often combined or supplanted by a microgranulomatous reaction (Figure 8-24); on occasion, true epithelioid granulomas may develop, and, in some cases, large abscesses detectable radiographically are noted.^158,171 In early untreated lesions, the causative L. monocytogenes can be readily identified as short, pleomorphic, Gram-positive bacilli, and, with appropriate therapy, the histologic changes rapidly regress.¹⁶⁶

Melioidosis is caused by Pseudomonas pseudomallei, a Gram-negative bacillus found primarily in Southeast Asia and adjacent locales. The clinical manifestations are variable, with pneumonitis the most common presentation, but liver involvement often occurs in the acute septicemic form of the disease. Histologically, multiple small microabscesses with a variable contribution of macrophages are noted, and the bipolar bacterial organisms can be demonstrated by special stains. In chronic melioidosis, the liver is less often affected, but localized suppurative foci with a surrounding rim of granulomatous inflammation and fibrosis may be seen.^186,187

Tularemia, the result of Francisella tularensis infection, is commonly accompanied by hepatic involvement, but this is seldom of clinical importance. The early lesions consist of small microabscesses with scattered macrophages. These later become surrounded by palisading epithelioid cells and fibroblasts, encircled by peripheral lymphocytes and occasional giant cells.¹⁰

Actinomycosis can secondarily involve the liver by portal venous spread from an antecedent intestinal infection or by direct extension from a contiguous infected site; in rare cases, no primary source is apparent. Overall, hepatic involvement is noted in approximately 15% of cases of abdominal actinomycosis and about 50% of disseminated disease.¹⁶³ Patients typically present with fever, hepatomegaly, and abdominal tenderness, and a history of prior appendicitis or abdominal surgery is frequently recorded.^172,180,183

Hepatic actinomycosis usually manifests as a large, solitary abscess composed of smaller pus-filled locules that impart a honeycomb-like appearance, but multiple abscesses or disseminated microabscesses may also occur.^160,163 On occasion, the lesions may extend beyond the liver and penetrate into adjacent organs, the diaphragm, the retroperitoneum, or the abdominal wall. The abscesses are encircled by a zone of active granulation tissue containing foamy macrophages and occasional giant cells, and their purulent centers contain the distinctive actinomycotic sulfur granules; these represent colonies of the actinomycete (usually A. israelii) and are composed of a tangled aggregate of Gram-positive filaments with an eosinophilic, club-like periphery of Splendore-Hoeppli material. In early cases, before discrete abscesses have formed, the histologic changes may consist only of mild nonspecific portal infiltrates.¹⁸⁰

Nocardiosis is primarily a pulmonary infection, but, with dissemination, almost any organ -- including the liver -- can be affected. The pathologic changes comprise encapsulated abscesses similar to those seen in actinomycosis, and a granulomatous response is sometimes present.¹⁰ The Nocardia organism are seen as thin, delicate filaments, Gram-positive and weakly acid-fast, that are scattered within the purulent exudate and, unlike Actinomyces, do not aggregate into granules.

In addition, disseminated candidiasis and cryptococcosis may be associated with hepatic suppuration and microabscess formation, although an accompanying granulomatous response is often predominant.

Small neutrophil aggregates within the parenchyma are also found in opportunistic cytomegalovirus hepatitis. In the right setting, they may serve as a diagnostic prompt, but the distinctive intranuclear inclusions are required to confirm the diagnosis (Chapter 2).^189,191

On occasion, an isolated microabscess is noted without any explanation.

Bacterial sepsis and bacteremia can produce a broad range of hepatic injury. The incriminated agents encompass all manner of Gram-negative and Gram-positive organisms, with E. coli, Streptococcus pneumoniae, Neisseria gonorrhoeae, and Legionella pneumophila as particular examples, and numerous extrahepatic infections may serve as the primary source including appendicitis, diverticulitis, pneumonia, pyelonephritis, endocarditis, and pelvic, subphrenic, or pelvic abscesses.

The most striking form of hepatic injury is suppurative inflammation with abscess and microabscess formation, as noted above, but there are, in addition, a number of less dramatic changes. Although these may result from the direct presence of the organism, in many instances they represent secondary alterations related to the actions of bacterial toxins or circulating inflammatory mediators and the nonspecific cellular injury that may accompany fever, malnutrition, hepatic hypoxia, hemolysis, and metabolic disturbances.

Among the most common of these secondary manifestations is cholestasis. Jaundice has a well-recognized association with bacteremia and extrahepatic infections, particularly in newborns, and, in prospective studies, up to 54% of bacteremic patients have elevated serum bilirubin levels, often with mildly increased serum alkaline phosphatase and aminotransferase values.^219,251,260 The corresponding histologic appearance can adopt several patterns. Canalicular cholestasis is frequently identified: bile plugs are found within dilated bile canaliculi, primarily in the centrilobular regions. This may occur as an uncomplicated lesion, but it may also be combined with minor lobular inflammatory infiltrates, Kupffer cell hyperplasia, or mild fatty change.^{201,208,272,278}

A more remarkable histologic pattern is ductular cholestasis, in which proliferated bile ductules at the margins of portal tracts accumulate dense masses of inspissated bile (Figure 8-25).^201,238 This is accompanied by neutrophil infiltrates in and around the ductules, and canalicular cholestasis may also be present. The pathogenesis of this lesion is uncertain, but bacterial endotoxins are thought to disrupt ductular processes involved in bile secretion. Ductular cholestasis is seen in settings other than sepsis, but its presence should suggest that diagnosis. Other cases are characterized by damage to the interlobular bile ducts with varying degrees of epithelial vacuolation, disruption, and necrosis. The extreme example is staphylococcal-induced toxic shock syndrome, in which acute cholangitis, presumably due to the bacterial toxin, may develop in the absence of biliary infection or obstruction.^226,273

A variety of nonspecific reactive alterations may also be noted, including focal hepatocyte necroses, mild parenchymal or portal inflammation by mononuclear cells or neutrophils, Kupffer cell hypertrophy and hyperplasia, and fatty change. At the more marked end of the spectrum, these changes may be difficult to distinguish from mild acute hepatitis. In cases of bacterial sepsis complicated by the development of septic shock, venous congestion and ischemic necrosis can supervene.^{201,208,269,275,278}

Acute systemic Salmonella infections are an uncommon but well-established cause of hepatic dysfunction, primarily in the clinical setting of enteric fever, which includes typhoid and paratyphoid fever. In general, the involvement is characterized by hepatomegaly and mild elevation of serum bilirubin and aminotransferases levels; jaundice or an acute hepatitis-like presentation are noted in fewer than 10% of patients.^{232,246,249,253} The most striking histologic feature is the marked hypertrophy and hyperplasia of the Kupffer cells (Figure 8-26). Aggregates of Kupffer cells, together with scattered lymphocytes and macrophages, create the classic lesions referred to as typhoid nodules. These microgranulomatous-like bodies are haphazardly scattered across the parenchyma, and the larger lesions may undergo central necrosis. In addition, focal hepatocyte necroses, fatty change, erythrophagocytosis, and portal infiltration by mononuclear cells may be present.^{199,233,246,249,253} The overall picture can simulate the mononucleosis pattern of acute hepatitis, but, in some cases, the changes are simply those of a mild nonspecific reactive hepatitis. The organism are not often detected in Gram-stained tissue sections, but they may be identified through immunohistochemical techniques.²⁰⁷ Salmonella may also infect preexisting hepatic cysts and masses and give rise to localized bacterial abscesses.²¹¹

Syphilis at any stage may be complicated by liver involvement. In congenital syphilis, hepatomegaly and jaundice are common but variable features, and elevated serum bilirubin and aminotransferase levels are often present.^241,248,271 The characteristic histologic changes include diffuse intralobular fibrosis, extending along the sinusoids and segregating small groups of hepatocytes (Figure 8-27). An accompanying mononuclear inflammatory infiltrate is focally or diffusely distributed, extramedullary hematopoiesis may be prominent, and, in rare instances, small granulomas are seen. Milder cases may demonstrate giant multinucleated hepatocytes with portal fibrosis and inflammation and be indistinguishable from other forms of neonatal hepatitis.^{241,248,258,277} In untreated cases, treponemes are plentiful and, with appropriate stains, can be demonstrated within the connective tissue, parenchymal cells, and small blood vessels. With therapy, the histologic abnormalities resolve, and permanent liver injury rarely ensues.²⁴¹

Hepatic involvement in early acquired syphilis is the subject of several case reports and a few larger series, but the prevalence is difficult to ascertain: Although figures ranging from 1% to as high as 50% have been proffered, the affected patients are susceptible to many other potential causes of hepatic injury, and the nosologic status of syphilitic hepatitis therefore remains uncertain.^267,270 The hepatic dysfunction is usually manifest only by abnormal laboratory tests, typically an unusually high serum alkaline phosphatase level and mildly increased serum bilirubin and aminotransferase levels, but jaundice, hepatomegaly, or an acute hepatitis-like clinical picture are sometimes recorded.^{204,217,256,268} The histologic features encompass a broad spectrum ranging from normal appearances or mild nonspecific reactive alterations to more severe inflammatory changes.^{206,217,231,261,267} Varying degrees of hepatocyte necrosis are accompanied by focal parenchymal infiltration by lymphocytes, eosinophils, neutrophils, and enlarged Kupffer cells. Mild fatty change and, in some instances, epithelioid granulomas may be seen.²⁴⁵ The portal tracts contain a mixed inflammatory infiltrate of lymphocytes, plasma cells, neutrophils, and macrophages, and active vasculitis or bile duct damage are described in sporadic cases.²⁵⁴ Although difficult to identify, spirochetes have been demonstrated with Warthin-Starry stains in some examples.²¹⁷ With treatment, the histologic changes generally regress, but persistent sinusoidal fibrosis has been reported.

The classic but rarely encountered hepatic lesion of late syphilis is the gumma, a variably-sized focus of central caseous-like necrosis surrounded by a inflamed fibrous wall with scattered granulomas and adjacent obliterative endarteritis. Gummas can be confused clinically with neoplasms or other space-occupying lesions and may be complicated by calcification, amyloid deposition, or hepatic vein compression with subsequent Budd-Chiari syndrome.^10,250,259 Healing leads to the irregularly distorted and densely scarred liver historically referred to as hepar lobatum.

Hepatic injury may also develop in infections by the arthropod-borne Borrelia spirochetes. Relapsing fever caused by B. recurrentis and several other species is occasionally associated with hepatomegaly, jaundice, and liver enzyme abnormalities, and hepatic failure supervenes in rare instances. Although the histologic features are not well documented in nonfatal cases, at autopsy, multiple foci of hepatocyte necrosis with neutrophils, macrophages, and hemorrhage have been described.²²⁹ In Lyme disease caused by B. burgdorferi, a mild clinical hepatitis manifest by minor elevations of serum transaminase levels may develop in the early stages and is histologically characterized by moderate portal tract inflammation. A more dramatic acute hepatitis pattern with hepatocellular injury and necrosis and parenchymal inflammation has been noted in one patient with recurrent disease.²²²

The spotted fever group rickettsioses may cause mild derangement of hepatic function but seldom give rise to clinically evident liver disease. The histologic picture varies from nonspecific reactive alterations with focal hepatocyte necroses and modest inflammation to scattered acidophilic necroses. Pronounced portal inflammation by neutrophils and large mononuclear cells may be accompanied by vasculitis of portal vessels in fatal cases of Rocky Mountain Spotted Fever caused by R. rickettsii, and poorly formed granulomas and fibrin-ring granulomas have been described in R. conorii infections.^{14,49,198,274} In addition, the zoonotic rickettsial organism Ehrlichia canis has been associated with biochemical evidence of hepatic disease, and a liver biopsy specimen from a severely ill patient showed portal and lobular inflammation with canalicular and ductular cholestasis.²⁴⁴

Hepatic amebiasis is one of the most common and serious complications of intestinal infection by the protozoan parasite Entamoeba histolytica. This infection is endemic in developing regions including much of Africa, Asia, and Latin America, but, with immigration and foreign travel, it is increasingly encountered in industrialized countries, where the prevalence in the general population is estimated at 1% to 5%.²⁴² Hepatic involvement occurs with invasion of the colonic mucosa and subsequent spread via the portal venous system; the amebae may then lodge in the sinusoids and produce lytic parenchymal necrosis that, with progression and confluence, eventually forms the grossly-identifiable amebic abscess.

The disease primarily affects young to middle-aged men: In most series, males account for over 80% of cases, and the peak incidence ranges from the third to fifth decade. Affected patients present with the acute or gradual onset of right-sided abdominal pain and tenderness, hepatomegaly, fever, and, in some cases, weight loss, and many have no clinical indication of intestinal disease.¹⁶⁹ The laboratory abnormalities include variable elevation of serum alkaline phosphatase and aminotransferase levels, mild or absent hyperbilirubinemia, and leukocytosis. Radiographic imaging by ultrasonography, computed tomography, or radionuclide scans is useful in detecting and localizing the abscesses, and the sensitive and specific serologic tests for ameba help establish an etiologic diagnosis. Aspiration of the abscess contents may be employed, particularly if the lesion is large or in danger of rupture, and may permit detection of the organism although the diagnostic yield is low. In most cases, treatment with metronidazole (or similar agents) rapidly leads to resolution, and the prognosis of uncomplicated cases is excellent.^{159,223,230,242}

Amebic abscesses are typically single and located in the right lobe, particularly near the dome, but some are multiple or situated elsewhere in the liver. Early lesions develop as a well-circumscribed foci of coagulative necrosis and progress to ragged, yellowish cavities, ranging from a few cm to over 15 cm in diameter, that are filled with thick, opaque, reddish-brown necrotic material. This represents the remains of lysed hepatocytes and is almost invariably described in gastronomic terms as resembling anchovy paste or chocolate pus. In established lesions, the necrotic cavity of amorphous, eosinophilic debris is surrounding by a sparsely inflamed fibrinous zone, a fibrous wall of varying thickness, and a peripheral zone of compressed normal liver (Figure 8-28). Neutrophilic inflammation is minimal unless secondary bacterial infection has supervened, and therefore the appellation "abscess", although traditional, is strictly a misnomer. The adjacent liver may show a variety of reactive alterations including focal hepatocyte necrosis, Kupffer cell hyperplasia, canalicular cholestasis, fatty change, and portal inflammation.^205,213,228

Hepatic involvement is common in malaria but seldom of great clinical consequence, despite the key role of the hepatocyte in the exoerythrocytic phase of the Plasmodium life cycle.²²⁵ Hepatomegaly, abdominal tenderness, and modestly elevated serum transaminase levels are frequently present, and mild hyperbilirubinemia, occasionally associated with jaundice, is noted in occasional cases.²²⁷ The histologic findings during the acute stages include sinusoidal congestion and pronounced Kupffer cell hypertrophy and hyperplasia, but the most distinctive feature is the presence of finely granular, dark-brown malarial pigment, accumulating initially in Kupffer cells and, with resolution, migrating to portal macrophages (Figure 8-29).²¹⁴ This pigment, also known as hemozoin, is birefringent, negative with PAS and iron stains, and consists of insoluble polymers of ferriprotoporphyrin derived from the parasite's breakdown of hemoglobin. Malarial pigment is similar in appearance to artifactual formalin pigment, and it strongly resembles schistosomal pigment, although the two are biochemically distinct; hemosiderin, which may coexist with malarial pigment, is distinguished by its positivity with iron stains, and anthracotic pigment by its lack of birefringence.^243,252 Additional histologic changes may include focal hepatocyte necrosis, microgranulomas, fatty change, and mild portal infiltration by mononuclear cells. In severe infections, parasitized red blood cells may be observed within the congested sinusoids, and centrilobular necrosis may develop.²²⁷

An unusual manifestation of chronic malaria is the so-called tropical splenomegaly syndrome, also known as the hyperreactive malarial syndrome or, more graphically, the big spleen syndrome.^215,216 This is characterized by a massively enlarged spleen, evidence of hypersplenism, and prominent infiltration of hepatic sinusoids by lymphocytes. The portal tract may also acquire a lymphocytic infiltrate and mild portal fibrosis can be seen, but malarial pigment is absent or sparse. The histologic appearances simulate chronic lymphocytic leukemia or the mononucleosis pattern of acute hepatitis, but the distinction can be made on clinical and laboratory grounds.

The biliary trematodes, or liver flukes, include Clonorchis sinensis, various species of Opisthorchis, and Fasciola hepatica, parasitic worms distinguished by their residence in human bile ducts. These organisms differ in certain aspects of epidemiology and life cycle, but, because of their biliary habitation, they all share similar clinical and pathologic manifestations. Clonorchiasis and opisthorchiasis are seen primarily in eastern Asia, while fascioliasis has a more widespread distribution, being particularly common in sheep-breeding regions. The infections are acquired through ingestion of freshwater fish or plants contaminated by encysted metacercariae. This infective form of the organism then excysts, gains access to the liver by migrating up the common bile duct or -- in the case of Fasciola -- by directly invading the hepatic parenchyma, and eventually matures and settles within the biliary tract. Clonorchis and Opisthorchis tend to locate in the smaller, more distal branches, but Fasciola, being a bulkier worm, generally occupies the larger bile ducts.^209,239,264

The histologic features comprise hyperplasia of the biliary epithelium with mucinous metaplasia and the adenomatous proliferation of small periductal glandular structures (Figure 8-30). These changes are accompanied by varying degrees of periductal fibrosis and inflammatory infiltration, often with prominent eosinophilia, and, in some cases, the culpable adult trematodes are identified within the ducts.^197,209,212 With advanced disease, the ducts may develop multiple saccular or cystic dilatations. Complicating episodes of biliary obstruction and secondary bacterial cholangitis can result in portal tract inflammation, cholangitic abscesses, and generation of intrahepatic pigment gallstones (hepatolithiasis). The end result in some cases corresponds to the clinicopathologic syndrome known as recurrent pyogenic cholangitis, although the exact pathogenetic contribution of the parasite, usually Clonorchis, remains controversial (Chapter 6).^210,264,276

In addition, granulomas associated with egg deposition may be found in sporadic instances.^10,197 Fascioliasis is further characterized by migration tracks that develop as the metacercariae pass from the peritoneal cavity, penetrate into the liver, and travel to the bile ducts. These tracks are variously composed of necrotic debris, eosinophil-rich inflammatory infiltrates, palisading histiocytes, and, with resolution, granulation tissue and fibrosis. They appear grossly as capsular and subcapsular nodules, gray-white to yellow, and may be mistaken for metastatic tumor.¹⁹⁷

An important complication of long-term Clonorchis and Opisthorchis infections is the development of cholangiocarcinoma. Although a causal relationship is not proved, the association is supported by several epidemiologic and experimental animal studies.^{209,218,247,257} In prospective studies, for example, there is a strong correlation between the presence of O. viverrini infection and the remarkably high incidence of cholangiocarcinoma found in northeast Thailand, and infected patients are at a estimated five-fold increased risk.^237,263 Histologic investigations suggest that the hyperplastic biliary epithelium and adenomatous proliferation induced by the parasite serve as precursor lesions, with subsequent epithelial dysplasia eventually giving rise to the carcinoma.^236,265

Although primarily an intestinal infection, ascariasis may also, on occasion, involve the liver. The adult nematodes may wander into the large bile ducts and sometimes even invade the liver parenchyma; the consequences include destruction and inflammation of ductal mucosa, biliary obstruction with secondary bacterial infection, hepatic abscesses, and the formation of biliary calculi. Death of the worm and subsequent release of eggs may be followed by a granulomatous inflammatory response.^234,235,240

Echinococcal hydatid disease is a zoonosis caused by the larval stages of cestodes of the genus Echinococcus, most often E. granulosus. Humans are infected accidentally by exposure to contaminated canine feces and thereby become the hosts of the slowly enlarging hydatid cysts. The infection is often asymptomatic, but patients may present with abdominal discomfort or an abdominal mass; more striking manifestations include bile duct compression, secondary bacterial infection, rupture into the biliary tract with consequent cholangitis, and penetration or rupture into the peritoneal or pleural cavities. Since the cyst fluid is highly antigenic, leakage can result in urticaria or anaphylaxis. Radiographic imaging is a reliable means of detecting the cysts, and, when internal septations and calcification are present, the diagnosis is virtually assured. Although sometimes employed, percutaneous cyst aspiration is generally discouraged because the risk of spilling cyst contents. The treatment of hydatid cysts is primarily surgical, with complete cystectomy the procedure of choice.^67,202,255 Intracystic injection of caustic agents can sterilize the cysts prior to resection, but this may damage the biliary tract and has, in some instances, produced secondary sclerosing cholangitis.^203,266

Hydatid cysts are typically single, unilocular, and spherical, with diameters ranging up to 35 cm and a predilection for the right lobe. Viable cysts are characteristically composed of three microscopic layers.^67,262 Innermost is the delicate germinal membrane, a thin lining of epithelial cells from which the brood capsules and their enclosed scolices develop. The scolices, which represent the incipient heads of the adult tapeworms, are the diagnostic feature serving to distinguish hydatid cysts from amebic abscesses and other cystic lesions (Figure 8-31). The inner layer is surrounded by a hyalinzed, white membrane of laminated, acellular PAS-positive material secreted by the parasite and then encompassed by an outer peripheral zone of granulation tissue and fibrosis that merges into adjacent parenchyma. In larger lesions, daughter cysts may develop; these can rupture, detach from the germinal membrane, and collect within the cyst fluid as so-called hydatid sand. The neighboring liver may show a variety of secondary alterations including compressed hepatic plates, irregular sinusoidal dilatation, or obstructive-type portal changes.

The cysts of E. multilocularis grow and develop in a rather different manner. Instead of being sequestered within an enclosed cyst, the germinal membrane forms small vesicles that invade into surrounding tissues, producing a multilocular fibrotic mass that infiltrates adjacent structures and spreads to distant sites in a manner reminiscent of a malignant neoplasm. The infection progresses through a protracted clinical course and is frequently fatal despite surgical excision; liver transplantation has been attempted in some recent cases.^67,221,224

Hepatic involvement in infections by the lung fluke Paragonimus and the pentastomids, a group of peculiar arthropod parasites, is characterized by fibrous-walled cysts filled with necrotic or suppurative debris, occasionally with a granulomatous response. These are typically inconsequential lesions discovered incidentally at surgery or during radiologic studies.^10,200,220

THE LIVER IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION^{280,288,290,294,300,301,305,307,310,311}

Evidence of hepatic dysfunction is common in human immunodeficiency virus (HIV) infection and its severe, life-threatening complication, the acquired immunodeficiency syndrome (AIDS), and will likely become a growing problem, particularly given the extent of the HIV pandemic, which is estimated to affect some 40 million people by the year 2000. Hepatomegaly and elevations in serum transaminase and alkaline phosphatase levels are noted in over two-thirds of these patients, and histologic abnormalities identified in over 85% of biopsy or autopsy specimens. Despite this frequency, however, liver disease is generally a minor component of the illness and, alone, contributes little to morbidity or mortality.

The liver is not a primary target of HIV infection, and most of the hepatic manifestations reflect disseminated infectious or neoplastic processes. Nonetheless, the p24 viral capsid protein has been identified in Kupffer cells and sinusoidal endothelial cells by immunohistochemical and in situ hybridization techniques, and, moreover, these cells in primary culture systems have supported replication of the virus. The implications of these observations are unclear, but they suggest that Kupffer cells serve as a reservoir for the virus and may, in addition, play a pathogenetic role in the hepatic dysfunction of AIDS.^292,299

The histologic features entail a wide spectrum of abnormalities, none of them unique to AIDS or HIV infection. Most commonly noted are various nonspecific alterations, largely reactive in nature, that likely reflect inflammatory and other processes elsewhere. These are identified in up to 60% of cases and include fatty change, focal hepatocyte necroses, Kupffer cell hypertrophy and hyperplasia, microgranulomas, and mononuclear portal inflammation.^280,312,319 Sinusoidal dilatation and, on occasion, peliosis hepatis have also been described; these may be associated with bacteria-like organisms, as discussed below, or Kaposi's sarcoma, but they may also be related to HIV-induced injury of sinusoidal lining cells.^285,292,313

Specific opportunistic infections are noted in about 30% of cases and, among reported cases, have encompassed virtually the entire range of microbial agents. Most of these infections are disseminated, and hepatic involvement is typically a secondary feature of the overall disease. The histologic findings generally correspond to those seen in other immunocompromised settings: reaction patterns are often poorly-formed or absent, and multiple infections are not uncommon. Biopsy specimens therefore require careful scrutiny and special stains for microorganisms should be routinely employed.

In most reported series, the most common culprits are M. avium-intracellulare and cytomegalovirus. On occasion, herpes simplex virus, adenovirus, M. tuberculosis, and various other atypical mycobacteria are also described.^291,296-298 Fungal infections such as cryptococcosis, coccidioidomycosis, histoplasmosis, and candidiasis may also occur, usually as widespread processes, although primary hepatic infections have been uncommonly reported.^{288,293,312,318} Although they typically produce extrahepatic disease, several protozoa have been described as hepatic pathogens, including Pneumocystis carinii and Microsporidia.^309,314,319 Histologically, P. carinii hepatitis is characterized by multiple foci of eosinophilic foamy exudate similar to that seen in pulmonary infection.

A curious AIDS-related infection is so-called bacillary peliosis hepatitis or hepatic bacillary angiomatosis.^295,308 Histologically, this infection gives rise to dilated, blood-filled parenchymal spaces containing foci of fibromyxoid stroma with proliferated capillaries and, as demonstrated by Warthin-Starry or similar stains, clumps of rod-shaped bacteria-like organisms. Although this agent resembles the cat scratch bacillus, it is now recognized as a rickettsial agent, Rochalimaea henselae, and is also responsible for cutaneous bacillary angiomatosis.³¹⁷

Granulomas are a frequent histologic feature, recognized in as many as 48% of biopsy specimens. These are often ill-defined and poorly-developed lesions with few multinucleated giant cells and little attendant inflammation. Mycobacteria or fungal infections account for most cases, but drug-induced granulomas, particularly to sulfonamides or isoniazid, are another possibility. In some instances, of course, the etiology is not apparent.^306,312

Additional histologic patterns are examples of chronic hepatitis, and the hepatitis B virus is frequently responsible. Overall, some 75% of AIDS patients have serologic evidence of past hepatitis B exposure, and an existing chronic infection is documented in about 10%; this prevalence is not surprising given the epidemiologic similarities between hepatitis B and HIV infections. In this setting, however, the resulting liver disease tends to be mild in both clinical and histologic terms. For example, liver biopsy specimens from HIV-positive patients are more apt to have chronic persistent hepatitis and display lesser degrees of inflammatory activity and fibrosis than do specimens from comparable HIV-positive patients, even when markers of active viral replication are present, although occasional examples of chronic active hepatitis and cirrhosis are nonetheless described.^289,304 The pathology of chronic hepatitis C and D in the HIV-infected patient is not well established, but there is some evidence for a more rapidly progressive course with coinfection with HIV and non-A, non-B hepatitis (presumably hepatitis C).³⁰³

Chronic active hepatitis have been reported in children with AIDS; the cause has not been established, but Epstein-Barr virus has been implicated in some cases.^287,315 In addition, neonatal hepatitis with giant cell transformation reported in one infected infant.³²⁰

On occasion, the interlobular bile ducts exhibit epithelial damage and destruction with intraepithelial lymphocytic infiltration and periductal fibrosis.^287,315,316 The large bile ducts are the focus of more striking alterations: irregular stricturing and dilation of the extrahepatic and major intrahepatic ducts and stenosis of the ampulla of Vater. These changes produce biliary obstruction of varying degree and are best recognized by cholangiography, where they yield a picture of secondary sclerosing cholangitis. Affected patients typically present with fever, abdominal pain, nausea and vomiting, and occasionally jaundice, and serum alkaline phosphatase levels are moderately increased. The histologic appearances on liver biopsy are inconsistent but portal inflammation, acute cholangitis, and changes of acute or chronic biliary obstruction may be noted. The cause of this AIDS-related cholangiopathy is not known, but biliary infections with cytomegalovirus or Cryptosporidium are commonly present and may even be identified on liver biopsy specimens.^{279,283,284,286,302}

The liver is also involved with such AIDS-associated neoplasms as Kaposi's sarcoma, high-grade B-cell lymphomas, and Hodgkin's disease. On occasion, these malignancies present as primary hepatic processes, but more often hepatic involvement simply reflects dissemination.^281,310

The role of liver biopsy in HIV infection is the subject of ongoing controversy. Although histologic abnormalities are common, a specific diagnosis is established in only about 40% of cases overall; the diagnostic yield is greater, however, in patients with elevated alkaline phosphatase levels or disease of longer duration.^212,306 Unfortunately, a precise diagnosis often does not translate into improved clinical management, since effective treatment is not available for many of the identified conditions, and therefore the advantages and disadvantages of liver biopsy need to weighed in each individual case.