Sanjeev S. Pattni

Managing bile acid diarrhoea

Bowel symptoms including diarrhoea can be produced when excess bile acids (BA) are present in the colon. This condition, known as bile acid or bile salt malabsorption, has been under recognized, as the best diagnostic method, the 75Se-homocholic acid taurine (SeHCAT) test, is not available in many countries and is not fully utilized in others. Reduced SeHCAT retention establishes that this is a complication of many other gastrointestinal diseases. Repeated studies show SeHCAT tests are abnormal in about 30% of patients otherwise diagnosed as diarrhoea-predominant irritable bowel syndrome or functional diarrhoea, with an estimated population prevalence of around 1%. Recent work suggests that the condition previously called idiopathic bile acid malabsorption (BAM) is not in fact due to a defect in absorption, but results from an overproduction of BA because of defective feedback inhibition of hepatic bile acid synthesis, a function of the ileal hormone fibroblast growth factor 19 (FGF19). The approach to treatment currently depends on binding excess BA, to reduce their secretory actions, using colestyramine, colestipol and, most recently, colesevelam. Colesevelam has a number of potential advantages that merit further investigation in trials directed at patients with bile acid diarrhoea.

Recent advances in the understanding of bile acid malabsorption

INTRODUCTION Bile acid malabsorption (BAM) is a syndrome of chronic watery diarrhoea with excess faecal bile acids. Disruption of the enterohepatic circulation of bile acids following surgical resection is a common cause of BAM. The condition is easily diagnosed by the selenium homocholic acid taurine (SeHCAT) test and responds to bile acid sequestrants. Idiopathic BAM (IBAM, primary bile acid diarrhoea) is the condition where no definitive cause for low SeHCAT retention can be identified. SOURCES OF DATA Review of PubMed and major journals. AREAS OF AGREEMENT Evidence is accumulating that BAM is more prevalent than first thought. Management of chronic diarrhoea involves excluding secondary causes. Treatment of the condition is with bile acid binders. AREAS OF CONTROVERSY SeHCAT testing is not widely performed, limiting awareness of how common this condition can be. The underlying mechanism for IBAM has been unclear. GROWING POINTS Increasing awareness of the condition is important. Alternative mechanisms of IBAM have been suggested which involve an increased bile acid pool size and reduced negative feedback regulation of bile acid synthesis by FGF19. New sequestrants are available. AREAS TIMELY FOR DEVELOPING RESEARCH Further research into the precise mechanism of IBAM is needed. Improvements in the recognition of the condition and optimization of treatment are required.

Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention

Bile acid diarrhoea is a common, under‐diagnosed cause of chronic watery diarrhoea, responding to specific treatment with bile acid sequestrants. We previously showed patients with bile acid diarrhoea have lower median levels compared with healthy controls, of the ileal hormone fibroblast growth factor 19 (FGF19), which regulates bile acid synthesis.

Fibroblast Growth Factor 19 and 7α-Hydroxy-4-Cholesten-3-one in the Diagnosis of Patients With Possible Bile Acid Diarrhea

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 (rs=−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.

New Insights into Bile Acid Malabsorption

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.

Characterizing Factors Associated With Differences in FGF19 Blood Levels and Synthesis in Patients With Primary Bile Acid Diarrhea

OBJECTIVES: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.METHODS:Patients with PBAD, defined by reduced 75Se-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.RESULTS: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).CONCLUSIONS:These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.

A positive SeHCAT test results in fewer subsequent investigations in patients with chronic diarrhoea

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. Methods Patients 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. Results 90 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). Conclusion A positive diagnosis of bile acid diarrhoea, made by a SeHCAT test, resulted in reduced use of diagnostic investigations over the subsequent 5 years.

Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis

Background Bile 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. Methods A 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. Findings Of 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. Interpretation The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into potential metabolic causes.

PTH-251 Bile acid diarrhoea is associated with gallstones

Introduction Bile acid diarrhoea (BAD) is a common disorder which in the primary, idiopathic form may result from low serum fibroblast growth factor 19 (FGF19) producing impaired regulation of bile acid synthesis. 75Selenium Homocholic Acid Taurate (SeHCAT) 7day retention is used in diagnosis, predicting faecal bile acid loss and correlating with fasting serum FGF19. Several groups have shown that overweight and obesity are associated with BAD and low FGF19. Reduced FXR target gene expression, of which FGF19 is one, is associated with gallstones. We hypothesised that the two conditions might share pathophysiologic mechanisms and commonly coexist. Method SeHCAT 7 day retention values were collected between 2003–2014 in patients being investigated for chronic diarrhoea. Other conditions known to be associated with BAD such as cholecystectomy or Crohn’s disease were recorded. A subset of these patients had fasting FGF19 measured. Retrospectively, gallbladder imaging was added to database following cross-referencing with the NHS trust’s PACS system. Where multiple investigations had been performed, the test nearest to the date of the SeHCAT test was recorded. Imaging reporting gallbladder polyps without gallstones were excluded from the final analysis. Results Of 578 SeHCAT values on the database, 303 (52%) were positive with a value <15%. 183 had imaging that reported upon the gallbladder, of which 7 were excluded due to the presence of polyps, leaving 176. Of these 103 (59%) had a positive SeHCAT scan, 47 (27%) had gallstones, 12 (7%) had a cholecystectomy, so 59 (34%) had either gallstones or cholecystectomy. There was no significant difference in the rate of gallstones or cholecystectomy by gender (64% v 72%, p = 0.2), but mean age in the gallstones/cholecystectomy group was higher (50 v 57, p < 0.005). Median SeHCAT for the whole cohort was 11.7%. The median SeHCAT for those with gallstones or cholecystectomy was significantly lower than those without (7.2% v 14%, p < 0.001). With cholecystectomy excluded, the median SeHCAT was still lower for those with gallstones (3.8% v 14%, p < 0.0001). Overall, a SeHCAT value of <15% conferred an increased risk of gallstones or cholecystectomy (OR=2.0, 95% CI 1.04–3.919, p < 0.05) and the presence of primary bile acid diarrhoea was associated with gallstones, although this did not reach statistical significance (OR=1.98, 95% CI 0.65–5.99, p = 0.23). FGF19 was measured in 60 patients with imaging, of whom 15 had gallstones or cholecystectomy. There was no significant difference in the median serum FGF19 between those with gallstones or cholecystectomy and those without (224 v 227 pg/ml, p = 0.7). Conclusion Bile acid diarrhoea is associated with gallstones, even when adjusted for cholecystectomy which is a known risk factor for BAD. Bile acid diarrhoea and gallstones may share a pathophysiological mechanism. Disclosure of interest None Declared.

PTU-198 Serum FGF19 Levels are Related to Disease Activity in Ileal Crohn’S Disease

Introduction FGF19 is a polypeptide hormone produced in the ileum. It’s transcription is stimulated by bile acid (BA) activation of the Farnesoid X receptor (FXR). In human cell lines the transcription of FGF19 is suppressed by pro inflammatory cytokines (TNF-α, IL-1β) via inhibitory effects on ‘FXR’. We hypothesised that circulating FGF19 levels will be low in patients with active ileal Crohn’s disease and that these levels will increase after the administration of anti-inflammatory treatments commonly used to induce clinical remission. Methods Fasting circulating FGF19 levels were measured using ELISA. Disease activity was assessed using the Harvey Bradshaw index. In a cross sectional study, 30 patients with Crohn’s disease involving the ileum (and no previous intestinal resections) were recruited, 12 with active disease (HBI > 4) and 8 with inactive disease. In longitudinal studies, 4 patients with active colonic disease and 5 patients with active disease involving the ileum had samples taken whilst their disease was active and again during medically induced clinical remission (HBI < 4 induced by corticosteroids or anti-TNF) over 6 weeks later. 6 patients with CD involving the ileum (5 with previous ileal resection) whose disease remained inactive, had FGF19 levels samples measured taken on 2 separate occasions over 6 weeks apart. Non parametric statistical tests were used (Mann whitney, medians and ranges shown). Results In the cross sectional study serum FGF19 levels were significantly lower in those patient with CD involving the ileum with active disease (median 40, 3- 338) compared to inactive disease (median 147, 46 –255, p = 0.0486). In the longitudinal studies, serum FGF19 levels were significantly lower in the patients with CD involving the ileum whilst their disease was active (median 35, range 3 – 54) compared to paired levels taken after medically induced remission (median 141, range 116 – 184, p = 0.002). Paired FGF19 levels were not statistically different in the 4 patients with colonic Crohn’s disease during active disease (median 105, range 36 – 151) compared to medically induced clinical remission (median 86, range 40 – 120, p = 0.48). There was no significant difference in paired FGF19 levels In the 6 patients with CD involving the ileum with inactive disease taken on 2 seperate occasions (5 with previous ileal resections). Conclusion Circulating FGF19 levels are lower during active ileal or ileo-colonic crohn’s disease and increase after medically induced clinical remission. FGF19 levels may be induced by anti-inflammatory treatments either as a result of the inhibition of inflammtory cytokines within the ileum or due to enhanced BA absorption post treatment. Disclosure of Interest None Declared.