Hepatitis: Zakhari S

Zakhari S, Li TK. · National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9304, USA. · Hepatology. · Pubmed #18046720 No free full text.

Abstract: More than 70% of alcohol is consumed by 10% of the population in the United States. Implicit in this statistic is that tremendous variation in the pattern of drinking (quantity, frequency, and duration) exists among alcohol consumers. Individuals who are binge or chronic drinkers will have different health outcomes than social drinkers. Therefore, knowing the pattern of drinking will shed light on how severely individuals are alcohol-dependent and on the extent of liver damage. Thus, these parameters assume particular relevance for the treatment-providing physician. Genetic factors contribute substantially to differences in alcohol metabolism. Variations in the activities of the alcohol-metabolizing enzymes, cytosolic alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase, in part determine blood alcohol concentration, thereby contributing to the predisposition to becoming alcohol-dependent and to susceptibility to alcohol-induced liver damage. Chronic alcohol consumption induces cytochrome P450 2E1, a microsomal enzyme that metabolizes alcohol at high concentrations and also metabolizes medications such as acetaminophen and protease inhibitors. Alcohol metabolism changes the redox state of the liver, which leads to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. The quantity and frequency of alcohol consumption severely impact the liver in the presence of comorbid conditions such as infection with hepatitis B or C and/or human immunodeficiency virus, type 2 diabetes, hemochromatosis, or obesity and thus have implications with respect to the extent of injury and response to medications. Conclusion: Knowledge of the relationships between the quantity, frequency, and patterns of drinking and alcoholic liver disease is limited. A better understanding of these relationships will guide hepatologists in managing alcoholic liver disease.

Neuman MG, Sha K, Esguerra R, Zakhari S, Winkler RE, Hilzenrat N, Wyse J, Cooper CL, Seth D, Gorrell MD, Haber PS, McCaughan GW, Leo MA, Lieber CS, Voiculescu M, Buzatu E, Ionescu C, Dudas J, Saile B, Ramadori G. · In Vitro Drug Safety and Biotechnology, Department of Pharmacology, Biophysics and Global Health, Institute of Drug Research, University of Toronto, Toronto, ON, Canada. · Dig Dis Sci. · Pubmed #17994278 No free full text.

Abstract: Hepatitis C viral infection (HCV) results in liver damage leading to inflammation and fibrosis of the liver and increasing rates of hepatic decompensation and hepatocellular carcinoma (HCC). However, the host's immune response and viral determinants of liver disease progression are poorly understood. This review will address the determinants of liver injury in chronic HCV infection and the risk factors leading to rapid disease progression. We aim to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. We will accomplish this task by discussion of three topics: (1) the role of cytokines in the adaptive immune response against the HCV infection; (2) the progression of fibrosis; and (3) the risk factors of co-morbidity with alcohol and human immunodeficiency virus (HIV) in HCV-infected individuals. Despite recent improvements in treating HCV infection using pegylated interferon alpha (PEGIFN-alpha) and ribavirin, about half of individuals infected with some genotypes, for example genotypes 1 and 4, will not respond to treatment or cannot be treated because of contraindications. This review will also aim to describe the importance of IFN-alpha-based therapies in HCV infection, ways of monitoring them, and associated complications.

Szabo G, Aloman C, Polyak SJ, Weinman SA, Wands J, Zakhari S. · Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. · Alcohol Clin Exp Res. · Pubmed #16573590 No free full text.

Abstract: This article presents the proceedings of a symposium presented at the meeting of the Research Society on Alcoholism, held in Santa Barbara, California, in June 2005. The organizers and chairs were Sam Zakhari and Gyongyi Szabo. The presentations included (1) Mitochondrial Abnormalities Induced by Hepatitis C -Alcohol Interaction by Steven Weinman; (2) Effects of Acute and Chronic Ethanol on Innate Antiviral Signaling Pathways, Hepatitis C Replication, and Human Liver Cell Transcription by Stephen Polyak; (3) Ethanol Alters Dendritic Cell Function In Vivo and Impairs the Subsequent Cellular Immune Responses to Hepatitis C Proteins by Costica Aloman; and (4) Pathogenic Interactions Between Hepatitis C Virus and Alcohol Use in Humans: Dendritic Cells as Common Targets by Gyongyi Szabo. This symposium summarizes the state of knowledge of cellular and molecular pathways by which alcohol and HCV have pathogenic interactions resulting in depression of the immune response and liver damage in chronic HCV infection.

Hoek J, Thiele GM, Klassen LW, Mandrekar P, Zakhari S, Cook RT, Ray NB, Happel KI, Kolls JK, Kovacs EJ, Szab G. · Department of The University of Massachusetts Medical Center (GS and PM), Department of Medicine, Worcester, MA 01605-2324, USA. · Alcohol Clin Exp Res. · Pubmed #16205374 No free full text.

Abstract: This article summarizes content proceedings of a satellite meeting held at the 2004 Research Society on Alcoholism Annual Scientific Meeting in Vancouver, Canada. The aim of the satellite conference was to facilitate the interaction of scientists investigating the mechanisms of alcohol-mediated organ or tissue damage, and enable the discussion and sharing of new ideas and concepts that may be common in each of the organs or tissues affected by chronic ethanol consumption. The original planned program on immunity was expanded to incorporate a session on a closely related topic "Alcohol and Mitochondrial Metabolism: At the Crossroads of Life and Death" organized by Dr. Jan Hoek and Dr. Sam Zakhari. The conference was arranged into four sessions: 1) Alcohol, Cellular and Organ Damage 2) Toll-like receptors and Organ Damage 3) Alcohol and Mitochondrial Metabolism: At the Crossroads of Life and Death and 4) Hepatitis virus and alcohol interactions in Immunity and Liver Disease. The keynote address was given by Dr. Bruce Beutler from the Scripps Institute on "TLRs in Inflammation and Immunity."The Combined Basic Research Satellite Symposium entitled, "Mechanisms of Alcohol-Mediated Organ and Tissue Damage: Inflammation and Immunity and Alcohol and Mitochondrial Metabolism: At the Crossroads of Life and Death" was convened at the 2004 Research Society on Alcoholism meeting in Vancouver, BC. Session One featured five speakers who discussed various aspects of the role of the immune system in initiating or exacerbating cellular and organ damage following alcohol consumption. The presentations were (1) Innate Immune responses of Alcohol-exposed mice and macrophage-like cells following infections with Listeria monocytogenes by Robert T. Cook 2) Alcohol, cytokines and host defense by Kyle Happel 3) Decreased antigen presentation and anergy induced by alcohol in myeloid dendritic cells by Pranoti Mandrekar 4) Transcriptional regulation of TNF-alpha in human monocytes by chronic ethanol: role of the cellular redox state by Jay Kolls 5) Estrogen and gender differences in inflammatory responses after alcohol and burn injury by Elizabeth Kovacs. This session highlighted the growing information on the role of pattern recognition molecules in alcohol-mediated tissue damage or dysfunction. The new techniques and ideas presented will be helpful in future studies in this area of research, and should result in some exciting avenues of study.