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Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis

Published:April 11, 2018DOI:https://doi.org/10.1016/j.jhep.2018.03.031

      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

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      References

        • Chacko K.R.
        • Reinus J.
        Spectrum of alcoholic liver disease.
        Clin Liver Dis. 2016; 20: 419-427
        • Thursz M.R.
        • Forrest E.H.
        • Ryder S.
        • STOPAH investigators
        Prednisolone or pentoxifylline for alcoholic hepatitis.
        N Engl J Med. 2015; 373: 282-283
        • Maddrey W.C.
        • Boitnott J.K.
        • Bedine M.S.
        • Weber Jr., F.L.
        • Mezey E.
        • White Jr., R.I.
        Corticosteroid therapy of alcoholic hepatitis.
        Gastroenterology. 1978; 75: 193-199
        • Dominguez M.
        • Rincon D.
        • Abraldes J.G.
        • Miquel R.
        • Colmenero J.
        • Bellot P.
        • et al.
        A new scoring system for prognostic stratification of patients with alcoholic hepatitis.
        Am J Gastroenterol. 2008; 103: 2747-2756
        • Mathurin P.
        • Lucey M.R.
        Management of alcoholic hepatitis.
        J Hepatol. 2012; 56: S39-S45
        • Altamirano J.
        • Miquel R.
        • Katoonizadeh A.
        • Abraldes J.G.
        • Duarte-Rojo A.
        • Louvet A.
        • et al.
        A histologic scoring system for prognosis of patients with alcoholic hepatitis.
        Gastroenterology. 2014; 146 (e1231–e1236): 1231-1239
        • Halilbasic E.
        • Baghdasaryan A.
        • Trauner M.
        Nuclear receptors as drug targets in cholestatic liver diseases.
        Clin Liver Dis. 2013; 17: 161-189
        • Trinchet J.C.
        • Gerhardt M.F.
        • Balkau B.
        • Munz C.
        • Poupon R.E.
        Serum bile acids and cholestasis in alcoholic hepatitis. Relationship with usual liver tests and histological features.
        J Hepatol. 1994; 21: 235-240
        • Schaap F.G.
        • van der Gaag N.A.
        • Gouma D.J.
        • Jansen P.L.
        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
        • Wunsch E.
        • Milkiewicz M.
        • Wasik U.
        • Trottier J.
        • Kempinska-Podhorodecka A.
        • Elias E.
        • et al.
        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
        • Li Z.
        • Lin B.
        • Lin G.
        • Wu Y.
        • Jie Y.
        • Li X.
        • et al.
        Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis.
        PLoS One. 2017; 12e0178580
        • Bajaj J.S.
        • Kakiyama G.
        • Zhao D.
        • Takei H.
        • Fagan A.
        • Hylemon P.
        • et al.
        Continued alcohol misuse in human cirrhosis is associated with an impaired gut-liver axis.
        Alcohol Clin Exp Res. 2017; 41: 1857-1865
        • Fang S.
        • Suh J.M.
        • Reilly S.M.
        • Yu E.
        • Osborn O.
        • Lackey D.
        • et al.
        Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.
        Nat Med. 2015; 21: 159-165
      1. R: A language and environment for statistical computing [computer program]. http://www.R-project.org/2014.

        • Mouzaki M.
        • Wang A.Y.
        • Bandsma R.
        • Comelli E.M.
        • Arendt B.M.
        • Zhang L.
        • et al.
        Bile acids and dysbiosis in non-alcoholic fatty liver disease.
        PLoS One. 2016; 11e0151829
        • Li Y.
        • Zhang W.
        • Doughtie A.
        • Cui G.
        • Li X.
        • Pandit H.
        • et al.
        Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma.
        Oncotarget. 2016; 7: 52329-52339
        • Li T.
        • Apte U.
        Bile acid metabolism and signaling in cholestasis, inflammation, and cancer.
        Adv Pharmacol. 2015; 74: 263-302
        • Song K.H.
        • Li T.
        • Owsley E.
        • Strom S.
        • Chiang J.Y.
        Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.
        Hepatology. 2009; 49: 297-305
        • Lee J.M.
        • Trauner M.
        • Soroka C.J.
        • Stieger B.
        • Meier P.J.
        • Boyer J.L.
        Expression of the bile salt export pump is maintained after chronic cholestasis in the rat.
        Gastroenterology. 2000; 118: 163-172
        • Denk G.U.
        • Soroka C.J.
        • Takeyama Y.
        • Chen W.S.
        • Schuetz J.D.
        • Boyer J.L.
        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
        • Bohan A.
        • Chen W.S.
        • Denson L.A.
        • Held M.A.
        • Boyer J.L.
        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
        • Kakiyama G.
        • Hylemon P.B.
        • Zhou H.
        • Pandak W.M.
        • Heuman D.M.
        • Kang D.J.
        • et al.
        Colonic inflammation and secondary bile acids in alcoholic cirrhosis.
        Am J Physiol Gastrointest Liver Physiol. 2014; 306: G929-G937
        • Naugler W.E.
        • Tarlow B.D.
        • Fedorov L.M.
        • Taylor M.
        • Pelz C.
        • Li B.
        • et al.
        Fibroblast growth factor signaling controls liver size in mice with humanized livers.
        Gastroenterology. 2015; 149 (e715): 728-740
        • Mutanen A.
        • Lohi J.
        • Heikkila P.
        • Jalanko H.
        • Pakarinen M.P.
        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
        • Zhou M.
        • Learned R.M.
        • Rossi S.J.
        • DePaoli A.M.
        • Tian H.
        • Ling L.
        Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.
        Hepatology. 2016; 63: 914-929
        • Hartmann P.
        • Hochrath K.
        • Horvath A.
        • Chen P.
        • Seebauer C.T.
        • Llorente C.
        • et al.
        Modulation of the intestinal bile acid-FXR-FGF15 axis improves alcoholic liver disease in mice.
        Hepatology. 2017 Nov 21; ([Epub ahead of print])
        • Alvarez-Sola G.
        • Uriarte I.
        • Latasa M.U.
        • Jimenez M.
        • Barcena-Varela M.
        • Santamaria E.
        • et al.
        Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice.
        Cell Death Dis. 2017; 8e3083
        • Nevens F.
        • Andreone P.
        • Mazzella G.
        • Strasser S.I.
        • Bowlus C.
        • Invernizzi P.
        • et al.
        A placebo-controlled trial of obeticholic acid in primary biliary cholangitis.
        N Engl J Med. 2016; 375: 631-643
        • Neuschwander-Tetri B.A.
        • Loomba R.
        • Sanyal A.J.
        • Lavine J.E.
        • Van Natta M.L.
        • Abdelmalek M.F.
        • et al.
        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
        • Harrison S.A.
        • Rinella M.E.
        • Abdelmalek M.F.
        • Trotter J.F.
        • Paredes A.H.
        • Arnold H.L.
        • et al.
        NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
        Lancet. 2018; 391: 1174-1185