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Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis

Research output: Contribution to journalArticlepeer-review

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. Verna & 10 more Juan G. Abraldes, Robert S. Brown Jr, Victor Vargas, Jose Altamirano, Juan Caballería, Debbie Shawcross, Peter Stärkel, Samuel B. Ho, Ramon Bataller, Bernd Schnabl

Original languageEnglish
Pages (from-to)396-405
JournalJournal of Hepatology
Volume69
Issue number2
Early online date11 Apr 2018
DOIs
Accepted/In press23 Mar 2018
E-pub ahead of print11 Apr 2018
Published1 Aug 2018

Documents

  • Dysregulation of serum bile_BRANDL_Accepted23March2018_GREEN AAM (CC BY-NC-ND)

    Dysregulation_of_serum_bile_BRANDL_Accepted23March2018_GREEN_AAM_CC_BY_NC_ND_.pdf, 7.83 MB, application/pdf

    Uploaded date:13 Apr 2018

    Version:Accepted author manuscript

    Licence:CC BY-NC-ND

    © <2018> This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode

King's Authors

Abstract

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. The mechanisms and biomarkers linked to cholestasis are largely unknown.

METHODS: Here, 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 acids 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 alcoholic hepatitis patients. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (MELD). FGF19 correlated best with conjugated cholic acid (CA), and MELD best with taurine-conjugated chenodeoxycholic acid (T-CDCA). Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma-glutamyl-transferase (GGT), and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte (PMN) infiltration in all alcoholic hepatitis patients.

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 underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Here we describe a molecule that is increased in patients with alcoholic hepatitis and modulating this pathway might lead to promising targets for the treatment of alcoholic hepatitis.

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