title: Prolonged fibroblast growth factor 19 response in patients with primary sclerosing cholangitis after an oral chenodeoxycholic acid challenge.
abstract: BACKGROUND
  Bile salts likely contribute to liver injury in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Fibroblast growth factor 19 (FGF19) is a bile salt-induced enterokine with hepatoprotective potential as it suppresses de novo bile salt synthesis. Here, we evaluated the bile salt receptor FXR/FGF19 gut-liver axis in PSC and PBC patients.
  
  
  METHODS
  Fasted patients with PSC (n = 12) and PBC (n = 10), and healthy controls (HC; n = 10) were orally challenged with the natural FXR agonist chenodeoxycholic acid (CDCA 15 mg/kg). Blood was sampled hourly until 8 h afterwards. Serum FGF19 and bile salt excursions were determined. Serum levels of 7α-hydroxy-4-cholesten-3-one (C4), reflecting bile salt synthesis, were measured as a biomarker of FGF19 response.
  
  
  RESULTS
  Baseline serum FGF19 levels were comparable between groups, while fasted bile salt levels in PSC patients were elevated. Upon CDCA challenge, HC and PBC patients showed a serum FGF19 peak after 4 h followed by a decline. PSC patients showed a prolonged and elevated serum FGF19 response up to 8 h, combined with a sustained serum elevation of CDCA and other bile salts. In general, C4 levels declined following FGF19 elevation. In PSC patients with less favorable prognosis, baseline C4 levels were drastically suppressed and did not further decline.
  
  
  CONCLUSIONS
  Following an oral CDCA challenge, PSC patients showed an impaired clearance of CDCA and a prolonged serum FGF19 response. FXR agonist therapy in PSC could cause prolonged exposure to elevated levels of FGF19, and we propose careful monitoring for detrimental side effects in patient studies.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands.
authors.forename: Serge J
authors.initials: SJ
authors.lastname: Zweers
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: de Vries
authors.affiliation: Department of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Lenicek
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Tolenaars
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands.
authors.forename: D Rudi
authors.initials: DR
authors.lastname: de Waart
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Kiran V K
authors.initials: KV
authors.lastname: Koelfat
authors.affiliation: Departments of Pediatrics, Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Steven W M
authors.initials: SW
authors.lastname: Olde Damink
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cyriel
authors.initials: C
authors.lastname: Ponsioen
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands.|Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Peter L M
authors.initials: PL
authors.lastname: Jansen
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands. frank.schaap@maastrichtuniversity.nl.|Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD, Maastricht, The Netherlands. frank.schaap@maastrichtuniversity.nl.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Schaap
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002400:Cathartics / Q000008:administration & dosage*; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage*; D015209:Cholangitis, Sclerosing / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D002783:Cholestenones / Q000097:blood; D002985:Clinical Protocols; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged
chemical_list: D002400:Cathartics; D002783:Cholestenones; C117476:FGF19 protein, human; D002635:Chenodeoxycholic Acid; C002656:7 alpha-hydroxy-4-cholesten-3-one; D005346:Fibroblast Growth Factors
keywords: Chenodeoxycholic acid; Farnesoid X receptor; Fibroblast growth factor 19; Primary sclerosing cholangitis