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Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD. Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR. FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01). These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.

Correspondence to Dr Mohamed G Shiha, Department of Gastroenterology, University Hospitals of Leicester NHS Trust, Leicester, UK; Mohamed.shiha1@nhs.net We read with interest the recent paper by Raju et al that highlighted the impact of the COVID-19 pandemic on gastroenterology training in the UK.1 This national survey of gastroenterology trainees showed a significant reduction in all aspects of training experiences including endoscopy, clinics, referrals and specialty ward cover. [...]it is easy to incorporate within the rota alongside the general medical commitments. [...]we agree with Raju et al that innovative solutions are needed to ensure adequate training and to mitigate the challenges of the pandemic and the forthcoming shorter specialty training.

Chronic diarrhoea is a common condition, resulting from a number of different disorders. Bile acid diarrhoea, occurring in about a third of these patients, is often undiagnosed. We hypothesised that a positive diagnosis of bile acid diarrhoea would reduce the need for subsequent investigations for alternative diagnoses.MethodsPatients previously recruited to a study of chronic diarrhoea who had selenium homocholic acid taurine (SeHCAT) testing and subsequent follow-up at our institution were identified. In a retrospective analysis, the numbers of defined investigations undertaken from the first 3 months after SeHCAT in the following 5 years were compared.Results90 patients were identified with primary bile acid diarrhoea (SeHCAT retention <15%, n=36) or idiopathic diarrhoea (SeHCAT retention >15%, n=54). Follow-up had been performed on 29 and 39 subjects, respectively, with no differences in previous investigations or the last contact date. In the follow-up period, the proportions of these patients who had undergone endoscopic procedures (gastroscopy, colonoscopy and sigmoidoscopy) were the same. However, there was a higher proportion of patients in the SeHCAT-negative group who had other investigations, including imaging, physiological tests and blood tests (p=0.037). The use of cross-sectional imaging was significantly higher in this group (p=0.015) with greater proportions having CT (0.44 vs 0.10) and MRI (0.26 vs 0.07). Ultrasound use and the number of blood tests were higher in the SeHCAT-negative group whereas the SeHCAT-positive group attended more clinic appointments (p=0.013).ConclusionA positive diagnosis of bile acid diarrhoea, made by a SeHCAT test, resulted in reduced use of diagnostic investigations over the subsequent 5 years.

Increased colonic bile acids can cause chronic diarrhea. Bile acid diarrhea (BAD) is treatable by sequestrants, and may be secondary to ileal disease or primary BAD. It is underdiagnosed, partly because the selenium-75-homocholic acid taurine (SeHCAT) retention test is not available in many countries, and is underutilized in others. Serum 7α-hydroxy-4-cholesten-3-one (C4), a measure of bile acid synthesis, is available for diagnosis in specialist centers. Recently, deficiency of the ileal hormone fibroblast growth factor 19 (FGF19) has been shown in BAD. Our aim is to evaluate the diagnostic value of FGF19 in a large and prospective group of patients with chronic diarrhea, previously investigated with C4. Patients undergoing routine investigation provided fasting blood samples. C4 was determined by high-performance liquid chromatography, and used to stratify two groups: group 1 (n=119), consisting of patients with normal C4 (≤ 28 ng/ml), and group 2 (n=139), consisting of patients with high C4 (>28 ng/ml), including any of the possible causes of BAD. Serum FGF19 was measured in stored samples by enzyme-linked immunosorbent assay. FGF19 and C4 were significantly inversely related (r(s)=-0.64, P<0.001). Patients with raised C4 had significantly lower median FGF19 values. Both of these were more marked when secondary to ileal disease, in particular ileal resection, than in primary BAD. The sensitivity and specificity of FGF19 at 145 pg/ml for detecting a C4 level >28 ng/ml were 58% and 79%, respectively. For C4 >60 ng/ml, these were 74% and 72%; on receiver-operating characteristic analysis, the area under the curve was 0.80 (95% confidence interval 0.74-0.87). Serum FGF19 could be developed as a simple blood test to increase the diagnostic rates of BAD.

Bile acid malabsorption occurs when there is impaired absorption of bile acids in the terminal ileum, so interrupting the normal enterohepatic circulation. The excess bile acids in the colon cause diarrhea, and treatment with bile acid sequestrants is beneficial. The condition can be diagnosed with difficulty by measuring fecal bile acids, or more easily by retention of selenohomocholyltaurine (SeHCAT), where this is available. Chronic diarrhea caused by primary bile acid diarrhea appears to be common, but is under-recognized where SeHCAT testing is not performed. Measuring excessive bile acid synthesis with 7α-hydroxy-4-cholesten-3-one may be an alternative means of diagnosis. It appears that there is no absorption defect in primary bile acid diarrhea but, instead, an overproduction of bile acids. Fibroblast growth factor 19 (FGF19) inhibits hepatic bile acid synthesis. Defective production of FGF19 from the ileum may be the cause of primary bile acid diarrhea.

BackgroundBile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD.MethodsA cohort of patients with chronic diarrhoea who underwent 75selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea.FindingsOf 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (rs=−0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis.InterpretationThe diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into potential metabolic causes.

OBJECTIVES:Increased colonic bile acids can cause chronic diarrhea. Bile acid diarrhea (BAD) is treatable by sequestrants, and may be secondary to ileal disease or primary BAD. It is underdiagnosed, partly because the selenium-75-homocholic acid taurine (SeHCAT) retention test is not available in many countries, and is underutilized in others. Serum 7α-hydroxy-4-cholesten-3-one (C4), a measure of bile acid synthesis, is available for diagnosis in specialist centers. Recently, deficiency of the ileal hormone fibroblast growth factor 19 (FGF19) has been shown in BAD. Our aim is to evaluate the diagnostic value of FGF19 in a large and prospective group of patients with chronic diarrhea, previously investigated with C4.METHODS:Patients undergoing routine investigation provided fasting blood samples. C4 was determined by high-performance liquid chromatography, and used to stratify two groups: group 1 (n=119), consisting of patients with normal C4 (≤ 28 ng/ml), and group 2 (n=139), consisting of patients with high C4 (>28 ng/ml), including any of the possible causes of BAD. Serum FGF19 was measured in stored samples by enzyme-linked immunosorbent assay.RESULTS:FGF19 and C4 were significantly inversely related (r s =-0.64, P<0.001). Patients with raised C4 had significantly lower median FGF19 values. Both of these were more marked when secondary to ileal disease, in particular ileal resection, than in primary BAD. The sensitivity and specificity of FGF19 at 145 pg/ml for detecting a C4 level >28 ng/ml were 58% and 79%, respectively. For C4 >60 ng/ml, these were 74% and 72%; on receiver-operating characteristic analysis, the area under the curve was 0.80 (95% confidence interval 0.74-0.87).CONCLUSIONS:Serum FGF19 could be developed as a simple blood test to increase the diagnostic rates of BAD.

Introduction and aimsInfliximab (IFX) is a recognised effective therapy in moderate to severe inflammatory bowel disease (IBD). There has been an evolvement in IBD management towards a treat-to-target approach, with therapeutic drug monitoring (TDM) playing an increasingly essential part to optimise personalised care. Presently there is no standardised guidance defining a treatment strategy for patients on IFX although several treatment algorithms have been proposed. The aim of this project is to evaluate the utility of IFX TDM in patients with IBD, in our hospital.MethodsThis is a single centre retrospective cohort analysis of patients with IBD receiving IFX that had TDM between January 1st2017 to June 30th2018. The indications of requests, IFX trough levels, presence of anti-drug antibody (ADA) and clinical outcomes were analysed. The outcome was to compare the clinical outcomes for TDM done reactively versus proactive monitoring. Reactive TDM was requested in a patient due to active symptoms or asymptomatic patients with evidence of active inflammation on radiology and/or endoscopy.ResultsA total of 54 patients were included in this study. 37 had Crohn’s Disease (CD) and 17 had Ulcerative Colitis (UC) with a mean age of 43 years and 51 years respectively. These patients were tested at least once within 71 TDM results obtained. Out of these TDM results, 49% (n=35) were requested reactively, 39% (n=28) for proactive monitoring and 12% (n=8) unclear reasons. The mean and median infliximab trough levels were 3.8 μg/ml and 4.7 μg/ml respectively (range <0.4 to greater than 10 μg/ml). 37% (n= 20) had subtherapeutic levels with positive ADA.Results of TDM in 60% (n=21) and 75% (n=21) in the reactive and proactive group respectively did not alter patients’ management (p=0.284). 17% (n=6) switched to an alternate biologic agent in the reactive group and 7.1% (n=2) in the proactive made a switch. There was a need of 5.7% (n=2) and 7.1% (n=2) in the reactive and proactive groups respectively for intestinal surgery. 8.5% (n=3) stopped biologic therapy in the reactive group and nil in proactive group.ConclusionIn our experience, IFX TDM reactively or proactively, did not alter clinical outcome/management in the majority or our patients. It is likely that TDM served to ensure on going continuation of the drug. We were able to change patient’s treatment (biologic switch) in a small number of patients through proactive monitoring and stop therapy in a small proportion of patients when taking a reactive TDM approach. Ideally TDM pathways need to be formulated to deliver a more organised personalised care with anti-TNF prescribing.

IntroductionThe Inflammatory Bowel Disease (IBD) Standards of Care recommend that defined arrangements are in place to allow for direct admission or assessment to a gastroenterology unit for patients with UC or Crohn’s. Currently in Leicester there is no facility for rapid access or direct admission to inpatient GI services. The aim of this study was to establish how patients with (IBD) accessed secondary-care services when admission was required.MethodsConsecutive patients admitted to gastroenterology with an established diagnosis of IBD were asked to complete a questionnaire exploring their point of access, admission process, waiting times and treatment during admission before their discharge from hospitalResults50 patients were recruited (30 UC,19 CD,1 indeterminate) First point of access after admission was recommended included 30 pts arriving at A&E,11 via medical admission unit, 7 directly via gastroenterology services and 2 to other departments.Other pathways once admitted involved 14 pts transferring to 2-wards and 29 pts to 3 wards.32 patients were commenced Intravenous steroids in first 24 hours, 8 patients waited longer than 24 hours. 8 patients did not commence any treatment relating to an acute exacerbation of IBD ConclusionsPatients were admitted to a number of different wards via a variety of routes. Many were waiting for long periods of time & some patients did not require hospital admission. As a result of this evaluation we have established a ‘Hot Clinic’

BackgroundIBD, both Crohn’s disease and ulcerative colitis, is associated with significant functional disability. Gastrointestinal symptoms alone are not the sole purpose of the interaction between patients and providers. In order to ascertain patients’ disabilities, we utilized the recently developed IBD Disk to help determine their functional concerns and initiate relevant conversation. We aimed to ascertain patient acceptability and their major disabilities.Patients and MethodsIn this multicenter study, IBD patients at their outpatient visit were given the paper version of the IBD Disk. Patients were asked to score their level of disability for each item of the IBD Disk. The completed scores were then shared with their healthcare provider to act as a focus of discussion during the consultation. Patients and clinicians were also asked to provide informal qualitative feedback as to the benefits of the IBD Disk and areas for improvement.ResultsA total of 377 (female 60%) patients completed the questionnaires over the study period. Patient acceptability scored on a 0–10 Likert scale was excellent. All patients scored all domains of disability. Sleep, energy, and joint pain were the highest scoring domains of the IBD Disk, scoring higher than digestive symptoms. Clinicians and patients agreed that the IBD Disk allowed for ease of communication about disability symptoms and relevance to their day-to-day functioning.ConclusionThe IBD Disk is a novel easy-to-use tool to assess the functional disability of patients. We next plan to utilize it in the form of an electronic app internationally and in relation to treatment commencement and escalation.