Clinical features

Bacterial infections in the liver may be manifested by pyogenic abscess, scattered microabscesses with small granulomas (tularemia and listeriosis), noncaseating granulomas (brucellosis), or necrotizing granulomas (tuberculosis). In addition, the liver in sepsis may show a wide spectrum of hepatic injury, such as predominantly neutrophilic inflammation (both portal and lobular) with microabscesses, centrilobular canalicular cholestasis, and ductular cholestasis with ductular proliferation and inspissated bile. Only pyogenic abscess will be considered further here.

Pyogenic abscess usually occurs in older adults; presenting symptoms are nonspecific and include abdominal pain, hepatomegaly, malaise, fever, and, rarely, jaundice. Transaminases and alkaline phosphatase are usually elevated.

In general, pyogenic abscesses are secondary infections seeded from other sites, particularly biliary tree, and gastrointestinal tract. More than one microorganism, most commonly gram-negative aerobes, Escherichia coli , and Klebsiella species, is isolated in most cases. Underlying or predisposing conditions include hepatobiliary or pancreatic malignancy (approximately 40% of patients), diabetes mellitus (10%), cholangitis, idiopathic inflammatory bowel disease, appendicitis, and diverticulosis. Tumors, cysts, and infarctions may also become secondarily infected, leading to abscess formation.

Pathologic features

Microscopic findings

Pyogenic abscesses consist of central necrotic purulent debris surrounded by a fibrous rind containing inflammatory cells, predominantly neutrophils ( Fig. 19-1 ). The adjacent liver often shows nonspecific reactive changes due to mass effect, including cholestasis, portal inflammation, and bile ductular reaction. Bacteria are occasionally detectable with special stains. In sepsis, inspissated bile may be seen in periportal cholangioles ( Fig. 19-2 ).

Pyogenic abscesses in the liver often have thick fibrous rinds; the abscess cavity is filled with purulent exudate and necrotic debris.

The most characteristic finding in the liver in sepsis is inspissated bile in periportal cholangioles. Microabscesses may also be seen in the parenchyma.

PYOGENIC ABSCESS—PATHOLOGIC FEATURES

Gross findings

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  Single or multiple abscesses of variable size containing pus

Microscopic findings

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  Exudate contains necrotic liver tissue and numerous neutrophils

  
  
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  Fibrous capsule in many cases

Fine-needle aspiration biopsy findings

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  Numerous neutrophils in a background of debris

  
  
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  Organisms rarely identified on Gram stain

Differential diagnosis

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  Amebic abscess

  
  
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  Secondarily infected tumor, cyst, or infarct

Ancillary studies

Culture of aspirated abscess contents is useful but may not be necessary if blood cultures are positive.

Differential diagnosis

The differential diagnosis of bacterial hepatic abscess primarily includes other causes of hepatic abscess, including amebas, hydatid disease, and necrotic tumors. Amebic abscess is distinguished by finding amebas in the cyst contents. Hydatid disease has a characteristic gross appearance, and scolices are identified histologically. Necrotic tumors may require further biopsy material for diagnosis if only necrotic tissue is received.

Prognosis and therapy

Outcome for hepatic abscesses is highly dependent on underlying comorbid conditions. Traditional treatment of hepatic abscess has been open surgical drainage, although percutaneous drainage or intermittent needle aspiration followed by antibiotic therapy is now widely used. Risk factors for poor outcome include multiple abscesses, malignant etiology, septic shock, hyperbilirubinemia, and fungal infection. Mortality is roughly 14% for patients treated with surgical drainage, followed by antibiotic therapy.

Clinical features

The liver is affected in more than 90% of cases of Epstein-Barr virus (EBV)-related mononucleosis. Hepatic involvement is indicated by elevated aminotransferases, often accompanied by the other symptoms of mononucleosis. Jaundice occurs in only a minority of patients. Fulminant liver failure secondary to EBV infection has been described, particularly in immunocompromised children but also in healthy ones. Fulminant hepatic failure due to EBV may not be accompanied by the typical features of mononucleosis.

Pathologic features

Microscopic findings

The most characteristic histologic feature in healthy patients is a diffuse lymphocytic sinusoidal infiltrate in a single-file, “string-of-beads” pattern, occasionally containing atypical lymphocytes. Focal apoptotic hepatocytes and steatosis may be seen; cholestasis is not typical. Small Kupffer cell clusters and non-necrotizing granulomas can be seen. EBV hepatitis may also develop after solid organ transplantation, most often in children ( Fig. 19-3 ). The histologic picture may be more severe in this context, with a marked portal and periportal inflammatory infiltrate containing numerous atypical lymphocytes, immunoblasts, and plasma cells, and mild bile duct damage.

Prominent sinusoidal lymphocytosis with minimal hepatocellular injury is characteristic of Epstein-Barr virus (EBV) hepatitis.

NONHEPATOTROPIC VIRAL INFECTIONS—PATHOLOGIC FEATURES

Gross findings

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  Hepatomegaly

  
  
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  HSV: geographic areas of necrosis with hyperemic borders

Microscopic findings

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  EBV: sinusoidal lymphocytosis with “string of pearls” pattern of lymphocytes in sinusoids

  
  
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  CMV: nuclear inclusions in enlarged cells

  
  
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  Involves biliary epithelium, endothelium, and less commonly, hepatocytes

  
  
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  Hepatic microabscesses in transplant patients

  
  
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  HSV: randomly distributed areas of coagulative necrosis; multinucleated hepatocytes with ground-glass nuclear inclusions

Ultrastructural findings

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  Demonstration of viral particles in infected cells

Immunohistochemistry

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  EBV: positive staining in lymphocytes for EBV

  
  
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  CMV: positive nuclear staining in infected cells

  
  
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  HSV: positive nuclear staining in infected cells

Differential diagnosis

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  EBV: other causes of hepatitis

  
  
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  CMV: other causes of hepatitis, especially in immunocompetent host

  
  
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  HSV: varicella zoster infection

Ancillary studies

Confirmatory tests include serologic, immunohistochemical, and in situ hybridization studies. Infiltrating lymphocytes are positive by immunohistochemistry for EBV viral antigens.

Differential diagnosis

The differential diagnosis predominantly includes other viruses, most importantly cytomegalovirus (CMV) infection. Hepatic involvement by leukemia or lymphoma must also be excluded when atypical lymphocytes are numerous. Human herpesvirus-6 has been implicated in a similar mononucleosis-like illness with hepatic involvement.

Prognosis and therapy

Most patients recover within 4 to 6 weeks without specific therapy; treatment is generally supportive. Rarely, death occurs secondary to overwhelming infection. Reduction of immunosuppression in transplant patients may be indicated.

Clinical features

The clinical and histologic features of CMV hepatitis depend on the immune status and age of the host. Liver involvement is a common feature of neonatal/ perinatal CMV infection, with affected infants usually demonstrating marked hepatosplenomegaly and jaundice. CMV hepatitis in immunocompetent persons is often part of a multiorgan infectious process and is usually self-limited. Rare cases of fulminant liver failure have been described, but chronic liver disease does not develop in this population. Patients with CMV hepatitis may show an increase in transaminases and/or a cholestatic pattern of enzyme elevation.

Clinically significant CMV infection of the liver is more commonly seen in immunocompromised persons, and CMV is the single most important pathogen in solid organ transplant patients of all types. CMV infection may be acquired through primary infection, reactivation, or superinfection by a new strain in a previously seropositive patient. Infection occurs approximately 2 to 16 weeks following solid organ transplantation, and symptoms range from mild to life threatening. Although any organ may be involved in these patients, hepatic involvement may predominate; in liver transplant patients particularly, the allograft is the most common site of involvement.

Pathologic features

Microscopic findings

In immunocompromised patients, CMV-infected cells are markedly enlarged and contain the characteristic “owl’s eye” inclusions ( Fig. 19-4 ). Inclusions may be seen in any cell type within the liver, including hepatocytes, bile duct cells, and endothelial cells. Infected cells are often surrounded by neutrophilic microabscesses, with or without admixed mononuclear cells, but may have only minimal accompanying inflammation. Other associated features include hepatocyte apoptosis and focal necrosis; a portal and lobular mononuclear cell infiltrate; and rarely granulomas. In immunocompetent patients, liver biopsy resembles EBV infection histologically. Viral inclusions are not seen on routine stains or immunohistochemical studies in these patients. In the neonate, CMV infection may cause a neonatal hepatitis pattern of injury, with marked cholestasis, giant cell transformation, focal necrosis, and prominent extramedullary hematopoiesis. Viral inclusions are variable in number. Bile duct damage may lead to nonsyndromic paucity of intrahepatic bile ducts.

In immunocompromised hosts, enlarged cells with intranuclear inclusions are found in variable numbers. Associated microabscesses are often seen in liver transplant cases, but are not specific for cytomegalovirus (CMV) infection.

Ancillary studies

Viral inclusions may be demonstrated by immunohistochemical stains for CMV, most commonly in immunocompromised hosts. Other useful diagnostic aids include viral culture, polymerase chain reaction assays, in situ hybridization, and CMV serologic studies/antigen tests.

Differential diagnosis

Other viral infections, particularly EBV, should be considered in the differential diagnosis in healthy persons. In immunocompromised patients, the differential diagnosis is broader and includes herpes virus and adenovirus; in most cases, characteristic viral inclusions or immunohistochemical staining is diagnostic. Other causes of microabscesses, such as sepsis, should be considered, particularly in transplant patients. In the neonate, the differential diagnosis includes other causes of neonatal hepatitis and paucity of interlobular bile ducts, depending on the pattern of injury.

Prognosis and therapy

Treatment for immunocompromised patients and neonates is with ganciclovir. In most immunocompetent patients, CMV hepatitis is mild and self-limited. CMV infection in early childhood may result in hepatomegaly and chronic low-grade liver dysfunction. In the first year after liver transplantation, CMV infection is associated with a fourfold increase in the relative risk for death.

Clinical features

Herpes simplex virus (HSV) hepatitis is usually seen in immunocompromised patients or neonates as part of disseminated infection, although it can be seen in otherwise healthy persons. Patients present with fever and may have concomitant oral or mucosal herpetic lesions, as well as nonspecific constitutional symptoms. Transaminases are markedly elevated, and hepatomegaly is frequently present. HSV hepatitis is rapidly progressive and usually fatal.

Pathologic features

Gross findings

Grossly, the liver is enlarged, mottled, and shows multiple foci of geographic necrosis, often surrounded by a hyperemic zone ( Fig. 19-5 ).

Areas of geographic necrosis with hyperemic borders are seen in herpes simplex hepatitis.

Microscopic findings

Randomly distributed zones of coagulative necrosis surrounded by congested parenchyma are typical of HSV hepatitis. Infected hepatocytes contain nuclear ground-glass inclusions and are often multinucleated ( Fig. 19-6 ). Cowdry A-type inclusions are also seen. Inflammatory response is generally minimal.

Herpes simplex hepatitis: Infected cells contain ground-glass nuclear inclusions; multinucleated cells may be seen.

Ancillary studies

Even though HSV inclusions are readily visualized in liver biopsy material, viral culture is a valuable confirmatory tool. Immunohistochemistry is commonly used, and in situ hybridization is available in some centers.

Differential diagnosis

The differential diagnosis predominantly includes other viral infections, including CMV and adenovirus. Herpesvirus and varicella-zoster virus may produce an identical histologic lesion, and viral cultures may be needed to make the distinction. Coagulative necrosis in ischemia or toxic injury is usually zonal in distribution, and viral inclusions are not seen.

Prognosis and therapy

Treatment is with acyclovir. Outcome is poor, with rapid progression to hepatic failure and death. Many cases are recognized only at autopsy.

Clinical features

Schistosomiasis is a trematode fluke infection common in tropical areas. Infecting more than 200 million people, it is the most common cause of portal hypertension in the world. Most hepatobiliary disease is caused by Schistosoma mansoni , S. japonicum , and S. mekongi , which prefer the mesenteric vascular bed. Adult worms lodge in species-specific target vessels, where they may live for decades. Liver disease is the result of entrapment of eggs that lodge in small portal vein radicals; hypersensitivity reaction to the eggs results in inflammation, leading to fibrosis and obstructive hepatobiliary disease. Presinusoidal portal hypertension leads to hepatosplenomegaly and esophageal and gastric varices. Hepatic function is usually preserved.

Pathologic features

Microscopic findings

In early schistosomiasis, eosinophilic abscesses may be seen surrounding ova newly lodged in small portal vein radicals. In chronic disease, epithelioid granulomas and fibrous scar tissue develop around the eggs. Calcified shells of dead ova are seen in long-standing lesions ( Fig. 19-7 ). Whereas the eggs of various species differ in morphology, speciation of schistosomes within the liver may be difficult.

Calcified schistosomal eggs may be found in portal tracts; earlier, a granulomatous response to the eggs may be seen.

Progressive fibrosis leads to enlarged, sclerotic portal tracts. Although portal-portal bridging fibrous septa develop, the hepatic parenchyma remains largely unaffected, and cirrhosis does not develop. Portal hypertension is the result of the inflammatory process and fibrosis in the portal tracts with resulting obliteration of portal vein branches. Schistosomal pigment, brown pigment derived from hemoglobin metabolism by the adult worms, accumulates within Kupffer cells and macrophages.

PARASITIC INFECTIONS—PATHOLOGIC FEATURES

Gross findings

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  Schistosomiasis exhibits characteristic thick periportal fibrosis (Symmers clay pipestem fibrosis)

  
  
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  Hydatid cysts contain daughter cysts surrounded by white membranes. Infiltrative lesions may occur in E. multilocularis infection

  
  
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  Biliary strictures and calculi are frequent in liver fluke infection; the liver is enlarged but not cirrhotic; worms may be identified in the bile duct lumen

Microscopic findings

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  Schistosomal eggs are surrounded by epithelioid granulomas; the eggs may be obliterated by fibrous tissue or calcified and are usually located in portal tracts

  
  
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  Hydatid cysts are surrounded by a multi-layered cyst wall; protoscolices bud from the inner germinal membrane; shed hooklets are found within the cyst

  
  
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  Liver flukes are found in the distal bile ducts; associated biliary epithelium is hyperplastic; ascending cholangitis may be seen

Fine-needle aspiration biopsy findings

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  For hydatid cyst, scolices with hooklets, positive with modified acid-fast stain. Scolices rarely present in E. multilocularis infection

Differential diagnosis

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  Pyogenic abscess

  
  
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  Amebic abscess

  
  
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  Sarcoidosis and other causes of hepatic granulomas

  
  
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  Recurrent pyogenic cholangitis

Ancillary studies

Stool examination for eggs is the diagnostic method of choice in active infection; rectal biopsy may be necessary to demonstrate eggs in some cases. An enzyme-linked immunosorbent assay (ELISA) is also available.

Differential diagnosis

The differential diagnosis includes other trematodes infecting the liver and biliary tree, such as the flukes, Clonorchis sinensis and Opisthorchis species, and Fasciola hepatica , which may cause calculi, cholangitis, obstructive jaundice, and a granulomatous hepatitis. Identification of schistosomal eggs within the liver is diagnostic; stool tests may also aid in the diagnosis.

Prognosis and therapy

Effective oral drugs include praziquantel and oxamniquine; cure rate is up to 90%. Surgical intervention, such as shunt operation, for control of portal hypertension may be indicated.

Clinical features

Hydatid disease, caused by larval stages of the cestodes of the genus Echinococcus , is often subclinical, but some patients develop hepatomegaly, marked abdominal enlargement and distension, and ascites. In cystic echinoccocosis ( E. granulosus ), the most common form of the disease, eggs are transmitted to humans from infected dog feces, whereas sheep represent the main intermediate host in the natural cycle. A more aggressive form of the disease—alveolar echinococcosis ( E. multilocularis )—is transmitted to humans through infected feces of wild foxes (rarely other canids), whereas rodents serve as the natural intermediate host. The majority of cases of hydatid cysts involve the liver, but pulmonary disease is also common. Brain, bones, and other sites may also be involved.

Radiologic features

Hepatic cysts with internal septations and calcification are characteristic of echinococcal infection.

Pathologic features

Gross findings

Grossly, hydatid cysts in cystic echinoccocosis are large (up to 35 cm), unilocular, and rounded, with a predilection for the right lobe. Multiple daughter cysts are usually present within the cyst, which has a fibrous rim ( Fig. 19-8 ). In alveolar echinoccocosis, numerous small vesicles are present, often forming an infiltrative mass in a pattern reminiscent of a malignant neoplasm. “Metastatic” spread is a well-described phenomenon in this form of the disease.

Echinococcal infection: Hydatid cysts have a characteristic multiloculated appearance due to the presence of numerous daughter cysts. The yellow, gelatinous wall represents the acellular, laminated layer of the endocyst ( arrow ). Also note the outer, white, reactive connective tissue capsule surrounding the endocyst (pericyst).

Microscopic findings

The endocyst consists of an internal cellular layer (germinal membrane), from which scolices, or immature heads of adult worms, develop, and an outer layer, composed of hyalinized, laminated, periodic acid-Schiff (PAS)-positive material ( Fig. 19-9 ). Scolices, however, are rarely present in E. multilocularis infection. As the endocyst expands, reactive fibrosis occurs and a connective tissue layer (the pericyst) is formed.

Echinococcal infection: The outer, acellular laminated layer forms the outer layer of the endocyst ( left ). The cellular (germinal) layer containing protoscoleces ( larger arrow ) and scattered refractile hooklets ( small arrows ) are seen at the center of the image.

Ancillary studies

Aspiration of cyst fluid is not indicated because of risk for spread of infection and anaphylaxis. Serology (indirect hemaglutination test or ELISA) or detection of circulating antigens to hydatid infection is the preferred form of diagnosis.

Differential diagnosis

The differential diagnosis includes other cystic lesions. The scolex of the worm distinguishes hydatid disease from amebic abscess, pyogenic abscess, or noninfectious processes such as fibropolycystic liver disease. Grossly, alveolar echinoccocosis may be confused with infiltrating malignant tumors.

Prognosis and therapy

Treatment is largely surgical, with complete excision of the cysts being the preferred therapy. The cyst fluid is strikingly antigenic and may lead to anaphylaxis if spilled during operation. Intraperitoneal spread of infective material can also occur during surgery. Albendazole may prove effective in inoperable cases and is an effective treatment for small, incidentally discovered cysts. Ultimately, some patients develop liver failure, portal hypertension, involvement of adjacent organs, and death. Because of its infiltrative growth pattern and potential for distant spread, alveolar echinoccocosis is usually fatal if left untreated.

Clinical features

Acute viral hepatitis is often asymptomatic and undiagnosed and recognized only in retrospect when serologic testing reveals past infection. In many patients, symptoms are mild and nonspecific and include malaise, fatigue, low-grade fever, and flulike complaints. Asymptomatic or mild inapparent cases of acute viral hepatitis are more common in children; adults are more likely to be symptomatic.

Symptomatic acute viral hepatitis is generally preceded by a prodrome phase lasting from a few days to several weeks and characterized by nonspecific symptoms such as nausea and vomiting, myalgias, anorexia, and malaise. Once jaundice appears, the constitutional symptoms typically begin to wane. Physical examination is notable only for jaundice and hepatomegaly; the liver may be tender to palpation in some patients. Serum transaminases are elevated, usually in the range of five- to 10-fold above normal. Alkaline phosphatase is only mildly elevated; conjugated hyperbilirubinemia is present in some but not all patients. Full recovery usually occurs within weeks, but in some cases convalescence may be prolonged. In a small minority of cases of acute viral hepatitis (<1%), fulminant hepatic failure may develop, as evidenced by the rapid development of liver failure. The clinical course is characterized by coagulopathy and encephalopathy; the mortality rate may exceed 80% without liver transplantation.

Hepatitis A and E are transmitted by fecal-oral routes or ingestion of contaminated water. Hepatitis B and C are transmitted parenterally ( Table 19-1 ), although in a significant number of hepatitis C cases, the route of transmission is unknown.

Pathologic features

Ancillary studies

Special studies such as immunohistochemistry for viral antigens are generally not useful in the evaluation of acute hepatitis, even in massive hepatic necrosis, because virus is rapidly eliminated from liver cells and is not detectable using immunostains. Serologic studies are generally readily available and are more reliable.

Differential diagnosis

Major entities that may be confused with acute viral hepatitis are chronic hepatitis, autoimmune hepatitis (AIH), and drug-induced hepatitis. Serologic tests are useful in definitive diagnosis of acute viral hepatitis. If the lobular inflammatory component is prominent, chronic hepatitis may be confused with acute hepatitis, but concentration of the inflammatory infiltrate in portal areas, with formation of dense lymphoid aggregates, and periportal fibrosis favor chronic hepatitis. AIH may have a prominent lobular component and prove difficult to distinguish from acute viral hepatitis; autoimmune markers such as antinuclear antibody (ANA) are helpful but are not always positive early in the course of AIH.

The histologic features of submassive and massive hepatic necrosis are not specific for acute viral hepatitis but may be the result of a variety of insults, such as toxic injury, severe drug reactions, and Wilson’s disease. Trichrome stain for connective tissue is useful in distinguishing massive hepatic necrosis from cirrhosis, by demonstrating the lack of dense collagen deposition in massive necrosis. Reticulin stain is also helpful in demonstrating the collapsed reticulin framework of the liver.

Although drug reaction and acute viral hepatitis may have considerable morphologic overlap, prominent eosinophils, granulomas, sinusoidal dilatation, and fatty change suggest drug reaction.

Prognosis and therapy

Full recovery from acute viral hepatitis usually occurs within weeks, but in some cases convalescence may be prolonged. Treatment is generally supportive. In a small minority of cases of acute viral hepatitis (<1%), fulminant hepatic failure may develop, as evidenced by the rapid development of liver failure. Mortality is more common in older patients and in those with chronic liver disease. The clinical course is characterized by coagulopathy and encephalopathy; mortality may exceed 80% without liver transplantation.

Histopathologic features generally are not predictive of progression of acute hepatitis to chronicity. For instance, interface hepatitis is not a reliable predictive feature because it may be seen in cases of acute hepatitis A, which does not progress to chronic hepatitis. Bridging necrosis is predictive of progression to chronic hepatitis in some but not all studies. In patients with massive hepatic necrosis, liver biopsy may not be representative of the overall status of the liver, given the heterogeneity of regeneration and necrosis from region to region.

Clinical features

Chronic hepatitis is generally defined as liver disease with persistent necroinflammatory activity lasting more than 6 months. As with acute hepatitis, chronic hepatitis has a wide spectrum of clinical manifestations, ranging from asymptomatic infection to decompensated cirrhosis. Many patients are asymptomatic or have only mild nonspecific complaints such as fatigue. Findings on physical examination are few but include hepatomegaly and stigmata of chronic liver disease such as palmar erythema. Patients with advanced cirrhosis may also have ascites and varices. Serum transaminase levels are usually elevated in the two- to 10-fold range, although patients with mild chronic hepatitis C may have persistently normal transaminase levels. Alkaline phosphatase and bilirubin levels are usually normal to mildly elevated, unless hepatic decompensation occurs. Fibrosing cholestatic hepatitis (FCH) is a severe, rapidly progressive form of hepatitis that occurs in immunosuppressed patients in a variety of clinical settings. Although most commonly seen after liver transplantation, FCH has also been reported in patients with chronic viral hepatitis after other solid organ transplants, new HCV infection post solid organ transplant, and in patients with HIV coinfection.

CHRONIC VIRAL HEPATITIS—FACT SHEET

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