Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis

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 ...