IVACAFTOR restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation

Ivo P van de Peppel, Marcela Doktorova, Gitte Berkers, Hugo R de Jonge, Roderick H J Houwen, Henkjan J Verkade, Johan W Jonker, Frank A J A Bodewes

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Objective: Disruption of the enterohepatic circulation of bile acids (BAs) is part of the gastrointestinal phenotype of cystic fibrosis (CF). Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, improves pulmonary function in CF patients with class III gating mutations. We studied the effect of ivacaftor on the enterohepatic circulation by assessing markers of BA homeostasis and their changes in CF patients.

Methods: In CF patients with an S1251N mutation (N = 16; age 9-35 years S125N study/NTR4873) or a G551D mutation (N = 101; age 10-24 years; GOAL study/ NCT01521338) we analyzed plasma fibroblast growth factor 19 (FGF19) and 7 alpha-hydroxy-4-cholesten-3-one (C4) levels, surrogate markers for intestinal BA absorption and hepatic synthesis, respectively, before and after treatment with ivacaftor.

Results: At baseline, median FGF19 was lower (52% and 53%, P

Conclusions: We demonstrate that patients with CFTR gating mutations display interruption of the enterohepatic circulation of BAs reflected by lower FGF19 and elevated C4 levels. Treatment with ivacaftor partially restored this disruption of BA homeostasis. The improvement did not correlate with established outcome measures of CF, suggesting involvement of modulating factors of CFTR correction in different organs. (C) 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)286-293
Number of pages8
JournalJournal of Cystic Fibrosis
Issue number2
Publication statusPublished - Mar-2019


  • Enterohepatic circulation
  • FXR
  • FGF15
  • FGF19
  • Bile acid metabolism
  • G551D mutation
  • S125N mutation
  • Ivacaftor
  • CFTR
  • FGF21

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