Hepatitis: Lefkowitch JH

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. · Hum Pathol. · Pubmed #19289183 No free full text.

Abstract: Progress in liver histopathology continues to be made, as evidenced by recent publications in all areas of hepatobiliary disease. Multinucleated giant hepatocytes, known to be associated with autoimmune and drug hepatitis, now have been seen in chronic hepatitis C with or without HIV infection and in patients with infection by human herpesvirus-6A. The new term Mallory-Denk body (formerly the Mallory body) recognizes the substantial contributions to this field by Professor Helmut Denk of Austria. The problems of fatty liver and hepatic iron overload have been addressed in studies highlighting their complex pathogenesis. Genomic and immunohistochemical analysis of liver tumors provides important diagnostic information, particularly regarding the use of glypican-3 in the diagnosis of hepatocellular carcinoma.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, USA. · Curr Opin Gastroenterol. · Pubmed #18408454 No free full text.

Abstract: PURPOSE OF REVIEW: Studies are reviewed from the past year concerning the histopathology of liver and biliary diseases and their pathogenesis. RECENT FINDINGS: Several cases of acute hepatitis E showed portal and periportal hepatitis, with polarization of neutrophils to the interface region and lymphocytes more centrally in the portal tracts. Transfection of hepatitis C virus into cultured fetal hepatocytes resulted in sustained growth of 50-90 nm diameter viral particles. The ductular reaction in nonalcoholic steatohepatitis appears to evolve with fibrosis in response to hepatocyte replicative senescence. Hepatocellular release of hepcidin is critical for iron homeostasis in a manner analogous to pancreatic insulin for glucose homeostasis; this 'endocrine' focus was elaborated in an overview of hemochromatosis. Specific microscopic features of liver-cell adenomas combined with genetic analysis for hepatocyte nuclear factor 1alpha and beta-catenin mutations allows differentiation into four variants. Steroid-sensitive biliary strictures resembling primary sclerosing cholangitis but with increased serum immunoglobulin G4 and infiltrating immunoglobulin G4-positive plasma cells ('immunoglobulin associated cholangitis') are part of a spectrum of disorders including autoimmune pancreatitis and inflammatory pseudotumor. SUMMARY: Pathologic features of viral hepatitis C and E, immunohistochemistry for the ductular reaction and malignant liver tumors and several systemic disorders are among recent important pathology studies.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. · Curr Opin Gastroenterol. · Pubmed #17414836 No free full text.

Abstract: PURPOSE OF REVIEW: Recent papers on disorders of the liver and biliary tract which clarify their pathogenesis and attendant morphologic changes are highlighted. RECENT FINDINGS: The concept of 'bystander hepatitis' was cited in studies showing hepatic infiltration of CD8-positive T cells in the setting of extrahepatic infections such as influenza virus and severe acute respiratory syndrome. Diabetic liver lesions include glycogenic hepatopathy (in which poor diabetic control leads to swollen, glycogen-filled hepatocytes without fat, steatohepatitis or fibrosis) and diabetic hepatosclerosis in which there is diffuse perisinusoidal fibrosis (type IV collagen) without zonal predilection. Ground-glass hepatocellular inclusions (positive with periodic acid-Schiff stain for glycogen) were reported in three separate series of patients who were hepatitis B virus-negative, often transplant recipients, immunosuppressed and on multiple medications. A Banff consensus paper expertly compared and contrasted the histologic features which characterize the various causes of late liver allograft dysfunction. SUMMARY: Informative papers emerged this past year concerning collateral damage to the liver in extrahepatic infections, diabetic lesions and causes of liver dysfunction after transplantation, among other topics.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. · Semin Diagn Pathol. · Pubmed #17355092 No free full text.

Abstract: The comprehensive histopathologic evaluation of liver tissue, including biopsy, explant, and postmortem specimens, utilizes a standard panel of special histochemical stains as well as selective immunohistochemistry. These methods provide increased accuracy in addressing common diagnostic problems such as determining the stage of fibrosis in chronic hepatitis, documenting the presence of cirrhosis or other causes of portal hypertension, iron, and copper overload, disorders of the biliary tract, and tumor histogenesis. This review discusses the indications for various staining methods and the specific uses of trichrome and reticulin connective tissue stains, periodic acid-Schiff (PAS) and diastase-pretreated PAS (DPAS), iron, and Victoria blue methods. Diagnostic applications of immunohistochemical stains are also described.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Curr Opin Gastroenterol. · Pubmed #16550033 No free full text.

Abstract: PURPOSE OF REVIEW: Publications concerning liver histopathology in fatty liver disease and chronic hepatitis C, iron and copper overload, and liver transplantation from the past year have been surveyed to highlight useful concepts and diagnostic information. RECENT FINDINGS: Two microscopic forms of pediatric nonalcoholic steatohepatitis have been described: type 1 in which hepatocyte ballooning and/or pericellular fibrosis accompany the steatosis; and type 2 which has portal tract inflammation and/or fibrosis as the salient accompanying feature. In chronic hepatitis C, the ductular reaction appears to be a major factor associated with fibrosis. In patients transplanted for hepatitis C virus-related cirrhosis, immunostaining of post-transplant liver biopsies for alpha-smooth muscle actin (i.e. in activated hepatic stellate cells) may identify those individuals at risk for severe recurrence. Clinicopathological papers on several forms of non-HFE hemochromatosis were published and Wilson's disease was described in individuals of 60 years or more in age. Cholestasis in childhood was expertly reviewed and histopathologic precursor lesions of hepatocellular carcinoma were also examined in a comprehensive article. SUMMARY: Recent publications with impact on liver biopsy interpretation include a morphologic classification of nonalcoholic steatohepatitis in childhood, the differential diagnosis of childhood cholestasis and pathogenetic factors involved in fibrogenesis in chronic hepatitis C.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Curr Opin Gastroenterol. · Pubmed #15818145 No free full text.

Abstract: PURPOSE OF REVIEW: This review highlights recent publications on hepatobiliary pathology concerning several unusual types of hepatitis, fatty liver disease, disorders of the biliary tree and other topics that have a substantial impact on liver biopsy interpretation. RECENT FINDINGS: In the outbreak of severe acute respiratory syndrome (SARS), many patients had abnormalities in liver function tests. Liver biopsy findings in three cases were reported that showed a generic picture of hepatitis, with exceptionally increased mitotic activity. The role of portal myofibroblasts in cirrhosis was examined in several studies. A newly described lesion, isolated ductular hyperplasia (IDH) was found in patients with prolonged abnormalities of liver function tests of uncertain origin. Hyperplastic, well-differentiated bile ductules were seen on liver biopsy in the absence of any identifiable biliary disease. Hereditary hemochromatosis is now a complex entity with various clinicopathological forms based on mutations in the HFE gene and other iron-homeostatic genes such as transferrin receptor 2 and ferroportin 1. In some of these heritable forms of primary iron overload, stainable iron is present in both hepatocytes and Kupffer cells. After liver transplantation, differentiating recurrent HCV infection from acute rejection on liver biopsy is problematic, with exceptionally low inter- and intra-observer reliability shown in one study. SUMMARY: The hepatitis associated with the SARS coronavirus, Isolated Ductular Hyperplasia in patients with liver function test abnormalities and other topics with pathologic relevance are reviewed.

Lefkowitch JH. · Columbia University, Department of Surgical Pathology, PH 1564W, 630 W 168th Streest, VC 14th Floor, Room 215, New York, NY 10032, USA. · Clin Liver Dis. · Pubmed #15763228 No free full text.

Abstract: The major pathologic manifestations of alcoholic liver injury have been well described, and include three major lesions: steatosis (fatty liver), steatohepatitis (formerly alcoholic hepatitis), and cirrhosis. Recent attention to the problem of nonalcoholic fatty liver disease (NAFLD) in individuals with obesity, diabetes, and other risk factors has shed light on the mechanisms of cellular injury associated with hepatic steatosis and on the potential pathways to steatohepatitis and cirrhosis. Pathologists need to be familiar with the spectrum of changes seen in steatohepatitis, including hepatocyte ballooning, Mallory bodies, mixed inflammatory cell infiltrates, and a distinctive perivenular and pericellular "chicken-wire" fibrosis. These features and other less common histopathologic lesions in the liver are reviewed and illustrated.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, PH 15 West-1574, New York, NY 10032, USA. · Clin Liver Dis. · Pubmed #15062191 No free full text.

Abstract: The microscopic identification of bile in sections of liver provides an important diagnostic challenge for the histopathologist, particularly in differentiating the many causes of intrahepatic cholestasis from mechanical bile duct obstruction. The pathologist's chief goal in evaluating the cholestatic liver is to distinguish intrahepatic cholestasis (seen in conditions such as drug hepatotoxicity, viral hepatitis, sepsis, or mutations affecting bile transporters) from large bile duct obstruction caused by conditions such as choledocholithiasis, pancreatic carcinoma, biliary stricture, or primary sclerosing cholangitis (PSC). This distinction carries major therapeutic and prognostic significance, because surgical, endoscopic,or radiologically guided intervention is likely to be undertaken if the pathologic features point to mechanical obstruction of the bile ducts. The histologic assessment of cholestasis, in broad terms, therefore, is a morphologic approach to distinguish between medical jaundice and surgical jaundice.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street-PH15 West 1574, New York, NY 10032, USA. · Clin Liver Dis. · Pubmed #12122870 No free full text.

Abstract: Liver biopsy is used to determine the pathogenesis of liver dysfunction after liver transplantation. One or more causative factors may be identified on biopsy. The pathologist must be familiar with the histopathology of acute rejection to differentiate it from other potential complications, including biliary obstruction, intercurrent cytomegalovirus hepatitis, or recurrent disease. Consensus documents from the Banff international panel provide useful guidelines for the appropriate grading of acute and chronic rejection.

Lo IJ, Lefkowitch JH, Feirt N, Alkofer B, Kin C, Samstein B, Guarrera JV, Renz JF. · Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA. · Liver Transpl. · Pubmed #18324657 links to  free full text

Abstract: Extended-donor criteria (EDC) liver allografts potentiate the role of procurement biopsy in organ utilization. To expedite allocation, histologic evaluation is routinely performed upon frozen-section (FS) specimens by local pathologists. This descriptive study compares FS reports by local pathologists with permanent-section (PS) evaluation by dedicated hepatopathologists, identifies histologic characteristics underrepresented by FS evaluation, and evaluates the efficacy of a biopsy decision analysis based on organ visualization. Fifty-two liver transplants using EDC allografts evaluated by FS with PS were studied. Pathologic worksheets created by an organ procurement organization were applied in 34 FS. PS analysis included 7 staining procedures for 8 histologic criteria. PS from 56 additional allografts determined not to require donor biopsy were also analyzed. A high correlation was observed between FS and PS. Underestimation of steatosis by FS was associated with allograft dysfunction. Surgical assessment of cholestasis, congestion, and steatosis was accurate whereas inflammation, necrosis, and fibrosis were underestimated in allografts suffering parenchymal injury. In conclusion, the correlation between FS and PS is high, and significant discrepancies are rare. Biopsy is not a prerequisite for EDC utilization but is suggested in hepatitis C, hypernatremia, donation after cardiac death, or multiple EDC indications. Implementation of a universal FS worksheet could standardize histologic reporting and facilitate data collection, allocation, and research.

Puius YA, Dove LM, Brust DG, Shah DP, Lefkowitch JH. · Division of Infectious Diseases, Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA. · J Clin Gastroenterol. · Pubmed #18277893 No free full text.

Abstract: Autoimmune hepatitis (AIH) is an uncommon liver disease that has previously been reported only 4 times in HIV-infected patients. Our report describes 3 new cases of AIH, 2 probable, and 1 definite. Two of these cases developed while the patient was virologically suppressed on antiretroviral therapy. Liver biopsy findings were critical in establishing the diagnosis of AIH. Because abnormal liver function tests in HIV-positive patients are often ascribed to antiretroviral medications and/or comorbid conditions, AIH may be underdiagnosed in this population. These cases underscore the value of liver biopsy in evaluating hepatitis of unclear etiology in HIV-positive patients. The clinical course of these cases also suggests that standard immunosuppressive therapy for AIH remains the optimal treatment regimen, even in HIV-positive patients.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. · Arch Med Res. · Pubmed #17613355 No free full text.

Abstract: Liver biopsy has been a major diagnostic tool in the evaluation of individuals with chronic hepatitis for many decades and remains the most direct way of visualizing hepatic necroinflammation and fibrosis. In chronic viral hepatitis B and C, immune attack on hepatocytes bearing viral antigens results in the entry of lymphocytes and other effector cells through the portal tracts from which other lesions may evolve, including interface and lobular hepatitis as well as fibrosis or cirrhosis. Classification systems have been developed in order to provide semiquantitative grading of necroinflammation and staging of fibrosis and include the Scheuer, Batts and Ludwig, Ishak, and METAVIR systems. This review provides an historical perspective on histopathological methods of analyzing chronic hepatitis, describes the essential criteria of each of the major scoring systems and discusses problems related to sampling error, observer variation, and specimen size.

Vakiani E, Hunt KK, Mazziotta RM, Emond JC, Brown RS, Lefkowitch JH, Bhagat G. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Am J Clin Pathol. · Pubmed #17145627 links to  free full text

Abstract: Liver granulomas have been described in biopsy specimens from people with de novo chronic hepatitis C virus (HCV) infection and in allograft biopsy specimens from recipients of transplants for HCV-related liver disease. The latter have not been well studied, and there are no data regarding the prevalence, morphologic spectrum, and clinical significance of HCV-associated granulomas after liver transplantation. We observed granulomas in allograft liver biopsy specimens of 4 (8%) of 53 recipients of transplants for HCV-related end-stage liver disease during a 3-year period. Initial appearance of granulomas ranged from 4 to 41 weeks after transplantation. Lobular and portal nonnecrotizing, epithelioid granulomas and lobular microgranulomas were observed, with the latter predominating. Serum transaminase and alkaline phosphatase levels were significantly higher in patients with granulomas than in age- and sex-matched control subjects, but histologic disease activity, cellular rejection scores, HCV genotypes, viral titers, and retransplantation rate owing to recurrent disease were not significantly different. Our study suggests that a granulomatous response to HCV infection occurs in a subset of patients after transplantation; however, this histologic finding does not portend a worse clinical outcome.

Lefkowitch JH. · College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. · Curr Opin Gastroenterol. · Pubmed #17033299 No free full text.

Abstract: Technologic advances using cDNA microarray hybridization, liver diseases characterized by mitochondrial DNA depletion, and new work characterizing bile salt transport problems in familial intrahepatic cholestasis syndromes were some of the major highlights of this past year. Analysis of normal livers by cDNA microarrays disclosed 2418 unique gene transcripts encoding a host of cellular structural and functional proteins. This technique was also applied to hepatocellular carcinoma, where enhanced expression of a number of genes involved in antiapoptosis and cell transformation may shed additional light on the process of hepatocarcinogenesis. Mitochondrial DNA depletion seen in Navajo neurohepatopathy and in respiratory chain disorders of infancy was associated with cholestasis and cirrhosis in the former and microvesicular steatosis and oncocytic transformation (mitochondrial hyperplasia) in the latter. Pathologists who routinely examine liver biopsies after liver or bone marrow transplantation should be aware of unusual biopsy features that mimic other diseases, such as the autoimmune hepatitis-like syndrome that may follow liver transplantation and chronic graft-versus-host disease that clinically and pathologically resembles acute hepatitis.

Lefkowitch JH. · College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. · Curr Opin Gastroenterol. · Pubmed #17031160 No free full text.

Abstract: 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.

Lefkowitch JH. · College of Physicians and Surgeons of Columbia University, New York, New York, USA. · Curr Opin Gastroenterol. · Pubmed #17023945 No free full text.

Abstract: 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.

Lefkowitch JH. · College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. · Curr Opin Gastroenterol. · Pubmed #17023877 No free full text.

Abstract: 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.

Lefkowitch JH, Lobritto SJ, Brown RS, Emond JC, Schilsky ML, Rosenthal LA, George DM, Cairo MS. · Department of Pathology, Columbia University Medical Center, New York, New York, USA. · Gastroenterology. · Pubmed #16952540 No free full text.

Abstract: BACKGROUND & AIMS: Ground-glass (GG) inclusions within hepatocytes are an important histopathologic marker of chronic hepatitis B virus (HBV) infection but may also be seen in Lafora's disease (myoclonus epilepsy), cyanamide alcohol aversion therapy, and type IV glycogenosis. We have noted a recent increased incidence of liver biopsy and postmortem specimens with GG inclusions associated with none of these etiologic factors. This study was undertaken to further delineate the clinical and liver pathologic features in such cases and their possible pathogenesis. METHODS: Ten cases with GG inclusions (8 biopsy, 2 postmortem) were examined by light and electron microscopy, and the patients' clinical records were reviewed. RESULTS: Light microscopy demonstrated pale pink, oval to crescentic intracytoplasmic inclusions with a predilection for periportal hepatocytes but sometimes present throughout the lobules. The inclusions were intensely positive on periodic acid-Schiff stain and digested with diastase. Transmission electron microscopy of two cases showed non-membrane-bound cytoplasmic collections of granules with mild-to-moderate electron density, consistent with abnormal glycogen granules. The patients included 7 transplant recipients (liver, hematopoietic stem cell), 3 with type 2 diabetes and a child on chronic parenteral nutrition for short bowel syndrome. Medications included immunosuppressive agents, antibiotics, and insulin. CONCLUSIONS: GG hepatocellular inclusions may be seen in individuals without HBV infection or other recognized etiologies, appear to be composed of abnormal glycogen and closely resemble polyglucosan bodies described in humans, animals, and experimental models. The possible pathogenetic roles of disturbed glycogen metabolism and polypharmacotherapy are stressed.

Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. · Curr Opin Gastroenterol. · Pubmed #15703643 No free full text.

Abstract: PURPOSE OF REVIEW: Liver biopsy continues to be an essential component in the evaluation of many widely prevalent liver diseases, including chronic hepatitis C, fatty liver, and liver tumors. This annual review of publications in hepatobiliary pathology highlights recent pathologic studies that can be applied to the daily practice of interpreting liver biopsy, explant, and postmortem specimens. RECENT FINDINGS: The problem of the fatty liver was the subject of many studies. In chronic hepatitis C, genotype 3 infection results in moderate to marked fat that is ameliorated with successful antiviral therapy. In nonalcoholic steatohepatitis, in which the metabolic syndrome is often operative, gene microarray analysis showed altered expression of genes involved in insulin sensitivity and maintenance of mitochondrial function. Pathologic changes affecting centrilobular regions were described in the context of heart disease, Budd-Chiari syndrome, and the sinusoidal obstruction syndrome (venoocclusive disease). A mutation in ferroportin 1 produced a form of hemochromatosis with excessive iron in hepatocytes and also in Kupffer cells and macrophages. Immunostains for Hep Par 1 and polyclonal carcinoembryonic antigen remain important cornerstones in the immunohistochemical diagnosis of hepatocellular carcinoma and its distinction from metastatic adenocarcinoma and cholangiocarcinoma. SUMMARY: This report reviews recent articles addressing hepatobiliary pathology. In the areas of viral and drug hepatitis, fatty liver, hemochromatosis, Wilson disease, several biliary tract disorders, and pathology of liver tumors, the emerging data have important diagnostic applications.

Lefkowitch JH. · College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. · Curr Opin Gastroenterol. · Pubmed #15703559 No free full text.

Abstract: Insights provided by molecular biology, immunohistochemistry, and transmission electron microscopy have increased our understanding of the pathogenesis and histopathology of hepatitis C virus (HCV) infection, nonalcoholic steatohepatitis (NASH), and bile ductular proliferative reactions in a number of liver diseases. Human and chimpanzee liver infected with HCV showed viral-like particles (50 to 60 nm in diameter) as well as aggregates of short tubules that represent viral envelope material. Interactions of HCV core protein with apolipoproteins have a role in the pathogenesis of HCV-related steatosis. Pathologists should be aware of the spectrum of liver pathology described with the use of highly active antiretroviral therapy (HAART) agents for the human immunodeficiency virus infection, which includes microvesicular steatosis and more severe hepatic injury with confluent necrosis. Proliferation of bile ductular structures is influenced by specific molecules and proteins (eg, the mucin-associated trefoil proteins and estrogens). The interplay between Notch receptors and Jagged 1 protein, as expressed by many cells of the liver (including bile duct epithelium) varies in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Cholangiocarcinoma does not appear to be a long-term complication of small duct PSC. The fatty liver diseases, both alcoholic and nonalcoholic, are characterized by production of reactive oxygen species that have detrimental effects such as opening mitochondrial permeability transition pores with resultant release of cytochrome c into the cytosol. Hepatocellular carcinoma is now a recognized late complication of NASH. The derivation of hepatic stem cells, the roles of HFE protein and other hepatic and intestinal transport proteins in hemochromatosis, and the histopathologic interpretive challenge of centrilobular lesions in posttransplant liver biopsies are among other recent studies considered in this review.

Eleazar JA, Memeo L, Jhang JS, Mansukhani MM, Chin S, Park SM, Lefkowitch JH, Bhagat G. · Department of Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. · J Hepatol. · Pubmed #15582132 No free full text.

Abstract: BACKGROUND/AIMS: Progenitor cell activation with subsequent maturation to hepatocytes and cells of the biliary lineage has been demonstrated in a variety of chronic liver diseases but the kinetics and magnitude of the progenitor cell response has not been adequately studied in detail in chronic hepatitis. We undertook this study to evaluate factors responsible for the progenitor cell/ductular response and further dissect the role of disease grade and stage as determinants of hepatocellular differentiation of bipotential progenitor cells in chronic hepatitis. METHODS: Cytokeratin 7 (and 19) stained biopsies from patients with chronic hepatitis C (n = 47), hepatitis B (n = 20), and autoimmune hepatitis (n = 20) were studied. Ploidy analysis and proliferation indices were evaluated in a subset of cases. RESULTS: Ductular reactions were present in the majority of cases (97%), appeared early in disease, and correlated with disease activity, while progenitor cell derived hepatocyes appeared later in disease and their extent correlated with disease stage. Proliferation indices of all cell types correlated with disease activity. CONCLUSIONS: Progenitor cell derived hepatocytes accrue in chronic hepatitis, possibly related to native hepatocellular dysfunction. However, the fate of these hepatocytes is unclear.

Tanji K, Bhagat G, Vu TH, Monzon L, Bonilla E, Lefkowitch JH. · Department of Pathology, College of Physicians and Surgeons, Columbia University, NY, New York 10032, USA. · Liver Int. · Pubmed #14708902 No free full text.

Abstract: Hepatic oncocytes with abundant granular, eosinophilic cytoplasm due to mitochondrial hyperplasia are seen in various chronic liver diseases, particularly chronic hepatitis and cirrhosis. Increased mitochondria in oncocytes are thought to be a compensatory mechanism for deficiencies in the hepatocellular respiratory chain, although the pathogenesis of these deficiencies has been uncertain. We selected seven cases of cirrhosis (six with oncocytes, one without) for the following analysis: histoenzymatic and immunohistochemical staining of several mitochondrial DNA (mtDNA)- and nuclear DNA (nDNA)-encoded respiratory chain enzymes; immunostaining using antibodies against double-strand-DNA (anti-DNA) and against Ki-67 (a cell proliferation marker); and Southern blot analysis for mtDNA and nDNA. Eighty percent of oncocytes showed histoenzymatic and immunohistochemical deficiencies of cytochrome c oxidase and the mtDNA-encoded subunit I of complex IV, with preserved expression of nDNA-encoded succinate dehydrogenase and the iron-sulfur subunit of complex III (FeS). Cytoplasmic (but not nuclear) anti-DNA staining was partially or completely absent in approximately 50% of oncocytes. Three cases with oncocytes studied by Southern blot showed mtDNA reductions of 66%, 71%, and 85%. In conclusion, hepatic oncocytes demonstrate significant deficiencies of mtDNA and mtDNA-encoded respiratory chain enzymes. We propose that mtDNA depletion plays an important role in hepatocellular oncocytic transformation.

Larghi A, Leffler D, Frucht H, Rubin M, Semrad CE, Lefkowitch JH, Worman HJ. · Department of Medicine, College of Physicians and Seurgeons, Columbia University, New York, New York 10032, USA. · J Clin Gastroenterol. · Pubmed #12590243 No free full text.

Abstract: A case of hepatitis B virus (HBV) reactivation after kidney transplantation is reported. The presence of antibodies against hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) before transplantation indicated previous infection with HBV. Eight years after transplantation, a diffuse, large B-cell lymphoma occurred, and the patient was positive for HBsAg and hepatitis B e antigen, in association with normal activity of serum aminotransferases. Postmortem liver histology did not show any sign of portal tract or lobular inflammation despite the presence at immunostaining of extensive intranuclear and cytoplasmic positivity for HBcAg, indicating active viral replication. Natural immunity to HBV may not protect against reactivation in patients with a suppressed immune system. In this setting, periodic follow-up of HBV serology in patients at highest risk for HBV reactivation to allow for early diagnosis and prompt treatment with lamivudine is highly recommended.

May LD, Lefkowitch JH, Kram MT, Rubin DE. · Good Samaritan Hospital, Suffern, NY 10901, USA. · Ann Intern Med. · Pubmed #11900497 links to  free full text

Abstract: BACKGROUND: Pioglitazone is an oral hypoglycemic agent in the thiazolidinedione class. Only one case of hepatotoxicity related to this agent has previously been reported. OBJECTIVE: To report the clinical course of a patient with hepatitis after therapy with pioglitazone. DESIGN: Case report. SETTING: A community hospital. PATIENT: A 49-year-old diabetic man taking pioglitazone, 30 mg/d. INTERVENTION: Discontinuation of pioglitazone therapy. MEASUREMENTS: Serum aminotransferase and bilirubin levels, standard blood tests for causes of hepatitis and cirrhosis other than drug toxicity, and liver biopsy. RESULTS: After 6 months of pioglitazone therapy, significant hepatic dysfunction developed. Blood tests excluded viral, metabolic, and autoimmune disorders. Liver biopsy showed mixed hepatocellular-cholestatic injury compatible with drug toxicity. After treatment with pioglitazone was discontinued, liver enzyme values returned to normal. CONCLUSION: Patients receiving pioglitazone may develop serious liver injury and should be observed for evidence of hepatitis.