P03 Mortality from severe alcoholic hepatitis is associated with increased oxidative stress and epigenetic alterations. (20th September 2022)

• Record Type: Journal Article
• Authors: Tan, Huey; Boeira, Paula; Cramp, Matthew; Dhanda, Ashwin
• Is Part Of: Gut. Volume 71(2022)Supplement 3
• Page Start: A32
• Page End: A33
• Publication Date: 2022-09-20
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2022-BASL.54
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: Severe alcoholic hepatitis (SAH) is an orchestrated inflammatory liver condition driven by immune dysfunction that results in liver failure and death in 30% within 90 days. Improved understanding of the mechanisms of immune dysfunction may identify new targets for therapy. In other inflammatory diseases, oxidative stress alters epigenetic regulation of inflammatory genes through changes in expression of histone deacetylases (HDACs) and acetyltransferases (HATs). We aimed to determine whether oxidative stress and HDAC/HAT expression and function are associated with outcome in patients with SAH. Method: Patients with SAH (new jaundice, coagulopathy, heavy alcohol use, Discriminant Function [DF]>32) and healthy volunteers (HV) were recruited from our institution. Peripheral blood from SAH patients was obtained at baseline before treatment with corticosteroid (if clinically appropriate). Survival at day 90 from baseline was recorded. CD4+ T cells were isolated from peripheral blood by magnet-activated cell sorting. Oxidative stress was determined by flow cytometry measurement of oxidation of dichlorofluorescein diacetate to dichlorofluorescein and expressed as a percentage of maximal oxidative stress with positive control (tert-butyl alcohol). HDAC and HAT gene expression were assessed by qPCR normalised to a pool of HV RNA. Functional activity of Class 1 HDACs and HATs was measured by commercial fluorogenic assays. Results: Forty-seven SAH patients were recruited (59.6% male, mean age 53.5, mean DF 72.3, mean MELD 22.6). Percentage maximal oxidative stress in all 47 SAH patients was significantly higher in non-survivors compared to survivors at day 90 (67% vs 54.8%; p=0.045). There was no correlation between MELD or DF scores and percentage maximal oxidative stress. In 15 SAH patients, HDAC 2 and 8 gene expression was significantly lower in non-survivors, while HDAC 11 was significantly higher in the non-survivor group. Expression of HAT genes (GCN5, p300, CBP and SRC-1) was significantly higher in non-survivors compared to survivors. Class 1 HDAC activity was significantly higher in HVs (n=10) than SAH patients (n=21; 80.6% vs 44.5%; p=0.001) and in SAH survivors than non-survivors (58.2% vs 22%; p=0.001). Conclusion: These findings suggest that oxidative stress is associated with epigenetic changes of reduced HDAC expression and activity in patients with poor outcome from SAH. Targeting this pathway may improve outcomes in patients with SAH.