title: Characterizing Factors Associated With Differences in FGF19 Blood Levels and Synthesis in Patients With Primary Bile Acid Diarrhea.
abstract: OBJECTIVE
  Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD.
  
  
  METHODS
  Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR.
  
  
  RESULTS
  FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01).
  
  
  CONCLUSIONS
  These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Ian M
authors: IM
authors: Johnston
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Jonathan D
authors: JD
authors: Nolan
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Sanjeev S
authors: SS
authors: Pattni
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Richard N
authors: RN
authors: Appleby
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Justine H
authors: JH
authors: Zhang
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Sarah L
authors: SL
authors: Kennie
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Gaganjit K
authors: GK
authors: Madhan
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Sina
authors: S
authors: Jameie-Oskooei
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Shivani
authors: S
authors: Pathmasrirengam
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Jeremy
authors: J
authors: Lin
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Albert
authors: A
authors: Hong
authors: Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.|Division of Women's Health, King's College London, Guy's Hospital, London, UK.
authors: Peter H
authors: PH
authors: Dixon
authors: Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.|Division of Women's Health, King's College London, Guy's Hospital, London, UK.
authors: Catherine
authors: C
authors: Williamson
authors: Department of Gastroenterology, Imperial College Healthcare NHS Trust, and Division of Digestive Diseases, Imperial College London, London, UK.
authors: Julian R F
authors: JR
authors: Walters
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D015992:Body Mass Index; D003967:Diarrhea / Q000097:blood / Q000175:diagnosis / Q000209:etiology; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000235:genetics; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012644:Selenium Radioisotopes / Q000494:pharmacology; D013223:Statistics as Topic; D013656:Taurocholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins; D008565:Membrane Proteins; D051499:Receptor, Fibroblast Growth Factor, Type 4; D018160:Receptors, Cytoplasmic and Nuclear; D012644:Selenium Radioisotopes; D013656:Taurocholic Acid; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human; C538995:KLB protein, human; C033638:23-seleno-25-homotaurocholic acid; C496371:FGFR4 protein, human