Development and validation of a novel 7α-hydroxy-4-cholesten-3-one (C4) liquid chromatography tandem mass spectrometry method and its utility to assess pre-analytical stability.

OBJECTIVES: 7α-Hydroxy-4-cholesten-3-one (C4) is the common intermediary of both primary bile acids. C4 is recommended by the British Society of Gastroenterology for the investigation of bile acid diarrhoea (BAD) in patients with chronic diarrhoea. This project aimed to develop and validate an assay to quantitate C4 in serum and assess the stability of C4 in unseparated blood. METHODS: Accuracy was underpinned by calibrating to quantitative nuclear magnetic resonance analysis. C4 was analysed in a 96-well plate format with a deuterated C4 internal standard and liquid-liquid extraction. Validation followed the 2018 Food and Drug Administration guidelines. To assess C4 stability, healthy volunteers (n=12) donated 8 fasted samples each. Samples were incubated at 20 °C for up to 72 h and retrieved, centrifuged, aliquoted and frozen for storage at different time points prior to C4 analysis. RESULTS: The C4 method demonstrated excellent analytical performance and passed all validation criteria. The method was found to be accurate, precise, free from matrix effects and interference. After 72 h of delayed sample separation, C4 concentration gradually declined by up to 14 % from baseline. However, the change was not significant for up to 12 h. CONCLUSIONS: We present a robust method of analysing serum C4, offering a convenient alternative to 75SeHCAT for BAD investigation. C4 was found to decline in unseparated blood over time; however, after 12 h the mean change was <5 % from baseline. Our results suggest C4 is suitable for collection from both primary and secondary care prior to gastroenterology referral.

Differences in Fecal Microbiomes and Metabolomes of People With vs Without Irritable Bowel Syndrome and Bile Acid Malabsorption.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a heterogeneous disorder, but diagnoses and determination of subtypes are made based on symptoms. We profiled the fecal microbiomes of patients with and without IBS to identify biomarkers of this disorder. METHODS: We collected fecal and urine samples from 80 patients with IBS (Rome IV criteria; 16-70 years old) and 65 matched individuals without IBS (control individuals), along with anthropometric, medical, and dietary information. Shotgun and 16S ribosomal RNA amplicon sequencing were performed on feces, whereas urine and fecal metabolites were analyzed by gas chromatography and liquid chromatography-mass spectrometry. Co-occurrence networks were generated based on significant Spearman correlations between data. Bile acid malabsorption (BAM) was identified in patients with diarrhea by retention of radiolabeled selenium-75 homocholic acid taurine. RESULTS: Patients with IBS had significant differences in network connections between diet and fecal microbiomes compared with control individuals; these were accompanied by differences in fecal metabolomes. We did not find significant differences in fecal microbiota composition among patients with different IBS symptom subtypes. Fecal metabolome profiles could discriminate patients with IBS from control individuals. Urine metabolomes also differed significantly between patients with IBS and control individuals, but most discriminatory metabolites were related to diet or medications. Fecal metabolomes, but not microbiomes, could distinguish patients with IBS with vs those without BAM. CONCLUSIONS: Despite the heterogeneity of IBS, patients have significant differences in urine and fecal metabolomes and fecal microbiome vs control individuals, independent of symptom-based subtypes of IBS. Fecal metabolome analysis can be used to distinguish patients with IBS with vs those without BAM. These findings might be used for developing microbe-based treatments for these disorders.

Prevalence of biliary acid malabsorption in patients with chronic diarrhoea of functional characteristics: a prospective study.

BACKGROUND: Bile acid malabsorption occurs in up to one third of patients with chronic diarrhoea of functional characteristics. The gold standard test for its diagnosis is the 75Selenium homocholic acid taurine (75SeHCAT) test. The aim of this work is to confirm previous data suggesting that bile acid malabsorption, diagnosed by 75Se-HCAT test, is the underlying cause of diarrhoea in a significant proportion of patients previously diagnosed with a functional disorder. In addition, we have analysed the clinical response of bile acid sequestrants in those patients with a bile acid diarrhoea diagnosis. METHODS: This is a prospective, single-centre study including consecutive adult patients diagnosed with chronic diarrhoea of unknown origin and with functional characteristics; systematic rule out of common causes of chronic diarrhoea was performed before bile acid malabsorption evaluation by 75SeHCAT scanning. A retention percentage less than 10% was considered positive. Clinical response to cholestyramine was further evaluated in those patients with a positive diagnosis of bile acid diarrhoea RESULTS: 38 patients (20 male, mean age 37.5 years) were finally included. Twenty (52.6%) patients included had a positive 75SeHCAT test. Median body mass index was significantly higher in those patients. We did not find significant differences in other clinical or biochemical variables 75SeHCAT-positive and 75SeHCAT-negative groups. Only 6 of 17 (35.3%) patients responded to cholestyramine treatment; 10 patients did not have response or withdraw the drug due to adverse events. Logistic regression analysis showed that none of the included variables was a predictor of clinical response to cholestyramine. CONCLUSIONS: Bile acid malabsorption occurs in a high proportion of patients suffering from chronic diarrhoea with functional characteristics. Systematic investigation of bile acid malabsorption should be included in the diagnostic algorithms of patients with chronic watery diarrhoea in the routine clinical practice. Absence of response to cholestyramine does not rule out bile acid diarrhoea.

Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea.

BACKGROUND & AIMS: Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. METHODS: We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator, and outcome questions were developed through an iterative process and were voted on by a group of specialists. RESULTS: The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy, or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea, and Crohn's disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn's disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review, and reinvestigation for patients whose symptoms persist despite BAST. CONCLUSIONS: Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.

Incidence and predictive factors for positive 75SeHCAT test: improving the diagnosis of bile acid diarrhoea.

AIMS: To determine the value of 75SeHCAT retention in determining bile acid diarrhoea (BAD), treatment response and predictors of a positive result. METHODS: Retrospective casenote review of consecutive patients undergoing 75SeHCAT from 2008 to 2014, including gender, age, history, clinical, and laboratory parameters. This included diseases associated with Type 1 BAD (ileal resection, Crohn's disease) and Type 3 BAD. Chi-squared test and logistic regression determined factors predictive of BAD. Subjective response to treatment with bile acid sequestrants (BAS) was analysed with respect to the 75SeHCAT result. RESULTS: Of 387 patients, 154 (39.7%) were male and average age was 50 years. Ninety-five patients (24.5%) were investigated for Type 1 BAD, 86 (22.2%) for Type 3, and 206 patients (53.2%) for Type 2 or idiopathic BAD. There was a large increase in the number performed with time but no difference in percentage positive tests. One hundred and seventy-nine patients (46.2%) had BAD. Positive result was commonest in possible Type 1 and they had most severe BAD. Ninety-nine patients had severe BAD (<5% 75SeHCAT retention), 47 moderate BAD (5% to <10% retention), and 33 mild BAD (10% to <15% retention). Predictors of a positive 75SeHCAT were right hemicolectomy (OR 4.88), cholecystectomy (OR 2.44), and Crohn's (OR 1.86). A positive 75SeHCAT predicted a good or partial response to BAS of 66.7% (mild), 78.6% (moderate), or 75.9% (severe BAD). CONCLUSION: 75SeHCAT test use increased in 2008-2014, with high positive results throughout. Ileal resection, Crohn's, and cholecystectomy independently predict BAD. 75SeHCAT predicted response to BAS.

Are bile acid malabsorption and bile acid diarrhoea important causes of loose stool complicating cancer therapy?

AIM: Gastrointestinal (GI) symptoms during and after cancer therapy can significantly affect quality of life and interfere with treatment. This study assessed whether bile acid malabsorption (BAM) or bile acid diarrhoea (BAD) are important causes of diarrhoea associated with cancer treatment. METHOD: A retrospective analysis was carried out of consecutive patients assessed for BAM using ((75) Se) Selenium homocholic acid taurocholate (SeHCAT) scanning, after reporting any episodes of loose stool, attending a gastroenterology clinic in a cancer centre. RESULTS: Between 2009 and 2013, 506 consecutive patients (54.5% male; age range: 20-91 years), were scanned. BAM/BAD was diagnosed in 215 (42.5%). It was mild in 25.6%, moderate in 29.3% and severe in 45.1%. Pelvic chemoradiation had induced BAM in > 50% of patients. BAM was also frequent after treatment for conditions not previously associated with BAM, such as anal and colorectal cancer, and was present in > 75% of patients referred after pancreatic surgery. It was also unexpectedly frequent in patients who were treated for malignancy outside the GI tract, such as breast cancer and haematological malignancy. CONCLUSION: BAM/BAD are very common and under-appreciated causes of GI symptoms after cancer treatment. Health professionals should have a low threshold in suspecting this condition, as diagnosis and treatment can significantly improve quality of life.

Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy.

Although recognised as a cause of chronic diarrhoea for over forty years, diagnostic tests and treatments for bile acid malabsorption (BAM) remain controversial. Recent National Institute for Health and Care Excellence (NICE) guidelines highlighted the lack of evidence in the field, and called for further research. This retrospective study explores the BAM subtype and severity, the use and response to bile acid sequestrants (BAS) and the prevalence of abnormal colonic histology. 264 selenium-75-labelled homocholic acid conjugated taurine (SeHCAT)-tested patient records were reviewed and the severity and subtype of BAM, presence of colonic histopathology and response to BAS were recorded. 53% of patients tested had BAM, with type-2 BAM in 45% of patients with presumed irritable bowel syndrome. Colonic histological abnormalities were similar overall between patients with (29%) or without (23%) BAM (p = 0.46) and between BAM subtypes, with no significant presence of inflammatory changes. 63% of patients with BAM had a successful BAS response which showed a trend to decreased response with reduced severity. Colestyramine was unsuccessful in 44% (38/87) and 45% of these (17/38) were related to medication intolerance, despite a positive SeHCAT. 47% (7/15) of colestyramine failures had a successful colesevelam response. No patient reported colesevelam intolerance. Quantifying severity of BAM appears to be useful in predicting BAS response. Colesevelam was better tolerated than colestyramine and showed some efficacy in colestyramine failures. Colestyramine failure should not be used to exclude BAM. Colonic histology is of no relevance.

Comparison between SeHCAT test and clinical response to cholestyramine in patients with chronic diarrhea and high suspicion of bile acid malabsorption: A single-center prospective study.

OBJECTIVES: We aimed to evaluate the clinical response to cholestyramine in patients with functional chronic diarrhea and a high clinical suspicion of bile-acid diarrhea (BAD) investigated with 75-selenium homocholic acid taurine (SeHCAT) test. METHODS: Adult patients attending our outpatient clinic between January and December 2021 for chronic diarrhea with suspicion of BAD were proposed SeHCAT testing and a therapeutic trial of cholestyramine 4-8 g daily. Clinical response to cholestyramine was evaluated at 1, 3, 6, and 12 months. Clinical and demographic data were analyzed according to SeHCAT test results. RESULTS: Among the 50 patients with chronic diarrhea and clinical suspicion of BAD, 13 (26.0%) refused either SeHCAT testing or cholestyramine therapy. Finally, 37 patients (31 females, age 44 ± 14 years) agreed to undergo SeHCAT and were started on cholestyramine (median follow-up 14 months [interquartile range 6-16 months]). Initial response to cholestyramine was similar in patients with positive and negative SeHCAT test results, but improved over time in those with a positive test result. Long-term response (100% vs 65.2%, P = 0.02) and necessity of maintenance therapy for symptom control were more common in those with positive SeHCAT test result (71.4% vs 26.1%, P = 0.02). However, response to cholestyramine was also frequent in patients with a negative test result. CONCLUSIONS: The SeHCAT test accurately identifies patients with BAD who benefit from long-term cholestyramine treatment. Nevertheless, cholestyramine may be also effective in patients with chronic diarrhea but negative SeHCAT test result.

[Bile Acid Diarrhea].

Diarrhea is a very common gastrointestinal symptom, and the presence of higher concentrations of bile acid in the colon leads to bile acid diarrhea (BAD). In BAD patients, a portion of bile from the small intestine that is normally controlled by enterohepatic circulation is present at a high concentration in the lumen of the large intestine, resulting in increased motility and secretion of the large intestine. The prevalence of BAD is estimated to be 1-2% of the general population, and it comprises one-third of the instances of diarrhea-predominant irritable bowel syndrome. The clinical symptoms of BAD include chronic diarrhea, increased frequency of defecation, urgency to defecate, fecal incontinence, and cramping abdominal pain. The pathophysiology of BAD has not yet been fully elucidated. However, recent studies have reported increased intestinal permeability, shortened intestinal transit time, and changes in the intestinal microbial community to be the possible causes of BAD. Although fecal and serum bile acid tests are widely used for diagnosis, new test methods that are non-invasive, inexpensive, and have high sensitivity and specificity are needed at various institutions to facilitate the diagnosis. The selenium homo-tauro-cholic acid (SeHCAT) test is the gold standard for BAD diagnosis and severity assessment. The validation of several other serum markers, such as 7-hydroxy-4-cholesten-3-one (serum 7αC4) and the fibroblast growth factor 19 (FGF19) for use in clinical practice is ongoing. Although bile acid sequestrants are the mainstay of treatment, the development of drugs that are more effective and have better compliance is required. Farnesoid X receptor (FXR) agonists are showing promising results.

Managing bile acid diarrhea: aspects of contention.

INTRODUCTION: Bile acid diarrhea is a common cause of bowel symptoms and often goes unrecognized or misdiagnosed. Many aspects of management remain contentious. AREAS COVERED: The primary, idiopathic condition should be suspected in people with functional diarrhea or diarrhea-predominant irritable bowel syndrome. Secondary causes include ileal resection, inflammation, and post-cholecystectomy. Diagnostic tests vary globally, being unavailable in many countries, and further refinement of testing strategy is needed. Management is usually long-term symptom control, rather than reversal of the causative factors, which are still being defined. Bile acid sequestrants remain the main drugs used. They are relatively inexpensive, and better-quality data is now available for colesevelam. However, optimal use, including timing and formulation, needs clarification. The GLP-1 receptor agonist, liraglutide, is also effective, although mechanisms of action and whether this effect is common to other class members is unclear. They are more expensive, and availability varies. FXR agonists can also be effective but require further validation. The role of dietary factors in symptom development is a major patient concern, needing more formal studies. EXPERT OPINION: To build on recent findings, bile acid diarrhea needs further investment into causes, diagnosis and therapy to guide present and future patient care.

The condition known as bile acid diarrhea (BAD) causes frequent loose stools, which need to be passed urgently, sometimes causing incontinence. It can be a complication of surgery or other intestinal disorders, and gives similar symptoms to IBS. It is not widely known and clinicians often fail to diagnose it. In this article, we review recent publications about how to make the diagnosis of BAD. Some of these are contentious and there may be limited availability of the tests or poor accuracy. We then review current treatments and how to best manage BAD. There are some new treatments, which are not yet fully proven or accepted for general use. We review these and express opinions regarding the current best practices in diagnosis and treatment, and how these may change in the next 5 years.

Methods for diagnosis of bile acid malabsorption in clinical practice.

Altered concentrations of bile acid (BA) in the colon can cause diarrhea or constipation. More than 25% of patients with irritable bowel syndrome with diarrhea or chronic diarrhea in Western countries have BA malabsorption (BAM). As BAM is increasingly recognized, proper diagnostic methods are needed to help direct the most effective course of treatment for the chronic bowel dysfunction. We review the methodologies, advantages, and disadvantages of tools that directly measure BAM: the (14)C-glycocholate breath and stool test, the (75)selenium homotaurocholic acid test (SeHCAT), and measurements of 7 α-hydroxy-4-cholesten-3-one (C4) and fecal BAs. The (14)C-glycocholate test is laborious and no longer widely used. The (75)SeHCAT has been validated but is not available in the United States. Measurement of serum C4 is a simple and accurate method that can be used for most patients but requires further clinical validation. Assays to quantify fecal BA (total and individual levels) are technically cumbersome and not widely available. Regrettably, none of these tests are routinely available in the United States; assessment of the therapeutic effects of a BA binder is used as a surrogate for diagnosis of BAM. Recent data indicate the advantages to studying fecal excretion of individual BAs and their role in BAM; these could support the use of the fecal BA assay, compared with other tests. Measurement of fecal BA levels could become a routine addition to the measurement of fecal fat in patients with unexplained diarrhea. Availability ultimately determines whether the C4, SeHCAT, or fecal BA test is used; more widespread availability of such tests would enhance clinical management of these patients.

Recent developments in diagnosing bile acid diarrhea.

INTRODUCTION: Bile acid diarrhea (BAD) commonly causes chronic diarrhea. Symptoms may be mistaken for disorders of gut brain interaction. Due to the lack of widely available diagnostic tests and poor recognition of BAD, there is a delay in diagnosis leading to increased healthcare system burden and decreased patient quality of life. AREAS COVERED: A thorough review of the literature was conducted using PubMed for articles on the biological functions of bile acids, pathophysiology and management of BAD, but focusing on diagnostic testing including 75SeHCAT retention, 7αC4, FGF-19, fecal bile acids, and single stool tests. This narrative review discusses available modalities focusing on noninvasive stool and serum testing that are more widely available and show good sensitivity and specificity for diagnosis of BAD. 75SeHCAT retention is not available in many countries. Alternative diagnostic tests include total and primary fecal bile acid (BA) excretion in 48-hour collection or a single stool sample, serum7αC4 >46 or 52.5 ng/mL, and combination of single stool and serum 7αC4 ±watery stools (Bristol Stool Form Scale 6-7). EXPERT OPINION: Given the ease of serum and single stool sample acquisition and diagnostic advances, clinical practice should embrace positive diagnosis, rather than BAS therapeutic trial. BAD needs to be considered in diverse gastrointestinal diseases.

Bile Acid Diarrhea in Adults and Adolescents.

BACKGROUND: Bile acids are central to enterohepatic signaling pathways activated through natural receptors, farnesoid X receptor [FXR mediates synthesis of fibroblast growth factor-19 (FGF-19)], and G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Although bile acid diarrhea (BAD) is more commonly encountered in ileal resection or disease, there is evidence documenting "idiopathic" BAD in about 20% of adolescents and 30% of adults presenting with chronic, non-bloody diarrhea often attributed to irritable bowel syndrome. Mechanism(s) leading to increased hepatic synthesis and colonic bile acid levels in "idiopathic" BAD include reduced synthesis of FGF-19 by the ileal mucosa, or genetic variation in hepatocyte proteins klotho ß and FGF receptor 4 (FGFR4) that mediate negative feedback of bile acid synthesis. PURPOSE: The objective of this review is to summarize the diagnosis of BAD in adults and adolescents. In addition to 75 SeHCAT retention for diagnosis of BAD, studies have validated fasting serum 7αC4 and FGF-19, respectively, by-product and inhibitor of hepatic bile acid synthesis, as well as fecal bile acid measurements. These assays are widely available through reference laboratories, and they are being simplified (eg, measurement of primary fecal bile acids in a random stool sample). BAD has also been identified as a co-factor contributing to persistent diarrhea in other diseases in remission including inflammatory bowel disease, microscopic colitis, celiac disease, and neuroendocrine tumors. In summary, advances in diagnosis of BAD provide opportunities for generalists and pediatric and adult gastroenterologists to provide targeted treatment for BAD presenting as chronic non-bloody diarrhea.

Variation of enterohepatic circulation through the image with 75SeHCAT in the first 3 hours. Scintigraphic patterns and análisis of its association with the diagnosis of bile acid malabsorption. / Variación de la circulación enterohepática a través de la imagen con 75SeHCAT en las 3 primeras horas. Patrones gammagráficos y análisis de su asociación con el diagnóstico de malabsorción de ácidos biliares.

OBJETIVE: To evaluate the enterohepatic circulation of 75-Selenium turoselecolic acid (75Se-SeHCAT) during the first 3 hours and its correlation with the abdominal retention at the 7th day (AR7), as contribution to the clinical study of biliar acid malabsorption (BAM). MATERIALS AND METHODS: 38 patients with chronic diarrhea were retrospectively studied. Acquisition protocol included static abdominal images at 1st, 2nd and 3rd hour and the 7th day after oral administration of the radiopharmaceutical. Images of 1 to 3 hours determined 5 patterns of enterohepatic circulation that, due to their location, were characterized as: 1) gallbladder 2-3 hours, 2) gallbladder 3 hours, 3) gallbladder-abdomen 2-3 hours, 4) abdomen, 5) upper left abdomen. The association of these patterns with the AR7 (Fisher, STATA) were investigated. Patients were classified as Non BAM (AR7>15%), mild-BAM (AR7: 15-10%), moderate-BAM (AR7: 10-5%) or severe-BAM (AR7<5%). RESULTS: 19 patients had an AR7 diagnostic of BAM (7 mild-BAM, 5 moderate-BAM, 7 severe-BAM). The pattern "gallbladder at 2-3 hours" was statistically associated with Non BAM (p 0,008), while "gallbladder-abdomen at 2-3 hours" was correlated with having BAM (p 0,029). CONCLUSION: Variations detected at the abdominal level in images during the first 3 hours were associated with changes in intestinal absorption and the incorporation of the radiopharmaceutical into the pool of bile acids, so visual interpretation of the images at 2nd and 3rd hour could be useful in the final assessment of the study.

Variation of enterohepatic circulation observed with 75SeHCAT images in the first three hours. Scintigraphic patterns and analysis of their association with the diagnosis of bile acid malabsorption.

OBJETIVE: To evaluate the enterohepatic circulation of 75-Selenium turoselecolic acid (75Se-SeHCAT) during the first 3 h and its correlation with the abdominal retention at the 7th day (AR7), as contribution to the clinical study of biliar acid malabsorption (BAM). MATERIALS AND METHODS: 38 patients with chronic diarrhea were retrospectively studied. Acquisition protocol included static abdominal images at 1st, 2nd and 3rd hour and the 7th day after oral administration of the radiopharmaceutical. Images of 1-3 h determined 5 patterns of enterohepatic circulation that, due to their location, were characterized as: 1) gallbladder 2-3 h, 2) gallbladder 3 h, 3) gallbladder-abdomen 2-3 h, 4) abdomen, 5) upper left abdomen. The association of these patterns with the AR7 (Fisher, STATA) were investigated. Patients were classified as Non BAM (AR7 > 15%), mild-BAM (AR7 15-10%), moderate-BAM (AR7 10-5%) or severe-BAM (AR7 < 5%). RESULTS: 19 patients had an AR7 diagnostic of BAM (7 mild-BAM, 5 moderate-BAM, 7 severe-BAM). The pattern "gallbladder at 2-3 h" was statistically associated with Non BAM (p 0,008), while "gallbladder-abdomen at 2-3 h" was correlated with having BAM (p 0,029). CONCLUSION: Variations detected at the abdominal level in images during the first 3 h were associated with changes in intestinal absorption and the incorporation of the radiopharmaceutical into the pool of bile acids, so visual interpretation of the images at 2nd and 3rd hour could be useful in the final assessment of the study.

Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea.

BACKGROUND AND AIMS: Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. METHODS: We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator and outcome questions were developed through an iterative process and were voted on by a group of specialists. RESULTS: The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea and Crohn's disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn's disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review and reinvestigation for patients whose symptoms persist despite BAST. CONCLUSIONS: Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.

High prevalence of primary bile acid diarrhoea in patients with functional diarrhoea and irritable bowel syndrome-diarrhoea, based on Rome III and Rome IV criteria.

BACKGROUND: A high prevalence of primary bile acid diarrhoea (BAD) has been reported for Rome III defined irritable bowel syndrome (IBS)-diarrhoea and functional diarrhoea. We determined whether this still applies under the contemporaneous Rome IV criteria, given that the latter characterises IBS-diarrhoea as having more frequent abdominal pain compared with previous iterations, whilst no longer recognising abdominal discomfort. METHODS: Patients referred for a 75SeHCAT test completed a baseline questionnaire comprising, i) demographic data, ii) risk factors for BAD (inflammatory bowel disease, bowel resection, cholecystectomy, microscopic colitis, celiac disease, abdominal-pelvic radiotherapy), iii) the Rome III and IV bowel disorder questionnaire, and iv) mood and somatisation scores. A diagnosis of BAD constituted a 75SeHCAT of ≤15%, with moderate to severe disease being defined as ≤10% and ≤5%, respectively. FINDINGS: Of 300 patients with complete dataset, 184 had no risk factors for BAD and fulfilled criteria for either IBS-diarrhoea or functional diarrhoea. The prevalence of primary BAD was 38% (n = 70/184), with almost half having moderate (n = 16) to severe (n = 17) disease. Using the Rome III criteria, the prevalence of primary BAD was 36% in IBS-diarrhoea (n = 63/173) and 64% (n = 7/11) in functional diarrhoea; p = 0.11. Using the Rome IV criteria, the prevalence of primary BAD was 38% (n = 53/139) in IBS-diarrhoea and 38% (n = 17/45) in functional diarrhoea; p = 0.97. Patients with primary BAD experienced more frequent loose stools (p = 0.01) and had a higher body mass index (p<0.0001) compared to those without BAD, but otherwise no significant differences were seen in age, gender, mood, somatisation, or abdominal pain. The presence of primary BAD in patients classified as overweight or obese was approximately 40% and 60%, respectively. INTERPRETATION: Over a third of patients with Rome IV IBS-diarrhoea or functional diarrhoea have primary BAD, similar to Rome III. We therefore recommend that, in secondary care settings, generic testing for primary BAD should be considered in patients presenting with chronic diarrhoea of presumed functional origin regardless of concomitant abdominal pain. Centres that lack tests for primary BAD, and who empirically treat instead, may consider targeting patients who are overweight or obese.

Prevalence of, and predictors of, bile acid diarrhea in outpatients with chronic diarrhea: A follow-up study.

BACKGROUND: 23-seleno-25-homo-tauro-cholic acid (SeHCAT) scanning to rule out bile acid diarrhea (BAD) in patients with chronic diarrhea has a high yield. Our previous study showed that patients with terminal ileal (TI) Crohn's disease, TI resection, or cholecystectomy were highly likely to have an abnormal scan. As a result, we encouraged clinicians to use a therapeutic trial of a bile acid sequestrant in these patients, instead of scanning. This may have reduced diagnostic yield of the test, so we examined this issue, as well as factors predicting an abnormal scan, in a large cohort of patients referred subsequently. METHODS: We retrospectively identified 1,071 consecutive patients with chronic diarrhea undergoing SeHCAT scanning at Leeds Teaching Hospitals Trust from 2012 to 2016. We reviewed electronic patient records to obtain information on presenting gastrointestinal symptoms and any proposed risk factors for BAD. BAD was categorized according to subtype and severity. KEY RESULTS: As expected, indications for scanning changed between 2012 and 2016, with a significant reduction in referrals with TI Crohn's disease or resection year-on-year (P < 0.001). Despite this, 457 (42.7%) patients had BAD and there was no downward trend in yield of SeHCAT during the 5 year period (P = 0.39). Overall, 51.6% had type II BAD, 36.1% type III, and 12.3% type I. BAD was mild in 31.7%, moderate in 34.4%, and severe in 33.9%. In total, 653 (61.0%) patients had no known risk factors, other than chronic diarrhea, but 233 (35.7%) of these individuals had BAD, and in 143 (61.4%), this was moderate or severe. CONCLUSIONS AND INFERENCES: Despite reduced referrals for SeHCAT scanning in those with clear risk factors for BAD, the yield remained > 40%. One-third of those without known risk factors had BAD.

75Se-Homocholic acid taurine scintigraphy (75SeHCAT®), a standard benchmark test in bile acid malabsorption? / Gammagrafía con 75Se-ácido tauroselcólico (75SeHCAT®), ¿prueba de referencia en la malabsorción de ácidos biliares?

Chronic diarrhoea due to bile acid malabsorption (BAM) is an underdiagnosed pathology. Different diagnostic tools are available. However, there is currently no consensus on which of these would be the benchmark test or gold standard. This review evaluates the possibility of using 75Se-taurocholic acid (75SeHCAT®) scintigraphy as a benchmark diagnostic test and its perspective for the future. A literature review was conducted in Pubmed and OVID obtaining a total of 57 papers, 26 of which were finally used after being selected under the concepts of gold standard, diagnostic accuracy and other biomarkers. We evaluated the advantages and disadvantages of the different diagnostic tools: 14C-glycocholate, measurement of bile acids in faeces, C4 in serum, FGF19 in serum, cholestyramine, and 75Se-tauroselcolic acid scintigraphy. We consider that the 75SeHCAT® scan is the most recommended diagnostic test in Europe for diagnosing BAM as it presents the highest values of sensitivity and specificity. It has a significant cost-benefit ratio, making it the test with the highest degree of recommendation. However, it is still not possible to use it in a recognised way as a gold standard due to the lack of studies that provide conclusive data that allow consensus. In the meantime, the combined use of cholestyramine testing in all patients we want to evaluate, regardless of the scintigraphy result, could be encouraged as a benchmark standard.

The efficacy of a low-fat diet to manage the symptoms of bile acid malabsorption - outcomes in patients previously treated for cancer.

Dietary fat ingestion triggers bile secretion into the gastrointestinal tract. Bile acid malabsorption affects >1% of the population, causing loose stool and other gastrointestinal symptoms. The diagnosis is frequently missed. Treatments are often considered ineffective. We evaluated low-fat diets for managing gastrointestinal symptoms in these patients. All patients reporting type 6 or 7 stool were offered a selenium-75 homocholic acid taurine (SeHCAT) scan. Prospective data in patients with 7-day scan retention <20% were analysed. -Patients requiring a bile acid sequestrant were given this before receiving dietary advice. Patients completed a 7-day food diary before dietetic consultations. Personalised dietary interventions, providing 20% of daily energy from fat, were prescribed. Symptoms were assessed using a modified gastrointestinal symptom rating scale questionnaire before and 4-12 weeks after dietary intervention. A total of 114 patients (49 male, median age 64 years, median body mass index 27 kg/m2) were evaluated. 44% of these patients were taking colesevelam. After dietary intervention, there was statistically significant improvement in abdominal pain and nocturnal defecation (0.2% alpha, p=0.001). Improvement in bowel frequency, urgency, flatulence, belching, borborygmi and stool consistency were seen, but did not reach statistical significance (p≤0.004-0.031). Dietary intervention is an effective treatment option for patients with symptomatic bile acid malabsorption and should be routinely considered.