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Reply to: “Finding fibroblast growth factor 19 during cholestasis: Does x mark the spot?

Published:October 06, 2018DOI:https://doi.org/10.1016/j.jhep.2018.09.017

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      • Finding fibroblast growth factor 19 during cholestasis: Does x mark the spot?
        Journal of HepatologyVol. 69Issue 6
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          Reducing hepatocyte bile salt levels under cholestatic conditions is crucial to avoid the deterioration of liver function through bile salt toxicity. Hepatocyte bile salt production is largely controlled by fibroblast growth factor 19 (FGF19), normally produced by ileal enterocytes in response to activation of the intestinal bile salt receptor FXR.1 Enterohepatic cycling of FGF19 prevents hepatic bile salt toxicity by downregulating hepatocyte bile salt production by CYP7A1. Although undetectable in native livers, the compensatory induction of hepatic FGF19 expression has been noted in patients with extrahepatic cholestasis.
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      • Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis
        Journal of HepatologyVol. 69Issue 2
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          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.2–4 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.
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      What is the cellular source of FGF19 during chronic liver disease?

      To the Editor:
      We thank Drs. de Haan and van Golen for discussing our recent study of bile acid metabolism and FGF19 in patients with alcohol use disorder and alcoholic hepatitis. Under physiological conditions, FGF19 is primarily expressed in intestinal epithelial cells of the terminal ileum and reaches the liver via the portal circulation to regulate bile acid synthesis in hepatocytes. Very high serum FGF19 level in patients with alcoholic hepatitis prompted us to test the hypothesis that hepatic expression contributes to elevated systemic levels. Plasma FGF19 and hepatic FGF19 mRNA levels are elevated in patients with extrahepatic cholestasis, with a decrease in systemic and hepatic FGF19 following biliary drainage.
      • 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.
      Indeed, we found a robust increase in hepatic FGF19 expression, while positive staining was confined to the cytoplasm of predominantly cholangiocytes and ductular cells from smaller ductules (likely progenitor cells) in patients with alcoholic hepatitis.
      • Brandl K.
      • Hartmann P.
      • Jih L.J.
      • Pizzo D.P.
      • Argemi J.
      • Ventura-Cots M.
      • et al.
      Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.
      Gallbladder epithelial cells from a resected gall bladder served as appropriate positive staining control,
      • Zweers S.J.
      • Booij K.A.
      • Komuta M.
      • Roskams T.
      • Gouma D.J.
      • Jansen P.L.
      • et al.
      The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract.
      while non-neoplastic liver with portal tracts was negative for FGF19 protein,
      • Zweers S.J.
      • Booij K.A.
      • Komuta M.
      • Roskams T.
      • Gouma D.J.
      • Jansen P.L.
      • et al.
      The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract.
      • 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.
      although large caliber bile ducts showed weak positive staining for FGF19.
      • Zweers S.J.
      • Booij K.A.
      • Komuta M.
      • Roskams T.
      • Gouma D.J.
      • Jansen P.L.
      • et al.
      The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract.
      Our expression pattern is consistent with high FGF19 expression in non-parenchymal cells from human liver with biliary cirrhosis.
      • 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.
      The latter study used flow cytometry sorting to separate hepatocytes from bile duct cells. A pure biliary ductal cell population expressed considerably higher amounts of FGF19 than hepatocytes.
      • 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.
      Patients with primary biliary cholangitis (PBC) also have increased serum FGF19, hepatic FGF19 gene and protein expression.
      • 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.
      In contrast to the expression pattern in alcoholic hepatitis and biliary cirrhosis, FGF19 co-localized with FGFR4 suggesting a predominant expression in hepatocytes.
      • 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.
      Co-localization with other non-parenchymal liver cell markers was not performed.
      Different disease etiologies might account for different cellular expression patterns. PBC is a cholangiocyte disease causing intrahepatic cholestasis, while alcoholic hepatitis is a hepatocellular disease associated with cholestasis and accumulation of bile acids in the liver. The severity of cholestasis is different between PBC (e.g. mean bilirubin 1.81 mg/dl5) and alcoholic hepatitis (e.g. mean bilirubin 15.5 mg/dl2), which might contribute to differences in FXR activity. Bile acid – FXR signaling induces FGF19 in cultured human hepatocytes.
      • 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.
      Alcoholic hepatitis is often accompanied by a profound hepatic and systemic inflammatory response, which is not seen in PBC. Finally, alcoholic hepatitis is characterized by a strong ductular reaction. Hepatic progenitor cells fail to differentiate into hepatocytes contributing to impaired hepatocyte regeneration, but instead differentiate into biliary cells.
      • Dubuquoy L.
      • Louvet A.
      • Lassailly G.
      • Truant S.
      • Boleslawski E.
      • Artru F.
      • et al.
      Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis.
      Failed differentiation might induce FGF19 in progenitor cells during alcoholic hepatitis.
      As elaborated by Drs. de Haan and van Golen, although induction of hepatic FGF19 likely increases serum FGF19 in patients with alcoholic hepatitis, other sites, such as the terminal ileum as the primary source for FGF19, might contribute to this systemic increase as well. Increased ileal FGF19 mRNA expression was observed in actively drinking patients with cirrhosis when compared with patients with cirrhosis of non-alcoholic etiology.
      • 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.
      • 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.
      Further analysis is required, although the severity of the disease often prohibits routine colonoscopies in patients with alcoholic hepatitis.
      One of the questions that needs to be addressed is whether very high serum FGF19 may eventually lead to resistance in downstream signaling. This will be important to determine, in particular if FGF19 (analogs) are being considered as a therapeutic option in patients with alcoholic hepatitis.

      Conflict of interest

      B.S. reports a laboratory service agreement with NGM Bio. All other authors report no conflicts of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      B.S. wrote, and K.B., P.H., L.J.J., and D.P.P. edited the manuscript.

      Supplementary data

      References

      Author names in bold designate shared co-first authorship

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