Gut and Liver https://doi.org/10.5009/gnl19035 Ex Vivo T Cell Cytokine Expression Predicts Survival in Patients with Severe Alcoholic Hepatitis
Author Information
Ashwin D. Dhanda1,2*, Euan Yates2, Lauren P. Schewitz-Bowers3, Philippa J. Lait3, Richard W.J. Lee3, and Matthew E. Cramp1,2
1South West Liver Unit, University Hospitals Plymouth NHS Trust, UK
2Hepatology Research Group, University of Plymouth, UK
3Translational Health Sciences, University of Bristol, Bristol, UK

Ashwin Dhanda
South West Liver Unit, Level 7, Derriford Hospital, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, UK
Tel: +44-1752-432723, Fax: +44-1752-517576, E-mail: ashwin.dhanda@plymouth.ac.uk
© The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer. All rights reserved.

Abstract
Alcoholic hepatitis (AH) is an acute inflammatory liver condition with high early mortality rate. Steroids have been demonstrated to lead to short-term survival benefits but nonresponders have the worst outcomes. There is a clinical need to identify these high-risk individuals at the time of presentation. T cells have been implicated in AH and steroid responsiveness. We aimed to measure ex vivo T cell cytokine expression as a candidate biomarker of outcomes in patients with AH. Consecutive patients with AH (patients with bilirubin levels >80 µmol/L and the ratio of aspartate aminotransferase to alanine aminotransferase >1.5 who were heavy alcohol consumers with discriminant function [DF] ≥32), were recruited from University Hospitals Plymouth NHS Trust. T cells were obtained and stimulated ex vivo before cytokine expression levels were determined by flow cytometry and protein multiplex analysis. Twenty-three patients were recruited (10 male; median age 51 years; baseline DF 67; 30% 90-day mortality). Compared to T cells from nonsurvivors at day 90, T cells from survivors had higher baseline intracellular IL-10:IL-17A ratios (0.43 vs 1.20, p=0.02). Multiplex protein analysis identified interferon γ (IFNγ) and tumor necrosis factor-α (TNF-α) as independent predictors of 90-day mortality (p=0.04, p=0.01, respectively). The ratio of IFNγ to TNF-α was predictive of 90-day mortality (1.4 vs 0.2, p=0.03). These data demonstrate the potential utility of T cell cytokine release assays performed on pretreatment blood samples as biomarkers of survival in patients with severe AH. Our key findings were that both the ratio of intracellular interleukin (IL)-10 to IL-17A and the ratio of IFNγ to TNF-α in culture supernatants were predictors of 90-day mortality. This offers the promise of developing T cell-based diagnostic tools for risk stratification.
Keywords: Alcoholic hepatitis; T cells; Cytokines; Biomarker
Abstract
Alcoholic hepatitis (AH) is an acute inflammatory liver condition with high early mortality rate. Steroids have been demonstrated to lead to short-term survival benefits but nonresponders have the worst outcomes. There is a clinical need to identify these high-risk individuals at the time of presentation. T cells have been implicated in AH and steroid responsiveness. We aimed to measure ex vivo T cell cytokine expression as a candidate biomarker of outcomes in patients with AH. Consecutive patients with AH (patients with bilirubin levels >80 µmol/L and the ratio of aspartate aminotransferase to alanine aminotransferase >1.5 who were heavy alcohol consumers with discriminant function [DF] ≥32), were recruited from University Hospitals Plymouth NHS Trust. T cells were obtained and stimulated ex vivo before cytokine expression levels were determined by flow cytometry and protein multiplex analysis. Twenty-three patients were recruited (10 male; median age 51 years; baseline DF 67; 30% 90-day mortality). Compared to T cells from nonsurvivors at day 90, T cells from survivors had higher baseline intracellular IL-10:IL-17A ratios (0.43 vs 1.20, p=0.02). Multiplex protein analysis identified interferon γ (IFNγ) and tumor necrosis factor-α (TNF-α) as independent predictors of 90-day mortality (p=0.04, p=0.01, respectively). The ratio of IFNγ to TNF-α was predictive of 90-day mortality (1.4 vs 0.2, p=0.03). These data demonstrate the potential utility of T cell cytokine release assays performed on pretreatment blood samples as biomarkers of survival in patients with severe AH. Our key findings were that both the ratio of intracellular interleukin (IL)-10 to IL-17A and the ratio of IFNγ to TNF-α in culture supernatants were predictors of 90-day mortality. This offers the promise of developing T cell-based diagnostic tools for risk stratification.
Keywords: Alcoholic hepatitis; T cells; Cytokines; Biomarker
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