Survival Times of Patients With Menetrier's Disease and Risk of Gastric Cancer.

BACKGROUND & AIMS: Menetrier's disease is a rare acquired disorder associated with giant gastric folds along with protein-losing enteropathy, low stomach acid, or achlorhydria, and histologic features of massive foveolar hyperplasia. Little is known about the etiology, clinical features, or epidemiology of this disorder, including risk of gastric cancer. We investigated the outcomes and characteristics of patients with Menetrier's disease, including development of gastric cancer and survival times. METHODS: We performed a case-control study of all Menetrier's disease cases (n = 76; mean age, 56 ± 45 y; 59% male; mean body mass index, 24) diagnosed at Mayo Clinic, Rochester, MN, from January 1975 through 2005. Diagnosis of Menetrier's disease was based on a combination of clinical, endoscopic, radiologic, and histologic features. Patients with dyspepsia who underwent gastric biopsy analysis were included as controls. We obtained demographic, clinical history, laboratory, imaging, histopathology, and follow-up data from medical records. Clinical characteristics of Menetrier's disease were analyzed using descriptive statistics. The Kaplan-Meier method was used to estimate overall survival in cases. RESULTS: Clinical features found in a significantly higher proportion of patients with Menetrier's disease than controls included vomiting, abdominal pain, postprandial fullness, and weight loss of 10 lb or more. Smoking was associated with Menetrier's disease (P = .002 vs controls), but not alcohol use. Infection with Helicobacter pylori was not associated with Menetrier's disease (2.6% of patients vs 4.0% of controls; P = 1.00). There was no significant difference between patients with Menetrier's disease vs controls in proportions with inflammatory bowel disease. Gastric cancer developed in 8.9% of patients with Menetrier's disease by 10 years after the Menetrier's disease diagnosis vs 3.7% of controls over the same time period (P = .09). Of patients with Menetrier's disease, 72.7% and 65.0% survived for 5 and 10 years, respectively, compared with 100% of controls (P < .0001 for both time periods). CONCLUSIONS: In a case-control study of 76 patients with Menetrier's disease, we found this rare disorder to be associated with increased mortality. Patients with Menetrier's disease therefore should be followed up with surveillance endoscopy.

Comparison of Lactase Variant MCM6 -13910 C>T Testing and Self-report of Dairy Sensitivity in Patients With Irritable Bowel Syndrome.

GOALS: To evaluate agreement of MCM6-13910 with self-report of dairy sensitivity (DS) and lactose hydrogen methane breath test (LHMBT) results in subjects with irritable bowel syndrome (IBS). BACKGROUND: IBS is a functional gastrointestinal disorder with symptoms including abdominal pain, variable bowel habits, and bloating. Adult patients with lactose malabsorption may present with similar symptoms. Patients with lactose malabsorption have a lactase nonpersistent (LNP) phenotype. Recent studies found 2 single nucleotide polymorphisms associated with LNP: G/A-22018 and C/T-13910. STUDY: Genotyping the MCM6-13910 variant of LNP in 538 IBS patients and 317 controls (without IBS). Subjects completed questionnaires pertaining to gastrointestinal problems and dietary consumption, with charts abstracted. RESULTS: Self-reported DS was higher in IBS (45%) than controls (9.8%, odds ratio=6.46, P<0.001). The C/C-13910 genotype was similar in IBS cases and controls, 81 (15.1%) and 47 (14.8%). Among subjects reporting DS, 49 (18.0%) had the C/C genotype. Overall agreement between genotype and self-reported DS was 0.06 in IBS and 0.07 in controls. There were 20 subjects with LHMBT results; 3 had positive results, 17 were negative. LNP genotypes were found in all 3 of positive LHMBT results; 16 had negative LHMBT among the 17 who were lactase persistent. Agreement between C/C-13910 genotype and LHMBT was excellent with κ-statistic of 0.83 (0.50-1.00). CONCLUSIONS: In IBS patients, self-report of lactose intolerance are highly prevalent but are a poor indicator of underlying C/C-13910 genotype. LHMBT had excellent agreement with C/C-13910 genotype.

Irritable bowel syndrome patients have SCN5A channelopathies that lead to decreased NaV1.5 current and mechanosensitivity.

The SCN5A-encoded voltage-gated mechanosensitive Na+ channel NaV1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2-3% of patients have SCN5A missense mutations that alter NaV1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered NaV1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function. NEW & NOTEWORTHY The voltage-gated Na+ channel NaV1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the NaV1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant NaV1.5 channels were loss of function in voltage dependence or mechanosensitivity.

Effects of Amitriptyline and Escitalopram on Sleep and Mood in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Tricyclic antidepressants are effective in reducing symptoms of functional dyspepsia (FD). We performed a post hoc analysis of data from a previous randomized clinical trial to determine whether the benefits of an antidepressant on gastrointestinal symptoms in patients with FD were mediated by improving sleep or reducing anxiety. We explored the relationships between psychological measures, quality of sleep, and relief of symptoms. METHODS: We analyzed data from a multicenter, double-blind trial that evaluated the efficacy of antidepressants on symptoms of FD, from October 2006 through October 2012. Patients (n = 292) were randomly assigned to groups given 50 mg amitriptyline, 10 mg escitalopram, or placebo for 12 weeks. During the study, participants completed the following validated psychological questionnaires: Symptom Check List 90, Symptom Somatic Checklist, Hospital Anxiety Depression Scale, Profile of Mood States, State Trait Anxiety Inventory, and Pittsburgh Sleep Quality Index at baseline and 12 weeks following treatment. RESULTS: Baseline scores for the psychological and sleep measures were similar among groups; after 12 weeks there were no significant differences in scores among groups. Baseline mean global Pittsburgh Sleep Quality Index scores indicated poor sleep quality in all groups at baseline and after 12 weeks. Overall, antidepressants affected sleep duration scores: patients given amitriptyline had lower (better) scores than patients given placebo or escitalopram (P = .019). In all groups, responders had decreased anxiety and improvements in some sleep components. CONCLUSIONS: In a post hoc analysis of data from a clinical trial that evaluated the effects of antidepressants in patients with FD, amitriptyline was found to reduce symptoms of FD, but its mechanism is unlikely to involve reductions in psychological distress. The drug may modestly improve sleep. Clinicaltrials.gov no: NCT00248651.

A Systematic Review and Meta-Analysis Evaluating the Efficacy of a Gluten-Free Diet and a Low FODMAPs Diet in Treating Symptoms of Irritable Bowel Syndrome.

OBJECTIVE: Dietary triggers such as gluten and highly fermentable oligo-, di- and monosaccharides and polyols (FODMAP)-containing foods have been associated with worsening irritable bowel syndrome (IBS) symptoms. However, the true impact of dietary restriction on IBS symptoms has remained unclear. The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) examining the efficacy of exclusion diets (we focused on low FODMAP and gluten-free diets (GFD)) in IBS. METHODS: We conducted a search of the literature using the electronic databases MEDLINE (1946 to November 2017), EMBASE (1974 to November 2017), Cochrane Central Register of Controlled Trials (November 2017), and Cochrane Database of Systematic Reviews (2005 to November, 2017) for RCTs of exclusion diets in IBS. Two independent reviewers screened citations and a third reviewer resolved disagreement. Two independent reviewers performed eligibility assessment and data abstraction. For inclusion, RCTs that evaluated an exclusion diet versus an alternative or usual diet and assessed improvement in either global IBS symptoms or abdominal pain were required. Data were synthesized as relative risk of symptoms remaining using a random effects model. Quality of evidence was assessed using GRADE methodology. RESULTS: A total of 1726 citations were identified. After full-text screening a total of nine studies were eligible for the systematic review. There were two RCTs of a GFD, involving 111 participants. Both selected patients who responded to a GFD and then randomized them to continue the diet or have the diet "spiked" with gluten. A GFD was associated with reduced global symptoms compared with a control diet (RR = 0.42; 95% CI 0.11 to 1.55; I2 = 88%), although this was not statistically significant. There were seven RCTs comparing a low FODMAP diet with various control interventions in 397 participants. A low FODMAP diet was associated with reduced global symptoms compared with control interventions (RR = 0.69; 95% CI 0.54 to 0.88; I2 = 25%). The three RCTS that compared low FODMAP diet with rigorous control diets had the least heterogeneity between studies, but also the least magnitude of effect. The overall quality of the data was "very low" according to GRADE criteria. CONCLUSIONS: There is insufficient evidence to recommend a GFD to reduce IBS symptoms. There is very low quality evidence that a low FODMAP diet is effective in reducing symptoms in IBS patients.

Early Infections and the Risk of Irritable Bowel Syndrome: A Case-Control Study.

GOALS: The goal of this study is to evaluate the association between early life infections and subsequent adult onset irritable bowel syndrome (IBS). BACKGROUND: Infections during adulthood are a known risk factor for adult-onset IBS. This investigation examined the role of childhood infections and infection risk factors in the development of IBS symptoms. STUDY: In total, 1010 subjects (509 outpatients with IBS, 501 matched controls) were mailed questionnaires regarding early-life infections during infancy (0 to 12 mo), toddler years (1 to 3 y), and child years (4 to 18 y). Comparisons between cases and controls were performed using logistic regression adjusting for age, gender, and somatization score. RESULTS: Around 648 (64.2%) subjects responded. The median age was 51.3 years (range, 18.0 to 70.7 y) and 535 (83%) were female. Childhood (below 18 y) infections were common in cases and controls (98% vs. 98%; P=0.465), with no differences between cases and controls during infant, toddler, and child-age periods. For gastrointestinal infections experienced below 18 years, no differences were observed by infection type (bacterial, viral, or parasitic) or age group. Cases were more likely to report bronchitis by age 18 [43% vs. 25%; P=0.003; odds ratio, 1.73 (1.20-2.51)], but not other common infections. Regular antibiotic exposure was greater amongst cases (43%) than controls (30%) [P=0.09; odds ratio, 1.37 (0.96-1.96)]. The association between bronchitis and IBS case status remained significant after adjusting for antibiotic use (P=0.01). CONCLUSIONS: Greater early childhood gastrointestinal infections rates were not observed in adult individuals with IBS compared with adult controls. The study does not support a statistically significant link between early life infections and IBS aside from bronchitis.

Polymorphisms of 5-HTT LPR and GNß3 825C>T and Response to Antidepressant Treatment in Functional Dyspepsia: A Study from The Functional Dyspepsia Treatment Trial.

OBJECTIVES: The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNß3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNß3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy. METHODS: Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNß3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods. RESULTS: GNß3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy-Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNß3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43). CONCLUSIONS: GNß3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.

Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study.

BACKGROUND & AIMS: Antidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. METHODS: We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use antidepressants. Patients (n = 292; 44 ± 15 years old, 75% were female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary end point was adequate relief of FD symptoms for ≥5 weeks of the last 10 weeks (of 12). Secondary end points included GE time, maximum tolerated volume in Nutrient Drink Test, and FD-related quality of life. RESULTS: An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P = .05, after treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life. CONCLUSIONS: Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. ClinicalTrials.gov ID: NCT00248651.

Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.

BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.

Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis.

OBJECTIVES: Irritable bowel syndrome (IBS) and chronic idiopathic constipation (CIC) are functional bowel disorders. Evidence suggests that disturbance in the gastrointestinal microbiota may be implicated in both conditions. We performed a systematic review and meta-analysis to examine the efficacy of prebiotics, probiotics, and synbiotics in IBS and CIC. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Randomized controlled trials (RCTs) recruiting adults with IBS or CIC, which compared prebiotics, probiotics, or synbiotics with placebo or no therapy, were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). Continuous data were pooled using a standardized or weighted mean difference with a 95% CI. RESULTS: The search strategy identified 3,216 citations. Forty-three RCTs were eligible for inclusion. The RR of IBS symptoms persisting with probiotics vs. placebo was 0.79 (95% CI 0.70-0.89). Probiotics had beneficial effects on global IBS, abdominal pain, bloating, and flatulence scores. Data for prebiotics and synbiotics in IBS were sparse. Probiotics appeared to have beneficial effects in CIC (mean increase in number of stools per week=1.49; 95% CI=1.02-1.96), but there were only two RCTs. Synbiotics also appeared beneficial (RR of failure to respond to therapy=0.78; 95% CI 0.67-0.92). Again, trials for prebiotics were few in number, and no definite conclusions could be drawn. CONCLUSIONS: Probiotics are effective treatments for IBS, although which individual species and strains are the most beneficial remains unclear. Further evidence is required before the role of prebiotics or synbiotics in IBS is known. The efficacy of all three therapies in CIC is also uncertain.

The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis.

OBJECTIVES: Fiber has been used for many years to treat irritable bowel syndrome (IBS). This approach had fallen out of favor until a recent resurgence, which was based on new randomized controlled trial (RCT) data that suggested it might be effective. We have previously conducted a systematic review of fiber in IBS, but new RCT data for fiber therapy necessitate a new analysis; thus, we have conducted a systematic review of this intervention. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched up to December 2013. Trials recruiting adults with IBS, which compared fiber supplements with placebo, control therapy, or "usual management", were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy as well as number needed to treat (NNT) with a 95% confidence interval (CI). RESULTS: We identified 14 RCTs involving 906 patients that had evaluated fiber in IBS. There was a significant benefit of fiber in IBS (RR=0.86; 95% CI 0.80-0.94 with an NNT=10; 95% CI=6-33). There was no significant heterogeneity between results (I(2)=0%, Cochran Q=13.85 (d.f.=14), P=0.46). The benefit was only seen in RCTs on soluble fiber (RR=0.83; 95% CI 0.73-0.94 with an NNT=7; 95% CI 4-25) with no effect seen with bran (RR=0.90; 95% CI 0.79-1.03). CONCLUSIONS: Soluble fiber is effective in treating IBS. Bran did not appear to be of benefit, although we did not uncover any evidence of harm from this intervention, as others have speculated from uncontrolled data.

Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis.

OBJECTIVES: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence relating to the treatment of this condition with antidepressants and psychological therapies continues to accumulate. METHODS: We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Trials recruiting adults with IBS, which compared antidepressants with placebo, or psychological therapies with control therapy or "usual management," were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). RESULTS: The search strategy identified 3,788 citations. Forty-eight RCTs were eligible for inclusion: thirty-one compared psychological therapies with control therapy or "usual management," sixteen compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Ten of the trials of psychological therapies, and four of the RCTs of antidepressants, had been published since our previous meta-analysis. The RR of IBS symptom not improving with antidepressants vs. placebo was 0.67 (95% CI=0.58-0.77), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms not improving with psychological therapies was 0.68 (95% CI=0.61-0.76). Cognitive behavioral therapy, hypnotherapy, multicomponent psychological therapy, and dynamic psychotherapy were all beneficial. CONCLUSIONS: Antidepressants and some psychological therapies are effective treatments for IBS. Despite the considerable number of studies published in the intervening 5 years since we last examined this issue, the overall summary estimates of treatment effect have remained remarkably stable.

The role of 5-HTT LPR and GNß3 825C>T polymorphisms and gene-environment interactions in irritable bowel syndrome (IBS).

BACKGROUND: Smaller studies have evaluated SLC6A4 5-HTTLPR and GNß3 825C>T polymorphisms in IBS, and interactions between 5-HTT LPR with life events have been reported in the psychiatric literature, but gene-environment studies in IBS are lacking. AIMS: The purpose of this study was to assess the association of two polymorphisms with IBS and age of onset, and whether there are gene-environment interactions with IBS. METHODS: Outpatients with IBS and controls completed a validated questionnaire and provided blood for DNA. Comparisons of genotype/allele frequencies between cases and controls were performed with logistic regression. Linear regression was used to evaluate the association between the variants and age of onset. Environmental variables tested included abuse, parental alcohol abuse, parental psychiatric disorders, and gastrointestinal infections. RESULTS: Genotyping was performed in 385 cases and 262 controls with median age of 50 years (range, 18.0-70.0) and 498 (77 %) females. The IBS subtype distribution among cases was: 102 (26 %) D-IBS, 40 (10 %) C-IBS, 125 (32 %) M-IBS, 118 (31 %) other. No association was observed between IBS or age of onset and both variants. Significant interactions were observed between GI infection and the GNß3 825T allele. For those reporting gastrointestinal infection, the OR for IBS was 3.9 (95 % CI 1.2-12.7) whereas the OR was 0.86 (95 % CI 0.65-1.13) for those without prior infection. CONCLUSIONS: There was a significant interaction between the GNß3 polymorphism and infection in the development of IBS, suggesting that its etiology is the result of a combination of specific genetic and environmental risk factors.

Genetic approaches to functional gastrointestinal disorders.

Functional gastrointestinal disorders are complex symptom-based disorders without agreed upon biomarkers or pathophysiology. A better understanding of the genetic architecture of these disorders would help to better identify their complex biology and explain the common comorbidity with other disorders of persistent pain, mood, and affect, as well as possibly make it possible to identify subgroups of patients who respond to customized therapies. In contrast to monogenic diseases, polygenic diseases and traits are characterized by the contribution of common variants in a large number of genes, as well as environmental factors, to the vulnerability of an individual. Family and twin studies have clearly established a genetic component in irritable bowel syndrome. Although candidate gene studies have identified a few gene polymorphisms that may be correlated with the syndrome, small sample size, lack of reproducibility in large data sets, and the unreliability of the clinical phenotype require caution when extrapolating to a major role of any of the reported polymorphisms in the pathophysiology of irritable bowel syndrome. Future progress in this area will require better characterization of intermediate phenotypes with large effect size for the clinical phenotype, as well as consideration of gene-gene, environment-gene (epigenetics), and sex-gene interactions, genome-wide association, and whole genome sequencing approaches in large data sets.

Characteristics of acute pain attacks in patients with irritable bowel syndrome meeting Rome III criteria.

OBJECTIVES: An international multicenter, prospective, non-interventional, 2-month study characterized acute pain attacks in patients with irritable bowel syndrome (IBS). METHODS: Adult patients meeting the Rome III IBS diagnostic criteria with a history of ≥ 3 pain attacks per month participated in a survey that captured daily and episodic information regarding IBS symptoms and pain attacks for 2 months. Acute pain attacks were defined as a sudden onset or increase in the intensity of IBS abdominal pain with a minimum intensity of 4 (0-10 scale). RESULTS: The majority (84%) of the 158 patients taking the survey were women with a mean age of 41 years and time since IBS diagnosis of 5 years. The median pain attack frequency was 5.4 attacks per month and was significantly higher in the IBS with diarrhea (IBS-D, 6.4 per month) group vs. the IBS with constipation (4.4 per month) and the IBS with mixed pattern (5.5 per month) groups (P=0.019). The median pain attack duration was 2.8 h and the median intensity score was 7. The majority of pain attacks resulted in defecation (78%), and occurred more often in IBS-D patients than in other subgroups. The majority of pain attacks (63%) interfered with work and/or daily activities. Medication to manage pain attacks was used by 44% of patients during 29% of attacks. Although used by less than half of all patients, medication helped 66% of attacks treated. CONCLUSIONS: The frequency of severe pain attacks was 1.4 per week and the majority affected daily activities. However, most of the pain attacks were untreated in IBS patients. Pain attack management is an unmet need of IBS treatment.

The Natural History of Chronic Unexplained Gastrointestinal Disorders and Gastroesophageal Reflux During 20 Years: A US Population-Based Study.

OBJECTIVE: To explore the natural history of chronic unexplained gastrointestinal (GI) symptoms and to determine the longitudinal trends of prevalence during a 20-year period in a single US community. METHODS: Between January 1, 1990, and December 31, 2009, valid self-report questionnaires of GI symptoms were mailed to randomly selected cohorts of a community. The study used respondents who answered questions on 1 or more of 3 surveys (initial, 1990-1992; second, 2003-2004; and third, 2008-2009). The trends of prevalence of GI symptoms over time were analyzed in responders who completed 3 surveys, and the natural history or transition was evaluated. RESULTS: The overall prevalence of major symptom groupings including gastroesophageal reflux disease was consistent among residents in a community on 3 survey time points (1990-1992, 2003-2004, and 2008-2009). The transitions of GI symptoms were common in 228 patients who responded to all 3 surveys; only 29% had the same symptom category in 3 surveys; otherwise, symptoms changed over time, resolving, recurring, or transitioning to another disorder. Observed proportions of symptom transitions were significantly different from expected during 20 years (P<.001). Higher non-GI somatic symptom scores were significantly associated with both symptom transitions (odds ratio, 3.9; 95% CI, 1.38 to 10.77) and having sustained symptoms (odds ratio, 12.7; 95% CI, 4.62 to 34.90). CONCLUSION: The overall population prevalence of chronic unexplained GI symptoms is stable, but in individuals, transitions seem to be the rule. As these various GI syndromes appear to be so intimately interconnected, the common underlying pathogenesis may account for a major subgroup of chronic unexplained GI disorders.

A randomized, double-blind, placebo-controlled trial of St John's wort for treating irritable bowel syndrome.

OBJECTIVES: St John's wort (SJW) is known to effectively treat patients with mild-to-moderate depression. Antidepressants are frequently used to treat irritable bowel syndrome (IBS). To date, no study that examines the efficacy of SJW in IBS has been carried out. The aim of this study was to evaluate the efficacy of SJW in IBS after 12 weeks. METHODS: In this randomized, double-blind, placebo-controlled trial, 70 participants with an established diagnosis of IBS were randomized and assigned by concealed allocation to either SJW or placebo. Both treatment arms were balanced on symptom subtype. The primary end point was self-reported overall bowel symptom score (BSS) at 12 weeks. Secondary end points were individual BSS for diarrhea (D-BSS), constipation (C-BSS), pain or discomfort, and bloating; adequate relief (AR) of IBS on at least 50% of the last 4 weeks of therapy; and IBS quality-of-life score at 12 weeks. RESULTS: In all, 86% of the participants were women, and the median age was 42 years. Overall, 29% had C-IBS, 37% D-IBS, and 31% had mixed IBS. Both groups reported decreases in overall BSS from baseline, with the placebo arm having significantly lower scores at 12 weeks (P=0.03) compared with SJW. These patterns of improvement were mirrored in the secondary end points with the placebo group faring better than the SJW-treated group, with significant differences observed at week 12 for D-BSS (P=0.03) and percent with AR (P=0.02). A similar proportion of subjects in each treatment group (SJW: 51% vs. placebo: 54%) believed that the study drug they received decreased IBS life interferences (P=0.79). CONCLUSIONS: SJW was a less effective treatment for IBS than placebo.

Familial aggregation of irritable bowel syndrome: a family case-control study.

OBJECTIVES: Irritable bowel syndrome (IBS) clusters in families, but previous studies documented family history only from patients. We have shown that patient-relative agreement on IBS status is poor. Thus, we conducted a family case-control study with direct survey of symptoms from family members to better quantitate the aggregation of IBS in families. The aims of this study were to (i) compare the prevalence of IBS in case-relatives with control-relatives, and (ii) determine whether gender, relationship, predominant symptom, and environmental risk factors affect familial aggregation. METHODS: Outpatients with IBS, matched controls, and their first-degree relatives completed a bowel symptom questionnaire. Percent of cases and controls with a family history were compared and odds ratios were computed using chi(2)-test; recurrence risks to relatives were computed using logistic regression and generalized estimating equations. RESULTS: Data were collected from 477 cases, 297 controls, 1,492 case-relatives, and 936 control-relatives. Probands had a median age of 50 and 78% were women. 50% of case and 27% of control families had at least another relative with IBS yielding an odds ratio of 2.75 (95% CI: 2.01-3.76, P<0.0001). When aggregation estimates were reevaluated stratifying by relative relationship or proband gender, generational and gender effects were not observed. Familial clustering by bowel habit was weakest for diarrhea, and strongest for alternating bowel habits. CONCLUSIONS: IBS aggregates strongly in families. The strength of the association does vary somewhat by relationship to proband, but the lack of association in spouses supports either a possible genetic etiology or a shared household environmental exposure as an underlying cause of IBS.

AJG series: molecular biology for clinicians.

Pharmacogenetics is an evolving field that provides the link between an individual's genetic code and drug metabolism and drug response. This field offers the great promise of individualized medication selection and optimized dosage to maximize treatment response and to minimize adverse side effects. As our understanding of the role of the effects of genetic variants on drug metabolism and body drug processing grows, so does our ability to educate and inform our patients about expected treatment response to the medications being prescribed to them. This brief review will provide an overview of genetics, pharmacogenetics, and current and future examples of genetic variants predicting drug response in gastrointestinal disease, and the limitations and the promise of this exciting and developing field.