Bile acid malabsorption in chronic diarrhea: Pathophysiology and treatment

BACKGROUND:

Bile acid malabsorption (BAM) is a common but frequently under-recognized cause of chronic diarrhea, with an estimated prevalence of 4% to 5%.

METHODS:

The published literature for the period 1965 to 2012 was examined for articles regarding the pathophysiology and treatment of BAM to provide an overview of the management of BAM in gastroenterology practice.

RESULTS:

BAM is classified as type 1 (secondary to ileal dysfunction), type 2 (idiopathic) or type 3 (secondary to gastrointestinal disorders not associated with ileal dysfunction). The estimated prevalence of BAM is >90% in patients with resected Crohn disease (CD) and 11% to 52% of unresected CD patients (type 1); 33% in diarrhea-predominant irritable bowel syndrome (type 2); and is a frequent finding postcholecystectomy or postvagotomy (type 3). Investigations include BAM fecal bile acid assay, 23-seleno-25-homo-tauro-cholic acid (SeHCAT) testing and high-performance liquid chromatography of serum 7-α-OH-4-cholesten-3-one (C4), to determine the level of bile acid synthesis. A less time-consuming and expensive alternative in practice is an empirical trial of the bile acid sequestering agent cholestyramine. An estimated 70% to 96% of chronic diarrhea patients with BAM respond to short-course cholestyramine. Adverse effects include constipation, nausea, borborygmi, flatulence, bloating and abdominal pain. Other bile acid sequestering agents, such as colestipol and colesevelam, are currently being investigated for the treatment of BAM-associated diarrhea.

CONCLUSIONS:

BAM is a common cause of chronic diarrhea presenting in gastroenterology practice. In accordance with current guidelines, an empirical trial of a bile acid sequestering agent is warranted as part of the clinical workup to rule out BAM.     

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: 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.     

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

     

Folic acid absorption in patients infected with the human immunodeficiency virus.

To determine the folic acid absorption characteristics of patients with human immunodeficiency virus (HIV) infection, a prospective, controlled, result-blind single-dose oral absorption study was conducted. A total of 25 subjects were fasted and given 5 mg oral folic acid; blood samples were taken at time zero and after 30, 60, 90 and 180 min. Absorption of folic acid appears to be significantly impaired in HIV disease, irrespective of the stage of the disease and notwithstanding gastro-intestinal complaints, pathogen-negative diarrhoea or drug treatment. We here present functional data, complementary to previously reported structural and biochemical findings, to support the hypothesis that the virus can cause an enteropathy in the absence of opportunist infection. Folinic acid is absorbed by the same gut mechanism as folic acid, so caution may be needed when employing oral folinic acid rescue procedures in these patients, even when resting serum and red cell folate levels appear to be normal.     

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.     

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 > or = 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.     

Macronutrient intake and malabsorption in HIV infection: a comparison with other malabsorptive states

Background—Wasting is a major complication of HIVinfection. The role of malabsorption in wasting is controversial.
Aims—To assess oral intake and malabsorption in acohort of weight losing HIV infected patients, with or without chronic diarrhoea.
Methods—A prospective study using a predefinedprotocol for HIV infected patients was performed in a gastroenterologyand nutrition unit in a university hospital. A retrospective comparison was made with HIV negative patients with malabsorption due either tosmall bowel disease or resection. Body weight and height, serum albumin, oral intake of macronutrients, faecal weight, and faecal fatwere measured.
Results—Seventy nine weight losing HIV infectedpatients were studied. Among the 66 patients with more than 5% lipidmalabsorption, wasting was significantly greater in patients withcryptosporidiosis (n=22) than in patients with microsporidiosis (n=18)who exhibited significantly more wasting than patients with noidentified enteropathogen (n=26) (body mass index 16.8 (14.0-20.7),18.9 (16.5-21.3), 19.7(15.9-23), respectively). When controlling forthe level of lipid malabsorption, HIV infected patients had asignificantly lower energy intake than HIV negative patients withchronic malabsorption. In HIV infected patients, but not in othercategories of malabsorbers, body mass index correlated significantlywith energy intake (r=0.33, 95% confidence intervals 0.12 to 0.51).
Conclusion—In weight losing HIV infectedpatients, reduced energy intake is superimposed on malabsorption andsignificantly contributes to wasting.

     

Incidence and predictive factors for positive 75SeHCAT test: improving the diagnosis of bile acid diarrhoea

Aims: To determine the value of ⁷⁵SeHCAT retention in determining bile acid diarrhoea (BAD), treatment response and predictors of a positive result.

Methods: Retrospective casenote review of consecutive patients undergoing ⁷⁵SeHCAT from 2008 to 2014, including gender, age, history, clinical, and laboratory parameters. This included diseases associated with Type 1 BAD (ileal resection, Crohn’s disease) and Type 3 BAD. Chi-squared test and logistic regression determined factors predictive of BAD. Subjective response to treatment with bile acid sequestrants (BAS) was analysed with respect to the ⁷⁵SeHCAT result.

Results: Of 387 patients, 154 (39.7%) were male and average age was 50 years. Ninety-five patients (24.5%) were investigated for Type 1 BAD, 86 (22.2%) for Type 3, and 206 patients (53.2%) for Type 2 or idiopathic BAD. There was a large increase in the number performed with time but no difference in percentage positive tests. One hundred and seventy-nine patients (46.2%) had BAD. Positive result was commonest in possible Type 1 and they had most severe BAD. Ninety-nine patients had severe BAD (<5% ⁷⁵SeHCAT retention), 47 moderate BAD (5% to <10% retention), and 33 mild BAD (10% to <15% retention). Predictors of a positive ⁷⁵SeHCAT were right hemicolectomy (OR 4.88), cholecystectomy (OR 2.44), and Crohn’s (OR 1.86). A positive ⁷⁵SeHCAT predicted a good or partial response to BAS of 66.7% (mild), 78.6% (moderate), or 75.9% (severe BAD).

Conclusion: ⁷⁵SeHCAT test use increased in 2008–2014, with high positive results throughout. Ileal resection, Crohn’s, and cholecystectomy independently predict BAD. ⁷⁵SeHCAT predicted response to BAS.     

161例人免疫缺陷病毒感染者肝损伤相关因素分析

回顾性分析了我院161例人免疫缺陷病毒(IIIV)感染病例的临床特征与患者肝功能的相关性,探讨我国HIV感染者发生肝功能损伤的相关危险因素.     

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.     

Impact of bile acid malabsorption on steatorrhoea and symptoms in patients with chronic diarrhoea

OBJECTIVE: Bile acids are important for fat absorption. The relationship between bile acid malabsorption and steatorrhoea and gastrointestinal symptoms in patients with chronic diarrhoea has only been studied on a limited scale. DESIGN: Ninety-four patients referred for chronic diarrhoea were prospectively investigated with the 75SeHCAT test, a faecal fat excretion test and registration of symptoms in addition to the standard clinical work-up. METHODS: The correlation between the 75SeHCAT value and the faecal fat excretion was calculated for different groups of patients. Symptoms were registered in a questionnaire over a period of seven consecutive days. RESULTS: Forty-two patients had a 75SeHCAT value < 10%. Mild steatorrhoea was common in patients with non-organic bile acid malabsorption (50%) and in patients with functional diarrhoea (38%). There was no correlation between low 75SeHCAT values and steatorrhoea, although some patients with severe organic disease had a concomitant malabsorption of fat and of bile acids. In coeliac disease, severe steatorrhoea was common even in patients with high 75SeHCAT values. Patients with bile acid malabsorption had more frequent (P < 0.008) and looser (P= 0.0021) stools compared with patients with functional diarrhoea. There was no difference in abdominal pain, distension or flatulence. CONCLUSION: Mild steatorrhoea is common in both non-organic bile acid malabsorption and functional diarrhoea. The 75SeHCAT value cannot predict the risk of steatorrhoea. The high prevalence of bile acid malabsorption in patients with chronic diarrhoea and the absence of specific symptoms, except frequent and more liquid stools, indicates that the 75SeHCAT test should be performed early in the investigation of these patients.     

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…     

Role of bile acids and bile acid binding agents in patients with collagenous colitis

BACKGROUND: In a retrospective study bile acid malabsorption was observed in patients with collagenous colitis. AIMS: To study the occurrence of bile acid malabsorption and the effect of bile acid binders prospectively in patients with chronic diarrhoea and collagenous colitis. METHODS: Over 36 months all patients referred because of chronic diarrhoea completed a diagnostic programme, including gastroscopy with duodenal biopsy, colonoscopy with biopsies, and the (75)Se-homocholic acid taurine ((75)SeHCAT) test for bile acid malabsorption. Treatment with a bile acid binder (cholestyramine in 24, colestipol in three) was given, irrespective of the results of the (75)SeHCAT test. RESULTS: Collagenous colitis was found in 28 patients (six men, 22 women), 27 of whom had persistent symptoms and completed the programme. Four patients had had a previous cholecystectomy or a distal gastric resection. The (75)SeHCAT test was abnormal in 12/27 (44%) of the collagenous colitis patients with (75)SeHCAT values 0.5-9.7%, and normal in 15 patients (56%). Bile acid binding treatment was followed by a rapid, marked, or complete improvement in 21/27 (78%) of the collagenous colitis patients. Rapid improvement occurred in 11/12 (92%) of the patients with bile acid malabsorption compared with 10/15 (67%) of the patients with normal (75)SeHCAT tests. CONCLUSION: Bile acid malabsorption is common in patients with collagenous colitis and is probably an important pathophysiological factor. Because of a high response rate without serious side effects, bile acid binding treatment should be considered for collagenous colitis, particularly patients with bile acid malabsorption.     

Review: Bile acid diarrhoea: pathophysiology,diagnosis and management

The actual incidence of bile acid diarrhoea (BAD) is unknown, however, there is increasing evidence that it is misdiagnosed in up to 30% with diarrhoea-predominant patients with irritable bowel syndrome. Besides this, it may also occur following cholecystectomy, infectious diarrhoea and pelvic chemoradiotherapy.BAD may result from either hepatic overproduction of bile acids or their malabsorption in the terminal ileum. It can result in symptoms such as bowel frequency, urgency, nocturnal defecation, excessive flatulence, abdominal pain and incontinence of stool. Bile acid synthesis is regulated by negative feedback loops related to the enterohepatic circulation, which are dependent on the farnesoid X receptor and fibroblast growth factor 19. Interruption of these feedback loops is thought to cause bile acid overproduction leading to BAD. This process may occur idiopathically or following a specific trigger such as cholecystectomy. There may also be an interplay with the gut microbiota, which has been reported to be significantly different in patients with severe BAD.Patients with suspected BAD are investigated in various ways including radionucleotide imaging such as SeHCAT scans (though this is not available worldwide) and blood tests. However, other methods such as bile acid measurement in stool (either spot test or 48 hours samples) and urine tests have been explored. Importantly, delay in diagnosis and treatment of BAD greatly affects patient’s quality of life and may double the overall cost of diagnosis.     

Urinary bile acid sulfate levels in patients with hepatitis C virus-related chronic liver diseases

Aim:  Urinary bile acids are mainly conjugated with sulfuric acid, and urinary sulfated bile acid (USBA) levels in hepatobiliary diseases have been reported. However, the relationship between USBA and fasting serum total bile acid (TBA) has not been studied in hepatobiliary diseases. In the present study, we measured USBA levels in patients with hepatitis C virus-related chronic liver diseases, and the relationship between TBA and various laboratory tests was studied.
Methods:  USBA was measured using an automatic assay kit in 66 patients with chronic hepatitis and 28 patients with liver cirrhosis, and its relationship between TBA and various laboratory tests was studied.
Results:  The median USBA level was 10.7 µmol/g creatinine in patients with chronic hepatitis and 41.1 µmol/g creatinine in liver cirrhosis ( P  = 0.000). More patients with chronic hepatitis had elevated USBA levels (61%) compared to TBA level (39%) ( P  = 0.002). USBA level was well correlated with TBA (r_s = 0.680), and negatively correlated with albumin (r_s = −0.488), prothrombin time (r_s = −0.385) and platelet counts (r_s = −0.394). In patients with liver cirrhosis, USBA was significantly elevated in Child–Pugh class B compared to Child–Pugh class A ( P  = 0.036).
Conclusion:  Although the metabolic pathways of USBA and TBA are different, these levels correlated very well, and USBA is considered to be a useful indicator of hepatic function like TBA in patients with chronic hepatitis C.     

我院肺结核病人中HIV感染情况的调查分析

目的了解本院肺结核病患者中HIV的感染情况以及HIV阳性者的流行病学特征。方法对2004年1月～2008年12月本院收治的16128名活动性结核患者进行HIV血清学检测。结果16128例患者中,14611例(90.6%)进行HIV检测,确认HIV抗体阳性98例,阳性率0.671%,男性79例,女性19例,平均年龄32.4岁±7.6岁。98例HIV检测阳性患者中,21岁～40岁年龄段患者感染者60例(61.2%),其它年龄段38例(38.8%)。静脉注射吸毒者70例(71.4%)和性传播者16例(16.3%)。结论肺结核合并HIV人群以男性和青年人为主,静脉注射吸毒和性途径是传播的主要方式。     

Bile acid sequestration by the solid phase of stools in cystic fibrosis patients

The distribution of bile acids in the stool of seven cystic fibrosis (CF) patients with severe or mild steatorrhea was examined and compared with that of three controls. Results indicated significantly lower endogenous bile acid concentrations in the stool water phase, obtained by centrifugation, in the CF patients (12.0±3.5%), compared with the controls (25.5±8.1%). In vitroincorporation of labeled cholic acid (CA) and deoxycholic acid (DCA) demonstrated a stronger binding of both to the paniculate matter of stools in the CF group. Using equilibrium dialysis, the calculated concentrations of unbound CA and DCA in the CF group measured 0.78 and 0.3 mol/g homogenate, respectively, and in the control patients 1.76 and 1.39 mol/g homogenate, respectively. Partial release of bile acids from CF stool pellets was achieved by the addition of trypsin and elastase, as well as by alkalinization. It is suggested that in patients with CF, stool bile acids are bound to the undigested protein fraction, which makes them unavailable for colonic resorption.     

Significance of immune status, genotype and viral load in the severity of chronic hepatitis C in HIV infected haemophilia patients

Chronic hepatitis C is associated with more severe liver disease in patients coinfected with HIV, but the pathogenic mechanism of this more aggressive course is still unclear. The aim of this study was to assess the relationship of HCV genotype, viral load and epidemiological factors with the histological severity of chronic hepatitis in haemophilia patients with HCV/HIV coinfection, taking into consideration the immune status of the patients. Twenty-one HIV/HCV coinfected haemophilia patients, with mean age +/- SD 35.7 +/- 8.7 years, underwent transcutaneous liver biopsy 6-15 years (median 12 years) after HIV and 6-32 (median 21.5 years) years after HCV infection. Twelve patients were stage A (CDC), six stage B and three stage C. CD4 cells were < 50 microL(-1) in three patients (14.3%), 50-200 in 11(52.4%) and > 200 in 7(33.3%). Mean +/- SD log(10) HCV-RNA was 6.87 +/- 0.7 copies mL(-1) (range 5.4-7.9), and mean +/- SD log(10) HIV-RNA was 3.75 +/- 0.98 copies mL(-1) (range 2.7-6), at the time of liver biopsy. Minimal hepatitis was diagnosed in five patients (24%), mild in 10 (48%) and moderate in six (28%). Hepatitis stage 0-2 was found in seven cases (33%) and cirrhosis in six (29%). Statistical analysis showed a significant association of CD4 count < 50 with minimal hepatitis and of CD > 200 with mild and moderate hepatitis (P = 0.033). In addition, minimal hepatitis was found only in patients with stage C, while the majority of subjects with HIV stage A showed mild and moderate hepatitis (P = 0.003). Moreover genotype 1 was independently associated with advanced hepatitis stage (P = 0.04). No relationship was found between hepatitis severity, HIV or HCV RNA levels, patient's age and duration of HIV or HCV infection. Our results suggest that HCV/HIV coinfection may aggravate the course of hepatitis in the phase of immunocompetence, most probably through an immune mediated process. Genotype 1 seems to be associated with advanced liver disease.