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

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 7α-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 <.001) and median C4 higher (350% and 364%, P <.001), respectively, for the S1251 N and G551D mutation patient groups compared to healthy controls. Treatment with ivacaftor significantly increased FGF19 and reduced C4 levels towards normalization in both cohorts but this did not correlate with CFTR function in other organs, as measured by sweat chloride levels or pulmonary function. 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.