Original article—alimentary tract
A New Mechanism for Bile Acid Diarrhea: Defective Feedback Inhibition of Bile Acid Biosynthesis

https://doi.org/10.1016/j.cgh.2009.04.024Get rights and content

Background & Aims

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 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.

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.

Section snippets

Subjects

Patients with chronic diarrhea were identified in gastroenterology outpatient clinics and gave informed consent. The study was approved by the local Institutional Review Board, the Hammersmith, Queen Charlotte's & Chelsea Hospital's Research Ethics Committee. All 17 patients had troublesome watery diarrhea with more than 3 stools per day for more than 3 months. Other causes of diarrhea including Crohn's disease, celiac disease, lactose intolerance, and short bowel syndrome had been excluded.

Results

The details of the patient group and the control subects are shown in Table 1. As expected, there was a highly significant difference in bowel frequency. Fasting serum C4 values were significantly higher in the patient group than in control subjects (median 51 vs 18 ng/mL; P < .0001, Mann–Whitney test) (Figure 1A).

FGF19 was detected in the serum of all the patients and control subjects, with fasting values ranging from 16–655 pg/mL. Fasting serum FGF19 values were significantly lower (P =

Discussion

This is the first study to our knowledge where serum FGF19 has been investigated in patients with bile acid malabsorption. We found reduced levels of FGF19 in patients, associated with increased C4, indicating increased bile acid synthesis. These changes were present in the patients irrespective of whether their symptoms were associated with previous bowel resection or cholecystectomy, or whether they appeared to have primary BAM.

In our patients with primary BAM, serum bile acids were higher

Acknowledgments

The authors are grateful to their colleagues for referring patients. They acknowledge the help of Dr John Meek for serum bile acid assays, and Prof K. D. Bardhan and Dr H. J. N. Andreyev for fruitful discussions.

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    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.

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