Richard N. Appleby

The role of bile acids in functional GI disorders

Bile acids are increasingly implicated in the pathogenesis of functional GI disorders. New mechanisms have recently been described in the irritable bowel syndrome, chronic diarrhea and chronic idiopathic constipation. Identification of bile acid signaling through farnesoid X receptor (FXR), transmembrane G‐coupled receptor 5 (TGR5) and fibroblast growth factor 19 (FGF19) has led to the development of new, directly acting therapeutic agents. Despite these advances primary bile acid diarrhea remains under‐recognized partly because of the lack of a widely available diagnostic test.

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 variant of FGF19 for treatment of disorders of cholestasis and bile acid metabolism.

Fibroblast growth factor 19 (FGF19) is increasingly recognized as a key hormone regulating many functions. A recent publication by Luo et al. in Science Translational Medicine has advanced understanding of the diverse actions of FGF19 and has suggested how therapeutics with this protein may be optimized (1).

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.

A young woman with abdominal distension

We present the case of a 34-year-old woman with haemorrhagic ascites and an extrinsic rectal mass on endoscopy. Endometrioma was subsequently confirmed by laparoscopy and biopsy. Intestinal endometriosis is common, and often mimics other gastrointestinal pathology. Haemorrhagic ascites or intestinal masses are rare presentations of endometriosis, and this is the only reported case of both occurring together. Endometriosis and ascites are more common in women of African descent, and although histological diagnosis requires laparoscopy, MRI has a high negative predictive value; 95% for intestinal endometriosis. Re-accumulation of ascites were prevented by starting a gonadotrophin antagonist.

Editorial: colesevelam effects on faecal bile acids in IBS with diarrhoea

therapy. The results of our study are straightforward and confirm a superiority of 14-day concomitant therapy over 14-day triple therapy in areas where increasing clarithromycin resistance have diminished the effectiveness of triple therapy. Similar good results have been recently reported for concomitant therapy in Southern Europe (Italy, Greece and Spain), where clarithromycin resistance ranges from 18% to 40%, and metronidazole resistance remains only modest (<30–40%). However, concomitant therapy is not infallible and typically will fail to achieve 90% cure rates in regions with high clarithromycin and metronidazole resistance, making dual resistance likely (e.g. Turkey, Korea, and Latin America) and in specific high-risk patients (e.g. previous use of both clarithromycin and metronidazole). Therefore, the golden rules for choice of treatment are: (i) use only what works best locally (preferably >90– 95% success), (ii) use only regimens optimised to maximise efficacy (i.e. optimised duration, acid suppression, antibiotic doses and dosing intervals) and (iii) to closely monitor treatment effectiveness over time.

PTH-123 In patients with chronic diarrhoea, diagnosing bile acid diarrhoea with a positive sehcat test results in fewer subsequent investigations

Introduction Chronic diarrhoea is a common condition which may result from a number of different disorders, including bile acid diarrhoea. Primary bile acid diarrhoea is found in around 36% of patients with functional diarrhoea or diarrhoea-predominant irritable bowel syndrome, but is often undiagnosed. We hypothesised that a positive diagnosis of bile acid diarrhoea would reduce the need in these patients for subsequent investigations to look for alternative diagnoses. Method Patients previously recruited to a prospective study of chronic diarrhoea, who had SeHCAT testing and subsequent follow-up at our institution, were identified and their electronic records were reviewed. The numbers of defined investigations undertaken between 3 months and 5 years after SeHCAT were compared. Results 90 patients were identified with primary bile acid diarrhoea (SeHCAT <15%, n=36) or with idiopathic diarrhoea (SeHCAT >15%, n=54). Follow-up had been performed on 29 and 39 respectively. There was no difference between these groups in the number of previous investigations or the date of the last contact. In the follow-up period, there was no significant difference in the proportion of these patients who had undergone endoscopic procedures (gastroscopy, colonoscopy, sigmoidoscopy). However there was a higher proportion of patients in the SeHCAT-negative group who had undergone other investigations including imaging, physiological tests and blood tests (p=0.037). 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 (0.72 vs. 0.55) and the number of blood tests (median 33 vs. 21 tests per patient) 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 five years. Disclosure of Interest J. Turner: None Declared, S Pattni: None Declared, R Appleby: None Declared, J Walters Conflict with: Intercept, Novartis, Conflict with: GE Healthcare

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-326 A positive faecal calprotectin does not predict bile acid diarrhoea

Introduction Bile acid diarrhoea (BAD) is a common disorder which in the primary, idiopathic form may affect up to 1% of the population. 75Selenium Homocholic Acid Taurate (SeHCAT) 7 day retention is used in diagnosis, predicting faecal bile acid loss but is not available to primary care practitioners. The condition is chronic, causes significant morbidity and is easily treatable with bile acid sequestrants. Calprotectin is released into the intestinal lumen during neutrophil activation and apoptosis. A Faecal Calprotectin (FC) of >50 µg/g in the primary care setting has been reported to have a sensitivity and specificity of 82% and 77% respectively for organic GI disease.1In 2013 NICE recommended its use in primary care as a decision aid.2Since primary BAD does not have an inflammatory pathogenesis, we hypothesised that the faecal calprotectin test was not sensitive for bile acid diarrhoea. Method Faecal calprotectin was measured in patients attending for SeHCAT testing at Imperial Healthcare NHS trust between March 2014 and July 2014. Patients with known bile acid diarrhoea, or inflammatory bowel disease were also recruited from the gastroenterology clinic during the same period. All patients had undergone lower GI endoscopy previously. Faecal samples were analysed in the Imperial Healthcare Biochemistry Laboratory using a commercially available ELISA kit (EliA, Phadia AB, Uppsala, Sweden). Results 55 patients were recruited. Of these 32 (58%) were female, the mean age was 53 (range 23–88) and 41 (75%) had a SeHCAT scan, of which 25 (61%) were positive (<15% 7d retention). Overall 23 (42%) had a positive FC (>50 µg/g); 21 (38%) were known, or subsequently found to have traditional organic GI disease (14 Crohn’s, 3 ulcerative colitis, 1 radiation colitis, 3 hepatobiliary). 9 (22%) patients with a positive SeHCAT had a positive FC, all patients (n = 5, 12%) with IBD and a positive SeHCAT had a positive FC. If primary bile acid diarrhoea was excluded in the definition of organic disease, FC had a negative predictive value of 88% (95% CI: 71–96%) and a sensitivity and specificity of 83% (95% CI: 61–95%) and 88% (95% CI: 71–96%) respectively. However, if primary bile acid diarrhoea was included in the definition of organic disease, then FC has a negative predictive value of 43% (95% CI: 26–62%) and a sensitivity and specificity of 54% (35% CI: 37–70%) and 88% (95% CI: 62–98%) respectively. Conclusion By including primary bile acid diarrhoea in the definition of organic disease the sensitivity of FC falls to 54%, which is unacceptable for a screening test. Patients with undiagnosed BAD are likely to be denied referral to secondary care for diagnosis and subsequent treatment due to the current guidance. Disclosure of interest None Declared. References Polychronis P, et al. Scand J Gastroenterol. 2013;48:1048–1054 NICE diagnostics guidance 11, Issued Oct 2013