The liver is the target of many infectious agents, most notably hepatotropic viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV). Additionally, many infectious organisms can involve the liver in the setting of disseminated infection, in immune-suppressed 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.
Viruses
Hepatitis A
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 of age, 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. About 100 cases of HAV-related 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. 10-1 ).7 In rare cases, perivenular cholestasis with relatively little inflammation mimics cholestatic drug reactions. Fibrin ring granulomas have been reported.8 , 9
Figure 10-1.
Liver biopsy in hepatitis A. A, Panlobular inflammation and lobular disarray. B, High power shows many plasma cells within the infiltrate (arrows).
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
Virology
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 early 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
Pathophysiology
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 rigorous immune responses cause more severe liver injury. Patients with a vigorous immune 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
Natural History
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. 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 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 , 15
Seroconversion is followed by the low or nonreplicative HBsAg carrier stage, characterized by normalization of aminotransferases and low or undetectable HBV DNA levels.10 , 15 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 , 16 Up to 20% of patients serorevert to HBeAg-positive status, with a flare of activity.10 , 16 In up to one third of patients, chronic hepatitis recurs without seroreversion; this is known as HBeAg-negative chronic hepatitis, due to mutations in the precore or core-promoter regions of the HBV genome.10 , 16 In this phase, despite the presence of anti-HBeAg antibody (HBeAb) and the absence of HBeAg, HBV DNA is detectable, serum aminotransferases rise, and histologic examination of the liver shows chronic hepatitis.10 Patients with HBeAg-negative chronic hepatitis tend to be older and to have more advanced liver fibrosis.10
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 , 15 Additional risk factors for HCC include abnormal alanine aminotransferase levels, long duration of infection, coinfection with HCV or hepatitis D (HDV), a family history of HCC, excessive alcohol intake, cigarette smoking, HBV genotype C, and core-promoter mutations.10
Histopathology
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. 10-2 ). In the immune clearance phase, chronic hepatitis B shows portal mononuclear infiltrates with interface hepatitis and variable fibrosis (Fig. 10-3 ). 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 ground glass hepatocytes (Fig. 10-4 ), which contain HBsAg. These hepatocytes show a finely granular cytoplasmic inclusion that displaces the nucleus and is surrounded by a pale halo. Ground glass hepatocytes can be demonstrated by various histochemical stains such as Victoria blue, orcein, or aldehyde fuchsin17 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.17
Figure 10-2.
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 (HBsAg) shows strong membranous staining of hepatocytes as well as individual hepatocytes with strong cytoplasmic staining, consistent with high viremia. C, Immunohistochemical stain for the core antigen (HBcAg) shows nuclear staining of many hepatocytes, consistent with high viral replication.
Figure 10-3.
Liver biopsy in the immune clearance phase of hepatitis B. A, Low-power view of a portal tract with a dense mononuclear infiltrate and focal interface hepatitis (arrow). B, Aldehyde fuchsin stain confirms the accumulation of hepatitis B surface antigen (HBsAg) within hepatocytes. C, Immunohistochemical stain for HBsAg shows cytoplasmic staining of clusters of hepatocytes, indicative of low viremia.
Figure 10-4.
Ground glass hepatocytes in chronic hepatitis B (arrows). 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.
Immunohistochemistry
Immunohistochemistry for HBV antigens can be used to evaluate the pattern of antigen expression, which correlates with viral replication and disease activity (Table 10-1 ). Strong cytoplasmic expression of HBsAg in scattered individual hepatocytes, associated with membranous staining of many hepatocytes, indicates high viremia and is seen in the immune tolerance phase.18 , 19 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.18 , 19
Table 10-1.
Immunohistochemistry for Hepatitis B
| HBsAg | HBcAg | |||
| Membranous | Cytoplasmic | Nuclear | Cytoplasmic | |
| Immune tolerance phase | ++ | ++ (individual cells) | ++ | |
| Immune clearance phase | −/+ | + (individual cells) | + (few cells) | +/− |
| Low-replication states (chronic carriers) | − | ++ (clustered cells) | −/+ (rare cells) | − |
| HDV/HCV coinfection | + | +/− | − | |
| HBV in immune-deficiency states | ++ | +/− | ++ | + |
−, absent; +, present; HBcAg, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus.
Expression of HBcAg can be cytoplasmic or nuclear. Nuclear expression correlates with the degree of viral replication; therefore, 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 suggests that HBcAg is the likely target for immune-mediated cytolysis.18 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.
Management
The management of chronic HBV infection has improved significantly in the last decade with the introduction of nucleoside and nucleotide analogues. These agents are orally administered, safe, well tolerated, and very effective at suppressing HBV DNA replication. However, sustained virologic suppression is not maintained after withdrawal of the agents, and long-term, indefinite therapy is often required. Long-term use of these agents is also associated with the development of resistance, loss of clinical response, hepatitis flares, and even death.
Viral Mutants
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.15 Other mutations in the basic core promoter downregulate HBeAg synthesis at the transcriptional level.15 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 , 20 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.20
Post-transplantation Hepatitis B
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.21 The risk of reinfection is greater after transplantation for chronic HBV infection with cirrhosis, compared to acute HBV.22 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.21 Acute HBV hepatitis after transplantation may show marked ballooning and degenerative changes in the hepatocytes, scattered acidophil bodies, and extensive immunohistochemical evidence of viral antigen expression, but with remarkably scant inflammation.21 , 22
A distinctive pattern of hepatitis in the transplantation population is known as fibrosing cholestatic hepatitis, initially described by Davies and colleagues in 1991.21., 22., 23., 24. 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.21., 23., 24. 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.21., 22., 24. Fibrosing cholestatic hepatitis is associated with a high rate of viral replication, with high serum HBV DNA, high serum HBsAg titers, and rapid deterioration.22., 23., 24. It has also been described in HBV infection in other settings involving immunosuppression, including human immunodeficiency virus (HIV) infection25 and bone marrow transplantation.26
Coinfection with Hepatitis B Virus and Human Immunodeficiency Virus
Approximately 90% of HIV-infected persons show evidence of prior HBV infection, and 5% to 15% have chronic HBV infection.27 In patients coinfected with HIV and HBV, the rate of clearance of HBsAg and HBeAg is reduced, compared with non–HIV-infected individuals.28 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.28 Even though there is reduced inflammation, HBV infection is more progressive in HIV-positive patients, including development of cirrhosis and its complications.28 A pattern of hepatitis similar to fibrosing cholestatic hepatitis has been described in HIV patients with concurrent HBV infection.25 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.28 Conversely, the use of antiretroviral agents that also have activity against HBV may slow the progression of chronic HBV and even result in seroconversion, whereas their discontinuation can cause significant liver disease due to re-emergence of HBV replication.27
Hepatitis C
Hepatitis C affects between 123 and 170 million people worldwide.29
Virology
HCV is an RNA flavivirus that was characterized in the late 1980s.29 Its genome is a positive, single-stranded RNA with a large open reading frame that encodes a 3010- to 3030-amino-acid polyprotein.30 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 E2.30 The nonstructural proteins are NS2, -3, -4A, -4B, -5A, and -5B (RNA polymerase).30
There are 6 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.30 , 31 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.31 Genotypes 1, 2, and 3 have worldwide distribution, but their relative prevalence varies geographically.32 Genotype 1a is the predominant genotype in North America (70%).33 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.33 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.32 , 33
The genotype affects the rate of evolution to chronic hepatitis, the severity of liver disease, and the response to interferon (IFN) therapy.32 For example, genotype 1 is associated with a poor response to IFN therapy, whereas genotypes 2 and 3 respond more favorably.33 An association between genotype 1b and an increased risk of developing severe liver disease and HCC has been reported.33 , 34
Natural History
HCV is primarily transmitted parenterally, such as by recreational drug use, injection with contaminated syringes or needles, or blood transfusion.29 , 35 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.31
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.36., 37., 38. The mean incubation time for HCV is 6 to 8 weeks.29 Although the majority (60% to 75%) of affected patients do not experience symptoms when acutely infected,29 acute HCV still accounts for approximately 20% of cases of acute hepatitis.35 , 39 The symptoms of acute HCV are malaise, fatigue, lethargy, anorexia, abdominal pain, jaundice, mild hepatosplenomegaly, maculopapular rash, and arthralgia.29 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.39 The serologic diagnosis of chronic HCV infection is made by detection of HCV antibodies, usually by enzyme immunoassay.29 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.29 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.35 Patients with elevated transaminases may suffer from fatigue or from nonspecific symptoms.35
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.29., 35., 40. A subset of patients with HCV demonstrate autoantibodies similar to those seen in autoimmune hepatitis, namely antinuclear antibodies (ANA), 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.40 Less often, liver-kidney microsomal (LKM1) autoantibodies are detected, although the epitopes recognized by these antibodies in HCV differ from those in autoimmune hepatitis type 2.40 Patients with autoantibodies tend to be females and to have higher transaminase levels.41 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.29 The risk of developing cirrhosis is approximately 20% to 30% after 10 to 20 years of infection.35 Once 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.35
Histopathology
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 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. 10-5 ). Bile duct injury may be present. Cholestatic forms of acute HCV infection occur rarely, predominantly in the immunosuppressed population.
Figure 10-5.
Liver biopsy in acute hepatitis C. A, Low-power view shows mononuclear cell infiltrates within portal tracts, similar in appearance to chronic hepatitis C virus infection. B, High-power view of the centrilobular region shows sinusoidal lymphocytic infiltrates surrounding a central vein.
Chronic HCV infection is characterized by dense mononuclear cell aggregates or follicles in portal tracts, with mild to moderate interface hepatitis.42 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. 10-6 ).42 Kupffer cell prominence and lymphocytic infiltration of sinusoids may be seen.17 , 42 Variable fibrosis is present, and its extent often drives the decision of whether to treat the infection.
Figure 10-6.
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 virus infection.
Mild to moderate steatosis is characteristic of chronic HCV infection.42 Steatosis may be related to direct viral cytopathic effects in patients with genotype 3 but to underlying metabolic status in patients with other genotypes.43 , 44 HCV core protein expression produces steatosis in mice through mitochondrial toxicity and production of reactive oxygen species.43 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.45 In another series, 5 (10%) of 52 liver explants for HCV-related cirrhosis had granulomas for which no other cause could be identified.46 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, or mycobacterial infection).47 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.48 Others have described granulomas in HCV after treatment with IFN-α in patients who did not respond well to IFN-α.49., 50., 51. 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 duct injury. If the granulomas are in the portal area, their presence in conjunction with injured bile ducts may mimic primary biliary cirrhosis. Other clinical information (e.g., AMA, alkaline phosphatase level) may be needed to distinguish the two.
Management
Acute HCV infection is typically observed for 3 months after the onset of symptoms; antiviral therapy is offered to patients who have persistent viremia after that period.36., 37., 38. The management of chronic HCV depends to some extent on viral genotype. Genotype 1 is associated with reduced likelihood of treatment success compared to genotypes 2 and 3. The mainstay of treatment is combination IFN and ribavirin. Treatment success has been improved with the introduction of pegylated IFN, which consists of a polyethylene glycol (PEG) polymer attached to the IFN molecule, which results in reduced drug clearance rates and allows once-weekly dosing.29 Therapy may need to be continued for up to 24 weeks for genotypes 2 or 3 and up to 48 weeks for genotype 1.29
Post-transplantation Hepatitis C
After transplantation for chronic HCV, reinfection of the graft is almost universal. 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.52 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.53 Fibrosing cholestatic hepatitis secondary to HCV has also been described in other immunosuppressed patient populations, such as in HIV patients54 and after heart or kidney transplantation.55., 56., 57.
Coinfection with Hepatitis C Virus and Human Immunodeficiency Virus
In the United States and Europe, 33% of HIV-infected persons are coinfected with HCV.27 The clearance rate of HCV after acute infection is reduced in HIV-infected patients.27 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.20., 27., 28. 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.58 , 59 Fibrosing cholestatic hepatitis related to HCV has been described in patients with HIV coinfection.54 With the introduction of HAART, HCV-related liver disease has become an important factor in hospitalizations and mortality of HIV patients.28 Patients with HCV are more likely to suffer from hepatotoxicity related to HAART and to have impaired immune reconstitution.27
Hepatitis D
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. There are two modes of infection: coinfection with HBV and superinfection of prior HBV infection. Coinfection results in severe acute hepatitis with high mortality, but resolution produces immunity to both viruses. Superinfection is associated with a high likelihood of chronic infection by both viruses and a propensity for more severe inflammation than with HBV alone. HDV infection inhibits HBV replication, resulting in decreased expression of HBcAg, although expression of HBsAg continues.7 Treatment with IFN-α inhibits HDV replication, but relapse is common.
HDV infection may be associated with autoimmune manifestations in a subset of patients. LKM3 autoantibodies are detected in 13% of patients with HDV.40 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.60 The pathology of HBV and delta virus is indistinguishable from that of HBV alone, except that the degree of inflammation and hepatocyte necrosis is often more prominent than with HBV alone.
Hepatitis E
Hepatitis E virus (HEV) is a nonenveloped, positive-sense, single-stranded RNA virus of the calicivirus family. Along with HAV, HEV accounts for the majority of cases of enterically transmitted viral hepatitis worldwide. However, unlike HAV, HEV is not easily transmitted from person to person, so familial clusters are unusual.61 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.61 , 62 Clinically, hepatitis E is indistinguishable from hepatitis A, and serology for anti-HEV IgM or PCR is required to make the diagnosis. Both are acute infections without progression to chronic hepatitis, and both can range from asymptomatic infection to fulminant hepatitis. The mortality rate is 1% to 4% overall, but it is approximately 20% among pregnant women.61 , 62
Although HEV is spread by the fecal-oral route, similar to HAV, there are some curious differences between the two viruses. In some countries where both viruses are endemic, such as India, children are universally infected with HAV by age 5 years, whereas HEV infects young adults and many adults are seronegative. In other countries, such as Egypt, seroconversion to anti-HEV occurs in a greater percentage of the population and at an earlier age. In the United States, anti-HEV is actually more common than anti-HAV, although HAV is more often diagnosed.61 In developed countries, HEV infection is still only rarely diagnosed, although its incidence is increasing. Some evidence suggests that HEV may be a zoonotic infection: swine have been shown to be frequently infected, and cases of zoonotic transmission to humans via ingestion of undercooked pork or deer meat have been reported.61
The histopathology of HEV is similar to HAV in that it can produce a classic acute hepatitis or cholestatic hepatitis with lobular canalicular cholestasis and relatively little inflammation. In some cases, cholangiolar proliferation with bile plugs in dilated cholangioles can be seen.
Epstein-Barr Virus
The liver is involved in more than 90% of cases of infectious mononucleosis, which is caused by Epstein-Barr virus (EBV) infection; hepatomegaly is present in 10% to 15% of cases, splenomegaly in 50%, and jaundice occurs 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,63 severe hepatitis with prolonged jaundice,64 or liver failure.65., 66., 67.
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. 10-7 ).68 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 non-necrotizing granulomas69 and fibrin ring granulomas have been reported in patients with EBV hepatitis.70 In fatal cases, submassive lobular necrosis has been seen.65
Figure 10-7.
Liver biopsy in Epstein-Barr virus infection. A, A portal tract shows a mild mononuclear infiltrate, and the lobules show infiltration of sinusoids by mononuclear cells. B, High magnification shows prominent sinusoidal lymphocytic infiltration without hepatocyte necrosis.
Detection of EBV is done by in situ hybridization for EBV-encoded RNA (EBER) (Fig. 10-8 ) or by PCR for EBV DNA.71 Immunohistochemistry for EBV latent membrane protein has not proved to be a reliable method for detecting EBV in EBV hepatitis.
Figure 10-8.
In situ hybridization for EBV-encoded RNA (EBER) shows nuclear staining of a single infected lymphocyte (arrow).
Cytomegalovirus
Cytomegalovirus (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.72 , 73 CMV infection is rarely associated with well-formed non-necrotizing granulomas74 or fibrin ring granulomas.75 In immunocompromised patients, viral inclusions may be found in hepatocytes, endothelial cells, Kupffer cells, and duct epithelium (Fig. 10-9 ). 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.72 In HIV-positive patients, bile duct involvement may result in sclerosing cholangitis (HIV-associated cholangiopathy). Immunohistochemical stains for CMV can highlight cells with inclusions, including atypical inclusions.
Figure 10-9.
Cytomegalovirus (CMV) infection, demonstrating a CMV inclusion in bile duct epithelium (arrow).
(Courtesy of Dr. Laura Lamps.)
Herpes Simplex Virus
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.76 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. 10-10 ). Intranuclear inclusions of two types can be found in hepatocytes at the edge of the necrotic foci, and virally infected cells are often multinucleated.76 Cowdry type A inclusions are large, eosinophilic intranuclear inclusions surrounded by a halo, whereas type B inclusions replace the entire nucleus with a basophilic ground glass appearance. Immunohistochemistry for herpes type I and type II antigens highlights the nuclear inclusions, and overlap between the two antibodies is frequent.76
Figure 10-10.
Herpes simplex virus (HSV) infection. A, The liver shows necrotic regions without an inflammatory response. B, Hepatocytes at the edge of the necrotic regions show glassy nuclear inclusions and multinucleation, consistent with HSV infection.
Treatment with antiviral drugs before the biopsy is obtained may result in a biopsy specimen with extensive necrosis but without diagnostic inclusions.76 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.
Varicella-Zoster Virus
Rarely, the rash of VZV can be accompanied by potentially life-threatening noncutaneous manifestations, including encephalitis, pneumonitis, myocarditis, and hepatitis, especially in immunocompromised patients. In children, the convalescent phase can be associated with Reye's syndrome (microvesicular steatosis, hyperammonemia, coagulopathy, and cerebral edema), particularly if aspirin has been administered. 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.
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.
Adenovirus
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. Postmortem livers in patients with adenovirus hepatitis have shown widespread necrosis with little inflammation, mild steatosis, and viral inclusions similar to the Cowdry type A inclusions of HSV infection (Fig. 10-11 ).77 , 78 Immunohistochemistry, electron microscopy, and viral culture are helpful in making the diagnosis.78
Figure 10-11.
Adenovirus hepatitis. A, Low-power view shows several regions of necrosis without an inflammatory reaction. B, High-power view shows hepatocytes with smudgy nuclear inclusions similar to the Cowdry type A inclusions of herpes simplex virus.
Parvovirus B19
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. Parvovirus B19 DNA has been found in the liver of patients with fulminant hepatic failure and in the serum of patients with acute or fulminant hepatitis, suggesting a role for this virus in cases of unexplained acute hepatitis or acute liver failure.79., 80., 81. In one study,80 parvovirus B19 DNA was found in liver tissue in four of six patients with fulminant hepatic failure associated with aplastic anemia and in two of four patients with cryptogenic acute liver failure (without aplastic anemia), but not in six patients with known causes of acute liver failure. Histology studies in DNA-positive cases showed massive hepatic necrosis and collapse without inflammatory infiltrates or viral inclusions. 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.82 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. Furthermore, RNA transcripts could not be detected in any of the liver tissue samples, arguing against active viral replication.83 These studies suggest that low levels of PCR positivity may reflect remote infection, and they raise questions about the role of parvovirus B19 in hepatitis and acute liver failure.
Rubella (German Measles)
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.84 , 85
Rubeola (Measles)
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.86 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. 10-12 ). At autopsy, viral inclusions were noted in hepatocytes.87
Figure 10-12.
Liver biopsy in a patient with measles hepatitis. A, Portal tracts show inflammation, cholangitis with bile duct injury, periportal hepatocyte loss, and ballooning degeneration. B, The lobules show widespread hepatocyte ballooning degeneration, cholestasis, and multinucleated hepatocytes.
Severe Acute Respiratory Syndrome Coronavirus
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.88
Human Immunodeficiency Virus
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.89 , 90 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 the acquired immunodeficiency syndrome (AIDS) may develop unusual reactions to certain pathogens, such as bacillary epithelioid angiomatosis secondary to Bartonella henselae or Bartonella quintana infection (discussed later).91 , 92
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.93 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. Several opportunistic pathogens have been implicated in this disorder, including Cryptosporidium, CMV, and microsporidia (Enterocytozoon bieneusi).94., 95., 96., 97., 98., 99. 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 primary sclerosing cholangitis coincidentally occurring in patients with AIDS.98 , 99
The liver can be involved by HIV-associated neoplasms such as lymphoma or Kaposi sarcoma.100 The latter is caused by another virus, Kaposi sarcoma–associated herpesvirus (KSHV), also known as Human herpesvirus 8 (HHV-8). Finally, immune reconstitution with HAART can precipitate autoimmune hepatitis.101
Yellow Fever
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.102., 103., 104., 105. Others describe panlobular injury with only a collar (one or two cells thick) of preserved hepatocytes around central veins and portal tracts.106 The key findings are necrosis with numerous apoptotic hepatocytes (Councilman bodies), microvesicular steatosis, and absence of inflammation (Fig. 10-13 ).102., 103., 104., 105., 106. Eosinophilic intranuclear inclusions, Torres bodies, are rarely seen in humans.106 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.
Figure 10-13.
Yellow fever. A, Low-power view shows panlobular necrosis with numerous necrotic hepatocytes primarily in zones 2 and 3. B, High-power view shows relative preservation of periportal hepatocytes with steatosis, ballooning degeneration, and scattered necrotic hepatocytes.
(Courtesy of Dr. Shu-Yuan Xiao.)
Dengue
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 2 decades may be related to human population growth, inadequate wastewater management, lack of effective mosquito eradication programs, and emergence of more virulent strains.107 The clinical manifestations include 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.107 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.107
The severity of hepatic involvement parallels the severity of the dengue infection. Serotypes 3 and 4 are associated with more severe liver disease.107 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. 10-14 ).105 , 106 The contributions of virus or shock to the centrilobular necrosis remain uncertain.106 Microvesicular steatosis is frequent, although relatively mild. As with other arboviruses, little inflammation is present.108 , 109 The distinction from yellow fever may require geographic data, clinical features, and virologic studies. Immunohistochemical demonstration of the virus within hepatocytes has been described.108 , 109
Figure 10-14.
Liver biopsy specimen from a patient who died of dengue shock demonstrates centrilobular necrosis with numerous acidophil bodies (right) and no inflammatory reaction.
Rift Valley Fever
Rift Valley Fever primarily affects sheep and cattle in Africa, although humans who have direct contact with animals or carcasses may become infected. Fever, severe headache, and myalgia may be followed by facial inflammation, encephalitis, and macular degeneration.102 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; numerous acidophil bodies; and hemorrhage.102 , 106
Lassa Virus
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.102 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.106 , 110 There is little inflammatory reaction apart from histiocytes phagocytosing necrotic debris.110 The nonzonal distribution of the necrosis distinguishes this disease from yellow fever.102 , 110
Ebola Virus
Ebola virus causes a severe and frequently fatal viral hemorrhagic fever; outbreaks in Sudan and Zaire have caused international concern. The disease is similar to Marburg virus infection, with disseminated intravascular coagulopathy and bleeding occurring in the majority of patients.102 The histology is characterized by foci of hepatocellular necrosis randomly distributed throughout the parenchyma and eosinophilic inclusions within hepatocytes.102 , 106 Mild to moderate steatosis, mild mononuclear infiltrates in the periportal area, and Kupffer cell activation are additional findings.106
Marburg Virus
Marburg virus has been associated with African green monkeys. Fever, malaise, headache, and myalgia may be accompanied by a maculopapular rash and conjunctivitis.102 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.102
Mycobacteria
Tuberculosis
Worldwide, M. tuberculosis is one of the most common causes of hepatic granulomas. The organisms may reach the liver hematogenously from the lungs, through the portal circulation in the setting of gastrointestinal tuberculosis, or via lymphatics.111 Tuberculosis (TB) can affect the liver in several forms. Most often, the liver is affected in the setting of generalized miliary TB.112 Less often, hepatitic 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.111 , 113 Localized hepatic involvement can occur in primary infection, in which case there is no evidence of antecedent infection, or as reactivation TB.114 Tuberculous cholangitis, in which the bacillus primarily infects the biliary tree, is extremely rare.115
The most common presentation of hepatic TB is abdominal pain, hepatomegaly, jaundice, fever, and chills. Alkaline phosphatase elevations and hyponatremia usually are prominent features.114., 116., 117. In 65% to 78% of patients with hepatic TB, respiratory symptoms or chest radiographs suggest pulmonary TB as well.111., 114., 116., 117. Abdominal imaging shows liver calcifications in approximately half of patients.111., 112., 118. Caseating granulomas are a hallmark of hepatic TB, particularly miliary TB in the setting of primary infection; in reactivation TB, noncaseating granulomas may be present instead (Fig. 10-15 ). The granulomas may reside in the lobules or in portal tracts. Acid-fast stains or cultures are positive in 0% to 59% of cases, but organisms are more likely to be found with caseating necrosis.114., 115., 116. PCR for M. tuberculosis DNA has a 53% to 88% sensitivity and a 96% to 100% specificity for detecting hepatic TB.111., 119., 120. 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. Acid-fast stain shows numerous organisms in these lesions.121
Figure 10-15.
Miliary tuberculosis involving the liver. A, Low-power view shows several necrotizing granulomas. B, High-power view of a necrotizing granuloma. Note the central region of necrosis surrounded by histiocytes and a giant cell. C, An acid-fast stain highlights a single bacillus (arrow) within the granuloma.
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.113 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 immune-competent 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.112 The latter may result in bile duct strictures that can be mistaken for cholangiocarcinoma or primary sclerosing cholangitis.112 , 122
Mycobacterium avium-intracellulare Complex
Of the atypical mycobacteria, Mycobacterium avium and Mycobacterium 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 phosphatase, and hepatomegaly.123 The histopathologic findings range from numerous well-formed, nonnecrotizing granulomas with rare acid-fast organisms on Ziehl-Neelsen stain to less well-formed granulomas with large numbers of acid-fast organisms spilling out of the loose granulomas into nearby Kupffer cells (Fig. 10-16 ).121 , 124 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.121 , 123
Figure 10-16.
Mycobacterium avium-intracellulare complex (MAC) infection in an immunocompromised patient. A, The liver shows loose collections of histiocytes, suggestive of poorly formed granulomas. B, On acid-fast staining, several bacilli are present (arrows).
Leprosy
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 leprosy.125 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 acid-fast bacilli.125 , 126 In tuberculoid leprosy, epithelioid granulomas with rare or no acid-fast organisms are seen (Fig. 10-17 ).125 An individual patient may have both lepromatous and tuberculoid granulomas.
Figure 10-17.
Liver biopsy sample from a patient with leprosy. Several noncaseating granulomas are present.
Bacillus Calmette-Guérin
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.127 , 128 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.129 The liver shows noncaseating epithelioid granulomas, mild steatosis, and hepatocyte necrosis. Often, acid-fast bacilli 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,127 particularly because some cases show additional features of extrahepatic granulomas, leukocytoclastic vasculitis, or bile duct injury and eosinophils (Fig. 10-18 ).130 , 131 However, in some reported cases, acid-fast bacilli 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.131., 132., 133. 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.131
Figure 10-18.
Liver biopsy in a patient with bacillus Calmette-Guérin infection. A, Several small granulomas are present in this view. B, In some portal tracts, bile duct injury and scattered eosinophils are present, suggesting a hypersensitivity reaction.
Nonmycobacterial Bacteria
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 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 (Table 10-2 ).134., 135., 136. 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 granulomas, the diagnosis of “granulomatous hepatitis” in these cases is best avoided. Biliary involvement can produce acute cholangitis or cholecystitis.
Table 10-2.
Infections Associated with Granulomatous Inflammation in the Liver
| Viral |
|
| Mycobacterial |
|
| Bacterial |
| Rickettsial |
| Q fever |
| Chlamydial |
|
| Spirochetal |
|
| Fungal |
|
| Helminthic |
|
| Protozoal |
|
Pyogenic Liver Abscess
Historically, pyogenic liver abscess was associated with acute appendicitis or intra-abdominal infection, and in those settings it was seen more often in children.137 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.138., 139., 140. Diabetes mellitus is a strong risk factor for the development of pyogenic liver abscess.140 , 141 Other frequent comorbidities are malignancy, alcohol abuse, cirrhosis, hypertension, recent surgery, and immunosuppression.138., 139., 142. 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%.138 , 142 Patients typically present with fever, chills, right upper quadrant pain, and elevated alkaline phosphatase.138 , 139 Men are affected more often than women in most series.138., 139., 140. Most abscesses are solitary; multiple abscesses occur in 25% to 45% of cases.138., 139., 140., 142. Most abscesses are right sided (55% to 70%), with left-sided and bilateral disease occurring less often.137., 138., 140.
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.138 Depending on the organism, serology may be useful. The most commonly isolated organisms are Escherichia coli, Klebsiella pneumoniae, Enterococcus, Streptococcus, and Pseudomonas species.138., 139., 142. A third of infections are polymicrobial (Fig. 10-19 ). 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.143 Abscesses secondary to Yersinia enterocolitica or Yersinia pseudotuberculosis are often associated with underlying hemochromatosis.144., 145., 146., 147. Anaerobes are isolated in up to 25% of cases, sometimes together with aerobes.139., 148., 149. 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. 10-20 ); these organisms may be associated with the formation of sinus tracts.150., 151., 152., 153. Rarely, Francisella tularensis,154 Burkholderia pseudomallei (the agent of melioidosis),155 , 156 or Listeria monocytogenes 157 causes liver abscesses. Fungi, such as Candida and Aspergillus, are found in about 15% of cases.148 , 158
Figure 10-19.
Hepatic abscesses arising from polymicrobial cholangitis with Enterococcus and Candida in a liver transplant recipient. A, The abscess contains a center of necrotic debris, fibrin, and neutrophils surrounded by granulation tissue and inflammation, with a fibrotic rim. B, In some areas, residual bile duct epithelium at the abscess edge betrays origin from cholangitis. C, Yeast forms (lower left) are present adjacent to bacterial cocci (upper right) in the bile duct lumen. D, Gram-positive cocci are revealed by Brown-Hopps stain. E, Yeast forms and pseudohyphae consistent with Candida (upper right) and bacterial cocci (lower left) are present (GMS stain).
Figure 10-20.
Actinomyces.A, Sulfur granule with aggregate of filamentous bacteria and neutrophils. B, Brown-Hopps stain shows gram-positive filamentous bacteria in the sulfur granule.
(Courtesy of Dr. Laura Lamps.)
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.142., 159., 160. Although surgical management was once the mainstay of therapy, percutaneous drainage and antibiotics have become the first-line approach.138
Acute Cholangitis
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.161 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.161 Obstruction is most often due to 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.161
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.162 About 70% of patients present with the full triad. Reynolds arrived at a pentad in 1959 by adding hypotension and delirium.163 Although rare, the pentad describes patients with high mortality risk.164 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. 161 , 165 Improved culture techniques have shown a significant incidence of infection by anaerobes, such as B. fragilis and clostridial species, frequently in association with previous biliary-intestinal anastomosis, an elderly patient, and more severe illness.161 , 166 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.161
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.167 , 168 In some cases, neutrophils accumulate within the duct lumina; although this is suggestive of infection, the association is not sufficiently reliable to be predictive.167 , 168 Microabscesses and macroscopic abscesses may be seen. Thrombophlebitis may result in portal vein thrombi.168 Patients suffering from shock may show necrosis of the liver.168 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 relatively minor histologic changes, and patients with mild symptoms can have frank abscesses.168 Histology is also not predictive of survival.164 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.164 Complications of acute cholangitis include renal failure and the development of hepatic abscesses.161
Recurrent Pyogenic Cholangitis (Oriental Cholangiohepatitis)
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.169 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.169 Bacteria deconjugate bilirubin glucuronide, which then precipitates with calcium in the bile as soft, brown, friable calcium bilirubinate stones.169 , 170 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.169 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.170 Morphologically, large ducts show chronic and acute cholangitis, fibrosis, and peribiliary gland hyperplasia. Pigmented stones and pus are seen in ducts; liver abscesses may be present.169 Bile ductular proliferation with cholangiolitis and periductal fibrosis develops. Cholangiocarcinoma is a complication.
Brucellosis
Brucellosis largely affects handlers of livestock, particularly those in the meatpacking industry. Most patients present with an acute illness characterized by malaise, fever, chills, sweats, weight loss, and headache, but some patients become symptomatic after many years of dormancy or are episodically symptomatic.171 Viral illness or trauma may precipitate relapse of chronic brucellosis.171 The most common histopathologic pattern is granulomatous hepatitis.172 , 173 In a series of 14 patients with brucellosis, all had hepatic granulomas in both portal tracts and lobules.174 These granulomas may be indistinguishable from TB or sarcoidosis, and brucellosis should be considered in any patient with hepatic granulomas.173 The presence of granulomas does not reliably distinguish among the various species of Brucella, 175., 176., 177., 178. despite a report that Brucella melitensis is not associated with granulomas.179 Other findings may include nonspecific acute hepatitis with hepatocyte necrosis, inflammation, and Kupffer cell hyperplasia.171., 174., 178.
Rarely, patients present with a mass mimicking a tumor in the liver or spleen, known as a brucelloma.171 , 180 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.181 Radiologically, brucellomas have central calcification with peripheral necrotic areas.171., 180., 181. Histologically, a brucelloma shows necrotic areas surrounded by a palisaded granulomatous reaction.180 , 181
Hepatic pyogenic abscess due to Brucella is rare and may be associated with Brucella suis.171 The diagnosis is established by Brucella agglutination titer or culture, although the latter is difficult.
Bartonella (Cat-Scratch Disease)
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.182 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.183 Most patients with hepatosplenic presentation are children 5 to 10 years of age.182., 184., 185. Patients often have nonspecific symptoms, including fever, abdominal pain, chills, headache, malaise, and weight loss. About 25% of patients have lymphadenopathy, but often the classic skin papule of cat-scratch disease is absent.182., 183., 184. Hepatic lesions are typically multiple and associated with abdominal lymphadenopathy and, in some cases, splenic lesions; many patients come to biopsy to exclude neoplasia.183., 185., 186. On laparotomy, the liver may be found to be studded with hard nodules of varying sizes.186
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. 10-21 ).183 , 186 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.183 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.183 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.183 These changes are attributed to mass effect and are also seen in other infections that result in space-occupying lesions, such as pyogenic abscesses.183
Figure 10-21.
Cat-scratch disease involving the liver. A, Low-power view of a section of liver shows multiple stellate abscesses (arrows) and several older, hyalinized scars (arrowheads). B, Medium-power view of stellate abscesses shows central necrosis surrounded by palisaded histiocytes, chronic inflammation, and fibrotic tissue.
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.184 Culture is difficult. The diagnosis can be confirmed by PCR and Southern blot for Bartonella DNA on tissue, skin testing, or serology.182., 183., 187. 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 Kaposi sarcoma.91 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.92 The latter lesions can be mistaken for nonbacillary peliosis hepatis. Although these infections can be progressive and fatal, they respond to antibiotics.
Enteric Fever (Typhoid and Paratyphoid Fever)
Enteric fever (the inclusive term for typhoid and paratyphoid fever) is caused by infection with Salmonella enterica serotype Typhi (S. typhi) or serotype Paratyphi (S. paratyphi). The disease is transmitted via the fecal-oral route from food or water contaminated by an acutely ill person or a chronic carrier.188 Human beings are the only known reservoir. Most infections today occur in countries where sanitary conditions are poor; the Indian subcontinent has a particularly high incidence.188 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 only protects against S. typhi. 188 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.188
Ingestion of the organism is followed by an asymptomatic period of about 7 days, during which the organism multiplies within mononuclear phagocytic cells in Peyer patches, mesenteric lymph nodes, liver, and spleen.189 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, the elderly, and patients with cholelithiasis.188 , 189 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 very high transaminases or even fulminant hepatic failure, although coinfection with HAV or HEV may be responsible for some of these cases.188 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. 10-22 ).190 , 191 Typhoid nodules are lobular collections of macrophages that ingest bacteria, erythrocytes, and degenerated lymphocytes.191 These nodules may resemble granulomas but are not true epithelioid granulomas, although granulomatous hepatitis has been described as well.192 Abscesses are rare.
Figure 10-22.
Typhoid nodule in typhoid fever. An aggregate of mononuclear cells, including histiocytes and lymphocytes, is present in the lobule. The surrounding liver shows prominent Kupffer cells in the sinusoids.
Tularemia
Tularemia is caused by the coccobacillus Francisella 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.154 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.193 Severe cases may show jaundice. Liver histology shows suppurative microabscesses and areas of necrosis (Fig. 10-23 ). As the lesions age, they become more granulomatous.194 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.154
Figure 10-23.
Tularemia involving the liver. Several small abscesses are present throughout the lobules.
Melioidosis
Melioidosis is a glanders-like 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.156 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.195 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.195 Predisposing factors include diabetes mellitus, renal disease, alcoholism, cirrhosis, and immunosuppression.155 , 156 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.155., 156., 196. Chronic melioidosis shows granulomatous inflammation with central irregular abscesses, indistinguishable from the stellate abscesses of cat-scratch disease, tularemia, or lymphogranuloma venereum.196 The granulomas may show caseous-type necrosis, mimicking TB.196 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.155
Listeriosis
Listeria 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.197 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. Once the organisms escape the granulomas and are released into the blood, they have a predilection for the central nervous system and placenta.197
Hepatic involvement can manifest as solitary liver abscess, multiple liver abscesses, or hepatitis (Fig. 10-24 ).157 , 197 Solitary liver abscess is associated with diabetes mellitus, absence of bacteremia or extrahepatic manifestations, and a relatively good prognosis.157 , 197 Multiple liver abscesses are more often associated with bacteremia, extrahepatic sites of involvement, and meningitis and carry a worse prognosis.157 , 197 Diffuse hepatitis is associated with underlying conditions such as viral hepatitis, pregnancy, or alcohol abuse.197 , 198 Bacteremia is highly likely in cases with diffuse hepatitis. The histology is that of chronic active hepatitis with extensive necroinflammatory activity and occasionally granulomas.198 The diagnosis is made by culture of the organism from blood or abscess material.
Figure 10-24.
Liver from a patient who died of systemic listeriosis, showing microabscess and steatosis in the surrounding hepatocytes.
Spirochetes
Syphilis
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. Several cases have been reported among homosexual men,199., 200., 201., 202., 203. possibly from portal transport of the organism after anal intercourse.203 A characteristic clinical picture is cholestatic jaundice, hepatomegaly, and a disproportionately elevated alkaline phosphatase level.199., 201., 202., 204., 205., 206. The trademark palmar rash of syphilis may be the key to diagnosis.204 , 205 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.200., 201., 206., 207. Scattered foci of necrosis may be present in the lobules, sometimes accompanied by inflammation around the central veins and Glisson's capsule.201., 203., 207., 208. Granulomatous hepatitis is described in some cases (Fig. 10-25 ).208 , 209 Spirochetes are only rarely identified in histologic sections with silver stains such as Warthin-Starry or Steiner.199., 204., 207.
Figure 10-25.
Secondary syphilis in the liver. Granulomatous inflammation is seen adjacent to an inflamed portal tract.
In tertiary syphilis, multiple gummas in the liver may mimic metastatic carcinoma.210 Histologically, gummas resemble TB, in that they are composed of masses of granulomas with caseating necrosis, surrounding fibrosis, chronic inflammation, and histiocytic inflammation.210 Healed gummas may be replaced by fibrous scars (Fig. 10-26 ). Retraction of these scars can distort the liver by producing pseudolobules or so-called hepar lobatum.210 Scars near the hilum may result in portal hypertension.
Figure 10-26.
Old gumma in the liver, showing a hyalinized nodule with mild chronic inflammation at the periphery.
(Courtesy of Dr. Laura Lamps.)
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.211
Leptospirosis
Leptospirosis is an acute febrile illness caused by Leptospira interrogans that affects humans and animals in all parts of the world.212 The disease is biphasic, with a septicemic phase followed by an immune phase with antibody production and urinary excretion of the organism.212 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.212 Liver pathology is predominantly a cholestatic hepatitis with reactive hepatocellular changes and Kupffer cell hyperplasia.191., 212., 213. Scattered Councilman bodies, bile within canaliculi, and mild portal inflammation may be seen.191 , 214 Very rarely, spirochetes can be demonstrated on silver stain. The diagnosis is based on serologic assays.
Lyme Disease
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.193 In the liver, mononuclear cells, plasma cells, and granulocytes are seen in sinusoids. Kupffer cell hyperplasia, steatosis, and hepatocyte ballooning are also described.193 , 215 Granulomatous hepatitis is uncommon; necrotizing granulomas have been reported.216 Organisms are only rarely seen in hepatic sinusoids and parenchyma with silver stain such as Dieterle.215
Rickettsia
Q fever (Coxiella burnetii)
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 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.217 Hepatic involvement is common, and the disease may even manifest as hepatic disease without pulmonary symptoms.218 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. 10-27 ).217., 218., 219., 220., 221., 222. Also known as donut 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 infectious and in noninfectious conditions, including hepatitis A,8 , 9 Staphylococcus epidermidis infection,223 allopurinol hypersensitivity,224., 225., 226., 227. visceral leishmaniasis,226 , 227 giant cell arteritis,228 CMV,75 EBV,70 , 229 Hodgkin disease,227 , 230 toxoplasmosis,226 and Boutonneuse fever.226
Figure 10-27.
Fibrin ring granuloma. A collection of histiocytes contains a central fat droplet surrounded by a rim of histiocytes, a ring of fibrin (arrow), and another rim of histiocytes.
In addition to fibrin ring granulomas, epithelioid granulomas with or without central necrosis may be seen and can be mistaken for TB.217., 221., 226., 231. Other findings in Q fever hepatitis include moderate steatosis, focal liver cell necrosis, Kupffer cell hyperplasia, hemosiderin deposits, and, rarely, microabscesses.221
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. 193 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.232 , 233 Transaminases are often mildly 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.232 , 233 Liver biopsy may show lobular lymphohistiocytic aggregates and sinusoidal infiltration by lymphohistiocytic cells associated with erythroleukophagocytosis.234 In cholestatic cases, bile stasis, duct epithelial injury, and neutrophilic infiltration of medium-sized ducts may suggest extrahepatic obstruction.232 , 234 Other reported findings include focal hepatic necrosis, steatosis, granulomas, and foamy Kupffer cells with scattered apoptotic bodies.233 , 234
Rocky Mountain Spotted Fever
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 or portal blood vessels, especially arteries and arterioles, and sinusoidal lining cells.193 , 235 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.235 , 236 Immunofluorescence techniques can be used to identify the organisms in tissue.
Boutonneuse Fever
Boutonneuse fever is caused by Rickettsia conorii and is transmitted by the dog tick. The disease is found in Mediterranean countries between the months of June and September. 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.237 , 238 The mononuclear cell aggregates in the areas of necrosis may resemble poorly formed granulomas, but they are not true epithelioid granulomas.
Fungi
Histoplasma
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.239 In one series from that region, 15 (65%) of 23 children with hepatic granulomas had histoplasmosis demonstrated by PCR.240 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.240 Progressive disseminated histoplasmosis often involves the liver, with hepatomegaly in 62% of patients and abnormal liver function studies in 84%.241
Histologically, the appearance is identical to sarcoidosis, with numerous well-formed epithelioid granulomas (Fig. 10-28 ).115 In immunocompromised hosts, loose collections of histiocytes with numerous intracellular organisms can mimic leishmaniasis (Fig. 10-29 ). The absence of a kinetoplast on Giemsa stain helps distinguish Histoplasma from Leishmania.242 The diagnosis can be established with methenamine silver staining of involved tissue, fungal culture, or complement fixation tests.241
Figure 10-28.
Liver biopsy sample in an immune-competent patient with hepatic and splenic histoplasmosis. A solitary, well-formed granuloma is present in the liver.
Figure 10-29.
Histoplasmosis in an AIDS patient. A, Necrotic lesions are composed of histiocytes and debris. B, GMS stain shows yeast in macrophages in the necrotic lesion.
Candida
Candidiasis is especially problematic in immunocompromised patients, particularly those with leukemia or cytotoxic chemotherapy-related neutropenia.243 Candida accounts for 62% to 91% of fungal infections in the liver transplantation population, affecting 5% to 42% of all liver transplant recipients.72 Patients present with fever, abdominal pain, and elevated alkaline phosphatase; blood cultures are negative in at least half of the cases.244 Usually, patients are in the recovery phase from the neutropenic episode, suggesting a role for the host inflammatory response in defining the lesions.243 The diagnosis is often not made until postmortem examination.
Radiologically, the lesions appear targetoid and, in the case of older lesions, calcified.243 , 244 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. 10-30 ).244 Eventually, well-defined granulomas with giant cells may be seen.243 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.244 Candidal infection of the biliary tree and gallbladder occurs in disseminated candidiasis, with bacterial cholangitis, or as isolated candidal cholangitis or cholecystitis.245 , 246
Figure 10-30.
Candidal abscess in a patient with leukemia. A, Abscess with necrosis and neutrophils (upper left) surrounded by a palisaded histiocytic reaction. B, Rare yeast and pseudohyphae on GMS staining.
Pneumocystis jiroveci
Pneumocystis 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.247 , 248 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. 10-31 ).247 , 248 The organism appears as indented, helmet-shaped “cysts” on silver stains.
Figure 10-31.
Pneumocystis jiroveci in the liver. A, Necrotic lesion composed of granular eosinophilic material with mild histiocytic reaction at the periphery. B, GMS stain demonstrates that the granular material is composed of masses of Pneumocystis organisms.
Aspergillus
Aspergillus fumigatus involving the liver is seen in cases of disseminated aspergillosis and in immunosuppressed patients. Liver abscess and cholangitis secondary to Aspergillus infection have been described.158 , 249 The organism is easily demonstrated on methenamine silver or PAS stains and shows characteristic septate hyphae with acute-angle branching.
Zygomycetes
Fungi of the class 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. 250 Hepatic zygomycosis has been reported in immuno-compromised patients, in patients receiving chemotherapy, in stem cell transplant recipients, and in solid organ transplant recipients.250., 251., 252., 253., 254. Hepatic infection in the absence of pulmonary disease may be caused by spread from a gastrointestinal source.250 These fungi have broad (10 to 20 µm), aseptate or hyposeptate, ribbon-like hyphae with right-angle branching, and they have a propensity to invade blood vessels, leading to extensive necrosis, infarctions, and dissemination.250., 251., 252., 253. 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.250 Blood cultures are always negative. In tissue identification, erroneous classification as Aspergillus may occur if the hyphae are hyposeptate.250
Penicilliosis
Penicilliosis is an infection caused by the dimorphic fungus, Penicillium marneffei, which is endemic in Southeast Asia.255 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.256 Pathologic findings include granulomatous inflammation with relatively few organisms, suppurative abscesses, and necrotic lesions consisting of histiocytes filled with organisms, the latter being typical in immuno-compromised patients.255 , 256 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. 10-32 ).255 , 256 The main differential diagnosis is H. capsulatum.
Figure 10-32.
Penicilliosis. A GMS stain shows numerous yeast forms in macrophages. The organisms are round to oval, with a few slightly elongate and septate forms.
(Courtesy of Drs. David Walker and Laura Lamps.)
Cryptococcosis
Cryptococcosis is caused by the encapsulated yeast, Cryptococcus neoformans, and hepatic infection has been reported in both immunocompromised and immune-competent patients.257 , 258 In the immune-competent cases, granulomas are seen, whereas in AIDS patients, an inflammatory reaction is poorly developed. 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. 10-33 ).259 Infection of the bile duct can mimic sclerosing cholangitis.260 The organism can be demonstrated on silver stains, and mucicarmine stain can be used to highlight the capsule. The capsule is a virulence factor and is helpful in the diagnosis, but in rare instances, capsule-deficient strains can cause infection, particularly in immunocompromised patients (see Fig. 10-33). Capsule-deficient forms can be confused with other yeasts.
Figure 10-33.
Capsule-deficient Cryptococcus. A GMS stain shows yeast cells of varying sizes within a collection of histiocytes in the liver.
(Courtesy of Dr. Laura Lamps.)
Coccidioidomycosis
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.261., 262., 263. The spherules may or may not contain endospores; immature spherules without endospores can be mistaken for Blastomyces dermatitidis or C. neoformans.263 Serology and culture results can be used to establish the diagnosis.
Blastomycosis
Blastomyces 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.264 Thick-walled yeast forms with broad-based budding are seen on PAS or silver stains (Fig. 10-34 ).
Figure 10-34.
Blastomycosis. A, Broad-based, budding yeast forms are present in an area of suppurative inflammation. B, GMS stain shows broad-based, thick-walled yeast cells.
(Courtesy of Dr. Laura Lamps.)
Paracoccidioidomycosis (South American Blastomycosis)
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 exudates containing numerous organisms.265
Microsporidiosis
Microsporidia are obligate intracellular organisms that were originally believed to be primitive eukaryotes but have recently been reclassified as fungi based on DNA sequence data. Several species have been implicated in human disease. Infection of bile duct epithelium has been described as a cause of AIDS-related cholangitis.95 , 97 A case of hepatitis has also been reported, with sinusoidal congestion and microgranulomas on light microscopy.94 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.
Helminths
Schistosomiasis
Schistosomiasis is the second most common parasitic infection of humans after malaria. Several species of schistosomes affect humans: Schistosoma japonicum is associated with hepatic pathology more often than Schistosoma mansoni. The intermediate host is a population of snails that is not found in North America or Europe.266 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.266 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. Granuloma formation around the eggs leads to pyelophlebitis and periportal fibrosis.
Histology shows portal fibrosis with partial or complete destruction of the main branches of the portal vein but sparing of arteries and ducts.266 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. This pattern of fibrosis is known as Symmers pipe-stem fibrosis because of the clay pipe-stem appearance on gross pathology (Fig. 10-35 ).266
Figure 10-35.
Schistosomiasis. A, The liver shows marked expansion of two portal areas with fibrosis and numerous granulomas, consistent with Symmers pipe-stem fibrosis. Note the absence of cirrhosis in the background liver. B, A high-power view of a granuloma surrounding a schistosome ovum with the characteristic lateral spine.
Eventually, portal hypertension supervenes with splenomegaly and esophagogastric varices. However, compensatory increase in hepatic arterial blood flow maintains hepatic perfusion and hepatic function.266 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. Enzyme-linked immunosorbent assays (ELISA) have been developed that detect schistosomal antigens in the serum and urine of actively infected patients. Antigen levels correlate with worm burden.266
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. 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. 10-36 ).267 Occasionally, the larvae do not provoke an inflammatory reaction.267 Steatosis and cholestasis are additional features.
Figure 10-36.
Strongyloides in an AIDS patient with disseminated Strongyloides infestation. A larval form is present in a small portal lymphatic channel.
Enterobiasis (Pinworm)
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.268 Subcapsular nodules in the liver may be found at the time of surgery; on histologic examination, they prove to be hyalinizing or calcifying granulomas containing remnants of pinworms with characteristic lateral alae and possibly ova.268 , 269
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, whereas Echinococcus multilocularis is endemic in central Europe, the Near East, Russia, China, northern Japan, and Alaska.270 , 271 The adult tapeworms live in the jejunum of dogs and other carnivores, the final hosts; the larvae infect herbivores, the intermediate hosts, when they ingest the eggs. Humans are incidental intermediate hosts, because further development of the cestode requires ingestion of the larvae by a carnivore.
Once ingested, the egg develops into a larval oncosphere, which penetrates the intestinal mucosa, enters the portal circulation, and, on reaching the target organ (usually liver or lung), forms a rounded, multinucleated mass that becomes cystic and progressively enlarges.271 The hydatid cyst consists of an external, acellular, laminated cuticle and an inner germinal membrane that gives rise to brood capsules containing new larvae called protoscolices (Fig. 10-37 ).271 , 272 Hydatid cysts form daughter cysts, either from the germinal membrane or from the protoscolices or brood capsules. In the case of E. granulosus, the cysts are slowly enlarging masses that remain asymptomatic for a long period. Eventually, they may cause dull abdominal pain and a palpable mass.246 About 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.246 In alveolar hydatid disease due to E. multilocularis, the hepatic parenchyma is invaded and replaced by fibrous tissue with numerous embedded vesicles that mimics carcinoma.270 Dense granulomatous inflammation, microcalcifications, and necrotic cavitation may be present.272
Figure 10-37.
Echinococcal cyst. A, Collapsed cyst wall is composed of an acellular laminated cuticle. B, High-power view of a refractile hooklet (arrow) within cyst debris.
Alveolar hydatid disease carries a high mortality without surgery, due to liver failure, invasion of contiguous structures, or, less often, metastases to the brain.270 , 272 Transplantation has been attempted, but there is a high risk of recurrence in the donor liver.272 The diagnosis can be made radiologically and confirmed serologically, although some patients do not develop an immune response.270 , 272
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 disease is known as visceral larva migrans.273 Humans acquire the infection by ingesting the eggs from contaminated soil or by eating raw animal tissue (e.g., cow liver), that is 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.273 Most patients are asymptomatic but demonstrate peripheral eosinophilia. Vague abdominal pain, fever, cough, and dyspnea are occasional complaints.273 Radiologic studies show multiple, ill-defined, oval or angular lesions that improve or resolve spontaneously, similar to F. hepatica. Serology is used to detect IgG to Toxocara antigens.
In liver biopsy specimens, multiple granulomas and confluent granulomas may be the main finding.274 , 275 Grossly, the liver may show 0.3- to 1-cm, white-gray lesions, primarily in the subcapsular region of the right lobe.276 , 277 These granulomatous lesions show central necrosis surrounded by a mixed inflammatory infiltrate that includes numerous eosinophils and palisaded granulomas. 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.276 The differential diagnosis includes other causes of visceral larva migrans, including Capillaria hepatica and Ascaris.
Capillariasis
Capillaria hepatica 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.278 Eggs are deposited in soil, where, under favorable conditions, 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 and is not associated with passage of eggs in the stool.278 Infection of humans is rare; children are more commonly affected, probably because of frequent soil-to-mouth contact.278 Patients present with chronic fever, hepatomegaly, and peripheral eosinophilia. 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.276 Remnants of the parasite and its eggs may be identified.278 The parasite measures 50 µm or larger in diameter.276 The elliptical eggs are 54 to 64 µm by 29 to 33 µm and have bipolar plugs.278
Fascioliasis
Fasciola hepatica and Fasciola gigantica are trematode bile duct flukes found primarily in sheep and cattle.270 , 279 The leaf-shaped worms reach a size of about 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.270 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 infection.280 Once ingested, metacercariae penetrate the intestine, traverse the peritoneal cavity, and penetrate the liver capsule.281 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.279 Infrequently, patients experience respiratory, cardiac, or neurologic symptoms that are believed to be immune-allergic in origin, because the organism only rarely appears at these sites.279 As the flukes course through the liver, they create tracks of necrosis infiltrated by eosinophils, sometimes surrounded by a reaction of palisaded histiocytes (Fig. 10-38 ).280 , 281 These tracks appear as yellow-white subcapsular nodules or cords at laparoscopy.280 , 281 As the lesions age, they become cavities bound by granulation tissue, fibrous tissue, and calcifications.281 Immature flukes that fail to reach the liver may produce ectopic abscesses, most often in the skin.279
Figure 10-38.
Fascioliasis. Necrotic tract is surrounded by a palisaded histiocytic reaction in a patient with Fasciola infestation.
Once 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.279 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.281 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. 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.279
Clonorchiasis
Clonorchis sinensis, Opisthorchis viverrini, and Opisthorchis felineus are similar and are usually considered together. C. sinensis infects persons in China and east Asia and is common among immigrants to New York City. O. viverrini is limited to Thailand, Laos, Vietnam, and Cambodia, and O. felineus infects cats and humans in parts of Russia and eastern Europe.282 , 283 These bile duct flukes are acquired through ingestion of raw fish containing the metacercariae.282 , 283
The flukes migrate into the ducts via the ampulla of Vater, where they mature in about 25 days.282 , 283 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.282 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. 10-39 ).282 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.282 Stones often have dead worms as their nidus. Diagnosis is made by identifying the ova in stool or by ultrasonography. Patients are at risk for cholangiocarcinoma, which is often intrahepatic, multicentric, and mucin-secreting. Serology does not distinguish between present and past infection. Therefore, the diagnosis of active infection may require the detection of ova in stool.282
Figure 10-39.
Clonorchis infestation. A, A fluke is present within a large duct that shows squamous metaplasia and periductal chronic inflammation. B, Higher magnification shows cross-sections of the uterus filled with ova.
Ascariasis
Ascaris lumbricoides rarely causes biliary ascariasis when the roundworms 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.284 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. 10-40 ).167 The worms can also penetrate liver tissue (visceral larva migrans), perforate Glisson's capsule, and exit into the subdiaphragmatic space.167 The ova can cause granulomas and pseudotumors.285 Ultrasonography can identify worms within the gallbladder or extrahepatic ducts or the presence of a dilated common bile duct.284 Ova or adult worms can be found in stool in 91% of patients.284 In some patients, the worms exit the ducts spontaneously; in others, anti-helminthic therapy or surgery is required.284
Figure 10-40.
Ascaris infection in a patient with the clinical diagnosis of recurrent pyogenic cholangitis. 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.
Protozoans
Amebiasis
Liver abscess is the most common extraintestinal manifestation of amebiasis. Amebic liver abscesses most likely arise from hematogenous spread of the trophozoites, probably via the portal circulation.286 Often, patients with liver abscess have no bowel symptoms, and stool microscopy is negative for Entamoeba histolytica trophozoites and cysts.286 Patients may present years after travel to an endemic area with fever, right upper quadrant pain, and hepatic tenderness.
The histopathologic findings in hepatic amebiasis consists 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. 10-41 ). The adjacent hepatic parenchyma is often completely unaffected.286 The number of trophozoites may be 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.
Figure 10-41.
Amebic abscess in the liver. A, Low-power view shows the edge of an abscess cavity with inflammation and debris. B, High-power view of an amebic trophozoite (arrow) within the necrotic debris.
(Courtesy of Drs. David Walker and Laura Lamps.)
Malaria
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.287
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. 288 Hepatic encephalopathy is rare. Hepatic dysfunction and jaundice may be multifactorial in etiology, including hemolysis, sequestration of infected red blood cells in sinusoids, or coexistent viral hepatitis.288
The histologic hallmarks of malarial hepatitis are varying degrees of hepatocyte injury and deposition of malarial pigment or hemozoin (Fig. 10-42 ). Inflammation 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.288 Exoerythrocytic forms of the parasite in liver biopsy material can be demonstrated by immunofluorescence.289
Figure 10-42.
Malarial pigment within Kupffer cells.
Leishmania
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.290 In this population, the majority of patients are intravenous drug users, and the organism is transmitted by the sharing of syringes.290 Also, reactivation of latent disease may occur in immunocompromised patients years after travel to endemic areas, making the infection difficult to suspect.291 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.292 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.292 In the liver, the typical pattern consists of marked hyperplasia of Kupffer cells, many of them parasitized by numerous amastigotes (Fig. 10-43 ).293 Well-formed granulomas may be seen alongside Kupffer cells with intracellular amastigotes.292 , 294 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.293 The differential diagnosis includes H. capsulatum, P. marneffei, and Toxoplasma gondii. 291 Fibrin ring granulomas have been reported.227 The diagnosis depends on demonstration of the organism in tissue, typically bone marrow smears or spleen aspirates.292 In liver tissue, demonstration of the parasites is best done with Giemsa staining, preferably of touch preparations on glass slides.289 The presence of a kinetoplast on Giemsa stain is characteristic of Leishmania and distinguishes this parasite from Histoplasma.289 Serologic assays are available.
Figure 10-43.
Visceral leishmaniasis (kala-azar) in the liver. In the sinusoids, Kupffer cells are filled with amastigotes.
Toxoplasmosis
Toxoplasma 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.295 , 296
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.295 Granulomatous hepatitis has also been described.296 In some cases, Toxoplasma cysts have been identified in histiocytes and granulomas.297 Free tachyzoites have been described within degenerating or necrotic hepatocytes, although they can be difficult to distinguish from detritus.296 Giemsa stain 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.
Cryptosporidiosis
Cryptosporidium is a protozoan that causes an opportunistic infection of the gastrointestinal tract resulting in diarrhea. In patients with AIDS, the organism has been known to infect the biliary tree, producing a syndrome similar to primary sclerosing cholangitis.96 Signs and symptoms include right upper quadrant abdominal pain, nausea, vomiting, fever, and biochemical evidence of anicteric cholestasis.96 Dilatation of the common bile duct is often seen on ultrasonography or computed tomography 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.96 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. Organisms can be detected on the luminal surface of the epithelial lining of small biliary radicles, peribiliary glands, the pancreatic duct, and the gallbladder.96 Concomitant CMV infection may be found.
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