title: The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.
abstract: 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 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation.
  
  
  OBJECTIVE
  To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 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 FGF19, 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 FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025.
authors.affiliation: Imperial College London & Imperial College Healthcare NHS Trust, London, UK.
authors.forename: J R F
authors.initials: JR
authors.lastname: Walters
authors.forename: I M
authors.initials: IM
authors.lastname: Johnston
authors.forename: J D
authors.initials: JD
authors.lastname: Nolan
authors.forename: C
authors.initials: C
authors.lastname: Vassie
authors.forename: M E
authors.initials: ME
authors.lastname: Pruzanski
authors.forename: D A
authors.initials: DA
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D001647:Bile Acids and Salts / Q000009:adverse effects*; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002783:Cholestenones / Q000037:antagonists & inhibitors; D003967:Diarrhea / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D006801:Humans; D007082:Ileum / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D002783:Cholestenones; D005346:Fibroblast Growth Factors; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human; C464660:obeticholic acid; C000475:cholest-4-en-3-one