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The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid
Author(s) -
Walters J. R. F.,
Johnston I. M.,
Nolan J. D.,
Vassie C.,
Pruzanski M. E.,
Shapiro D. A.
Publication year - 2015
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.12999
Subject(s) - obeticholic acid , fgf19 , farnesoid x receptor , bile acid , medicine , gastroenterology , enterohepatic circulation , chenodeoxycholic acid , agonist , endocrinology , receptor , fibroblast growth factor , nuclear receptor , chemistry , biochemistry , transcription factor , gene
Summary Background Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 ( FGF 19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor ( FXR ) activation. Aim To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF 19 in patients with bile acid diarrhoea, and produce clinical benefits. Methods After a 2 week run‐in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea ( n = 10), secondary bile acid diarrhoea ( n = 10) or idiopathic chronic diarrhoea ( n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF 19, total bile acids and 7α‐ OH ‐4‐cholesten‐3‐one (C4) were measured, symptoms recorded and a diarrhoea index calculated. Results In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133–237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (−24% after 2 weeks treatment, P = 0.03), stool form (−14%, P = 0.05) and diarrhoea index (−34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL‐cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. Conclusions This proof‐of‐concept study indicates that obeticholic acid stimulates FGF 19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea . FXR agonists have therapeutic potential in chronic diarrhoea. Eudra CT 2011‐003777‐28; Clinical Trials: NCT 01585025