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AIM There is increasing interest in using collimated gamma cameras for [75Se]tauroselcholic acid (SeHCAT) studies to image the distribution and to make use of the collimator pressure sensitive devices (PSD) for patient safety. However, the use of a collimator will substantially decrease the sensitivity of the gamma camera. The aim of this article is to enable departments to calculate the uncertainty of SeHCAT retention measurements so that the acquisition time can be optimised to perform a reliable SeHCAT study. METHOD We derive a mathematical equation from the first principles that can be used to calculate the uncertainty in SeHCAT retention measurements on the basis of Poisson counting statistics. The equation takes account of background subtraction, use of the geometric mean for anterior/posterior attenuation compensation and the day 7 to day 0 quotient calculation. RESULTS Uncertainties in SeHCAT retention measurement using an intrinsic (uncollimated) gamma camera counting for 100 s are very low, typically of the order 15 ± 0.1%. Uncertainties from collimated gamma camera counting significantly increase for the same 100 s counting duration: 15 ± 0.8% for slim patients and 15 ± 4% for obese patients. CONCLUSION The acquisition time must be increased for collimated gamma camera SeHCAT counting to achieve acceptable counting statistics for an acceptable total uncertainty in the SeHCAT retention measurement. For slim patients, a minimum counting time of 2 min is required. For larger patients, the acquisition time needs to be increased to 30 min and further increased to 50 min for obese patients.

The actual incidence of bile acid diarrhoea (BAD) is unknown, however, there is increasing evidence that it is misdiagnosed in up to 30% with diarrhoea-predominant patients with irritable bowel syndrome. Besides this, it may also occur following cholecystectomy, infectious diarrhoea and pelvic chemoradiotherapy.BAD may result from either hepatic overproduction of bile acids or their malabsorption in the terminal ileum. It can result in symptoms such as bowel frequency, urgency, nocturnal defecation, excessive flatulence, abdominal pain and incontinence of stool. Bile acid synthesis is regulated by negative feedback loops related to the enterohepatic circulation, which are dependent on the farnesoid X receptor and fibroblast growth factor 19. Interruption of these feedback loops is thought to cause bile acid overproduction leading to BAD. This process may occur idiopathically or following a specific trigger such as cholecystectomy. There may also be an interplay with the gut microbiota, which has been reported to be significantly different in patients with severe BAD.Patients with suspected BAD are investigated in various ways including radionucleotide imaging such as SeHCAT scans (though this is not available worldwide) and blood tests. However, other methods such as bile acid measurement in stool (either spot test or 48 hours samples) and urine tests have been explored. Importantly, delay in diagnosis and treatment of BAD greatly affects patient’s quality of life and may double the overall cost of diagnosis.

Introduction Microscopic colitis (MC) is an important cause of chronic, watery diarrhoea. Currently, there is no specific biomarker available to guide diagnosis. The use of faecal calprotectin (FCP) as a potential marker has been addressed in only a few studies. Further, bile acid malabsorption (BAM) often accompanies MC. Current practice recommends the selenium-labelled homocholic acid-taurine (SeHCAT) test, but at our centre, 7 alpha-hydroxy-4-cholesten-3-one (7αC) is used as a simpler and less expensive alternative to SeHCAT, with values over 22ng/mL indicating BAM. This study aims to evaluate the use of FCP as a biomarker in the diagnosis of MC and the role of 7αC in detecting concomitant BAM with MC. Methods Pathology records were retrospectively reviewed for patients diagnosed with collagenous colitis (CC) between 2000 and 2018 and lymphocytic colitis (LC) between 1995 and 2011. FCP and 7αc results, if measured within 6 months of pathological diagnosis, were extracted for analysis. Results Between 2000 and 2018, 646 CC cases were confirmed on histology. Of 646 patients, 147 had FCP measured; in 111 (75.5%) FCP was elevated with mean levels 238.1μg/g (SD±273.0); 140/646 had 7αC measured; 16 (11.4%) indicated BAM. Mean levels were 10.2ng/mL (SD±9.4). During a 21-year period (1995-2011), 204 LC diagnoses were made: 14/204 had FCP measured ; 8 (57.1%) were elevated. Mean levels were 128.4μg/g (SD±107.7). Of 204 LC patients, 20 had 7αC measured, 5 (25%) indicating BAM. Mean levels were 13.95ng/mL (SD±9.4). Discussion Both CC and LC were associated with raised FCP during the diagnostic phase, supporting the potential role of its use in clinical practice. Furthermore, we present results of using 7αC in identifying BAM amongst patients with MC. In our cohort, low levels of 7αC suggest relatively low concordance of BAM with MC.

PTH-2 Table 1Baseline demographic and clinical details Number(%) Demographic Data Male 26(28%) Female 67(72%) Age(range) 57(27-85) Primary Cancers Cervical 33(35%) Prostate 18(19%) Anorectal 16(17%) Endometrial 12(13%) Vaginal 3(3%) Vulval 3(3%) Sarcoma 1(1%) Bowel 1(1%) Lymphoma 1(1%) Ovarian and endometrial 1(1%) Chordoma 1(1%) Cancer Treatments EBRT* 67(72%) EBRT* followed by brachytherapy 26(28%) Brachytherapy without EBRT* 1(1%) Chemotherapy 53(57%) Surgery 17(18%) *External beam radiotherapy44(47%) patients were treated for BAM. Of those, 13(30%) had severe BAM (SeHCAT retention 0-5%), 5(11%) had moderate BAM (SeHCAT retention 5-10%), and 15(34%) had mild BAM (SeHCAT retention 10-15%), with 10(23%) having a borderline result (SeHCAT retention 15-20%), which can be associated with symptoms. SeHCAT result was not recorded for one (performed elsewhere).17(18%) patients were diagnosed with SIBO. Of those diagnosed, 10(59%) had positive hydrogen breath tests and 7(41%) patients were diagnosed clinically with SIBO. 8(9%) patients were diagnosed with both BAM and SIBO.ConclusionThis large case series confirms BAM is a common cause of chronic diarrhoea following pelvic radiotherapy, affecting over a third of patients. As per BSG guidelines1, SeHCAT scans and breath tests should be initial investigations in this patient group. SIBO remains a difficult condition to diagnose due to limitations of the investigations currently available, exacerbated by limited access during the Covid-19 pandemic. This may account for our lower diagnostic yield2. Further work is needed to improve the detection of SIBO.ReferencesAndreyev HJ, Davidson SE, Gillespie C, et al. Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer. Gut. 2012;61(2):179-92.Stacey R, Turner J, Green J. OC-026;Diagnostic Yields Of SeHCAT Scanning And Glucose Hydrogen Breath Testing In Pelvic Radiation Disease Gut 2014;63:A13.

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 β 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.

OBJECTIVES As part of the 75-Selenium homocholic acid taurine (SeHCAT) study, counts are acquired as a baseline to allow the calculation of the retention at 7 days. In this work, we evaluated whether it was possible to replace the baseline image with a predictive model based on the patient's height and weight. METHOD Height and weight data from 723 patients scanned at three hospitals using seven gamma cameras were compiled. A number of different models were trialled, with fitting parameters determined by regression. A predictive model based on height and logarithm of weight was found to have the best correlation with the measured counts in the 3-h study. RESULTS There was a strong correlation (R2 = 0.91) between the measured counts and the predicted counts using a model based on height and logarithm of weight. Treating the standard SeHCAT test result as the gold standard, the test result when predicted baseline counts were used had a sensitivity and specificity of 97.5 and 98.0%, respectively, at a threshold of 15%. In total 694/723 (96.0%) of patients had no change to their severity grading when using the predicted baseline counts. CONCLUSION This work presents a model that was able to predict the counts in the 3 h SeHCAT study for patients on seven gamma cameras. This can enable a single scan study, giving significant savings to patient and staff time and imaging resources.

Bile acid malabsorption (BAM) is caused by excessive spill-over of bile acids to the colon and is estimated to affect ∼1% of the general population. It is a socially debilitating disease with watery diarrhea and high stool frequency as main symptoms. BAM is diagnosed by the 75selenium homotaurocholic acid test (SeHCAT) measuring the retention of bile acids. Bile acid sequestrant (BAS) treatment, which is the only recommended treatment of BAM, is associated with poor effect and low compliance. Case reports suggest that the glucagon-like peptide 1 receptor analog (GLP-1RA) liraglutide may be an effective treatment of BAM. In this double-blind, double-dummy, non-inferiority study, nondiabetic individuals with SeHCAT-verified BAM, age 18-75 years and BMI 18.5-40 kg/m2 were randomized to receive the GLP-1RA liraglutide (uptitrated to 1.8 mg per day) or the BAS colesevelam (1.875 mg × 2 per day) for 6 weeks prior to a 7-day run-in period without treatment. SeHCAT was made at baseline, week 3 and week 6. The primary outcome was the proportion of patients experiencing a reduction in stool frequency of ≥25% per day. Of 52 randomized subjects (18 males, 34 females, mean age 50.2 years and BMI 29.9 kg/m2), one patient from each group dropped out due to gastrointestinal side effects. At end-of-treatment, 20 (77%) individuals on liraglutide had experienced a reduction in stool frequency of ≥25% per day vs. 13 (50%) on colesevelam treatment, corresponding to a statistically superior risk difference of -0.27 (one-sided 95% CI: -1; -0.06). In contrast to the colesevelam-treated group, the liraglutide-treated group exhibited a significant increase in SeHCAT values resulting in significantly higher values at end-of-treatment (mean (SD) 8.9 (7.3) vs. 0.9 (2.0) %, P In conclusion, we show that liraglutide enhances the reabsorption of bile acids and constitutes a safe and effective treatment of BAM which is superior compared to current standard of care (colesevelam). Disclosure M. L. Kårhus: None. A. Brønden: None. J. Forman: None. A. Haaber: None. E. Langholz: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. D. P. Sonne: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Novo Nordisk Foundation (NNF17OC0029710); A.P. Møller and Chastine Mc-Kinney Møller Foundation (19-L-0002)

Background & Aims The evaluation of patients with chronic watery diarrhea represents a diagnostic challenge for clinicians because organic causes, including inflammatory bowel disease, microscopic colitis, and chronic infection, must be differentiated from functional diarrhea and diarrhea-predominant irritable bowel syndrome. The purpose of this review is to summarize the available evidence on the usefulness of diagnostic tests in such patients. Methods We searched MEDLINE and EMBASE via OVID, from 1978 until April 2017. We included diagnostic test accuracy studies reporting on the use of fecal and blood tests for the evaluation of adult patients with functional diarrhea, including irritable bowel syndrome. We assessed the risk of bias of included studies using a modified version of the Quality Assessment of Diagnostic Accuracy Studies II, and the certainty in the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We calculated pooled sensitivity and specificity, and the proportion of patients with true and false positive and negative results. We evaluated the following tests: erythrocyte sedimentation rate, C-reactive protein, fecal lactoferrin, fecal calprotectin, serologic tests for celiac disease, tests for bile acid diarrhea, the commercially available version of anti–cytolethal distending toxin B and anti-vinculin antibodies, and tests for Giardia infection. We did not evaluate breath tests for small intestinal bacterial overgrowth, as they are not part of a standard diarrhea workup. Results Thirty-eight studies proved eligible to evaluate 1 or more of these tests. Erythrocyte sedimentation rate and C-reactive protein were similar at discriminating organic from functional disease, with sensitivity and specificity, respectively, of 0.54–0.78 and 0.46–0.95 for erythrocyte sedimentation rate and 0.73 and 0.78 for C-reactive protein. Among fecal tests, fecal calprotectin in a range of 50–60 μg/g (pooled sensitivity 0.81; 95% confidence interval [CI], 0.75–0.86; pooled specificity 0.87; 95% CI, 0.78–0.92) and fecal lactoferrin in a range of 4.0–7.25 μg/g (pooled sensitivity 0.79; 95% CI, 0.73–0.84; pooled specificity 0.93; 95%CI 0.63–0.99) presented the lowest proportion of false-negative results (low certainty in the evidence). Among tests for celiac disease, IgA tissue transglutaminase presented the best diagnostic test accuracy (sensitivity range, 0.79–0.99; specificity range, 0.90–0.99) with moderate certainty in the evidence. Among tests for bile acid diarrhea, the 75selenium homotaurocholic acid test performed better than serum fibroblast growth factor 19 and 7α-hydroxy-4-cholesten-3-one, but is not available in the United States. There was insufficient evidence to recommend serologic tests for irritable bowel syndrome at this time. There are several good diagnostic tests for Giardia infection. Conclusions Moderate to low certainty in the evidence indicates that available fecal and blood tests may play a role in the diagnostic workup of adult patients with functional diarrhea. At the moment, no tests are available to reliably rule in irritable bowel syndrome.

ObjectiveBile acid diarrhoea (BAD), which includes bile acid malabsorption, causes a variety of digestive symptoms. Diagnostic rates and management vary considerably. We conducted a survey of current practice to review expert opinion and provide guidance on diagnosis and management.Design/methodAn online survey was conducted of clinical members of the UK Bile Acid Related Diarrhoea Network, who had all published research on BAD (n=21). Most were National Health Service consultants who had diagnosed over 50 patients with the condition.ResultsThe preferred terminology was to use BAD, with primary and secondary to classify causes. A wide range of presenting symptoms and associated conditions were recognised. SeHCAT (tauroselcholic acid) was the preferred diagnostic test, and 50% of respondents thought general practitioners should have access to this. Patients who met the Rome IV diagnostic criteria for functional diarrhoea, irritable bowel syndrome (IBS) with predominant diarrhoea or postcholecystectomy diarrhoea were usually investigated by SeHCAT, which was used sometimes in other types of IBS. Treatment with a bile acid sequestrant was offered to patients with low SeHCAT values, with expected response rates >70% in the most severe. Colestyramine was the usual sequestrant, starting between 2 g and 8 g daily; colesevelam was an alternative. In patients who had an incomplete response, increasing the dose, changing to an alternative sequestrant, use of loperamide and a low fat diet were suggested. Recommendations for follow-up and to improve the overall patient experience were made.ConclusionThis expert survey indicates current best practice in the diagnosis and management of BAD.

In up to 50% of people diagnosed with a common ailment, diarrhea-predominant irritable bowel syndrome, diarrhea results from excess spillage of bile acids into the colon—data emerging over the past decade identified deficient release of a gut hormone, fibroblast growth factor 19 (FGF19), and a consequent lack of feedback suppression of bile acid synthesis as the most common cause. 75Selenium homotaurocholic acid (SeHCAT) testing, considered the most sensitive and specific means of identifying individuals with bile acid diarrhea, is unavailable in many countries, including the United States. Other than SeHCAT, tests to diagnose bile acid diarrhea are cumbersome, non-specific, or insufficiently validated; clinicians commonly rely on a therapeutic trial of bile acid binders. Here, we review bile acid synthesis and transport, the pathogenesis of bile acid diarrhea, the reasons clinicians frequently overlook this disorder, including the limitations of currently available tests, and our efforts to develop a novel 19F magnetic resonance imaging (MRI)-based diagnostic approach. We created 19F-labeled bile acid analogues whose in vitro and in vivo transport mimics that of naturally occurring bile acids. Using dual 1H/19F MRI of the gallbladders of live mice fed 19F-labeled bile acid analogues, we were able to differentiate wild-type mice from strains deficient in intestinal expression of a key bile acid transporter, the apical sodium-dependent bile acid transporter (ASBT), or FGF15, the mouse homologue of FGF19. In addition to reviewing our development of 19F-labeled bile acid analogue-MRI to diagnose bile acid diarrhea, we discuss challenges to its clinical implementation. A major limitation is the paucity of clinical MRI facilities equipped with the appropriate coil and software needed to detect 19F signals.

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.

Introduction The coordination of biliary and pancreatic secretions is vital for normal digestion. However, it is unknown if bile acid malabsorption (BAM) is associated with pancreatic exocrine insufficiency (PEI). Faecal elastase-1 (FE1) is the only widely available test for PEI. Its limitations include a falsely low (positive) result in patients submitting dilute stool samples, as might occur in patients with BAM. We studied the association between BAM and PEI, and the impact of coexisting BAM on the management of patients with low FE1. Methods We carried out a retrospective study at a London teaching hospital. All outpatients investigated with both FE1 and a SeHCAT scan between 2012 and 2018 were identified. Demographic and clinical information was retrieved from the electronic medical record. PEI was defined as FE1 Results 258 patients were identified; mean age 51 years; 65.5% female; 61.6% white ethnicity. BAM was diagnosed in 111 patients (43%). PEI was diagnosed in 39 patients (15.1%), with no subjective difference between those with and without BAM (15.3 v. 15.0%). On univariable analysis, BAM was not associated with PEI (OR 1.03; 95% CI 0.52 to 2.04; p=0.94). After adjusting for age, sex and ethnicity, this lack of association held (OR 0.78; 95% CI 0.37 to 1.64; p=0.52). 43 patients (16.7%) had FE1 repeated, with 9 patients (20.9%) reclassified from PEI to normal as a result. There was no difference between patients with and without BAM in FE1 being repeated (15.3% v. 17.7%; p=0.61) or the repeat FE1 leading to reclassification of PEI status (23.5% v. 19.2%; p=0.74). In patients with PEI, there was no difference in the rate of pancreatic imaging between those with and without BAM (64.7% v. 63.6%; p=0.61), but pancreatic abnormalities were detected more frequently in patients with coexisting BAM (58.3% v. 20.0%; p=0.04). Findings included atrophic or fatty pancreas, and one pancreatic cancer. There was a non-significant trend towards fewer patients with PEI and BAM receiving PERT (58.8% v. 72.7%; p=0.36), but no difference in clinical response when treated (77.8% v. 76.9%; p=0.96). Conclusions BAM is not associated with PEI. However, when a patient with BAM does have a low FE1, our findings suggest most are representative of PEI, rather than false positives.

Introduction Studies have suggested that organic diseases particularly bile acid diarrhoea/malabsorption, carbohydrate malabsorption, microscopic colitis, pancreatic exocrine insufficiency and small intestinal bacterial overgrowth, may be misdiagnosed as irritable bowel syndrome (IBS). We conducted a systematic review and meta-analysis of the prevalence of these conditions in adults with IBS-like symptoms. Methods PubMed, EMBASE, CINAHL and Cochrane were searched from January 1978 (1st publication of the Manning Criteria) to July 2019. Studies were included if they prospectively or retrospectively evaluated the prevalence of any of these conditions in consecutive patients meeting Manning, Kruis or Rome I-IV criteria for IBS. These disorders were defined as follows: Bile acid diarrhoea/malabsorption –a 75Selenium taurocholic acid scan (SeHCAT) with 7-day retention 105 cfu/mL in the jejunal aspirate. Results Bile acid diarrhoea/malabsorption: the pooled prevalence of an abnormal scan in 8 studies (n=706) was 36.1%. Carbohydrate malabsorption: 36 papers (n=7,667) gave a pooled prevalence of a positive lactose, fructose, sorbitol or mannitol breath test as 47.4%, 67.8%, 60% and 20%, respectively. Microscopic colitis: the pooled prevalence from 16 studies (n=4,770) was 2.9%. Pancreatic exocrine insufficiency: the pooled prevalence from 2 papers (n=478) was 4.6%. Small intestinal bacterial overgrowth: 32 and 18 studies (n=4,381 and 1,710) used LHBT and GHBT giving a pooled prevalence of a positive LHBT or GHBT of 40.4% and 26.5% respectively. Prevalence was 18.3% from the 5 studies (n=448) using bacterial count. There was significant heterogeneity in effect sizes of each of these conditions. Conclusion Systematic review suggests that organic conditions in the gastrointestinal tract in patients with IBS-like symptoms are not rare. The need to exclude these treatable organic disorders systematically will be challenging in clinical practice in view of the large number of patients presenting with these symptoms. Future international guidelines on management of IBS should be revised accordingly.

Introduction Primary bile acid diarrhoea (BAD), also known as idiopathic bile acid malabsorption, is a common cause of chronic functional diarrhoea and irritable bowel syndrome with diarrhoea. BAD has been shown to be associated with fatty liver disease including non-alcoholic steatohepatitis (NASH), with shared mechanisms being reported. In our previous proof-of-concept study, patients with BAD had significant clinical improvements in stool type and frequency when treated for two weeks with the first-in-class farnesoid X receptor (FXR) agonist obeticholic acid (OCA). In a case report using OCA for 6 months, in addition to clinical improvement, normalisation of the diagnostic SeHCAT test was found. The aim of this study was to see if further evidence for benefits of FXR agonists on diarrhoea could be found in the recently published results from the 18-month interim analysis of a large phase 3 study of OCA in NASH (Younossi ZM, et al. Lancet 2019; 394:2184–2196). Methods The published results of the interim analysis were analysed independently. Patients with NASH fibrosis (n=1968) had been randomly allocated to placebo, OCA 10 mg, or OCA 25 mg daily. Patient-reported adverse reactions had been recorded per protocol. Figures for newly incident events of diarrhoea and constipation were given. The frequencies of these events were compared between the groups. Results Incidents of diarrhoea were reported in 12% of patients in the placebo-treated group. These were significantly fewer in both OCA-treatment groups, at 7% (p

Introduction Chronic diarrhoea causes significant morbidity and these patients are commonly referred to gastroenterology clinic. Bile acid diarrhoea (BAD) is considered causal in up to 1/3 of people investigated for IBS-D. BSG guidelines recommend investigation for BAD in secondary care using SeHCAT scanning/serum bile acid precursors.1 Empirical trial of treatment is not recommended. Access to tests can be limited in district general hospital settings. We report our experience in a DGH where diagnostic testing is provided by a centre 39 miles away. Methods A retrospective notes review was performed for all outpatients from East and North Herts NHS trust (catchment population 600,000) who had SeHCAT scans performed by a regional service (Mount Vernon Hospital) in 2019. Data were collected on demographics, symptoms, risk factors, other investigations, time between first clinic and scanning and prior empirical treatment. Comparison were made between positive and negative groups using multiple regression analysis. Results 50 scans were requested of which 48 results were available. Median age was 49 (23 – 84 y), 33(69%) female. 21 scans (44%) were positive for BAD, 3 (14%) mild, 10 (48%) moderate 8 (38%) severe. Only patients with complete data (45) were included in subsequent analyses. Risk factors are presented in table 1. A statistically significant association between cholecystectomy and positive SeHCAT scan was found (P=0.026). There was considerable delay in diagnostic confirmation for some patients with a positive test taking 1 month to 10 years. Overall 41/45 patients had prior testing with faecal calprotectin (FC), 32 patients had colonoscopies of whom 24 had colonic biopsies, 43/50 had thyroid function checked and 39/50 were screened for coeliac disease. 10 patients had empirical treatment with bile acid sequestrants before scanning. Conclusions Our study has shown a burden of incident BAD in the outpatient DGH setting. This is underestimated due to use of empirical treatment without testing, lack of investigation of some patients with disease and referral for SeHCAT scanning in other centres not identified. Patients had appropriate initial investigations performed for chronic diarrhoea. In keeping with larger studies from tertiary centres prior cholecystectomy is the commonest predisposing factor (type III) and >1/3 of patients had no identified risk factor (type II). There are limited data regarding BAD investigation and management in DGH setting where patients have to travel considerable distance for testing. There are problems associated with empirical treatment including current drug availability in the UK. National management guidelines based on large studies and wider availability of economically viable testing are needed. Reference Arasaradnam RP, Brown S, Forbes A et al. Gut Epub ahead of print (13 April 2018) doi:10.1136/gutjnl-2017-315909

Background: Bile acid diarrhoea (BAD) is common, often unrecognised, or thought to be irritable bowel syndrome with diarrhoea (IBS-D). It results from increased loss of bile acids (BAs) into the colon but mechanisms are unclear. The gut microbiota plays key roles in the metabolism of primary BAs to form secondary BAs, which have differing impacts on intestinal metabolism and homeostasis. The aim of this study was to profile the gut microbiome in BAD and to investigate the differences in bacterial metabolic products and specific bile acids. Methods: Patients with BAD diagnosed by SeHCAT testing, were compared with other IBS-D patients, and healthy controls. Faecal 16S ribosomal RNA gene analysis was undertaken. Faecal short chain fatty acid (SCFA) and urinary fermentation metabolite profiles (volatile organic compounds; VOCs) were measured. BAs were quantified in serum and faeces. Findings: Faecal bacterial diversity was significantly reduced in patients with BAD, but several taxa were enriched compared to IBS-D. SCFA amounts differed in BAD, controls and IBS-D, with significantly more propionate in BAD. Separation of VOC profiles was evident between all groups with the greatest discrimination between IBS-D and controls. Unconjugated and primary BA in serum and faeces were significantly higher in BAD. The proportion of faecal primary BA was inversely related to SeHCAT values. Interpretation: BAD results in dysbiosis, with differences in metabolites including VOC, SCFA and higher concentrations of primary BAs when compared to IBS-D. These findings provide new mechanistic insights into the pathophysiology of BAD. Funding Statement: Funding was from UHCW Trust’s charity as well as the Midlands Gastroenterology Society and Bardhan Research and Education Trust (BRET). Declaration of Interests: JW has been a consultant for, and reports institutional grant funding from GE Healthcare, and Prometheus diagnostics. RA has delivered educational talks for GE Healthcare. No disclosures are made by all authors Ethics Approval Statement: Scientific and ethical approval was acquired from the local Research and Development Office as well as Warwickshire Ethical committee ref: 09/H1211/38. Written informed consent was obtained from all participants in the study.

INTRODUCTION: The diagnosis of bile acid diarrhea is often missed because the availability of the seleno-taurohomocholic acid (SeHCAT) test is limited. We aimed to compare the biomarkers 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19) with the SeHCAT test.METHODS: Patients with chronic diarrhea without intestinal resection referred for SeHCAT were prospectively recruited for this diagnostic accuracy study. Blood was sampled at fasting and after a stimulation meal with chenodeoxycholic acid. SeHCAT retention ≤10% defined bile acid diarrhea and >10% defined miscellaneous diarrhea. Receiver operating characteristics (ROC) were analyzed with SeHCAT as the gold standard. www.clinicaltrials.gov (NCT03059537).RESULTS: Patients with bile acid diarrhea (n = 26) had mean C4 of 30 ng/mL (95% confidence interval: 19-46) vs 8 (7-11; P < 0.001) in the miscellaneous diarrhea group (n = 45). Area under the ROC curve (ROCAUC) for C4 was 0.83 (0.72-0.93). C4 < 15 ng/mL had 85% (74%-96%) negative predictive value; C4 > 48 ng/mL had 82% (59%-100%) positive predictive value. Twenty patients had C4 values 15-48 ng/mL, of whom 11/20 had SeHCAT ≤10%. Median fasting FGF19 was 72 pg/mL (interquartile range: 53-146) vs 119 (84-240) (P = 0.004); ROCAUC was 0.71 (0.58-0.83). Stimulated FGF19 responses did not differ (P = 0.54).DISCUSSION: We identified C4 thresholds with clinically useful predictive values for the diagnosis of and screening for bile acid diarrhea in patients with chronic watery diarrhea. Further validation of the cutoff values with the placebo-controlled effect of sequestrant therapy is warranted (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B603).

Background\ud \ud 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.\ud \ud \ud \ud Methods\ud \ud 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.\ud \ud \ud \ud Findings\ud \ud 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

Introduction Bile acid (BA) diarrhea is the cause in ∼26% of chronic unexplained (nonbloody) diarrhea (CUD) based on SeHCAT testing. To assess fecal BA excretion and healthcare utilization in patients with CUD. Methods In a retrospective review of 1,071 consecutive patients with CUD who completed 48-hour fecal BA testing, we analyzed the symptoms, diagnostic tests performed, and final diagnoses. Results After 135 patients were excluded because of mucosal diseases, increased BA excretion was identified in 476 (51%) of the 936 patients with CUD: 29% with selective increase in primary BA and 22% with increased total BA excretion (35% with normal primary BA excretion). There were no differences in demographics, clinical symptoms, or history of cholecystectomy in patients with elevated total or selective primary fecal BA excretion compared with patients with normal excretion. Before the 48-hour fecal BA excretion test was performed, patients completed on average 1.2 transaxial imaging, 2.6 endoscopic procedures, and 1.6 miscellaneous tests/person. Less than 10% of these tests identified the etiology of CUD. Total fecal BAs >3,033 µmol/48 hour or primary BAs >25% had a 93% negative predictive value to exclude mucosal disease. Among patients with increased fecal BA excretion, >70% reported diarrhea improved with BA sequestrant compared with 26% with normal fecal BA excretion. Patients with selective elevation in primary fecal BAs were 3.1 times (95% confidence interval, 1.5-6.63) more likely to respond to BA sequestrant therapy compared with those with elevated total fecal BAs. Discussion Increased fecal BA excretion is frequent (51%) in patients with CUD. Early 48-hour fecal BA evaluation has the potential to decrease healthcare utilization in CUD.

AIM It has previously been proposed that entero-hepatic bile acid recycling frequency is a major determinant of whole-body retention (WBR) of SeHCAT. Hepatocyte to terminal ileum accounts for almost the entire cycle. The study aim was to test this hypothesis by comparing WBR with an estimate of speed of transit of bile acids using Tc-HIDA scintigraphy performed on a separate occasion. METHODS Using an un-collimated gamma camera and patient-to-camera distance of 1.5 m, WBR at 7 days after oral SeHCAT administration was measured in 14 patients with chronic diarrhoea, of whom 10 had previous cholecystectomy. The distance reached within the intestine of Tc-HIDA at 1 h (n = 14) and 2 h (n = 7) following iv injection was graded as follows: grades 1 and 2: small bowel on left and right sides of abdomen, respectively; and grade 3: colon. Relationships between WBR and grade were assessed using Spearman rank correlation. RESULTS Interval between studies ranged from 3 to 1219 (median 330) days. Grading correlated with WBR at 1 h (rs = -0.63; P = 0.02) and weakly at 2 h (rs = -0.68; P = 0.09) post-injection of Tc-HIDA. In nine patients in whom Tc-HIDA and SeHCAT scans were performed within 1 year of each other, the correlation remained significant at 1 h (rs = -0.73; P = 0.03). There was no difference in WBR or grading between patients with or without a gall bladder. CONCLUSION Entero-hepatic bile acid recycling frequency is a major determinant of whole-body SeHCAT retention.

Bile acid diarrhea, or bile acid malabsorption, is a syndrome of chronic watery diarrhea. It can be diagnosed by measuring fecal bile acids or by the SeHCAT (selenium-homocholic acid taurine) test. Symptoms usually respond to bile acid sequestrants. Bile acid diarrhea may be secondary to ileal resection or Crohn's disease, affecting the enterohepatic circulation of bile acids, and is often recognized after cholecystectomy. Primary bile acid diarrhea (PBAD) is a common condition affecting approximately 1% of the population and has no definitive cause. PBAD is under-diagnosed, but accounts for around 30% of IBS-diarrhea, with a large associated burden of disease.

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.

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

Background: Primary bile acid diarrhoea (BAD) is associated with increased bile acid synthesis and low fibroblast growth factor 19 (FGF19). Bile acid sequestrants are used as therapy, but are poorly tolerated and may exacerbate FGF19 deficiency. Aim: The purpose of this study was to evaluate the pharmacological effects of conventional sequestrants and a colonic-release formulation preparation of colestyramine (A3384) on bile acid metabolism and bowel function in patients with BAD. Methods: Patients with seven-day 75selenium-homocholic acid taurine (SeHCAT) scan retention

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.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.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.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.

Introduction Bile acid diarrhoea (BAD), including bile acid malabsorption (BAM), causes a variety of digestive symptoms and is increasingly recognised, although diagnostic rates and management vary considerably. The UK Bile Acid Related Diarrhoea Network (UK-BARDN), established in 2017, conducted a survey of current practice to provide a review of expert opinion and guidance on diagnosis and management. Methods An on-line survey was sent at the end of 2018 to 21 clinical members of UK-BARDN, who had all published research on BAD. Results A response rate of 100% was obtained. 95% were NHS Consultants; 85% estimated they had diagnosed over 50 patients with the condition. BAD was the terminology preferred by 57%, with another 29% using BAD or BAM depending on the clinical circumstances. Primary and secondary were the preferred terms to classify the different causes. A wide range of presenting symptoms and associated conditions were recognised. SeHCAT was the preferred diagnostic test, with a therapeutic trial the second choice. Access to SeHCAT by GPs was thought appropriate by 50%, with greater availability of specific blood tests in hospitals. SeHCAT would usually be requested (>70%) in patients who met the diagnostic criteria for functional diarrhoea, IBS-D, or post-cholecystectomy diarrhoea, and sometimes be requested (>30%) in other types of IBS, and in Crohn’s disease with ileal resection and negative inflammatory markers, where a therapeutic trial was also commonly used. Treatment with a bile acid sequestrant (BAS) would always be given if SeHCAT was 70%, falling to 30% in these groups. Colestyramine was the usual first line BAS, with starting doses varying between 2 g od and 4 g bd. Colesevelam was also used. There was a slight preference to give the drug at bedtime. Warnings about drug interactions were usual. In patients who had an incomplete response, increasing the dose, changing to an alternative BAS, increasing use of drugs such as loperamide, and advice on a low fat (40 g/d) diet were commonly recommended. During follow-up, annual review by a specialist or GP, patient support groups, dietetic and pharmacist review, and monitoring of blood vitamins and lipids were given varying importance. To improve the overall patient experience, greater recognition by various professional groups and in the popular press, with improved diagnosis and drugs, were considered important. Conclusions This expert consensus provides a basis for current best practice in the diagnosis and management of patients with BAD.

Introduction NICE DG7 (2012) highlights the problems of SeHCAT scanning in the diagnosis of Bile Acid Malabsorption (BAM) for patients presenting with IBS-D. 2018 BSG guidelines for the investigation of chronic diarrhoea recommend both SeHCAT scanning (for the diagnosis of BAM) and colonoscopy (for diagnosis of microscopic colitis), which can occur in up to 25% and 10% of cases of IBS-D, respectively. Nocturnal symptoms and incontinence are ‘hallmark’ symptoms for microscopic colitis. This retrospective study evaluates the use of SeHCAT scanning at a London teaching hospital and explores if similar ‘hallmarks’ exist for BAM. Methods The patient cohort was identified by searching the CRIS database from inception to Oct 2018 whilst clinical data was extracted from the electronic patient record system. SeHCAT scans were performed using 75Se-hemoefolic acid taurine capsules at a dose of 0.4MBq and 0.3mSv. Gamma counts were recorded 3 hours and then 7 days post capsule administration using a camera detecting the 27–80keV photo peak and retentions of Results From Jan 2013 to Oct 2018, 524 patients underwent a SeHCAT scan (65% female, mean age 51) and the rate of testing increased sequentially from 26 per annum to 124 per annum over five years. Detailed statistical analysis of symptom cluster failed to identify any ‘hallmark’, but nevertheless 49.8% of patients had abnormal tests, 56.7% of which were requested by 4/16 consultant gastroenterologists. Sixty-four patients developed diarrhoea following a laparoscopic cholecystectomy (n=2476) of whom 41 (64%) had positive scans. In the same time period as this study, 1719 patients underwent colonoscopy and biopsy due to unexplained diarrhoea. Conclusions These data confirm that BAM is common but is under-investigated in comparison with microscopic colitis. Although it is not associated with any ‘hallmark’ symptoms, it is readily identified by experienced clinicians as suggested by the high pick up rate, presumably on the basis of clinical acumen. It occurs in approximately 2% of patients following cholecystectomy, although the true prevalence in this population may be greater. These data also support the BSG guideline audit recommendation of SeHCAT in IBS-D as a quality improvement target.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which accounts for a substantial proportion of a gastroenterologist’s time in the outpatient clinic. However, there is variability in approaches to diagnosis and investigation between physicians, dependent on expertise. Many patients express disappointment over the lack of a patient-centred approach. Consequently, there have been calls for the care of patients with IBS to be standardised, a process which aims to promote high-quality and high-value care. Making an early diagnosis, based on a clinical assessment of symptoms, while limiting use of investigations, are key tenets of this process. Exhaustive investigation to exclude all organic pathology is unnecessary, and may be counterproductive. Routine blood tests in suspected IBS have low yield, but are an acceptable part of routine practice. All patients should have coeliac serology tested, regardless of their predominant stool form. Patients with diarrhoea should have a faecal calprotectin measured, and should proceed to colonoscopy to exclude inflammatory bowel disease (IBD) if this is positive. Beyond this, the need for investigations should be made on a case-by-case basis, contingent on the reporting of known risk factors for organic pathology. Colonoscopy should be considered in any patient with alarm features for colorectal cancer, and in those whose clinical features are suggestive of microscopic colitis. A 23-seleno-25-homotaurocholic acid (SeHCAT) scan should be considered in patients with IBS-D, a third of whom may actually have bile acid diarrhoea. There is no role for routine hydrogen breath tests for lactose malabsorption or small intestinal bacterial overgrowth.

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.