key: cord-0040704-vl6m232o
authors: Masia, Ricard; Misdraji, Joseph
title: Liver and Bile Duct Infections
date: 2017-07-21
journal: Diagnostic Pathology of Infectious Disease
DOI: 10.1016/b978-0-323-44585-6.00011-4
sha: 5d9bcd526f7f5ea2052abc6aa7d33862b9460c2e
doc_id: 40704
cord_uid: vl6m232o

nan

T he liver is the target of many infectious agents, most notably hepatotropic viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV). In addition, many infectious organisms can involve the liver in the setting of disseminated infection, in immunosuppressed patients, or as a medical curiosity. The major challenge facing the pathologist in diagnosing these conditions is that many of these diseases have overlapping histopathologic characteristics. Hepatitis, necrosis, or granulomas are characteristic of many liver infections, and distinguishing the exact cause often requires a meticulous search for organisms, attention to subtle morphologic clues, or, not uncommonly, clinical, epidemiologic, or serologic data. Although some organisms can be readily detected in tissue, many are not, even with the use of ancillary techniques. Furthermore, many of the ancillary techniques used to detect organisms in tissue are not widely available. Therefore, although the pattern of injury can provide a differential diagnosis, in some cases the final diagnosis relies on culture or serologic studies.

Hepatitis A virus (HAV) is an RNA virus in the Picornaviridae family. Although the incidence of HAV infection has fallen dramatically since the introduction of vaccines, it still causes approximately 60,000 infections per year and occasionally causes dramatic outbreaks with fulminant hepatitis and death. 1 Fecal-oral transmission is facilitated by extensive viral shedding in feces during the 3-to 6-week incubation period, which reaches a maximum just before the onset of hepatocellular injury. 1 An increasing incidence has been noted among urban homosexual men. An effective vaccine has been developed.

The signs and symptoms of hepatitis A are related to patient age. In children younger than 3 years, more than 80% of infections are clinically silent, whereas in adolescents and adults, more than 75% of cases are symptomatic. 2 Symptoms include fever, malaise, abdominal pain, and jaundice. Marked transaminase elevations are characteristic. Approximately 100 cases of HAVrelated fulminant liver failure are reported each year, predominantly in adults. 2 Chronic infection does not occur. However, HAV infection can precipitate autoimmune hepatitis, which can progress to chronic hepatitis with fibrosis or cirrhosis. [3] [4] [5] [6] Liver injury in HAV infection is the result of an immunopathologic response to infected hepatocytes rather than a direct cytopathic effect of the virus. 1 The adaptive immune response is highly effective in eliminating the virus. The earliest antibody response is largely that of immunoglobulin M (IgM), with IgG production beginning shortly thereafter; therefore the diagnosis is established by the detection of anti-HAV IgM (with or without IgG). Anti-HAV IgG persists for life and confers protection against reinfection. 1 Acute HAV infection may be indistinguishable from other acute viral hepatitides (see discussion of hepatitis B). However, portal plasma cell infiltrates and periportal necrosis may be prominent, causing confusion with autoimmune hepatitis (Fig.  11 .1). 7 In rare cases, perivenular cholestasis with relatively little inflammation mimics cholestatic drug reactions. Fibrin ring granulomas have been reported. 8, 9 Hepatitis B Chronic hepatitis B affects an estimated 400 million persons worldwide, of whom 1 million die annually. 10, 11 Three-quarters of patients with chronic hepatitis B in the world are Chinese, and sub-Saharan Africa also has high prevalence. 11 In the United States the incidence of newly acquired HBV infection has been declining due to screening of pregnant women, vaccination, and safer injection practices. 10 

HBV is a DNA-containing virus with four overlapping open reading frames. 12 Its four genes are core, surface, X, and polymerase genes. The core gene encodes the core nucleocapsid protein, which is important in viral packaging, and hepatitis B e antigen (HBeAg). The surface gene encodes pre-S1, pre-S2, and S protein, which are large, middle, and small surface proteins, respectively. The X gene encodes the X protein, which may be important in carcinogenesis. The polymerase gene encodes a large protein that has a role in packaging and DNA replication. 12 There are eight major HBV genotypes: A is pandemic, B and C are found in Asia, D in southern Europe, E in Africa, F in the United States and South America, G in the United States and France, and H in South America. 11 To some extent, genotype influences the severity of hepatitis and its outcome. The severity of chronic hepatitis is greater with genotype C than with B, and there is a higher frequency of cirrhosis and hepatocellular carcinoma (HCC) in patients infected with HBV genotype C. A higher rate of virologic response is achieved among patients infected with genotype B, compared with genotype C. 13 

Hepatitis B is not directly cytotoxic to hepatocytes. Instead, the pathogenesis of HBV infection is related to the host immune response to viral infection. More vigorous immune responses cause more severe liver injury. Patients with a vigorous immune B A examination of the liver shows chronic hepatitis. 10 However, patients with HBeAg-negative chronic hepatitis tend to have lower HBV DNA levels than patients with HBeAg-positive chronic hepatitis and to have a more fluctuating course. 15 In addition, they are generally older and have more advanced liver fibrosis. 10 Resolved chronic hepatitis B is defined by the loss of HBsAg and acquisition of antibody to HBsAg. Approximately 0.5% of persons with inactive chronic hepatitis clear HBsAg yearly, and most of these will develop antibodies to HBsAg. 15 However, covalently closed circular DNA remains in the nucleus of hepatocytes, even in patients with serologic evidence of resolved infection, and poses a livelong risk for reactivation of infection. 15 Cirrhosis develops at an annual incidence of 8% to 10% in patients with HBeAg-negative chronic hepatitis and 2% to 5% in patients with HBeAg-positive chronic hepatitis. 10 Cirrhosis is the major risk factor for the development of HCC; the annual incidence of HCC is 1% for HBV carriers without cirrhosis and 2% to 3% for those with cirrhosis. 10 The risk factors for cirrhosis and HCC are similar and include high HBV DNA levels, HBeAg positivity, older age, and male gender. 10, 16 Additional risk factors for HCC include abnormal alanine aminotransferase (ALT) levels, long duration of infection, coinfection with HCV or hepatitis D virus (HDV), a family history of HCC, excessive alcohol intake, cigarette smoking, HBV genotype C, and core-promoter mutations. 10 

Acute HBV infection is indistinguishable from other forms of acute viral hepatitis. Portal tracts exhibit a moderate to marked lymphocytic infiltrate. Lobular mononuclear inflammation is associated with widespread lobular injury in the form of hepatocyte ballooning, although in the early stages the injury may be confined to centrilobular regions. Numerous acidophil bodies, canalicular cholestasis, and Kupffer cell hyperplasia may be seen. In more severe cases, bridging necrosis may span between portal tracts and central veins. Panacinar necrosis or multiacinar necrosis may also be a feature. Fulminant cases are characterized by submassive or massive necrosis with marked ductular reaction. Numerous macrophages laden with lipofuscin and hemosiderin may be seen in necrotic areas. Hepatic lobular regeneration may also be evident, with mitotic figures and lobular disarray. The latter can be highlighted by reticulin stains, which serve to delineate the loss of normal hepatic plate architecture.

The histology of chronic hepatitis B varies according to the phase of the disease and host immunity. The immune tolerance phase may show no or minimal portal and lobular inflammation and no fibrosis, despite rapid viral replication ( Fig. 11.2 ). In the immune clearance phase, chronic hepatitis B shows portal mononuclear infiltrates with interface hepatitis and variable fibrosis ( Fig. 11.3 ). Varying degrees of lobular necroinflammatory activity are present, but typically not to the extent seen in acute viral hepatitis. Hepatocyte anisonucleosis may be conspicuous. A characteristic feature of chronic HBV is the presence of groundglass hepatocytes (Fig. 11.4) , which contain HBsAg. These hepatocytes show a finely granular cytoplasmic inclusion that displaces the nucleus and is surrounded by a pale halo. Groundglass hepatocytes can be demonstrated by various histochemical stains, such as Victoria blue, orcein, or aldehyde fuchsin, 18 and by immunohistochemical stains for HBsAg. In some cases the hepatocyte nuclei have a "sanded" appearance due to the accumulation of HBcAg, although these are difficult to recognize and also are seen in delta hepatitis. 18 response may suffer fulminant infection with severe liver injury followed by rapid viral clearance, whereas hosts with less vigorous immune responses may become asymptomatic carriers. 10 

Transmission of HBV is parenteral. In developed countries, sexual contact, intravenous drug use, acupuncture, and transfusion constitute the most common modes of transmission. In developing countries, vertical transmission is more significant.

Acute hepatitis B manifests as an icteric illness after an incubation period of 6 weeks to 6 months in up to 50% of infected persons. 10 A subset of patients experience a prodromal phase characterized by arthralgias and urticarial skin rash. 14 Acute infection is diagnosed by the detection of hepatitis B surface antigen (HBsAg), IgM antibodies to hepatitis B core antigen (anti-HBcAg), and HBeAg. The outcome of acute hepatitis depends on the immune status and age of the host. Chronic HBV infection develops in as many as 90% of neonates and infants but in only 1% to 5% of immunocompetent adults. 10, 11 Patients with chronic HBV infection rarely have extrahepatic manifestations, such as polyarteritis nodosa or glomerulonephritis. 14 Many remain asymptomatic until they present with cirrhosis, HCC, or both.

The presence of HBsAg in serum for 6 months or longer is indicative of chronic HBV infection. Chronic HBV infection manifests in one of several well-defined stages. The immune tolerance phase is seen largely in patients who acquire infection at birth or in early childhood. These patients have high levels of HBV replication but little to no liver inflammation and normal serum aminotransferase levels. Serum HBeAg is detectable, and HBV DNA is markedly elevated. 10, 11, 15, 16 As the host immune system matures, the patient enters the immune clearance phase, which is characterized by immune-mediated liver injury. Patients who acquire infection as children come to clinical attention in this stage, and those who acquire infection as adolescents or adults have a very short or no immune tolerance phase and rapidly move into this second phase of the infection. Viral levels decrease, but HBV DNA is still elevated, and HBeAg is detectable. Serum aminotransferases increase, and liver histology shows active chronic hepatitis with evolving fibrosis. 10 Although most patients remain asymptomatic, some present with flares that mimic acute hepatitis, and this may precede the development of antibodies to HBeAg and remission of hepatitis activity. 10 Spontaneous seroconversion to anti-HBeAg antibody (HBeAb)-positive status occurs in up to 90% of white adults with chronic hepatitis B within 10 years of follow-up, and it is more likely in those with high transaminase levels, which indicate a vigorous immune response to HBV. 10, 16 Seroconversion is followed by the low or nonreplicative HBsAg carrier stage, characterized by normalization of aminotransferases and low or undetectable HBV DNA levels. 10, 16 Histologically, minimal to mild hepatitis with variable fibrosis is seen. 10 Most patients remain in this stage, particularly if they acquired the infection as adults; viral clearance may occur, but in patients with established cirrhosis, monitoring for HCC must continue. 10, 17 Up to 20% of patients serorevert to HBeAg-positive status, with a flare of activity. 10, 15, 17 In approximately 20% of patients, chronic hepatitis recurs without seroreversion; this is known as HBeAgnegative chronic hepatitis, due to mutations in the precore or core-promoter regions of the HBV genome. 10, 15, 17 In this phase, despite the presence of HBeAb and the absence of HBeAg, HBV DNA is detectable, serum aminotransferases rise, and histologic cytolysis. 19 Coinfection with delta virus can suppress HBcAg production and is one possible cause of a negative HBcAg stain in the setting of active hepatitis.

In general, immunohistochemistry findings for HBV antigens are negative in acute or fulminant hepatitis. Presumably, the inability to detect HBV antigen expression is a result of the short time interval of infection and insufficient accumulation of the proteins in hepatocytes to permit detection by immunohistochemistry.

The management of chronic HBV infection has improved significantly in the past decade with the introduction of nucleoside and nucleotide analogues. These agents are orally administered, well tolerated, and very effective at suppressing HBV DNA replication. 23 However, HBsAg clearance is rarely observed, and lifelong therapy is often required. Because lifelong treatment exposes patients to adverse reactions and high costs and may induce viral resistance, 23 the question of when to begin treatment remains an important one in the management of these patients. In general, patients with active disease benefit most from therapy. Although

Immunohistochemistry for HBV antigens can be used to evaluate the pattern of antigen expression, which correlates with viral replication and disease activity (Table 11 .1). Membranous expression of HBsAg in hepatocytes with strong cytoplasmic expression in individual hepatocytes indicates high viremia and is seen in the immune tolerance phase. 19, 20 In contrast, cytoplasmic expression of HBsAg in clusters of hepatocytes is more often seen in patients with low or absent viremia and without active viral replication; these cells contain integrated HBV DNA, and clonal expansion of such cells may explain their clustering. 19, 20 Expression of HBcAg can be cytoplasmic, nuclear, or a mixed pattern. Nuclear expression correlates with the degree of viral replication and the level of HBV DNA 21 ; biopsy specimens from patients in the immune tolerance phase or from immunosuppressed patients often show widespread nuclear staining, whereas those from patients with chronic hepatitis and low-replicative states have rare positive nuclei. Cytoplasmic HBcAg expression is associated with active liver damage and higher ALT level, 22 suggesting that HBcAg is the likely target for immune-mediated • Figure 11 .2 Liver biopsy in the immune tolerance phase of hepatitis B. A, Portal tract without inflammation or fibrosis. B, Immunohistochemical staining for hepatitis B surface antigen shows strong membranous staining of hepatocytes, as well as individual hepatocytes with strong cytoplasmic staining, consistent with high viremia. C, Immunohistochemical stain for the hepatitis B core antigen shows nuclear staining of many hepatocytes, consistent with high viral replication.

ALT can be an indicator of active disease, it has been shown that approximately 20% of patients with normal ALT levels have significant inflammation and/or fibrosis on biopsy, particularly among patients who are older than 35 years of age, who are HBeAg negative, or who have fluctuating ALT levels. 24 Therefore a liver biopsy is frequently used in questionable cases to determine whether there is sufficient necroinflammatory activity to warrant therapy. Current American Association for the Study of Liver Diseases (AASLD) guidelines recommend antiviral therapy for adults with immune-active chronic hepatitis B, whether HBeAg negative or positive. 15 Immune-active disease is defined as elevation of ALT greater than 2 times the upper limit of normal or evidence of significant histologic disease plus elevated HBV DNA above 2000 IU/mL (HBeAg negative) or above 20,000 IU/mL (HBeAg positive). 15 Additional factors, including gender, age, family history of HCC, and presence of extrahepatic manifestations, may be taken into consideration for patients whose ALT or HBV DNA levels do not meet these criteria. The AASLD recommends against treating adults with immune-tolerant hepatitis B, but ALT levels should be tested periodically to monitor for the transition to immune-active stage. 15 Moderate to severe necroinflammatory Ground-glass hepatocytes show finely granular cytoplasmic inclusions that displace the nucleus to the edge of the cell and are surrounded by a clear halo.

bodies, and extensive immunohistochemical evidence of viral antigen expression but with remarkably scant inflammation. 26, 27 A distinctive pattern of hepatitis in the transplantation population is known as fibrosing cholestatic hepatitis, initially described by Davies et al. in 1991. 26-29 This pattern is characterized by canalicular and cellular cholestasis, ballooning of hepatocytes, and scattered acidophil bodies with relatively scant parenchymal inflammation. Portal tracts are mildly to moderately inflamed and show periportal fibrosis, with immature fibrous tissue extending as thin perisinusoidal strands into the acinus. At the interface, a proliferation of ductal-type cells lends a hypercellularity to the portal areas. Immunohistochemical stains show extensive cytoplasmic and membranous expression with HBsAg and extensive nuclear and cytoplasmic HBcAg. 26, 28, 29 The combination of high HBV antigen expression, marked hepatocyte injury, and relatively little inflammation suggests that the virus itself may be cytopathic in this setting. 26, 27, 29 Fibrosing cholestatic hepatitis is associated with a high rate of viral replication, with high serum HBV DNA, high serum HBsAg titers, and rapid deterioration. [27] [28] [29] It has also been described in HBV infection in other settings involving immunosuppression, including human immunodeficiency virus (HIV) infection 30 and bone marrow transplantation. 31

Approximately 90% of HIV-infected persons show evidence of prior HBV infection, and 5% to 15% have chronic HBV infection. 32 In patients coinfected with HIV and HBV, the rate of clearance of HBsAg and HBeAg is reduced, compared with non-HIV-infected individuals. 33 This reduced clearance rate is most likely due to a weakened immune system. However, the reduced immune reaction is potentially responsible for the relatively reduced inflammation in these patients despite their higher HBV viral replication rates. 33 Even though there is reduced inflammation, HBV infection is more progressive in HIV-positive patients, including development of cirrhosis and its complications. 33 A pattern of hepatitis similar to fibrosing cholestatic hepatitis has been described in HIV patients with concurrent HBV infection. 30 The HBV-related mortality in HIV patients has increased since the introduction of highly active antiretroviral therapy (HAART), possibly because of increased immunologic injury to the liver with immune reconstitution, toxicity of the antiviral drugs, or longer life spans in HIV patients. 33 Conversely, the use of antiretroviral agents that also have activity against HBV may slow the progression of chronic HBV and even result in activity or fibrosis on liver biopsy warrants consideration to initiate antiviral therapy. 15 All guidelines recommend continuing therapy in HBeAgpositive individuals at least until they achieve HBeAg seroconversion and have undetectable HBV DNA levels followed by 12 months of consolidation therapy. However, many experts feel that HBeAg seroconversion is not an acceptable endpoint and recommend therapy until HBsAg is lost, particularly in patients with advanced fibrosis or cirrhosis. Because HBsAg clearance is rare, most patients will be treated for life. 23

Precore and Core Gene Mutations. Precore and core gene mutations are associated with decreased production of HBeAg despite continued production of infectious virions. The most common mutation results in a stop codon that prematurely terminates the synthesis of HBeAg. 16 Other mutations in the basic core promoter downregulate HBeAg synthesis at the transcriptional level. 16 Patients infected with these mutants exhibit absent HBeAg but positive HBsAg, elevated serum HBV DNA, and elevated transaminases.

Surface Gene Mutations. Surface gene mutations are responsible for vaccine escape. Although patients infected with these mutants are infectious, HBsAg is not detectable. 12 Polymerase Gene Mutations. Mutations in the YMDD catalytic site of the polymerase significantly reduce the effectiveness of lamivudine and famciclovir. 12, 25 Despite developing this mutation, patients continue to receive some benefit from lamivudine therapy because the YMDD variant HBV exhibits reduced replication competence and reduced virulence. 12 Discontinuation of lamivudine may cause mutant virus to revert to wild-type, with renewed efficacy of lamivudine. 25

HBV frequently infects liver allografts after transplantation for HBV and may lead to deterioration of graft function, although some patients enjoy excellent graft function for many years despite active viral replication. 26 The risk of reinfection is greater after transplantation for chronic HBV infection with cirrhosis, compared with acute HBV. 27 The pattern of hepatitis in this setting ranges from purely immunohistochemical evidence of viral antigen expression without histologic features of HBV infection, to acute hepatitis, and to chronic hepatitis with cirrhosis. 26 Acute HBV hepatitis after transplantation may show marked ballooning and degenerative changes in the hepatocytes, scattered acidophil jaundice, mild hepatosplenomegaly, maculopapular rash, and arthralgia. 35 Fulminant hepatitis is rare. A minority of patients (approximately 15% to 50%) clear the infection, but most develop chronic viral hepatitis. Symptomatic onset of disease and female gender are associated with a higher chance of viral clearance after acute infection. 45 The serologic diagnosis of chronic HCV infection is made by detection of HCV antibodies, usually by enzyme immunoassay. 35 These assays have a 95% to 99% sensitivity and can detect antibodies 6 to 8 weeks after exposure. Polymerase chain reaction (PCR)-based methods can detect HCV RNA 1 to 3 weeks after exposure. 35 Patients with chronic HCV infection may present with normal transaminases. These patients are often identified during blood donation or screening. The rate of progression to fibrosis or cirrhosis is very low in this group. 41 Patients with elevated transaminases may suffer from fatigue or from nonspecific symptoms. 41 Extrahepatic manifestations may include mixed essential cryoglobulinemia, membranous or membranoproliferative glomerulonephritis, non-Hodgkin lymphoma, Sjögren syndrome, lichen planus, autoimmune thyroid disease, and porphyria cutanea tarda. 35, 41, 46 A subset of patients with HCV demonstrate autoantibodies similar to those seen in autoimmune hepatitis, namely antinuclear antibodies (ANAs), smooth muscle antibody (SMA), perinuclear antineutrophilic cytoplasmic antibody (p-ANCA), and anti-asialoglycoprotein receptor, although often at lower titer than is typically seen in autoimmune hepatitis. 46 Less often, liverkidney microsomal (LKM1) autoantibodies are detected, although the epitopes recognized by these antibodies in HCV differ from those in autoimmune hepatitis type 2. 46 Patients with autoantibodies tend to be females and to have higher transaminase levels. 47 Some of these patients experience exacerbation during IFN-α therapy that may respond to steroid therapy, suggesting either preexisting autoimmune hepatitis or induction of autoimmune hepatitis in these patients.

The rate at which chronic hepatitis C progresses to cirrhosis depends on several factors. Factors that increase the rate of progression include male gender, older age at infection acquisition, longer duration of infection, immune suppression (e.g., HIV coinfection), HBV coinfection, alcohol use, and obesity. 35 The risk of developing cirrhosis is approximately 20% to 30% after 10 to 20 years of infection. 41 After cirrhosis has developed, the risk of liver disease-related mortality is 2% to 5% per year and the risk of developing HCC is 3% to 5% each year. 41

Acute hepatitis C is characterized by panlobular inflammation, numerous acidophil bodies, and lobular disarray similar to that seen in other acute hepatitides. A sinusoidal pattern of inflammation can mimic Epstein-Barr virus (EBV) hepatitis. More severe patterns of acute hepatitis, such as bridging necrosis or panacinar necrosis, are typically absent. Portal tracts harbor dense mononuclear infiltrates, resembling chronic HCV infection (Fig. 11 .5). Bile duct injury may be present. Cholestatic forms of acute HCV infection occur rarely, predominantly in the immunosuppressed population.

Chronic HCV infection is characterized by dense mononuclear cell aggregates or follicles in portal tracts, with mild to moderate interface hepatitis. 48 Bile duct injury may be prominent, although typically it is mild. The lobules show scattered acidophil bodies (Councilman bodies) or foci of lytic necrosis marked by a small cluster of mononuclear cells (Fig. 11.6 ). 48 Kupffer cell prominence and lymphocytic infiltration of sinusoids may be seen. 18, 48 Variable seroconversion, whereas their discontinuation can cause significant liver disease due to reemergence of HBV replication. 32

Hepatitis C affects between more than 170 million people worldwide. 34

HCV is an RNA flavivirus that was characterized in the late 1980s. 35 Its genome is a positive, single-stranded RNA with a large open reading frame that encodes a 3011-to 3030-amino-acid polyprotein. 36 This polyprotein is processed into an array of structural and nonstructural proteins. The structural proteins include the core protein and two envelope proteins, E1 and E2. 36 The nonstructural proteins are p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B (RNA polymerase). 34, 36 There are six major genotypes and more than 50 subtypes. However, the genome of HCV is highly mutagenic, and a given host carries a mixture of viral particles with closely related sequences known as quasispecies. 36, 37 The high mutation rate may allow the virus to escape the immune system; patients with chronic infection harbor highly diverse quasispecies, whereas those who clear the infection have low virus diversity and patients with fulminant hepatitis have the lowest level of viral diversity. 37 Genotypes 1, 2, and 3 have worldwide distribution, but their relative prevalence varies geographically. 38 Genotype 1a is the predominant genotype in North America (70%). 39 In Japan, subtype 1b is responsible for up to 73% of infections. Subtypes 2a and 2b are common in North America, Europe, and Japan, whereas subtype 2c is common in northern Italy. Genotype 3 is endemic in Southeast Asia, and it is also prevalent among intravenous drug users in Europe and the United States. 39 Genotype 4 is prevalent in North Africa and the Middle East; genotype 5 is largely confined to South Africa; and genotype 6 is found in Hong Kong, Macao, and Vietnam. 38, 39 The genotype affects the rate of evolution to chronic hepatitis, the severity of liver disease, and the response to interferon (IFN) therapy. 38 For example, genotype 1 is associated with a poor response to IFN therapy, whereas genotypes 2 and 3 respond more favorably. 39 An association between genotype 1b and an increased risk of developing severe liver disease and HCC has been reported. 39, 40 

HCV is primarily transmitted parenterally, such as by recreational drug use, injection with contaminated syringes or needles, or blood transfusion. 35, 41 Although sexual and vertical transmission occur, they are less important with HCV than with HBV. The incidence of HCV in the United States has fallen since the introduction of widespread blood donor screening and needle exchange programs. 37 However, since 2000, there has been an increase in the number of cases of acute HCV occurring in HIV-positive men who have sex with men (MSM). 34 Acute infection can be diagnosed in a variety of ways, including documentation of anti-HCV seroconversion and detection of HCV RNA in the absence of HCV antibodies. [42] [43] [44] The mean incubation time for HCV is 6 to 8 weeks. 35 Although the majority (60% to 75%) of affected patients do not experience symptoms when acutely infected, 35 acute HCV still accounts for approximately 20% of cases of acute hepatitis. 41, 45 The symptoms of acute HCV are malaise, fatigue, lethargy, anorexia, abdominal pain, of 52 liver explants for HCV-related cirrhosis had granulomas for which no other cause could be identified. 54 In a biopsy series, 14 of 155 biopsies for HCV had granulomas, but half of them could be ascribed to another cause (sarcoidosis, schistosomiasis, primary biliary cirrhosis [PBC], or mycobacterial infection). 55 In a large series of 542 biopsies for HCV, only 2% had granulomas. In that series, the presence of granulomas predicted a better response to IFN-α therapy. 56 Others have described granulomas in HCV after treatment with IFN-α in patients who did not respond well to IFN-α. [57] [58] [59] In short, when a granulomatous process is encountered in a patient with HCV, other causes of granulomas in the liver must be rigorously excluded before they can be attributed to HCV. A history of IFN-α therapy should be sought.

The granulomas in HCV may occur in portal tracts or in the lobules. It is well known that HCV can be associated with mild bile fibrosis is present, and its extent often drives the decision of whether to treat the infection. Demonstration of virus by immunohistochemistry 49 or in situ hybridization 50 has been described but does not play a significant role in the routine evaluation of liver biopsies in hepatitis C.

Mild to moderate steatosis is characteristic of chronic HCV infection. 48 Steatosis may be related to direct viral cytopathic effects in patients with genotype 3 but to underlying metabolic status in patients with other genotypes. 51,52 HCV core protein expression produces steatosis in mice through mitochondrial toxicity and production of reactive oxygen species. 51 The severity of steatosis correlates with fibrosis.

Sarcoid-like granulomas are occasionally seen in liver biopsy specimens from patients with HCV. In one series, 9.5% of hepatic granulomas were attributed to HCV. 53 In another series, 5 (10%) A B

• Figure 11 .6 Liver biopsy in chronic hepatitis C. A, Low-power view shows a dense lymphoid aggregate within a portal tract. Bridging fibrosis is also evident, with mononuclear infiltrates in the septum. B, Lobular inflammation shows lytic necrosis on the left with a cluster of mononuclear cells indicating a focus of hepatocyte necrosis and a Councilman body (apoptotic hepatocyte) on the right; the latter is characteristic of hepatitis C virusinfection.

those with genotype 1. Still, genotype may continue to be useful information in the decision of which combination to use because some, not all, DAAs have consistent activity across all genotypes and some genotypes are more likely to harbor resistance mutations. Despite the excitement IFN-free treatment of HCV has produced, the high cost of these drugs and other barriers to access remain as challenges to the eradication of HCV.

Historically, after transplantation for chronic HCV, reinfection of the graft was almost universal, although with the advent of highly successful therapy, patients will increasingly be treated before transplantation to prevent reinfection of the allograft. Although most patients do well in the long term, recurrent HCV can be progressive and can lead to graft dysfunction. The histologic features of recurrent HCV hepatitis progress from acute lobular hepatitis with scattered acidophil bodies and sinusoidal lymphocytic infiltration in the early stage to portal-based hepatitis with portal lymphoid aggregates typical of HCV infection in the chronic phase. 64, 65 Progressive fibrosis and cirrhosis of the graft may result. A rapidly progressive cholestatic form of HCV infection has been described in the transplantation population, similar to the fibrosing cholestatic hepatitis described with HBV. 66 Fibrosing cholestatic hepatitis secondary to HCV has also been described in other immunosuppressed patient populations, such as in HIV patients 67 and after heart or kidney transplantation. [68] [69] [70] 

In the United States and Europe 33% of HIV-infected persons are coinfected with HCV. 32 The clearance rate of HCV after acute infection is reduced in HIV-infected patients. 32 In chronic infection, HCV RNA levels are higher in HIV-coinfected patients, the efficacy of anti-HCV therapy is reduced, and the incidence of cirrhosis and HCC is higher. 25, 32, 33 In hemophiliac patients infected with HCV, coinfection with HIV has been associated with increased severity of hepatitis and increased risk of developing cirrhosis and liver failure. 71, 72 Fibrosing cholestatic hepatitis related to HCV has been described in patients with HIV coinfection. 67 With the introduction of HAART, HCV-related liver disease has become an important factor in hospitalizations and mortality of HIV patients. 33 Patients with HCV are more likely to suffer from hepatotoxicity related to HAART and to have impaired immune reconstitution. 32

HDV (delta virus) is a defective, single-stranded, circular RNA virus that requires the lipoprotein coat of HBV for its replication; therefore infection from HDV alone does not occur. Eight genotypes are known; genotype 1 is the most common worldwide. There are two modes of infection: coinfection with HBV and superinfection of prior HBV infection. The severity of hepatitis in coinfection depends on the virulence of the concomitant HBV infection and ranges from mild hepatitis to severe acute hepatitis with high mortality. 73 The usual outcome is complete recovery, and only 2% of patients develop chronic disease; resolution produces immunity to both viruses. Superinfection presents as exacerbation in a patient with preexisting chronic hepatitis or as a new hepatitis in a previously asymptomatic HBV carrier. In superinfection, chronic infection develops in more than 90% of cases. 73 HDV infection inhibits HBV replication, resulting in duct injury. If the granulomas are in the portal area, their presence in conjunction with injured bile ducts may mimic PBC. Other clinical information (e.g., antimitochondrial antibody [AMA], alkaline phosphatase level) may be needed to distinguish the two. After successful treatment of hepatitis C, most patients experience either stable or reduced fibrosis and have a reduced risk for hepatic decompensation and HCC. However, curiously, a small percentage of patients who appear to have been successfully treated for HCV actually continue to progress and may still have inflammation in liver biopsies. 60, 61 One factor that might explain this variable response is that patients with early cirrhosis are more likely to regress than those with advanced cirrhosis. In advanced cirrhosis, the extensive deposition of elastin and increased crosslinking of the extracellular matrix may prove more resistant to degradation. 61 Another theory that has been proposed as a possible explanation for this phenomenon is the concept of "occult HCV" in which very sensitive assays are able to detect the presence of virus in plasma, lymphocytes, and macrophages in patients with a confirmed sustained viral response (SVR). 61 Finally, genetic variants may be responsible because the rate of fibrosis regression differs among different ethnic groups. 61 Patients who did not enjoy a good response to therapy tend to progress similarly to those who were not treated. 60

The management of HCV has changed dramatically in the past several years. From the mid-1980s until 2014, the mainstay of treatment for chronic HCV included IFN. Standard IFN therapy was administered 3 times weekly and resulted in a fluctuating HCV RNA level. 62 By attaching a polyethylene glycol moiety to IFN (pegylated interferon [peg-IFN]), a single weekly injection became possible. The addition of ribavirin (RBV) to peg-IFN improved SVR rates and became the mainstay of therapy. 62 This combination achieved an SVR in approximately 40% to 50% of patients with genotype 1 and in approximately 80% of patients with genotypes 2, 3, 5, and 6. 63 An important discovery during this era was that polymorphisms of the interleukin-28B (IL-28B) gene predicted response to therapy in patients with genotype 1. 62 Among persons with genotype 1, the non-C/C genotype (CT or TT) was associated with reduced rates of SVR.

After the HCV genome had been mapped out, it became possible to target structural components of the virus itself. Directacting antivirals (DAAs) target several steps in the life cycle of HCV, including NS3-NS4A, NS5A, and NS5B RNA-dependent RNA polymerase. 63 In 2011 the first DAAs, boceprevir and telaprevir, protease inhibitors (PIs) of NS3-NS4, were approved for the treatment of chronic HCV, in combination with peg-IFN and RBV. 63 However, the initial enthusiasm for these agents was dampened by their significant toxicity. Second-generation PIs, such as simeprevir, have fewer drug-drug interactions and less severe side effects, with increased efficacy against genotype 1. 63 NS5B inhibitors include nucleotide/nucleoside polymerase inhibitors (NPIs) and nonnucleotide/nucleoside polymerase inhibitors (NNPIs). NPIs are incorporated into the nascent RNA chain and cause chain termination, whereas NNPIs act as allosteric inhibitors of the polymerase. 63 Sofosbuvir is the first NS5B NPI available in the United States and has become the backbone of HCV therapy given its high barrier to resistance, pangenotypic activity, and favorable pharmacologic profile. In 2014 IFN-free combinations became available that proved to have extremely high efficacy in achieving SVR in patients with chronic HCV, including patients considered difficult to treat, such as cirrhotics and disease largely restricted to underdeveloped countries with warm climates, it is being increasingly recognized in industrialized countries; indeed, a small percentage of presumed cases of drug hepatitis may be acute hepatitis E. 80 Among 400 patients with acute hepatitis in Montenegro, 6% were demonstrated to have HEV by the presence of IgM anti-HEV. 81 In immunosuppressed patients, chronic HEV infection with prolonged viremia has been described. Chronic HEV infection occurs largely in the solid organ transplant population, 82,83 but rare cases in HIV-positive individuals are described. 84 Chronic HEV might explain some cases of otherwise unexplained chronic hepatitis in liver allografts that, in some patients, leads to cirrhosis, sometimes requiring retransplantation. 85 Factors that predispose to chronic HEV include liver transplantation (relative to kidney transplantation) and tacrolimus immunosuppression rather than cyclosporin A. 82 Most patients eventually clear the virus, usually because of reduced immunosuppression, although treatment with RBV and peg-IFN may be beneficial in some patients.

Serologic diagnosis of HEV infection is hampered by the high prevalence of anti-HEV in the general population and a high false negative rate in immunocompromised individuals. The prevalence of anti-HEV ranges from 6% to 53% of the population, depending on the region surveyed. For example, in a nationwide survey of blood donors in France, 22.4% of the population had IgG to HEV and 1% of the population had IgM to HEV. 86 Areas of highest prevalence of IgG corresponded to areas of higher consumption of pork meat, raw pork liver sausage, game meat, offal, and oysters. In the United States the seroprevalence rate between 1988 and 1994 was 21%, with the likelihood of exposure increasing with age. 87 The presence of anti-HEV IgM is required to make the diagnosis of acute infection, but specific testing may not be available in all geographic locations. A rising IgG anti-HEV titer can provide evidence of infection, and PCR for HEV RNA provides additional supportive evidence.

The histopathology of acute HEV is similar to HAV in that it usually produces classic acute hepatitis ( Fig. 11 .7). Cases from endemic regions have been described as having ballooning degeneration of hepatocytes, apoptotic bodies, pseudorosette formation of hepatocytes, steatosis, and portal plasma cells. 88 Cases of little to no evidence of HBV replication, with antibodies to HBeAg and low HBV DNA. 73 Treatment with IFN-α inhibits HDV replication, but relapse is common.

HDV infection may be associated with autoimmune manifestations in a subset of patients. Anti-liver kidney microsomal 3 (LKM3) autoantibodies are detected in 13% of patients with HDV. 46 However, one study found liver-specific autoantibodies (anti-asialoglycoprotein receptor) and non-organ-specific autoantibodies (e.g., ANA, anti-SMA) in 60.3% and 22.1% of HBV patients, respectively, regardless of whether HDV was present. 74 The pathology of HBV and delta virus is indistinguishable from that of HBV alone, 75 except that the degree of inflammation and hepatocyte necrosis is often more prominent than with HBV alone. Liver specimens from an outbreak among Venezuelan Indians showed a range of histologic severity from diffuse small-droplet steatosis with focal necrosis in the earliest stages to confluent necrosis and, in the late stage, postnecrotic cirrhosis with massive collapse. 76 Immunohistochemistry in cases of hepatitis D demonstrates delta antigen in nuclei of hepatocytes, reduced or absent expression of HBcAg, but continued expression of HBsAg. [75] [76] [77] 

Hepatitis E virus (HEV) is a nonenveloped, positive-sense, singlestranded RNA virus of the Hepeviridae family. There are four genotypes: genotypes 1 and 2 cause human disease in endemic areas, predominantly in developing countries, whereas genotypes 3 and 4 infect animals and cause zoonotic infections in humans in nonendemic areas. The virus is spread through fecally contaminated water or food, and epidemics have occurred in central and Southeast Asia, the Middle East, and North Africa. 78, 79 In contrast, genotype 3 has been detected in domesticated pigs, wild boars, deer, and rodents and can be transmitted by porcine meat.

Most often, hepatitis E presents as acute hepatitis that is clinically indistinguishable from hepatitis A, ranging from asymptomatic infection to fulminant hepatitis. Mortality rate is 1% to 4% overall, but it is approximately 20% among pregnant women. 78, 79 In immunocompetent individuals, there is no progression to chronic hepatitis. Although hepatitis E has been regarded as a 

autochthonous HEV hepatitis due to genotype 3 show acinar and portal inflammation with lymphocytes, plasma cells, and polymorphs, with equal numbers of eosinophils and neutrophils. Neutrophilic or lymphocytic cholangitis, cholestasis, lobular disarray with ballooning degeneration, hepatocyte rosettes, perivenular edema, confluent necrosis, anisonucleosis, and Kupffer cell aggregates are also described. 89, 90 In transplant patients, biopsies may show mild portal and lobular hepatitis with acidophil bodies, progression to portal-based chronic hepatitis, and variable fibrosis including cirrhosis. 83, 85 George Barker Virus Type C (Hepatitis G)

During the investigation for the cause of non-A, non-B hepatitis, a virus was discovered that was initially classified as hepatitis G but is now considered nonpathogenic. In 1966 a surgeon, George Barker (GB), became ill with acute hepatitis, and his blood was used to infect marmosets, which developed hepatitis. Serum from these animals was used to infect other primates. Eventually, two viruses were discovered in this primate group and called GB virus A (GBV-A) and GB virus B (GBV-B), after the surgeon. 91, 92 Attempts to isolate these viruses from humans failed, but a related virus, GB virus C (GBV-C), was isolated from patient material. 91 Meanwhile, independent investigators discovered a novel virus that they classified as hepatitis G, and soon it was discovered that GBV-C and hepatitis G were genetically identical. 91 Like HCV, GBV is classified as members of the family Flaviviridae. 92 Most immunocompetent people clear the virus in approximately 2 years, although some patients have persistent viremia. Clearance of the virus is associated with the production of antibodies to the envelope glycoprotein E2. Infection with GBV-C is worldwide and common. One percent to 4% of blood donors are viremic at the time of donation, and another 13% have antibodies. 93 Among HIV-positive homosexual men, approximately 85% are viremic or have antibodies indicating prior infection, 93 evidence of sexual transmission. Prostitutes also have high prevalence. Other methods of transmission are transfusion and maternal transmission. 91 Because GBV-C was found in patients with hepatitis and at risk of developing parenteral hepatitis, it was initially believed to be a hepatotropic virus responsible for some cases of transfusionrelated hepatitis, acute hepatitis, or chronic hepatitis. However, the virus is actually lymphotropic, not hepatotropic, and no convincing association between the virus and human disease has been identified. 92 Therefore the virus is currently believed to be nonpathogenic.

The liver is involved in more than 90% of cases of infectious mononucleosis, which is caused by EBV infection; hepatomegaly is present in 10% to 15% of cases, splenomegaly in 50%, and jaundice in only 5%. Most often, the hepatic manifestations of EBV infection consist of self-limited elevations of hepatic transaminases. Rarely, EBV hepatitis has more serious consequences, such as the induction of autoimmune hepatitis, 94 severe hepatitis with jaundice, 95, 96 or liver failure. [97] [98] [99] Liver biopsy shows portal and periportal infiltrates of small and large lymphocytes, with occasional larger immunoblastic cells resembling the Reed-Sternberg cells of Hodgkin disease. A characteristic feature is sinusoidal infiltration by these same lymphocytes, which creates a beaded appearance ( Fig. 11.8 ). 100 Bile duct injury may be subtle. 95 Liver cell ballooning is not prominent, although hepatocyte regeneration, canalicular cholestasis, and Kupffer cell hyperplasia are variably seen. Areas of necrosis may be infiltrated by collections of mononuclear cells, creating a granulomatous appearance. Although these histiocytes usually do not form true epithelioid granulomas, well-developed nonnecrotizing granulomas 101 and fibrin ring granulomas have been reported in patients with EBV hepatitis. 102 In fatal cases, submassive lobular necrosis has been seen. 97 Detection of EBV is done by in situ hybridization for EBVencoded RNA (EBER) or by PCR for EBV DNA. 103 Immunohistochemistry for EBV latent membrane protein has not proved to be a reliable method for detecting EBV in EBV hepatitis.

In neonates, cytomegalovirus (CMV) infection has been associated with neonatal hepatitis or neonatal cholestasis, although establishing a serologic diagnosis in these cases is challenging due to maternal transfer of antibodies and poor IgM production in neonates. 104 Several studies have found CMV DNA in the serum or liver tissue of neonates with liver dysfunction or cholestasis. 104, 105 The histology in these cases may resemble extrahepatic biliary atresia, with portal expansion, bile ductular proliferation, and bile stasis. Fatal cases may show widespread hepatocyte necrosis, lobular disarray with pseudorosettes, giant cell transformation of hepatocytes, and ductular metaplasia of hepatocytes. 106 Cytomegalic inclusion bodies have been described in hepatocytes, endothelial cells, and bile duct epithelium. 106 However, inclusions may be absent by routine histologic assessment, and immunohistochemistry or in situ hybridization may be useful, although their utility in this population has not been formally studied. 105 CMV has also been implicated in extrahepatic biliary atresia, based on studies demonstrating CMV DNA in liver tissue, serologic evidence of CMV infection, or positive urine cultures in a subset of infants with biliary atresia. 107-109 Inclusions have not been described by histologic assessment. 108 Although intriguing, the possible association between biliary atresia and CMV may lead to delay in diagnosis of biliary atresia when a child presenting with cholestasis is found to have clinical evidence of CMV infection. 107, 108 Clinical evidence of CMV infection should not preclude evaluation for other causes of cholestasis, particularly biliary atresia, which requires early surgical intervention.

In adults, CMV infection is clinically mild and self-limited; CMV accounts for 8% of cases of infectious mononucleosis-like syndrome with hepatic involvement. Rare cases of massive hepatic necrosis have been reported, usually in immunocompromised hosts. In immunocompetent hosts, CMV infection can result in a histologic picture virtually identical to that of EBV hepatitis, with sinusoidal beading, atypical lymphocytes within sinusoids, lymphocytic infiltrates in portal tracts, and areas of necrosis with aggregates of Kupffer cells resulting in a granulomatous appearance. 110, 111 CMV infection is rarely associated with well-formed nonnecrotizing granulomas 112 or fibrin ring granulomas. 113 In immunocompromised patients, viral inclusions may be found in hepatocytes, endothelial cells, Kupffer cells, and duct epithelium ( Fig. 11.9 ). Virally infected cells show a large amphophilic nuclear inclusion surrounded by a halo, known as an "owl's-eye" nuclear inclusion, and coarsely granular cytoplasmic inclusions. The inclusions may be isolated, or they may elicit an inflammatory reaction that can be granulomatous or neutrophilic, the latter being especially common in transplantation patients. 110 In fact, a 

Herpes simplex virus (HSV) viremia can result in visceral involvement, affecting mainly the esophagus, lungs, and liver. Liver involvement occurs primarily in neonates, pregnant patients, and immunocompromised patients, although immunocompetent adults are rarely affected as well. 115, 116 Dissemination usually occurs in primary infection (particularly if the patient is immunocompetent) but has also been described in reactivation. 117 In children, severe protein-calorie malnutrition and the postmeasles Serology is of little use, especially in the immunocompromised patient. The appearance on liver biopsy resembles HSV. Immunohistochemistry can confirm the presence of a herpes virus, but, depending on the antibody, may not distinguish which one. PCR may be necessary to distinguish HSV from VZV infection.

Although infection by adenoviruses is generally restricted to the upper respiratory tract and conjunctivae in the normal host, disseminated infection can occur in immunodeficient patients, particularly liver transplant recipients, bone marrow transplant recipients, and patients receiving chemotherapy. 118 Sixty-four percent of cases in the literature occurred in patients younger than 18 years of age. 118 Liver biopsies or postmortem livers in patients with adenovirus hepatitis have shown widespread necrosis with little inflammation, mild steatosis, and viral inclusions with a deep blue-purple smudged appearance ( Fig. 11 .11). [118] [119] [120] Immunohistochemistry, in situ hybridization, electron microscopy, PCR, or viral culture can be helpful in confirming the diagnosis. 118,120

Parvovirus B19 produces several clinical manifestations, including erythema infectiosum (fifth disease) in children; hydrops fetalis; arthritis associated with acute infection in adults; various hematologic disorders (e.g., leukopenia, thrombocytopenia, transient aplastic crisis); and, rarely, involvement of other organs, including neurologic, cardiac, hepatic, and vascular disease.

The role of parvovirus B19 infection in acute or fulminant hepatitis is controversial. Several reports raise the possibility that parvovirus B19 may cause acute hepatitis, fulminant hepatitis, or fulminant hepatic failure. These cases describe several lines of evidence that implicate parvovirus B19, including the presence of parvovirus B19 DNA in the liver of patients with fulminant hepatic failure, the presence of parvovirus B19 DNA in liver tissue or serum of patients with acute or fulminant hepatitis, and the presence of IgM to parvovirus B19 in serum in patients with acute hepatitis. [121] [122] [123] [124] [125] [126] In patients with fulminant hepatic failure, 123 state predispose to disseminated HSV infection. 117 Oral ulcers and skin lesions may or may not be present. HSV hepatitis is rapidly lethal and requires early recognition and institution of antiviral therapy to improve outcome.

HSV hepatitis is characterized by patchy, nonzonal coagulative necrosis with minimal to absent inflammatory response ( Fig.  11 .10). Mild to severe fatty change may be present. 117 Intranuclear inclusions of two types can be found in hepatocytes at the edge of the necrotic foci, and virally infected cells are often multinucleated. 115, 116 Cowdry type A inclusions are large, eosinophilic intranuclear inclusions surrounded by a halo, whereas type B inclusions replace the entire nucleus with a basophilic groundglass appearance. Immunohistochemistry for herpes type I and type II antigens highlights the nuclear inclusions, and overlap between the two antibodies is frequent. 115, 116 Treatment with antiviral drugs before the biopsy is obtained may result in a biopsy specimen with extensive necrosis but without diagnostic inclusions. 116 The main differential is varicella zoster virus (VZV) infection and adenovirus infection, both of which have a similar histologic appearance; immunohistochemical staining or PCR may be necessary to distinguish these infections. HSV serologic studies are not helpful in establishing the diagnosis but virologic cultures may be positive.

Rarely, the rash of VZV can be accompanied by potentially lifethreatening noncutaneous manifestations, including encephalitis, pneumonitis, myocarditis, and hepatitis, especially in immunocompromised patients, neonates, and adults. Dissemination is virtually always seen in primary infection, although dissemination in reactivation can occur in the immunocompromised patient. 117 Primary infection in immunocompetent adults can cause severe acute hepatitis and, rarely, fulminant hepatic failure. Transplantation patients and immunocompromised patients are at higher risk for a fatal fulminant hepatitis. In children, the convalescent phase can be associated with Reye syndrome (microvesicular steatosis, hyperammonemia, coagulopathy, and cerebral edema), particularly if aspirin has been administered. 

Measles is a contagious, acute, febrile illness that predominantly affects children and causes a maculopapular rash, Koplik spots, cough, conjunctivitis, fever, and lymphadenopathy. The virus enters the body through the lungs or conjunctivae, replicates at these sites, and then is transported to the reticuloendothelial system, where further replication and lymphoid proliferation occur. Transient transaminase elevation is not uncommon in measles. 137 In one reported case, liver biopsy demonstrated acute cholangitis, periportal inflammation with lymphocytes, eosinophils and neutrophils, periportal hepatocyte necrosis, ballooning degeneration and cholestasis, and multinucleated giant cells ( Fig. 11.12 ). At autopsy, viral inclusions were noted in hepatocytes. 138

In 2003 a novel coronavirus was found to be the causative agent of severe acute respiratory syndrome (SARS), an atypical pneumonia that can progress rapidly to acute respiratory distress syndrome. Hepatic impairment is common in these patients, with elevated transaminases seen in approximately 60% of cases. Liver histology shows lobular hepatitis with occasional acidophil bodies, prominent Kupffer cells, increased numbers of hepatocyte mitoses, focal mild ballooning degeneration, and mild portal tract inflammation. 139

HIV is associated with liver disease in several ways. During seroconversion, a small proportion of patients may experience hepatitis with transaminase elevations, although the histology of this hepatitis has not been described. 140, 141 Opportunistic infections such as CMV, Histoplasma capsulatum, Mycobacterium avium-intracellulare complex (MAC), and Pneumocystis jiroveci can infect the liver. HIV can also increase the risk of progression of nonopportunistic pathogens, such as Mycobacterium tuberculosis, HBV, or HCV (see earlier discussions). Patients with acquired parvovirus B19 DNA was found in liver tissue in four of six patients with associated aplastic anemia and in two of four patients without aplastic anemia but not in six patients with known causes of acute liver failure. Histology studies in these and other 125 cases showed a range of injury, from mild lobular hepatitis to massive or submassive hepatic necrosis and collapse with either no inflammatory infiltrates or small aggregates of lymphocytes. Viral inclusions are not seen on routinely stained slides, but parvovirus VP1 antigen (a structural protein produced by the virus) was detected by immunohistochemistry in one case report. 125 In contrast, other investigators found no parvovirus B19 DNA by PCR in 33 cases of cryptogenic acute liver failure but detected parvovirus B19 DNA in several patients with known causes of acute liver failure. 127 In that study, several patients had low-titer IgM positivity without confirmatory PCR positivity. In another study, parvovirus B19 DNA was found with similar frequency in patients with fulminant hepatitis and with hepatitis B or C. 128 Furthermore, RNA transcripts could not be detected in any of the liver tissue samples, arguing against active viral replication. 120 These studies suggest that low levels of PCR positivity may reflect remote infection, and they raise questions about the role of parvovirus B19 in acute hepatitis and acute liver failure. The role for parvovirus B19 in chronic hepatitis is equally controversial. Although there are reported cases of chronic hepatitis secondary to parvovirus B19, 129 studies have shown that parvovirus B19 DNA can persist in liver tissue for prolonged periods. 130, 131 Whether coinfection with parvovirus B19 worsens the prognosis of patients with hepatitis B or hepatitis C is uncertain. Some studies found that coinfected patients have more severe disease, but most studies do not corroborate that finding. [131] [132] [133] 

Acute hepatitis has been reported in adults who acquire rubella. The morphology shows ballooning degeneration of hepatocytes, focal hepatocyte necrosis, and infiltrating mononuclear cells, similar to classic acute hepatitis. 134, 135 In addition, a case of fatal fulminant hepatic failure with giant cell transformation of hepatocytes in a child has been reported. 136 

The key findings are necrosis with numerous apoptotic hepatocytes (Councilman bodies), microvesicular steatosis, and absence of inflammation ( Fig. 11 .13). [153] [154] [155] [156] Eosinophilic intranuclear inclusions, Torres bodies, are rarely seen in humans. 157 Immunoperoxidase assays are not widely available, but the diagnosis can be confirmed serologically. The differential diagnosis includes other viral hemorrhagic fevers, such as dengue and Rift Valley fever.

The dengue virus, a member of the Flaviviridae family, is also transmitted by the Aedes mosquito. Dengue virus infection is one of the most important mosquito-borne diseases in the world, and the resurgence of this disease in the last few decades may be related to human population growth, inadequate wastewater management, lack of effective mosquito eradication programs, and emergence of more virulent strains. 158 There are four serotypes of dengue virus, and infection with one serotype confers future protective immunity against that serotype only. Infection with a second serotype may result in antibody-dependent enhancement of the illness with immune complex formation. 158 The clinical manifestations range from asymptomatic infection to severe infections known as dengue fever, dengue hemorrhagic fever, or dengue shock syndrome. Dengue fever manifests as high fever, severe headache, arthralgias, myalgias, and sometimes a rash. Patients with dengue hemorrhagic fever suffer from bleeding phenomena and circulatory failure. Dengue shock is caused by severe plasma leakage and manifests as cyanosis, hypotension, and encephalopathy. 158 The severity of hepatic involvement parallels the severity of the dengue infection. Serotypes 3 and 4 are associated with more severe liver disease. 158 Acute liver failure may develop at a median of 7.5 days after the onset of fever. 159 The prognosis varies; children may have higher mortality than adults. [159] [160] [161] The histology is characterized by necrosis, with Councilman bodies involving the centrilobular region or, as in yellow fever, zone 2, although in most cases the degree of necrosis is not as severe as in yellow fever (Fig. 11 .14). 156, 157 Other features include hemorrhage, edema, macrophages in sinusoids, and platelets in immune deficiency syndrome (AIDS) may develop unusual reactions to certain pathogens, such as bacillary epithelioid angiomatosis secondary to Bartonella henselae or Bartonella quintana infection (discussed later). 142, 143 Granulomas are a common finding in liver biopsy of patients with HIV infection. The more common causes are M. tuberculosis, MAC, Histoplasma, Candida, CMV, and Cryptococcus. 144 In some of these patients the granulomatous response is poorly developed and composed of loose aggregates of histiocytes, but silver or acid-fast stains show numerous organisms. Therefore acid-fast and silver stains should be done routinely on biopsy specimens from patients with HIV/AIDS. AIDS-related cholangiopathy is a syndrome that manifests with right upper quadrant abdominal pain, fever, and marked elevations of serum alkaline phosphatase. On cholangiography, the bile duct shows strictures and irregularities indistinguishable from those of primary sclerosing cholangitis (PSC). Several opportunistic pathogens have been implicated in this disorder, including Cryptosporidium, CMV, and microsporidia (Enterocytozoon bieneusi). [145] [146] [147] [148] [149] [150] In a significant minority of cases, there is no identifiable pathogen; it is unclear whether these cases are due to unknown pathogens, occult infection, altered immunity, direct infiltration of the bile duct mucosa by HIV, or PSC coincidentally occurring in patients with AIDS. 149, 150 The liver can be involved by HIV-associated neoplasms, such as lymphoma or Kaposi sarcoma. 151 The latter is caused by another virus, Kaposi sarcoma-associated herpes virus (KSHV), also known as human herpesvirus 8 (HHV-8). Finally, immune reconstitution with HAART can precipitate autoimmune hepatitis. 152

Yellow fever is a viral hemorrhagic fever that can vary from subclinical to rapidly fatal. It is transmitted by the Aedes mosquito. Classic symptoms include sudden onset of fever, rigors, and headache. Jaundice and hemorrhagic manifestations portend a poor prognosis. The pattern of injury is frequently described as midzonal and sometimes centrilobular. [153] [154] [155] [156] Others describe panlobular injury with only a collar (one or two cells thick) of preserved hepatocytes around central veins and portal tracts. 157 B A carcasses may become infected. Fever, severe headache, and myalgia may be followed by facial inflammation, encephalitis, and macular degeneration. 153 Hemorrhage and jaundice are poor prognostic features. Autopsies of cases with hemorrhage show hepatic necrosis, either widespread or predominantly in the periportal and midzonal areas, without prominent inflammatory infiltrates; numerous acidophil bodies; and hemorrhage. 153, 157, 168 

Lassa virus is associated with severe febrile illness among missionaries and travelers returning from West Africa. Symptoms include chills, malaise, headache, and myalgia. Petechiae, ulcerative tonsillitis, and lymphadenopathy are common. 153 The liver shows haphazardly distributed areas of hepatocyte necrosis, both as foci of contiguous cells and as individual cells, either acidophilic or coagulative in type. 157, 169 There is little inflammatory reaction apart from histiocytes phagocytosing necrotic debris. 169 The nonzonal distribution of the necrosis distinguishes this disease from yellow fever. 153, 169 

Ebola virus causes a severe and frequently fatal viral hemorrhagic fever. Outbreaks occur intermittently in Sub-Saharan Africa; the largest outbreak to date occurred in 2014-2016 and primarily affected Guinea, Liberia, and Sierra Leone. The disease is similar to Marburg virus infection, with disseminated intravascular coagulopathy and bleeding occurring in the majority of patients. 153 The histology is characterized by foci of hepatocellular necrosis randomly distributed throughout the parenchyma and eosinophilic inclusions within hepatocytes. 153, 157 Mild to moderate steatosis, mild mononuclear infiltrates in the periportal area, and Kupffer cell activation are additional findings. 157

Marburg virus has been associated with African green monkeys. Fever, malaise, headache, and myalgia may be accompanied by a the sinusoids with loss of endothelium. 162 Microvesicular steatosis is frequent, although relatively mild, and often localizes to the periportal space. 162 As with other arboviruses, little inflammation is present. 163, 164 The distinction from yellow fever may require geographic data, clinical features, and virologic studies. The contributions of virus, the immune response, or shock to the pathologic changes remain uncertain. 157, 165, 166 However, immunohistochemical demonstration of the virus within hepatocytes has been described. [162] [163] [164] Viruslike particles have also been detected in hepatocytes using transmission electron microscopy, and in the same case, dengue virus polypeptides were found by electron immunomicroscopy. 167

Rift Valley fever primarily affects sheep and cattle in Africa, although humans who have direct contact with animals or A B

• Figure 11 .14 Liver biopsy specimen from a patient who died of dengue shock demonstrates centrilobular necrosis with numerous acidophil bodies (right) and no inflammatory reaction.

is the most common cause of hepatic granulomas (accounting for approximately 50%), as opposed to non-TB-endemic countries where histoplasmosis, sarcoidosis, or PBC are more common etiologies. 171 Sinusoidal congestion and peliosis hepatis may also be seen. 183 Acid-fast bacilli (AFB) smears are positive in 0% to 59% of cases (median 25%), and organisms are more likely to be found with caseating necrosis, but smears may be positive due to infection from nontuberculous mycobacteria. 171, 175, 176, 178 Cultures provide the strongest evidence of hepatic TB, but the sensitivity may be less than 10%. Histologic evidence of caseating granulomas has a median sensitivity of 68% (range: 14% to 100%) and is generally sufficient to establish the diagnosis in TB-endemic areas. 171 PCR for M. tuberculosis DNA has a 53% to 88% sensitivity and a 96% to 100% specificity for detecting hepatic TB. 170, 184, 185 Immunocompromised patients may present with a wasting syndrome in which multiple organs, including the liver, contain necrotic miliary nodules surrounded by histiocytes that do not aggregate into well-formed granulomas. AFB stain shows numerous organisms in these lesions. 186 Prompt initiation of four-drug anti-TB therapy should lead to clinical improvement in most patients with hepatic TB. Localized hepatic TB includes tuberculoma and tuberculous abscess. Radiologically, it mimics tumors except that calcification may be prominent and may assume a bull's-eye configuration. 174, [187] [188] [189] The diagnosis in these cases is more elusive because liver biopsy, unlike in the setting of diffuse hepatic involvement, often shows nonspecific findings. Combined with the clinical and radiologic suspicion of malignancy, this may lead to surgical resection of localized hepatic TB. 190, 191 Grossly, localized hepatic TB appears as cheesy or chalky white, irregular nodules. Histologically, tuberculomas are composed of confluent granulomas, contain few organisms, and are encountered in immunocompetent patients, whereas tuberculous abscesses are centrally suppurative, contain numerous organisms, and are encountered mainly in immunodeficient patients.

Biliary involvement manifests as obstructive jaundice, which might have as its cause compression of the bile duct by a hepatic tuberculoma, small duct involvement by granulomas, or isolated biliary tree involvement. 173 The latter may result in bile duct strictures that can be mistaken for cholangiocarcinoma or PSC. 173, 180, 192 Biliary involvement mimicking cholangiocarcioma has also been reported with the atypical Mycobacterium abscessus. 193 In HIV patients initiating HAART, coinfection with TB may precipitate an inflammatory reaction to TB antigens known as the immune reconstitution inflammatory syndrome (IRIS). IRIS is characterized clinically by hepatomegaly, abdominal pain, elevated liver enzymes, jaundice, and constitutional symptoms, such as fever. The syndrome, which generally occurs within 8 weeks of initiation of HAART, may be difficult to distinguish from druginduced liver injury. Liver biopsy shows necrotizing and nonnecrotizing granulomas, but the granulomas may exhibit a more "inflamed" or "activated" appearance than is typical in TB (with numerous admixed neutrophils, lymphocytes, and plasma cells). 194

Of the atypical mycobacteria, M. avium and M. intracellulare are significant hepatic pathogens. MAC is commonly encountered in immunocompromised patients, particularly those with AIDS. These organisms cause disseminated infection that commonly affects lung, liver, spleen, lymph nodes, and bone marrow. Patients with hepatic involvement present with fever, elevated alkaline maculopapular rash and conjunctivitis. 153 The histology is similar to that of Ebola virus infection. On electron microscopy, many hepatocytes contain inclusions composed of uniformly packed filaments arranged in parallel arrays. 153

Worldwide, M. tuberculosis is one of the most common causes of hepatic granulomas. The organisms may reach the liver hematogenously from the lungs (or less commonly an extrapulmonary site), through the portal circulation in the setting of gastrointestinal tuberculosis (TB), or via lymphatics. 170 The prevalence of hepatic involvement in patients with active TB has been estimated at approximately 1%. 171 TB can affect the liver in several forms. Most often (approximately 80% of cases of hepatic TB), the liver is affected in the setting of generalized miliary TB. 172, 173 Less often (approximately 20%), hepatic TB manifests as a localized mass lesion that mimics a neoplasm, causes obstructive jaundice from extrinsic compression of the hepatic duct, or causes portal hypertension from compression of the portal vein. 170, 174 Localized hepatic involvement can occur in primary infection, in which case there is no evidence of antecedent infection, or as reactivation TB. 175 Tuberculous cholangitis, in which the bacillus primarily infects the biliary tree, is extremely rare. 176 Hepatic TB is common among HIV-positive individuals: it was identified in 26% of untreated HIV-positive patients undergoing liver biopsy in one series from Brazil 177 and may be found in the liver at autopsy in approximately a third of HIV-positive patients. 171 HIV-positive patients tend to have more severe manifestations of hepatic TB.

The most common presenting symptoms of hepatic TB are hepatomegaly, fever, respiratory symptoms, abdominal pain, and weight loss; splenomegaly, ascites, and jaundice may also be seen but are less common. 171 Diffuse abdominal pain is more common in localized hepatic TB, whereas respiratory symptoms (such as cough with or without sputum production) are more common in miliary hepatic TB. The relatively nonspecific presentation makes the diagnosis difficult in the absence of a high index of suspicion. Alkaline phosphatase elevations and hyponatremia usually are prominent features. 175, 178, 179 An inverted albumin to globulin ratio (A/G), in which serum globulin is 1.25 to 1.86 times higher than serum albumin, is common. 171 In 65% to 78% of patients with hepatic TB, respiratory symptoms or chest radiographs suggest pulmonary TB as well. 170, 175, 178, 179 Abdominal computed tomography imaging shows multiple hypodense micronodules throughout the liver or hepatomegaly without nodules, whereas in localized TB it shows one large solitary nodule or 2 to 3 hypodense nodules. 171 Liver calcifications are seen in approximately half of patients. 170, 173, 180, 181 Presentation with acute liver failure is rare but has been reported. 182 Liver biopsy with mycobacterial culture is considered the most specific diagnostic test for hepatic TB. Caseating granulomas are a hallmark of hepatic TB (seen in 51% to 83% of cases), particularly miliary TB in the setting of primary infection; in reactivation TB, noncaseating granulomas may be present instead (Fig.  11.15 ). 171 The granulomas may reside in the lobules or in portal tracts; the former location may be more common in miliary TB, whereas the latter may be more common in localized TB. 171 In TB-endemic countries, such as Iran, India, and Saudi Arabia, TB A B C leprosy. 199 The appearance of the granulomas depends on the type of leprosy. In lepromatous leprosy, collections of foam cells within the lobules or portal tracts contain numerous AFB. 199, 200 In tuberculoid leprosy, epithelioid granulomas with rare or no acidfast organisms are seen (Fig. 11.17) . 199 An individual patient may have both lepromatous and tuberculoid granulomas.

Bacillus Calmette-Guérin (BCG) is an attenuated form of Mycobacterium bovis, immunologically related to M. tuberculosis, that has been used as a vaccine against TB, as intralesional treatment of dermal malignancies, and as intravesical therapy for superficial bladder cancer. Hepatic granulomas have been described in patients after intradermal injections of BCG. 201, 202 Pneumonitis or granulomatous hepatitis, or both, affect 0.7% of patients who receive multiple intravesical instillations of BCG and are more likely after traumatic catheterization, extensive tumor resection, or bladder perforation. 203 Rarely, acute hepatic failure with encephalopathy may develop. 204 The liver shows noncaseating epithelioid granulomas, epithelioid giant cells, mild steatosis, hepatocyte necrosis, and portal inflammation. [205] [206] [207] Often, AFB phosphatase, and hepatomegaly. 195 The histopathologic findings range from numerous well-formed, nonnecrotizing granulomas with rare acid-fast organisms on Ziehl-Neelsen stain to less wellformed granulomas with large numbers of acid-fast organisms spilling out of the loose granulomas into nearby Kupffer cells (Fig.  11.16 ). 186, 196 Although the latter pattern differs from the usual case of hepatic TB, the degree of immune compromise, rather than the species of mycobacteria, may be the more important factor in determining the number of organisms and type of granulomas seen, because T-cell function is required for the formation of well-formed granulomas, and hepatic TB in patients with AIDS also may show large numbers of organisms and few well-formed granulomas. 186, 195 Granulomas in hepatic MAC may exhibit a portal or periportal distribution. 197 IRIS in HIV patients has been described with hepatic MAC. 198

Infection by Mycobacterium leprae commonly involves the liver, although clinical manifestations are often mild or absent. Hepatic granulomas are found in 90% of patients with lepromatous leprosy but in fewer than 20% of patients with tuberculoid several patterns. Microabscesses or pyogenic liver abscesses can be caused by a multitude of aerobic and anaerobic organisms, fungi, and parasites. Granulomatous hepatitis with or without a necrotizing component can be seen in a number of infections (Box 11.1). [213] [214] [215] However, in some entities the granulomas are not true epithelioid granulomas but rather aggregates of histiocytes in foci of parenchymal necrosis. Because these "microgranulomas" do not generate the same differential diagnosis as true epithelioid A B

• Figure 11 .17 Liver biopsy sample from a patient with leprosy. Several noncaseating granulomas are present. are not identified, and cultures are negative. This has led to the suggestion that the granulomatous hepatitis represents a hypersensitivity reaction to antigens present in the BCG preparation, 201 particularly because some cases show additional features of extrahepatic granulomas, leukocytoclastic vasculitis, or bile duct injury and eosinophils (Fig. 11.18 ). 208, 209 However, in some reported cases, AFB have been identified in the granulomas, blood cultures have been positive for M. bovis, or PCR for mycobacterial DNA has been positive, indicating disseminated BCG infection. [209] [210] [211] [212] Some have suggested that two types of adverse reactions may occur, one a disseminated infection that responds to anti-TB therapy and the other a sterile hypersensitivity reaction that is delayed in appearance and responds to steroids. 209

Bacterial infections of the liver can produce a wide range of pathology, including hepatitis, parenchymal necrosis, microabscesses, pyogenic liver abscess, and granulomatous hepatitis. Mixed patterns are frequent, and many organisms can produce B A granulomas, the diagnosis of "granulomatous hepatitis" in these cases is best avoided. Biliary involvement can produce acute cholangitis or cholecystitis.

Historically, pyogenic liver abscess was associated with acute appendicitis or intra-abdominal infection, and in those settings it was seen more often in children. 216 More recently, biliary disease has emerged as a common etiology, and with that shift, the age of the patients has also increased, to 55 to 60 years of age. [217] [218] [219] Diabetes mellitus is a strong risk factor for the development of pyogenic liver abscess. 219, 220 Other frequent comorbidities are malignancy, alcohol abuse, cirrhosis, hypertension, recent surgery, and immunosuppression. 217,218,221 A significant minority of cases remain cryptogenic. Although the disease carries a high mortality, improved diagnosis, abscess drainage, and antibiotic therapy have reduced the mortality rate to 5% to 31%. 217, 221 Patients typically present with fever, chills, right upper quadrant pain, and elevated alkaline phosphatase. 217, 218 Men are affected more often than women in most series. [217] [218] [219] Most abscesses are solitary; multiple abscesses occur in 25% to 45% of cases. [217] [218] [219] 221 Most abscesses are right sided (55% to 70%), with left-sided and bilateral disease occurring less often. 216, 217, 219 Liver abscesses are rare in neonates but may be seen in the setting of sepsis, particularly if there is a history of umbilical catheterization. 222 Culture of aspirated purulent material from the abscess or of blood may yield the offending organisms, although both of these are occasionally negative. Sometimes blood culture results do not correlate with pus culture results; therefore blood culture alone is not sufficient to determine the etiology. 217 Depending on the organism, serology may be useful. The most commonly isolated organisms are Escherichia coli, Klebsiella pneumoniae, Enterococcus, Streptococcus, and Pseudomonas spp. 217, 219, 221 A third of infections are polymicrobial (Fig. 11.19 ). Organisms that produce formic hydrogenlyase, such as Klebsiella spp. and E. coli, can convert acids that accumulate within the abscess to carbon dioxide and hydrogen gas; infection with these organisms can result in gas-forming pyogenic abscess, which carries a higher risk of septic shock, bacteremia, and mortality. 223 The incidence of K. pneumoniae abscesses has increased in recent years, and this organism is now the leading cause of pyogenic liver abscesses in Asia. K. pneumoniae abscess may be suspected on the basis of the following features on abdominal CT: a thin abscess wall, presence of necrotic debris within the abscess cavity, presence of metastatic infection, and absence of underlying biliary disease. 224 Abscesses secondary to Yersinia enterocolitica or Yersinia pseudotuberculosis are often associated with underlying hemochromatosis. [225] [226] [227] [228] Anaerobes are isolated in up to 25% of cases, sometimes together with aerobes. 218, 229, 230 Microaerophilic streptococci, Bacteroides fragilis, Fusobacterium necrophorum, and Clostridium spp. are the most commonly implicated anaerobes. Actinomyces spp. are infrequently found by either anaerobic culture of aspirated pus or identification of filamentous bacteria and sulfur granules on histologic examination of resection material (Fig. 11 .20); these organisms may be associated with the formation of sinus tracts. [231] [232] [233] [234] Rarely, Francisella tularensis, 235 Burkholderia pseudomallei (the agent of melioidosis), 236, 237 or Listeria monocytogenes 238 causes liver abscesses. Fungi, such as Candida and Aspergillus, are found in approximately 15% of cases. 229, 239 Complications of pyogenic liver abscess include metastatic infections, such as endophthalmitis, meningitis, osteomyelitis, pyelonephritis, and pneumonia. The two main risk factors for metastatic infection are infection with K. pneumoniae and underlying diabetes mellitus. 221, 240, 241 Although surgical management was once the mainstay of therapy, percutaneous drainage and antibiotics have become the first line approach. 217

The term acute cholangitis refers to an infection of the bile ducts characterized by jaundice, abdominal pain, and sepsis, in combination with biliary obstruction. Bacterial colonization of the biliary tree in the absence of obstruction produces no symptoms; conversely, sterile obstruction of the bile duct produces a picture of aseptic obstructive jaundice. 242 The route by which bacteria colonize the bile ducts is uncertain. Possible sources include reflux of intestinal contents through the choledochal sphincter; passage from an infected gallbladder; and lymphatic, hepatic arterial, or portal venous bacteremia. 242 Obstruction is most often due to 

C D E relatively minor histologic changes, and patients with mild symptoms can have frank abscesses. 249 Histology is also not predictive of survival. 245 Therefore clinical and microbiologic correlation is frequently required to make the diagnosis of acute bacterial cholangitis.

Most patients respond well to antibiotics. The efficacy of a specific antibiotic depends on its biliary secretion, which is affected by the size of the compound. The inflammatory process also can cause impairment of secretion. Treatment of the obstruction is necessary to prevent recurrence. Some patients require emergent biliary drainage in addition to antibiotics, and there may be a survival advantage to surgical management of the obstruction. 245 Complications of acute cholangitis include renal failure and the development of hepatic abscesses. 242

Recurrent pyogenic cholangitis is a disease that historically was seen largely in the Far East but is reported in increasing numbers in the West, largely among Asian immigrants. The disease is characterized by abdominal pain, fever, chills, and jaundice, resulting from recurrent attacks of suppurative cholangitis associated with intrahepatic biliary stones. 251 The cause is not fully known, but bacterial infection of the biliary tree is perhaps the inciting event. Enteric organisms, particularly E. coli, are cultured from bile in most cases. 251 Bacteria deconjugate bilirubin glucuronide, which then precipitates with calcium in the bile as soft, brown, friable calcium bilirubinate stones. 251, 252 Exactly what predisposes patients to biliary tract infection is unknown, but the geographic distribution of this disease mirrors that of Clonorchis sinensis and Ascaris lumbricoides, and biliary parasites are detected in a significant minority of patients. 251 Dead flukes and ova within the bile ducts, accompanied by bile stasis, may lead to bacterial infection. However, large numbers of people in endemic areas are infested with liver flukes without recurrent pyogenic cholangitis. In any case, the recurrent cholangitis results in intense periductal inflammation and fibrosis, strictures, and dilated ducts filled with sludge, predominantly affecting the left lobe. 252 Morphologically, large ducts show chronic and acute cholangitis, fibrosis, and peribiliary gland hyperplasia ("chronic proliferative cholangitis"). Pigmented stones and pus are seen in ducts;

gallstones. Other causes include strictures, malignancy, and congenital anomalies of the ampulla of Vater. How bactibilia and obstruction leads to biliary septicemia is uncertain. Cholangiovenous reflux with increased intrabiliary pressure can be demonstrated using contrast, and higher biliary pressures are associated with an increased incidence of purulent bile, sepsis, and bacteremia. 242 Manifestations of acute cholangitis range from mild, recurrent illness to overwhelming sepsis. Most patients are middle aged, and men and women are affected equally. Fever and jaundice are the most common symptoms. In 1877 Charcot proposed a clinical triad: right upper quadrant abdominal pain, fever, and jaundice. 243 Approximately 70% of patients present with the full triad. Reynolds arrived at a pentad in 1959 by adding hypotension and delirium. 244 Although rare, the pentad describes patients with high mortality risk. 245 Alkaline phosphatase and bilirubin are elevated in most patients, but blood cultures are positive in fewer than half of patients.

The bacteria that infect the biliary tree usually derive from the gut. The bacteria most commonly isolated from bile are E. coli, Enterococcus, Klebsiella, Proteus, Pseudomonas, and Enterobacter. 242, 246 Improved culture techniques have shown a significant incidence of infection by anaerobes, such as B. fragilis and clostridial species, frequently in association with previous biliaryintestinal anastomosis, an older adult patient, and more severe illness. 242, 247 Overall, 56% of cases are polymicrobial. Mycotic infection of the bile duct, principally by Candida albicans, is rare and affects older patients, patients with malignancy, immunosuppressed patients, and diabetics. 242 The histology of acute cholangitis is similar to that of large duct obstruction, with portal edema, neutrophilic portal and periductal inflammation, and neutrophils within duct epithelium. 248, 249 Ductular reaction and canalicular and ductular cholestasis may also be seen. 250 In some cases, neutrophils accumulate within the duct lumina; although this is suggestive of infection, the association is not sufficiently reliable to be predictive. 248, 249 Microabscesses and macroscopic abscesses may be seen. Thrombophlebitis may result in portal vein thrombi. 249 Patients suffering from shock may show necrosis of the liver. 249 Chronic changes include strictures, dilatations, portal fibrosis, and potentially ductopenia. Histologic findings frequently do not correlate with clinical status, in that most cases of acute cholangitis show should be considered in any patient with hepatic granulomas. 260 Some authors consider granulomas in brucellosis to be smaller and less clearly defined than in TB, sarcoidosis, or histoplasmosis 258 ; the term "microgranuloma" has also been used to describe them. 262 The presence of granulomas does not reliably distinguish among the various species of Brucella, 263-266 despite a report that B. melitensis is not associated with granulomas. 267 Other findings may include nonspecific acute hepatitis with hepatocyte necrosis, portal inflammation, and Kupffer cell hyperplasia. [256] [257] [258] 261, 266 Liver involvement by brucellosis generally follows a benign course, and a full recovery in greater than 95% patients is expected after treatment with doxycycline in combination with an aminoglycoside and/or rifampin. 256 Relapse of chronic brucellosis may be precipitated by viral illness or trauma. 257 The diagnosis is established by rose bengal test or Brucella agglutination titer (Wright serum agglutination test or standard tube agglutination [STA]), which are positive in greater than 90% of cases. 255, 256 Indirect Coombs test is almost invariably positive and may be used to make the diagnosis in patients with negative STA tests. Culturing the organism from blood, body fluids, or tissue is difficult; cultures are positive in only approximately 40% of patients, although the yield has increased in recent years due to improvements in technique. PCR testing for Brucella spp. DNA may also be performed.

Rarely, patients present with hepatosplenic abscesses or masslike lesions (brucelloma) mimicking a tumor. 257, 268, 269 In one series of 15 patients with brucelloma in the liver or spleen, half had suffered from brucellosis many years before, suggesting reactivation of latent disease. 270 Radiologically, brucellomas have central calcification with peripheral necrotic areas. 257, [268] [269] [270] [271] [272] Two general presentations of hepatosplenic Brucella abscesses are seen. The most common is a solitary liver abscess, often large and located in the right lobe, with a central calcification, which occurs only in adults and should immediately prompt suspicion of brucellosis in an endemic setting. A less common presentation is multiple small abscesses in the liver and spleen, known as "miliary" pattern, which occurs in children and adults and mimics disseminated TB. 268 Histologically, a brucelloma shows necrotic areas surrounded by a palisaded granulomatous reaction. 269, 270 Some cases may show only fibrosis with dense chronic inflammation. 272 Organisms are isolated from cultures of abscess material in only 18% of cases. When an organism is identified in patients with liver abscesses (combining cultures of blood and abscess material), the majority (80%) are due to B. melitensis, and the remainder are due to B. abortus (12%) and B. suis (8%). 268 In addition to antibiotics, management of brucellomas requires surgery in approximately half of cases, and resolution of the lesions is expected in the overwhelming majority of cases.

Cat-scratch disease is a self-limited infection caused by infection with Bartonella spp. after inoculation by a cat, which usually manifests as a local skin reaction and lymphadenopathy. Most cases are attributed to B. henselae, but B. quintana has been implicated in some. 273 Approximately 1% to 2% of patients with Bartonella infection develop severe systemic disease with involvement of the liver, spleen, bone, central nervous system, or lung. 274 Most patients with hepatosplenic presentation are children 5 to 10 years of age. 273, 275, 276 Patients often have nonspecific symptoms, including fever, abdominal pain, chills, headache, malaise, and weight loss. Approximately 25% of patients have liver abscesses may be present. 251 During acute infection, there is acute cholangitis with portal edema, erosion/ulceration of large ducts, and thrombophlebitis of portal vein branches. 253 Bile ductular proliferation with cholangiolitis and periductal fibrosis develops in small interlobular portal tracts. Small portal vein branches are reduced in number and may show fibrous obliteration. 253 Atrophy of liver parenchyma may also be seen. Biliary dysplasia and cholangiocarcinoma are complications and were seen in 13% and 23% of patients undergoing hepatic resection in one study, respectively. 254 The changes in small interlobular tracts may lead to consideration of PSC, particularly in the West; however, ductopenia in recurrent pyogenic cholangitis is not as significant as PSC, and ductular reaction is only rarely observed. 253 In addition, chronic cholestatic changes (such as copper deposition in periportal hepatocytes) are typically not seen, and progression to biliary cirrhosis is rare. These differences, as well as the different clinical presentations and epidemiologic associations, should allow distinction of recurrent pyogenic cholangitis from PSC and other biliary diseases in which secondary stone formation may occur. 253

Brucellosis is the most common zoonotic disease in the world, with 500,000 cases per year, and is particularly common in the Mediterranean basin, the Middle East, India, and Central and South America. It largely affects handlers of livestock, particularly those in the meatpacking industry, due to direct contact with animals and animal parts. It may also be acquired by ingestion of unpasteurized dairy products or infected meat, or by occupational exposure in veterinarians and clinical laboratory workers. The organism escapes destruction by replicating intracellularly within phagocytic cells, and thus involvement of the liver is common given its large population of reticuloendothelial cells. Although mildly elevated transaminases or hepatomegaly are seen in almost all patients, a true hepatitis (defined as a five-fold or greater increase in transaminases) is seen in approximately 25% of cases. 255 A cholestatic presentation may also be seen. Brucella melitensis accounts for most cases of hepatic involvement, whereas Brucella abortus and Brucella suis are seen in a minority of cases. Most (approximately 90%) patients present with an acute illness (0 to 2 months in duration) characterized by malaise, fever, chills, sweats, arthralgia, weight loss, and headache, but some patients become symptomatic after many years of dormancy or are episodically symptomatic. [255] [256] [257] Fever in brucellosis patients can be intermittent and has been described as "undulant fever." Subacute and chronic presentations are less common but do occur.

The characteristic histopathologic pattern of hepatic brucellosis is a granulomatous hepatitis. [258] [259] [260] In a series of 14 patients with brucellosis, all had hepatic granulomas in both portal tracts and lobules 261 ; in another, 28 of 40 patients (70%) had granulomas. 258 However, in a prospective study in which patients presenting with acute brucellosis underwent liver biopsy, the most common finding (15 of 20 cases, 75%) was a nonspecific hepatitis characterized by portal and/or lobular mononuclear inflammation. Of these cases, only four (20%) also showed granulomas. 262 The remainder of the cases showed mixed inflammation (one case, 5%) or no significant inflammation (four cases, 20%). Thus granulomas may correlate with more severe liver disease because in other studies liver biopsies were usually done because of biochemical evidence of liver dysfunction. Granulomas in brucellosis may be indistinguishable from TB or sarcoidosis, and brucellosis Kaposi sarcoma. 142 Similar lesions have been designated as bacillary peliosis hepatis; these are characterized by the presence of multiple blood-filled cystic spaces, foci of necrosis, fibromyxoid stroma, and clumps of granular purple material that correspond to organisms on Warthin-Starry stain and electron microscopy. 142 The latter lesions can be mistaken for nonbacillary peliosis hepatis. Although these infections can be progressive and fatal, they respond to antibiotics.

Enteric fever (the inclusive term for typhoid and paratyphoid fever) is caused by infection with Salmonella enterica serotype Typhi (Salmonella typhi) or serotype Paratyphi (Salmonella paratyphi). The disease is transmitted via the fecal-oral route from food or water contaminated by an acutely ill person or a chronic carrier. 280 Human beings are the only known reservoir. Most infections nowadays occur in countries where sanitary conditions are poor; the Indian subcontinent has a particularly high incidence. 280 Travelers to these areas can also be affected. Although S. typhi causes 80% of infections, S. paratyphi may be more important among travelers, possibly due to a vaccine effect that protects only against S. typhi. 280 In indigenous populations, enteric fever is a disease of young children and adolescents, whereas among travelers, the age of the patients reflects the age of travelers. 280 Ingestion of the organism is followed by an asymptomatic period of approximately 7 days, during which the organism multiplies within mononuclear phagocytic cells in Peyer patches, mesenteric lymph nodes, liver, and spleen. 281 This is followed by a bacteremic phase, with fever, chills, headache, and rose spots. During this phase, invasion of the gallbladder occurs, either directly or from infected bile. Chronic biliary carriage occurs in 2% to 5% of cases, even after treatment, particularly among women, older adults, and patients with cholelithiasis. 280, 281 In these cases, shedding of virus continues for more than a year and is a public health risk. The majority of patients experience minor degrees of hepatomegaly and elevated transaminases. However, the presentation can resemble acute viral hepatitis, with jaundice and very high transaminases or even fulminant hepatic failure, although coinfection with HAV or HEV may be responsible for lymphadenopathy, but often the classic skin papule of cat-scratch disease is absent. [273] [274] [275] Hepatic lesions are typically multiple and associated with abdominal lymphadenopathy and, in some cases, splenic lesions; many patients come to biopsy to exclude neoplasia. 274, 276, 277 On laparotomy, the liver may be found to be studded with hard nodules of varying sizes. 277 The hallmark lesion in hepatic cat-scratch disease is an irregular, stellate microabscess surrounded by a layer of palisading histiocytes, lymphocytes, and a rim of fibrous tissue (Fig. 11.21) . 274, 277, 278 Younger lesions may show more necrosis with less organization of the inflammatory granulomatous response, whereas older lesions may show confluent granulomas with scarring and scant residual necrosis. 274 These hepatic lesions are similar to the ones seen in lymph nodes in patients with cat-scratch disease, but they have also been noted in infections with Y. enterocolitica, F. tularensis, lymphogranuloma venereum, mycobacterial species, Candida, and Actinomyces. 274 Other lesions may appear as small, rounded granulomas with giant cells and small foci of central necrosis, similar to caseating granulomas in mycobacterial or fungal infections. The background liver parenchyma shows sinusoidal dilatation, portal mixed but predominantly lymphocytic inflammatory infiltrates, portal fibrosis, periductal concentric fibrosis, and focal bile ductular proliferation. 274 These changes are attributed to mass effect and are also seen in other infections that result in spaceoccupying lesions, such as pyogenic abscesses. 274 Warthin-Starry stains identify bacilli in some cases, and the organisms often cluster around vessels or along collagen fibers; the stain is not specific for the organism. 275 Culture is difficult. The diagnosis can be confirmed by PCR and Southern blot for Bartonella DNA on tissue, skin testing, or serology. 273, 274, 278, 279 The disease is self-limited without long-term hepatic dysfunction. The infection responds dramatically to rifampin, erythromycin, or doxycycline, but antibiotics are unnecessary in most cases.

Bartonella also may cause vascular proliferative lesions in the liver. Bacillary epithelioid angiomatosis is a vasoproliferative tissue reaction to B. henselae or B. quintana that usually occurs in immunocompromised hosts. Hepatic involvement shows sharply demarcated periportal areas in which the normal parenchyma is replaced by vascular tissue with extravasated erythrocytes, delicate spindle cells, neutrophils, and karyorrhexic debris, mimicking 

Percutaneous inoculation and inhalation are modes of transmission. Travelers can be exposed when they come in contact with wet soil, such as during adventure tours. 289 Occasionally, patients have chronic disease or reactivation of a latent focus years after leaving an endemic area, a possibility that caused concern for veterans returning from Vietnam. 289 Predisposing factors include diabetes mellitus, renal disease, alcoholism, cirrhosis, and immunosuppression. 236, 237 The acute form of the disease is characterized by abscess formation, predominantly in the lung, but seeding and abscess formation also occur in the liver, spleen, skeletal muscle, and lymph nodes; often, multiple sites are involved. 236, 237, 290 Large abscesses tend to be multiseptate and multiloculated, resulting in a "honeycomb" appearance on radiology. 235 Chronic melioidosis shows granulomatous inflammation with central irregular abscesses, indistinguishable from the stellate abscesses of catscratch disease, tularemia, or lymphogranuloma venereum. 290 The granulomas may show caseous-type necrosis, mimicking TB. 290 The lesions in chronic melioidosis are usually confined to a single organ. Serology is not completely reliable, but B. pseudomallei can be readily cultured from abscess material. 236 The organism can also be detected in Gram stains as a gram-negative bacillus with a characteristic "safety pin" appearance.

L. monocytogenes is a gram-positive, facultative intracellular bacillus that is an occasional contaminant of food, even despite proper refrigeration. Infection is associated with pregnancy, extremes of age, diabetes mellitus, and immunosuppression. Transplacental transmission causes granulomatosis infantisepticum, which is characterized by abscesses and granulomas in various fetal organs. 291 After ingestion, the organisms invade the Peyer patches and are transported to the liver, where they are cleared from the bloodstream by Kupffer cells. Some organisms escape from Kupffer cells and invade hepatocytes, where, protected from the host immune response, they replicate. Neutrophils are recruited to the area, forming abscesses, and after a few days, granulomas form in an attempt to impede further spread. After the organisms escape the granulomas and are released into the blood, they have a predilection for the central nervous system and placenta. 291 some of these cases. 280 Intestinal perforation, hemorrhage, and encephalopathy are the most important complications. The diagnosis is made by blood culture or Widal serology assay.

In the liver, hyperplasia of the reticuloendothelial system results in prominence of mononuclear cells in the sinusoids and typhoid nodules (Fig. 11.22) . 282, 283 Typhoid nodules are lobular collections of macrophages that ingest bacteria, erythrocytes, and degenerated lymphocytes. 283 These nodules may resemble granulomas but are not true epithelioid granulomas, although granulomatous hepatitis has also been described. 284, 285 Abscesses are rare. 286

Tularemia is caused by the coccobacillus F. tularensis. The disease is most often transmitted to humans by ticks or by animal contact, especially with rabbits. Inhalation outbreaks have been associated with lawn mowing and brush cutting in contaminated areas. 235 Most patients have pulmonary involvement. Other features include fever, cutaneous ulcers, lymphadenopathy, headache, and malaise. Hepatic involvement occurs in up to 75% of patients and includes hepatosplenomegaly and mild to moderate elevations of transaminases. 287 Severe cases may show jaundice. Liver histology shows suppurative microabscesses and areas of necrosis ( Fig.  11 .23). As the lesions age, they become more granulomatous. 288 The diagnosis is often established serologically because the organism is difficult to culture and is rarely seen on tissue Gram stain. PCR assays for F. tularensis in fresh tissue and on formalin-fixed tissue have been described. 235 

Melioidosis is a glanderslike disease caused by B. pseudomallei, a gram-negative aerobic bacillus that survives within phagocytic cells. The organism is a soil saprophyte that prefers wet soils and is an important community-acquired pathogen in Southeast Asia and northern Australia, particularly during rainy seasons. 237 Histologic examination of liver may show a variety of pathologic patterns. In most cases, portal inflammation with mononuclear cells or neutrophils surrounding damaged bile ducts (pericholangitis) is the main finding. 306, 307, [313] [314] [315] [316] Scattered foci of necrosis may be present in the lobules, sometimes accompanied by inflammation around the central veins and Glisson capsule. 304, 307, 309, 316, 317 Granulomatous hepatitis is described in some cases (Fig. 11.25) . 310, 317, 318 Rarely, other patterns can be seen, such as diffuse sinusoidal histiocytic infiltration or postinfantile giant cell hepatitis. 319 Spirochetes are only rarely identified in histologic sections with silver stains, such as Warthin-Starry or Steiner. 305, 311, 316 Organisms can be demonstrated with immunohistochemical stains. 303, [320] [321] [322] In tertiary syphilis, multiple gummas in the liver may mimic metastatic carcinoma. 323, 324 Histologically, gummas resemble TB, in that they are composed of masses of granulomas with caseating necrosis, surrounding fibrosis, chronic inflammation, and histiocytic inflammation. 324 Organizing abscesses with abundant eosinophils have also been reported. 323 Healed gummas may be replaced by fibrous scars (Fig. 11.26 ). Retraction of these scars can distort the liver by producing pseudolobules or so-called hepar lobatum. 324 Scars near the hilum may result in portal hypertension. Less commonly, secondary syphilis may also present as mass-forming lesions in the liver, leading to a radiologic diagnosis of malignancy. 303, 321, 322, 325 Lesions are typically multiple in number, ranging from two to innumerable, and may be up to 5.7 cm in size. Histologically the lesions consist of a variably cellular storiform spindle cell proliferation with mixed inflammation, sometimes with abscesses. 303, 323, 325 The lesions contain numerous spirochetes, particularly within the walls of small blood vessels. 303, 321, 322 The background liver may show mixed inflammation with portal edema, pericholangitis/cholangitis with duct injury, and granulomas. Although pathologically the lesions mimic a spindle cell neoplasm, awareness of the clinical scenario, as well as the background inflamed liver, should enable the pathologist to suspect syphilis. Treatment with intramuscular benzathine penicillin or, less commonly, oral ceftriaxone or doxycycline, should result in resolution of mass lesions and LFT abnormalities.

Congenital syphilis is frequently fatal, but surviving infants may have hepatomegaly and jaundice, with diffuse fibrosis. Spirochetes can be seen within connective tissue septa, parenchymal cells, and the walls of small vessels. 326

Leptospirosis is an acute febrile illness caused by Leptospira interrogans that affects humans and animals in all parts of the world. 327 The disease is biphasic, with a septicemic phase followed by an immune phase with antibody production and urinary excretion of the organism. 327 Most patients experience a mild anicteric illness, with fever, headaches, and myalgias. Severe cases, characterized by hepatic, renal, and pulmonary involvement, are known as Weil syndrome. 327 Liver pathology is predominantly a cholestatic hepatitis with reactive hepatocellular changes and Kupffer cell hyperplasia. 283, [327] [328] [329] Scattered Councilman bodies, bile within canaliculi, and mild portal inflammation may be seen. 283, 330 Very rarely, spirochetes can be demonstrated on silver stain. Immunohistochemical staining for Leptospira is also available from the Centers for Disease Control and Prevention, 328 and PCR assays can be performed from formalin-fixed, paraffin-embedded tissue. 331 However, the diagnosis is usually based on serologic assays.

Hepatic involvement can manifest as solitary liver abscess, multiple liver abscesses, or diffuse hepatitis (Fig. 11.24 ). 238, [291] [292] [293] Solitary liver abscess is associated with diabetes mellitus, absence of bacteremia or extrahepatic manifestations, and a relatively good prognosis. 238, 291 Multiple liver abscesses are more often associated with bacteremia, extrahepatic sites of involvement, and meningitis and carry a worse prognosis. 238, 291 Diffuse hepatitis is associated with underlying conditions, such as viral hepatitis, pregnancy, or alcohol abuse, 291, 294 although it may also occur in healthy individuals. 295 Bacteremia is highly likely in cases with diffuse hepatitis. The histology is that of an active hepatitis with extensive necroinflammatory activity, or sometimes a granulomatous hepatitis. 291, 294 Cholestasis and sinusoidal infiltration by mononuclear inflammatory cells may also be seen. 296 Diffuse hepatitis due to Listeria often mimics acute viral hepatitis clinically and pathologically (fever, jaundice, substantially elevated transaminases, active hepatitis on biopsy) and may lead to misdiagnosis and delayed treatment. [293] [294] [295] [296] [297] The diagnosis is made by culture of the organism from blood or abscess material.

Treponema pallidum infection can affect the liver in secondary syphilis, in tertiary syphilis, or congenitally. Involvement by the liver in secondary syphilis has been reported in men and women. It is common in HIV-positive individuals. Among HIV-positive patients with syphilis, the rate of liver involvement (based on abnormal liver function tests [LFTs]) is between 19% and 38%. [298] [299] [300] [301] However, others have argued that the true rate of syphilitic hepatitis in this patient population is substantially lower, given that many other etiologies may cause liver dysfunction in HIV-positive patients, including viral hepatitis, drug hepatotoxicity, and fatty liver disease. 302 Liver involvement by syphilis is also common among MSM, [303] [304] [305] [306] [307] [308] [309] possibly from portal transport of the organism after anal intercourse, 309 although this may be confounded by high rates of MSM among HIV-positive patients. [299] [300] [301] [302] [303] [304] A characteristic clinical picture is cholestatic jaundice, hepatomegaly, and a disproportionately elevated alkaline phosphatase level. 305, 307, 308, [310] [311] [312] [313] The trademark palmar rash of syphilis may be the key to diagnosis. 298 

Lyme disease is caused by Borrelia burgdorferi and is transmitted by Ixodid ticks, usually during the months of May through October. Hepatomegaly and symptoms of hepatitis are uncommon. Elevated transaminases indicate mild hepatocellular injury, although a nonhepatic source is possible in the case of Lyme disease-associated myositis. 287 In the liver, mononuclear cells, plasma cells, and granulocytes are seen in sinusoids. Kupffer cell hyperplasia, steatosis, and hepatocyte ballooning are also described. 287, 332 Granulomatous hepatitis is uncommon; necrotizing granulomas have been reported. 333 Organisms are only rarely seen in hepatic sinusoids and parenchyma with silver stain, such as Dieterle. 332

Q fever is a zoonotic rickettsial disease that is caused by the aerosol spread of Coxiella burnetii from infected sheep and cattle. The disease is endemic in the southwestern United States and in elevated, although they may be in the range of viral hepatitis. Alkaline phosphatase and bilirubin are less likely to be elevated but may be so with severe cholestasis. 355, 356 Liver biopsy may show lobular lymphohistiocytic aggregates and sinusoidal infiltration by lymphohistiocytic cells associated with erythroleukophagocytosis. 357 In cholestatic cases, bile stasis, duct epithelial injury, and neutrophilic infiltration of medium-sized ducts may suggest extrahepatic obstruction. 355, 357 Other reported findings include focal hepatic necrosis, steatosis, granulomas, and foamy Kupffer cells with scattered apoptotic bodies. 356, 357 

Rickettsia rickettsii is transmitted by the wood tick, Dermacentor andersoni, in the Rocky Mountain region and by the dog tick, Dermacentor variabilis, in the eastern United States. Mild to moderate transaminase elevations and occasionally jaundice may be seen. The main pathologic lesion is vasculitis, and rickettsiae are capable of infecting the endothelial lining cells of portal blood vessels, especially arteries and arterioles, and sinusoidal lining cells. 287, 358 Reports of autopsy livers describe portal inflammation, portal vasculitis with subendothelial and intramural mononuclear leukocytes, portal vascular thrombi, portal tract hemorrhage, sinusoidal leukocytosis, and erythrophagocytosis by Kupffer cells. 358, 359 Immunofluorescence techniques can be used to identify the organisms in tissue.

Boutonneuse fever, also known as Mediterranean spotted fever, is caused by Rickettsia conorii and is transmitted by the dog tick Rhipicephalus sanguineus. The disease is found in Mediterranean countries between the months of June and September and classically presents with fever, maculopapular rash, and a black eschar at the bite site (known as "tache noire," or black spot in French). 360 As is the case with Q fever, boutonneuse fever may be associated with the hemophagocytic syndrome. 337 Hepatic involvement shows Kupffer cell swelling and increased sinusoidal cellularity. Small foci of hepatocyte necrosis are seen, associated with collections of histiocytes, a few neutrophils, and lymphocytes. 361, 362 The mononuclear cell aggregates in the areas of necrosis may resemble poorly formed granulomas, but they are not true epithelioid granulomas. The diagnosis is typically made by serology.

Histoplasma is considered to be the most common fungal cause of hepatic granulomas, and it is a common cause of granulomatous hepatitis in areas where H. capsulatum is endemic, such as in the Ohio River valley. 363 In one series from that region, 15 (65%) of 23 children with hepatic granulomas had histoplasmosis demonstrated by PCR. 364 In another series, 50% of liver biopsy specimens with granulomas cultured positively for Histoplasma. Although histoplasmosis is usually self-limited in infants or immunocompromised patients, it can manifest with progressive disseminated disease requiring treatment. 364 Progressive disseminated histoplasmosis often involves the liver, with hepatomegaly in 62% of patients and abnormal liver function studies in 84%. 365 Histologically the appearance is identical to sarcoidosis, with numerous well-formed epithelioid granulomas (Fig. 11.28) . 176, 366 In immunocompromised hosts, loose collections of histiocytes southwestern Ontario. Most patients suffer an acute, self-limited infection that typically manifests as pneumonitis, although chronic infection with endocarditis is well known. Unlike other rickettsial diseases, Q fever does not produce a rash. 334 Hepatic involvement is common, and the disease may even manifest as hepatic disease without pulmonary symptoms. 335 Hepatic abscess formation detected radiologically has been reported. 336 Some cases may be associated with the hemophagocytic syndrome. 337 The diagnosis is established by complement-fixing antibodies to phase II C. burnetii antigen in serum.

The classic lesion of Q fever is the fibrin ring granuloma, which can be found in liver or bone marrow (Fig. 11.27) . 334, 335, [337] [338] [339] [340] [341] [342] [343] [344] Also known as doughnut or ring granulomas, these lesions contain a central fat vacuole that can lead to their being mistaken for lipogranulomas, but on closer inspection a ring of fibrin surrounds the fat vacuole. The fibrin ring is highlighted on trichrome stain. Q fever is the most commonly reported etiology, but fibrin ring granulomas have also been reported in other infections and in noninfectious conditions, including hepatitis A, 8, 9 Staphylococcus epidermidis infection, 345 allopurinol hypersensitivity, [346] [347] [348] [349] visceral leishmaniasis, 348,349 giant cell arteritis, 350 CMV, 113 EBV, 102, 351 Hodgkin disease, 349,352 toxoplasmosis, 348 and boutonneuse fever. 348 In addition to fibrin ring granulomas, epithelioid granulomas with or without central necrosis may be seen and can be mistaken for TB. 334, 340, 343, 348, 353, 354 Other findings in Q fever hepatitis include moderate steatosis, focal liver cell necrosis, Kupffer cell hyperplasia, hemosiderin deposits, acute cholangitis, and, rarely, microabscesses. 340, 343 Ehrlichiosis Ehrlichiosis is caused by gram-negative obligate intracellular organisms that are transmitted by a tick vector, predominantly in the southeastern United States. Human monocytic ehrlichiosis is caused by Ehrlichia chaffeensis and Ehrlichia canis, whereas human granulocytic ehrlichiosis is caused by Ehrlichia phagocytophila and Ehrlichia equi. 287 Symptoms include fever, headache, anorexia, and myalgia. The relatively low incidence of rash (20%) contrasts with the frequent presence of a rash in Lyme disease and Rocky Mountain spotted fever. 355, 356 Transaminases are often mildly until postmortem examination. Candida is an uncommon but important cause of hepatic abscesses in preterm neonates. [370] [371] [372] Radiologically the lesions appear targetoid and, in the case of older lesions, calcified. 368, 369 Grossly the liver and spleen are studded with white to yellow nodules. In the early stages, the nodule consists of a necrotic center and surrounding neutrophilic infiltrate. Periodic acid-Schiff (PAS) or Gomori methenamine silver (GMS) stains demonstrate yeast or pseudohyphae in the center of the abscess. As the lesion matures, a palisaded histiocytic reaction may develop at the periphery of the lesion, surrounded by a fibrous wall (Fig. 11.30 ). 369 Eventually, well-defined granulomas with giant cells may be seen. 368 As the lesions progress with increasing fibrosis, organisms become more difficult to detect, so their absence does not exclude the diagnosis. The adjacent liver parenchyma frequently shows sinusoidal dilatation, portal edema, neutrophilic infiltrate, and ductular reaction, presumably due to mass effect. 369 Candidal infection of the biliary tree and gallbladder occurs in disseminated candidiasis, with bacterial cholangitis, or as isolated candidal cholangitis or cholecystitis. 373, 374 Candida species can be identified from liver biopsies using PCR techniques, which may be useful in cases in which patients are on antifungal treatment and organisms are not identified by pathologic examination. 375

P. jiroveci (formerly Pneumocystis carinii) is a fungal organism that typically causes lung infections in immunocompromised patients. Extrapulmonary infection is rare but has been associated with the use of prophylactic aerosolized pentamidine, which suppresses pulmonary disease but might allow for dissemination of the organism. 376, 377 Grossly the liver is studded with yellow-white nodules. The pathology ranges from caseating granulomas to massive infiltration of sinusoids and vessels by the organism with little inflammatory reaction (Fig. 11.31) . 376, 377 The organism appears as indented, helmet-shaped "cysts" on silver stains.

Aspergillus spp. (Aspergillus fumigatus or Aspergillus flavus) involving the liver is seen in cases of disseminated aspergillosis and with numerous intracellular organisms can mimic leishmaniasis (Fig. 11.29) . The absence of a kinetoplast on Giemsa stain helps to distinguish Histoplasma from Leishmania. 367 The diagnosis can be established with methenamine silver staining of involved tissue, fungal culture, or complement fixation tests. 365

Candidiasis is especially problematic in immunocompromised patients, particularly those with leukemia or cytotoxic chemotherapy-related neutropenia. 368 Candida accounts for 62% to 91% of fungal infections in the liver transplantation population, affecting 5% to 42% of all liver transplant recipients. 110 Patients present with fever, abdominal pain, and elevated alkaline phosphatase; blood cultures are negative in at least half of the cases. 369 Usually, patients are in the recovery phase from the neutropenic episode, suggesting a role for the host inflammatory response in defining the lesions. 368 The diagnosis is often not made • Figure 11 .28 Liver biopsy sample in an immunocompetent patient with hepatic and splenic histoplasmosis. A solitary, well-formed granuloma is present in the liver.

• Figure 11 .29 Histoplasmosis in an acquired immune deficiency syndrome patient. A, Necrotic lesions are composed of histiocytes and debris. B, Gomori methenamine silver stain shows yeast in macrophages in the necrotic lesion.

allografts leading to retransplantation has been described. 387, 388 Less commonly, it may affect immunocompetent patients. 389 Hepatic infection in the absence of pulmonary disease may be caused by spread from a gastrointestinal source, and thus many patients have concurrent involvement of a site in the tubular gastrointestinal tract. 382, 390, 391 Patients may present with single or multiple hypodense lesions on abdominal CT. 392, 393 Mass effect may lead to stenosis and dilatation of the extrahepatic bile ducts, mimicking cholangiocarcinoma. 389 Peripheral eosinophilia may be present.

Pathologic specimens commonly show organizing abscesses with necrosis, with or without granulomatous inflammation. Some cases contain abundant eosinophilic infiltration and may be described as eosinophilic granulomas; this is common in zygomycosis due to Basidiobolus ranarum. 390, [394] [395] [396] These fungi have broad (10 to 20 µm), aseptate or hyposeptate, ribbonlike hyphae with right-angle branching, and they have a propensity in immunosuppressed patients, particularly organ transplant recipients. Liver abscess and cholangitis secondary to Aspergillus infection have been described. 239, [378] [379] [380] [381] The organism is easily demonstrated on methenamine silver or PAS stains and shows characteristic septate hyphae with acute-angle branching. Speciation can be accomplished by culture (with examination of fruiting bodies) or PCR-based techniques.

Fungi of the class Mucormycetes (formerly Zygomycetes) are ubiquitous in nature, occurring in decaying material and soil. The members of this class most often implicated in human disease are Rhizopus, Rhizomucor, Mucor, and Absidia. 382 Hepatic zygomycosis has been reported in immunocompromised patients, in patients receiving chemotherapy, in stem cell transplant recipients, and in solid organ transplant recipients. [382] [383] [384] [385] [386] Involvement of liver 

organisms grow as mold at 25°C on Sabouraud glucose agar and produce a characteristic soluble red pigment that diffuses into the agar. 399, 400 The main differential diagnosis is H. capsulatum.

Cryptococcosis is caused by the encapsulated yeast, Cryptococcus neoformans. Lung and central nervous system are the two most commonly affected organs, but hepatic infection has been reported in both immunocompromised and immunocompetent patients. 402, 403 In immunocompromised patients, hepatic involvement commonly occurs in the setting of disseminated infection or multiorgan involvement. [404] [405] [406] In contrast, immunocompetent patients tend to present with an isolated biliary infection that clinically and radiologically mimics sclerosing cholangitis or cholangiocarcinoma. [407] [408] [409] [410] [411] [412] These patients exhibit obstructive jaundice, and radiologic studies may show dilatation of intrahepatic bile duct dilatation, stricturing and wall thickening of extrahepatic bile ducts, and masslike lesions in the hilum. Most reported immunocompetent patients with biliary cryptococcosis are children or young adults. [407] [408] [409] 412 Histopathologically, immunocompetent cases are characterized by granulomas, whereas in AIDS patients, an inflammatory reaction is poorly developed or absent. Autopsies in cases of disseminated infection have shown areas of necrosis with innumerable yeast cells, yeast cells diffusely within tissue admixed with cellular debris and inflammation, or yeast cells within Kupffer cells ( Fig.  11.33) . 406, 411 The organism can be demonstrated on special stains (silver impregnation, PAS), and mucicarmine stain can be used to highlight the capsule. [404] [405] [406] 409, 410 The capsule is a virulence factor and is helpful in the diagnosis, but in rare instances, capsuledeficient strains can cause infection, particularly in immunocompromised patients (see Fig. 11 .33). Capsule-deficient forms can be confused with other yeasts. The diagnosis can be made by serology but may be elusive in cases with atypical presentations to invade blood vessels, leading to extensive necrosis, infarctions, and dissemination. [382] [383] [384] [385] 393, 397 When eosinophilic inflammation is prominent, degenerated fungal organisms may be associated with dense, hyalinized, eosinophilic material (Splendore-Hoeppli phenomenon). Diagnosis requires identification of the fungus in tissue or culture. However, tissue culture sensitivity is poor, possibly because the grinding of tissue in preparation for plating destroys the delicate hyphae, and this technique is no longer recommended. 382 PCR-based techniques for diagnosis are also available. Blood cultures are always negative. In tissue identification, erroneous classification as Aspergillus may occur if the hyphae are hyposeptate. 382 Some evidence suggests that iron is required for growth of zygomycetes, and thus there is interest in using iron chelators in combination with antifungal agents to treat zygomycosis; however, it is not established whether this approach is more effective.

Penicilliosis is an infection caused by the dimorphic fungus, Penicillium marneffei, which is endemic in Southeast Asia. 398 This pathogen has emerged as the third most common opportunistic infection among AIDS patients in Southeast Asia and southern China, although it affects people with apparently normal immunity as well. 399 Disseminated infection commonly presents with fever and skin lesions, and hepatic abscess formation may occur. 400 Pathologic findings include a granulomatous hepatitis with relatively few organisms, diffuse sinusoidal infiltration by foamy macrophages containing numerous organisms, and suppurative abscesses or necrotic lesions consisting of histiocytes filled with organisms, the latter being typical in immunocompromised patients. 398, 399, 401 The organisms appear as small spherules, 2 to 4 µm in diameter, along with some elongated and septate forms; they are highlighted with methenamine silver stain or by PAS stain with diastase digestion (Fig. 11.32) . 398 exudates containing numerous organisms. 417 The inflammatory reaction may involve the portal tracts and be associated with bile duct injury, ductular reaction, and portal fibrosis, which may progress to bridging. 418 Yeast forms can be demonstrated by silver impregnation stains. Intrahepatic ductal dilatation may result from biliary involvement and may mimic cholangiocarcinoma radiologically. 419

Microsporidia are obligate intracellular organisms that were originally believed to be primitive eukaryotes but have been reclassified as fungi, based on DNA sequence data. Infection of bile duct epithelium has been described as a cause of AIDS-related cholangitis. 146, 148 Several species have been implicated in AIDS-related cholangitis: E. bieneusi (the most common), Encephalitozoon cuniculi, and Septata intestinalis (previously Encephalitozoon intestinalis). 420 The presentation is similar to AIDS cholangitis due to other organisms, including elevation of alkaline phosphatase and PSC-like changes on endoscopic retrograde cholangiopancreatography (ERCP). S. intestinalis may also cause radiologically detected hypodense parenchymal lesions, which on biopsy show necrotizing cholangitis consisting of periportal mixed inflammation coalescing into granulomatous microabscesses with foamy macrophages that contain organisms. 421 S. intestinalis, unlike E. bieneusi, may infect macrophages, fibroblasts, and endothelial cells, in addition to epithelial cells; thus the presence of foamy macrophages suggests S. intestinalis infection. 422 The organisms may be seen on Brown-Hopps or Giemsa stains and appear as ovoid to ellipsoid spores measuring 2.2 to 2.4 µm in greatest dimension, with characteristic cross-banding and polar vacuoles. 421 A case of hepatitis has also been reported, with (e.g., without prominent pulmonary symptoms), leading to delayed treatment and poor outcomes.

Coccidioides immitis is endemic to the southwestern United States and northern Mexico. Disseminated infection can show granulomatous hepatitis or microabscesses containing the thick-walled spherules of C. immitis, which can be highlighted with PAS and methenamine silver stains. [413] [414] [415] The spherules may or may not contain endospores; immature spherules without endospores can be mistaken for Blastomyces dermatitidis or C. neoformans. 415 Serology and culture results can be used to establish the diagnosis.

B. dermatitidis is a dimorphic fungus that usually involves skin and lungs. The fungus is endemic to the southeastern and south central United States, the areas bordering the Great Lakes, and the Ohio and Mississippi River basins. Hepatic granulomas and cholangitis have been described. 416 Thick-walled yeast forms with broad-based budding are seen on PAS or silver stains (Fig. 11 .34).

Paracoccidioides brasiliensis causes a chronic granulomatous disease known as South American blastomycosis. The disease is endemic in rural South America and affects males more often than females. Although pulmonary lesions are typical, extrapulmonary disease can occur. In the liver the fungus usually causes a granulomatous reaction. Less often, it causes focal necrosis with neutrophilic that is often obscured. 423 Degenerated eggs may become calcified, which is more commonly seen with S. japonicum than with S. mansoni. Histology shows portal fibrosis with partial or complete destruction of the main branches of the portal vein but sparing of arteries and ducts. 424 Adult worms metabolize large amounts of hemoglobin and regurgitate hemozoin pigment, which is engulfed by macrophages in the sinusoids and portal tracts and can be accentuated by Prussian blue stain. Despite the scarring, lobular architecture is maintained, so the fibrosis does not represent true cirrhosis, and there is evidence that it may undergo regression with clearance of the organisms. 425 This pattern of fibrosis is known as Symmers pipestem fibrosis because of the clay pipestem appearance on gross pathology (Fig. 11.35 ). 424 The dense periportal fibrosis can also be seen on radiology as characteristic low-attenuation bands or rings around large portal vein branches, which may be associated with calcified eggs. 426 Eventually, portal hypertension supervenes with splenomegaly and esophagogastric varices. However, compensatory increase in hepatic arterial blood flow maintains hepatic perfusion and hepatic function. 424 Often, patients lack other stigmata of chronic liver disease. The diagnosis is based on the demonstration of ova in stool specimens. Serology to detect anti-schistosomal antibodies does not distinguish active from resolved infection. Enzymelinked immunosorbent assays (ELISAs) have been developed that detect schistosomal antigens in the serum and urine of actively infected patients. Antigen levels correlate with worm burden. 424 Coinfection with HBV or HCV is associated with a more aggressive course of hepatitis B or C and accelerated progression of fibrosis. 423 In endemic areas, recently infected patients may present with an acute form of the disease (sometimes referred to as Katayama fever) caused by a systemic hypersensitivity reaction to migrating cercariae and eggs. 423 Clinical symptoms include fever, headache, myalgias, pneumonia, diarrhea, hepatosplenomegaly, and peripheral eosinophilia. Pathologic examination shows granulomas with extensive central necrosis and dense eosinophilic infiltrates surrounding eggs in the liver, intestines, and other organs. 427 sinusoidal congestion and microgranulomas on light microscopy. 145 Electron microscopy is necessary to identify the organisms in most cases, but often the organism has already been identified in intestinal biopsy specimens by the time cholangitis develops. Treatment with albendazole may eradicate the organism, but microsporidial cholangitis in HIV patients has a poor prognosis (as does AIDS cholangitis in general) and often follows a progressive course.

Schistosomiasis is the second most common parasitic infection of humans after malaria. Several species of schistosomes affect humans. Schistosoma japonicum and Schistosoma mansoni are the two major species associated with hepatic and intestinal schistosomiasis and account for the disease burden in endemic areas. 423 Uncommonly, hepatic involvement has also been documented with Schistosoma hematobium, Schistosoma intercalatum, and Schistosoma mekongi. The intermediate host is a population of snails that is not found in North America or Europe. 424 Infection occurs when the cercariae exit the snail and penetrate the skin of a vertebrate host. In the human host the cercariae migrate to the lungs, where they mature, reach the left side of the heart, and then are carried to the portal hepatic circulation. In the mesenteric venous plexus, the male occupies the gynecophoric canal of the female, and the worms remain in a state of continuous copulation for their life span of 3 to 5 years. 424 Eggs released in the mesenteric venous plexus can migrate to the intestine (intestinal form) or into the liver (hepatosplenic form), where they lodge in the small portal vein tributaries and release antigens that elicit a granulomatous immunologic reaction. Granuloma formation around the eggs leads to pyelophlebitis and periportal fibrosis. S. mansoni eggs are ovoid, measure 140 × 60 µm, and have a prominent lateral spine, whereas S. japonicum eggs are smaller and more rounded (100 × 60 µm) and have a smaller lateral spine 436 After being ingested, the egg develops into a larval oncosphere, which penetrates the intestinal mucosa, enters the portal circulation or lymphatics, and, on reaching the target organ (usually the liver, in 70% of cases, or the lung, in 20%), forms a rounded, multinucleated mass that becomes cystic and progressively enlarges. 435 The hydatid cyst or metacestode consists of an external, acellular, laminated cuticle and an inner germinal membrane that gives rise to brood capsules containing new larvae called protoscolices ( Fig. 11.37) . 435, 437 The fully developed protoscolex stage contains suckers, hooks, a cup-shaped foramen, and calcareous corpuscles, which are irregularly spherical or ovoid in shape and have a diameter of 2 to 16 µm. 438 The central region of the calcareous corpuscles is composed of an electron-lucent matrix containing granular deposits of inorganic salts (chiefly calcium and magnesium carbonate) and paired membrane lamellae. 439 Hydatid cysts are initially uniloculated but develop internal septations as they form daughter cysts, either from the germinal membrane or from the protoscolices or brood capsules. Cysts cause a granulomatous host reaction that leads to development of a fibrous tissue layer or pericyst. 436 In the case of E. granulosus the cysts are slowly enlarging masses that remain asymptomatic for a long period. They may eventually cause dull abdominal pain and a palpable mass. 374 Abdominal ultrasound is key for the diagnosis of cystic echinoccocosis and further classifies the cysts as active, transitional, or inactive based on a classification scheme developed by the World Health Organization (WHO) which helps to guide management. 440 Serologic testing is available but has low sensitivity and is used primarily as a confirmatory test. Approximately 40% of cases are associated with complications, including erosion into bile ducts, through the hepatic capsule into the peritoneal cavity, into adherent organs, or through the diaphragm. 374 Therapeutic options include medical therapy, percutaneous aspiration injection and reaspiration (PAIR), and surgical resection. 441 In alveolar hydatid disease due to E. multilocularis, the hepatic parenchyma is invaded and replaced by fibrous tissue with numerous embedded vesicles (each with a germinal layer and laminated cuticle) that mimics carcinoma. 434 Dense granulomatous inflammation, microcalcifications, and necrotic cavitation may be present. 437 Alveolar hydatid disease carries a high mortality without surgery, due to liver failure, invasion of contiguous structures, or, less often, metastases to the lung and brain. 434, 437 Transplantation has been attempted, but there is a high risk of recurrence in the donor liver. 437 As with cystic echinococcosis, the diagnosis can be made radiologically and confirmed serologically, although some patients do not develop an immune response. 434, 437 Toxocara Toxocariasis refers to infection by larvae of the dog ascarid, Toxocara canis, or, less commonly, the cat ascarid, Toxocara cati. In humans, these larvae do not develop into adult worms but travel throughout host tissue, primarily liver and lungs; therefore the Strongyloides Strongyloides stercoralis exist as rhabditiform larvae in soil and as filariform larvae in humans. The organisms reside in the intestine, where they produce eggs that develop into rhabditiform larvae, which are shed in feces. In certain settings, rhabditiform larvae may develop into the infectious filariform larvae within the intestine; this form is capable of invading the intestinal mucosa and traveling throughout the body, typically the central nervous system, liver, and lungs. This unique cycle of autoinfection is accelerated in immunosuppressed patients, particularly those receiving corticosteroids, and is referred to as hyperinfection syndrome or disseminated strongyloidiasis; untreated, its mortality rate approaches 100%. 428 The diagnosis is based on detection of larvae in stool in conjunction with serologic testing. In the liver the larvae can cause granulomatous hepatitis with or without larval remnants. The larvae measure between 6 and 13 µm, and they may be seen in sinusoids, portal tract lymphatics, or branches of the portal vein (Fig. 11.36 ). 429 The larvae occasionally do not provoke an inflammatory reaction. 429 Steatosis and cholestasis are additional features.

Rarely, Enterobius vermicularis travels from the anus to unusual locations, such as the urethra or vagina. Rupture of the appendix or other intestinal disease may also provide the nematode with a mode of reaching the liver. 430 Subcapsular nodules in the liver may be found at the time of surgery or may be radiologically detected during staging of patients with carcinoma, leading to misdiagnosis as metastases. 431, 432 Histologic examination shows large necrotic nodules with surrounding histiocytic reaction and fibrosis, hyalinizing granulomas, or calcifying granulomas; the lesions contain remnants of pinworms with characteristic lateral alae and multiple ova. [430] [431] [432] [433] Echinococcosis Echinococcosis or hydatid cyst disease is caused by species of the tapeworm, Echinococcus. Echinococcus granulosus is endemic in Mediterranean countries, Iran, India, China, Chile, and Argentina they embryonate. Ingestion of the unembryonated eggs does not result in hepatic disease but only in abdominal discomfort; in these spurious cases, eggs are passed in the stool. Ingestion of embryonated eggs results in hepatic disease; the larvae bore through the intestinal wall and reach the liver via the portal circulation where they mature into adults. Eggs are not passed into stool. 449 Infection of humans is rare; children are more commonly affected, probably because of frequent soil-to-mouth contact. 449 Patients present with chronic fever, hepatomegaly, and peripheral eosinophilia. 450 Imaging may show portal lymphadenopathy and multiple ill-defined, subcentimeter hypodense nodules throughout the liver. 451 Liver biopsy specimens may show granulomas and eosinophils. Granulomatous lesions with central eosinophilic necrosis rimmed by palisaded histiocytes and numerous eosinophils similar to toxocariasis may be seen. 447, [451] [452] [453] [454] Fibrosis may develop over time. Remnants of the parasite and its eggs may be identified. 449 The parasite measures 50 µm or larger in diameter 447 and can be identified by the presence of its internal organs (bacillary bands, esophagus, and associated stichosome). 450 The eggs are elliptical, measure 54 to 64 µm by 29 to 33 µm, and have a double-layered envelope with an outer striated wall and bipolar plugs ("bioperculated eggs"). 449, 450, [453] [454] [455] Serology for Capillaria is not available. Thus, unlike other helminthic diseases in which the diagnosis is made primarily by serology, a definitive diagnosis of hepatic capillariasis requires pathologic identification of the adult or eggs in biopsy material. Serology should still be performed to exclude other infections in the differential diagnosis, particularly toxocariasis.

F. hepatica and Fasciola gigantica are trematode bile duct flukes found primarily in sheep and cattle, with a broad geographic distribution. 434, 456 The leaf-shaped worms reach a size of approximately 2 cm and may remain viable in the bile ducts for more than a decade. The eggs pass in feces, hatch in water, and infect lymnaeid snails. 434 Snails release a cercarial stage of the parasite that contaminates aquatic plants that are ingested by sheep, cattle, or humans. Watercress is often associated with human disease is known as visceral larva migrans. 442 Humans acquire the infection by ingesting the eggs from contaminated soil or by eating undercooked meat or other animal tissues (e.g., cow liver) that are infected by the encapsulated larvae. The larvae are released in the intestines, burrow through the intestinal wall, and reach the liver via the portal vein. From there, they travel to various other organs, causing eosinophilic inflammation, granulomas, and abscesses. 442 Most patients are asymptomatic but demonstrate peripheral eosinophilia and hypergammaglobulinemia. Vague abdominal pain, fever, cough, and dyspnea are occasional complaints. 442 In the United States, visceral toxocariasis affects primarily children between 2 and 7 years old. 443 Radiologic studies show multiple, ill-defined, oval or angular hypoechoic lesions that improve or resolve spontaneously, similar to Fasciola hepatica and Capillaria hepatica. The nonspecific radiologic appearance may lead to consideration of other etiologies, such as microabscesses, sarcoidosis, and malignancies. 444 Serologic testing for IgG to Toxocara antigens has high sensitivity and specificity and is used to make the diagnosis.

In liver biopsy specimens, multiple granulomas and confluent granulomas may be the main finding. 445, 446 Grossly the liver may show 0.3-to 1-cm, white-gray lesions, primarily in the subcapsular region of the right lobe. 447, 448 These granulomatous lesions show central necrosis surrounded by a mixed inflammatory infiltrate that includes numerous eosinophils and palisading epithelioid histiocytes and may be referred to as eosinophilic granulomas. 444 The central necrotic zone shows granular debris or eosinophilic material. Charcot-Leyden crystals may be seen in the areas of necrosis. Remnants of parasites are found in a minority of cases and measure 15 to 21 µm in diameter. 447 The differential diagnosis includes other causes of visceral larva migrans, including C. hepatica and Ascaris.

C. hepatica is a nematode that mainly affects rodents but is also found in carnivores. The organism requires only a single host, with the liver containing both the adult parasite and its ova. 449 Eggs are deposited in soil, where, under favorable conditions, 459, 460 These bile duct flukes are acquired through ingestion of raw fish containing the metacercariae. 459, 460 In contradistinction to Fasciola, The flukes migrate into the ducts via the ampulla of Vater, where they mature in approximately 25 days. 459, 460 The adults reside in medium-sized and small intrahepatic ducts and occasionally in the extrahepatic ducts, gallbladder, or pancreatic duct, where they can live for a decade or longer. 459 Human hosts excrete eggs that hatch in water, pass through snails and fish, and infect other humans or animals. Patients are usually asymptomatic but may present with abdominal pain, hepatomegaly, and eosinophilia or with the syndrome of recurrent pyogenic cholangitis.

Grossly, focal dilatation of segments of smaller ducts may be seen, with thickened walls and possibly worms in the lumen. The left lobe is affected more often because the left intrahepatic bile duct is straighter and wider, allowing easier access for the worms. Bile ducts that harbor these flukes show dilatation, irregular thickening, adenomatous epithelial hyperplasia, and variable eosinophilia (Fig. 11.39 ). 459 Opisthorchis flukes contain an eggfilled branched uterus flanked by paired ceca. 461 Eggs are not usually seen in tissues. Ascending cholangitis, usually from E. coli, can lead to purulent exudates in dilated ducts. Bile duct obstruction can result from the worms, strictures, or calculus formation. 459 Stones often have dead worms as their nidus. Imaging may show intrahepatic duct dilatation, increased periductal echogenicity, and gallbladder sludge. Diagnosis is made by identifying the ova in stool or by ultrasonography. Infection with O. viverrini or C. sinensis is strongly associated with development of cholangiocarcinoma, which is often intrahepatic, multicentric, and mucin secreting. In fact, O. viverrini is considered a group 1 carcinogen. The mechanisms of carcinogenesis in chlonorchiasis are not well understood but may be multifactorial. Serology does not distinguish between present and past infection. Therefore the diagnosis of active infection may require the detection of ova in stool. 459 

A. lumbricoides rarely causes biliary ascariasis when the roundworms, which usually reside in the lumen of the small intestine, ascend the bile duct; this occurs usually in patients who live in endemic areas, have biliary abnormalities, or have undergone sphincterotomy. Although children are infected with Ascaris commonly, biliary involvement is rare in children, probably because of the narrow ampulla of Vater and bile duct lumen. 462 Bile duct infestation manifests as biliary colic, obstructive jaundice, or pancreatitis. Dying worms, in conjunction with E. coli and other bacteria that they transport into the liver, can cause suppurative cholangitis, liver abscesses, or the syndrome of recurrent pyogenic cholangitis (Fig. 11.40) . 248, 463, 464 Hepatolithiasis in association with ascariasis has also been described. 465 The worms can also penetrate liver tissue (visceral larva migrans), perforate the Glisson capsule, and exit into the subdiaphragmatic space. 248 Adult worms or ova may be present in tissue sections. The ova can cause granulomas and pseudotumors. 466 Bile ducts may show infection. 457 After being ingested, metacercariae penetrate the intestine, traverse the peritoneal cavity, and penetrate the liver capsule. 458 They burrow through the liver parenchyma for 1 to 3 months, while maturing, and finally enter the bile ducts to complete the life cycle.

Acute (invasive) fascioliasis manifests with fever, right upper quadrant discomfort, hepatomegaly, and eosinophilia. 456 Infrequently, patients experience respiratory, cardiac, or neurologic symptoms that are believed to be immunoallergic in origin because the organism only rarely appears at these sites. 456 As the flukes course through the liver, they create tracks of necrosis infiltrated by eosinophils, sometimes surrounded by a reaction of palisaded histiocytes (Fig. 11.38) . 457, 458 These tracks appear as yellow-white subcapsular nodules or cords at laparoscopy. 457, 458 Common findings on CT or magnetic resonance imaging (MRI) include the classic picture of multiple lesions which change in position, attenuation, and shape over time; tracklike subcapsular hypodense lesions; and subcapsular hematomas. 459 As the lesions age, they become cavities bound by granulation tissue, fibrous tissue, and calcifications. 458 Immature flukes that fail to reach the liver may produce ectopic abscesses, most often in the skin. 456 After the flukes penetrate ducts, egg production initiates chronic (obstructive) fascioliasis, characterized by local inflammation, fibrous thickening of the duct wall, ascending cholangitis, episodic biliary pain, and obstructive jaundice. 456 Peripheral eosinophilia is mild or absent in this stage. The flukes attach to the bile duct epithelium using suckers and cause ductal epithelial proliferation, possibly due to their production of proline. 458 Large necrotic granulomas can develop around entrapped eggs, and tissue eosinophilia is typical in these lesions. Adult flukes can be found in the bile ducts or gallbladder, along with stones, hypertrophied muscle coat, and mucosal hyperplasia. Cholangiocarcinoma is not associated with fascioliasis, but development of cirrhosis has been described. Radiologic findings in the chronic phase are nonspecific and may include hepatosplenomegaly, periportal fibrosis, cystic lesions, and calcifications, as well as dilated common bile duct and thickened gallbladder. 459 Diagnosis is made with serologic and antigen-identification tests or stool examination for ova, although the latter is useful only in chronic disease and may be negative if ova production is intermittent. 456 A, Gross photograph of a section of liver shows dilated bile ducts inspissated with darkly stained sludge. B, On microscopic examination, the inspissated sludge is found to contain laminated, bile-stained structures suggestive of dead Ascaris. C, Focally, a collection of Ascaris ova is present in the sludge. D, Elsewhere in the liver, granulomatous inflammation was seen in the lobules adjacent to portal tracts.

C D surprisingly small relative to the size of the abscess. The diagnosis is often made by identification of a lesion in the liver in the setting of positive amebic serology.

The Plasmodium parasite has a life cycle that involves both mosquitoes and humans. When the parasite is first transmitted to a human host, it is incapable of infecting red blood cells and must first pass through the liver. The parasite grows rapidly within hepatocytes, producing merozoites that can infect red blood cells. Through unknown mechanisms, the parasites render hepatocytes resistant to apoptotic signals. 473 Hepatic dysfunction is well described in malaria, particularly with infection by Plasmodium falciparum or mixed infection with both P. falciparum and Plasmodium vivax, and usually involves mild abnormalities of liver function studies or jaundice, although in some instances there may be a more severe acute hepatitis. [474] [475] [476] Hepatic dysfunction has also been reported with Plasmodium malariae and Plasmodium knowlesi. 477, 478 Hepatomegaly and abdominal pain may be seen. The combination of fever and jaundice may lead to a misdiagnosis of acute viral hepatitis. Hepatic encephalopathy is rare but does occur. 479 Hepatic dysfunction and jaundice may be multifactorial in etiology, including hemolysis, sequestration of infected red blood cells in sinusoids, or coexistent viral hepatitis. 476 The histologic hallmarks of malarial hepatitis are Kupffer cell hyperplasia and deposition of malarial pigment or hemozoin in Kupffer cells and macrophages (Fig. 11.42 ). [480] [481] [482] [483] Hemozoin pigment is coarse and birefringent when examined with polarized light. Pigment is seen throughout the lobule in parasitemic cases but is concentrated in portal areas in nonparasitemic cases, suggesting movement towards portal areas with resolution of infection. 481 The degree of inflammation and hepatocyte injury is generally mild. Sinusoidal congestion and centrilobular necrosis may be caused by adherence of red blood cells in sinusoids, resulting in ischemia. Kupffer cell activation, fatty change, and cholestasis are other common findings. 476, 482 Exoerythrocytic forms of the parasite in liver biopsy material can be demonstrated by immunofluorescence. 484 In cases of fatal malaria, examination of the liver at autopsy may also show submassive coagulative-type mucosal ulceration and a mixed inflammatory infiltrate associated with embedded ova. 467 Fine-needle aspiration cytology from a liver abscess may reveal numerous fertilized, decorticated Ascaris eggs in a background of necrosis, inflammation, and Charcot-Leyden crystals. 468 Ultrasonography can identify worms within the gallbladder or extrahepatic ducts or the presence of a dilated common bile duct. 462 Ova or adult worms can be found in stool in 91% of patients. 462 In some patients the worms exit the ducts spontaneously; in others, antihelminthic therapy or surgery is required, particularly if abscess formation has occurred. [462] [463] [464] Protozoal Infections of the Liver and Bile Duct Amebiasis Liver abscess is the most common extraintestinal manifestation of amebiasis, which is endemic in several tropical regions of India, Southeast Asia, Central America, and Africa. Amebic liver abscesses most likely arise from hematogenous spread of the trophozoites, probably via the portal circulation. 469 The classic presentation is fever, right upper quadrant pain, and hepatic tenderness. 470 Often, patients with liver abscess have no bowel symptoms, and stool microscopy is negative for Entamoeba histolytica trophozoites and cysts. 469 Amebic abscesses are approximately 10 times more common in men; proposed explanations for this disparity include inhibition of amebic growth by iron deficiency anemia (which is common in women in affected areas), hormonal factors, and higher rates of alcohol consumption in men. In North America, patients may present years after travel to an endemic area. 471 Compared with pyogenic liver abscesses, amebic abscesses are more likely to be solitary, are more common in men, and tend to occur in younger patients without underlying liver disease or other comorbidities. 471, 472 In the United States the disease commonly affects young Hispanic men from southwestern states.

The histopathologic findings in hepatic amebiasis consist of well-circumscribed regions of dead hepatocytes, liquefied cells, and cellular debris. A rim of connective tissue with few inflammatory cells and amebic trophozoites surrounds the necrotic lesion ( Fig. 11.41 ). The adjacent hepatic parenchyma is often completely unaffected. 469 The number of trophozoites may be trophozoites of T. gondii. 484 In addition, Leishmania, unlike Histoplasma, lacks a cell wall and is negative on PAS and silver impregnation stains. Immunohistochemical stains and serologic assays are available.

T. gondii is an obligate intracellular parasite usually acquired from ingestion of undercooked pork or lamb, or transplacentally. Cats are a major reservoir. Disseminated infection occurs in bone marrow and solid organ transplant recipients and in AIDS patients. Hepatitis has been reported in apparently healthy persons during acute infection; these patients present with jaundice, rash, and elevated levels of transaminases and alkaline phosphatase. [492] [493] [494] [495] Histologically, Toxoplasma hepatitis is characterized as a diffuse hepatitis with infiltration of portal tracts and sinusoids by mononuclear cells associated with focal hepatic necrosis, similar to EBV or CMV hepatitis. [492] [493] [494] Granulomatous hepatitis has also been described. 495 In some cases, bradyzoite-containing Toxoplasma cysts have been identified in histiocytes and granulomas or within the hepatic parenchyma. [493] [494] [495] [496] Free tachyzoites have been described within degenerating or necrotic hepatocytes, although they can be difficult to distinguish from detritus. 492, 495 Giemsa stain, PAS, immunohistochemical stains, or immunofluorescent stains may assist in the detection of organisms in tissue. Serologic assay for IgM antibodies to T. gondii can be used to establish the diagnosis.

Cryptosporidium is a protozoan that causes an opportunistic infection of the gastrointestinal tract, resulting in diarrhea. In patients with AIDS or other immunocompromised states, including primary immunodeficiency syndromes and solid organ transplantation, the organism has been known to infect the biliary tree, producing a syndrome similar to PSC. 147, [497] [498] [499] [500] [501] The incidence of Cryptosporidium biliary infection is particularly high in patients with X-linked hyper-IgM syndrome; these patients lack the CD40 receptor CD40L, which suggests an essential role of the CD40-CD40L interaction in the immune response to Cryptosporidium. [500] [501] [502] [503] Signs and symptoms include right upper quadrant abdominal pain, nausea, vomiting, fever, and necrosis, likely as a result of shock and hypoperfusion in the setting of multiorgan system failure. 482

Visceral leishmaniasis, or kala-azar, is caused by an obligate intracellular protozoan, Leishmania donovani, that is transmitted to humans by the sandfly, Phlebotomus argentipes. Worldwide, India has the highest incidence of kala-azar. Children comprise the majority of patients. In southwest Europe, visceral leishmaniasis affects adults, many of whom are coinfected with HIV. 485 In this population, the majority of patients are intravenous drug users, and the organism is transmitted by the sharing of syringes. 485 In addition, reactivation of latent disease may occur in immunocompromised patients years after travel to endemic areas, making the infection difficult to suspect. 486 The organisms exist as flagellated promastigotes in the gut of female sandflies and as amastigotes in animal or human hosts. In visceral leishmaniasis, an incubation period of 10 days to 1 year is followed by low-grade recurrent fevers, malaise, wasting, anemia, and hepatosplenomegaly. 487 Death follows in 2 to 3 years, commonly from secondary infections.

The accumulation of mononuclear phagocytic cells in infected tissues leads to reticuloendothelial hyperplasia affecting the liver, spleen, intestinal mucosa, bone marrow, and lymph nodes. 487 In the liver, the typical pattern consists of marked hyperplasia of Kupffer cells, many of them parasitized by numerous amastigotes (Fig. 11.43 ). 488 Well-formed granulomas may be seen alongside Kupffer cells with intracellular amastigotes. 487, 489 Other patterns include a nodular pattern, with collections of macrophages, lymphocytes, and plasma cells within the lobules and portal tracts harboring few parasites, and a fibrogenic pattern, with perisinusoidal fibrosis that isolates small groups of liver cells with regenerative changes. 488, 490 The differential diagnosis includes H. capsulatum, P. marneffei, and Toxoplasma gondii. 486 Fibrin ring granulomas have been reported. 349, 491 The diagnosis depends on demonstration of the organism in tissue, typically bone marrow smears or spleen aspirates. 487 In liver tissue, demonstration of the parasites is best done with Giemsa staining, preferably of touch preparations on glass slides. 484 The presence of an eccentrically located rodlike kinetoplast on Giemsa stain is characteristic of Leishmania and distinguishes this parasite from Histoplasma and biochemical evidence of anicteric cholestasis. 147 Dilatation of the common bile duct is often seen on ultrasonography or CT scanning, and cholangiography reveals attenuation and pruning of duct branches, stricturing and beading of the proximal intrahepatic bile ducts, and dilatation or stricturing of the extrahepatic duct. 147, 503, 504 The histologic picture reflects the intense periductal inflammatory response elicited by the organism, with portal edema, inflammation, and hyperplastic periductal glands. The biliary epithelium may be reactive or frankly necrotic. Some cases may show prominent periductal "onion-skinning" fibrosis with minimal inflammation, indistinguishable from PSC. 499 Portal fibrosis and ductular reaction may develop, and progression to biliary-type cirrhosis has been reported. 497, 502 Organisms can be detected on the luminal surface of the epithelial lining of small biliary radicles, peribiliary glands, the pancreatic duct, and the gallbladder. 147, 498, 501 Concomitant CMV infection may be found. Cryptosporidium-associated sclerosing cholangitis may lead to biliary dysplasia and cholangiocarcinoma in patients with X-linked hyper-IgM syndrome. 500, 502, 504 Although the organism may be cleared in non-AIDS patients, leading to resolution of liver disease, the infection appears difficult or impossible to cure in AIDS patients.

Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors

Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B

Chronic hepatitis: morphology and nomenclature

Detection of hepatitis B virus antigens in liver tissue: a relation to viral replication and histology in chronic hepatitis B infection

Correlation of hepatocyte HBsAg expression with virus replication and liver pathology

The degrees of hepatocyte nuclear but not cytoplasmic expression of hepatitis B core antigen reflect the level of viral replication in chronic hepatitis B virus infection

Core antigen expression is associated with hepatic necroinflammation in e antigen-negative chronic hepatitis B patients with low DNA loads

Strategies to control hepatitis B: public policy, epidemiology, vaccine and drugs

Histological disease in Asian-Americans with chronic hepatitis B, high hepatitis B virus DNA, and normal alanine aminotransferase levels

Advances in hepatitis B and C

Hepatitis B virus infection in liver allografts

Recurrent hepatitis B in liver allografts: a distinctive form of rapidly developing cirrhosis

Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis

Fibrosing cytolytic liver failure secondary to recurrent hepatitis B after liver transplantation

Fibrosing cholestatic hepatitis in patient with HIV and hepatitis B

Fatal reactivation of precore mutant hepatitis B virus associated with fibrosing cholestatic hepatitis after bone marrow transplantation

Viral hepatitis and HIV coinfection

Hepatitis B or hepatitis C and human immunodeficiency virus infection

Hepatitis C: a review for primary care physicians

Hepatitis C virus biology

Acute hepatitis C

Clinical significance of hepatitis C virus genotypes

Clinical significance of hepatitis C virus genotypes

Hepatitis A virus: from discovery to vaccines

Hepatitis A in the United States

Autoimmune hepatitis preceded by acute hepatitis A infection

Autoimmune hepatitis following hepatitis A virus infection

Autoimmune hepatitis in a genetically susceptible patient: is it triggered by acute viral hepatitis A?

Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals

Viral hepatitis

Fibrin ring granulomas in hepatitis A

Hepatic fibrin-ring granulomas in a patient with hepatitis A. Gastroenterology

Natural history of hepatitis B virus infection: an update for clinicians

Viral hepatitis B

Clinical relevance of hepatitis B viral mutations

Influence of hepatitis B virus genotypes on the response to antiviral therapies

Polyarteritis nodosa and extrahepatic manifestations of HBV infection: the case against autoimmune intervention in pathogenesis

AASLD guidelines for treatment of chronic hepatitis B

Histologic progression of recurrent hepatitis C in liver transplant allografts

Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology

Rapidly progressive fibrosing cholestatic hepatitis: hepatitis C virus in HIV coinfection

Cholestatic hepatitis leading to hepatic failure in a patient with organtransmitted hepatitis C virus infection

Hepatitis C virus-related fibrosing cholestatic hepatitis after renal transplantation

Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferon-alpha therapy

The natural history of chronic hepatitis C in haemophiliacs

Investigation of chronic hepatitis C infection in individuals with haemophilia: assessment of invasive and non-invasive methods

Clinical features of hepatitis D

Autoimmune mechanisms in chronic hepatitis B and delta virus infections

A histological study of hepatitis delta virus liver disease

Histologic studies of severe delta agent infection in Venezuelan Indians

Role of immunohistochemistry for hepatitis D and hepatitis B virus in hepatitis delta

Hepatitis E: an overview and recent advances in vaccine research

Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury

Acute hepatitis E in Montenegro: epidemiology, clinical and laboratory features

Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants

Molecular detection of hepatitis E virus (HEV) in liver biopsies after liver transplantation

Acute and chronic hepatitis E virus infection in human immunodeficiency virusinfected U.S. women

Chronic hepatitis E virus infection in liver transplant recipients

A nationwide survey of hepatitis E viral infection in French blood donors

Hepatitis C virus 1b is the dominant genotype in HCV-related carcinogenesis: a case-control study

Hepatitis C: the clinical spectrum of the disease

Acute hepatitis C: diagnosis and management

Acute hepatitis C virus infection

Acute hepatitis C virus infection: diagnosis, pathogenesis, treatment

Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance

Hepatitis C and D, retroviruses and autoimmune manifestations

Serum autoantibodies in chronic hepatitis C: comparison with autoimmune hepatitis and impact on the disease profile

The pathology of hepatitis C

Immunohistochemical detection of hepatitis C virus (HCV) in liver biopsies of hepatitis C patients

In situ hybridization for the detection of hepatitis C virus RNA in human liver tissue

Hepatitis C virus and liver steatosis: when fat is not beautiful

Hepatitis C virus-induced hepatocellular steatosis

Hepatic granulomas: a 10 year single centre experience

The presence of epithelioid granulomas in hepatitis C virus-related cirrhosis

Granulomas and hepatitis C

Epithelioid cell granulomas in chronic hepatitis C: immunohistochemical character and histological marker of favourable response to interferon-alpha therapy

Granulomatous hepatitis in a patient with chronic hepatitis C treated with interferon-alpha

Development of granulomatous hepatitis during treatment with interferon-alpha 2b

Hepatic granulomas in chronic hepatitis C

Long term changes in liver histology following treatment of chronic hepatitis C virus

Reversal, maintenance or progression: what happens to the liver after a virologic cure of hepatitis C?

From non-A, non-B hepatitis to hepatitis C virus cure

Chronic hepatitis C: this and the new era of treatment

Histopathological evaluation of recurrent hepatitis C after liver transplantation: a review

The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia

Update on post-liver transplantation infections, malignancies, and surgical complications

Acute granulomatous hepatitis: occurrence in cytomegalovirus mononucleosis

Cytomegalovirus granulomatous hepatitis

Ring" granulomas in cytomegalovirus hepatitis

Histological diagnosis of cytomegalovirus hepatitis in liver allografts

Fatal herpes simplex virus hepatitis following neoadjuvant chemoradiotherapy and anterior resection for rectal cancer

Herpes simplex hepatitis in apparently immunocompetent adults

Herpesvirus infection of the liver

Fulminant hepatitis due to human adenovirus

Disseminated adenovirus infection with hepatic necrosis in patients with human immunodeficiency virus infection and other immunodeficiency states

Fatal adenovirus infection in a child with acquired immunodeficiency syndrome

Acute hepatitis as a manifestation of parvovirus B19 infection

Acute parvovirus B19 infection associated with fulminant hepatitis of favourable prognosis in young children

Parvovirus B19 as a possible causative agent of fulminant liver failure and associated aplastic anemia

Human parvovirus B19 infection associated with acute hepatitis

Detection of human parvovirus B19 in a patient with hepatitis

Characterization of erythrovirus B19 genomes isolated in liver tissues from patients with fulminant hepatitis and biliary atresia who underwent liver transplantation

Brief report: no evidence for parvovirus B19 or hepatitis E virus as a cause of acute liver failure

Prevalence of parvovirus B19 in liver tissue: no association with fulminant hepatitis or hepatitisassociated aplastic anemia

Chronic hepatitis caused by persistent parvovirus B19 infection

Evidence for persistence of parvovirus B19 DNA in livers of adults

Intrahepatic long-term persistence of parvovirus B19 and its role in chronic viral hepatitis

States: results from the Third National Health and Nutrition Examination Survey, 1988-1994

Histological and immunohistochemical features in fatal acute fulminant hepatitis E

The histology of acute autochthonous hepatitis E virus infection

Liver histology in patients with sporadic acute hepatitis E: a study of 11 patients from South-West France

Hepatitis G virus

GB virus type C interactions with HIV: the role of envelope glycoproteins

The GB viruses: a review and proposed classification of GBV-A, GBV-C (HGV), and GBV-D in genus Pegivirus within the family Flaviviridae

Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals

Unusual presentation of Epstein-Barr virus hepatitis treated successfully with valganciclovir

Severe hepatitis caused by Epstein-Barr virus without infection of hepatocytes

Fatal liver failure: molecular evidence for chronic active Epstein-Barr virus infection

Infectious mononucleosis hepatitis

Fulminant Epstein-Barr viral hepatitis: orthotopic liver transplantation and review of the literature

Epstein-Barr virus infection in liver transplantation patients: correlation of histopathology and semiquantitative Epstein-Barr virus-DNA recovery using polymerase chain reaction

Chronic Epstein-Barr virus infection: a cause of granulomatous hepatitis?

Epstein-Barr virus infection and hepatic fibrin-ring granulomas

Epstein-Barr virus hepatitis: diagnostic value of in situ hybridization, polymerase chain reaction, and immunohistochemistry on liver biopsy from immunocompetent patients

Association of cytomegalovirus with infantile hepatitis

Cytomegalovirus frequency in neonatal intrahepatic cholestasis determined by serology, histology, immunohistochemistry and PCR

Liver findings in infantile cytomegalovirus infection: similarity to extrahepatic biliary obstruction

Biliary atresia, cytomegalovirus, and age at referral

High frequency of human cytomegalovirus DNA in the liver of infants with extrahepatic neonatal cholestasis

Midzonal lesions in yellow fever: a specific pattern of liver injury caused by direct virus action and in situ inflammatory response

A clinicopathological study of human yellow fever

Pathogenesis and pathophysiology of yellow fever

Viral hemorrhagic fevers with hepatic involvement: pathologic aspects with clinical correlations

Dengue viral infections

The clinical features and outcomes of acute liver failure associated with dengue infection in adults: a case series

Dengue and liver disease

Liver function test results and outcomes in children with acute liver failure due to dengue infection

The pathology of severe dengue in multiple organs of human fatal cases: histopathology, ultrastructure and virus replication

Histologic, viral, and molecular correlates of dengue fever infection of the liver using highly sensitive immunohistochemistry

Liver histopathology and biological correlates in five cases of fatal dengue fever in Vietnamese children

Immunopathogenesis of dengue hemorrhagic fever: contribution to the study of human liver lesions

Intrahepatic infiltrating NK and CD8 T cells cause liver cell death in different phases of dengue virus infection

Dengue virus identification by transmission electron microscopy and molecular methods in fatal dengue hemorrhagic fever

Pathologic studies on suspect animal and human cases of Rift Valley fever from an outbreak in Eastern Africa

Pathologic and virologic study of fatal Lassa fever in man

Hepatobiliary tuberculosis

A systematic review of hepatic tuberculosis with considerations in human immunodeficiency virus co-infection

Case records of the Massachusetts General Hospital. Case 5-2012. A 39-year-old man with a recent diagnosis of HIV infection and acute psychosis

Hepatobiliary tuberculosis: a review of presentations and outcomes

The nodular form of hepatic tuberculosis: a review with five additional new cases

Tuberculosis hepatitis: a clinical review of 96 cases

Co-infection of human parvovirus B19 in Vietnamese patients with hepatitis B virus infection

Human parvovirus B19 infection in patients with chronic hepatitis B or hepatitis C infection

Hepatitis in an adult with rubella

Intrahepatic lymphocyte subpopulations in acute hepatitis in an adult with rubella

Scatena Rdos S. Fatal acute liver failure in a child due to acquired rubella infection

Acute hepatitis in an adult with rubeola

Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 34-1988: progressive pulmonary consolidations in a 11-year-old boy with Evans' syndrome

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

Abnormalities of liver function during HIV seroconversion illness

Hepatitis associated with primary HIV infection

Bacillary epithelioid angiomatosis involving the liver, spleen, and skin in an AIDS patient with concurrent Kaposi's sarcoma

Clinical and pathological features of bacillary peliosis hepatis in association with human immunodeficiency virus infection

Granulomatous inflammation in the acquired immune deficiency syndrome

Microsporidan hepatitis in the acquired immunodeficiency syndrome

Cholangiopathy associated with Microsporidia infection of the common bile duct mucosa in a patient with HIV infection

Cryptosporidiosis of the biliary tract in AIDS

Microsporidia infection in patients with the human immunodeficiency virus and unexplained cholangitis

Acquired immunodeficiency syndrome cholangiopathy: spectrum of disease

Natural history of AIDS related sclerosing cholangitis: a study of 20 cases

Hepatic involvement as the primary manifestation of Kaposi's sarcoma in the acquired immune deficiency syndrome

De novo autoimmune hepatitis during immune reconstitution in an HIV-infected patient receiving highly active antiretroviral therapy

Exotic viruses and the liver

HIV-negative, nonimmunosuppressed patient

Nontuberculous mycobacteria immune reconstitution syndrome

Hepatic granulomas in leprosy: their relation to bacteremia

Hepatic involvement in lepromatous leprosy

Hepatic granulomas and other hepatic lesions associated with BCG immunotherapy for cancer

Granulomatous hepatitis: a complication of B.C.G. immunotherapy

Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer

Multi-organ failure with atypical liver granulomas following intravesical Bacillus Calmette-Guerin instillation

Granulomatous hepatitis following intravesical bacillus Calmette-Guerin therapy

Peritoneal tuberculosis and granulomatous hepatitis secondary to treatment of bladder cancer with Bacillus Calmette-Guerin

Concurrent granulomatous hepatitis, pneumonitis and sepsis as a complication of intravesical BCG immunotherapy

Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 29-1998: a 57-year-old man with fever and jaundice after intravesical instillation of bacille Calmette-Guerin for bladder cancer

Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette-Guerin immunotherapy

Granulomatous hepatitis as a rare complication of Bacillus Calmette-Guerin vaccination

Mycobacteremia and granulomatous hepatitis following initial intravesical bacillus Calmette-Guerin instillation for bladder carcinoma

Granulomatous hepatitis caused by bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation

Hepatic granulomas in Whipple's disease

Granulomatous hepatitis in Pasteurella multocida infection

Granulomatous hepatitis in Yersinia enterocolitica infection

Liver abscesses in children: a single center experience in the developed world

Pyogenic liver abscess: recent trends in etiology and mortality

Granulomatous hepatitis

Evaluation of the histopathological hepatic lesions and opportunistic agents in Brazilian HIV patients

A prospective study of hepatic tuberculosis in 41 black patients

Disseminated tuberculosis: a 11-year experience in a medical center

Hepatobiliary tuberculosis

Patterns of calcifications and cholangiographic findings in hepatobiliary tuberculosis

Fulminant hepatic failure caused by tuberculosis

Peliosis hepatis due to disseminated tuberculosis in a patient with

Direct detection of Mycobacterium tuberculosis using polymerase chain reaction assay among patients with hepatic granuloma

Polymerase chain reaction for the detection of Mycobacterium tuberculosis DNA in tissue and assessment of its utility in the diagnosis of hepatic granulomas

Granulomatous involvement of the liver in patients with AIDS

A case of multiple macronodular hepatic tuberculosis difficult to differentiate from hepatocellular carcinoma with intrahepatic metastasis: CT-guided fine needle aspiration biopsy confirmed the diagnosis

Isolated liver tuberculosis abscess in a patient without immunodeficiency: a case report

Isolated giant tuberculomata of the liver detected by computed tomography

The nodular form of local hepatic tuberculosis. A review

Primary hepatic tuberculosis mimicking intrahepatic cholangiocarcinoma: report of two cases

Acute hepatobiliary tuberculosis: a report of two cases and a review of the literature

Atypical mycobacterial infection mimicking metastatic cholangiocarcinoma

Clinicopathological correlates in HIV seropositive tuberculosis cases presenting with jaundice after initiating antiretroviral therapy with a structured review of the literature

Hepatic disorders in the acquired immune deficiency syndrome: a clinical and pathological study

Pathologic findings in disseminated Mycobacterium avium-intracellulare infection: a report of 11 cases

Hepatic granulomas as primary presentation of Mycobacterium avium infection in an 243

Acute obstructive cholangitis: a distinct clinical syndrome

Acute bacterial cholangitis: an analysis of clinical manifestation

Isolated bacteria and susceptibilities to antimicrobial agents in biliary infections

Approach to the patient who has suspected acute bacterial cholangitis

Bacterial and parasitic cholangitis

Acute cholangitis: a histopathologic study

Relevant histopathologic findings that distinguish acute cellular rejection from cholangitis in hepatic allograft biopsy specimens

Oriental cholangiohepatitis: pathologic, clinical, and radiologic features

Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 28-2001: a 44-year-old woman with chills, fever, jaundice, and hepatic abscesses

Hepatolithiasis and the syndrome of recurrent pyogenic cholangitis: clinical, radiologic, and pathologic features

Hepatic resection for primary hepatolithiasis: a single-center Western experience

Clinical manifestations and complications in 1028 cases of brucellosis: a retrospective evaluation and review of the literature

Liver involvement in patients with brucellosis: results of the Marmara study

Acute and chronic hepatic involvement of brucellosis

Liver disease in brucellosis. A clinical and pathological study of 40 cases

Histological findings in human brucellosis

Histopathology of the liver in human brucellosis

The liver in brucellosis

Liver histology of acute brucellosis caused by Brucella melitensis

Granulomas in Brucella melitensis infection

The presence of granulomas due to Brucella melitensis in hepatitis

Hepatic granulomas in brucellosis

Hepatic granulomas in brucellosis

Brucella melitensis hepatitis: the absence of granulomas

liver abscesses: mortality-related factors

Pyogenic liver abscess caused by Klebsiella pneumoniae: analysis of the clinical characteristics and outcomes of 84 patients

Diabetes mellitus and pyogenic liver abscess: risk and prognosis

Clinical outcome and prognostic factors of patients with pyogenic liver abscess requiring intensive care

Liver abscess in neonates

Gas-forming pyogenic liver abscess

CT differentiation of pyogenic liver abscesses caused by Klebsiella pneumoniae vs non-Klebsiella pneumoniae

Multiple liver abscesses due to Yersinia enterocolitica discloses primary hemochromatosis: three cases reports and review

Yersinia pseudotuberculosis sepsis presenting as multiple liver abscesses

Yersinia enterocolitica liver abscesses unmasking idiopathic hemochromatosis

Multiple hepatic abscesses due to Yersinia enterocolitica infection secondary to primary haemochromatosis

Anaerobes in liver abscess

Role of anaerobic bacteria in liver abscesses in children

Primary hepatic actinomycosis: a diagnostic problem

Actinomycotic liver abscess: case report and review of the literature

Disseminated actinomycosis presenting as a renal tumor with metastases

Hepatic actinomycosis: an overview of salient features and outcome of therapy

Histologic and molecular diagnosis of tularemia: a potential bioterrorism agent endemic to North America

Computed tomography characteristics of Burkholderia pseudomallei liver abscess

Liver abscess due to Listeria monocytogenes: case report and review

Successful management of Aspergillus liver abscess in a patient with necrotizing fasciitis

Klebsiella pneumoniae genotype K1: an emerging pathogen that causes septic ocular or central nervous system complications from pyogenic liver abscess

Ocular manifestations and complications of pyogenic liver abscess

Acute cholangitis

Clinical features of liver involvement in adult patients with listeriosis: review of the literature

Multiple listerial liver abscesses

Disseminated listeriosis presenting as acute hepatitis. Case reports and review of hepatic involvement in listeriosis

Acute hepatitis by Listeria monocytogenes in an HIV patient with chronic HBV hepatitis

Adult listeriosis presenting as acute hepatitis

Listeria monocytogenes hepatitis in a liver transplant recipient: a case report and review of the literature

Listeria monocytogenesassociated acute hepatitis in a liver transplant recipient

Syphilitic hepatitis among HIV-infected patients

Prevalence of hepatitis in early syphilis among an HIV cohort

Liver involvement in HIV-infected patients diagnosed with syphilis

Liver involvement in HIV-infected patients with early syphilis

Liver dysfunction in patients with early syphilis: a retrospective study

Syphilis presenting as inflammatory tumors of the liver in HIV-positive homosexual men

Early syphilitic hepatitis in an immunocompetent patient: really so uncommon?

Early syphilis with liver involvement

Liver disease in early syphilis

Liver disease associated with early syphilis

Severe cholestatic hepatitis as the first symptom of secondary syphilis

Secondary syphilitic hepatitis in a fourteen-year-old male youth

Early syphilitic hepatitis concomitant with nephrotic syndrome followed by acute kidney injury

Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature

Clinical problem solving: a hand-carried diagnosis

Liver involvement in secondary syphilis

A case of syphilis presenting with initial syphilitic hepatitis and serological recurrence with cerebrospinal abnormality

Patterns of hepatosplenic Brucella abscesses on cross-sectional imaging: a review of clinical and imaging features

Hepatic brucelloma

Current understanding and management of chronic hepatosplenic suppurative brucellosis

Brucella liver abscess; imaging approach, differential diagnosis, and therapeutic management: a case report

Hepatic brucelloma

Hepatosplenic cat-scratch disease in children: selected clinical features and treatment

The histologic spectrum of hepatic cat scratch disease: a series of six cases with confirmed Bartonella henselae infection

Granulomatous hepatitis associated with cat scratch disease

Systemic Bartonella henselae infection with hepatosplenic involvement

Granulomatous hepatitis in three children due to cat-scratch disease without peripheral adenopathy: an unrecognized cause of fever of unknown origin

Granulomatous hepatitis due to Bartonella henselae infection in an immunocompetent patient

Granulomatous hepatitis and necrotizing splenitis due to Bartonella henselae in a patient with cancer: case report and review of hepatosplenic manifestations of bartonella infection

Typhoid and paratyphoid fever in travellers

Typhoid fever

Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 22-2001: a 25-year-old woman with fever and abnormal liver function

The liver in enteric fever and leptospirosis

A case of typhoid fever with hepatic granulomas and enteritis

A hepatitis like picture in typhoid fever

Hepatic abscess caused by Salmonella typhi. A case report and review of the literature

Gastrointestinal and hepatic manifestations of tickborne diseases in the United States

Hepatic granulomas, with an emphasis on infectious causes

Melioidosis: an important cause of pneumonia in residents of and travellers returned from endemic regions

Human melioidosis: a histopathologic study of acute and chronic melioidosis

Q fever and Mediterranean spotted fever associated with hemophagocytic syndrome: case study and literature review

Granulomatous hepatitis caused by Q fever: a differential diagnosis of fever of unknown origin

Prolonged pyrexia and hepatitis: Q fever

Clinicopathologic features of Q fever patients with acute hepatitis

Acute abdominal pain and Q fever

Q fever: a clinicopathologic study of five cases

The pathology of Q fever as seen on liver biopsy

Doughnut" granulomas in Q fever

Hepatic fibrin-ring granulomas caused by Staphylococcus epidermidis generalized infection

Fibrin ring granulomas and allopurinol

Allopurinol hypersensitivity syndrome as a cause of hepatic fibrinring granulomas

Hepatic fibrin-ring granulomas: a clinicopathologic study of 23 patients

Hepatic fibrin-ring granulomas in visceral leishmaniasis

Hepatic fibrin-ring granulomas in giant cell arteritis

Liver and bone marrow granulomas in Q fever

Diagnostic value of granuloma with fibrinoid ring

Acute Q fever presenting as fever of unknown origin with rapidly progressive hepatic failure in a patient with alcoholism

Granulomatous hepatitis in Q fever

Human ehrlichiosis: a rickettsial disease associated with severe cholestasis and multisystemic disease

Gastrointestinal and hepatic manifestations of human ehrlichiosis: 8 cases and a review of the literature

Hepatic pathology in human monocytic ehrlichiosis: Ehrlichia chaffeensis infection

Rocky mountain spotted fever: hepatic lesions in childhood cases

The liver in Rocky Mountain spotted fever

Mediterranean spotted fever in children in the Pazardjik region

Frequent occurrence of hepatic lesions in boutonneuse fever

Syphilitic hepatitis treated with doxycycline in an HIV-infected patient and review of the literature

Liver involvement in early syphilis

Hepatitis and bone destruction as uncommon manifestations of early syphilis: report of a case

Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 27-1983: a 25 year old man with liver disease

Syphilitic hepatitis uncommon presentation of an old scourge

Spirochetes as an almost forgotten cause of hepatitis

Hepatic lesions with secondary syphilis in an HIV-infected patient

Syphilitic gummas mistaken for liver metastases

Tertiary syphilis mimicking hepatic metastases of underlying primary peritoneal serous carcinoma

Tertiary hepatic syphilis: a treatable cause of multinodular liver

Pseudohepatic tumour associated with secondary syphilis in an HIV-positive male

Bacterial infections of the liver and biliary tract: laboratory studies to determine etiology

Immunohistochemical and in situ hybridization studies of the liver and kidney in human leptospirosis

Leptospirosis with acute liver injury

Cholestasis in human leptospirosis: a clinical, histochemical, biochemical and electron microscopy study based on liver biopsies

Liver biopsy in human leptospirosis: a light and electron microscopy study

Comparison of two PCR methods for detection of Leptospira interrogans in formalin-fixed and paraffin-embedded tissues

Hepatitis due to recurrent Lyme disease

Necrotizing granulomatous hepatitis as an unusual manifestation of Lyme disease

Q-fever: the liver and bone marrow pathology

Q fever hepatitis: clinical manifestations and pathological findings

Two rare manifestations of Q fever: splenic and hepatic abscesses and cerebral venous thrombosis, with literature review ma non troppo

Hepatic arterial thrombosis due to Mucor species in a child following orthotopic liver transplantation

Hepatic mucormycosis in a renal transplant recipient

Hepatic and small bowel mucormycosis after chemotherapy in a patient with acute lymphocytic leukemia

Hepatic mucormycosis in a bone marrow transplant recipient who ingested naturopathic medicine

Mucormycosis in a liver allograft: salvage re-transplantation and targeted immunosuppressive management

Fulminant zygomycosis of graft liver following liver transplantation

Hepatic mucormycosis mimicking hilar cholangiocarcinoma: a case report and literature review

Emergence of gastrointestinal basidiobolomycosis in the United States, with a review of worldwide cases

A fatal pseudo-tumour: disseminated basidiobolomycosis

Hepatic mucormycosis with abscess formation

Gastrointestinal mucormycosis-four cases with different risk factors, involving different anatomical sites

Isolated hepatic basidiobolomycosis in a 2-year-old girl: the first case report

Eosinophilic granulomatous gastrointestinal and hepatic abscesses attributable to basidiobolomycosis and fasciolias: a simultaneous emergence in Iraqi Kurdistan

Gastrointestinal basidiobolomycosis accompanied by liver involvement: a case report

Combined antifungal therapy, iron chelation and surgical resection as treatment of hepatic zygomycosis in a patient with haematological malignancy

Disseminated Penicillium marneffei infection in HIV-infected subject

Infection due to Penicillium marneffei, an emerging pathogen: review of 155 reported cases

Disseminated Penicillium marneffei infection with IRIS

Clinicopathologic study of hepatic Penicillium marneffei in Northern Thailand

Gastrointestinal, hepatic, and pancreatic involvement with Cryptococcus neoformans in AIDS

Primary hepatic cryptococcosis

Hepatic cryptococcosis in a heart transplant recipient

Hepatic involvement in a liver transplant recipient with disseminated cryptococcosis

The liver in boutonneuse fever

Granulomatous hepatitis: a review of 50 cases

Hepatic granulomas in children: a clinicopathologic analysis of 23 cases including polymerase chain reaction for Histoplasma

Progressive disseminated histoplasmosis: a prospective study of 26 patients

Histoplasmosis presenting as granulomatous hepatitis: case report and review of the literature

Diagnostic procedures in the evaluation of hepatic diseases: studies to determine mycotic etiology

Hepatic candidiasis in cancer patients: the evolving picture of the syndrome

Candida hepatitis: histopathologic diagnosis

Neonatal liver abscesses associated with candidemia: three cases and review of literature

Neonatal liver abscesses due to Candida infection in a preterm infant, secondary to malpositioned umbilical lines-a rare entity

Pharmacological resolution of a multiloculated Candida spp. liver abscess in a preterm neonate

Gallbladder and biliary tract candidiasis

Parasitic and mycotic causes of biliary obstruction

Diagnosis of chronic disseminated candidosis from liver biopsies by a novel PCR in patients with haematological malignancies

Alteration of the natural history of Pneumocystis carinii infection in patients with acquired immunodeficiency syndrome receiving aerosolized pentamidine

Acute hepatic and renal failure caused by Pneumocystis carinii in patients with AIDS

Aspergillosis of biliary tract after liver transplantation: a case report

Successful treatment of Aspergillus liver abscesses in a patient with acute monoblastic leukemia using combination antifungal therapy including micafungin as a key drug

Progression of hepatic aspergillosis following second renal transplantation in a patient with recurrent glomerulonephritis

Aspergillus cholangitis: a late complication after Kasai portoenterostomy

Two cases of hepatic zygomycosis in allogeneic stem cell transplant recipients and review of literature

Pinworm infection masquerading as colorectal liver metastasis

Enterobius vermicularis infection of the liver in a patient with colorectal carcinoma with suspected liver metastasis

Pinworm granuloma of the liver

Zoonotic helminth infections of humans: echinococcosis, cysticercosis and fascioliasis

Advances in liver echinococcosis: diagnosis and treatment

Hepatic echinococcosis: clinical and therapeutic aspects

Echinococcus multilocularis

Cellular organization and appearance of differentiated structures in developing stages of the parasitic platyhelminth Echinococcus granulosus

Ultrastructure and microanalyses of the calcareous corpuscles of the protoscoleces of Echinococcus granulosus

Cystic echinococcosis of the liver: a primer for hepatologists

Hepatic echinococcal cysts: a review

Toxocariasis of the liver: visceral larva migrans

Toxocariasis: a review for pediatricians

A case of adult hepatic toxocariasis

Severe hepatic involvement in visceral larva migrans

Toxocara canis infection and granulomatous hepatitis

Eosinophilic granuloma of the liver: a characteristic lesion with relationship to visceral larva migrans

Visceral larva migrans presenting as acute abdomen in a child

Hepatic capillariasis in a 1-year-old child

Hepatic capillariasis: first case report in the Republic of Korea

Capillaria hepatica infection: a rare differential for peripheral eosinophilia and an imaging dilemma for abdominal lymphadenopathy

Hepatic capillariasis in Maine presenting as a hepatic mass

Hepatic capillariasis in children: report of 3 cases in Brazil

Hepatic capillariasis in a 2-year-old boy

Disseminated cryptococcosis with hepatic dysfuction as the initial manifestation in an immunocompetent adult

Isolated biliary cryptococcosis manifesting as obstructive jaundice in an immunocompetent adult

Diagnostic and post-treatment CT appearance of biopsy proven mixed Cryptococcus and Candida cholangitis

Isolated hepatobiliary cryptococcosis manifesting as obstructive jaundice in an immunocompetent child: case report and review of the literature

Liver cryptococcosis manifesting as obstructive jaundice in a young immunocompetent man: report of a case

Hepatic failure as a manifestation of cryptococcosis

Cholangitis associated with Cryptococcus neoformans

Fatal coccidioidomycosis: report of two cases

Kokzidioidomykose als Ursache einer granulomatosen hepatitis

Diagnosis of disseminated coccidioidomycosis by liver biopsy

Cholangitis due to Blastomyces dermatitidis

Morphological patterns of the liver in South American blastomycosis

Hepatic involvement in paediatric patients with paracoccidioidomycosis: a histological study

Intrahepatic biliary paracoccidioidomycosis mimicking cholangiocarcinoma

Microsporidial AIDS cholangiopathy due to Encephalitozoon intestinalis: case report and review

Human immunodeficiency virus 1-associated necrotizing cholangitis caused by infection with Septata intestinalis

Foamy macrophages in acquired immunodeficiency syndrome cholangiopathy with Encephalitozoon intestinalis

Hepatic schistosomiasis

Hepatic and intestinal schistosomiasis: review

Schistosomiasis of the liver

Acute schistosomiasis mansoni: revisited and reconsidered

Strongyloides stercoralis infection in the immunocompromised host

Granulomatous hepatitis due to Strongyloides stercoralis

Hepatic granuloma resulting from Enterobius vermicularis

Severe malaria-a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report

Hepatocyte dysfunction and hepatic encephalopathy in Plasmodium falciparum malaria

Malarial hepatitis: a heterogeneous syndrome

Liver pathology in Malawian children with fatal encephalopathy

Hepatic changes in fatal malaria: an emerging problem

Liver changes in severe Plasmodium falciparum malaria: histopathology, apoptosis and nuclear factor kappa B expression

Diagnostic procedures in the evaluation of hepatic diseases: studies to determine parasitologic etiology

Leishmania/HIV co-infections in the second decade

Visceral leishmaniasis emerging as an important opportunistic infection in HIV-infected persons living in areas nonendemic for Leishmania donovani

Pathophysiology of visceral leishmaniasis: some recent concepts

Histopathological patterns of the liver involvement in visceral leishmaniasis

Leishmaniasis diagnosed by liver biopsy: management of two atypical cases

Human visceral leishmaniasis expresses Th1 pattern in situ liver lesions

Hepatitis with fibrin-ring granulomas

Toxoplasmic hepatitis in an immunocompetent patient

Severe toxoplasmic hepatitis in an immunocompetent patient

Cholestatic jaundice due to toxoplasma hepatitis

Acute granulomatous hepatitis in the course of acquired toxoplasmosis

Duodenal and hepatic toxoplasmosis in a patient with HIV infection: review of the literature

Sclerosing cholangitis associated to cryptosporidiosis in liver-transplanted children

Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy

Reversible sclerosing cholangitis secondary to cryptosporidiosis in a renal transplant patient

Liver disease in children with primary immunodeficiencies

Cryptosporidium parvum-associated sclerosing cholangitis in a liver transplant patient

Capillaria hepatica infestation

Fascioliasis in developed countries: a review of classic and aberrant forms of the disease

Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 12-2002: a 50-year-old man with eosinophilia and fluctuating hepatic lesions

Fasciola hepatica human infection: histopathological study of sixteen cases

Update on hepatobiliary flukes: fascioliasis, opisthorchiasis and clonorchiasis

Parasitic diseases of the biliary tract

Histopathological diagnosis of opisthorchiasis in an immigrant

Biliary ascariasis: the value of ultrasound in the diagnosis and management

Ascaris-induced liver abscess

Ascaris liver abscess in children

Intrahepatic duct stones harboring Ascariasis ova: a case report

Liver pseudotumor: a rare manifestation of hepatic granulomata caused by Ascaris lumbricoides ova

Massive hepatobiliary ascariasis at autopsy

Radio-pathological diagnosis of hepatobiliary ascariasis: a rare entity

Amebic liver abscess in northern region of Bangladesh: sociodemographic determinants and clinical outcomes

A review of amoebic liver abscess for clinicians in a nonendemic setting

Amoebic liver abscess in USA: a population-based study of incidence, temporal trends and mortality

A clash to conquer: the malaria parasite liver infection

Jaundice with hepatic dysfunction in P. falciparum malaria

Malarial hepatopathy in falciparum malaria

Plasmodium malariae-infected erythrocytes in the peripheral blood, liver, stomach and duodenum: an ultrastructural study

Cholangiocarcinoma complicating secondary sclerosing cholangitis from cryptosporidiosis in an adult patient with CD40 ligand deficiency: case report and review of the literature

Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM

Complete recovery from Cryptosporidium parvum infection with gastroenteritis and sclerosing cholangitis after successful bone marrow transplantation