The Diarrhea Stopped Will I Have to Take Cholestryamine Again
Can J Gastroenterol. 2013 November; 27(11): 653–659.
Linguistic communication: English language | French
Bile acid malabsorption in chronic diarrhea: Pathophysiology and treatment
Alan Barkun
iDivision of Gastroenterology, McGill Academy, Montreal, Quebec;
Jonathan Love
2Division of Gastroenterology, Academy of Calgary, Calgary, Alberta;
Michael Gould
3Toronto Digestive Disease Associates Inc, Toronto, Ontario;
Henryk Pluta
ivGastroenterology and Hepatology Clinic, Abbotsford, British Columbia;
A Hillary Steinhart
5Sectionalisation of Gastroenterology, Mount Sinai Infirmary and the University Wellness Network, Toronto, Ontario
Received 2013 Jan 24; Accepted 2013 Aug 26.
Abstract
Groundwork:
Bile acid malabsorption (BAM) is a mutual but oftentimes 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 handling of BAM to provide an overview of the direction of BAM in gastroenterology practice.
RESULTS:
BAM is classified as type 1 (secondary to ileal dysfunction), type 2 (idiopathic) or blazon 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-human-tauro-cholic acrid (SeHCAT) testing and high-performance liquid chromatography of serum seven-α-OH-4-cholesten-iii-one (C4), to determine the level of bile acrid synthesis. A less time-consuming and expensive alternative in exercise is an empirical trial of the bile acid sequestering agent cholestyramine. An estimated 70% to 96% of chronic diarrhea patients with BAM respond to brusk-course cholestyramine. Adverse effects include constipation, nausea, borborygmi, flatulence, bloating and abdominal pain. Other bile acrid sequestering agents, such as colestipol and colesevelam, are currently existence investigated for the treatment of BAM-associated diarrhea.
CONCLUSIONS:
BAM is a mutual crusade of chronic diarrhea presenting in gastroenterology practise. In accordance with electric current guidelines, an empirical trial of a bile acid sequestering agent is warranted as function of the clinical workup to rule out BAM.
Keywords: Bile acrid malabsorption, Cholestyramine, Chronic diarrhea, Enterohepatic circulation, FGF19, SeHCAT
Résumé
HISTORIQUE :
La malabsorption de fifty'acide biliaire (MAB) est une cause de diarrhée chronique fréquente mais souvent sous-diagnostiquée, dont la prévalence est évaluée entre iv % et 5 %.
MÉTHODOLOGIE :
Les chercheurs ont examiné les publications de 1965 à 2012 pour en extraire les articles portant sur la physiopathologie et le traitement de la MAB en gastroentérologie.
RÉSULTATS :
La MAB est divisée en type ane (secondaire à une dysfonction iléale), blazon 2 (idiopathique) et type iii (secondaire à des troubles gastro-intestinaux non associés à une dysfonction iléale). La prévalence estimée de la MAB dépasse les xc % chez les patients ayant une résection causée par la maladie de Crohn (MC) et se situe entre 11 % et 52 % chez les patients atteints d'une MC sans résection (type ane). Elle stand for à 33 % en cas de syndrome du côlon irritable qui se manifeste surtout par de la diarrhée (type ii) et est fréquente après une cholecystectomie ou une vagotomie (blazon iii). Les examens incluent le titrage de l'acide biliaire fécale, de l'acide 23-séléno-25-homotauro-cholique (SeHCAT) et de la chromatographie à haute performance du sérum 7-α-OH-4-cholesten-three-1 (C4) causés par la MAB, afin de déterminer le taux de synthèse de l'acide biliaire. En pratique, une solution moins chronophage et moins coûteuse consiste à procéder à un essai empirique de la cholestyramine, 50'agent séquestrant des acides biliaires. On estime que de lxx % à 96 % des patients atteints de diarrhée chronique présentant une MAB répondent à un court traitement à la cholestyramine. Les effets indésirables incluent la constipation, les nausées, les borborygmes, les flatulences, les gonflements et les douleurs abdominales. D'autres agents séquestrants des acides biliaires, comme le colestipol et le colésévélam, sont en cours d'évaluation en vue du traitement de la diarrhée associée à la MAB.
CONCLUSIONS :
La MAB est une cause fréquente de diarrhée chronique en gastroentérologie. Conformément aux directives à jour, un essai empirique de l'agent séquestrant des acides biliaires s'impose dans le core du bilan clinique pour écarter la MAB.
Chronic diarrhea is one of the most common presentations in gastroenterology and general do (1). While prevalence rates in Canada are difficult to make up one's mind, an estimated 4% to v% of the overall population and seven% to 14% of elderly individuals in the customs experience chronic diarrhea (2–4). In the period 2003 to 2008, annual sales of over-the-counter antidiarrheal medications in Canada reportedly doubled to $fifty million (five).
Diarrhea is defined every bit the abnormal passage of loose or liquid stools more than iii times per day, and/or stool book >200 g/day (i). Chronic diarrhea is defined as an increase in stool frequency and/or volume that persists for longer than three to four weeks. Chronic symptoms generally do non suggest an infectious etiology, although patients may written report that symptoms are preceded past gastrointestinal infection or food poisoning. The most common causes in clinical exercise are inflammatory syndromes of the small bowel or colon (eg, Crohn disease [CD], celiac disease); functional bowel disorders (eg, irritable bowel syndrome [IBS]); neoplasia; pancreatic insufficiency resulting in maldigestion; intestinal dysmotility; and minor bowel malabsorption (eg, postgastrointestinal surgery) (Table one).
Table 1
Potential causes of chronic diarrhea in clinical practice
| Colon | Colonic neoplasia |
| Inflammatory bowel illness (ulcerative colitis, Crohn's colitis) | |
| Microscopic colitis | |
| Small bowel | Celiac disease |
| Crohn disease | |
| Other pocket-sized bowel enteropathies | |
| Bile acid malabsorption | |
| Disaccharidase deficiency | |
| Small bowel bacterial overgrowth | |
| Mesenteric ischemia | |
| Radiation enteritis | |
| Lymphoma | |
| Chronic infection (eg, giardiasis) | |
| Pancreas | Chronic pancreatitis |
| Pancreatic carcinoma | |
| Cystic fibrosis | |
| Endocrine | Hyperthyroidism |
| Diabetes | |
| Hypoparathyroidism | |
| Addison disease | |
| Hormone-secreting tumours (eg, VIPoma, carcinoid, gastrinoma) | |
| Other | Factitious diarrhea |
| Surgery (eg, pocket-size bowel resection, internal fistulas) | |
| Drugs (eg, nonsteroidal anti-inflammatory drugs, antihypertensives, antibiotics, antiarrhythmics, antineoplastics, drugs containing magnesium) | |
| Nutrient additives (eg, sorbitol, fructose) | |
| Booze abuse | |
| Autonomic neuropathy |
A common but ofttimes underinvestigated cause of chronic diarrhea is bile acid malabsorption (BAM) resulting from dysregulation of the enterohepatic recycling of bile acids and of bile acid production. The present review summarizes contempo developments in the pathophysiology, investigation and handling of BAM, and addresses its relevance to the clinical management of chronic diarrhea.
METHODS
For the nowadays narrative review, the PubMed database was searched using a combination of controlled vocabulary and text words to identify reports related to bile acid diarrhea for the catamenia October 1965 to October 2012. The search terms "bile acrid malabsorption" filtered for "Humans" obtained 923 results, which were manually searched for relevance to providing an overview of the pathophysiology, investigation and treatment of BAM. Supplemental information was obtained through secondary searches using the terms "chronic diarrhea", "inflammatory bowel disease" or "IBD", "irritable bowel syndrome" or "IBS", "enterohepatic circulation", "cholestyramine", "colestipol" and "colesevelam".
Bile acid production and the enterohepatic circulation
The enterohepatic circulation of bile acids was beginning described by Small et al (6) 4 decades ago (Figure 1). Primary bile acids, principally cholic acid (CA) and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver, conjugated with glycine or taurine to increase their h2o solubility and secreted to bile. Secondary bile acids, primarily deoxycholic acid (DCA) and lithocholic acid, are derived from primary bile acids as a result of modifications (eg, deconjugation, 7-dehydroxylation) past intestinal bacteria. These modifications increase passive absorption of secondary bile acids in the colon.
Enterohepatic circulation of bile acids. Reprinted with permission from reference 24. d Twenty-four hour period
The principal pathway for cholesterol conversion to CA and CDCA is the neutral pathway, in which the rate-limiting enzyme is the cytochrome P450 enzyme cholesterol 7α-hydroxylase (CYP7A1) (7). In the alternative (acidic) pathway, 27-hydroxylation of bile acid intermediates of the CYP7A1 pathway primarily results in CDCA synthesis; this pathway accounts for <20% of total bile acid production (eight). Other minor pathways involve cholesterol 25-hydroxylase, which is non part of the CYP450 system; and cholesterol 24-hydroxylase (CYP46), which converts 24S-cholesterol in the encephalon to bile acids (vii).
Approximately 95% of primary bile acids are reabsorbed by the distal ileum through agile uptake past the apical sodium-dependent bile acid transporter (ASBT), returned to the liver via the portal circulation and taken up by hepatocytes. A small percentage of bile acids entering the colon can be passively absorbed, resulting in an overall net loss of 1% to iii% (9). The conservation of the bile acid puddle is altered past more than rapid abdominal transit and changes in gut flora due to diet, medications or other factors.
Cholesterol and bile acid levels are tightly regulated. Of detail interest are the liver 10 receptor and the farnesoid X receptor (FXR), both of which deed as transcription factors regulating enzyme expression. The dimerized liver 10 receptor/retinoid X receptor (RXR) binds to oxidized cholesterol metabolites and induces the expression of CYP7A1, resulting in increased bile acid synthesis (seven,x).
Bile acid production is regulated past FXR, which is expressed primarily in ileal enterocytes and hepatocytes (Figure two). Bile acids activate FXR, which forms a dimerized FXR/RXR complex. In the liver, FXR/RXR downregulates CYP7A1 expression, resulting in decreased bile acrid synthesis and increased expression of the bile salt consign pump, and downregulates CYP8B1, which is necessary for CA synthesis (11,12). The result is a decrease in bile acrid synthesis and uptake, and increased export to bile (10). In enterocytes, FXR/RXR acts on ASBT to reduce ileal uptake of bile acids (13). Loftier intracellular bile acid levels in enterocytes also stimulate the release of fibroblast growth factor 19 (FGF19), which feeds back to the FGF receptor-4 (FGFR4) and its coreceptor Klothoβ on hepatocytes to downregulate CYP7A1 and reduce bile acid product (14,xv). This decreases abdominal bile acid absorption and prevents the intracellular accumulation of bile acids. Thus, bile acid production is regulated through negative feedback mechanisms in the liver and remotely in the ileum.
Regulation of bile acid (BA) assimilation and transport. Adapted and used with permission from reference 10. In ileal enterocytes, farnesoid X receptor (FXR)-retinoid X receptor (RXR) regulates BA homeostasis by reducing BA uptake by the apical sodium-dependent bile acrid transporter (ASBT), reducing intestinal absorption of BAs ( A ); and ( B ) increasing BA consign by organic solute transporter alpha/beta (OSTα/β), reducing intracellular aggregating of BA. C Ileal bile acid binding poly peptide (IBABP) is involved in FXR expression. D FXR effects are mediated by small heterodimer partner (SHP). E Ileal FXR also regulates BA production via fibroblast growth factor (FGF)nineteen. F In hepatocytes, intracellular BA levels are regulated by Na+ taurocholate cotransporting polypeptide transporter (NTCP) and ( G ) the bile salt export pump (BSEP). H FGF19 activates FGFR4. I FGF receptor 4 (FGFR4) via FXR-RXR downregulates cholesterol 7α-hydroxylase (CYP7A) synthesis of BAs
The composition of the bile acid pool is influenced past various factors. The chief constituents are the primary bile acids (CA, CDCA) and the secondary bile acid DCA; DCA accumulates in the bile pool because 7-dehydroxylation cannot be reversed (10). DCA formation from CA is increased by diet (eg, high fatty) and other factors that slow colonic transit times (x), as well as increased Gram-positive anaerobes and 7-alpha-dehydroxylase action (16). Absorption and bioavailability of DCA are influenced past colonic transit fourth dimension and pH in the distal colon (16).
Diets loftier in taurine (eg, seafood), or loftier in fat or depression in fibre volition increase the corporeality of taurine-conjugated bile acids (17,18). The ASBT is too more effective at transporting dihydroxy bile acids (ie, DCA, CDCA) (xiii), which influence the bile acid pool.
Medications as well play a role. Glucocorticoids upregulate ASBT (19), suggesting an alternative machinery of symptom control in patients with inflammatory bowel disease. Cholestyramine has been shown to preferentially reduce dihydroxy (CDCA, DCA) bile acids (eg, CA) and reduce the secondary bile acid pool (20). Cholestyramine also elevates the ratio of glycine- versus taurine-conjugated bile acids in bile. Because glycine conjugates are more than subject area to passive absorption, this may exist an alternative mechanism by which cholestyramine reduces malabsorption (twenty).
Some bile acids (eg, CA, ursoDCA) exercise non appear to contribute to diarrhea (10). Dihydroxy bile acids (eg, DCA, CDCA) are more active, causing mucosal damage and demonstrating prosecretory furnishings in the colon (21–23).
BAM
An estimated 0.5 yard of bile acids are synthesized in the liver per 24-hour interval (24). The total bile acid pool is approximately three g, of which 95% is reclaimed from the ileum and a pocket-size corporeality of unconjugated bile acids is recaptured in the colon via passive nonionic diffusion (25). This cycle is repeated four to 12 times per day, resulting in an estimated daily loss of 0.2 g/mean solar day to 0.6 1000/twenty-four hours in the feces, which must be replaced by new bile acrid synthesis in hepatocytes (24).
Excessive levels of bile acids in the lower gastrointestinal tract may cause diarrhea via ane or more mechanisms: altering h2o and sodium transport; increasing lower gastrointestinal motility; dissentious the mucosa; inducing mucus secretion; or stimulating defecation (22,26,27).
Iii subtypes of BAM have been categorized. Type 1 includes patients with terminal ileal illness (eg, CD, resection) or radiation injury resulting in impaired bile acid reabsorption; blazon 2 is idiopathic; and type 3 comprises conditions unrelated to ileal disease (eg, celiac affliction, cholecystectomy, bacterial overgrowth) that alter intestinal move or bile acid absorption (Tabular array two) (26).
Table two
Classification of bile acid malabsorption (BAM)
| Classification of BAM | Etiology |
|---|---|
| Type 1 Ileal dysfunction (secondary BAM) | Ileal Crohn affliction, ileal resection
|
| Type ii Idiopathic BAM/main bile acid diarrhea | Unknown cause
|
| Type 3 Other conditions | Postcholecystectomy, postvagotomy, celiac disease, bacterial overgrowth, pancreatic insufficiency (chronic pancreatitis and cystic fibrosis)
|
BAM is oftentimes regarded as a rare phenomenon, reflected in a survey of gastroenterologists in the United Kingdom (28). One-third of new patients presented with chronic diarrhea. BAM was considered in the diagnostic workup in 22% of chronic diarrhea cases. Overall, only one% of all new cases and 3% of chronic diarrhea cases were diagnosed with BAM; among BAM cases, 61% were type 1, 22% were type 2 and 15% were type 3. Thirty-9 per cent of clinicians investigated just a selected grouping of patients, and 22% reported they investigated BAM rarely or not at all.
Often under-recognized in practice is type ii BAM (idiopathic BAM), which potentially affects a broad range of patients with chronic diarrhea. While the etiology of idiopathic BAM is unclear, several underlying pathophysiological mechanisms have been proposed. Some (29–31), but non all (32), studies accept suggested that idiopathic BAM is associated with more rapid minor-bowel and colonic transit times. Genetic variants in the FGF19-FGFR4-Klothoβ pathway, which affects colonic transit times, take been reported in diarrhea-predominant IBS (IBS-D) (33). All the same, these variants may play a more important role in dysregulation of the bile acrid puddle. A recent written report reported that 38% of IBS-D patients exhibited increased bile acrid synthesis, as measured by serum levels of 7α-hydroxy-iv-cholesten-3-1 (C4), and college body mass index (34).
Similar results were found in a written report comparison idiopathic BAM patients with diarrhea versus healthy controls (35). Fasting C4 levels were significantly higher in patients with idiopathic BAM compared with controls (51 ng/mL versus 18 ng/mL), suggesting dysregulation of bile acrid synthesis. Moreover, median FGF19 levels were significantly lower in idiopathic BAM versus controls (120 pg/mL versus 231 pg/mL), indicating that a deficiency in FGF19 feedback inhibition of bile acrid synthesis may contribute to an overproduction of bile acids that cannot be accommodated past ileal reabsorption. FGF19 levels were also plant to exist low in patients postcholecystectomy (type 3 BAM).
BAM investigations
Traditional investigations of BAM, such as directly testing of bile acid content in fecal samples (36,37) or 14C cholylglycine testing of 14C in expired air and stool, are hard and unpleasant to perform (38). Another method to assess BAM is SeHCAT testing (sensitivity >80%, specificity >98%) (39,xl), in which 23-selena-25-homo-tauro-cholic acid is radiolabelled with 75Selenium homotaurocholic acid (41). This orally administered constructed conjugated bile acid is secreted in bile, reabsorbed in the terminal ileum and resecreted. A noncollimated gamma photographic camera measures abdominal radioactive decay on day 7. Early on studies indicated that retention of <12% of 23-selena-25-homotaurocholic acid was aberrant (42). A cutting-off value <10% to xv% retention at day seven is at present generally established. SeHCAT testing has proven invaluable in the inquiry setting, but is not routinely bachelor in practice. This is unfortunate because the cost of the test is comparable with other, more routine, studies. SeHCAT costs $250 per capsule while an octreotide scan costs $1,028 per dose, and a 99m Tc-methylene diphosphonate bone scan costs $28 (personal communication, J Honey, Foothills Medical Eye Nuclear Medicine Department, Calgary, Alberta). SeHCAT values are stable during long-term follow-up in patients with chronic diarrhea, suggesting that repeat testing is not required (43).
Determining the serum levels of C4, which are markedly elevated when bile acid synthesis is increased (44–46), is a potentially useful measure only is not widely used at nowadays; further standardization is needed (47). ELISA of serum FGF19 levels, which are inversely correlated with C4 levels, has been proposed (35) but is not generally available.
It should be noted that pathophysiological mechanisms other than BAM may contribute to diarrhea in some patients (eg, postcholecystectomy) with aberrant SeHCAT or C4 findings (48), and that abnormal SeHCAT/C4 may occur in patients without clinically relevant symptoms. The association amidst SeHCAT, BAM and symptom frequency/severity requires further study.
A practical alternative to SeHCAT/C4 testing of BAM in patients with chronic diarrhea is to utilise a bile acrid sequestering agent, which binds with loftier affinity to organic anions such every bit bile acids. American Gastroenterology Association guidelines recommend an empirical trial with an agent, such as cholestyramine, to diagnose BAM (49). British Lodge of Gastroenterology guidelines state that in the absence of diagnostic tests, an empirical trial of cholestyramine can be used (1), with the caveat that this arroyo has not been prospectively studied.
Prevalence of blazon one BAM
BAM secondary to ileal dysfunction is common. A retrospective review of 298 patients with chronic watery diarrhea found seven-day SeHCAT retention to be <10% in 15 of 29 patients (51.vii%) with unresected CD, 40 of 43 patients (93.0%) with resected CD, 12 of 12 patients (100%) post-obit small-scale bowel resection and two of three patients (66.7%) following radiation injury (49). Lenicek et al (50) reported that BAM severity was associated with the extent of ileal resection in CD patients. Elevated C4 levels were detected in 61.7% of resected CD patients, and less commonly in unresected ileitis or colitis patients (xiv% and 11%, respectively) (50,51). In an analysis of CD patients referred for SeHCAT testing for chronic diarrhea refractory to antidiarrheal medications or steroids, SeHCAT retention <five% was plant in 90% of resected and 28% of unresected CD patients (52).
Prevalence of type ii BAM in idiopathic chronic diarrhea
SeHCAT testing has proven to be a useful enquiry tool to discover BAM in patients with unexplained chronic diarrhea (49,53–74). The estimated prevalence of idiopathic BAM in chronic diarrhea ranges from 37.5% to 59.6% (Table three).
Tabular array three
Prevalence of idiopathic bile acrid malabsorption (BAM) (type two) in patients with unexplained chronic diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D)
| Author (reference), year | Patient grouping | n | SeHCAT at 7 days, % | BAM prevalence, % | Response to cholestyramine, % |
|---|---|---|---|---|---|
| Ford et al (53), 1992 | Idiopathic chronic diarrhea | 74 | <xv | 27.0 | 92.5 (SeHCAT <five) |
| 41.4 (SeHCAT 5–10) | |||||
| 46.7 (partial response but) (SeHCAT xi–15) | |||||
| Sinha et al (54), 1998 | Idiopathic BAM | 9 | <15 | n/a | 66.7 |
| Sciarretta et al (32), 1987 | IBS-D, postcholecystectomy | 46 | <eight | 39* | 43.4 |
| Cramp et al (56), 1996 | Chronic diarrhea secondary to HIV infection | 19 | <15 | 84.2* | 84.6 |
| Ung et al (57), 2000 | Idiopathic chronic diarrhea | 94 | <10 | 44.7 | n/a |
| Smith et al (58), 2000 | IBS-D | 197 | <x | 33.five | 70.0 |
| Wildt et al (59), 2003 | Idiopathic chronic diarrhea | 133 | <fifteen | 56* | n/a |
| Fernández-Bañares et al (61), 2007 | Chronic watery diarrhea | 62 | <xi | 59.7 | 45.ii (all) |
| 75.eight (BAM) | |||||
| Wedlake et al (62), 2009 | IBS-D | 1223† | SeHCAT | ||
| <v | 10 | 96 (SeHCAT <5) | |||
| <ten | 32 | fourscore (SeHCAT <x) | |||
| <xv | 26 | 70 (SeHCAT <fifteen) | |||
| Borghede et al (49), 2011 | Idiopathic chronic diarrhea | 114 | <15 | 59.half-dozen | 74.three (SeHCAT <5) |
| 85.7 (SeHCAT 5–10) | |||||
| 50.0 (SeHCAT 11–15) | |||||
| Kurien et al (63), 2011 | IBS-D | 273 | <10 | 39.two | n/a |
| Gracie et al (64), 2012 | Idiopathic chronic diarrhea | 373 | <15 | l.nine* | n/a |
| 27.iii (IBS-D) |
Approximately one-third of patients with a diagnosis of IBS-D have underlying BAM (Table iii). A systematic review of 18 studies (n=1223) reported that 10% of patients had BAM using a cut-off value of SeHCAT <5% of baseline (severe BAM) (62). Approximately 32% had BAM using a cut-off of SeHCAT <10% (severe and moderate BAM), and 26% had some caste of BAM (SeHCAT <xv%; severe, moderate and mild BAM).
Idiopathic BAM associated with postinfective diarrhea is some other interesting area of study. A case review institute sixteen of 29 patients (55%) with a positive SeHCAT test had a history of acute gastroenteritis before the onset of chronic diarrhea (65). Similarly, a retrospective analysis of 135 patients with SeHCAT <10% identified 25 cases of postinfective BAM responsive to cholestyramine (66). The precise mechanisms leading to postinfective BAM require further elucidation.
Prevalence of type three BAM
Type iii BAM is mutual in patients with a multifariousness of gastrointestinal disorders not associated with ileal dysfunction. BAM appears to be related to impaired bicarbonate secretion in patients with chronic pancreatitis (67). In celiac affliction, BAM has been attributed to atrophy of the minor intestinal mucosa, and impairments in gall bladder and pocket-size bowel motor function (68).
BAM is a frequent complication following gall bladder surgery, with 1 example series reporting a marked degree of BAM in 25 of 26 patients with postcholecystectomy diarrhea (69). While fecal bile acrid loss has been documented in this setting, one study found that rise C4 levels did non appear to be related to a alter in bowel habits (70). Animal studies have reported a significant increase in bile acrid production and an increased proportion of secondary bile acids following cholecystectomy and ileal resection (71), suggesting that astringent disruption of the enterohepatic circulation postsurgery results in chronic diarrhea. BAM may also exist a contributing factor in patients with postvagotomy diarrhea (72), although the mechanisms are poorly understood.
Response to bile acid sequestering agents
A large proportion of patients with severe BAM (SeHCAT <5%) volition respond to an empirical trial of cholestyramine (Olestyr; Pendopharm, Canada). In the case series reported by Nyhlin et al (52), response rates were 88% in resected CD and 28% in unresected CD. A full of 37 of 40 patients with astringent BAM (all types) responded to cholestyramine 1 one thousand/day to viii m/day in the series by Ford et al (53). A large series demonstrated a response in 71% of patients taking cholestyramine; handling with a bile acid sequestering agent was effective regardless of BAM type (49).
In addition, a substantial proportion of patients with IBS-D volition respond to cholestyramine. In their systematic review of 15 treatment studies, Wedlake et al (62) found that clinical response was correlated with BAM severity. The overall response to empirical therapy with cholestyramine was 96% for severe BAM (SeHCAT <5% of baseline), fourscore% for moderate or severe BAM (SeHCAT <10%), and 70% for whatsoever degree of BAM (SeHCAT <15%). Because 1-quarter of IBS-D patients accept some degree of BAM, it would be expected that a big proportion of patients would respond to empirical apply of cholestyramine. Wedlake et al (62) concluded that BAM is not a rare finding in IBS-D patients and speculated that as many as 500,000 adults in the U.k. could benefit from therapeutic intervention for bile acid malabsorption. A similar number of Canadians would be expected to benefit from treatment due to the higher prevalence of IBS-D in Canada (73).
A long-term follow-up (mean 99 months) of xiv patients with chronic diarrhea (74) found that seven of 14 experienced resolution of symptoms and no longer required cholestyramine. Of the remaining 7 symptomatic patients, diarrhea was well controlled in 5 using cholestyramine and in two using antidiarrheal medications.
Cholestyramine is the only amanuensis approved past Wellness Canada for the symptomatic control of bile acid-induced diarrhea due to short bowel syndrome to help reduce fecal bile acid loss (75). Cholestyramine powder is usually administered at a starting dose of four g/twenty-four hour period, increased as needed to 4 k one to six times/twenty-four hours; in clinical do, less frequent dosing (eg, 4 1000 twice/day) is frequently effective in relieving BAM-associated diarrhea. Lower doses (eg, 4 g twice/twenty-four hours) are generally used in patients with brusque-bowel syndrome. Adverse effects may include constipation, nausea, borborygmi, flatulence, bloating and abdominal hurting.
The bile acid sequestering agents colestipol (Colestid; Pfizer, Canada) and colesevelam (Lodalis, Welchol; Daiichi Sankyo, Japan) would too be expected to be clinically useful based on their mode of activity; nevertheless, neither is indicated for the treatment of BAM-associated diarrhea in Canada (76,77). At that place are no published reports of colestipol in BAM. Dosing for hyperlipidemia is 2 g/twenty-four hours to xvi g/solar day administered either once-daily or in divided doses, or 1 to six packets (5 chiliad/packet or 7.five chiliad/parcel) of colestipol given one time-daily or in divided doses. The about common adverse furnishings are constipation, abdominal pain/cramping, bloating/flatulence, heartburn, diarrhea and nausea/vomiting.
Colesevelam, a water-insoluble polymer, has been shown to have modest furnishings on abdominal transit time. A written report randomly assigned 24 patients with IBS-D to colesevelam 1.875 g twice/day or placebo for 12 to 14 days. Colesevelam eased stool passage and had a nonsignificant effect on 24 h colonic transit time (P=0.22). There was no outcome on the number of bowel movements per day; however, at that place was a tendency to improved stool consistency (78). A retrospective study in cancer patients with BAM symptoms receiving colesevelam reported improvements in diarrhea (83%), urgency of defecation (74%), frequency of defecation (72%), steatorrhea (71%), abdominal hurting (68%) and fecal incontinence (62%) (79). The optimal dosing of colesevelam for BAM has not been established. The dosing for hyperlipidemia is half-dozen 625 mg tablets/24-hour interval (or three tablets twice per mean solar day), or one three.75 one thousand package/day (or 1.875 thou bundle twice/day). The well-nigh mutual adverse furnishings are constipation, dyspepsia and nausea.
All bile acid sequestering agents have the potential to bind other drugs. Interactions may occur with drugs such as glyburide, glimepiride, glipizide, tetracycline, penicillin K, levothyroxine, cyclosporine, olmesartan, phenobarbital, warfarin, digitalis, and oral contraceptives containing ethinyl estradiol and norethindrone (75–77). Patients should generally be advised to accept medications either one h earlier or 4 h to 6 h after the bile acid sequestering agent (eighty).
In addition, bile sequestering agents may interfere with the absorption of fat-soluble vitamins (81,82). During long-term employ, periodic monitoring of serum vitamin A and E levels and prothrombin fourth dimension are brash.
Acknowledgments
Editorial assistance was provided by Steven Manners of Communications Lansdowne through a grant from Pendopharm, a partition of Pharmascience Inc.
Footnotes
DISCLOSURES: The authors have no fiscal disclosures or conflicts of interest to declare.
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