Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis

Katharina Brandl, Phillipp Hartmann, Lily J. Jih, Donald P. Pizzo, Josepmaria Argemi, Meritxell Ventura-Cots, Sally Coulter, Christopher Liddle, Lei Ling, Stephen J. Rossi, Alex M. DePaoli, Rohit Loomba, Wajahat Z. Mehal, Derrick E. Fouts, Michael R. Lucey, Francisco Bosques-Padilla, Philippe Mathurin, Alexander Louvet, Guadalupe Garcia-Tsao, Elizabeth C. VernaJuan G. Abraldes, Robert S. Brown, Victor Vargas, Jose Altamirano, Juan Caballería, Debbie Shawcross, Peter Stärkel, Samuel B. Ho, Ramon Bataller, Bernd Schnabl

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72 Citations (Scopus)

Abstract

© 2018 Background & Aims: The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis. Methods: Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis. Results: We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis. Conclusion: Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans. Lay summary: Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis.
Original languageEnglish
Pages (from-to)396-405
JournalJournal of Hepatology
Volume69
Issue number2
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • Bile acids
  • FGF19
  • Microbiome

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