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Immune dysfunction in acute alcoholic hepatitis.

ABSTRACT: Acute alcoholic hepatitis (AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and coagulopathy in a patient with a history of recent heavy alcohol use and is associated with profound immune dysfunction with a primed but ineffective immune response against pathogens. Here, we review the current knowledge of the pathogenesis and immune defects of AAH and identify areas requiring further study. Alcohol activates the immune system primarily through the disruption of gut tight junction integrity allowing the escape of pathogen-associated molecular particles (PAMPs) into the portal venous system. PAMPs stimulate cells expressing toll-like receptors (mainly myeloid derived cells) and initiate a network of intercellular signalling by secretion of many soluble mediators including cytokines and chemokines. The latter coordinates the infiltration of neutrophils, monocytes and T cells and results in hepatic stellate cell activation, cellular damage and hepatocyte death by necrosis or apoptosis. On the converse of this immune activation is the growing evidence of impaired microbial defence. Neutrophils have reduced phagocytic capacity and oxidative burst and there is recent evidence that T cell exhaustion plays a role in this.

SUBMITTER: Dhanda AD

PROVIDER: S-EPMC4641112 | biostudies-other | 2015 Nov

REPOSITORIES: biostudies-other

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Immune dysfunction in acute alcoholic hepatitis.

Dhanda Ashwin D AD Collins Peter L PL

World journal of gastroenterology 20151101 42

Acute alcoholic hepatitis (AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and coagulopathy in a patient with a history of recent heavy alcohol use and is associated with profound immune dysfunction with a primed but ineffective immune response against pathogens. Here, we review the current knowledge of the pathogenesis and immune defects of AAH and identify areas requiring further study. Alcohol activates th ...[more]

PMID: 26576079

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Project description:BackgroundAlcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH) and the underlying inflammatory crosstalk between adipose tissue (AT) and the liver.MethodsA cohort of 233 patients with AH from the UK and USA provided data to analyse the effects of obesity in AH. Body mass index was corrected for the severity of ascites, termed cBMI. Inflammatory and metabolic profiling was undertaken by proteome analysis of human serum samples. The effect of alcohol on adipose tissue and CXCL11 expression was studied in 3 T3-derived adipocytes and in mice using the high-fat diet-plus-binge ethanol model.FindingsObesity was common amongst patients with AH, seen in 19% of individuals. Obesity (HR 2.22, 95%CI 1.1-4.3, p = .022) and underweight (HR 2.38, 1.00-5.6, p = .049) were independently associated with mortality at 3 months. Proteome analysis demonstrated multiple metabolic and inflammatory factors differentially expressed in obese AH verse lean AH, with CXCL11 being the most elevated factor in obese AH. In vitro analysis of cultured adipocytes and in vivo analysis of mouse models showed that alcohol induced CXCL11 expression in AT, but not in liver.InterpretationObesity is common in AH and associated with a greater than two-fold increase in short-term mortality. Obese AH is associated with a different inflammatory phenotype, with the greatest elevation in CXCL11. These data confirm that adiposity is clinically important in acute alcohol-related liver disease and illustrate the adipose-liver inflammatory axis in AH. FUND: This work was supported in part by an EASL Sheila Sherlock Physician Scientist Fellowship. The funder played no role in gathering or analysing data or writing the manuscript. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Project description:Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. The immune system in patients with AH is hyperactive and yet dysfunctional. Here, we investigated whether this immune-dysregulated state is related to the alcoholic impact on immune checkpoints (ICPs). We used multiplex immunoassays and enzyme-linked immunosorbent assay to quantify plasma levels of 18 soluble ICPs (sICPs) from 81 patients with AH, 65 heavy drinkers without liver diseases (HDCs), and 39 healthy controls (HCs) at baseline, 33 patients with AH and 32 HDCs at 6-month follow-up, and 18 patients with AH and 29 HDCs at 12-month follow-up. We demonstrated that baseline levels of 6 sICPs (soluble T-cell immunoglobulin and mucin domain 3 [sTIM-3], soluble cluster of differentiation [sCD]27, sCD40, soluble Toll-like receptor-2 [sTLR-2], soluble herpesvirus entry mediator [sHVEM], and soluble lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells [sLIGHT]) were up-regulated, while 11 sICPs (soluble B- and T-lymphocyte attenuator [sBTLA], sCD160, soluble cytotoxic T-lymphocyte-associated protein 4 [sCTLA-4], soluble lymphocyte-activation gene 3 [sLAG-3], soluble programmed death 1 [sPD-1], sPD ligand 1 [sPD-L1], sCD28, soluble glucocorticoid-induced tumor necrosis factor receptor-related protein [sGITR], sGITR ligand [sGITRL], sCD80, and inducible T-cell costimulator [sICOS]) were down-regulated in patients with AH compared to HDCs. The up-regulated sICPs except sLIGHT and down-regulated sCD80, sCD160, sCTLA-4, and sLAG-3 correlated positively or negatively with AH disease severity, bacterial translocation, and inflammatory factors. At follow-up, abstinent patients with AH still had higher levels of several sICPs compared to HDCs. We also compared expression of 10 membrane-bound ICPs (mICPs) on peripheral blood mononuclear cells (PBMCs) from patients with AH and HCs by flow cytometry and found that several mICPs were dysregulated on blood cells from patients with AH. The function and regulation of sICPs and mICPs were studied using PBMCs from patients with AH and HCs. Recombinant sHVEM affected tumor necrosis factor (TNF)-α and interferon-γ production by T cells from patients with AH and HCs. Conclusion: Both sICPs and mICPs were dysregulated in patients with AH, and alcohol abstinence did not fully reverse these abnormalities. The HVEM axis plays a role in regulating T-cell function in patients with AH.

Project description:BackgroundAlcoholic hepatitis (AH) is associated with gut dysbiosis. Comparative gut microbial profiles of acute alcoholic pancreatitis (AAP) and acute biliary disease (ABD) are not demonstrated. We aimed to compare gut microbiota of AH, AAP, and ABD patients with each other and with their respective healthy controls (HCs).MethodsFrom December 2016 to September 2017, consecutive patients with AH, AAP, and ABD (acute cholecystitis, acute biliary pancreatitis, and choledocholithiasis with cholangitis) were included in the study. Qualitative and functional stool microbiota comparative analysis was performed between groups, with AH as the reference comparator.ResultsOf 3564, 882, and 224 patients with liver disease, pancreatic disease, and biliary disease, respectively, after exclusion, 29 patients with AH and 7 patients each with AAP and ABD and their corresponding HCs were included in the study analysis. The alpha diversity between patients with AH and AAP was found to be significantly different. Significant relative abundance (RA) of Acinetobacter and Moraxella was noted among patients with AAP. Enterobacter, Atopobium, Synergistia, and Devosia were significantly higher in patients with ABD compared to patients with AH, in whom Faecalibacterium and Megamonas were higher. Functional pathways associated with carbohydrate metabolism, phenylpropanoid biosynthesis, and ethylbenzene degradation were significantly higher in AAP when compared to AH. Fatty acid and inositol phosphate metabolism and dioxin degradation were significantly upregulated in patients with ABD while lipid and fatty acid biosynthetic pathways and pathways associated with immune processes were upregulated in patients with AH.ConclusionsDifferential gut dysbiosis is evident in both patients with AH, AAP, and ABD and also in comparison to HCs. The differential microbiota among patients with AH and AAP maybe important in promotion and progression of liver or pancreatic disease among alcohol users and may be a potential therapeutic target, which needs to be confirmed in larger multicenter studies.

Project description:Background and objectivesWhile animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis.MethodsThis prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival.ResultsLevels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH.ConclusionSevere AAH is characterized by a distinct metabolic phenotype spanning multiple pathways. Metabolomics profiling revealed a panel of biomarkers for disease prognosis, and future studies are planned to validate these findings in larger cohorts of patients with severe AAH.

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Immune dysfunction in acute alcoholic hepatitis.

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Immune dysfunction in acute alcoholic hepatitis.

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