Elsevier

Journal of Hepatology

Volume 69, Issue 2, August 2018, Pages 396-405
Journal of Hepatology

Research Article
Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis

https://doi.org/10.1016/j.jhep.2018.03.031Get rights and content

Highlights

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.

Introduction

Alcohol abuse is the most important cause of liver disease worldwide.1 The most severe form of alcoholic liver disease is alcoholic hepatitis with mortality rates of 20–40% at 1–6 months, and a 90-day mortality rate of up to 75% in severe alcoholic hepatitis.[2], [3], [4] Corticosteroids are the only effective medical therapy but failure in many patients has been reported.2 There is no cure for patients not responding to medical therapy, except for early liver transplantation that is offered in some centers to a highly selected group of patients.5

Alcoholic hepatitis is a hepatocellular disease associated with cholestasis and accumulation of bile acids in the liver and the systemic circulation.6 Accumulation of bile acids in the liver can result in hepatocellular damage followed by inflammation and fibrosis.7 Early studies using high-performance liquid chromatography (HPLC) have identified elevated bile acid levels in patients with alcoholic hepatitis and a positive correlation with the alcoholic hepatitis score.8 The liver controls bile acid homeostasis via a complicated network of pathways regulated by nuclear receptors.7 One important regulator is fibroblast growth factor 19 (FGF19), a hormone that is secreted in the intestine and reaches the liver via the portal circulation. Binding of FGF19 to its receptor, fibroblast growth factor receptor 4 and β-Klotho, activates mitogen-activated protein kinase pathways, resulting in the downregulation of the rate-limiting enzyme of bile acid synthesis, cytochrome P450 family 7 subfamily A member 1 (CYP7A1), gene expression and inhibition of bile acid synthesis.9 Although FGF19 is not detectable in the liver under normal conditions, previous studies suggest that FGF19 is expressed under cholestatic conditions, such as in patients with primary biliary cholangitis. Plasma/serum elevated FGF19 levels are elevated in patients with various hepatic disorders including non-cirrhotic and cirrhotic primary biliary cholangitis and in patients with extrahepatic cholestasis.[9], [10], [11] FGF19 mRNA expression was increased in the terminal ileum of actively drinking patients with cirrhosis when compared with patients with cirrhosis of non-alcoholic etiology.12

In this study, we first determined serum bile acid levels and bile acid composition in patients with alcoholic hepatitis using mass spectrometry. We further investigated the relationship between bile acids, FGF19 and histopathological parameters and clinical outcomes in the setting of alcoholic hepatitis. The results of this study can help to understand the pathophysiology of alcoholic hepatitis as well as to evaluate the role of recombinant FGF19 preparations used in treatment.

Section snippets

Patient cohorts

A total of 132 patients with alcoholic hepatitis, nine patients with alcohol use disorder, and nine non-alcoholic control patients were enrolled from the InTeam Consortium from the 12 participating centers. Inclusion criteria were: i) age >18 years and ≤70 years, ii) active alcohol abuse (>50 g/day for men and >40 g/day for women) in the last three months, iii) aspartate aminotransferase (AST) > alanine aminotransferase (ALT) and total bilirubin >3 mg/dl in the past three months, iv) liver

Demographic and laboratory data

A total of 33 individuals were initially assessed: Nine non-alcoholic control individuals, nine patients with alcohol use disorder and 15 untreated patients with alcoholic hepatitis. Their demographic and laboratory data are shown (Table 1). Patients with alcoholic hepatitis had significantly higher levels of bilirubin, AST, albumin and INR compared with alcohol dependent and control individuals. ALT levels were significantly elevated in patients with alcoholic hepatitis relative to controls.

Discussion

This study investigated the relationship between bile acids, FGF19 and clinical outcomes in patients with alcoholic hepatitis. Patients with alcoholic hepatitis had significantly increased total, and absolute and proportional conjugated bile acid levels in relation to controls and patients with alcohol use disorder. In particular, the proportional contribution of G-/T-CDCA and G-/T-CA was significantly higher and that of G-/T-DCA was significantly lower in patients with alcoholic hepatitis than

Financial support

The manuscript was supported in part by NIH grants R01 AA020703, U01 AA021856, U01 AA24726 (to BS), by a laboratory service agreement from NGM Bio (to BS) and by Award Number I01BX002213 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to BS). RB was supported by NIH grant U01AA021908.

Conflict of interest

L.L., S.J.R. and A.M.D. are employees and stockholders of NGM Bio. B.S. reports a laboratory service agreement with NGM Bio. J.G.A. reports lecture fees from Lupin Pharma, consulting fees from Theravance, outside the submitted work.

Please refer to the accompanying ICMJE disclosure forms for further details.

Authors’ contributions

K.B. and P.H. were responsible for data analysis and interpretation of data, and writing of the manuscript; L.J.J. and D.P.P. were responsible for immunohistochemistry; J.A., M.V., and R.B. performed and analyzed RNA sequencing; S.C. and C.L. performed bile acid and C4 analysis; L.L., S.J.R. and A.M.D. measured FGF19; R.L., W.Z.M. assisted with data analysis; D.E.F. assisted with study design and manuscript editing; M.L., F.B., P.M., A.L., G.G., E.C.V., J.G.A., R.S.B., V.V., J.A., J.C., D.S.,

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    Guest Editor Didier Samuel.

    These authors contributed equally.

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