Invited Editorial
Editorial: Colesevelam effectson faecal bile acids in IBS-diarrhoea.
Julian R.F. Walters & Richard N. Appleby
Imperial College London & Imperial College Healthcare NHS Trust, London, U.K.
Email:
Tel: +44-203-313-2361
Correspondence:
Professor Julian Walters
Department of Gastroenterology
Hammersmith Hospital,
Du Cane Road,
London W12 0HS, U.K.
Colesevelam is a bile acid sequestrant which, as a tablet, may be better tolerated and more efficacious than the established sequestrants, colestyramine and colestipol.1 The recent paper by Michael Camilleri and colleagues from the Mayo Clinic2 has added to our knowledge of the effects of this drug and how it can be beneficial in patients with diarrhoea-predominant irritable bowel syndrome (IBS-D) and bile acid diarrhoea.
It is increasingly being recognised that a sizeable proportion of patients with chronic functional diarrhoea diagnosed as IBS-D in fact have bile acid diarrhoea. A systemic review of studies of these patients who had SeHCAT tests found that about 30% had moderate or large increases in faecal bile acid loss, and these patients had responses to bile acid sequestrants which increased with the severity of the bile acid loss.3 The Mayo group have previously demonstrated the increase in faecal bile acid losses in their group of IBS-D patients.4
In the present study,the authorslooked at changes in faecal bile acid losses in a group of 12 patients with evidence of bile acid diarrhoea, known to haveincreased 48h faecal losses or raised serum 7α-hydroxy-4-cholesten-3-one (C4), showing increased bile acid synthesis. Colesevelam(1875mg twice daily) bound all faecal bile acids avidly, doubling faecal bile acid excretion and producing a further increase in new bile acid synthesis, as measured by C4. Importantly stool consistency improved significantly but there was no increase in faecal fat loss. Random stool samples were judged to provide inferior information compared with 48h collections.
This study has clarified the mechanism of action of colesevelam and provided important information to support its use in these patients. Furthermore, a recent randomised, double-blind, placebo-controlled study of colesevelam in patients with bile acid malabsorption after ileal resection for Crohn’s disease has shown significant improvements, with a reduction of the number of liquid stools and an improvement in stool consistency.5
Patients with a diagnosis of bile acid diarrhoea will be greatly benefitted from further well-designed studies with currently unlicensed drugs including colesevelam and other candidates. Increasingunderstanding of bile acid kinetics recognises the regulation of their synthesis by the farnesoid X receptor (FXR) - fibroblast growth factor 19 (FGF19) axis.6 In a condition that is characterised by increased faecal bile acid losses and hepatic overproduction, an alternative approach to increase FGF19 and decrease bile acid synthesis may eventually be shown to have value in many patients.1 However, colesevelam is currently available and is effective, andso should form an important part of the therapeutic armamentarium for bile acid malabsorption and diarrhoea.
ACKNOWLEDGEMENTS
Declaration of personal interests: Julian Walters has served as a speaker, advisory board member or consultant for Albireo, GE Healthcare,Intercept Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Pendopharm and Sanofi.
Declaration of funding interests: Richard Appleby has been supported by research funding from Albireo and Intercept Pharmaceuticals.
REFERENCES
1. Wilcox C, Turner J, Green J. Systematic review: the management of chronic diarrhoea due to bile acid malabsorption. Aliment Pharmacol Ther 2014; 39: 923-939.
2. Camilleri M and others. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2015.
3. Wedlake L, A'Hern R, Thomas K, Walters JRF, Andreyev HJN. Systematic review: the prevalence of idiopathic bile acid malabsorption (I-BAM) as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome (IBS). Aliment Pharmacol Ther 2009; 30: 707-717.
4. Camilleri M, Busciglio I, Acosta A, Shin A, Carlson P, Burton D, Ryks M, Rhoten D, Lamsam J, Lueke A, Donato LJ, Zinsmeister AR. Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndrome-diarrhea. Am J Gastroenterol 2014; 109: 1621-1630.
5. Beigel F, Teich N, Howaldt S, Lammert F, Maul J, Breiteneicher S, Rust C, Goke B, Brand S, Ochsenkuhn T. Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: A randomized, double-blind, placebo-controlled study. J Crohns Colitis 2014; 8: 1471-1479.
6. Walters JR. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol 2014; 11: 426-434.