Debra M. Geno

A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia

BACKGROUND & AIMS Dyspepsia is common in clinical practice and in the community. The relationship of the symptoms to meals and the pathophysiology in community dyspeptic patients is unclear. The purpose of this study was to measure symptoms, demographic features, and gastric motor and sensory functions associated with dyspepsia in the community. METHODS A Modified Bowel Disease Questionnaire was mailed to a random sample of Olmsted County, MN, residents. Dyspeptic patients and healthy controls identified among community respondents completed further questionnaires, Helicobacter pylori serology, gastric emptying by scintigraphy, gastric accommodation by 99mTc-single-photon emission computed tomography imaging, and postprandial symptoms and satiation by a nutrient drink test. RESULTS A total of 34.1% of community respondents reported dyspepsia within the past year, frequent (at least 25% of the time in the past year) in 17.5%, and 18.4% reported meal-related dyspepsia. Dyspepsia was frequent and related to meals in 10.8% of respondents. Compared with nondyspeptic controls, community dyspepsia was associated with higher aggregate symptom scores and bloating after a fully satiating meal. Community dyspepsia also was associated with higher somatization scores (P = .001), reporting of other somatic symptoms (P = .07), and general severity score on the symptom checklist 90 (P = .01), but not with disordered motor or sensory function. Gastric volumes, gastric emptying, and maximum tolerated volumes were not significantly different between community controls and dyspeptic patients. CONCLUSIONS Meal-related dyspepsia is an important component of dyspepsia in the community. Community dyspeptic patients have higher symptom scores after a fully satiating meal, consistent with gastric hypersensitivity. This is associated with higher somatization scores rather than disorders of gastric emptying or volumes.

Epidemiology and Natural History of Intestinal Metaplasia of the Gastroesophageal Junction and Barrett's Esophagus: A Population-Based Study

OBJECTIVES:Population-based data on the epidemiology and outcomes of subjects with intestinal metaplasia of the gastroesophageal junction (IMGEJ) and Barretts esophagus (BE) are limited. The objectives of this study were to (i) estimate the incidence of IMGEJ and BE diagnosed from clinically indicated endoscopy in Olmsted County, MN, over three decades (1976–2006) and prevalence as of 1 January 2007, (ii) compare baseline characteristics of subjects with IMGEJ and BE, and (iii) study the natural history and survival of both cohorts.METHODS:This was a population-based cohort study. The study setting was Olmsted County, MN. Patients with BE (columnar segment >1 cm with intestinal metaplasia) and IMGEJ (intestinal metaplasia in biopsies from the gastroesophageal junction) from 1976 to 2006 in Olmsted County, MN, were identified using Rochester Epidemiology Project resources. Demographic and clinical data were abstracted from medical records and pathology confirmed by gastrointestinal pathologists. The association of baseline characteristics with overall and progression-free survival was assessed using proportional hazards regression models. Outcome measures were baseline characteristics and overall survival of subjects with IMGEJ compared to those with BE.RESULTS:In all, 487 patients (401 with BE and 86 with IMGEJ) were identified and followed for a median interval of 7 (BE subjects) to 8 (IMGEJ subjects) years. Subjects with BE were older, heavier, reported reflux symptoms more often, and had higher prevalence of advanced neoplasia than those with IMGEJ. No patient with IMGEJ progressed to esophageal adenocarcinoma (EAC) in contrast to BE subjects who had a cumulative risk of progression of 7% at 10 years and increased risk of death from EAC (standardized mortality ratio 9.62). The overall survival of subjects with BE and IMGEJ did not differ from that expected in similar age- and sex-distributed white Minnesota populations.CONCLUSIONS:Subjects with IMGEJ appear to have distinct clinical characteristics and substantially lower cancer progression risk compared to those with BE.

A study of candidate genotypes associated with dyspepsia in a U.S. community.

BACKGROUND:The role of genetic predisposition to the development of dyspepsia is unclear. Recently, a significant association was reported with CC genotype of GNβ3.AIM:To explore the association of candidate genotypes altering adrenergic, serotonergic, CCKergic, and G protein functions, and dyspepsia in a sample from a U.S. community.METHODS:Dyspeptics and healthy controls were identified among community respondents who had been randomly selected to complete validated questionnaires. Other diseases were excluded by face-to-face history and physical examination. Polymorphisms of candidate genes for α2A, α2C, 5-HT1A, 5-HT2A, 5-HT2C, CCK-1 receptors and CCK promoter, GNβ3 protein, and SERT-promoter (SERT-P) were studied. The association between polymorphisms and meal-related or meal-unrelated dyspepsia, high somatic symptom scores, and somatization were evaluated using Fishers exact test.RESULTS:DNA was available from 41 dyspeptics and 47 healthy controls from Olmsted County. Community dyspepsia unrelated to meals was associated with both homozygous GNβ3 protein 825T and C alleles. There were no significant associations with meal-related dyspepsia. Using Rome II subgroups, the same genotype was associated with dysmotility-like and other dyspepsia. Higher somatization scores were not significantly associated with any of the candidate genes when considered as single factors.CONCLUSION:Meal-unrelated dyspepsia in a U.S. community study is associated with the homozygous 825T or C alleles of GNβ3 protein. Candidate genes controlling adrenergic, serotonergic, and CCKergic functions do not appear to be associated with dyspepsia.

Accuracy, Safety, and Tolerability of Tissue Collection by Cytosponge vs Endoscopy for Evaluation of Eosinophilic Esophagitis

BACKGROUND & AIMS Management of eosinophilic esophagitis (EoE) requires repeated endoscopic collection of mucosal samples to assess disease activity and response to therapy. An easier and less expensive means of monitoring of EoE is required. We compared the accuracy, safety, and tolerability of sample collection via Cytosponge (an ingestible gelatin capsule comprising compressed mesh attached to a string) with those of endoscopy for assessment of EoE. METHODS Esophageal tissues were collected from 20 patients with EoE (all with dysphagia, 15 with stricture, 13 with active EoE) via Cytosponge and then by endoscopy. Number of eosinophils/high-power field and levels of eosinophil-derived neurotoxin were determined; hematoxylin-eosin staining was performed. We compared the adequacy, diagnostic accuracy, safety, and patient preference for sample collection via Cytosponge vs endoscopy procedures. RESULTS All 20 samples collected by Cytosponge were adequate for analysis. By using a cutoff value of 15 eosinophils/high power field, analysis of samples collected by Cytosponge identified 11 of the 13 individuals with active EoE (83%); additional features such as abscesses were also identified. Numbers of eosinophils in samples collected by Cytosponge correlated with those in samples collected by endoscopy (r = 0.50, P = .025). Analysis of tissues collected by Cytosponge identified 4 of the 7 patients without active EoE (57% specificity), as well as 3 cases of active EoE not identified by analysis of endoscopy samples. Including information on level of eosinophil-derived neurotoxin did not increase the accuracy of diagnosis. No complications occurred during the Cytosponge procedure, which was preferred by all patients, compared with endoscopy. CONCLUSIONS In a feasibility study, the Cytosponge is a safe and well-tolerated method for collecting near mucosal specimens. Analysis of numbers of eosinophils/high-power field identified patients with active EoE with 83% sensitivity. Larger studies are needed to establish the efficacy and safety of this method of esophageal tissue collection. ClinicalTrials.gov number: NCT01585103.

Endoscopic Mucosal Impedance Measurements Correlate With Eosinophilia and Dilation of Intercellular Spaces in Patients With Eosinophilic Esophagitis

BACKGROUND & AIMS Penetration of the esophageal epithelium by food antigens is an early event in the pathogenesis of eosinophilic esophagitis (EoE), but the precise relationship among eosinophilia, dilated intercellular spaces (DIS), and decreased barrier function is unclear. We investigated the correlation between site-specific mucosal impedance (MI) measurements of ion flux and esophageal histology, and whether MI measurements can be used to distinguish between patients with active and inactive EoE. METHODS MI was measured (in Ω) in 10 patients with active EoE (>15 eosinophils [eos]/high-power field [HPF]) and in 10 with inactive EoE (<15 eos/HPF, as a result of treatment), and mucosal biopsy specimens were collected from 4 esophageal sites (2, 5, 10, and 15 cm above the Z-line). MI also was measured in 10 individuals without esophageal symptoms (controls). MI measurements, eos/HPF, and DIS grade were compared among patients with EoE and controls. RESULTS The esophageal MI values were significantly lower in patients with active EoE (1909 Ω) compared with inactive EoE (4349 Ω) or controls (5530 Ω) (P < .001). Biopsy specimens from 4 patients with active EoE contained fewer than 15 eos/HPF and lower-grade DIS than in patients with active disease. There were significant inverse correlations between MI and eos/HPF (rs = -.584), as well as between MI and DIS (rs = -.531; P < .001). The MI cut-off value of 2300 Ω identified patients with active EoE with 90% sensitivity and 91% specificity, and high-grade DIS with 89% sensitivity and 82% specificity. CONCLUSIONS In patients with EoE, eosinophilia and DIS correlate with MI measurements of ion flux. Endoscopic MI measurement in the esophagus is safe and easy to perform, and can be used to assess activity of diseases such as EoE.

Montelukast Does not Maintain Symptom Remission After Topical Steroid Therapy for Eosinophilic Esophagitis

BACKGROUND & AIMS: Montelukast, a cysteinyl leukotriene type‐1 receptor blocker, has been shown in small retrospective studies to reduce symptoms in patients with eosinophilic esophagitis (EoE). We performed a randomized, placebo‐controlled, double‐blind trial to determine whether montelukast maintains symptomatic remission induced by topical steroid therapy in patients with EoE. METHODS: We performed a prospective study of adult patients with EoE (solid‐food dysphagia and a peak esophageal eosinophil count of >20 cells/high‐powered field) enrolled at the Mayo Clinic in Rochester, Minnesota, from April 2008 through February 2015. All patients had been treated previously for at least 6 weeks with a topical steroid until their symptoms were in remission. Steroids were discontinued and patients then were assigned randomly to groups given montelukast (20 mg/day, n = 20) or placebo (n = 21) for 26 weeks (groups were matched for age, sex, history of allergic disease, reflux symptoms, and endoscopic findings of EoE). Study participants were assessed via a structured telephone interview at weeks 2, 4, 8, 12, 16, 20, and 24. Remission was defined as the absence of solid‐food dysphagia. RESULTS: Based on an intention‐to‐treat analysis, after 26 weeks, 40.0% of subjects in the montelukast group and 23.8% in the placebo group were in remission. The odds ratio for remission in the montelukast group was 0.48 (95% confidence interval, 0.10–2.16) (P = .33). No side effects were reported from either group. CONCLUSIONS: In a randomized controlled trial of the ability of montelukast to maintain remission in patients in remission from EoE after steroid therapy, we found montelukast to be well tolerated; 40% of patients remained in remission, but this proportion did not differ significantly from that of the placebo group. ClinicalTrials.gov no: NCT00511316.

The clinical significance of esophagogastric junction outflow obstruction and hypercontractile esophagus in high resolution esophageal manometry

Although major manometric abnormalities, the significance of esophagogastric junction outflow obstruction (EGJOO) and hypercontractile esophagus (HE) is poorly understood. We sought to determine long term outcomes for EGJOO and HE.

Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis

Although eosinophilic oesophagitis (EoE) is putatively mediated by an abnormal response to food antigen, the oesophagus is considered relatively impermeable to large molecules.

Oesophageal narrowing on barium oesophagram is more common in adult patients with eosinophilic oesophagitis than PPI-responsive oesophageal eosinophilia

To date there have been no clear features that aid in differentiating patients with eosinophilic oesophagitis (EoE) from PPI‐responsive oesophageal eosinophilia (PPI‐REE). However, barium swallow roentgenography is a more sensitive and specific measure to detect subtle fibrostenotic remodeling changes present in EoE. We aim to characterise any clinical, endoscopic, histiological or barium roentgenographic differences between EoE and PPI‐REE.

Esophageal cancer screening in achalasia: is there a consensus?

Achalasia is an important but relatively uncommon disorder. While highly effective therapeutic options exist, esophageal cancer remains a long-term potential complication. The risk of esophageal cancer in achalasia remains unclear, with current guidelines recommending against routine endoscopic screening. However, given limited data and conflicting opinion, it is unknown whether consensus regarding screening practices in achalasia among experts exists. A 10-question survey to assess screening practices in achalasia was created and distributed to 28 experts in the area of achalasia. Experts were identified based on publications and meeting presentations in the field. Survey responses were received from 17 of 28 (61%) experts. Wide geographic distribution was seen among respondents, with eight (47%) from Europe or Australia, seven (41%) from the United States, and two (12%) from Asia. Screening for esophageal cancer was inconsistent, with nine (53%) experts endorsing the practice and eight (47%) not. Screening practices did not differ among geographic regions. No consensus regarding the risk for esophageal cancer in achalasia was seen, with three experts reporting no increased risk compared with the general population, eight experts a lifetime risk of 0.1-0.5%, three experts a 0.5-1% risk, two experts a 1-2% risk, and one expert a 3-5% risk. However, these differences in perception of risk did not influence screening practices. Upper endoscopy was utilized among all experts who endorsed screening. However, practices still varied with screening commencing at or within 1 year of diagnosis in two practices compared with 5 and 10 years in three respective practices each. Surveillance intervals also varied, performed every 2 years in four practices, every 3 years in four practices, and every 5 years in one practice. Practice variation in the management of achalasia itself was also seen, with initial treatment with Heller myotomy endorsed by eight experts, pneumatic dilation by five experts, and two each endorsing peroral endoscopic myotomy or no specific preference. In addition, while 82% (14/17) of experts endorsed long-term follow up of patients, no consensus regarding long-term follow up existed, with annual follow up in eight practices, every 3-6 months in three practices, and every 2 years in three practices. Large practice variation in the long-term management of achalasia exists among experts in the field. Only a slight majority of experts endorse screening for esophageal cancer in achalasia, and no consensus exists regarding how surveillance should be structured even among this group. Interestingly, the lack of consensus on cancer screening parallels a lack of agreement on initial treatment of achalasia. These findings suggest a need for greater homogeneity in the management of longstanding achalasia and cancer screening. Further, this study highlights the need for more data on this topic to foster greater agreement.