Non-alcoholic fatty liver disease is associated with dysregulated bile acid synthesis and diarrhea: a prospective observational study

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Title: Non-alcoholic fatty liver disease is associated with dysregulated bile acid synthesis and diarrhea: a prospective observational study
Authors: Appleby, R
Moghul, I
Khan, S
Yee, M
Manousou, P
Dew Neal, T
Walters, J
Item Type: Journal Article
Abstract: Background Non-alcoholic fatty liver disease (NAFLD) may be associated with changes in bile acid (BA) metabolism. Hepatic BA production, measured by serum levels of the precursor 7α-hydroxy-4-cholesten-3-one (C4), is regulated by the farnesoid-X-receptor (FXR)-dependent ileal hormone fibroblast growth factor 19 (FGF19). Low FGF19 and high C4 are features of chronic BA diarrhea. Obeticholic acid, an FXR agonist, stimulates FGF19 and has shown therapeutic potential in both BA diarrhea and in NAFLD. We hypothesized there are associations of FGF19, C4 and BA diarrhea with NAFLD. Methods and findings 127 patients with known NAFLD were recruited prospectively. Clinical features, including metformin use, markers of NAFLD severity and BA synthesis were analyzed. The overall incidence of chronic diarrhea was 25%, with features of BA diarrhea in 12%. FGF19 negatively correlated with C4 (rs = -0.43, p = 0.001) and with alanine aminotransferase (rs = -0.22, p = 0.03), but not with either NAFLD fibrosis or Fibroscan scores. High C4 was associated with a higher NAFLD fibrosis score (p < 0.05), and with diarrhea (p = 0.001). The median NAFLD fibrosis score was higher in those with diarrhea (p = 0.002). Metformin use, in 44% overall, was particularly associated with diarrhea (in 36% vs 17%, p = 0.02), and a lower median FGF19 (74 vs 105 pg/mL, p < 0.05). Conclusions Increased hepatic BA production and diarrhea, but not low FGF19, were associated with increased NAFLD fibrosis score, indicating dysregulation of the FXR-FGF19 axis and suggesting hepatic FGF19 resistance. Metformin use was an important factor in a subgroup, lowering FGF19, and resulting in bile acid diarrhea.
Issue Date: 25-Jan-2019
Date of Acceptance: 11-Jan-2019
ISSN: 1932-6203
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS ONE
Volume: 14
Issue: 1
Copyright Statement: © 2019 Appleby et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Intercept Pharmaceuticals Inc
Imperial College Trust
Funder's Grant Number: N/A
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MD Multidisciplinary
General Science & Technology
Publication Status: Published
Article Number: e0211348
Appears in Collections:Division of Surgery
Faculty of Medicine

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