Mechanisms of Idiopathic Bile Acid Malabsorption and Diarrhoea

Abstract

Bile acid malabsorption or diarrhea (BAM or BAD) is a syndrome of chronic watery diarrhoea diagnosed predominantly by a SeHCAT test and less commonly by measuring levels of 7-hydroxy-4-cholesten-3-one (C4) and furthermore responds to bile acid sequestrants (BAS). Primary bile acid diarrhoea (PBAD) is the condition with no definitive cause and is under diagnosed, often being labelled as IBS-diarrhoea with an associated burden of disease for patients. Recently an alternative mechanism for PBAD involving impaired Fibroblast Growth Factor (FGF19) production has been proposed. Aims: The primary aims were to prospectively recruit patients with chronic diarrhea, and define them into groups of BAD, or chronic diarrhoea with normal SeHCAT; characterisation with SeHCAT, C4 and serum FGF19; investigation of genetic differences involved in bile acid metabolism. Methods: 152 patients recruited had routine investigations for chronic diarrhoea including SeHCAT test. Fasting serum FGF19, C4 and bile acids levels were measured from blood samples and relationships examined; FGF19 optimisation, response of BAS on PBAD patients and on FGF19 levels, effect of bowel preparation & short bowel syndrome (SBS) on FGF19 levels were measured. 11 PBAD patients were studied through the day to examine variations in FGF19. 6 SNPs in genes involved in bile acid metabolism were analysed in PBAD patients. Results: Significantly lower fasting levels of FGF19 and increased levels of C4 were seen in patients with BAD with associations with Body Mass Index. Sensitivities and specificities for FGF19 against known tests were calculated. Excellent responses to BAS with no significant effect of bowel preparation on FGF19 and variable patterns during the day were seen. Reduced FGF19 levels were seen in SBS. SNPs studied in PBAD and control patients have yet to show any significant differences in frequencies. Conclusion: This research has confirmed that levels of an easily measurable and stable hormone, FGF19 are reduced in patients with BAD and is not affected by chronic diarrhoea per se. The work provides evidence of a disordered FGF19 production in PBAD patients, failing to reduce bile acid secretion and resulting in excess bile acids entering the colon causing BAD.