Discovery of a Novel Hepatovirus (Phopivirus of Seals) Related to Human Hepatitis A Virus.

UNLABELLED: Describing the viral diversity of wildlife can provide interesting and useful insights into the natural history of established human pathogens. In this study, we describe a previously unknown picornavirus in harbor seals (tentatively named phopivirus) that is related to human hepatitis A virus (HAV). We show that phopivirus shares several genetic and phenotypic characteristics with HAV, including phylogenetic relatedness across the genome, a specific and seemingly quiescent tropism for hepatocytes, structural conservation in a key functional region of the type III internal ribosomal entry site (IRES), and a codon usage bias consistent with that of HAV. IMPORTANCE: Hepatitis A virus (HAV) is an important viral hepatitis in humans because of the substantial number of cases each year in regions with low socioeconomic status. The origin of HAV is unknown, and no nonprimate HAV-like viruses have been described. Here, we describe the discovery of an HAV-like virus in seals. This finding suggests that the diversity and evolutionary history of these viruses might be far greater than previously thought and may provide insight into the origin and pathogenicity of HAV.

Pathology of the liver.

Traditional anatomic pathology studies and molecular investigations both contributed to the breadth of current information in the field of liver pathology this year. Techniques such as reverse transcription polymerase chain reaction can identify recurrence of hepatitis C virus infection in the liver as early as 5 days after transplantation. Chronic rejection after transplantation may be characterized not only by ductopenia but also by loss of portal tract hepatic artery branches. There are many diseases of small bile ducts in adults, and idiopathic adulthood ductopenia has been identified in extended family members. Adverse reactions to drugs may precipitate their removal from the pharmacopoeia, such as the many cases reported of severe bridging and submassive necrosis due to troglitazone (a thiazolidinedione antidiabetic agent). Several publications highlighted the association of hepatitis C virus infection with lymphoproliferative diseases and, newly, with cholangiocarcinoma.

Trisomy 1q, 2, and 20 in a case of hepatoblastoma: possible significance of 2q35-q37 and 1q12-q21 rearrangements.

Combined cytogenetic, chromosome painting, and spectral karyotyping (SKY) analyses in a case of hepatoblastoma revealed a karyotype of 49,XY,+Y,+der(2)t(2;3)(q35;q25),der(3)t(1;3)(q12; q25),+20. Trisomy 1q, 2, and 20 identified in the present case are consistent with the previously reported cytogenetic alterations in hepatoblastoma. The breakpoints at 1q12 and 2q35 identified in this case have also been reported previously as nonrandom changes. The frequent occurrence of these rearrangements in hepatoblastoma suggests that they may be of pathogenic significance.

Pathology of the liver.

At the close of the 20th century, a selection of articles published in 1999 with relevance to liver pathology reflects the wealth of technological and intellectual progress made during the span of the century. Immunohistochemical staining for hepatitis B virus antigens focused attention on a correlation between cytoplasmic expression of core antigen in individuals with precore mutants and higher activity of hepatitis. Infection of ducklings with a presurface mutant strain of duck hepatitis B virus produced cytopathic liver cell damage. Fibrosing cholestatic hepatitis, originally described as an unusual form of recurrent hepatitis B after liver transplantation, has now been described in hepatitis C virus-positive patients with renal transplants. It may be related to the emergence or selection of hepatitis C virus quasispecies. In biliary tract disease, researchers investigated the canal of Hering as a possible source of hepatic stem cells, sporadic mutations in the JAGGED1 gene (involved in cell differentiation) in Alagille syndrome, and several models of nonsuppurative destructive cholangitis. Further work was accomplished on nonalcoholic steatohepatitis, including a proposal of a grading and staging system as well as its detection in workers exposed to volatile petrochemicals. Among hepatic neoplasms and proliferative disorders, epithelioid hemangioendothelioma, angiomyolipoma and Langerhans' cell histiocytosis received coverage in articles describing the diagnostic pathology in collected series of patients.

Long-term survival of a young woman with peripheral cholangiocarcinoma: a case report.

Cholangiocarcinoma is the second most common primary tumor of the liver after hepatocellular carcinoma and accounts for 5 to 25% of primary hepatic malignancies. Patients with intrahepatic or peripheral cholangiocarcinoma (ICC) most often present at an advanced stage leading to a poor prognosis. A review of the literature has produced only 10 patients who have survived over five years. We review the case of a young woman with a large cholangiocarcinoma, who has been disease free for eight years. The patient was treated with a right hepatic lobectomy, and received 4 cycles of 5-fluorouracil and levamisole postoperatively. Known factors associated with longer survival in patients with ICC include lack of evidence of local invasion (i.e. capsular, lymphatic, or vascular), negative margins, mucoblia, and well differentiation of the tumor, as well as the absence of lymph node metastases. Our patient had negative margins and lymph nodes, and showed no local invasion. However, no mucobilia was noted, and the tumor was only moderately differentiated. Young age has never been associated with increased survival. ICC remains a relatively uncommon tumor with an insidious onset and late presentation contributing to poor survival. Surgical resection remains the only therapeutic option. Since few patients are potentially resectable at the time of presentation, efforts at early diagnosis and options for adjuvant therapy are imperative.

Pathology of the liver.

Among the topics of recent investigation in liver pathology were an examination of normal portal tract structures in needle liver biopsies, computer reconstructions of the intrahepatic biliary tree, identification of oval cells (presumed progeny of hepatic stem cells) in a variety of biliary and nonbiliary diseases and tumors, the features and pathogenesis of nonalcoholic steatohepatitis, and further characterization of proliferating bile ductules. A morphometric study of portal structures in normal needle liver biopsies found that approximately one third in a given specimen may not show a portal vein and that a bile duct may not be seen in 7%. Apoptosis is a critical mechanism for the death of hepatocytes in viral hepatitis and also in endothelial injury in the cold perfusion-warm reperfusion sequence in liver transplantation. The results of two studies examining the relationship of steatosis to chronic hepatitis C virus infection in native and transplanted livers suggest that fatty change is a specific virus-mediated lesion. In the field of hepatic neoplasia, liver cell dysplasia (large cell change), long thought to be a premalignant lesion, was hypothesized to represent abnormal hepatocyte polyploidization.

Cholesterol 7-hydroxylase knockout mouse: a model for monohydroxy bile acid-related neonatal cholestasis.

BACKGROUND & AIMS: Cyp 7-/- mice lack a functional cholesterol 7alpha-hydroxylase enzyme and develop cholestasis before up-regulation of 27-hydroxycholesterol 7alpha-hydroxylase activity. Because 7alpha-hydroxylation is not the initial step in this metabolic pathway, we tested the hypothesis that cholesterol 27-hydroxylase is expressed at an earlier step and leads to the production of monohydroxy bile acids. METHODS: Polymerase chain reaction with specific oligonucleotides was used to detect messenger RNA (mRNA) coding for cholesterol 27-hydroxylase in 5-day-old normal and Cyp 7-/- mice. Gas-liquid chromatography-mass spectrometry and reverse isotope dilution were used to identify intermediates in the cholesterol 27-hydroxylase metabolic pathway. Light and electron microscopy were used to evaluate the morphological appearance of the liver. RESULTS: mRNA for cholesterol 27-hydroxylase was identified in the liver and spleen. The monohydroxy bile acids 3beta-hydroxy-5-cholenoate and 3alpha-hydroxy-5beta-cholanoate together with their precursor, 27-hydroxycholesterol, were identified in liver homogenates. Cholestasis, present focally, was manifested as dilated bile canaliculi, partial loss of microvilli, and retention of electron-dense biliary material. CONCLUSIONS: The cholesterol 27-hydroxylase metabolic pathway of bile acid synthesis is expressed in neonatal life. The absence of 7alpha-hydroxylase activities unmasks the cholestatic potential of monohydroxy bile acids. The Cyp 7-/- knockout mouse mimics cholestatic events known to occur in humans and provides a unique opportunity for studying regulatory determinants.

Iron-rich foci in chronic viral hepatitis.

Stainable iron in the liver (hemosiderosis) is most commonly seen in individuals with homozygous genetic hemochromatosis, prior transfusion, hemolysis, porphyria cutanea tarda, and chronic alcohol-induced liver disease. In chronic viral hepatitis, however, significant hepatocellular hemosiderosis is uncommon. This report describes unusual foci of hepatocellular hemosiderosis ("iron-rich foci" or IRF) in liver biopsy specimens from three patients with chronic hepatitis with or without cirrhosis (two hepatitis C-related, one hepatitis B-related). IRF present within the lobular parenchyma or cirrhotic nodules contrasted sharply with the immediately adjacent hemosiderin-negative liver tissue. Serum iron indices were abnormal in all three patients, but homozygous hemochromatosis was ruled out based on the hepatic iron concentration and hepatic iron index for each case. These cases highlight the potential for irregular iron storage in chronic viral liver disease and possible confusion with genetic hemochromatosis. The possible pathogenesis of IRF and the relationship of iron storage to the outcome of interferon therapy in chronic viral hepatitis are discussed.

Biliary atresia.

Extrahepatic biliary atresia is an obliterative cholangiopathy that involves all or part of the extrahepatic biliary tree and, in many cases, the intrahepatic bile ducts. In the United States, from 400 to 600 new cases of biliary atresia are encountered annually. The diagnosis is usually suggested by the persistence of jaundice for 6 weeks or more after birth. Several factors have been considered for the pathogenesis of extrahepatic biliary atresia, including viral infection, metabolic insults, and abnormalities in bile duct morphogenesis. Although selected patients benefit from prompt diagnosis and Kasai portoenterostomy surgical intervention within the first 60 days of life, many ultimately require liver transplantation because of portal hypertension, recurrent cholangitis, and cirrhosis.

The liver in AIDS.

Deficits in cell-mediated immunity in AIDS result in a wide variety of hepatic complications, including granulomas, cytomegalovirus hepatitis, multimicrobial AIDS cholangiopathy, Kaposi's sarcoma, and lymphoma. Kupffer cells are the major hepatic target cell population for human immunodeficiency virus-1 (HIV-1), and rhesus monkeys with simian immunodeficiency virus infection have served as a model for ultrastructural analysis of viral clearance by these cells. The majority of patients with established AIDS reveal abnormalities on serum liver tests. In these individuals, the differential diagnosis includes opportunistic infections and neoplasms, as well as possible concomitant chronic viral hepatitis B, C, D, and G, and drug hepatotoxicity. This article reviews the spectrum of hepatic pathology in AIDS and discusses the effects of HIV-1 infection on hepatitis virus infections.

The long-term pathological evolution of chronic hepatitis C.

Most patients infected with hepatitis C virus (HCV) develop chronic hepatitis. Unfortunately, the pathological evolution of this disease over time is not completely understood. We studied 70 HCV-positive patients, from whom 2 to 10 liver biopsy specimens (mean, 3.9) had been obtained during an interval of 1 to 26 years (mean, 8.8 years). Each biopsy specimen was evaluated independently by four pathologists who each provided a numerical score for the grade of portal/periportal necroinflammation (0-4), grade of lobular necroinflammation (0-4), their sum (final grade), and the stage of fibrosis (1-4). The scores were correlated with progression of disease, if any, and transition to cirrhosis. During follow-up, 35 patients (50%) developed cirrhosis. Cirrhosis developed in all patients with a high final grade (> or = 5) of necroinflammation on initial biopsy who were followed for 10 years and in 96% of patients with an intermediate final grade (3.5-4.9) who were followed for 17 years. Only 30.4% of patients with low final grade (< or = 3.4) on initial biopsy developed cirrhosis after 13 years. All patients with evidence of septal fibrosis with incomplete nodularity (stage 3.0-3.4) in the initial biopsy progressed to unequivocal cirrhosis by 10 years. The rate of progression to cirrhosis was accelerated in patients whose initial biopsies showed high-grade and -stage lesions. This study demonstrates the importance of grading and staging liver biopsy lesions in chronic hepatitis C, particularly for patients with high-grade necroinflammation, septal fibrosis, and regions of modularity on initial biopsy who are at high risk of developing advanced cirrhosis in the ensuing decade.

Pathology of AIDS-related liver disease.

Hepatomegaly and abnormalities of serum liver tests are common problems in patients with acquired immune deficiency syndrome. Opportunist infections (Mycobacterium avium-intracellulare and cytomegalovirus) and neoplasms (lymphoma, Kaposi's sarcoma) are among the most prevalent hepatic lesions in AIDS. Although Kupffer cells and endothelial cells are potential sites of human immunodeficiency virus 1 (HIV-1) infection, current studies do not indicate that the liver is a major reservoir for this virus. Drug hepatotoxicity, multimicrobial infections of the biliary tree resembling sclerosing cholangitis and a variety of nonspecific hepatic changes should be considered in evaluating AIDS patients or HIV-1-infected patients with evidence of liver dysfunction.

Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group.

BACKGROUND: Hepatic histological responses described in hepatitis C virus (HCV) infection include bile duct damage, lymphoid follicles and/or aggregates in portal tracts, large- and small-droplet fat, Mallory body-like material in hepatocytes, liver cell dysplasia and multinucleation, and activation of sinusoidal inflammatory cells. The specificity of these lesions for HCV infection is uncertain. METHODS: In two multicenter trials of recombinant interferon alfa therapy for chronic hepatitis C and B, the frequency of these eight lesions in pretherapy and posttherapy liver biopsy specimens was examined to determine the set of features, if any, that distinguishes HCV from hepatitis B virus (HBV) infection. The lesions were scored in 317 HCV biopsy specimens and 299 HBV specimens. RESULTS: Stepwise logistic regression determined a set of three features more likely to be seen in HCV than in HBV infection: bile duct damage [odds ratio (OR), 4.7; 95% confidence interval (Cl), 1.8-12.3], lymphoid follicles and/or aggregates (OR, 2.4; 95% Cl, 1.2-4.7), and large-droplet fat (OR, 2.4; 95% Cl, 1.4-4.1). A fourth lesion, Mallory body-like material, was seen only in HCV biopsy specimens (OR, 71.6; 95% Cl, 4.4-996.1). CONCLUSIONS: These four histological lesions are useful pathological parameters in the diagnosis of liver disease caused by HCV.

A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group.

BACKGROUND AND METHODS: Chronic hepatitis B is a common and often progressive liver disorder for which there is no accepted therapy. To assess the efficacy of treatment with interferon, we randomly assigned patients with chronic hepatitis B to one of the following regimens: prednisone for 6 weeks followed by 5 million units of recombinant interferon alfa-2b daily for 16 weeks; placebo followed by 5 million units of interferon daily for 16 weeks; placebo followed by 1 million units of interferon daily for 16 weeks; or observation with no treatment. RESULTS: Hepatitis B e antigen and hepatitis B viral DNA disappeared from serum significantly more often in the patients given prednisone plus interferon (16 of 44 patients, or 36 percent) or 5 million units of interferon alone (15 of 41; 37 percent) than in the untreated controls (3 of 43; 7 percent; P less than 0.001); the difference between those given 1 million units of interferon (7 of 41; 17 percent) and the controls was not significant. The strongest independent predictor of a response to treatment was the amount of hepatitis B viral DNA in serum at entry (P less than 0.0001). Of the 38 patients who responded to interferon, 33 (87 percent) had normal serum aminotransferase levels after therapy; 11 patients who responded (29 percent), but no controls, lost the hepatitis B surface antigen. Blinded histologic assessment revealed a significant improvement in periportal necrosis in the treated patients (P = 0.03). CONCLUSIONS: In chronic hepatitis B, treatment with interferon alfa-2b (5 million units per day for 16 weeks) was effective in inducing a sustained loss of viral replication and achieving remission, assessed biochemically and histologically, in over a third of patients. Moreover, in about 10 percent of the patients treated with interferon, hepatitis B surface antigen disappeared from serum.

Non-A, non-B hepatitis: characterization of liver biopsy pathology.

We reviewed 40 liver biopsy specimens from 36 patients with non-A, non-B (NANB) hepatitis by light microscopy to characterize the histopathologic features associated with this condition. NANB hepatitis had been acquired from intravenous drug use (6 patients), transfusion (11 patients), sporadic (13 patients), and other routes (6 patients). The major pathologic diagnoses included acute hepatitis, chronic persistent hepatitis, chronic lobular hepatitis, chronic active hepatitis with or without cirrhosis, and hepatocellular carcinoma. Histopathologic changes seen in varied combinations in these specimens included acidophilic degeneration of hepatocytes (100%), fat (85%), formation of portal tract lymphoid aggregates or follicles (52%), bile duct damage (30%), and multinucleate giant hepatocytes (25%). Prominence of sinusoidal cells was variable, but often striking. Hepatocyte atypia (liver cell dysplasia) was noted in 17 specimens. These histologic parameters appear to be diagnostically useful when applied in appropriate clinical settings and will require reevaluation when serologic tests for NANB hepatitis become available.

Jaundice and intrahepatic cholestasis following high-dose megestrol acetate for breast cancer.

High-dose megestrol acetate, a synthetic progestin, has been advocated recently in treating patients with metastatic breast carcinoma; no significant increase in adverse effects has been reported. This report describes a patient with jaundice and intrahepatic cholestasis after high-dose megestrol acetate therapy. This cholestatic lesion may have a pathogenesis similar to that observed with estrogens and oral contraceptives.

Unique vascular skin lesions associated with human immunodeficiency virus.

We report four patients with antibodies to human immunodeficiency virus and/or acquired immunodeficiency syndrome who were noted to have unique vascular lesions that clinically resembled Kaposi's sarcoma or pyogenic granulomas. The lesions were asymptomatic erythematous-violaceous papules and nodules. They erupted over several weeks, without predilection for a specific cutaneous site. Most lesions resolved spontaneously. Histologically these lesions revealed a proliferation of vascular spaces lined by plump, cuboidal endothelial cells embedded in an edematous stroma with an inflammatory infiltrate. It is unclear if these lesions represent Kaposi's sarcoma or pyogenic granulomas or if they are distinct neoplasms associated with human immunodeficiency virus.