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ABSTRACT: Despite years of advising patients to alter their dietary and supplementary fiber intake, the evidence surrounding the use of fiber for functional bowel disease is limited. This paper outlines the organization of fiber types and highlights the importance of assessing the fermentation characteristics of each fiber type when choosing a suitable strategy for patients. Fiber undergoes partial or total fermentation in the distal small bowel and colon leading to the production of short-chain fatty acids and gas, thereby affecting gastrointestinal function and sensation. When fiber is recommended for functional bowel disease, use of a soluble supplement such as ispaghula/psyllium is best supported by the available evidence. Even when used judiciously, fiber can exacerbate abdominal distension, flatulence, constipation, and diarrhea.Am J Gastroenterol advance online publication, 2 April 2013; doi:10.1038/ajg.2013.63.
The American Journal of Gastroenterology 04/2013; · 7.28 Impact Factor
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Joel H Rubenstein,
Hal Morgenstern, William D Chey,
Joseph Murray,
James M Scheiman,
Philip Schoenfeld,
Henry D Appelman,
Laurence McMahon,
Val Metko,
Joan Kellenberg,
Tal Kalish,
Jason Baker,
John M Inadomi
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ABSTRACT: OBJECTIVE: Abdominal obesity has been associated with erosive oesophagitis (EO) and Barrett's oesophagus (BO). As gluteofemoral obesity protects against diabetes mellitus and cardiovascular disease, we hypothesised that gluteofemoral obesity would be inversely associated with EO and BO. DESIGN: We conducted a cross-sectional study on 822 male colorectal cancer screenees who were recruited to also undergo upper endoscopy. An additional 80 patients with BO clinically detected by upper endoscopy referred for clinical indications were recruited shortly after their diagnoses of BO. Logistic regression was used to estimate the effects of abdominal obesity (waist circumference), gluteofemoral obesity (hip circumference) and waist-to-hip ratio (WHR) on EO and BO (vs neither condition). RESULTS: There were 225 cases of either BO or EO and 675 controls. After adjustment for potential confounders, a positive association was observed between waist circumference and BO and/or EO, which became stronger with further adjustment for hip circumference. In contrast, hip circumference was inversely associated with BO and/or EO. Compared with the lowest quartile of WHR, the adjusted ORs were 1.32 (95% CI 0.747 to 2.33) for the 2nd quartile, 1.54 (95% CI 0.898 to 2.63) for the 3rd quartile, and 2.68 (95% CI 1.57 to 4.55) for the highest quartile. Similar results were obtained for BO and EO treated as separate outcomes. CONCLUSIONS: In a population of older, mostly overweight men, the distribution of obesity is associated with the presence of EO and BO. Abdominal obesity appears to increase the risk of these outcomes, whereas gluteofemoral obesity may be protective.
Gut 03/2013; · 10.11 Impact Factor
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William D Chey,
Anthony J Lembo,
Bernard J Lavins,
Steven J Shiff,
Caroline B Kurtz,
Mark G Currie,
James E Macdougall,
Xinwei D Jia,
James Z Shao,
Donald A Fitch,
Mollie J Baird,
Harvey A Schneier,
Jeffrey M Johnston
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ABSTRACT: OBJECTIVES:Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide treatment in patients with irritable bowel syndrome with constipation (IBS-C) over 26 weeks.METHODS:This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg of oral linaclotide once daily for a 26-week treatment period. The primary and the secondary efficacy assessments were evaluated over the first 12 weeks of treatment. Primary end points included the Food and Drug Administration's (FDA's) end point for IBS-C (responder: a patient who reported (i) improvement of ≥30% from baseline in average daily worst abdominal pain score and (ii) increase of ≥1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for ≥6/12 weeks) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.RESULTS:In all, 804 patients (mean age=44 years, female=90%, white=78%) were evaluated; 33.7% of linaclotide-treated patients were FDA end point responders, vs. 13.9% of placebo-treated patients (P<0.0001) (number needed to treat=5.1, 95% confidence interval (CI): 3.9, 7.1). The pain responder criterion of the FDA end point was met by 48.9% of linaclotide-treated patients vs. 34.5% of placebo-treated patients (number needed to treat=7.0, 95% CI: 4.7, 13.1), and the CSBM responder criterion was met by 47.6% of linaclotide-treated patients, vs. 22.6% of placebo patients (number needed to treat=4.0, 95% CI: 3.2, 5.4). Remaining primary end points (P<0.0001) and all secondary end points (P<0.001), including abdominal pain, abdominal bloating, and bowel symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining), were also statistically significantly improved with linaclotide vs. placebo. Statistically significant differences from placebo were observed for responder and continuous end points over 26 weeks of treatment. AE incidence was similar between treatment groups, except for diarrhea, which caused discontinuation in 4.5% of linaclotide patients vs. 0.2% of placebo patients.CONCLUSIONS:Linaclotide 290 μg once daily significantly improved abdominal and bowel symptoms associated with IBS-C over 26 weeks of treatment.Am J Gastroenterol advance online publication, 18 September 2012; doi:10.1038/ajg.2012.254.
The American Journal of Gastroenterology 09/2012; · 7.28 Impact Factor
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ABSTRACT: Diarrhoea and constipation are common clinical complaints that negatively affect quality of life, reduce work productivity and lead to considerable health-care expenditure. A variety of therapies have been used to treat these conditions. Unlike drugs that require systemic absorption to exert their effects, luminally acting agents improve diarrhoea and constipation by altering intestinal and/or colonic motility, as well as mucosal absorption and secretion, through a variety of mechanisms. Examples of luminally acting agents for diarrhoea include peripherally acting opiate analogues, enkephalinase inhibitors, bile-acid binding agents, nonabsorbed antibiotics, probiotics, bismuth-containing compounds, berberine and agents with possible effects on intestinal secretion or permeability. Luminally acting drugs for constipation include bulking agents, surfactants, osmotics, stimulants, chloride-channel activators, probiotics, drugs that increase delivery of bile acids to the colon and natural therapies such as prunes and hemp seed extract. As the physiological effects of luminally acting drugs are largely confined to the gastrointestinal tract, these agents are unlikely to cause adverse effects outside of the gastrointestinal tract.
Nature Reviews Gastroenterology & Hepatology 09/2012; · 8.10 Impact Factor
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ABSTRACT: The gut microbiota play a role throughout the human lifecycle, not only in harvesting energy from otherwise indigestible components of the diet, but also in directing submucosal angiogenesis and the establishment of the intestinal mucosal barrier during development as well as modulating the host immune system throughout life. The composition of the gut microbiota reflects two-way interactions between the gut microbiota and the host that promote mutual cooperation and functional stability of this complex ecosystem. Dysregulation of this balance as a result of diet, antibiotic use, or other exogenous factors has been shown to lead to disease, either directly—as in the case of antibiotic-associated diarrhea—or indirectly, as might occur in patients predisposed to visceral hypersensitivity who are fed a highly fermentable, poorly absorbed diet. Manipulation of the gut flora through dietary modification, antibiotics, probiotics, and other routes represents a promising therapeutic avenue in patients with disorders caused or exacerbated by imbalances in the gastrointestinal microbiota.
The American Journal of Gastroenterology Supplements. 06/2012; 1(1):41-46.
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The American Journal of Gastroenterology 01/2012; 107(1):140-1. · 7.28 Impact Factor
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Expert review of gastroenterology & hepatology 12/2011; 5(6):657-9.
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ABSTRACT: Irritable bowel syndrome (IBS) affects 10-15% of the population, and treatment options are limited. Rifaximin is a minimally absorbed antibiotic that has shown efficacy in IBS patients. The objective of our study was to perform a meta-analysis and systematic review of available randomized, placebo controlled trials evaluating the efficacy and tolerability of rifaximin in patients with IBS.
We performed a systematic literature search of multiple online electronic databases regardless of language. Inclusion criteria entailed randomized, placebo controlled trials and IBS defined by accepted symptom-based criteria. Meta-analysis was conducted to evaluate the summary odds ratios (ORs) and 95% confidence intervals (CIs) of combined studies for the primary and secondary outcomes using a random-effects model based on the DerSimonian and Laird method to reflect both within- and between study variability. We assessed heterogeneity using χ(2) test and the inconsistency index statistic (I(2)). Significant heterogeneity was defined as I(2) ≥25%. Meta-regression was performed using generalized linear mixed-effects model and study as random effects to estimate the summary OR adjusting for covariate differences across studies and treatment group. Publication bias was assessed by funnel plot analysis.
Systematic review identified 13,700 citations. Eighteen were deemed to be potentially relevant, of which five articles met eligibility. Meta-analysis found rifaximin to be more efficacious than placebo for global IBS symptom improvement (OR=1.57; 95% CI=1.22, 2.01; therapeutic gain=9.8%; number needed to treat (NNT)=10.2), with mild heterogeneity (P=0.25, I(2)=26%). For the key secondary outcome of bloating, raw data were available for four studies. Rifaximin was significantly more likely to improve bloating than placebo (OR=1.55; 95% CI=1.23-1.96; therapeutic gain=9.9%; NNT=10.1), with no significant heterogeneity (P=0.27, I(2)=23%). We found that studies with older patients and more females demonstrated higher response rates, which was consistent regardless of treatment group. In addition, studies with higher cumulative dose tended to report a higher response rate. Of the covariates evaluated, we found age to be most predictive of response, with a correlation coefficient of 0.97 between aggregate response rate and mean age in the placebo groups. Although studies with higher cumulative dose tended to show increased response rates, this was also seen consistently in both the treated and placebo groups. Adverse effects were similar among patients receiving rifaximin or placebo in all studies. The most common adverse events (AEs) (≤10%) with rifaximin were headache, upper respiratory infection, nausea, nasopharygitis, diarrhea, and abdominal pain. Serious AEs were rare (<1%) and similar with rifaximin and placebo.
Rifaximin proved more effective than placebo for global symptoms and bloating in IBS patients. The modest therapeutic gain was similar to that yielded by other currently available therapies for IBS. AEs were similar between rifaximin and placebo.
The American Journal of Gastroenterology 11/2011; 107(1):28-35; quiz 36. · 7.28 Impact Factor
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Gastroenterology 09/2011; 141(5):1941-3. · 11.68 Impact Factor
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ABSTRACT: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by episodic abdominal pain or discomfort in association with altered bowel habits (diarrhea and/or constipation). Other gastrointestinal symptoms, such as bloating and flatulence, are also common. A variety of factors are believed to play a role in the development of IBS symptoms, including altered bowel motility, visceral hypersensitivity, psychosocial stressors, altered brain-gut interactions, immune activation/low grade inflammation, alterations in the gut microbiome, and genetic factors. In the absence of biomarkers that can distinguish between IBS subgroups on the basis of pathophysiology, treatment of this condition is predicated upon a patient's most bothersome symptoms. In clinical trials, effective therapies have only offered a therapeutic gain over placebos of 7-15%. Evidence based therapies for the global symptoms of constipation predominant IBS (IBS-C) include lubiprostone and tegaserod; evidence based therapies for the global symptoms of diarrhea predominant IBS (IBS-D) include the probiotic Bifidobacter infantis, the nonabsorbable antibiotic rifaximin, and alosetron. Additionally, there is persuasive evidence to suggest that selected antispasmodics and antidepressants are of benefit for the treatment of abdominal pain in IBS patients. Finally, several emerging therapies with novel mechanisms of action are in development. Complementary and alternative medicine therapies including probiotics, herbal therapies and acupuncture are gaining popularity among IBS sufferers, although concerns regarding manufacturing standards and the paucity of high quality efficacy and safety data remain.
Gut and liver 09/2011; 5(3):253-66. · 0.83 Impact Factor
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ABSTRACT: Guidelines recommend that patients with symptoms of nonconstipated irritable bowel syndrome (NC-IBS) undergo testing for celiac disease (CD). We evaluated the prevalence of CD antibodies, and biopsy confirmed CD among patients with NC-IBS in a large US population.
In a study conducted at 4 sites, from 2003 to 2008, we compared data from 492 patients with symptoms of NC-IBS to 458 asymptomatic individuals who underwent colonoscopy examinations for cancer screening or polyp surveillance (controls). All participants provided blood samples for specific and nonspecific CD-associated antibodies. Additionally, patients with IBS were analyzed for complete blood cell counts, metabolic factors, erythrocyte sedimentation rates, and levels of C-reactive protein and thyroid-stimulating hormone. Any subjects found to have CD-associated antibodies were offered esophagogastroduodenoscopy and duodenal biopsy analysis.
Of patients with NC-IBS, 7.3% had abnormal results for CD-associated antibodies, compared with 4.8% of controls (adjusted odds ratio, 1.49; 95% confidence interval: 0.76-2.90; P=.25). Within the NC-IBS group, 6.51% had antibodies against gliadin, 1.22% against tissue transglutaminase, and 0.61% against endomysium (P>.05 vs controls for all antibodies tested). CD was confirmed in 0.41% of patients in the NC-IBS group and 0.44% of controls (P>.99).
Although CD-associated antibodies are relatively common, the prevalence of CD among patients with NC-IBS is similar to that among controls in a large US population. These findings challenge recommendations to routinely screen patients with NC-IBS for CD. More than 7% of patients with NC-IBS had CD-associated antibodies, suggesting that gluten sensitivity might mediate IBS symptoms; further studies are needed.
Gastroenterology 07/2011; 141(4):1187-93. · 11.68 Impact Factor
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ABSTRACT: The prevalence of generalized transit delay and relation to symptoms in suspected gastroparesis, intestinal dysmotility, or slow transit constipation are unknown.
The aims of this study were (1) to define prevalence of generalized dysmotility using wireless motility capsules (WMC), (2) to relate to symptoms in suspected regional delay, (3) to compare results of WMC testing to conventional transit studies to quantify new diagnoses, and (4) to assess the impact of results of WMC testing on clinical decisions.
WMC transits were analyzed in 83 patients with suspected gastroparesis, intestinal dysmotility, or slow transit constipation.
Isolated regional delays were observed in 32% (9% stomach, 5% small bowel, 18% colon). Transits were normal in 32% and showed generalized delays in 35%. Symptom profiles were similar with normal transit, isolated delayed gastric, small intestinal, and colonic transit, and generalized delay (P = NS). Compared to conventional tests, WMC showed discordance in 38% and provided new diagnoses in 53%. WMC testing influenced management in 67% (new medications 60%; modified nutritional regimens 14%; surgical referrals 6%) and eliminated needs for testing not already done including gastric scintigraphy (17%), small bowel barium transit (54%), and radioopaque colon marker tests (68%).
WMC testing defines localized and generalized transit delays with suspected gastroparesis, intestinal dysmotility, or slow transit constipation. Symptoms do not predict the results of WMC testing. WMC findings provide new diagnoses in >50%, may be discordant with conventional tests, and can influence management by changing treatments and eliminating needs for other tests. These findings suggest potential benefits of this method in suspected dysmotility syndromes and mandate prospective investigation to further define its clinical role.
Digestive Diseases and Sciences 05/2011; 56(10):2928-38. · 2.12 Impact Factor
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ABSTRACT: A3309 is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor. We conducted an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, phase IIb study, which evaluated A3309 in patients with chronic idiopathic constipation (CIC).
Patients with CIC (modified Rome III criteria and <3 complete (CSBM) spontaneous bowel movements (SBMs)/week during the 2-week baseline) were randomized to 5, 10, or 15 mg A3309 or placebo once daily. The primary end point was change in SBM number during week 1 compared with baseline. Other bowel and abdominal symptoms were assessed as secondary end points. Serum 7αC4 and lipids were evaluated as biomarkers of BA synthesis/loss.
In all, 190 patients (mean 48 years, 90% female) were randomized. Mean increase (95% confidence interval) in SBM for week 1 were 1.7 (0.7-2.8) for placebo vs. 2.5 (1.5-3.5), 4.0 (2.9-5.0), and 5.4 (4.4-6.4) for 5 mg, 10 mg (P<0.002), and 15 mg (P<0.001) A3309, respectively. Increased stool frequency was maintained over 8 weeks. Time to first SBM and CSBM were significantly reduced in the 10- and 15-mg A3309 groups compared with placebo. Straining and bloating decreased with A3309 compared with placebo (P<0.05). Increased 7αC4 and reduced low-density lipoprotein cholesterol with A3309 suggested increased BA synthesis and BA loss. The most common adverse events (AEs) were abdominal pain and diarrhea, which occurred most commonly in the 15-mg A3309 group. No drug-related serious AEs were observed.
A3309 increased stool frequency and improved constipation-related symptoms in CIC; effects were maintained over 8 weeks of treatment.
The American Journal of Gastroenterology 05/2011; 106(10):1803-12. · 7.28 Impact Factor
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William D Chey
Gastroenterology clinics of North America 03/2011; 40(1):xiii-xiv. · 2.56 Impact Factor
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Gastroenterology 03/2011; 140(5):1682-5. · 11.68 Impact Factor
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ABSTRACT: The irritable bowel syndrome (IBS) is a symptom-based disorder defined by the presence of abdominal pain and altered bowel habits. Clinical presentations of IBS are diverse, with some patients reporting diarrhea, some constipation, and others a mixture of both. Like the varied clinical phenotypes, the pathogenesis of IBS is also diverse. IBS is not a single disease entity, but rather likely consists of several different disease states. This fact has important implications for the choices and efficacy of IBS treatment. This article reviews the IBS drugs that have reached phase II or III clinical trials.
Gastroenterology clinics of North America 03/2011; 40(1):223-43. · 2.56 Impact Factor
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ABSTRACT: After years of inattention, there is a growing body of evidence to suggest that dietary constituents at least exacerbate symptoms and perhaps contribute to the pathogenesis of the irritable bowel syndrome (IBS). Although patients with IBS self-report food allergies more often than the general population, the evidence suggests that true food allergies are relatively uncommon. Less clearly defined food intolerances may be an important contributor to symptoms in IBS patients. This article reviews the literature supporting a causal link between food and the symptoms of IBS as well as the evidence supporting dietary interventions as a means of managing IBS symptoms.
Gastroenterology clinics of North America 03/2011; 40(1):141-62. · 2.56 Impact Factor
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ABSTRACT: Since its discovery in 1982, Helicobacter pylori has been established as a common cause of gastritis and peptic ulcer disease. H pylori infection is also closely associated with several gastric malignancies and has consequently been designated a human carcinogen. As these associations have become increasingly recognized and pursued, a growing challenge facing today's clinicians is the management of patients with persistent H pylori despite previous attempts to treat the infection. In developed countries, the most popular treatment regimen remains traditional triple therapy consisting of a proton pump inhibitor, clarithromycin, and amoxicillin for 7 to 14 days. Unfortunately, eradication rates with traditional triple therapy are disappointing, with infection persisting in as many as 25% of those treated. This article addresses the management of patients with persistent H pylori infection, including indications for confirmatory testing, reasons for treatment failure, and established and emerging salvage regimens for patients with persistent infection.
Hospital practice (1995). 02/2011; 39(1):133-40.
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ABSTRACT: Evidence suggests that gut flora may play an important role in the pathophysiology of the irritable bowel syndrome (IBS). We evaluated rifaximin, a minimally absorbed antibiotic, as treatment for IBS.
In two identically designed, phase 3, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks. The primary end point, the proportion of patients who had adequate relief of global IBS symptoms, and the key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating, were assessed weekly. Adequate relief was defined as self-reported relief of symptoms for at least 2 of the first 4 weeks after treatment. Other secondary end points included the percentage of patients who had a response to treatment as assessed by daily self-ratings of global IBS symptoms and individual symptoms of bloating, abdominal pain, and stool consistency during the 4 weeks after treatment and during the entire 3 months of the study.
Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined). In addition, significantly more patients in the rifaximin group had a response to treatment as assessed by daily ratings of IBS symptoms, bloating, abdominal pain, and stool consistency. The incidence of adverse events was similar in the two groups.
Among patients who had IBS without constipation, treatment with rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools. (Funded by Salix Pharmaceuticals; ClinicalTrials.gov numbers, NCT00731679 and NCT00724126.).
New England Journal of Medicine 01/2011; 364(1):22-32. · 53.30 Impact Factor
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Daniel K Mullady,
Dhiraj Yadav,
Stephen T Amann,
Michael R O'Connell,
Michael M Barmada,
Grace H Elta,
James M Scheiman,
Erik-Jan Wamsteker, William D Chey,
Meredith L Korneffel, [......],
Randall E Brand,
Frank R Burton,
Michele D Lewis,
Timothy B Gardner,
Andres Gelrud,
James DiSario,
John Baillie,
Peter A Banks,
David C Whitcomb,
Michelle A Anderson
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ABSTRACT: To compare patients with chronic pancreatitis (CP) with constant pain patterns to patients with CP with intermittent pain patterns.
This was a prospective cohort study conducted at 20 tertiary medical centers in the USA comprising 540 subjects with CP. Patients with CP were asked to identify their pain from five pain patterns (A-E) defined by the temporal nature (intermittent or constant) and the severity of the pain (mild, moderate or severe). Pain pattern types were compared with respect to a variety of demographic, quality of life (QOL) and clinical parameters. Rates of disability were the primary outcome. Secondary outcomes included: use of pain medications, days lost from school or work, hospitalisations (preceding year and lifetime) and QOL as measured using the Short Form-12 (SF-12) questionnaire.
Of the 540 CP patients, 414 patients (77%) self-identified with a particular pain pattern and were analysed. Patients with constant pain, regardless of severity, had higher rates of disability, hospitalisation and pain medication use than patients with intermittent pain. Patients with constant pain had lower QOL (by SF-12) compared with patients who had intermittent pain. Additionally, patients with constant pain were more likely to have alcohol as the aetiology for their pancreatitis. There was no association between the duration of the disease and the quality or severity of the pain.
This is the largest study ever conducted of pain in CP. These findings suggest that the temporal nature of pain is a more important determinant of health-related QOL and healthcare utilisation than pain severity. In contrast to previous studies, the pain associated with CP was not found to change in quality over time. These results have important implications for improving our understanding of the mechanisms underlying pain in CP and for the goals of future treatments and interventions.
Gut 01/2011; 60(1):77-84. · 10.11 Impact Factor
