Bile Acid Malabsorption Research Articles

Functional intestinal symptoms in patients with inflammatory bowel disease: recommendations of the American Gastroenterological Association (2019)

The paper presents overview of the latest recommendations of the American Gastroenterological Association on the management of patients with functional intestinal symptoms (FIS). It was noted that the prevalence of irritable bowel syndrome (IBS) in patients with inflammatory bowel disease (IBD) amounts up to 39 % at average and more often observed at Crohn’s disease (CD) than at ulcerative colitis. The level of fecal calprotectin should be considered as a sensitive marker, allowing differential diagnosis between functional and inflammatory changes in intestine. The monitoring of fecal calprotectin is performed once every 3 — 6 months. In case of its increase, one can predict the risk of IBD exacerbation. In cases of appropriate symptoms, and if the fecal calprotectin level is elevated or borderline, a colonoscopy with a biopsy and histological examination is mandatory. At suspicious fibrostenosing CD form or if fistula is present, CT enterocolography is performed. Among the pathophysiological mechanisms that are potentially capable to affect the persistence of FIS in patients with IBD, inflammatory-associated deviations from the axis «central nervous system -gastrointestinal tract» are considered, mechanisms non-specifically associated with IBD, changes in the structure and function of the digestive tract due to IBD, such as malabsorption of bile acids, syndrome of intestinal bacterial overgrowth, exocrine pancreatic insufficiency, carbohydrate malabsorption and others. In the treatment of FIS and IBD, both non-drug (diet, psychotherapy) and drug-based symptom-based treatment methods can be used with account of the pathophysiological mechanisms. It has been concluded that at FIS and IBD combination, the restrictive diets, psychotherapy, antispasmodics and antidepressants, antibiotics (rifaximin) and probiotics are potentially useful. The additional randomized controlled trials are needed to work out more personalized approach to the management of patients with this pathology, as well as the study of new methods of treatment, such as fecal microbial transplantation.

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

Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. 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. 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. 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.

Diagnosis and management of bile acid diarrhoea: a survey of UK expert opinion and practice

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...

Management of Diarrhea in Patients With Carcinoid Syndrome.

Neuroendocrine tumors (NETs) arise from enterochromaffin cells found in neuroendocrine tissues, with most occurring in the gastrointestinal tract. The global incidence of NETs has increased in the past 15 years, likely due to better diagnostic methods. Small-bowel NETs are frequently associated with carcinoid syndrome (CS). Carcinoid syndrome diarrhea occurs in 80% of CS patients and poses a substantial symptomatic and economic burden. Patients with CS diarrhea frequently suffer from diarrhea and flushing and report corresponding impairment in quality of life, requiring substantial changes in daily activities and lifestyle. Treatment paradigms range from surgical debulking to liver-directed therapies to treatment with somatostatin analogs, nonspecific anti-diarrheal agents, and a tryptophan hydroxylase inhibitor. Other causes of diarrhea, including steatorrhea, short bowel syndrome, and bile acid malabsorption, should be considered in NET patients with refractory diarrhea. More therapeutic options are needed for symptomatic management of patients with NETs, and better understanding of the pathophysiology can empower clinicians with improved patient care.

Chemical synthesis of 7α-hydroxycholest-4-en-3-one, a biomarker for irritable bowel syndrome and bile acid malabsorption

7α-Hydroxy-cholest-4-en-3-one is a biomarker for bile acid loss, irritable bowel syndrome, and other diseases associated with defective bile acid biosynthesis. Furthermore, 7α-hydroxy-cholest-4-en-3-one is the physiological substrate for cytochrome P450 8B1 (P450 8B1 or CYP8B1), the oxysterol 12α-hydroxylase enzyme implicated in obesity and cardiovascular health. We report the chemical synthesis of this physiologically important oxysterol beginning with cholesterol. The key feature of this synthesis involves a regioselective C3-allylic oxidation of a 3-desoxy-Δ4-7α-formate steroid precursor to form 7α-formyloxy-cholest-4-en-3-one, which was saponified to yield 7α-hydroxy-cholest-4-en-3-one.

Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea.

Bile acid diarrhea (BAD) is common with ileal resection, Crohn's disease, and diarrhea-predominant irritable bowel syndrome. Here, we demonstrate the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor (R)-benzopyrimido-pyrrolo-oxazine-dione-27 (BPO-27) in reducing bile acid-induced fluid and electrolyte secretion in colon. Short-circuit current measurements in human T84 colonic epithelial cells and planar colonic enteroid cultures showed a robust secretory response following mucosal but not serosal addition of chenodeoxycholic acid (CDCA) or its taurine conjugate, which was fully blocked by CFTR inhibitors, including (R)-BPO-27. (R)-BPO-27 also fully blocked CDCA-induced secretory current in murine colon. CFTR activation by CDCA primarily involved Ca2+ signaling. In closed colonic loops in vivo, luminal CDCA produced a robust secretory response, which was reduced by ∼70% by (R)-BPO-27 or in CFTR-deficient mice. In a rat model of BAD produced by intracolonic infusion of CDCA, (R)-BPO-27 reduced the elevation in stool water content by >55%. These results implicate CFTR activation in the colon as a major prosecretory mechanism of CDCA, a bile acid implicated in BAD, and support the potential therapeutic efficacy of CFTR inhibition in bile acid-associated diarrheas.-Duan, T., Cil, O., Tse, C. M., Sarker, R., Lin, R., Donowitz, M., Verkman, A. S. Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea.

P3.25: INTESTINAL CHOLESTEROL ABSORPTION IS PRESERVED AFTER ISOLATED INTESTINAL TRANSPLANTATION DESPITE INCREASED CHOLESTEROL SYNTHESIS

Introduction. We aimed to investigate cholesterol metabolism in relation to nutritional status and serum lipids after isolated intestinal transplantation (ITX). Methods. Seven patients who had undergone isolated ITX including ascending colon at median age of 17.3 (range, 5.9–52) years due to intestinal failure caused by chronic intestinal pseudo obstruction (n=5) and total intestinal aganglionosis (n=2) were included median 3.5 (IQR, 2.9–7.4) years after ITX. Blood samples were analyzed for fat-soluble vitamins (A, E, D-25-OH), prealbumin, and cholesterol (total, LDL, HDL) and triglyceride levels. In six patients and 14 heathy age- and gender-matched controls, cholesterol metabolism was assessed with serum non-cholesterol sterols. The ratios to cholesterol (102 x µmol/mmol of cholesterol) of the serum cholesterol precursors (cholestenol, desmosterol and lathosterol) reflect cholesterol synthesis, while those of plant sterols (campesterol, sitosterol, and avenasterol) and cholestanol reflect cholesterol absorption efficiency. Lathosterol/cholestanol ratio reflects the balance between cholesterol absorption and synthesis and campesterol/cholestanol ratio reflects the plant sterol intake. Results. Patients were on tacrolimus-based maintenance immunosuppression without current signs of acute or chronic transplant rejection. All patients had weaned off PN median 39 days (IQR 21–215) after ITX and had a median body mass-index of 18.2 (IQR, 16.6–19.1) kg/m2. The levels of fat-soluble vitamins and prealbumin were mostly in normal range while plasma HDL cholesterol was low and triglyceride levels were increased in most patients (Table 1). Cholesterol precursor levels were significantly increased while plant sterols and cholestanol were not significantly different between patients and controls (Table 2). Increased lathosterol/cholestanol-ratio suggest that cholesterol synthesis markedly predominated absorption in patients’ whole body cholesterol homeostasis while the campesterol/cholestanol ratio suggest that the plant sterol intake was decreased in patients compared to controls (Table 2). Conclusion. Following isolated ITX, intestinal cholesterol absorption efficiency is preserved, while cholesterol synthesis increases likely to compensate malabsorption of bile acids. Satisfactory nutritional status, normal fat-soluble vitamin levels and preserved cholesterol absorption suggest that the compensatory increase was sufficient to maintain adequate lipid absorption.

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

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 5year 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.

1980-P: A Characterization of Postprandial Glucose Metabolism and Incretin Hormone Responses in Patients with Bile Acid Malabsorption

Bile acid malabsorption (BAM) is characterized by an excessive spill-over of bile acids to the colon leading to bile acid-induced diarrhea; the condition is usually treated with bile acid sequestrants. Bile acids have been demonstrated to modulate the secretion of the incretin hormone glucagon-like peptide 1 (GLP-1) and the aim of this study was to characterize postprandial glucose metabolism and incretin hormone responses in patients with BAM. Twelve patients with BAM (6 women; mean age 39.1 (SD 13.2); mean BMI 28.4 kg/m2 (SD 1.2); HbA1c 31.4 (SD 3.7)) and 12 healthy gender, age, BMI and HbA1c-matched controls (6 women; mean age 39.3 (SD 15.6); mean BMI 29,1 kg/m2 (SD 1.1); HbA1c 31.0 (SD 2.8)) were subjected to two 4-hour standardized liquid meal tests with double-blinded single-dose administration of the bile acid sequestrant colesevelam (3.75 g) and placebo, respectively, performed on separate days, and in randomized order. Fasting and postprandial plasma GIP and GLP-1 concentrations were comparable among patients with BAM and control subjects and unaffected by colesevelam administration. Peak plasma glucose concentrations were higher in BAM patients vs. control subjects, but area under curve for plasma glucose did not differ between the two groups. Patients with BAM exhibited significantly higher postprandial serum C-peptide concentrations and hyperglucagonemia compared to controls. Single-dose colesevelam had no effect on postprandial glucose or glucagon excursions in any of the groups but decreased the postprandial C-peptide response in BAM patients. Patients with BAM are characterized by elevated serum C-peptide concentrations and hyperglucagonemia whereas postprandial glucose tolerance and GLP-1 and GIP responses are similar to healthy controls. Disclosure M.L. Kårhus: None. D.P. Sonne: None. M.L. Thomasen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. A. Brønden: Other Relationship; Self; AstraZeneca. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding Novo Nordisk Foundation

Treatment of Bile Acid Malabsorption With Liraglutide

Treatment of Bile Acid Malabsorption With Liraglutide

976 – A Double-Blind, Randomized, Placebo-Controlled, Crossover, Multiple-Dose Study of Tropifexor, a Non Bile Acid Fxr Agonist, in Patients with Primary Bile Acid Diarrhea

976 – A Double-Blind, Randomized, Placebo-Controlled, Crossover, Multiple-Dose Study of Tropifexor, a Non Bile Acid Fxr Agonist, in Patients with Primary Bile Acid Diarrhea

Sa1947 – Randomized, Double-Blind, Placebo-Controlled Trial of Colesevelam in Patients with Bile Acid Diarrhea: Effects on Fecal Bile Acids, Colonic Transit, and Bowel Functions

Sa1947 – Randomized, Double-Blind, Placebo-Controlled Trial of Colesevelam in Patients with Bile Acid Diarrhea: Effects on Fecal Bile Acids, Colonic Transit, and Bowel Functions

Mo1857 – 7Alpha-Hydroxy-4-Cholesten-3-One for Diagnosis and Management of Bile Acid Malabsorption in IBD Patients: A 2-Year Clinical Experience

Mo1857 – 7Alpha-Hydroxy-4-Cholesten-3-One for Diagnosis and Management of Bile Acid Malabsorption in IBD Patients: A 2-Year Clinical Experience

Chronic diarrhoea in adults: what not to miss.

Chronic diarrhoea remains a diagnostic challenge, with numerous causes and few effective symptomatic treatments. This review focuses on new methods for diagnosis of common disorders and alerts readers to rarer causes through a systematic approach to the underlying mechanisms. New strategies are emerging to stratify the need for endoscopic investigation. Faecal immunochemical testing, combined with standard blood tests, shows promise in excluding colorectal cancers, adenoma and inflammatory bowel disease, challenging the current use of faecal calprotectin. Serum analysis for markers of bile acid synthesis has been refined, potentially streamlining diagnostic pathways of bile acid malabsorption for those who are unable to access nuclear medicine scans, but the positive predictive value of faecal elastase in low prevalence populations has been questioned. Novel markers such as volatile organic compounds and stool DNA analyses continue to develop. A systematic approach to investigation of chronic diarrhoea will ensure all relevant causes are considered and minimize the chance of a missed diagnosis. Combination of clinical features with noninvasive testing supports a judicious approach to endoscopic investigations but further innovation will be needed to resolve the diagnostic challenge that diarrhoea poses.

Mo1542 – Primary Bile Acids in a Single Fecal Sample for the Diagnosis of Bile Acid Diarrhea: Relationship to Sehcat Testing

Mo1542 – Primary Bile Acids in a Single Fecal Sample for the Diagnosis of Bile Acid Diarrhea: Relationship to Sehcat Testing

856 – Assessment of the Impact of Introducing Fecal Bile Acid Diagnostic Test for Bile Acid Diarrhea in 250 Patients in Clinical Practice and on Prediction of Response to Bile Acid Sequestrants

856 – Assessment of the Impact of Introducing Fecal Bile Acid Diagnostic Test for Bile Acid Diarrhea in 250 Patients in Clinical Practice and on Prediction of Response to Bile Acid Sequestrants

859 – Identification of Bile Acid Diarrhea in Adolescents with Diarrhea Predominant Irritable Bowel Syndrome

859 – Identification of Bile Acid Diarrhea in Adolescents with Diarrhea Predominant Irritable Bowel Syndrome

Primary bile acid diarrhea in a community gastroenterology practice

When first described in 1976, primary bile acid diarrhea (BAD Type 1) was regarded as a very rare cause of chronic diarrhea. Today, the incidence is estimated as > 1 %. Availability of diagnostic tools varies widely and, in Germany, there is no generally consented recommendation for their use. BAD is still widely underdiagnosed.Since the beginning of the '90 s, we have added a therapeutic trial with cholestyramine to our diagnostic approach of chronic diarrhea. Patients with a positive test were offered a Selenium-homocholic acid taurine (SeHCAT) test for confirmation of bile-acid-diarrhea (BAD), using a 7-day-retention of 20 % as cut-off value.From April 1991 to March 2017, after exclusion of other relevant causes for chronic diarrhea like IBD, celiac disease or microscopic colitis, 70 patients with a positive trial treatment of cholestyramine were identified for evaluation. Sixty ofthem had a SeHCAT test. Patients with BAD Type 1 and Type 3 were excluded, except for cholecystectomy.85 % (35/41) of patients with BAD Type 1 needed continued medical treatment (median follow-up time 8.3 (1 - 23.6) years). Among them, 68.6 % (24/35) took cholestyramine, 31.4 % (11/35) loperamide or another antidiarrheal treatment. 14.6 % (6/41) of patients reported a spontaneous remission after median 2.9 (0.7 - 5.7) years.In the group of patients with BAD after cholecystectomy, 82 % (8/11) still needed treatment after median 7.7 (1 - 24.5) years; 8 having taken cholestyramine, one patient nothing and two with spontaneous remissions.All (8/8) patients with a normal SeHCAT test (7-day retention > 20 %) had spontaneous relief after median 3.6 (1.2 - 6.3) months.Also, 70 % (7/10) of patients who had not been confirmed by the SeHCAT test still needed treatment after median 4.3 (3.7 - 18.3) years.Based on a trial treatment alone, diagnosis of BAD is possible but not assured. Due to its ubiquitous availability, it should be used consequently if other methods are not available. Despite the well-known shortcomings of cholestyramine, a therapeutic trial should be used more consequently. According to the current literature, using the SeHCAT test in the first place will give significantly better results and unnecessary follow-up examinations can be avoided. However, therapeutic consequences might be modest due to the well-known limitations of cholestyramine. A well-tolerated and licensed alternative to cholestyramine is urgently needed.

Effect of bile acid supplementation on endogenous lipid synthesis in patients with short bowel syndrome: A pilot study

Short bowel syndrome patients (SBS) receiving parenteral nutrition (PN) often have dyslipidaemia and can develop intestinal failure-associated liver disease (IFALD). These patients demonstrate increased cholesterol synthesis and hepatic lipogenesis. These lipid disturbances may be due to a decreased concentration of the bile acid pool or malabsorption. The aim of this pilot study was to evaluate the effect of bile acid administration on lipid synthesis in patients with SBS. The 24h fractional synthesis rate (FSR) of cholesterol and triglycerides was measured by the isotopic method (deuterated water) before and after 4 months of ursodeoxycholic acid (UDCA) treatment (20mg/kg/day). Five short bowel patients (age: 53.4±19.2 years) who had normal liver function and lipid plasmatic profiles received 1920±300ml of PN for 151±74 days (mean PN energy intake was 27.0±6.0kcal/kg body weight, composed with 3.87±1.38g/kg of carbohydrate, 0.72±0.25g/kg of fat and 1.10±0.23g/kg of amino acids). Plasma metabolites, liver enzymes, 7-α-OH-cholesterol and steatosis levels were also evaluated before and after treatment. Student's t-tests were performed, and the results were expressed in means (±SD). After treatment, decreases in the absolute values of cholesterol synthesis (0.31±0.12mmolL-1 to 0.24±0.11mmolL-1; p<0.05), FSR of cholesterol (31.6±4.7% to 26.4±4.7%; p=0.06) and FSR of triglycerides (12.8±5.8% to 9.2±5.5%; p<0.01) were observed. Cholesterol and alanine aminotransferase concentrations also decreased (ALT) (p<0.05). The absolute values of triglyceride synthesis and triglyceride concentrations remained unchanged. In SBS patients, UDCA decreases the hepatic synthesis of triglycerides and cholesterol. These results suggest that UDCA could prevent the onset of the IFALD.

Aquaporin Expression in Colonic Mucosal Biopsies From Irritable Bowel Syndrome With Diarrhea.

INTRODUCTION:Aquaporin (AQP) channels are involved in regulating fluid homeostasis in the colon. Several AQP channels were detected in human colon epithelial cells. In a previous study, rats fed 1% (wt/wt) sodium cholate had increased AQP3, 7, and 8 levels, suggesting AQP involvement in bile acid diarrhea (BAD). Our aim was to compare AQP expressions in rectosigmoid mucosal (RSM) biopsies from patients with irritable bowel syndrome–diarrhea (IBS-D) (divided into those with normal or high fecal BA excretion) and in patients with IBS-constipation (IBS-C) compared with healthy controls.METHODS:In RSM biopsies from 44 patients with IBS-D (with normal (<) or high (>2,337 μmol/48 hours (BAD)) fecal BA excretion), 10 patients with IBS-C, and 17 healthy controls, we measured expressions of AQP1, 3, 7, and 8, with RT-PCR (housekeeper gene GAPDH). We analyzed RNA for expression by RT2-PCR assays, with expression calculated using 2−ΔΔCT-based fold-change. Comparisons of IBS groups were corrected for false detection rate (Bonferroni correction for 12 comparisons; P < 0.0042). AQP protein measurements on biopsies from 3 healthy controls, 3 patients with IBS-D, and 3 patients with BAD were performed by western blots (GAPDH housekeeping protein).RESULTS:In RSM from patients with IBS-D (but not IBS-C), mRNA expression of AQP3 was decreased, and AQP7 and 8 were increased relative to controls. Fold differences were not different in IBS-D with or without BAD. Western blots confirmed increased expression of AQP7 and 8 and decreased AQP3 proteins in biopsies from patients with IBS-D compared with controls.CONCLUSIONS:Increased AQP7 and 8 and decreased AQP3 expressions in RSM suggest that further studies on AQPs' potential role in the pathophysiology of diarrhea in IBS-D are warranted.