Highlights
- •Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis.
- •Total and conjugated bile acids correlated positively with FGF19 and with disease severity (MELD score).
- •Modulation of bile acid metabolism or signaling could represent a promising target for treatment of 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. 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.
Graphical abstract
Graphical Abstract
Keywords
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References
- Spectrum of alcoholic liver disease.Clin Liver Dis. 2016; 20: 419-427
- Prednisolone or pentoxifylline for alcoholic hepatitis.N Engl J Med. 2015; 373: 282-283
- Corticosteroid therapy of alcoholic hepatitis.Gastroenterology. 1978; 75: 193-199
- A new scoring system for prognostic stratification of patients with alcoholic hepatitis.Am J Gastroenterol. 2008; 103: 2747-2756
- Management of alcoholic hepatitis.J Hepatol. 2012; 56: S39-S45
- A histologic scoring system for prognosis of patients with alcoholic hepatitis.Gastroenterology. 2014; 146 (e1231–e1236): 1231-1239
- Nuclear receptors as drug targets in cholestatic liver diseases.Clin Liver Dis. 2013; 17: 161-189
- Serum bile acids and cholestasis in alcoholic hepatitis. Relationship with usual liver tests and histological features.J Hepatol. 1994; 21: 235-240
- High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis.Hepatology. 2009; 49: 1228-1235
- Expression of hepatic Fibroblast Growth Factor 19 is enhanced in Primary Biliary Cirrhosis and correlates with severity of the disease.Sci Rep. 2015; 5: 13462
- Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis.PLoS One. 2017; 12e0178580
- Continued alcohol misuse in human cirrhosis is associated with an impaired gut-liver axis.Alcohol Clin Exp Res. 2017; 41: 1857-1865
- Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.Nat Med. 2015; 21: 159-165
R: A language and environment for statistical computing [computer program]. http://www.R-project.org/2014.
- Bile acids and dysbiosis in non-alcoholic fatty liver disease.PLoS One. 2016; 11e0151829
- Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma.Oncotarget. 2016; 7: 52329-52339
- Bile acid metabolism and signaling in cholestasis, inflammation, and cancer.Adv Pharmacol. 2015; 74: 263-302
- Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.Hepatology. 2009; 49: 297-305
- Expression of the bile salt export pump is maintained after chronic cholestasis in the rat.Gastroenterology. 2000; 118: 163-172
- Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive cholestasis in the rat.J Hepatol. 2004; 40: 585-591
- Tumor necrosis factor alpha-dependent up-regulation of Lrh-1 and Mrp3(Abcc3) reduces liver injury in obstructive cholestasis.J Biol Chem. 2003; 278: 36688-36698
- Colonic inflammation and secondary bile acids in alcoholic cirrhosis.Am J Physiol Gastrointest Liver Physiol. 2014; 306: G929-G937
- Fibroblast growth factor signaling controls liver size in mice with humanized livers.Gastroenterology. 2015; 149 (e715): 728-740
- Loss of ileum decreases serum fibroblast growth factor 19 in relation to liver inflammation and fibrosis in pediatric onset intestinal failure.J Hepatol. 2015; 62: 1391-1397
- Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.Hepatology. 2016; 63: 914-929
- Modulation of the intestinal bile acid-FXR-FGF15 axis improves alcoholic liver disease in mice.Hepatology. 2017 Nov 21; ([Epub ahead of print])
- Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice.Cell Death Dis. 2017; 8e3083
- A placebo-controlled trial of obeticholic acid in primary biliary cholangitis.N Engl J Med. 2016; 375: 631-643
- Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.Lancet. 2015; 385: 956-965
- NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.Lancet. 2018; 391: 1174-1185
Article info
Publication history
Published online: April 11, 2018
Accepted:
March 23,
2018
Received in revised form:
March 22,
2018
Received:
December 18,
2017
See Editorial, pages 275–277Footnotes
☆Guest Editor Didier Samuel.
Identification
Copyright
Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
