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Background & Aims Only a minority of heavy drinking individuals develop alcoholic hepatitis (AH), for unclear reasons. We analyzed data from the Translational Research and Evolving Alcoholic Hepatitis Treatment cohort, consisting of subjects who drink heavily with normal results from liver tests (controls) and patients with AH. We examined risk factors for the development of AH including body mass index (BMI), drinking pattern and quantity, and sex. Methods We compared data from 145 patients with AH and 124 controls based on BMI when they joined the cohort; groups were matched for sex and race. Drinking patterns were assessed using the timeline followback method, the Alcohol Use Disorders Identification Test, and the National Institute of Alcohol Abuse and Alcoholism 6-question survey. We performed univariable and multivariable analyses to assess the effects of these factors and their interaction in increasing the risk for AH. We also explored the association between PNPLA3 variants and AH. Results Cases with AH were older (47 vs 44 y; P = .03). For nearly all measures of quantity of alcohol consumed or frequency of binge drinking, controls drank more heavily than cases with AH. We did not find an association between BMI, sex, drinking patterns, and the presence of AH. Age and BMI were independent predictors for the severity of AH. When we analyzed cases and controls of European ancestry, the PNPLA3 single-nucleotide polymorphism rs738409 was associated with risk for AH (odds ratio, 1.89; P = .007). Conclusions Compared with heavy drinkers without liver disease, subjects with AH consumed lower levels of alcohol and had less binge drinking, suggesting an increased sensitivity to the toxic effects of alcohol. The risk for AH may be associated with the PNPLA3 rs738409 polymorphism.

Alcoholic hepatitis (AH) develops in a small percentage of heavy drinkers. The adaptive immune system of AH patients is hyper-activated, yet dysregulated and ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are found in liver, intestinal mucosa, and peripheral blood and contribute to protection against infectious diseases. To determine whether MAIT cells were dysregulated in heavy drinkers and the effect of alcohol abstinence on MAIT cell recovery, we compared peripheral MAIT cells between AH patients and heavy drinkers without liver disease (HDC) at baseline and 6- and 12-month followup. At baseline, AH patients had severely reduced frequency of MAIT cells than HDC and healthy donor controls (HC), whereas MAIT cell frequency was not significantly different between HDC and HC. In addition, MAIT cells in AH patients expressed higher levels of the activation markers (CD69, CD38, and HLA-DR) as well as the immune checkpoint inhibitor PD-1. Multiplex immunoassays showed that plasma levels of several cytokines related to MAIT cell activation were elevated in AH patients (IFN-s, IL-7, IL-15, IL-17, IL-18, and IL-23, and TNF-a). In AH patients, the frequency MAIT cells and CD38-expressing MAIT cells correlated with levels of several cytokines and AST. At followup, AH patients had increased MAIT cell frequency and decreased MAIT cell activation with cessation of alcohol. However, abstinent AH patients still had higher levels of CD38-expressing MAIT cells than HDC at 6-month followup. Conclusion Blood MAIT cells were severely reduced and were dysregulated in AH patients and alcohol abstinence partially reversed abnormalities in MAIT cell frequency and phenotype.

Up to 30% chronic heavy drinkers develop a spectrum of severe alcoholic liver diseases, including alcoholic hepatitis (AH). Alcohol-induced impairment of intestinal integrity and microbial translocation into the portal vein lead to immune activation and play a major role in the pathogenesis of AH. To better understand why AH develops only in some heavy drinkers and the effect of alcohol abstinence on immunity, we conducted a prospective study to compare plasma LPS levels and peripheral blood immunoprofiles between 68 AH patients and 65 heavy drinkers without liver disease (HDC) who were followed up to 12 months. Plasma samples were also obtained from 31 health donors (HD). Plasma LPS was detected in a higher portion of AH patients than HDC (80% vs 49%) at baseline, and in only 8% HD. However, LPS levels were not different between AH an HDC subjects with detectable LPS. Compared with HDC, AH patients had higher baseline plasma levels of sCD14, sCD163, sICAM-1, sVCAM-1, IL-22, TNF-α, IL-8, IP10, IL-4, IL-6, IL-9, IL-10, FGF2, IL-7, IL-15, and TGF-α, but lower levels of the anti-inflammatory chemokine MDC. AH patients also had more activated, yet dysfunctional monocytes, T cells, and B cells as they expressed higher levels of CD38 and CD69, but lower levels of HLA-DR, CD80, and CD86. In spite of having significant bacterial translocation, HDC showed little evidence of immune activation. With alcohol abstinence, levels of many dysregulated immune markers normalized in AH patients. However, TNF-α, IL-8, IL-10, sCD163, and sVCAM-1 levels remained higher. Conclusion AH patients were more susceptible to alcohol-induced bacterial translocation and immune activation. Alcohol abstinence reduced but did not fully reverse immunological abnormalities.