Alimentary Pharmacology and Therapeutics Invited Editorials 14-day bismuth quadruple therapy or 14-day concomitant therapy. The results of our study are straightforward and confirm a superiority of 14-day concomitant therapy over 14-day triple therapy in areas where increasing clarithromycin resistance have diminished the effectiveness of triple therapy.9 Similar good results have been recently reported for concomitant therapy in Southern Europe (Italy, Greece and Spain), where clarithromycin resistance ranges from 18% to 40%, and metronidazole resistance remains only modest (90– 95% success), (ii) use only regimens optimised to maximise efficacy (i.e. optimised duration, acid suppression, antibiotic doses and dosing intervals) and (iii) to closely monitor treatment effectiveness over time.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.9
Editorial: colesevelam effects on faecal bile acids in IBS with diarrhoea J. R. F. Walters & R. N. Appleby Imperial College London & Imperial College Healthcare NHS Trust, London, UK. E-mail: [email protected] doi:10.1111/apt.13109
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 article by Professor 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 696
REFERENCES 1. Vakil N. Editorial: quadruple therapy for H. pylori eradication is better than triple therapy. Aliment Pharmacol Ther 2015; 41: 694–5. 2. Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med 1992; 116: 705–8. 3. Treiber G, Ammon S, Schneider E, Klotz U. Amoxicillin/ metronidazole/omeprazole/clarithromycin: a new, short quadruple therapy for Helicobacter pylori eradication. Helicobacter 1998; 3: 54–8. 4. Okada M, Oki K, Shirotani T, et al. A new quadruple therapy for the eradication of Helicobacter pylori. Effect of pretreatment with omeprazole on the cure rate. J Gastroenterol 1998; 3: 640–5. 5. Gisbert JP, Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori. Aliment Pharmacol Ther 2011; 34: 604–17. 6. Gatta L, Vakil N, Vaira D, Scarpignato C. Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy. BMJ 2013; 347: f4587. 7. Feng L, Wen MY, Zhu YJ, Men RT, Yang L. Sequential therapy or standard triple therapy for Helicobacter pylori infection: an updated systematic review. Am J Ther 2015; Jan 7. [Epub ahead of print] PMID: 25569598. 8. Graham DY, Lee YC, Wu MS. Rational Helicobacter pylori therapy: evidence based medicine rather than medicine based evidence. Clin Gastroenterol Hepatol 2014; 12: 177–86. 9. Molina-Infante J, Lucendo AJ, Angueira T, et al. Optimized triple and concomitant therapy for Helicobacter pylori eradication: the OPTRICON study. Aliment Pharmacol Ther 2015; 41: 581–9. 10. Molina-Infante J, Gisbert JP. Optimizing clarithromycincontaining therapy for Helicobacter pylori in the era of antibiotic resistance. World J Gastroenterol 2014; 10: 10338–47.
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 authors looked at changes in faecal bile acid losses in a group of 12 patients with evidence of bile acid diarrhoea, known to have increased 48 h faecal losses or raised serum 7a-hydroxy-4-cholesten-3-one (C4), showing increased bile acid synthesis. Colesevelam (1875 mg 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 supAliment Pharmacol Ther 2015; 41: 694–697 ª 2015 John Wiley & Sons Ltd
Invited Editorials port 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 in 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. Increasing understanding 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, and so 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 Pharmaceuti-
Editorial: colesevelam effects on faecal bile acids in IBS with diarrhoea – author’s reply M. Camilleri Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN, USA. E-mail: [email protected] doi:10.1111/apt.13111
The comments provided by Julian Walters and Richard Appleby1 regarding the recent Mayo Clinic study of the effects of colesevelam on faecal bile acids in IBS with diarrhoea are very much appreciated.2 In addition to their excellent comments, I wish to clarify for the readers that the increased bile acids in stool were sequestered and only released during the methanol extraction step; therefore, the increase in bile acids reaching the colon were biologically inactive, thereby reducing their diarrhoeagenic potential, as manifested by the improvement in stool consistency. Aliment Pharmacol Ther 2015; 41: 694–697 ª 2015 John Wiley & Sons Ltd
cals, 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: 923–39. 2. Camilleri M, Acosta A, Busciglio I, et al. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2015; 41: 438–48. 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: 707–17. 4. Camilleri M, Busciglio I, Acosta A, et al. Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndromediarrhea. Am J Gastroenterol 2014; 109: 1621–30. 5. Beigel F, Teich N, Howaldt S, et al. 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: 1471–9. 6. Walters JR. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol 2014; 11: 426–34.
The observed increase in serum C4 level, a surrogate for the rate of hepatic synthesis of bile acids, may compensate for the intraluminal sequestration by colesevelam of bile acids in the small intestine, and avoid aggravating the mild steatorrhoea observed in these patients with IBS-diarrhoea.3
ACKNOWLEDGEMENT The author’s declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Walters JRF, Appleby RN. Editorial: colesevelam effects on faecal bile acids in IBS with diarrhea. Aliment Pharmacol Ther 2015; 41: 696–7. 2. Camilleri M, Acosta A, Busciglio I, et al. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2015; 41: 438–48. 3. Camilleri M, Busciglio I, Acosta A, et al. Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndromediarrhea. Am J Gastroenterol 2014; 109: 1621–30.
697
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.9
Editorial: colesevelam effects on faecal bile acids in IBS with diarrhoea J. R. F. Walters & R. N. Appleby Imperial College London & Imperial College Healthcare NHS Trust, London, UK. E-mail: [email protected] doi:10.1111/apt.13109
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 article by Professor 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 696
REFERENCES 1. Vakil N. Editorial: quadruple therapy for H. pylori eradication is better than triple therapy. Aliment Pharmacol Ther 2015; 41: 694–5. 2. Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med 1992; 116: 705–8. 3. Treiber G, Ammon S, Schneider E, Klotz U. Amoxicillin/ metronidazole/omeprazole/clarithromycin: a new, short quadruple therapy for Helicobacter pylori eradication. Helicobacter 1998; 3: 54–8. 4. Okada M, Oki K, Shirotani T, et al. A new quadruple therapy for the eradication of Helicobacter pylori. Effect of pretreatment with omeprazole on the cure rate. J Gastroenterol 1998; 3: 640–5. 5. Gisbert JP, Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori. Aliment Pharmacol Ther 2011; 34: 604–17. 6. Gatta L, Vakil N, Vaira D, Scarpignato C. Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy. BMJ 2013; 347: f4587. 7. Feng L, Wen MY, Zhu YJ, Men RT, Yang L. Sequential therapy or standard triple therapy for Helicobacter pylori infection: an updated systematic review. Am J Ther 2015; Jan 7. [Epub ahead of print] PMID: 25569598. 8. Graham DY, Lee YC, Wu MS. Rational Helicobacter pylori therapy: evidence based medicine rather than medicine based evidence. Clin Gastroenterol Hepatol 2014; 12: 177–86. 9. Molina-Infante J, Lucendo AJ, Angueira T, et al. Optimized triple and concomitant therapy for Helicobacter pylori eradication: the OPTRICON study. Aliment Pharmacol Ther 2015; 41: 581–9. 10. Molina-Infante J, Gisbert JP. Optimizing clarithromycincontaining therapy for Helicobacter pylori in the era of antibiotic resistance. World J Gastroenterol 2014; 10: 10338–47.
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 authors looked at changes in faecal bile acid losses in a group of 12 patients with evidence of bile acid diarrhoea, known to have increased 48 h faecal losses or raised serum 7a-hydroxy-4-cholesten-3-one (C4), showing increased bile acid synthesis. Colesevelam (1875 mg 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 supAliment Pharmacol Ther 2015; 41: 694–697 ª 2015 John Wiley & Sons Ltd
Invited Editorials port 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 in 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. Increasing understanding 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, and so 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 Pharmaceuti-
Editorial: colesevelam effects on faecal bile acids in IBS with diarrhoea – author’s reply M. Camilleri Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN, USA. E-mail: [email protected] doi:10.1111/apt.13111
The comments provided by Julian Walters and Richard Appleby1 regarding the recent Mayo Clinic study of the effects of colesevelam on faecal bile acids in IBS with diarrhoea are very much appreciated.2 In addition to their excellent comments, I wish to clarify for the readers that the increased bile acids in stool were sequestered and only released during the methanol extraction step; therefore, the increase in bile acids reaching the colon were biologically inactive, thereby reducing their diarrhoeagenic potential, as manifested by the improvement in stool consistency. Aliment Pharmacol Ther 2015; 41: 694–697 ª 2015 John Wiley & Sons Ltd
cals, 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: 923–39. 2. Camilleri M, Acosta A, Busciglio I, et al. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2015; 41: 438–48. 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: 707–17. 4. Camilleri M, Busciglio I, Acosta A, et al. Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndromediarrhea. Am J Gastroenterol 2014; 109: 1621–30. 5. Beigel F, Teich N, Howaldt S, et al. 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: 1471–9. 6. Walters JR. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol 2014; 11: 426–34.
The observed increase in serum C4 level, a surrogate for the rate of hepatic synthesis of bile acids, may compensate for the intraluminal sequestration by colesevelam of bile acids in the small intestine, and avoid aggravating the mild steatorrhoea observed in these patients with IBS-diarrhoea.3
ACKNOWLEDGEMENT The author’s declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Walters JRF, Appleby RN. Editorial: colesevelam effects on faecal bile acids in IBS with diarrhea. Aliment Pharmacol Ther 2015; 41: 696–7. 2. Camilleri M, Acosta A, Busciglio I, et al. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2015; 41: 438–48. 3. Camilleri M, Busciglio I, Acosta A, et al. Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndromediarrhea. Am J Gastroenterol 2014; 109: 1621–30.
697
