key: cord-018331-ovmtz4sb authors: Dancygier, Henryk title: Viral Infections by Nonhepatotropic Viruses date: 2010 journal: Clinical Hepatology DOI: 10.1007/978-3-642-04519-6_10 sha: doc_id: 18331 cord_uid: ovmtz4sb nan containing intranuclear viral inclusions (Cowdry A: inclusion surrounded by a clear halo; Cowdry B: homogeneous, ground glass like inclusion) are seen [12] . Typically there is only a minimal infl ammatory response. In neonatal HSV hepatitis multinucleated giant cells (giant cell hepatitis) occur. The viruses may be demonstrated by electron microscopy, immunocytochemistry, and by DNA-in situ hybridisation. However, the light microscopic appearance is so characteristic that these sophisticated techniques are not required to diagnose HSV hepatitis. Hepatitis is a rare complication of HSV infection, but when it occurs it usually presents as a fulminant disease with a high mortality rate of up to approximately 80% [15, 21] . HSV hepatitis in pregnant women (usually caused by HSV type 2) occurs in the late second and in the third trimester. The disease is heralded by nonspecifi c infl uenza-like symptoms, right upper quadrant pain, and eventually signs of hepatic encephalopathy. Indeed, the fi rst case of HSV infection associated fulminant liver necrosis in adults was described in a pregnant woman. Extended parenchymal necrosis in HSV hepatitis leads to marked elevation of aminotransferase levels up to several thousand U/L (AST > ALT) and to a coagulopathy demonstrated by a prolongation of prothrombin time. In contrast to aminotransferases, serum bilirubin concentration usually is only slightly (£ 5 mg/dL) elevated. Pregnancy specifi c liver diseases, such as acute fatty liver, HELLP-syndrome and cholestasis of pregnancy should be considered in the differential diagnosis (see Section XXI). The fatality rate of HSV hepatitis in pregnancy is high, approximately 40-50% for mother and child. Therefore, in pregnant women, HSV infection must be excluded in every case of acute hepatitis. Liver biopsy is the defi nitive diagnostic test (often a transvenous approach is necessary). Additionally, vaginal, cervical and pharyngeal smears should be obtained [18] . Opportunistic HSV hepatitis in patients after solid organ transplantation is not as frequent as CMV and EBV infection, but usually occurs earlier after the transplant than CMV and EBV hepatitis [21] . HSV infection in these patients is mostly due to reactivation of latent virus rather than to a de novo infection. HSV hepatitis requires immediate treatment. Acyclovir (30 mg/kg body weight i.v. daily) is life saving in many patients. Infections with the human herpesviruses 6 and 7 are ubiquitous in childhood. Rarely, especially in children, both viruses may cause a fulminant hepatitis during a primary infection. Viral reactivation in immunosuppressed patients after organ transplantation may also be responsible for hepatitis [4] . The laboratory fi ndings are nonspecifi c, and are characterized by elevation of aminotransferases, cholestatic enzymes, leuko-and thrombocytpenia. The viruses may be isolated from peripheral blood lymphocytes, and may be identifi ed by negative contrast and thin-section electron microscopy, DNA-hybridization, and immunofl uorescence [38] . Human herpesvirus 8 causes Kaposis's sarcoma (KS), and is linked with two other neoplasms, a B cell non-Hodgkin's lymphoma (body cavity based lymphoma) and multicentric Castleman's disease (MCD). The liver is frequently involved in visceral KS, predominantly in HIV infected persons with advanced immunodeficiency, and more rarely after organ transplantation. Peliosis hepatis, perisinusoidal fi brosis and nodular regenerative hyperplasia have been described in few cases of MCD. A disseminated varicella-zoster virus (VZV) infection is rare. It may occur in children within the context of chickenpox, while in adults immunosuppression with reactivation of VZV is the usual cause. Hepatic involvement with varicella (varicella hepatitis) is uncommon and predominantly affects immunosuppressed hosts, such as transplant recipients, cancer and AIDS patients, but also normal hosts. Histologically, focal liver cell necrosis as well as massive widespread hepatic necrosis with intranuclear hepatocellular inclusions and multinucleated giant cells at the periphery of necrotic parenchyma is seen. The lesions resemble those of HSV hepatitis. Clinically varicella hepatitis may manifest as a symptomatic or subclinical aminotransferase elevation coincident with the onset of varicella, or, especially in the immunocompromised host, as fulminant hepatic failure leading to death [20, 31] . The varicella skin rash may precede, appear coincident with, or follow the onset of hepatitis, but varicella hepatitis with fulminant failure with widespread visceral dissemination in the absence of a rash has also been documented in bone marrow transplant recipients [32] . In fulminant hepatic failure aminotransferase levels reach several thousand U/L, with levels of AST being generally higher than ALT. Reye's syndrome has been reported to be preceded by a VZV infection in approximately 10% of patients. A diffuse microvesicular steatosis, vomiting and signs of a hepatic encephalopathy are characteristic of Reye's syndrome [23] . Therapy of varicella hepatitis is early high dose acyclovir (30 mg/kg body weight i.v. daily) or liver transplantation in fulminant cases with organ failure [27, 37] . Congenital cytomegalovirus (CMV) infection may be due to intrauterine or peripartal contagion. Histologically steatosis, focal liver cell necrosis, mononuclear infl ammatory infi ltrates, and occasionally multinucleated giant cells (neonatal hepatitis) are seen. The typical intranuclear inclusions surrounded by a clear halo impart the cells an "owl's eye" appearance. They are found in hepatocytes, bile duct epithelia and in endothelial cells. The affected cells are enlarged. Intrauterine CMV infection may result in biliary atresia. CMV hepatitis in the immunocompetent host clinically resembles hepatitis of infectious mononucleosis [14] . The liver and spleen are enlarged and the clinical manifestations are mild, with mild increases of aminotransferase and bilirubin levels. Often hepatitis is anicteric. Occasionally alkaline phosphatase and gGT may be markedly elevated (up to >1,000 U/L), which, however, does not portend a serious prognosis. The course of CMV hepatitis is self-limited, and chronic hepatitis does not ensue. Isolated cases of Budd-Chiari syndrome and portal vein thrombosis associated with CMV hepatitis have been reported [34, 35] . Compared to viral hepatitis A, B and C, CMV hepatitis is characterized by prolonged fever, splenomegaly, atypical lymphocytosis, milder elevations of aminotransferases and milder histopathological alterations. Histologically, focal liver and bile duct injury, lymphocytic sinusoidal infi ltrates, and occasionally noncaseating histiocytic granulomas are seen (Fig. 64.1) . Thus, CMV hepatitis should be included in the differential diagnosis of granulomatous hepatitis [3] . Viral inclusions or immunocytochemically detectable viral antigens usually cannot be demonstrated. In CMV hepatitis in the immunocompromised host viral inclusions may be found in the absence of an infl ammatory reaction. If such inclusions are accompanied by hepatocellular injury and by lymphocytic infi ltration, hepatitis may be attributed to CMV infection. CMV hepatitis after liver transplantation usually manifests 1-4 months after the operation, either as a de novo infection of the donor liver through blood transfusion or as reactivation of a latent CMV infection in the recipient due to postoperative immunosuppressive therapy. Clinically the disease may be asymptomatic or resemble infectious mononucleosis, with mild elevation of aminotransferases, leuko-and thrombocytopenia. It must be differentiated from a rejection reaction. The histological appearance of CMV hepatitis in a transplanted liver is characteristic. Focal accumulations of neutrophils form so-called microabscesses or a necrotic hepatocyte is surrounded by a mixed infl ammatory cell infi ltrate ("microgranuloma"). Furthermore, the nuclear inclusions described above are present. Viral antigens may be demonstrated by immunocytochemistry. The portal infl ammatory infi ltrate varies in density. In contrast to cellular rejection, in CMV hepatitis neither an endothelitis nor a cholangtis are seen. Patients with CMV hepatitis after liver transplantation have an increased risk of developing a vanishing bile duct syndrome. Therapy of CMV hepatitis with ganciclovir (5 mg/ kg i.v. bid) is usually successful. Epstein-Barr virus (EBV) causes infectious mononucleosis. It infects and transforms B lymphocytes, and is associated with the development of hairy leukoplakia, certain lymphomas and nasopharyngeal carcinoma. Approximately 5% of patients with infectious mononucleosis develop jaundice and 15% have elevated serum aminotransferases. EBV hepatitis generally is a mild hepatitis accompanying a generalized EBV infection [16] . Its clinical manifestations are overshadowed by systemic signs and symptoms of infectious mononucleosis. Jaundice in a patient with EBV infection mostly is due to autoimmune hemolytic anemia and not to hepatitis. In the vast majority of cases EBV hepatitis is self-limited. Fulminant courses with liver failure are extremely rare [17, 33] . They occur predominantly in X chromosomal inherited lymphoproliferative syndrome (Duncan's syndrome) and in lymphoproliferative diseases after organ transplantation. On histologic examination the portal tracts are heavily infi ltrated by atypical lymphocytes and plasma cells. The infl ammatory infi ltrate spills over through the limiting plate to the lobular parenchyma. EBV antigens may be demonstrated in lymphocytes by immunocytochemistry and by in situ hybridization. The sinusoids are infi ltrated either diffusely or in the form of small aggregates by mononuclear cells. Intrasinusoidal lymphocytosis often has a characteristic "Indian-fi le" appearance ( Fig. 64.2) . Liver cells are usually only mildly affected with scattered apoptotic bodies or foci of parenchymal necrosis fi lled with lymphocytes. Hepatocellular injury is clearly less pronounced than in acute viral hepatitis A or B. Regenerative changes and mitoses may be prominent. A steatosis or non-caseating, fi brin-ring granulomas rarely occur. Cholestasis is not part of the typical microscopical picture of EBV hepatitis, and if present should prompt one to search for granulomas [6] . The main histological differential diagnosis of EBV hepatitis is from leukemia or lymphoma. Adenovirus infection may cause severe hepatitis with liver failure in children and in immunosuppressed adults [1, 19] . Pathology and clinical manifestations resemble that of HSV hepatitis. Coxsackie B and echoviruses [36] . Coxsackie virus, and more rarely echoviruses may cause a severe, hemorrhagic-necrotizing hepatitis in newborns. The clinical manifestations in adults are milder, generally refl ecting an acute cholestatic hepatitis. Histologically centrilobular cholestasis and ballooned hepatocytes are seen. The portal and sinusoidal infl ammatory infi ltrates are composed of mononuclear cells and neutrophil leukocytes. Liver involvement in measles virus infection is mild and self-limited [25] . The histological alterations are nonspecifi c, showing "hepatocellular unrest," nuclear vacuolization and a mild intrasinusoidal lymphocytosis. Isolated cases with clinically severe hepatitis and multinucleated giant cells have been documented, however, their paramyxovirus etiology has not been proven unequivocally [29] . Rubella virus may cause hepatitis in the newborn within the context of the congenital rubella syndrome. Focal hepatocellular necrosis, signs of cholestasis and a mild chronic infl ammatory portal infi ltrate are seen. In isolated cases extensive parenchymal necrosis has been described. Intrauterine infection with the rubella virus may cause biliary atresia. Rubella infection in adults may be accompanied by a mild anicteric, sublinical or asymptomatic hepatitis with slightly elevated aminotransferases [28] . Arthropode transmitted Flavi-and Bunyaviruses cause diseases that are characterized by disseminated intravascular coagulation with extended hemorrhages, and are therefore denominated hemorrhagic fevers. Liver injury in all arbovirus infections shows common features and is characterized by variably large areas of parenchymal necrosis and microvesicular steatosis, with a relatively mild infl ammatory reaction. If the patient survives, scavenger and regenerative processes dominate the histological picture. The yellow fever virus belongs to the genus of fl aviviruses. The disease is endemic in Africa and in South America. It manifests acutely with fever, myalgias and headaches that are followed by jaundice after a few days. Death is due to liver and renal failure. The histopathological appearance depends on the stage of the disease. Confl uent, centrilobular parenchymal necrosis, scattered apoptotic bodies (classic Councilman bodies), and eosinophilic intranuclear inclusions that are arranged concentrically around the nucleolus (Torres bodies) characterize the acute stage. In contrast to the marked parenchymal injury the infl ammatory response is scant. Surviving hepatocytes show microvesicular steatosis and ballooning. Regeneration is evidenced by hepatocellular hyperplasia and multinucleated hepatocytes [10] . International travel to endemic areas is a major risk factor for both primary and secondary dengue infection. The primary infection manifests as an exanthematic, infl uenza-like illness. Hemorrhagic fever is caused by reinfection with different serotypes of dengue virus (DEN 1-4) . Dengue remains a diagnostic challenge, given its protean nature, ranging from a mild febrile illness to profound shock. Dengue shock syndrome has an estimated mortality rate close to 50%. Liver involvement appears to occur more frequently when infections involve DEN-3 and DEN-4 serotypes. The liver is interspersed with extended, partly confl uent areas of hemorrhagic parenchymal necrosis. The infl ammatory reaction is mild. The surviving hepatocytes show a microvesicular steatosis. Fulminant liver failure is extremely rare in adults, but has been reported in single cases [11] . If the patient survives, diffuse parenchymal calcifi cations may be the only sign of previous liver involvement [7] . Certain types of hantavirus cause hemorrhagic fever with a renal syndrome (HFRS), while others are responsible for the hantavirus pulmonary syndrome (HPS). Primary involvement of the liver does not occur in either syndrome. In Chinese patients with acute hepatitis of unknown etiology hantavirus infection has been discussed as a possible cause [26] . Arenaviruses cause Lassa fever and hemorrhagic fevers in Argentina and Bolivia. Lassavirus infection is endemic in Central and West Africa. Fever, pharyngitis, diarrhea and a hemorrhagic diathesis characterize the clinical picture. Pain in the right upper quadrant may supervene. There is a marked rise of serum aminotransferases, while jaundice is rare. The mortality rate is approximately 30%. The liver has a mottled appearance caused by apoptotic hepatocytes (Councilman-like bodies) and hemorrhagic necrosis of groups of liver cells which may coalesce forming bridging necrosis. Liver injury is accompanied by a marked hyperplasia of Kupffer cells and by lipofuscin deposits in hepatocytes. Cholestasis and steatosis are lacking. The viral particles can easily be demonstrated by electron microscopy [5] . These viruses cause hemorrhagic fevers in South America. The clinical picture and pathological liver fi ndings correspond to those of Lassa fever. Marburg virus disease is a highly contagious, febrile infection. It is associated with disseminated intravascular coagulation, hemorrhages, and shock. The mortality rate is 20-25%. The pathology of the liver corresponds to that of Lassa fever. Ebola fever resembles clinically and pathologically Marburg virus infection. Mortality rate is close to 50%. Parvovirus B19 is the only human pathogenic parvovirus, causing erythema infectiosum (fi fth disease) in children. Epidemiologic data suggest that parvovirus B 19 may also cause an acute hepatitis in children [39] . Adults with parvovirus B 19 infection, especially patients with underlying hemoglobinopathies (e.g. sickle cell disease) or other erythrocytic disorders (e.g. hereditary spherocytosis) may develop transient aplastic crisis. Combined with aplastic anemia massive hepatic necrosis and acute liver failure may occur [22] . Parvovirus B 19 may be demonstrated by PCR in liver tissue. Human coronaviruses have long been known to cause the common cold. In 2002 the Severe Acute Respiratory Syndrome (SARS) was described for the fi rst time. It is caused by SARS Coronavirus (SCoV) that is genetically dissimilar from known human or animal coronaviruses. The disease presents with fever, infl uenza-like symptoms, dry cough, atypical pneumonia, and diarrhea. The liver is involved in up to 60% of cases and infection of the liver by SCoV was verifi ed for the fi rst time in 2004 by demonstrating SCoV-RNA in liver tissue. In approximately 25% of patients aminotransferases are elevated (ALT: 200-900 IU/L). Histological examination shows signs of hepatocyte injury, such as ballooning and apoptosis accompanied by mild to moderate lobular lymphocytic infi ltrates. Numerous mitoses probably denote regenerative activity [2, 13] . 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