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Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study.

ABSTRACT: Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma-induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. CONCLUSION:AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575-590).

SUBMITTER: Li W

PROVIDER: S-EPMC5548491 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study.

Li Wei W Amet Tohti T Xing Yanyan Y Yang Dennis D Liangpunsakul Suthat S Puri Puneet P Kamath Patrick S PS Sanyal Arun J AJ Shah Vijay H VH Katz Barry P BP Radaeva Svetlana S Crabb David W DW Chalasani Naga N Yu Qigui Q

Hepatology (Baltimore, Md.) 20170630 2

Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significa ...[more]

PMID: 28466561

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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:Persons with alcoholism who are abstinent exhibit persistent impairments in the capacity for response inhibition, and this form of impulsivity is significantly associated with heightened relapse risk. Brain-imaging studies implicate aberrant prefrontal cortical function in this behavioral pathology, although the underlying mechanisms are not understood. Here we present evidence that deficient activation of glycine and serine release in the ventral medial prefrontal cortex (vmPFC) contributes to increased motor impulsivity during protracted abstinence from long-term alcohol exposure. Levels of 12 neurotransmitters were monitored in the rat vmPFC during the performance of a challenging variant of the five-choice serial reaction time task (5-CSRTT) in which alcohol-exposed rats exhibit excessive premature responding. Following long-term ethanol exposure, rats showed blunted task-related recruitment of vmPFC glycine and serine release, and the loss of an inverse relationship between levels of these neurotransmitters and premature responding normally evident in alcohol-naive subjects. Intra-vmPFC administration of the glycine transport inhibitor ALX5407 prevented excessive premature responding by alcohol-exposed rats, and this was reliant on NMDA glycine site availability. Alcohol-exposed rats and controls did not differ in their premature responding and glycine and serine levels in vmPFC during the performance of the standard 5-CSRTT. Collectively, these findings provide novel insight into cortical neurochemical mechanisms contributing to increased impulsivity following long-term alcohol exposure and highlight the NMDA receptor coagonist site as a potential therapeutic target for increased impulsivity that may contribute to relapse risk.SIGNIFICANCE STATEMENT Persons with alcoholism demonstrate increased motor impulsivity during abstinence; however, the neuronal mechanisms underlying these behavioral effects remain unknown. Here, we took advantage of an animal model that shows deficiencies in inhibitory control following prolonged alcohol exposure to investigate the neurotransmitters that are potentially responsible for dysregulated motor impulsivity following long-term alcohol exposure. We found that increased motor impulsivity is associated with reduced recruitment of glycine and serine neurotransmitters in the ventromedial prefrontal cortex (vmPFC) cortex in rats following long-term alcohol exposure. Administration of glycine transport inhibitor ALX5407 in the vmPFC alleviated deficits in impulse control.

Project description:ObjectivesAlcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery.MethodsMR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively.ResultsAt baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%).DiscussionWe showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities.

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.

Project description:OBJECTIVE:The aim of present study is to quantitatively evaluate the association between different interventions and abstinence rates based on network meta-analysis. METHOD:Following PRISMA guidelines, randomized clinical trials that compared different alcoholic interventions for alcohol use disorders associated with abstinence rates in treatment sessions or/and follow-up sessions were recruited. Main data synthesis was performed by Bayesian random-effects network meta-analyses, and the relative ranking of interventions was estimated by cumulative probability P values (SUCRA). Funnel plot symmetry was used to detect publication bias. Moreover, pair-wised comparison was also conducted to determine the statistical difference and forest plots were generated to calculate the differences between the groups. The Grades of Recommendations Assessment, Development and Evaluation (GRADE) criteria were utilized for the recommendations of evidence from pairwise direct comparisons. RESULTS:A total of 137 RCTs containing 27,282 participants and 8 variations of psychotherapy, pharmacotherapy, contingency management, and brief intervention used as treatment interventions were included. In summary, contingency management plus psychotherapy was demonstrated to be effective and possessed the best rank of achieving the highest abstinence rate in treatment sessions (SUCRA, 0.61). Pharmacotherapy plus psychotherapy also revealed its efficacy and was associated with the highest abstinence rate in follow-up sessions (SUCRA, 0.40). More importantly, psychotherapy alone was demonstrated not to be associated with higher abstinence rates in both treatment (OR, 1.052; 95% CI, 0.907-1.220) and follow-up sessions (OR, 0.967; 95% CI, 0.552-1.693), yet pharmacotherapy seemed to be the only intervention associated with higher abstinence rates compared to controls in both sessions (treatment session: OR, 1.074; 95% CI, 1.002-1.152) (follow-up session: OR, 1.442; 95% CI, 1.094-1.900). CONCLUSIONS:Contingency management plus psychotherapy and pharmacotherapy plus psychotherapy were demonstrated to be associated with the highest abstinence rates in treatment sessions and follow-up sessions, respectively. However, contingency management and pharmacotherapy seemed to be the substantial crucial factors allowing for the maintenance of the highest abstinence rates in respective sessions, although we need more evidence for further validation.

Project description:Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver-specific enzyme, inhibits oxidation of phospholipids and prevents lipid-mediated oxidative damage. However, its functional contribution in macrophage-mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku-Hospital-Pediatrics-1 (THP1)-derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up-regulated and 176 down-regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r2 > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut-off, <18 μg/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low-density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate-binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28-day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH.

Dataset Information

Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study.

Publications

Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study.

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