A New Mechanism for Bile Acid Diarrhea: Defective Feedback Inhibition of Bile Acid Biosynthesis

Background & Aims: Primary (idiopathic) bile acid malabsorption (BAM) is a common chronic diarrheal syndrome which is under-recognized as diagnosis is difficult without selenium homocholic acid taurine (SeHCAT) testing. Diarrhea results from excess colonic bile acids producing secretion, but the pathogenesis is unclear. Fibroblast growth factor 19 (FGF19), produced in the ileum in response to bile acid absorption, has been shown to regulate hepatic bile acid synthesis. We hypothesized FGF19 could be involved in bile acid diarrhea and measured this in patients with BAM. Patients and Methods: Blood was collected from fasting patients with chronic diarrhea where BAM was diagnosed by SeHCAT. Serum FGF19 levels were measured by ELISAs. Serum 7α-hydroxy-4-cholesten-3-one (C4) levels were determined using HPLC, to quantify bile acid synthesis. Data were compared between patients and subjects without diarrhea (controls). Repeated samples were taken after meals from several subjects. Results: The median C4 level was significantly higher patients with primary BAM than controls (51 vs 18 ng/ml; p<0.0001); the median FGF19 level was significantly lower in patients with BAM (120 vs 231 pg/ml; p<0.0005). There was a significant inverse relationship between FGF19 and C4 levels (p<0.0004). Low levels of FGF19 were also found in patients with post-cholecystectomy 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 levels of FGF19; this finding might 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.