IVACAFTOR restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation |
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| Authors: | 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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| Affiliation: | 1. Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, Beatrix Children''s Hospital - University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands;2. Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Groningen, Beatrix Children''s Hospital - University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands;3. Department of Pediatric Pulmonology, Wilhelmina Children''s Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands;4. Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands;5. Department of Pediatric Gastroenterology, Wilhelmina Children''s Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands |
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| Abstract: | ObjectiveDisruption 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.MethodsIn 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 7α-hydroxy-4-cholesten-3-one (C4) levels, surrogate markers for intestinal BA absorption and hepatic synthesis, respectively, before and after treatment with ivacaftor. ResultsAt baseline, median FGF19 was lower (52% and 53%, P?P? ConclusionsWe 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. |
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| Keywords: | Enterohepatic circulation FXR FGF15 FGF19 Bile acid metabolism G551D mutation S125N mutation Ivacaftor BA bile acid BMI body mass index C4 α-hydroxy-4-cholesten-3-one CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator 1 forced expiratory volume in 1?s. FGF19 fibroblast growth factor 19 FGFR4 fibroblast growth factor receptor 4 FXR farnesoid X receptor GI gastrointestinal |
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