A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis.
OBJECTIVE
Primary (idiopathic) bile acid malabsorption (BAM) is a common, yet underrecognized, chronic diarrheal syndrome. Diagnosis is difficult without selenium homocholic acid taurine (SeHCAT) testing. The diarrhea results from excess colonic bile acids, but the pathogenesis is unclear. Fibroblast growth factor 19 (FGF19), produced in the ileum in response to bile acid absorption, regulates hepatic bile acid synthesis. We proposed that FGF19 is involved in bile acid diarrhea and measured its levels in patients with BAM.


METHODS
Blood was collected from fasting patients with chronic diarrhea; BAM was diagnosed by SeHCAT. Serum FGF19 was measured by enzyme-linked immunosorbent assay. Serum 7alpha-hydroxy-4-cholesten-3-one (C4) was determined using high-performance liquid chromatography, to quantify bile acid synthesis. Data were compared between patients and subjects without diarrhea (controls). Samples were taken repeatedly after meals from several subjects.


RESULTS
The median C4 level was significantly higher in patients with primary BAM than in controls (51 vs 18 ng/mL; P < .0001). The median FGF19 level was significantly lower in patients with BAM (120 vs 231 pg/mL; P < .0005). There was a significant inverse relationship between FGF19 and C4 levels (P < .0004). Low levels of FGF19 were also found in patients with postcholecystectomy and secondary bile acid diarrhea. Abnormal patterns of FGF19 levels were observed throughout the day in some patients with primary BAM.


CONCLUSIONS
Patients with BAM have reduced serum FGF19 which may be useful in diagnosis. We propose a mechanism whereby impaired FGF19 feedback inhibition causes excessive bile acid synthesis that exceeds the normal capacity for ileal reabsorption, producing bile acid diarrhea.
Walters
Julian R F
JR
Department of Gastroenterology, Imperial College, London, United Kingdom. julian.walters@imperial.ac.uk
Tasleem
Ali M
AM
Omer
Omer S
OS
Brydon
W Gordon
WG
Dew
Tracy
T
le Roux
Carel W
CW
D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000633:toxicity*; D002783:Cholestenones / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003967:Diarrhea / Q000139:chemically induced*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D025461:Feedback, Physiological; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D006801:Humans; D008286:Malabsorption Syndromes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D044967:Serum / Q000737:chemistry; D013656:Taurocholic Acid / Q000031:analogs & derivatives
D001647:Bile Acids and Salts; D002783:Cholestenones; C117476:FGF19 protein, human; C002656:7 alpha-hydroxy-4-cholesten-3-one; D013656:Taurocholic Acid; D005346:Fibroblast Growth Factors; C033638:23-seleno-25-homotaurocholic acid