Bile Acid Sequestrants in Microscopic Colitis: Clinical Outcomes and Utility of Bile Acid Testing.

BACKGROUND & AIMS: Bile acid sequestrants (BAS) may be a treatment in microscopic colitis (MC), but efficacy data are limited. We evaluated the effectiveness of BAS in MC and assessed the utility of bile acid testing to predict response. METHODS: Adults with MC treated with BAS (2010-2020) at Mayo Clinic were identified. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing using previously validated cutoffs. Response was defined at 12 ± 4 weeks after BAS initiation as: complete (resolution of diarrhea), partial (≥50% improvement in diarrhea), nonresponse (<50% improvement), and intolerance (discontinuation due to side effects). Logistic regression was used to identify predictors of response to BAS. RESULTS: We identified 282 patients (median age, 59 years [range, 20-87 years]; 88.3% women) with median follow-up of 4.5 years (range, 0.4-9.1 years). Patients were treated with the following BAS: 64.9% cholestyramine, 21.6% colesevelam, and 13.5% colestipol. Clinical outcomes were: 49.3% complete response, 16.3% partial response, 24.8% nonresponse, and 9.6% intolerance. There were no differences in outcomes between those on BAS alone or BAS combined with other medications (P = .98). The dose of BAS was not associated with response (P = .51). Bile acid testing was done in 31.9% of patients, and 56.7% were positive. No predictors of response to BAS were identified. After BAS discontinuation, 41.6% had recurrence at a median of 21 weeks (range, 1-172 weeks). CONCLUSION: In one of the largest cohorts evaluating BAS treatment in MC, nearly two-thirds had a partial or complete response. Additional research is needed to determine the role of BAS and bile acid malabsorption in MC.

Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. RESULTS: 563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. CONCLUSIONS: These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. GOV REGISTRATION NUMBER: NCT02400476.

The Role of Bile Acids in Chronic Diarrhea.

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.

Lipid-Lowering Agents and High HDL (High-Density Lipoprotein) Are Inversely Associated With Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. METHODS: The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women's Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. RESULTS: Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47-0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93-0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23-0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure-response curve between HDL levels and risk of aneurysmal rupture was obtained. CONCLUSIONS: Higher HDL values and the use of lipid-lowering agents are significantly inversely associated with ruptured intracranial aneurysms.

Tolerability and efficacy of colestipol hydrochloride for accelerated elimination of teriflunomide.

BACKGROUND: Teriflunomide is an oral disease modifying therapy approved for the treatment of relapsing forms of multiple sclerosis. Teriflunomide' s pharmacokinetics (PK) contribute to its slow elimination, on average taking 6-8 months, though it can take up to 2 years in some instances. This slow elimination can become problematic in certain clinical situations - such as during pregnancy, when teriflunomide has potential teratogenic effects. In such scenarios, an accelerated elimination procedure (AEP) is recommended. Currently, AEPs with oral cholestyramine or activated charcoal are available but are restricted by adverse effects, limited administration routes, and dosing frequencies. METHODS: A single-center, PK interaction study was performed in a total of 14 healthy volunteers, to investigate colestipol hydrochloride (HCl) as an alternative to cholestyramine for the elimination of teriflunomide. Participants received teriflunomide for 14 days, followed by an AEP with colestipol HCl for 15 days. RESULTS AND CONCLUSIONS: The administration of colestipol HCl for 15 days was sufficient to reduce plasma teriflunomide concentrations by greater than 96%. Although colestipol HCl did not completely eliminate teriflunomide with the same effectiveness as cholestyramine, it may offer an alternative method for accelerated elimination of teriflunomide with potentially improved tolerability and more favorable dosing and administration options.

75SeHCAT scan in bile acid malabsorption in chronic diarrhoea. / Gammagrafía con 75SeHCAT en la diarrea crónica por malabsorción de ácidos biliares.

Chronic diarrhoea is a common entity in daily clinical practice and it leads to a loss in these patients quality of life. It may be the main symptom of multiple ethiologies including bile acid malabsorption (BAM) which has a comparable prevalence to celiac disease. The BAM results from imbalances in the homeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease or ileal dysfunction (BAM type i), it can be considered idiopathic or primary (BAM type ii) or associated with other gastrointestinal entities (BAM type iii). Among the different diagnostic methods available, 75SeHCAT study is the primary current method due to its sensitivity, specificity, safety and low cost. The main disadvantage is that it's not available in all countries, so other diagnostic methods have appeared, such as serum measurement of FGF19 and C4, however they are significantly more complex and costly. The first-line treatment of bile acid diarrhoea is bile acid sequestrant, such as cholestyramine, which can be difficult to administer due to its poor tolerability and gastrointestinal side effects. These are less prominent with newer agents such as colesevelam. In summary, the BAM is a common entity underdiagnosed and undertreated, so it is essential to establish a diagnosis algorithm of chronic diarrhoea in which the 75SeHCAT study would be first or second line in the differential diagnosis of these patients.

Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study-Observational Study.

BACKGROUND: Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. OBJECTIVES: The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study. METHODS: Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. RESULTS: UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11). CONCLUSIONS: Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.

Long-term outcomes in patients diagnosed with bile-acid diarrhoea.

OBJECTIVE: Bile-acid diarrhoea (BAD) is a recognized cause of chronic diarrhoea; however, its detection remains suboptimal. Currently, there is a paucity of follow-up studies evaluating BAD. This work evaluates the natural history of BAD by examining individuals diagnosed with BAD [7 days of Se-homocholic acid taurine (SeHCAT) retention<10%] and determining the use of and response to bile-acid sequestrants (BAS). MATERIALS AND METHODS: Of the 515 patients, 40% (207/515) who underwent an SeHCAT test at Sheffield Teaching Hospitals (2001-2012) for chronic diarrhoea had BAD. Of the 207 (51%) patients, 107 were diagnosed between 2001 and 2009. In accordance with the guidelines, all of these patients were commenced on BAS. In March 2013, these individuals were reassessed either in the clinic or over the telephone as part of a local service evaluation project. Comparisons were made of both pretreatment and post-treatment variables using a Wilcoxon rank test. RESULTS: Of the 107 patients, 54% (58/107) were followed up, with a median time since diagnosis of 6 years. Among them, 38% were still using BAS at follow-up, with 28% using alternative antidiarrhoeals. The median stool frequency decreased from seven stools per day to three (P=0.0008) in those using BAS. The 34% of patients not receiving treatment had no change in their daily bowel frequency. The main reason for discontinuing treatment was poor tolerability of the BAS (colestyramine/colestipol). CONCLUSION: Our findings indicate that BAD is a chronic condition that best improves with BAS. Consideration should be given to therapeutic options that have a better tolerability profile.

Feasibility study of colestipol as an oral phosphate binder in hemodialysis patients.

BACKGROUND: Currently available calcium- and aluminium-based phosphate binders are dose limited because of potential toxicity, and newer proprietary phosphate binders are expensive. We examined phosphate-binding effects of the bile acid sequestrant colestipol, a non-proprietary drug that is in the same class as sevelamer. METHODS: The trial was an 8 week prospective feasibility study in stable hemodialysis patients using colestipol as the only phosphate binder, preceded and followed by a washout phase of all other phosphate binders. The primary study endpoint was weekly measurements of serum phosphate. Secondary endpoints were serum calcium, lipids and coagulation status. Analyses used random effects mixed models. RESULTS: Thirty patients were screened for participation of which 26 met criteria for treatment. At a mean dose of 8.8 g/24 h of colestipol by study end, serum phosphate dropped from 2.24 to 1.96 mmol/L (P < 0.001). Three patients required calcium supplementation. LDL cholesterol dropped from 1.75 to 1.2 mmol/L (P < 0.001). Three patients dropped out because of side effects or intolerance of the required dose. CONCLUSION: The results support the feasibility of a larger trial to determine the efficacy of colestipol as a phosphate binder and that other non-proprietary anion-exchange resins may also warrant investigation.

Colesevelam and colestipol: novel medication resins in the gastrointestinal tract.

We report the morphologic description of the bile acid sequestrants (BAS) colesevelam and colestipol, as well as the largest series of cholestyramine. Histologically similar medication resins from 4 institutions were prospectively collected over 1 year (26 specimens, 15 patients). Comorbidities included hyperlipidemia (4/15), hypertension (4/15), inflammatory bowel disease (4/15), coronary artery disease (3/15), diarrhea (7/15), hypothyroidism (2/15), and ischemic bowel (1/15). Sites of involvement included the esophagus (1/26), stomach (1/26), small intestine (1/26), ileocecal valve (1/26), and colorectum (22/26). Associated histologic diagnoses included normal (8/26), chronic mucosal injury (11/26), acute inflammation (9/26), erosion/ulceration (6/26), and cytomegalovirus (2/26). The BAS resins were histologically indistinguishable from each other; they were all eosinophilic on hematoxylin and eosin (H&E) and lacked internal "fish-scales." To validate these observations, respective medications were submitted for histologic processing; the processed medications were identical to those in the patient specimens. Rare, irregular "fracture" lines presented diagnostic pitfalls by mimicking the true "fish-scales" of Kayexalate and sevelamer. Clues to the correct identification of BAS include recognition that the "fracture" lines were subtle, irregular, and restricted to large fragments or thick sections, likely representing a processing artifact. Moreover, Kayexalate is violet on H&E and black on acid fast bacillus, and sevelamer characteristically displays a 2-tone color on H&E and is magenta on acid fast bacillus. An association with inflammatory injury was seen (15/26). We believe that the BAS are innocent bystanders in complicated patients, although we cannot exclude their ability to cause mucosal injury in specific settings.

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.

Alteration of aluminium inhibition of synaptosomal (Na(+)/K(+))ATPase by colestipol administration.

The ability of aluminium to inhibit the (Na(+)/K(+))ATPase activity has been observed by several authors. During chronic dietary exposure to AlCl3, brain (Na(+)/K(+))ATPase activity drops, even if no alterations of catalytic subunit protein expression and of energy charge potential are observed. The aluminium effect on (Na(+)/K(+))ATPase activity seems to implicate the reduction of interacting protomers within the oligomeric ensemble of the membrane-bound (Na(+)/K(+))ATPase. The activity of (Na(+)/K(+))ATPase is altered by the microviscosity of lipid environment. We studied if aluminium inhibitory effect on (Na(+)/K(+))ATPase is modified by alterations in synaptosomal membrane cholesterol content. Adult male Wistar rats were submitted to chronic dietary AlCl3 exposure (0.03 g/day of AlCl3) and/or to colestipol, a hypolidaemic drug (0.31 g/day) during 4 months. The activity of (Na(+)/K(+))ATPase was studied in brain cortex synaptosomes with different cholesterol contents. Additionally, we incubate synaptosomes with methyl-ß-cyclodextrin for both enrichment and depletion of membrane cholesterol content, with or without 300 µM AlCl3. This enzyme activity was significantly reduced by micromolar AlCl3 added in vitro and when aluminium was orally administered to rats. The oral administration of colestipol reduced the cholesterol content and concomitantly inhibited the (Na(+)/K(+))ATPase. The aluminium inhibitory effect on synaptosomal (Na(+)/K(+))ATPase was reduced by cholesterol depletion both in vitro and in vivo.

Clinical inquiry. Postcholecystectomy diarrhea: what relieves it?

A trial of a bile acid binder such as cholestyramine or colestipol may benefit patients with postcholecystectomy diarrhea.