Bile acid malabsorption: An under-investigated differential diagnosis in patients presenting with diarrhea predominant irritable bowel syndrome type symptoms

Abstract

Objective. Bile acid malabsorption (BAM) has been reported as a possible cause of diarrhea predominant irritable bowel syndrome (D-IBS) type symptoms. We aimed to determine how commonly patients with D-IBS type symptoms had a diagnosis of BAM as demonstrated by a positive SeHCAT (75 Selenium-homocholic acid taurine) test (retention <10% at seven days). Materials and methods. A retrospective analysis was undertaken of patient's records for all patients who underwent a SeHCAT test between 2001 and 2009 in a tertiary hospital (Group A). Concurrently, a cohort of patients with Rome II D-IBS type symptoms was examined to determine the potential utility of SeHCAT test (Group B). Results. In Group A 39.2% (n = 107/273) of patients had a positive SeHCAT result. The median time from first hospital visit to SeHCAT result was 30 weeks. Predictive factors for BAM: terminal ileal Crohn's disease (p < 0.01), terminal ileal resection (p < 0.01), and previous cholecystectomy (p < 0.01). 33.6% of patients who had a positive SeHCAT also had Rome II D-IBS. In Group B the D-IBS control cohort only 1.9% of patients had undergone a SeHCAT scan (p < 0.001 compared to Group A). Conclusion. BAM is common and should be considered earlier when investigating unselected patients with D-IBS type symptoms.     

Bile acid malabsorption investigated by selenium-75-homocholic acid taurine (SeHCAT) scans: Causes and treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea

Background

The liver produces and secretes bile acids into the small intestine. In the small intestine, most of the bile acids are absorbed in the distal ileum with portal vein transportation back to the liver and resecretion (enterohepatic recycling). Increased spillover of bile acids from the small intestine into the colon (bile acid malabsorption) may affect the secretion of colonic water and electrolytes and result in watery diarrhoea.The aim of this study was to investigate the frequency of bile acid malabsorption and treatment responses to cholestyramine with ⁷⁵SeHCAT scanning among patients suffering from chronic watery diarrhoea.

Methods

This was a retrospective study that included all patients who received a ⁷⁵SeHCAT scan over a five-year period (2004-2009).

Results

In total, 298 patients (198 females, 100 men) with a median age of 42 years (range 16-82 years) were investigated.Bile acid malabsorption (⁷⁵SeHCAT retention < 15% after seven days) was identified in 201 patients (68%, 95% confidence interval (CI): 62%-73%). Bile acid malabsorption due to ileal dysfunction (Type I) was found in 77 patients, idiopathic bile acid malabsorption (Type II) was found in 68 patients and 56 patients with other conditions had bile acid malabsorption (Type III).Of the 150 patients who were able to take cholestyramine continuously, 108 patients (71%, CI: 63%-78%) reported a positive effect on their bowel habits.

Conclusions

Bile acid malabsorption is a frequent problem in patients with chronic watery diarrhoea. Treatment with bile acid binders was effective regardless of type and severity.     

Bile acid malabsorption in HIV infected patients with chronic diarrhoea

Aims: To look for the presence of bile acid malabsorption in HIV infected patients with chronic diarrhoea and determine whether bile sequestering agents may have a role in palliating this common problem.
Methods: Nineteen HIV infected patients with chronic diarrhoea (duration >one month) poorly controlled on conventional treatment were investigated using the seven day retention of ⁷⁵seleno-23-homocholic acid taurine (SeHCAT) as a measure of bile acid loss from the enterohepatic circulation. Patients with evidence of bile acid malabsorption were offered cholestyramine.
Results: Sixteen (84%) had evidence of bile acid malabsorption (<15% retention at seven days). Ten of the 16 patients with bile acid malabsorption had terminal ileal biopsies -six had ileitis and four normal histology, suggesting that malabsorption is not always related to terminal ileitis. Thirteen patients with bile acid malabsorption have been treated with cholestyramine and 11 have reported a symptomatic response.
Conclusions: Bile acid malabsorption can be demonstrated in some cases of HIV associated chronic diarrhoea and we suggest a therapeutic trial of a bile sequestering agent in patients whose symptoms are not well controlled using conventional anti-diarrhoeal agents.     

An evaluation of the use of serum 7-alpha-hydroxycholestenone as a diagnostic test of bile acid malabsorption causing watery diarrhea

BACKGROUND:

Bile acid malabsorption (BAM) is a recognized cause of watery diarrhea, often diagnosed empirically based on clinical response to cholestyramine. The radionuclide selenium-labelled homocholic acid-taurine whole body retention test is expensive, labour intensive and of limited availability.

OBJECTIVE:

To report on the clinical performance of serum 7-alpha-hydroxy-4-cholesten-3-one (7HCO) as a test of BAM in adult patients with unexplained diarrhea.

METHODS:

Patients with unexplained diarrhea were investigated over a three-year period. Final diagnosis was determined based on medical history and investigations, serum levels of 7HCO and response to cholestyramine. ROC analysis was used to determine the ideal upper reference range cut-off value to optimize sensitivity/specificity for BAM. Time of blood specimen collection was recorded to investigate possible variation in results throughout the working day.

RESULTS:

ROC analysis yielded a sensitivity/specificity of 90%/77% for type 1 BAM (ileal disease/resection) and 97%/74% for type 2 BAM (idiopathic) using 30 ng/mL as the upper limit of normal for serum 7HCO when compared with all other patients. Of 813 patients, 196 tested positive. Serum 7HCO levels were significantly higher in blood specimens that were collected between 12:00 and 13:00 (median 24 ng/mL) than in specimens collected between 09:00 and 10:00 (median 17 ng/mL) (P<0.05).

CONCLUSION:

Serum 7HCO testing is a simple, sensitive, noninvasive, inexpensive alternative to other more commonly used tests for BAM. Time of specimen collection, however, resulted in small but significant result variations and, although unlikely to have much impact on test value, it should ideally be standardized.     

The Bile Acid Turnover Rate Assessed with the 75SeHCAT Test Is Stable in Chronic Diarrhoea but Slightly Decreased in Healthy Subjects After a Long Period of Time

The stability of bile acid turnover rate was evaluated retrospectively using repeat SeHCAT tests in patients with chronic diarrhoea and prospectively for 16 years in healthy subjects. The SeHCAT values were stable in 39 patients with chronic diarrhoea, as shown by a comparison of the test results [data presented as median and (25th–75th percentile)]: 18% (8–23) in the first test versus 14% (9–21) in the second test [n = 39, P = 0.37, time interval 44 months (16–68), repeatability index >95%]. In contrast, they were reduced after 16 years in healthy subjects: 38% (30–49.5) in the first test versus 31% (21–49.5) in the second test (P < 0.03). In healthy subjects, the body mass index increased by 13% from 23.2 kg/m² (21–24.6) to 26.2 kg/m² (22.5–27.8) (P < 0.01) during the 16 years. There was a negative correlation between hepatic bile acid synthesis and the SeHCAT values (r = −0.615, P = 0.02, n = 14). In conclusion, the turnover rate of bile acids is stable over a long period of time in patients with chronic diarrhoea irrespective of bile acid malabsorption, suggesting that a repeat SeHCAT test is dispensable. There is a significant negative correlation between bile acid synthesis and SeHCAT test results in healthy subjects. The SeHCAT test values are slightly reduced in healthy subjects after 16 years.     

Mechanisms of triglyceride metabolism in patients with bile acid diarrhea

Bile acids(BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor(FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins(VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-Ⅱ, very low-density lipoproteins receptor(VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-Ⅲ, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea(BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.     

Biliary lipid composition in idiopathic bile acid malabsorption

Background—Chronic diarrhoea is the clinicalhallmark of patients presenting with idiopathic bile acidmalabsorption. Its pathogenesis is unknown; colonic water secretion canbe induced by dihydroxy bile acids, but it is not known whetherenrichment of the bile acid pool with these bile acids occurs in suchpatients. Furthermore, bile acid malabsorption is known to affectbiliary lipid composition, but no information is available for theidiopathic type.
Aims—To verify: (a) whetherdiarrhoea in patients with idiopathic bile acid malabsorption isassociated with enrichment of the bile acid pool with dihydroxy bileacids; and (b) whether supersaturation with cholesterol ofduodenal bile occurs in such patients as a result of chronic bile acid depletion.
Patients—Thirteen patients with idiopathic bileacid malabsorption diagnosed according to abnormal ⁷⁵SeHCATtest and absence of other organic diseases, and 23 control subjects.
Methods—Bile rich duodenal fluid was collectedduring intravenous ceruletide infusion in the fasting state. Biliarylipids were analysed by enzymatic assays and bile acids by highperformance liquid chromatography.
Results—Patients with idiopathic bile acidmalabsorption had a cholesterol saturation index similar to controls.Bile acid composition showed only a decrease in percentage cholic acid(29(2)% versus 36 (2)%; p<0.05); the dihydroxy:trihydroxy bile acid ratio was similar to controls.
Conclusions—Patients with idiopathic bile acidmalabsorption do not have an increased risk of forming cholesterolgallstones. The mechanism of diarrhoea does not seem to depend on anenrichment of the bile acid pool with dihydroxy bile acids.

Keywords:primary bile acid malabsorption; bile acids; diarrhoea; ⁷⁵SeHCAT; biliary lipids; cholesterol saturationindex

     

Bile Acid Malabsorption in Patients with Chronic Diarrhoea

The presence of bile acid malabsorption was studied in 24 patients with chronic diarrhoea without established cause despite extensive investigations. Bile acid absorption was evaluated with the ⁷⁵Se-homocholic acid taurine (SeHCAT) test. A therapeutic trial of cholestyramine was performed in 11 patients. Fourteen of the patients (58%) showed evidence of bile acid malabsorption. Of the 11 patients who were treated with cholestyramine, 3 had no improvement of their diarrhoea and also had a normal SeHCAT test result. Of the other eight patients, who also had pathologic SeHCAT test result, five improved on treatment, whereas three had no change of their diarrhoea. Seven of the 24 patients had a previous history of cholecystectomy. Four of them showed bile acid malabsorption; three of these were treated with cholestyramine and responded favourably. The results suggest that bile acid malabsorption may be common in chronic diarrhoea patients but may not always be the primary cause of diarrhoea.     

Bile acid malabsorption and bile acid diarrhea in intestinal resection

Bile acid fecal excretion and dihydroxy bile acid concentration in the fecal water of patients with large (N=6) and small (N=8) ileal resection, colectomy (N=5), and healthy controls (N=10) have been studied in order to evaluate the degree of bile acid malabsorption and the occurrence of bile acid diarrhea in intestinal resections of different extent. Bile acid malabsorption was severe in large ileal resections, mild in small ones, and slight in colectomy. The fecal pH seems to be a limiting factor in the occurrence of a bile acid diarrhea, playing a critical role in determining the dihydroxy bile acid solubility in the fecal water. These results seem to suggest that the bile acids may induce water secretion in the colon not only in small but also in large ileal resections.     

Obeticholic acid for severe bile acid diarrhea with intestinal failure: A case report and review of the literature

Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequestrants, such as colestyramine and colesevelam, which may be given in combination with the opioid receptor agonist loperamide. Some patients are refractory to conventional treatments. We report the use of the farnesoid X receptor agonist obeticholic acid in a patient with refractory bile acid diarrhea and subsequent intestinal failure. A 32-year-old woman with quiescent colonic Crohn's disease and a normal terminal ileum had been diagnosed with severe bile acid malabsorption and complained of watery diarrhea and fatigue. The diarrhea resulted in hypokalemia and sodium depletion that made her dependent on twice weekly intravenous fluid and electrolyte infusions. Conventional therapies with colestyramine, colesevelam, and loperamide had no effect. Second-line antisecretory therapies with pantoprazole, liraglutide, and octreotide also failed. Third-line treatment with obeticholic acid reduced the number of stools from an average of 13 to an average of 7 per 24h and improved the patient's quality of life. The fluid and electrolyte balances normalized. The effect was sustained during follow-up for 6 mo with treatment at a daily dosage of 25 mg. The diarrhea worsened shortly after cessation of obeticholic acid. This case report supports the initial report that obeticholic acid may reduce bile acid production and improve symptoms in patients with bile acid diarrhea.     

Analysis of ileal sodium/bile acid cotransporter and related nuclear receptor genes in a family with multiple cases of idiopathic bile acid malabsorption

INTRODUCTION Bile acids are synthesized from cholesterol in the liver and secreted into the small intestine, where they facilitate absorption of fat, fat-soluble vitamins and cholesterol[1]. The bile acids are then reabsorbed from the intestine and return…     

Bile Acid Malabsorption in Patients with Chronic Diarrhoea: Clinical Value of SeHCAT Test

Background: Bile acid malabsorption (BAM), a cause of chronic diarrhoea, can be diagnosed by the SeHCAT test. The purpose of this study was to evaluate the usefulness of SeHCAT testing by assessing the extent of BAM and describing the clinical characteristics in a group of patients with chronic diarrhoea. Clinical outcome after treatment with cholestyramine was also evaluated. Methods: During a 5-year period (1997-2001) the SeHCAT test was performed in 135 patients in whom a primary programme for diagnostic evaluation of chronic diarrhoea had not revealed a cause. File data from 133 patients could be evaluated. Results: In 44% of patients, bile acid absorption was normal with SeHCAT retention &#83 15%. Impaired SeHCAT retention was found in 56%. All patients with ileocaecal resections had retention values <10%. Patients with microscopic colitis presented with BAM in 39%. Only one patient with idiopathic BAM presented with steatorrhoea as opposed to 11 patients with type 1 and 3 BAM. Patients with idiopathic BAM and/or SeHCAT retention values <5% had the best response to treatment with cholestyramine. Conclusions: The SeHCAT test is of value in evaluation of patients with chronic diarrhoea as a second-line investigation with a high diagnostic yield. The only a priori parameter to predict BAM was the existence of ileocaecal resections. The result of the SeHCAT test seems to predict the benefit of treatment with cholestyramine.     

胶囊内镜在慢性腹泻中的诊断价值

目的分析胶囊镜在慢性腹泻中的诊断价值及进行安全性评估.方法收集2002年10月至2005年1月在上海瑞金医院进行胶囊内镜检查的慢性腹泻患者共24例(4女/20男,年龄39.67±9.41)及无消化道症状体检者80例(21女/59男,年龄46.43±10.26),进行诊断结果的相关统计性分析.结果在慢性腹泻患者中发现:空肠-回肠多发性溃疡5例(20.83%),回肠黏膜糜烂2例(8.33%),空肠增殖性病灶1例(4.17%),小肠血管畸形1例(4.17%);无消化道症状的体检者中发现:回肠息肉2例(2.50%),小肠血管畸形2例(2.50%),小肠黏膜糜烂1例(1.25%),空肠孤立性溃疡1例(1.25%).两组检查后胶囊均能顺利排出.小肠疾病在慢性腹泻患者中的患病率(37.50%)明显高于无消化道症状的体检者(7.50%),两者相较有明显的统计学意义(P＜0.01).结论胶囊内镜对慢性腹泻的诊断有重要的参考的价值,临床安全性好.     

Bile acid malabsorption in children and adolescents with chronic colitis

Bile acid malabsorption was measured as the fecal excretion of 14C after intravenous administration of carboxyl-14C-cholic acid and was studied in 31 patients, 8-17 years old, with chronic colitis. There were 15 patients with proven or probable Crohn's disease and 16 patients with ulcerative colitis. The mean excretion was 14.7% and 19.9%, respectively. The patients with moderate or severe inflammatory activity in the ascending colon, assessed by colonoscopy, had a significantly higher 14C excretion than the patients with no or mild inflammatory activity, 24.1% and 6.6%, respectively. These findings suggest that the ascending colon is more important in the preservation of bile acids than has usually been postulated. When the inflammation in this part of the colon is pronounced, the 14C excretion is high, independent of the type of colitis and the clinical disease activity.     

Changes of gastrointestinal myoelectric activity and bile acid pool size after cholecystectomy in guinea pigs

AIM: To investigate the bile acid pool size after cholecystectomy whether or not correlated to the gastrointestinal migrating myoeiectric complex (MMC) in guinea pigs. METHODS: Gallbladder motilities were assessed before cholecystectomy. Furthermore, we continuously monitored interdigestive gastrointestinal motilities using bipolar electrodes in conscious guinea pigs before and after surgery at 4 wk in standard diet group and high cholesterol diet (cholesterol gallstone) group. Total bile acid pool sizes were measured by isotope dilution method at meantime. RESULTS: After cholecystectomy, there were parallel falls in duration of phase Ⅰ, Ⅱ, Ⅲ and MMC cycle duration but increase in amplitude in the guinea pigs with normal gallbladder function, and in the guinea pigs with cholesterol stones. However, There were not significantly differences. On the other hand, the bile acid pool was definitely small in the GS guinea pigs compared to normal guinea pigs and became slightly smaller after cholecystectomy. Similarly, bile acid in gallbladder bile, fecal bile acid was slightly increased in GS guinea pigs after cholecystectomy, to the same degree as normal. These differences, however, were not significant. CONCLUSION: It is concluded that in the guinea pigs with normal gallbladder function, and in the guinea pigs with cholesterol stones: (1) Cholecystectomy produce a similar but less marked trend in bile acid pool; and (2) MMC are linked to enterohepatic circulation of bile acids, rather than surgery, which is consistent with changes of the bile acid pool size. As a result, gastrointestinal dyskinesia is not involved in occurrence of postchole cystectomy syndrome.     

老年入及慢性非器质性腹泻患者的乳糖酶缺乏症

用乳糖氢呼吸试验检测了18例20～65岁正常人基础氢值均在30PPM以下,平均22.5±3.8PPM,服乳糖后氢上升≥20PPM者13例(72.2％),平均升高62.9±64.4MMP。基本健康的70～87岁老人共17例,基础氢值19.7±4.0PPM,乳糖试验异常者7例(41.1％),呼气中氢平均升高42.4±23.6PPM。21例非器质性慢性腹泻患者基础氢平均22.7±9.0PPM,有2例>30PPM,服乳糖后异常者18例(85.7％),平均升高60.4±34.5PPM。说明我国正常人中乳糖酶缺乏的阳性率约为72.2％。高龄老人中阳性率41.1％,有随年龄增高逐渐适应的趋势。非器质性腹泻组乳糖酶缺乏的阳性率85.7％,且有2例空腹氢含量升高,提示乳糖酶缺乏可能与部份慢性腹泻患者的病因有关,这类病人在症状发作期间限制乳类制品是值得推荐的。     

急慢性腹泻患者肠道菌群的改变

目的探讨急慢性腹泻患者肠道菌群的变化及其差异。方法对20例慢性腹泻、31例急性腹泻及20例对照组的粪便进行肠杆菌、肠球菌、双歧杆菌、乳酸杆菌及类杆菌的培养及检测分析。结果与对照组比较,急性腹泻患者肠杆菌增加,肠球菌、双歧杆菌、乳酸杆菌及类杆菌减少(P<0.01),慢性腹泻患者肠杆菌增加,乳酸杆菌减少(P<0.05)。急性腹泻与慢性腹泻比较,类杆菌和乳酸杆菌减少更明显(P<0.05)。结论急慢性腹泻患者均存在肠道菌群失调,其中急性腹泻更严重。     

Bile Acid Malabsorption in Microscopic Colitis and in Previously Unexplained Functional Chronic Diarrhea

Bile acid malabsorption (BAM) has been described in patients with collagenous colitis. There are no similar studies in lymphocytic colitis. The possibility that BAM might not necessarily be part of the microscopic colitis process and that both entities could simply be concomitant has not been evaluated. Our aim was to assess the frequency and severity of BAM in patients with microscopic colitis as well as in patients with previously unexplained functional chronic diarrhea. Likewise, we wanted to investigate the effect of cholestyramine on the induction and maintenance of remission of these conditions. A [⁷⁵Se]HCAT abdominal retention test was performed in 26 patients with collagenous colitis, 25 with lymphocytic colitis, and 32 with previously unexplained functional chronic diarrhea. Patients with microscopic colitis who had BAM as well as a subgroup of eight collagenous colitis patients without BAM received treatment with cholestyramine. All patients with previously unexplained chronic diarrhea who had BAM were treated with cholestyramine. Twenty-two (43.1%) patients with microscopic colitis and 24 (75%) patients with previously unexplained functional chronic diarrhea presented with BAM. The frequency of BAM was higher in lymphocytic colitis than in collagenous colitis (60% vs 27%; P = 0.025). Cholestyramine induced clinical remission in 19 of 22 patients with microscopic colitis and BAM, none of eight patients with collagenous colitis without BAM, and all patients with previously unexplained chronic diarrhea and BAM. In conclusion, BAM seems to be common in patients with microscopic colitis—mainly in lymphocytic colitis—and in those with previously unexplained functional chronic diarrhea, suggesting that idiopathic BAM and microscopic colitis are often concomitant conditions. In this setting, cholestyramine seems to be highly effective in stopping diarrhea.