Good News about BAD
2019; Elsevier BV; Volume: 18; Issue: 1 Linguagem: Inglês
10.1016/j.cgh.2019.10.031
ISSN1542-7714
Autores Tópico(s)Celiac Disease Research and Management
ResumoIn this issue of Clinical Gastroenterology and Hepatology the Canadian Association of Gastroenterology (CAG) presents its official guidelines for the management of bile acid diarrhea (BAD).1Sadowski D.C. Camilleri M. Chey W.D. et al.Canadian Association of Gastroenterology clinical practice guideline on the management of bile acid diarrhea.Clin Gastroenterol Hepatol. 2020; 18: 24-41Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar The American Gastroenterological Association (AGA) recently published its clinical guidelines for the laboratory diagnosis of chronic diarrhea in Gastroenterology,2Smalley W. Falck-Ytter C. Carrasco-Labra A. et al.AGA clinical practice guidelines on the laboratory evaluation of functional diarrhea and diarrhea-predominant irritable bowel syndrome in adults (IBS-D).Gastroenterology. 2019; 157: 851-854Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar and the British Society of Gastroenterology (BSG) published its guidelines for investigation of chronic diarrhea in Gut in 2018.3Arasaradnam R.P. Brown S. Forbes A. et al.Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition.Gut. 2018; 67: 1380-1399Crossref PubMed Scopus (155) Google Scholar All 3 guidelines and the reviews that present the underlying evidence highlight the importance of bile acid malabsorption (BAM) as a potential mechanism for chronic diarrhea. The concept that bile acid entering the colon might cause secretory diarrhea goes back more than 50 years. In 1967 Alan F. Hofmann, then at the Mayo Clinic, synthesized what was known about the physiology of bile acids with several clinical reports of diarrhea occurring in patients who had evidence of BAM into the concept of "cholegenic diarrhea" or "cholerheic enteropathy."4Hofmann A.F. The syndrome of ileal disease and the broken enterohepatic circulation: cholerheic enteropathy.Gastroenterology. 1967; 52: 752-757Abstract Full Text PDF PubMed Scopus (214) Google Scholar These patients had several features in common, including ileal disease or resection, diarrhea, steatorrhea, and evidence of accelerated bile acid turnover. Bile acids were known to be cathartic, and Hofmann postulated that the excess bile acid in the colon inhibited water transport and caused diarrhea through that mechanism. Subsequent investigations proved this insight to be correct; BAM was accepted as a major cause for diarrhea in patients with ileal disease or resection.5Mottacki N. Simrén M. Bajor A. Review article: bile acid diarrhoea—pathogenesis, diagnosis and management.Aliment Pharmacol Ther. 2016; 43: 884-898Crossref PubMed Scopus (68) Google Scholar Dihydroxy bile acids, such as deoxycholic acid and chenodeoxycholic acid, induced secretion of fluid and electrolytes by the colon, but cholic acid, a trihydroxy bile acid, did not. Unconjugated bile acid seems to cause these changes by interaction with mucosal and nuclear receptors in colonocytes and may activate enteric neurons directly or indirectly, thereby stimulating colonic motility.6Hegyi P. Maléth J. Walters J.R. et al.Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease.Physiol Rev. 2018; 98: 1983-2023Crossref PubMed Scopus (131) Google Scholar Bile acid sequestrant therapy (BAST) with resins, such as cholestyramine, colestipol, and colesevelam, have been used to mitigate diarrhea due to BAM. In addition to ileal disease or resection, BAM has been demonstrated after cholecystectomy, vagotomy, and other miscellaneous conditions and may be responsible for diarrhea in some of these situations.5Mottacki N. Simrén M. Bajor A. Review article: bile acid diarrhoea—pathogenesis, diagnosis and management.Aliment Pharmacol Ther. 2016; 43: 884-898Crossref PubMed Scopus (68) Google Scholar During the last few decades investigators have studied the possibility that BAM might be the mechanism of diarrhea in patients with otherwise idiopathic chronic diarrhea or irritable bowel syndrome with diarrhea (IBS-D).5Mottacki N. Simrén M. Bajor A. Review article: bile acid diarrhoea—pathogenesis, diagnosis and management.Aliment Pharmacol Ther. 2016; 43: 884-898Crossref PubMed Scopus (68) Google Scholar, 6Hegyi P. Maléth J. Walters J.R. et al.Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease.Physiol Rev. 2018; 98: 1983-2023Crossref PubMed Scopus (131) Google Scholar, 7Wedlake L. A'Hern R. Russell D. et al.Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome.Aliment Pharmacol Ther. 2009; 30: 707-717Crossref PubMed Scopus (302) Google Scholar, 8Camilleri M. Bile acid diarrhea: prevalence, pathogenesis, and therapy.Gut Liver. 2015; 9: 332-339Crossref PubMed Scopus (137) Google Scholar, 9Valentin N. Camilleri M. Altayar O. et al.Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis.Gut. 2016; 65: 1951-1959Crossref PubMed Scopus (86) Google Scholar These studies have used quantitation of fecal bile acid excretion, the radiolabeled selenium homotaurocholic acid taurine retention test (SeHCAT), or the clinical response to a trial of BAST to identify patients who might have idiopathic BAD. Although results vary, these studies suggest that about one-third of patients with otherwise unexplained chronic diarrhea or IBS-D might have BAM, albeit less severe than patients with ileal resection or disease and infrequently associated with steatorrhea.5Mottacki N. Simrén M. Bajor A. Review article: bile acid diarrhoea—pathogenesis, diagnosis and management.Aliment Pharmacol Ther. 2016; 43: 884-898Crossref PubMed Scopus (68) Google Scholar If so, it might be valuable to identify these patients with a diagnostic test before proceeding with a therapeutic trial of BAST in patients with chronic diarrhea. An abnormal test result might confirm the mechanism of diarrhea, predict the response to a therapeutic trial of BAST, and indicate the need for use of a different agent or alternative approaches if the first trial was unsuccessful. Guidelines from all 3 gastroenterology societies (CAG, AGA, and BSG) recommend this approach for patients with chronic diarrhea.1Sadowski D.C. Camilleri M. Chey W.D. et al.Canadian Association of Gastroenterology clinical practice guideline on the management of bile acid diarrhea.Clin Gastroenterol Hepatol. 2020; 18: 24-41Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 2Smalley W. Falck-Ytter C. Carrasco-Labra A. et al.AGA clinical practice guidelines on the laboratory evaluation of functional diarrhea and diarrhea-predominant irritable bowel syndrome in adults (IBS-D).Gastroenterology. 2019; 157: 851-854Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 3Arasaradnam R.P. Brown S. Forbes A. et al.Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition.Gut. 2018; 67: 1380-1399Crossref PubMed Scopus (155) Google Scholar The ideal test for BAD would reliably identify patients who would respond to treatment with BAST, not just those who happen to have BAM that is not contributing to diarrhea. The pathophysiology of BAD depends on having a sufficiently high concentration of the right kind of bile acid in the colon.6Hegyi P. Maléth J. Walters J.R. et al.Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease.Physiol Rev. 2018; 98: 1983-2023Crossref PubMed Scopus (131) Google Scholar This in turn is determined not only by the ileal bile acid absorption rate but also factors such as transit time through the ileum (which determines the contact time of luminal fluid with the mucosa), fluid and electrolyte absorption rates in the small bowel and colon (which in part determine the concentration of bile acid in the colon), and bacterial metabolism of bile acid (which produces the various types of secondary bile acids). Because of the multiplicity of factors, it is perhaps not surprising that existing tests are not ideal in predicting which patients will respond to BAST.10Vijayvargiya P. Camilleri M. Current practice in the diagnosis of bile acid diarrhea.Gastroenterology. 2019; 156: 1233-1238Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Quantifying fecal bile acid excretion involves collecting a timed stool collection, which can be challenging, and the chemical analysis of bile acid concentration is technically demanding. Measurement of endogenous bile acid in stool is the most direct test to identify BAM, but it does not confirm that BAM is driving the diarrhea. For example, years ago our group studied a small group of patients with idiopathic secretory diarrhea; many had BAM as determined by measurement of endogenous bile acid excretion or exogenous radiolabeled bile acid excretion, but only a handful had a substantial decrease in stool weight with cholestyramine, and that reduction did not correlate with the extent of BAM.11Schiller L.R. Hogan R.B. Morawski S.G. et al.Studies of the prevalence and significance of radiolabeled bile acid malabsorption in a group of patients with idiopathic chronic diarrhea.Gastroenterology. 1987; 92: 151-160Abstract Full Text PDF PubMed Scopus (47) Google Scholar,12Schiller L.R. Bilhartz L.E. Santa Ana C.A. et al.Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea.Gastroenterology. 1990; 98: 1036-1043Abstract Full Text PDF PubMed Scopus (34) Google Scholar The test used in most published studies and in clinical practice (where available) uses radiolabeled SeHCAT.13Fani B. Bertani L. Paglianiti I. et al.Pros and cons of the SeHCAT test in bile acid diarrhea: a more appropriate use of an old nuclear medicine technique.Gastroenterol Res Pract. 2018; 2018: 2097359Crossref PubMed Scopus (23) Google Scholar This test measures whole-body retention of a bolus of selenium-labeled homotaurocholic acid over 7 days. Normal retention is >15%; retention of 10%–15% is considered to represent mild BAM, 5%–10% moderate BAM, and 0%–5% severe BAM. One systematic review of pooled SeHCAT results in studies of patients with IBS-D showed that BAM was common, and the response to cholestyramine tended to be better in studies in which patients had more substantial BAM; response rates varied from 70% in the mild BAM group to 96% in the severe BAM group.7Wedlake L. A'Hern R. Russell D. et al.Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome.Aliment Pharmacol Ther. 2009; 30: 707-717Crossref PubMed Scopus (302) Google Scholar Although these studies were relatively small and heterogeneous, a subsequent detailed systematic review suggested that a response to BAST was much more likely in those with abnormal as opposed to normal SeHCAT results.13Fani B. Bertani L. Paglianiti I. et al.Pros and cons of the SeHCAT test in bile acid diarrhea: a more appropriate use of an old nuclear medicine technique.Gastroenterol Res Pract. 2018; 2018: 2097359Crossref PubMed Scopus (23) Google Scholar Biomarkers such as fasting serum 7α-hydroxy-4-cholesten-3-one or fibroblast growth factor 19 have good specificity and negative predictive value for BAM in patients with IBS-D or functional diarrhea, but a lower sensitivity for BAM than SeHCAT testing.9Valentin N. Camilleri M. Altayar O. et al.Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis.Gut. 2016; 65: 1951-1959Crossref PubMed Scopus (86) Google Scholar,10Vijayvargiya P. Camilleri M. Current practice in the diagnosis of bile acid diarrhea.Gastroenterology. 2019; 156: 1233-1238Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar,14Riemsma R. Al M. Ramos I.C. et al.SeHCAT [taurosecholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and cost-effectiveness analysis.Health Technol Assess. 2013; 127: 1-258Google Scholar Thus, these tests are more useful for excluding BAM than for making that diagnosis or predicting the effectiveness of BAST. On the basis of these performance characteristics, the guidelines from CAG, AGA, and BSG suggest that some measurement of BAM be done in patients with chronic diarrhea before considering an empiric trial of BAST.1Sadowski D.C. Camilleri M. Chey W.D. et al.Canadian Association of Gastroenterology clinical practice guideline on the management of bile acid diarrhea.Clin Gastroenterol Hepatol. 2020; 18: 24-41Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 2Smalley W. Falck-Ytter C. Carrasco-Labra A. et al.AGA clinical practice guidelines on the laboratory evaluation of functional diarrhea and diarrhea-predominant irritable bowel syndrome in adults (IBS-D).Gastroenterology. 2019; 157: 851-854Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 3Arasaradnam R.P. Brown S. Forbes A. et al.Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition.Gut. 2018; 67: 1380-1399Crossref PubMed Scopus (155) Google Scholar Does this make sense? The argument in favor of testing is that a failed empiric trial with BAST does not exclude BAD as a diagnosis; in one uncontrolled, retrospective study 87 patients with BAM of a variety of causes (including ileal resection) who had follow-up information available were tried on cholestyramine in various doses, with a successful response in 56%.15Orekoya O. McLaughlin J. Leitao E. et al.Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy.Clin Med. 2015; 15: 252-257Crossref PubMed Scopus (43) Google Scholar Half of these unsuccessfully treated patients then were tried on colesevelam therapy, and another 15 patients responded. Another point in favor of testing for BAM is that making a diagnosis of BAM may result in fewer subsequent diagnostic evaluations than in patients with chronic diarrhea with a negative SeHCAT test.16Turner J.M. Pattni S.S. Appleby R.N. et al.A positive SeHCAT test results in fewer subsequent investigations in patients with chronic diarrhoea.Frontline Gastroenterol. 2017; 8: 279-283Crossref PubMed Scopus (27) Google Scholar (This should not be surprising; once a diagnosis is made, there is little to be gained from more testing.) The argument against testing is that there is some expense related to it, and a positive test result leads to a trial of BAST in about one-third of idiopathic diarrhea patients. According to a British cost-effectiveness study published in 2013, a SeHCAT test in the United Kingdom costs upward of £381 ($480).14Riemsma R. Al M. Ramos I.C. et al.SeHCAT [taurosecholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and cost-effectiveness analysis.Health Technol Assess. 2013; 127: 1-258Google Scholar In contrast, a 2- to 4-week trial of BAST should be sufficient to see an effect on BAD and is much less expensive (even in the United States); cholestyramine 378 g can cost $101, colestipol 500-g bottle costs $209, and 90 colesevelam 625-mg tablets cost $308 (all prices represent the average US retail price on GoodRx, accessed October 14, 2019). A pragmatic approach using an empiric trial of BAST early in the management of patients with functional diarrhea or IBS-D would undoubtedly be cheaper than testing in the short term. In fact, the conclusion of the British cost-effectiveness study was that "When trial of treatment is considered a comparator, the analysis showed for the IBS-D population that for the short term, trial of treatment is the optimal choice across a range of scenarios."14Riemsma R. Al M. Ramos I.C. et al.SeHCAT [taurosecholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and cost-effectiveness analysis.Health Technol Assess. 2013; 127: 1-258Google Scholar Of course, for US physicians this discussion is pointless in a way; SeHCAT is not approved for use by the Food and Drug Administration, and SeHCAT testing is not available in the United States. The testing landscape in the United States is changing, however; Mayo Clinic Laboratories has introduced commercially available tests for fasting serum C4 and for fecal bile acid excretion in a 48-hour stool collection. These tests may be of use in dealing with specific patients with chronic watery diarrhea, in my mind mainly those with a high likelihood of having BAD who fail to respond to or cannot tolerate an empiric trial of BAST, before abandoning that diagnosis and chasing other etiologies for chronic diarrhea. Well-designed, prospective studies are needed to see whether that concept is true. The good news about BAD is that research during the last 50 years has established that it is a real mechanism for chronic diarrhea, not just with ileal disease or resection but in patients with functional diarrhea or IBS-D. It is incumbent on physicians now to consider this diagnosis in patients with chronic diarrhea. Whether one tests and then treats or just empirically treats, we will do a great service for many of our patients with chronic diarrhea by addressing this mechanism of disease. Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid DiarrheaClinical Gastroenterology and HepatologyVol. 18Issue 1PreviewChronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. Full-Text PDF
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