The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Bernd Schnabl - One of the best experts on this subject based on the ideXlab platform.
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intestinal dysbiosis and permeability the yin and yang in alcohol dependence and Alcoholic Liver Disease
Clinical Science, 2018Co-Authors: Peter Starkel, Bernd Schnabl, Sophie Leclercq, Philippe De TimaryAbstract:Alcohol dependence and Alcoholic Liver Disease represent a major public health problem with substantial morbidity and mortality. By yet incompletely understood mechanisms, chronic alcohol abuse is associated with increased intestinal permeability and alterations of the gut microbiota composition, allowing bacterial components, bacteria, and metabolites to reach the portal and the systemic circulation. These gut-derived bacterial products are recognized by immune cells circulating in the blood or residing in remote organs such as the Liver leading to the release of pro-inflammatory cytokines which are considered important mediators of the Liver-gut-brain communication. Although circulating cytokines are likely not the sole factors involved, they can induce Liver inflammation/damage and reach the central nervous system where they favor neuroinflammation which is associated with change in mood, cognition, and drinking behavior. In this review, the authors focus on the current evidence describing the changes that occur in the intestinal microbiota with chronic alcohol consumption in conjunction with intestinal barrier breakdown and inflammatory changes sustaining the concept of a gut-Liver-brain axis in the pathophysiology of alcohol dependence and Alcoholic Liver Disease.
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dysbiosis induced intestinal inflammation activates tumor necrosis factor receptor i and mediates Alcoholic Liver Disease in mice
Hepatology, 2015Co-Authors: Peng Chen, Peter Starkel, Jerrold R Turner, Samuel B Ho, Bernd SchnablAbstract:Intestinal barrier dysfunction is an important contributor to Alcoholic Liver Disease. Translocated microbial products trigger an inflammatory response in the Liver and contribute to steatohepatitis. Our aim was to investigate mechanisms of barrier disruption following chronic alcohol feeding. A Lieber-DeCarli model was used to induce intestinal dysbiosis, increased intestinal permeability and Liver Disease in mice. Alcohol feeding for 8 weeks induced intestinal inflammation in the jejunum, which is characterized by an increased number of TNFα producing monocytes and macrophages. These findings were confirmed in duodenal biopsies from patients with chronic alcohol abuse. Intestinal decontamination with non-absorbable antibiotics restored eubiosis, decreased intestinal inflammation and permeability, and reduced Alcoholic Liver Disease in mice. TNF-receptor I (TNFRI) mutant mice were protected from intestinal barrier dysfunction and Alcoholic Liver Disease. To investigate whether TNFRI on intestinal epithelial cells mediates intestinal barrier dysfunction and Alcoholic Liver Disease, we used TNFRI mutant mice carrying a conditional gain-of-function allele for this receptor. Reactivation of TNFRI on intestinal epithelial cells resulted in increased intestinal permeability and Liver Disease that is similar to wild type mice after alcohol feeding, suggesting that enteric TNFRI promotes intestinal barrier dysfunction. Myosin light chain kinase (MLCK) is a downstream target of TNFα and was phosphorylated in intestinal epithelial cells following alcohol administration. Using MLCK deficient mice, we further demonstrate a partial contribution of MLCK to intestinal barrier dysfunction and Liver Disease following chronic alcohol feeding. In conclusion, dysbiosis-induced intestinal inflammation and TNFRI signaling on intestinal epithelial cells are mediating a disruption of the intestinal barrier. Therefore, intestinal TNFRI is a crucial mediator of Alcoholic Liver Disease.
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928 Deficiency of Intestinal Mucin-2 Protects From Alcoholic Liver Disease in Mice
Gastroenterology, 2012Co-Authors: Phillipp Hartmann, Katharina Brandl, Claus Hellerbrand, Hidekazu Tsukamoto, Bruce Beutler, Bernd SchnablAbstract:Background: The intestinal mucus layer protects the epithelium against noxious agents and pathogenic bacteria present in the gastrointestinal tract. It is composed of mucins, predominantly mucin-2 (Muc2), secreted by goblet cells of the intestine. Experimental Alcoholic Liver Disease is dependent on the translocation of bacterial products across the intestinal barrier into the systemic circulation, which induces an inflammatory response in the Liver and contributes to steatohepatitis. The aim of our study was to investigate the impact of the intestinal mucus layer and in particular Muc2 on Alcoholic Liver Disease. Methods and Results: We used the Tsukamoto-French mouse model which involves continuous intragastric feeding of isocaloric diet (n=4-5) or alcohol for 1 week in Muc2-/(n=9) and wildtype (WT) mice (n=10). Muc2 was abundantly expressed in the small and large intestine of WT mice, but undetectable in the Liver. The intestinal mucus layer was considerably thinner in Muc2 deficient mice as shown by PAS staining. Alcohol feeding did not result in a compensatory upregulation of other intestinal mucins in Muc2-/mice. After alcohol feeding mice deficient in Muc2 were protected from steatohepatitis as evidenced by significantly lower ALT levels and hepatic triglyceride concentrations. In addition, hepatic oxidative stress was significantly reduced in Muc2-/mice following intragastric alcohol feeding as shown by immunohistochemistry for 4-hydroxynonenal (4-HNE) and by TBARS assay. There was no significant difference in plasma alcohol levels or hepatic alcohol metabolizing enzymes alcohol dehydrogenase 1 (ADH1) and cytochrome p450 enzyme 2E1 (Cyp2E1) in alcohol fed Muc2-/as compared to WT mice. Most notably, Muc2-/mice had significantly lower systemic plasma LPS levels after alcohol feeding. In contrast to WT mice, Muc2-/mice did not exhibit intestinal bacterial overgrowth, but a higher amount of intestinal probiotic Lactobacillus after alcohol administration as shown by qPCR for 16S rRNA and Lactobacillus spp. The antimicrobial proteins Reg3b and Reg3g were found to be expressed at significantly higher levels in the proximal small intestine in isocaloric diet and alcohol fed Muc2-/mice relative to WT mice as assessed by qPCR and Western blotting. As Reg3b and Reg3g are bactericidal c-type lectins, an increase in their expression might contribute to the observed reduction of the bacterial burden and suppression of bacterial overgrowth in the intestine. Conclusion: Intestinal mucin-2 deficiency protects from Alcoholic steatohepatitis. We suggest a pathway that involves higher expression of enteric antimicrobial molecules which suppresses alcohol-associated intestinal bacterial overgrowth. Subsequently, lower amounts of bacterial products such as endotoxin translocate into the systemic circulation and cause less Alcoholic Liver Disease.
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bacterial translocation and changes in the intestinal microbiome associated with Alcoholic Liver Disease
World Journal of Hepatology, 2012Co-Authors: Bernd SchnablAbstract:Alcoholic Liver Disease progresses through several stages of tissue damage, from simple steatosis to Alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability and changes the bacterial microflora. Liver Disease severity correlates with levels of systemic bacterial products in patients, and experimental Alcoholic Liver Disease is dependent on gut derived bacterial products in mice. Supporting evidence for the importance of bacterial translocation comes from animal studies demonstrating that intestinal decontamination is associated with decreased Liver fibrogenesis. In addition, mice with a gene mutation or deletion encoding receptors for either bacterial products or signaling molecules downstream from these receptors, are resistant to alcohol-induced Liver Disease. Despite this strong association, the exact molecular mechanism of bacterial translocation and of how changes in the intestinal microbiome contribute to Liver Disease progression remains largely unknown. In this review we will summarize evidence for bacterial translocation and enteric microbial changes in response to Alcoholic Liver injury and chronic Alcoholic Liver Disease. We will further describe consequences of intestinal dysbiosis on host biology. We finally discuss how therapeutic interventions may modify the gastrointestinal microflora and prevent or reduce Alcoholic Liver Disease progression.
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enteric dysbiosis associated with a mouse model of Alcoholic Liver Disease
Hepatology, 2011Co-Authors: Derrick E Fouts, Peter Starkel, Johannes Brandl, Manolito Torralba, E Schott, Hide Tsukamoto, Karen E Nelson, David A Brenner, Bernd SchnablAbstract:The translocation of bacteria and bacterial products into the circulation contributes to Alcoholic Liver Disease. Intestinal bacterial overgrowth is common in patients with Alcoholic Liver Disease. The aims of our study were to investigate bacterial translocation, changes in the enteric microbiome, and its regulation by mucosal antimicrobial proteins in Alcoholic Liver Disease. We used a mouse model of continuous intragastric feeding of alcohol or an isocaloric diet. Bacterial translocation occurred prior to changes observed in the microbiome. Quantitative changes in the intestinal microflora of these animals were assessed first using conventional culture techniques in the small and large intestine. Although we found no difference after 1 day or 1 week, intestinal bacterial overgrowth was observed in the gastrointestinal tract of mice fed alcohol for 3 weeks compared with control mice fed an isocaloric liquid diet. Because <20% of all gastrointestinal bacteria can be cultured using conventional methodologies, we performed massively parallel pyrosequencing to further assess the qualitative changes in the intestinal microbiome following alcohol exposure. Sequencing of 16S ribosomal RNA genes revealed a relative abundance of Bacteroidetes and Verrucomicrobia bacteria in mice fed alcohol compared with a relative predominance of Firmicutes bacteria in control mice. With respect to the host's transcriptome, alcohol feeding was associated with down-regulation in gene and protein expression of bactericidal c-type lectins Reg3b and Reg3g in the small intestine. Treatment with prebiotics partially restored Reg3g protein levels, reduced bacterial overgrowth, and lessened Alcoholic steatohepatitis. CONCLUSION: Alcohol feeding is associated with intestinal bacterial overgrowth and enteric dysbiosis. Intestinal antimicrobial molecules are dysregulated following chronic alcohol feeding contributing to changes in the enteric microbiome and to Alcoholic steatohepatitis.
Geoffrey W Mccaughan - One of the best experts on this subject based on the ideXlab platform.
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hypothalamic pituitary testicular function in end stage non Alcoholic Liver Disease before and after Liver transplantation
Clinical Endocrinology, 1995Co-Authors: Simone I Strasser, Ann J Conway, Geoffrey W Mccaughan, David J Handelsman, J.a. McdonaldAbstract:Summary OBJECTIVE Gonadal dysfunction is common in chronic Liver Disease, but most of the previous studies have been restricted to men with alcohol-Induced Liver Disease. We have evaluated hypothalamic-pituitary-testicular function In patients with end-stage non-Alcoholic Liver Disease before and at 6 and 12 months after hepatic transplantation. DESIGN A prospective study of hypothalamic-pituitary-testicular endocrine function before and after cadaveric hepatic transplantation. PATIENTS Fifty four consecutive patients with end-stage, non-alcohollic Liver Disease were evaluated before and after Liver transplanatation. MEASUREMENTS Hypothalamic-pitultary-testicular(HPT) axis function was evalutated under basal conditions by single morning measurements of plasma total and free testosterone, sex hormone-binding globulin and by plasma LH and FSH responses to 100 μg i.v. GnRH. RESULTS Men with chronic non-Alcoholic Liver Disease had reduced levels of total and free teststerone and increased levels of SHBG compared with controls with normal Liver function. Total and free testosterone were positively correlated with basal and stimulated LH (but not FSH) concentrations. Gonadotrophin responses to GnRH were preserved but delayed compared with healthy controls consistent with a predominantly hypothalamic defect in regulation of pitultary-testicular function. Increasing severity of underlying Liver Disease was associated with declining total and free testosterone as well as peak GnRH-stimulated LH concentrations. Splronolactone treatment was associated with decreased circulating testosterone levels only in men with Liver Disease of lntermedlate severity (Child-Pugh class B). Following hepatic transplantatlon, total and free testosterone and SHBG concentrations returned progressively towards eugonadal control levels over the first 12 months but total and free testosterone levels remained subnormal. CONCLUSIONS Hypothalamic-pitultary regulation of testicular function Is Impaired in end-stage non-Alcoholic Liver Disease In proportion to the severlty of underlying Liver Disease. Splronolactone reduces circulating testosterone but only among men with Chlld-Pugh B Liver cirrhosis. Gonadal function Improves, but is not normalized, over the first year following successful Liver transplantation.
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hypothalamic pituitary adrenal function in end stage non Alcoholic Liver Disease
Journal of Gastroenterology and Hepatology, 1993Co-Authors: J.a. Mcdonald, Ann J Conway, David J Handelsman, Pamela Dilworth, Geoffrey W MccaughanAbstract:Patients with end-stage Liver Disease have significant mortality often associated with intercurrent episodes of bleeding or sepsis. Intact adrenal function is essential in such situations. In order to test the hypothesis that adrenal insufficiency might be present in severe Liver Disease, hypothalamic-pituitary adrenal function was evaluated in patients with end-stage Liver Disease awaiting transplantation. The study had a prospective, open comparative design with patients restricted to those having non-Alcoholic Liver Disease in order to avoid the confounding direct effects of alcohol on adrenocortical function. Fifty-one consecutive patients with end-stage, non-Alcoholic Liver Disease undergoing evaluation for Liver transplantation and 40 healthy controls were studied. Patients who had used corticosteroids (n= 8) or who were unable to complete the investigations (n= 5) were excluded leaving 38 patients eligible for analysis. Adrenal function was evaluated under basal conditions by single morning measurements of plasma total and free cortisol, corticosteroid-binding globulin, dehydroepiandrosterone sulfate and by adrenal stimulation indirectly using insulin-induced (0.1 U/kg, i.v.) hypoglycaemia and/or directly by adrenocorticotrophic hormone (ACTH); 250 μg tetracosactrin, i.v.) stimulation. Compared with healthy controls, patients with Liver Disease had a 64% reduction in maximal increments of plasma cortisol to indirect adrenal stimulation via insulin-induced hypoglycaemia and a 39% reduction to direct adrenal stimulation by ACTH (all P < 0.001). There was a significant negative correlation between the severity of underlying Liver Disease as assessed by Child-Pugh scores and peak control responses to ACTH (r= -0.647, P < 0.0001) and insulin-induced hypoglycaemia (r= -0.597, P < 0.0001). Patients with Liver Disease also exhibited significantly blunted and delayed hypoglycaemic responses to insulin (0.1 U/kg), brisker growth hormone responses of reduced magnitude and decreased corticosteroid-binding globulin levels. Baseline morning cortisol, free cortisol and dehydroepiandrosterone sulfate levels were unchanged compared with healthy controls. Patients on spironolactone had lower basal and peak cortisol responses to ACTH and hypoglycaemia, but the reductions were unrelated to spironolactone dose. Although insulin resistance and spironolactone therapy are confounding factors, it can be concluded that hypothalamic-pituitary regulation of adrenal function is defective in end-stage non-Alcoholic Liver Disease. It is therefore possible that functional central adrenal insufficiency might contribute to the mortality of patients with end-stage Liver Disease and raises the question of the need for controlled studies of adrenocortical replacement therapy during acute deteriorations (sepsis and haemorrhage) in severe hepatic Disease.
Fumio Nomura - One of the best experts on this subject based on the ideXlab platform.
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fractionation of gamma glutamyltransferase in patients with nonAlcoholic fatty Liver Disease and Alcoholic Liver Disease
World Journal of Hepatology, 2016Co-Authors: Shigeo Sueyoshi, Masanori Seimiya, Atsushi Fukumura, Mikihiro Tsutsumi, Kazuyuki Sogawa, Setsu Sawai, Mamoru Satoh, Fumio NomuraAbstract:Fractionation of gamma-glutamyltransferase in patients with nonAlcoholic fatty Liver Disease and Alcoholic Liver Disease
Laura E Nagy - One of the best experts on this subject based on the ideXlab platform.
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irakm mincle axis links cell death to inflammation pathophysiological implications for chronic Alcoholic Liver Disease
Hepatology, 2016Co-Authors: Hao Zhou, Junjie Zhao, Bradley N Martin, Sanjoy Roychowdhury, Megan R Mcmullen, Emily Wang, Paul L Fox, Shou Yamasaki, Laura E NagyAbstract:Lipopolysaccharide (LPS)-mediated activation of Toll-like receptors (TLRs) in hepatic macrophages and injury to hepatocytes are major contributors to the pathogenesis of Alcoholic Liver Disease. However, the mechanisms by which TLR-dependent inflammatory responses and alcohol-induced hepatocellular damage coordinately lead to Alcoholic Liver Disease are not completely understood. In this study, we found that mice deficient in interleukin-1 receptor-associated kinase M (IRAKM), a proximal TLR pathway molecule typically associated with inhibition of TLR signaling, were actually protected from chronic ethanol-induced Liver injury. In bone marrow-derived macrophages challenged with low concentrations of LPS, which reflect the relevant pathophysiological levels of LPS in both Alcoholic patients and ethanol-fed mice, the IRAKM Myddosome was preferentially formed. Further, the IRAKM Myddosome mediated the up-regulation of Mincle, a sensor for cell death. Mincle-deficient mice were also protected from ethanol-induced Liver injury. The endogenous Mincle ligand spliceosome-associated protein 130 (SAP130) is a danger signal released by damaged cells; culture of hepatocytes with ethanol increased the release of SAP130. Ex vivo studies in bone marrow-derived macrophages suggested that SAP130 and LPS synergistically activated inflammatory responses, including inflammasome activation. Conclusion: This study reveals a novel IRAKM-Mincle axis that contributes to the pathogenesis of ethanol-induced Liver injury. (Hepatology 2016;64:1978-1993).
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redox signaling and the innate immune system in Alcoholic Liver Disease
Antioxidants & Redox Signaling, 2011Co-Authors: Jessica I Cohen, Xiaocong Chen, Laura E NagyAbstract:Abstract The development of Alcoholic Liver Disease (ALD) is a complex process involving both parenchymal and nonparenchymal cells resident in the Liver. Although the mechanisms for ALD are not completely understood, it is clear that increased oxidative stress, and activation of the innate immune system are essential elements in the pathophysiology of ALD. Oxidative stress from ethanol exposure results from increased generation of reactive oxygen species and decreased hepatocellular antioxidant activity, including changes in the thioredoxin/peroxiredoxin family of proteins. Both cellular and circulating components of the innate immune system are activated by exposure to ethanol. For example, ethanol exposure enhances toll-like receptor-4 (TLR-4)-dependent cytokine expression by Kupffer cells, likely due, at least in part, to dysregulation of redox signaling. Similarly, complement activation in response to ethanol leads to increased production of the anaphylatoxins, C3a and C5a, and activation C3a receptor...
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recent insights into the role of the innate immune system in the development of Alcoholic Liver Disease
Experimental Biology and Medicine, 2003Co-Authors: Laura E NagyAbstract:The innate immune system is responsible for the rapid, initial response of the organism to potentially dangerous stresses, including pathogens, tissue injury, and malignancy. Pattern-recognition receptors of the toll-like receptor (TLR) family expressed by macrophages provide a first line of defense against microbial invasion. Activation of these receptors results in a stimulus-specific expression of genes required to control the infection, including the production of inflammatory cytokines and chemokines, followed by the recruitment of neutrophils to the site of infection. The early stages in the development of Alcoholic Liver Disease (ALD) follow a pattern characteristic of an innate immune response. Kupffer cells, the resident macrophages in the Liver, are activated in response to bacterial endotoxins (lipopolysaccharide, LPS), leading to the production of inflammatory and fibrogenic cytokines, reactive oxygen species, as well as the recruitment of neutrophils to the Liver. One mechanism by which chronic ethanol can turn the highly regulated innate immune response into a pathway of Disease is by disrupting the signal transduction cascades mediating the innate immune response. Recent studies have identified specific modules in the TLR-4 signaling cascade that are disrupted after chronic ethanol exposure, including CD14 and the mitogen-activated protein kinase family members, ERK1/2 and p38. Enhanced activation of these TLR-4 dependent signaling pathways after chronic ethanol likely contributes to the development of Alcoholic Liver Disease.
Ramon Bataller - One of the best experts on this subject based on the ideXlab platform.
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acg clinical guideline Alcoholic Liver Disease
The American Journal of Gastroenterology, 2018Co-Authors: Ashwani K Singal, Ramon Bataller, Joseph Ahn, Patrick S Kamath, Vijay H ShahAbstract:Alcoholic Liver Disease (ALD) comprises a clinical-histologic spectrum including fatty Liver, Alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced stages and data on the prevalence and profile of patients with early Disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of Liver Disease. Prolonged abstinence is the most effective strategy to prevent Disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic Liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, may be as high as 20-50% at 1 month. Corticosteroids provide short-term survival benefit in about half of treated patients with severe AH and long-term mortality is related to severity of underlying Liver Disease and is dependent on abstinence from alcohol. General measures in patients hospitalized with ALD include inpatient management of Liver Disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder. Liver transplantation, a definitive treatment option in patients with advanced Alcoholic cirrhosis, may also be considered in selected patients with AH cases, who do not respond to medical therapy. There is a clinical unmet need to develop more effective and safer therapies for patients with ALD.
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histological parameters and alcohol abstinence determine long term prognosis in patients with Alcoholic Liver Disease
Journal of Hepatology, 2017Co-Authors: Carolin Lackner, Ramon Bataller, W Spindelboeck, Johannes Haybaeck, P Douschan, Florian Rainer, Luigi Terracciano, J Haas, Andrea Berghold, Rudolf E StauberAbstract:Background & Aims Few data exist on predictors of long-term prognosis in patients with Alcoholic Liver Disease (ALD). Most studies have only assessed short-term prognosis in patients with advanced ALD. We aimed to assess the prognostic impact of clinical, biochemical and histological parameters on long-term prognosis in patients with early/compensated and decompensated ALD. Methods Consecutive patients (n=192) with biopsy-proven Liver Disease due to alcohol abuse were analyzed retrospectively. Prognostic factors were evaluated in patients with early/compensated ALD (n=60) and in patients with decompensated ALD (clinical decompensation and/or bilirubin >3mg/dl at entry) (n=132). Factors that predict long-term survival were identified using Cox regression models. Results Liver-related mortality at 5years was 13% in early/compensated and 43% in decompensated ALD. In early/compensated ALD patients, long-term prognosis was determined by fibrosis stage, but not by clinical or biochemical variables. Severe fibrosis (F3/4) was present in 52% and had a major impact on 10-year mortality (F3/4: 45% vs. F0-2: 0%, p Conclusion Fibrosis stage is the main predictor of long-term survival in patients with early/compensated ALD, while clinical, biochemical and histological parameters predict survival in patients with decompensated Disease. Promoting abstinence may improve survival in patients with both early and advanced ALD. Lay summary In this study, we evaluated long-term outcome in 192 patients with Alcoholic Liver Disease who underwent Liver biopsy: 60 patients with early Disease (no symptoms) and 132 patients with advanced Disease (jaundice, complications of cirrhosis). Importantly, half of the patients with ‘early' Disease already had severe fibrosis or cirrhosis on Liver histology and dismal outcome (45% mortality at 10years). Abstinence from alcohol improved the prognosis in both early and advanced stages of the Disease.
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trends in the management and burden of Alcoholic Liver Disease
Journal of Hepatology, 2015Co-Authors: Philippe Mathurin, Ramon BatallerAbstract:Alcoholic Liver Disease (ALD) is the most prevalent cause of advanced Liver Disease in Europe and is the leading cause of death among adults with excessive alcohol consumption. There is a dose-response relationship between the amount of alcohol consumed and the risk of ALD. The relative risk of cirrhosis increases in subjects who consume more than 25 g/day. The burden of alcohol-attributable Liver cirrhosis and Liver cancer is high and is entirely preventable. Health agencies should develop population-based policies to reduce the prevalence of harmful and/or hazardous alcohol consumption and foster research in this field to provide new diagnostic and therapeutic tools. Disease progression of patients with ALD is heavily influenced by both genetic and environmental factors. Non-invasive methods for the diagnosis of fibrosis have opened new perspectives in the early detection of advanced ALD in asymptomatic patients. Alcoholic hepatitis, the most severe form of ALD, carries a high short-term mortality (around 30-50% at 3 months). Corticosteroids improve short-term survival in patients with severe Alcoholic hepatitis but duration of therapy should be adapted to early response. Liver transplantation is the best option for patients with severe Liver dysfunction. However, alcohol relapse after transplantation remains a critical issue and drinking habits of transplanted patients need to be routinely screened.
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Alcoholic Liver Disease pathogenesis and new therapeutic targets
Gastroenterology, 2011Co-Authors: Bin Gao, Ramon BatallerAbstract:Alcoholic Liver Disease (ALD) is a major cause of chronic Liver Disease worldwide and can lead to fibrosis and cirrhosis. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism showed that Liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related. The spectrum of ALD includes simple steatosis, Alcoholic hepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Early work on the pathogenesis of the Disease focused on ethanol metabolism–associated oxidative stress and glutathione depletion, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. We review findings from recent studies that have characterized specific intracellular signaling pathways, transcriptional factors, aspects of innate immunity, chemokines, epigenetic features, microRNAs, and stem cells that are associated with ALD, improving our understanding of its pathogenesis. Despite this progress, no targeted therapies are available. The cornerstone of treatment for Alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. There is an urgent need to develop new pathophysiology-oriented therapies. Recent translational studies of human samples and animal models have identified promising therapeutic targets.