Protoporphyrin hepatopathy. Effects of cholic acid ingestion in murine griseofulvin-induced protoporphyria.

Short-term effects of cholic acid ingestion on hepatic accumulation, fecal excretion, and blood levels of protoporphyrin were studied in vivo in griseofulvin-induced protoporphyric mice. Experimental mice that received feed with 2% griseofulvin and 0.5% cholic acid were compared with control mice that received feed with 2% griseofulvin for 4 wk. Five mice from each group were assessed each week for liver and blood porphyrin levels. Fecal protoporphyrin was compared weekly in the total pooled output of each population. Mean protoporphyrin levels were significantly lower for liver (P less than 0.0001), erythrocytes (P less than 0.05), and plasma (P less than 0.05), and higher for feces (P less than 0.001) for the mice that were fed cholic acid. Microscopic protoporphyrin deposits, inflammation, necrosis, and dysplasia were more severe in livers of control mice. A second experimental design compared four regimens in the feed given to all mice after 1-wk induction with 2% griseofulvin: (a) 0.5% cholic acid, (b) no adulterant, (c) 2% griseofulvin and 0.5% cholic acid, and (d) 2% griseofulvin. No difference in protoporphyrin removal from livers of mice in groups 1 and 2 was observed after 1 and 2 wk of these regimens. The apparent reduction in hepatic protoporphyrin content in mice of group 3 as compared with group 4 at weeks 2 and 3 was not significant at P less than 0.05. These data suggest that in selected circumstances, hepatic protoporphyrin secretion may be enhanced in protoporphyric disease states by bile salt supplementation.

Primary sclerosing cholangitis.

Recent investigations have clarified the clinical, radiologic, and pathologic features of primary sclerosing cholangitis, a chronic fibrosing disorder affecting the biliary tree. This progressive, cholestatic biliary disease is diagnosed when an elevated serum alkaline phosphatase level and stricturing and beading of bile ducts on cholangiography are found in a patient with jaundice, bouts of cholangitis, and, frequently, ulcerative colitis. The disease results in a spectrum of hepatic changes characterized by periductal and portal fibrosis, bile ductular proliferation, diminished numbers of normal bile ducts, piecemeal necrosis, and copper accumulation. The clinicopathologic features of primary sclerosing cholangitis, hypotheses on its pathogenesis, and possible forms of therapy are examined.

Fluctuating Kayser-Fleischer-like rings in a jaundiced patient.

An alcoholic patient had cirrhosis and pigmented corneal rings similar to Kayser-Fleischer rings. A slitlamp examination by two ophthalmologists, independently, showed bilateral and circumferential rings. Patients with altered copper metabolism in liver disease other than Wilson's disease have been described to have pigmented corneal rings seen only on slitlamp examination. The results of our patient's copper metabolism studies disclosed that the intensity of the rings correlated directly with the serum bilirubin concentrations. Thus, patients with severe cholestasis may be initially seen with Kayser-Fleischer-like rings that should be evaluated further with copper metabolism studies.

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.

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.

Bile ductular cholestasis: an ominous histopathologic sign related to sepsis and "cholangitis lenta".

An unusual form of intrahepatic cholestasis manifested by inspissated bile within dilated and proliferated portal and periportal bile ductules was seen in liver biopsy and autopsy specimens from three patients. Features of sepsis and sever systemic illness with jaundice dominated their clinical presentations, and no autopsy evidence of large bile duct obstruction could be found. This lesion may be related to the old entity, "cholangitis lenta," a form of chronic sepsis associated with biliary tract inflammation in the absence of demonstrable extrinsic obstruction. Identification of this pattern of cholestasis in liver biopsy specimens is useful in certain patients who may be a great risk of mortality and who require serous clinical attention directed toward elucidating a source for sepsis as well as aggressive management of other systemic disease. Laparotomy in such cases will be unrewarding and may hasten the patient's demise.

Liver disease in alcoholic cardiomyopathy: evidence against cirrhosis.

The authors examined in detail the clinical and laboratory data and pathologic findings for 12 patients with alcoholic cardiomyopathy who were autopsied in the preceding ten years to determine the types of liver disease prevalent in this population. Neither alcoholic hepatitis nor cirrhosis was present in any patient, and most of the hepatic changes could be related to the effects of acute and chronic congestive heart failure. The major hepatic lesions included centrilobular congestion and/or ischemic necrosis, cardiac sclerosis (fibrosis about central veins and in perisinusoidal spaces), mild canalicular cholestasis, portal fibrosis, and nodular regenerative hyperplasia. This last finding may account for macroscopic nodularity resembling cirrhosis as well as portal hypertension in patients with alcoholic cardiomyopathy. Although alcoholic cardiomyopathy and alcoholic hepatitis or cirrhosis were mutually exclusive in the patients studied, the factors responsible for this are at present uncertain.

Cryptosporidiosis of the human small intestine: a light and electron microscopic study.

Intestinal infection by the coccidian parasite Cryptosporidium is a well-recognized condition in immunocompromised hosts and in some normal persons. The authors studied a patient with acquired immunodeficiency syndrome and cryptosporidiosis of the small intestine. The parasite inhabits the microvillous brush border of the intestinal epithelium and must be carefully sought on light microscopic examination of intestinal biopsy specimens. Characteristic life cycle stages are observed on electron microscopy. The absence of significant light microscopic alterations of the villous architecture in this patient's biopsy specimen and in other cases suggests that other factors, such as toxin elaboration by cryptosporidia or other organisms, may be involved in the pathogenesis of diarrhea. Abnormal aggregation of lysosomes at the apices of intestinal epithelial cells may reflect ineffective host phagocytic mechanisms.

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.

Hepatitis B virus and myocarditis.

Myocarditis may be a serious extrahepatic complication of hepatitis. In this fatal case of serologically documented hepatitis B viral hepatitis, acute myocarditis was present, with histologic features consistent with a viral pathogenesis. Hepatitis B surface antigen was demonstrated by immunoperoxidase methods in small intramyocardial vessels, suggesting that hepatitis B virus infected the heart. The resulting inflammatory heart disease may have been caused either directly, by virus infecting the myocardium, or indirectly, by an immune-mediated mechanism.

Oxyphilic granular hepatocytes. Mitochondrion-rich liver cells in hepatic disease.

In the course of examining liver biopsy specimens, certain larger than normal liver cells whose cytoplasm is finely granular and strikingly acidophilic have been seen. These cells are called "oxyphilic granular hepatocytes" (oxyphils) because of their similarities to the "oncocytes" of the salivary glands and other endocrine organs. Oxyphilic liver cells can be readily differentiated from acidophilic bodies and groundglass hepatocytes by light and electron microscpy, the latter showing them to be extraordinarily rich in mitochondria. A retrospective study of 214 consecutive liver biopsies was undertaken to determine the prevalence of oxyphilic cells in a variety of liver diseases. Oxyphils were identified in 15% of the biopsy specimens, and were most strongly associated with chronic active hepatitis and cirrhosis in hepatitis B surface antigen (HBsAg)-positive patients. Subsequent reevaluation of 77 biopsy specimens from HBsAg-positive patients showed oxyphils in 28.6%. Their pathogenesis and significance in chronic liver disease are unknown.

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.

The epidemiology and morphology of primary malignant liver tumors.

The ubiquitous problem of cirrhosis may be complicated by the development of primary liver cell carcinoma, with rates of incidence so high in certain parts of the world as to make it a candidate for the most common cancer in humans. When cirrhosis reaches the macronodular stage, the risk of developing liver cell carcinoma increases, and at this point liver cell dysplasia may be seen in biopsy. Alcoholics, who classically have a micronodular cirrhosis, may attain the macronodular pattern through better clinical management, abstinence, and longer survival. Hepatitis B-related cirrhosis, on the other hand, is most often macronodular. Recent DNA hybridization studies strongly favor a viral role in oncogenesis, and this possibility is supported by the serologic and epidemiologic evidence complied in the last decade. Liver cell malignant tumors tend to recapitulate the characteristics of normal liver, namely, growth in cords, uniformity of cytologic appearances, and bile production, but also present distinctive histologic and immunohistochemical patterns that are unique to a malignant liver cell population. The other primary malignant tumors of the liver, arising in bile ducts, blood vessels, and mesenchymal elements, all carry their individual epidemiology and morphology, but in general invoke, as does liver cell carcinoma, the concept of a series of step by step cell-carcinogen and cell-carcinogen interactions by which normal cells give rise to malignant populations.

Liver cell dysplasia and hepatocellular carcinoma in non-A, non-B hepatitis.

Liver cell dysplasia (LCD) is a premalignant cytologic change of hepatocytes that has been statistically linked to cirrhosis, hepatocellular carcinoma (HCC), and chronic liver disease related to hepatitis B virus. The relationship of LCD to non-A, non-B (NANB) hepatitis is currently unknown. We studied liver biopsy and surgical resection specimens from 36 patients with NANB hepatitis, and identified LCD in 17 (42.5%) of 40 specimens, most often associated with cirrhosis. Dysplasia was present in individual hepatocytes, in clusters, and in a distinctive "spreading" pattern of hepatocytes about central veins. Three patients had HCC with a predominant giant cell pattern, as well as LCD. These findings suggest that LCD and HCC should be included among the potential pathologic sequelae of NANB hepatitis.

Hepatic Hodgkin's disease simulating cholestatic hepatitis with liver failure.

Fulminant liver failure is an unusual complication that may be seen in patients with hepatic infiltration by non-Hodgkin's lymphomas and leukemias. In such cases, hepatomegaly, marked abnormalities of serum liver function tests, and lactic acidosis may simulate severe viral, alcoholic, or drug hepatitis. We describe the clinical presentation of severe cholestatic hepatitis with liver failure in a patient who was found to have widespread liver involvement by Hodgkin's disease at autopsy. The major histologic findings included extensive portal and periportal Hodgkin's infiltrates, associated loss of periportal liver cells, and variable damage to small bile ducts.

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.

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.

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.

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.