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Jay H Lefkowitch

Publications and source records attributed to Jay H Lefkowitch.

At least 19 recordsLinked to original sources
PubMed2007

Hepatitis C-associated granulomas after liver transplantation: morphologic spectrum and clinical implications.

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.

Adult↗
PubMed2006

Multiple cutaneous infantile hemangiomas associated with hepatic angiosarcoma: case report and review of the literature.

Multiple cutaneous hemangiomas can be associated with internal hemangiomas, with the liver being the most common site. Here we report a case of a premature female neonate who presented with cardiac failure at birth and had typical-appearing infantile hemangiomas on the skin in association with vascular lesions in the liver. Her clinical presentation was felt to be consistent with cutaneous and hepatic infantile hemangiomas. After failure to respond to systemic steroids and chemotherapy, she underwent liver transplantation. Histopathologic evaluation of the liver revealed a diagnosis of type 2 infantile hepatic hemangioendothelioma (regarded as synonymous with angiosarcoma) rather than benign infantile hemangioma of the liver. Subsequent skin biopsies confirmed that her multiple cutaneous lesions were infantile hemangiomas and not metastatic angiosarcoma. We report this case and a review of the literature on pediatric angiosarcoma of the liver associated with cutaneous infantile hemangiomas.

Female↗
PubMed2006

Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway.

In vitro studies of hepatocytes have implicated over-activation of c-Jun N-terminal kinase (JNK) signaling as a mechanism of tumor necrosis factor-alpha (TNF)-induced apoptosis. However, the functional significance of JNK activation and the role of specific JNK isoforms in TNF-induced hepatic apoptosis in vivo remain unclear. JNK1 and JNK2 function was, therefore, investigated in the TNF-dependent, galactosamine/lipopolysaccharide (GalN/LPS) model of liver injury. The toxin GalN converted LPS-induced JNK signaling from a transient to prolonged activation. Liver injury and mortality from GalN/LPS was equivalent in wild-type and jnk1-/- mice but markedly decreased in jnk2-/- mice. This effect was not secondary to down-regulation of TNF receptor 1 expression or TNF production. In the absence of jnk2, the caspase-dependent, TNF death pathway was blocked, as reflected by the failure of caspase-3 and -7 and poly(ADP-ribose) polymerase cleavage to occur. JNK2 was critical for activation of the mitochondrial death pathway, as in jnk2-/- mice Bid cleavage and mitochondrial translocation and cytochrome c release were markedly decreased. This effect was secondary to the failure of jnk2-/- mice to activate caspase-8. Liver injury and caspase activation were similarly decreased in jnk2 null mice after GalN/TNF treatment. Ablation of jnk2 did not inhibit GalN/LPS-induced c-Jun kinase activity, although activity was completely blocked in jnk1-/- mice. Toxic liver injury is, therefore, associated with JNK over-activation and mediated by JNK2 promotion of caspase-8 activation and the TNF mitochondrial death pathway through a mechanism independent of c-Jun kinase activity.

Animals↗
PubMed2006

JNK1 but not JNK2 promotes the development of steatohepatitis in mice.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and varying degrees of necroinflammation. Although chronic oxidative stress, inflammatory cytokines, and insulin resistance have been implicated in the pathogenesis of NAFLD, the mechanisms that underlie the initiation and progression of this disease remain unknown. c-Jun N-terminal kinase (JNK) is activated by oxidants and cytokines and regulates hepatocellular injury and insulin resistance, suggesting that this kinase may mediate the development of steatohepatitis. The presence and function of JNK activation were therefore examined in the murine methionine- and choline-deficient (MCD) diet model of steatohepatitis. Activation of hepatic JNK, c-Jun, and AP-1 signaling occurred in parallel with the development of steatohepatitis in MCD diet-fed mice. Investigations in jnk1 and jnk2 knockout mice demonstrated that jnk1, but not jnk2, was critical for MCD diet-induced JNK activation. JNK promoted the development of steatohepatitis as MCD diet-fed jnk1 null mice had significantly reduced levels of hepatic triglyceride accumulation, inflammation, lipid peroxidation, liver injury, and apoptosis compared with wild-type and jnk2 -/- mice. Ablation of jnk1 led to an increase in serum adiponectin but had no effect on serum levels of tumor necrosis factor-alpha. In conclusion, JNK1 is responsible for JNK activation that promotes the development of steatohepatitis in the MCD diet model. These findings also provide additional support for the critical mechanistic involvement of JNK1 overactivation in conditions associated with insulin resistance and the metabolic syndrome.

Adiponectin↗
PubMed2006

Ground-glass, polyglucosan-like hepatocellular inclusions: A "new" diagnostic entity.

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.

Adolescent↗
PubMed2006

Hepatobiliary pathology.

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.

Amyloid↗
PubMed2005

Morphology of alcoholic liver disease.

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.

Biopsy, Needle↗
PubMed2005

Hepatobiliary pathology.

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.

Biliary Tract Diseases↗
PubMed2004

Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers.

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.

Biliary Tract↗
PubMed2004

Progenitor cell expansion: an important source of hepatocyte regeneration in chronic hepatitis.

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.

Adolescent↗
PubMed2004

Histological assessment of cholestasis.

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.

Cholestasis↗
PubMed2004

Hepatobiliary pathology.

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.

Journal Article↗
PubMed2003

Mitochondrial DNA dysfunction in oncocytic hepatocytes.

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.

Adult↗
PubMed2003

Hepatobiliary pathology.

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.

Journal Article↗
PubMed2003

Hepatitis B virus reactivation after kidney transplantation and new onset lymphoma.

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.

Aged↗
PubMed2002

Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy.

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.

Bilirubin↗
PubMed2002

Diagnostic issues in liver transplantation pathology.

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.

Acute Disease↗