Seth Sweetser

Prospective Study of Motor, Sensory, Psychologic, and Autonomic Functions in Patients With Irritable Bowel Syndrome

BACKGROUND & AIMS The aim of this study was to assess pathophysiology in irritable bowel syndrome (IBS). METHODS A total of 122 IBS patients (3 male) and 41 healthy females underwent the following: questionnaires (symptoms, psychology), autonomic function, gut transit, gastric volumes, satiation, rectal compliance, and sensation (thresholds and pain ratings) testing. Proportions of patients with abnormal (<10th and >90th percentiles) motor or sensory functions according to bowel symptoms (constipation [C], diarrhea [D], mixed [M),) pain/bloat, and number of primary symptoms were estimated. RESULTS IBS subgroups (C, D, M) were similar in age, gastric and small-bowel transit, satiation, gastric volumes, rectal compliance, sensory thresholds, and pain ratings. IBS was associated with body mass index, somatic symptoms, and anxiety and depression scores. Significant associations were observed with colonic transit (IBS-C [P = .078] and IBS-D [P < .05] at 24 h; IBS-D [P < .01] and IBS-M [P = .056] at 48 h): 32% of IBS patients had abnormal colonic transit: 20.5% at 24 hours and 11.5% at 48 hours. Overall, 20.5% of IBS patients had increased sensation to distensions: hypersensitivity (<10th percentile thresholds) in 7.6%, and hyperalgesia (pain sensation ratings to distension >90th percentile for ratings in health) in 13%. Conversely, 16.5% of IBS patients had reduced rectal sensation. Pain greater than 6 times per year and bloating were not associated significantly with motor, satiation, or sensory functions. Endorsing 1 to 2 or 3 to 4 primary IBS symptoms were associated with abnormal transit and sensation in IBS. CONCLUSIONS In tertiary referral (predominantly female) patients with IBS, colonic transit (32%) is the most prevalent physiologic abnormality; 21% had increased and 17% had decreased rectal pain sensations. Comprehensive physiologic assessment may help optimize management in IBS.

Measurement of serum 7α‐hydroxy‐4‐cholesten‐3‐one (or 7αC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography‐tandem mass spectrometry

Abstract  Bile acid malabsorption (BAM) is reported in up to 50% of patients with functional diarrhoea and irritable bowel syndrome with diarrhoea (IBS‐D). Serum 7α‐hydroxy‐4‐cholesten‐3‐one (7αHCO or 7αC4), an indirect measurement of hepatic bile acid synthesis, has been validated as a measurement of BAM relative to the 75SeHCAT retention test. Our aim was to develop a serum 7αC4 assay, normal values, and compare results from healthy controls, patients with ileal Crohn’s disease or resection, and patients with IBS‐D or IBS with constipation (IBS‐C). Stored serum samples were used from adult men and women in the following groups: 111 normal healthy controls, 15 IBS‐D, 15 IBS‐C, 24 with distal ileal Crohn’s disease and 20 with distal ileal resection for Crohn’s disease. We adapted a published high pressure liquid chromatography, tandem mass spectrometry (HPLC‐MS/MS) assay. The HPLC‐MS/MS assay showed good linearity in concentration range 0–200 ng mL−1, sensitivity (lowest limit of detection 0.04 ng mL−1), and high analytical recovery (average 99%, range 93–107%). The 5th to 95th percentile for 111 normal healthy controls was 6–60.7 ng mL−1. There were significant overall group differences (anovaon ranks, P < 0.001), with significantly higher values for terminal ileal disease or resection. There were significant differences between health and IBS (anova, P = 0.043) with higher mean values in IBS‐D relative to controls (rank sum test, P = 0.027). We have established a sensitive non‐isotopic assay based on HPLC‐MS/MS, determined normal 7αC4 values, and identified increased 7αC4 in IBS‐D and in distal ileal resection and disease. This assay has potential as a non‐invasive test for BAM in IBS.

Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome?

Corticotropin releasing factor (CRF), a mediator of stress response, alters gastrointestinal (GI) functions. Stress-related changes in colonic motility are blocked by selective CRF(1) receptor antagonists. Our aim was to assess whether modulation of central and peripheral CRF(1) receptors affects colonic transit and bowel function in female patients with diarrhea-predominant irritable bowel syndrome (D-IBS). This randomized, double-blind, placebo-controlled, 2-wk study evaluated the effects of oral pexacerfont (BMS-562086), a selective CRF(1) receptor antagonist, 25 and 100 mg qd, on GI and colonic transit of solids [by validated scintigraphy with primary end point colonic geometric center (GC) at 24 h] and bowel function (by validated daily diaries) in 39 women with D-IBS. The 100-mg dose was comparable to a dose that inhibited colonic motility in stressed rats. Treatment effects were compared by analysis of covariance with baseline colonic transit as covariate. The study had 80% power (alpha = 0.05) to detect clinically meaningful (26%) differences in colonic transit. Thirty-nine of 55 patients fulfilled eligibility criteria (9 screen failures, 5 baseline GC24 outside prespecified range). At baseline, three treatment groups had comparable age, body mass index, and GC 24 h. Significant effects of pexacerfont relative to placebo were not detected on colonic GC24 (P = 0.53), gastric emptying, orocecal transit, ascending colon emptying half-time, and stool frequency, consistency, and ease of passage. No safety issues were identified. We conclude that in women with D-IBS, pexacerfont, 25 or 100 mg qd, does not significantly alter colonic or other regional transit or bowel function. The role of central and peripheral CRF(1) receptors in bowel function in D-IBS requires further study.

Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation

Abstract  Velusetrag (TD‐5108) is a potent, selective high intrinsic activity serotonin 5‐HT4 receptor agonist. We assessed effects of Velusetrag on gastrointestinal transit and compared its pharmacokinetics in healthy volunteers (HV) and chronic constipation (CC) patients. Sixty HV were randomly assigned, double‐blind to placebo, 5, 15, 30 or 50 mg Velusetrag (single and 6‐day dosing). Primary endpoints were colonic transit (geometric centre at 24 h, GC24) and ascending colon emptying (ACE) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T1/2 at 15–50 mg. Pharmacokinetics studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of Velusetrag. Stimulation of bowel function after15 mg Velusetrag was similar in CC and controls. There were no serious adverse events; notable adverse events were the predictable gastrointestinal effects such as diarrhoea or altered bowel movements. Velusetrag significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted.

Effect of a chloride channel activator, lubiprostone, on colonic sensory and motor functions in healthy subjects

Lubiprostone, a bicyclic fatty acid chloride channel activator, is efficacious in treatment of chronic constipation and constipation-predominant irritable bowel syndrome. The study aim was to compare effects of lubiprostone and placebo on colonic sensory and motor functions in humans. In double-blind, randomized fashion, 60 healthy adults received three oral doses of placebo or 24 microg lubiprostone per day in a parallel-group, placebo-controlled trial. A barostat-manometry tube was placed in the left colon by flexible sigmoidoscopy and fluoroscopy. We measured treatment effects on colonic sensation and motility with validated methods, with the following end points: colonic compliance, fasting and postprandial tone and motility indexes, pain thresholds, and sensory ratings to distensions. Among participants receiving lubiprostone or placebo, 26 of 30 and 28 of 30, respectively, completed the study. There were no overall effects of lubiprostone on compliance, fasting tone, motility indexes, or sensation. However, there was a treatment-by-sex interaction effect for compliance (P = 0.02), with lubiprostone inducing decreased fasting compliance in women (P = 0.06) and an overall decreased colonic tone contraction after a standard meal relative to fasting tone (P = 0.014), with greater effect in women (P < 0.01). Numerical differences of first sensation and pain thresholds (P = 0.11 in women) in the two groups were not significant. We concluded that oral lubiprostone 24 microg does not increase colonic motor function. The findings of decreased colonic compliance and decreased postprandial colonic tone in women suggest that motor effects are unlikely to cause accelerated colonic transit with lubiprostone, although they may facilitate laxation. Effects of lubiprostone on sensitivity deserve further study.

Serrated Colon Polyps as Precursors to Colorectal Cancer

Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights include an increased recognition of the malignant potential of different types of serrated polyps such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors that have microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. These data have important implications for clinical practice and CRC prevention, because hyperplastic polyps were previously regarded as having no malignant potential. There is also evidence that the serrated pathway contributes to interval or missed cancers. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps to facilitate their detection and removal, and thereby ensure a high-quality colonoscopic examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in postpolypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence.

Understanding measurements of intestinal permeability in healthy humans with urine lactulose and mannitol excretion

Abstract  Our aim was to understand the information from differential two‐sugar excretion (2‐SE) in measuring intestinal permeability. In a crossover study in 12 healthy volunteers, we compared urinary excretion ratios of lactulose (L) to mannitol [(M) LMR] after ingestion in liquid formulation (LF) or in delayed‐release, methacrylate‐coated capsules (CAP). Both formulations were radiolabelled. Urine was collected every 2 h from 0 to 8 h, and from 8 to 24 h. Two hours after LF, gastric residual was 15.9 ± 6.2% (SEM), and the percentage in colon was 49.6 ± 7.8%; in 11/12 participants, liquid had entered colon within 2 h. Average CAP arrival time in colon was 5.16 ± 0.46 h (mode 6 h). After LF, mannitol was extensively absorbed in the first 8 h; lactulose absorption was low thoughout the 24 h. After the LF, the LMR (geometric mean, 95% CI per h) in the 0–2 h urine was [0.08 (0.05, 0.11)], which was lower than in 8–24 h urine [0.32 (0.16, 0.46); P < 0.05]. Urine LMRs at 8–24 h were similar after LF or CAP. We concluded that, after LF, sugar excretion in 0–2 h urine may reflect both SI and colon permeability. Colonic permeability is reflected by urine sugar excretion between 6 and 24 h. CAP delivery reduces mannitol excreted at 0–6 h, compared with LF. The 0–5 or 6 h 2‐SE urine likely reflects both SI and colon permeability; the higher LMR in the 8–24 h urine relative to 0–2 h urine should be interpreted with caution and does not mean that colon is more permeable than SI.

Colonic polyposis and neoplasia in Cowden syndrome.

OBJECTIVE To identify and describe the frequency, histologic features, and clinical outcome of colon polyposis and neoplasia in Cowden syndrome--a rare familial hamartoma tumor syndrome associated with mutations in the PTEN gene. PATIENTS AND METHODS Patients with a clinical diagnosis of PTEN hamartoma tumor syndrome-Cowden phenotype were retrospectively identified and studied. Only those who underwent colonoscopy or colon pathologic interpretation were included in the final analysis. RESULTS From 1994 to 2009, 13 patients met study inclusion criteria. Of the 10 patients who underwent colonoscopy, 9 (90%; 95% confidence interval [CI], 57%-100%) had polyps, and 7 (70%; 95% CI, 39%-90%) were estimated to have more than 50 polyps. Pathologic findings of the colon were reviewed in 11 patients, and the spectrum of tumors included hamartomatous, inflammatory, adenomatous, ganglioneuromatous, hyperplastic, and juvenile polyps. Of the 13 patients, 2 (15%; 95% CI, 3%-43%) had left-sided adenocarcinoma without microsatellite instability. Five (38%) of the 13 patients underwent colectomy secondary to polyp dysplasia. CONCLUSION Patients with Cowden syndrome have a heavy colon polyp burden with a wide pathologic spectrum, both benign and malignant. The colon polyposis results in a previously unreported morbidity with a high colectomy rate.

A Controlled Pharmacogenetic Trial of Sibutramine on Weight Loss and Body Composition in Obese or Overweight Adults

BACKGROUND & AIMS Weight loss in response to sibutramine is highly variable. We assessed the association of specific markers of polymorphisms of candidate alpha2A adrenoreceptor, 5-HT transporter, and GNbeta3 genes and weight loss with sibutramine. METHODS We conducted a randomized, double-blind, pharmacogenetic study of behavioral therapy and sibutramine (10 or 15 mg daily) or placebo for 12 weeks in 181 overweight or obese participants. We measured body weight, body mass index, body composition, gastric emptying, and genetic variation (alpha2A C1291G, 5-HTTLPR, and GNbeta3 C825T genotypes). Analysis of covariance was used to assess treatment effects on and associations of the specific markers of candidate genes with weight loss and body composition. RESULTS Sibutramine, 10 and 15 mg, caused weight loss (P = .009); there was a statistically significant gene by dose interaction for GNbeta3 genotype. For each candidate gene, significant treatment effects at 12 weeks were observed (P < .017) for all specific genotype variants (Delta weight loss in the 2 sibutramine doses vs placebo): alpha2A CC (Delta, approximately 5 kg), GNbeta3 TC/TT (Delta, approximately 6 kg), and 5-HTTLPR LS/SS (Delta, approximately 4.5 kg). Gene pairs resulted in significantly greater sibutramine treatment effects on weight (both P < .002): in participants with 5-HTTLPR LS/SS with GNbeta3 TC/TT; Delta, approximately 6 kg and those with alpha2A CC with GNbeta3 TC/TT; Delta, approximately 8 kg; however, effects were not synergistic. Treatment with sibutramine also resulted in significantly greater reduction of body fat for specific alpha2A CC and GNbeta3 TC/TT genotype variants individually (both P < .02). CONCLUSIONS Patient selection based on candidate genes may enhance response to multidimensional sibutramine and behavioral therapy for obesity.

A Population-based Study of Incidence, Risk Factors, Clinical Spectrum, and Outcomes of Ischemic Colitis

BACKGROUND & AIMS Little is known about progression of ischemic colitis (IC) among unselected patients. We aimed to estimate the incidence, risk factors, and natural history of IC in a population-based cohort in Olmsted County, Minnesota. METHODS We performed a retrospective population-based cohort and nested case-control study of IC. Each IC case was matched to 2 controls from the same population on the basis of sex, age, and closest registration number. Conditional logistic regression, the Kaplan-Meier method, and proportional hazards regression were used to assess comorbidities, estimate survival, and identify characteristics associated with survival, respectively. RESULTS Four hundred forty-five county residents (median age, 71.6 years; 67% female) were diagnosed with IC from 1976 through 2009 and were matched with 890 controls. The age-adjusted and sex-adjusted incidence rates of IC nearly quadrupled from 6.1 cases/100,000 person-years in 1976-1980 to 22.9/100,000 in 2005-2009. The odds for IC were significantly higher among subjects with atherosclerotic diseases; odds ratios ranged from 2.6 for individuals with coronary disease to 7.9 for individuals with peripheral vascular disease. Of IC cases, 59% survived for 5 years (95% confidence interval, 54%-64%), compared with 90% of controls (95% confidence interval, 88%-92%). Age >40 years, male sex, right-sided colon involvement, concomitant small bowel involvement, and chronic obstructive pulmonary disease were all independently associated with mortality (P < .05). CONCLUSIONS The incidence of IC increased during the past 3 decades in a population-based cohort in Minnesota. IC typically presents in older patients with multiple comorbidities and is associated with high in-hospital mortality (11.5%) and rates of surgery (17%).