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Background & AimsPrimary (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. MethodsBlood was collected from fasting patients with chronic diarrhea; BAM was diagnosed by SeHCAT. Serum FGF19 was measured by enzyme-linked immunosorbent assay. Serum 7α-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. ResultsThe 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. ConclusionsPatients 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. Abbreviations used in this paper: ASBT, apical sodium-dependent bile acid transporter, BA, bile acid, BAM, bile acid malabsorption, C4, 7α-hydroxy-4-cholesten-3-one, CYP7A1, cholesterol 7α hydroxylase, ELISA, enzyme-linked immunosorbent assay, FGFR4, fibroblast growth receptor 4, FGF15, fibroblast growth factor 15, FGF19, fibroblast growth factor 19, FXR, farnesoid X receptor, HOMA-HR, homeostasis model assessment of insulin resistance, HPLC, high performance liquid chromatography, IBABP, ileal bile acid binding protein, OST, organic solute transporter, SeHCAT, selenium homocholic acid taurine ⁎ Department of Gastroenterology, Imperial College, London, United Kingdom ‖ Department of Metabolic Medicine, Imperial College, London, United Kingdom ‡ Department of Clinical Chemistry, Western General Hospital, Edinburgh, United Kingdom § Department of Clinical Biochemistry, King's College Hospital, London, United Kingdom
Conflicts of interest The authors disclose no conflicts. Funding Parts of this study were funded by a project grant from the Wellcome Trust. The authors are grateful for support from the NIHR Biomedical Research Centre funding scheme and use of the facilities of the Sir John McMichael Centre. To view this article's video abstract, go to the AGA's YouTube Channel. PII: S1542-3565(09)00433-9 doi:10.1016/j.cgh.2009.04.024 © 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
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ABSTRACT
A New Mechanism for Bile Acid Diarrhea: Defective Feedback Inhibition of Bile Acid Biosynthesis