Prasad G. Iyer

ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus

Barrett’s esophagus (BE) is among the most common conditions encountered by the gastroenterologist. In this document, the American College of Gastroenterology updates its guidance for the best practices in caring for these patients. These guidelines continue to endorse screening of high-risk patients for BE; however, routine screening is limited to men with reflux symptoms and multiple other risk factors. Acknowledging recent data on the low risk of malignant progression in patients with nondysplastic BE, endoscopic surveillance intervals are attenuated in this population; patients with nondysplastic BE should undergo endoscopic surveillance no more frequently than every 3–5 years. Neither routine use of biomarker panels nor advanced endoscopic imaging techniques (beyond high-definition endoscopy) is recommended at this time. Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma. Based on recent level 1 evidence, endoscopic ablative therapy is also recommended for patients with BE and low-grade dysplasia, although endoscopic surveillance continues to be an acceptable alternative. Given the relatively common recurrence of BE after ablation, we suggest postablation endoscopic surveillance intervals. Although many of the recommendations provided are based on weak evidence or expert opinion, this document provides a pragmatic framework for the care of the patient with BE.

Central Adiposity Is Associated With Increased Risk of Esophageal Inflammation, Metaplasia, and Adenocarcinoma: A Systematic Review and Meta-analysis

BACKGROUND & AIMS Central adiposity has been implicated as a risk factor for Barretts esophagus (BE) and esophageal adenocarcinoma (EAC), possibly promoting the progression from inflammation to metaplasia and neoplasia. We performed a systematic review and meta-analysis of studies to evaluate the association between central adiposity and erosive esophagitis (EE), BE, and EAC, specifically exploring body mass index (BMI)-independent and gastroesophageal reflux (GERD)-independent effects of central adiposity on the risk of these outcomes. METHODS We performed a systematic search of multiple databases through March 2013. Studies were included if they reported effect of central adiposity (visceral adipose tissue area, waist-hip ratio, and/or waist circumference) on the risk of EE, BE, and EAC. Summary adjusted odds ratio (aOR) estimates with 95% confidence intervals (CIs), comparing highest category of adiposity with the lowest category of adiposity, were calculated by using random-effects model. RESULTS Forty relevant articles were identified. Compared with patients with normal body habitus, patients with central adiposity had a higher risk of EE (19 studies; aOR, 1.87; 95% CI, 1.51-2.31) and BE (17 studies; aOR, 1.98; 95% CI, 1.52-2.57). The association between central adiposity and BE persisted after adjusting for BMI (5 studies; aOR, 1.88; 95% CI, 1.20-2.95). Reflux-independent association of central adiposity and BE was observed in studies that used GERD patients as controls or adjusted for GERD symptoms (11 studies; aOR, 2.04; 95% CI, 1.44-2.90). In 6 studies, central adiposity was associated with higher risk of EAC (aOR, 2.51; 95% CI, 1.54-4.06), compared with normal body habitus. CONCLUSIONS On the basis of a meta-analysis, central adiposity, independent of BMI, is associated with esophageal inflammation (EE), metaplasia (BE), and neoplasia (EAC). Its effects are mediated by reflux-dependent and reflux-independent mechanisms.

Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis

Background and aims Acid-suppressive medications, particularly proton pump inhibitors (PPIs), may decrease the risk of oesophageal adenocarcinoma (OAC) in patients with Barretts oesophagus (BO). We performed a systematic review with meta-analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RAs)) and risk of OAC or high-grade dysplasia (BO-HGD) in patients with BO. Methods We performed a systematic search of multiple electronic databases and conference proceedings up to June 2013 to identify studies reporting the association between use of acid-suppressive medications and risk of OAC and/or BO-HGD in patients with BO. Summary ORs with 95% CIs were estimated. Results We identified seven observational studies (2813 patients with BO, 317 cases of OAC or BO-HGD, 84.4% PPI users). On meta-analysis, PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO (adjusted OR 0.29; 95% CI 0.12 to 0.79). There was a trend towards a dose–response relationship with PPI use for >2–3 years protective against OAC or BO-HGD (three studies; PPI use >2–3 years vs <2–3 years: OR 0.45 (95% CI 0.19 to 1.06) vs 1.09 (0.47 to 2.56)). Considerable heterogeneity was observed. Two studies reported the association between H2RA use and risk of OAC and/or BO-HGD (1352 patients with BO, 156 cases of OAC, 25.4% on H2RAs), and both studies did not show a significant effect. Conclusions Based on meta-analysis of observational studies, the use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC. PPI use should be considered in BO, and chemopreventive trials of PPIs in patients with BO are warranted.

Statins Are Associated with Reduced Risk of Esophageal Cancer, Particularly in Patients with Barrett’s Esophagus: A Systematic Review and Meta-Analysis

BACKGROUND & AIMS The incidence of esophageal cancer is increasing in the United States, especially among patients with Barretts esophagus (BE). Statins might prevent this cancer. We performed a systematic review with a meta-analysis of studies that evaluated the effect of statins on the risk of esophageal cancer. METHODS We conducted a systematic search of Medline, Embase, and Web of Science through August 2012. Studies were included if they evaluated exposure to statins, reported the development of esophageal cancer, and reported relative risks or odds ratios (OR), or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were calculated using the random-effects model. The analysis included 13 studies (including a post hoc analysis of 22 randomized controlled trials) reporting 9285 cases of esophageal cancer among 1,132,969 patients. RESULTS A meta-analysis of the studies showed a significant (28%) reduction in the risk of esophageal cancer among patients who took statins (adjusted OR, 0.72; 95% CI, 0.60-0.86), although there was considerable heterogeneity among studies. In analyzing a subset of patients known to have BE (5 studies, 312 esophageal adenocarcinomas [EAC] developed in 2125 patients), statins were associated with a significant (41%) decrease in the risk of EAC, after adjusting for potential confounders (adjusted OR, 0.59; 95% CI, 0.45-0.78) with consistent results among all studies. The number needed to treat with statins to prevent 1 case of EAC in patients with BE was 389. CONCLUSIONS Based on meta-analysis of observational studies, statin use may be associated with lower risk of esophageal cancer, particularly risk of EAC in patients with BE.

Incidence of esophageal adenocarcinoma in Barrett's esophagus with low-grade dysplasia: a systematic review and meta-analysis

BACKGROUND The natural history of low-grade dysplasia (LGD) in patients with Barretts esophagus (BE) is unclear. OBJECTIVE We performed a systematic review and meta-analysis of studies that reported the incidence of esophageal adenocarcinoma (EAC) and/or high-grade dysplasia (HGD) among patients with BE with LGD. DESIGN Systematic review and meta-analysis of cohort studies. PATIENTS Patients with BE-LGD, with mean cohort follow-up ≥ 2 years. MAIN OUTCOME MEASUREMENTS Pooled incidence rates with 95% confidence intervals (CI) of EAC and/or BE-HGD. RESULTS We identified 24 studies reporting on 2694 patients with BE-LGD, with 119 cases of EAC. Pooled annual incidence rates of EAC alone and EAC and/or HGD in patients with BE-LGD were 0.54% (95% CI, 0.32-0.76; 24 studies) and 1.73% (95% CI, 0.99-2.47; 17 studies). The results were stable across study setting and location and in high-quality studies. Substantial heterogeneity was observed, which could be explained by stratifying based on LGD/BE ratio as a surrogate for quality of pathology; the pooled annual incidence rates of EAC were 0.76% (95% CI, 0.44-1.09; 14 studies) for LGD/BE ratio <0.15 and 0.32% (95% CI, 0.07-0.58; 10 studies) for LGD/BE ratio >0.15. The annual rate of mortality not related to esophageal disease in patients with BE-LGD was 4.7% (95% CI, 3.2-6.2; 4 studies). LIMITATIONS Substantial heterogeneity was observed in the overall analysis. CONCLUSION The incidence of EAC among patients with BE-LGD is 0.54% annually. The LGD/BE ratio appears to explain the variation observed in the reported incidence of EAC in different cohorts. Conditions not related to esophageal disease are a major cause of mortality in patients with BE-LGD, although additional studies are warranted.

BOB CAT: a Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia

OBJECTIVES:Barrett’s esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD).METHODS:We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations.RESULTS:In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients.CONCLUSIONS:In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.

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.

Association of Barrett's Esophagus With Type II Diabetes Mellitus: Results From a Large Population-based Case-Control Study

BACKGROUND & AIMS Central obesity could increase the risk for Barretts esophagus (BE) and esophageal adenocarcinoma by mechanical and/or metabolic mechanisms, such as hyperinsulinemia. We performed an epidemiologic study to determine whether prior type 2 diabetes mellitus (DM2) is associated with BE. METHODS We performed a population-based case-control study using the General Practice Research Database, a UK primary care database that contains information on more than 8 million subjects, to identify cases of BE (using previously validated codes; n = 14,245) and matched controls without BE (by age, sex, enrollment date, duration of follow-up evaluation, and practice region by incidence density sampling; n = 70,361). We assessed the association of a prior diagnosis of DM2 with BE using conditional univariate and multivariable regression analysis. Confounders assessed included smoking, obesity measured by body mass index (BMI), and gastroesophageal reflux disease. RESULTS BE cases were more likely than controls to have smoked (52.4% vs 49.9%), have a higher mean BMI (27.2 vs 26.9), and a higher prevalence of DM2 than controls (5.8% vs 5.3%). On multivariable analysis, DM2 was associated with a 49% increase in the risk of BE, independent of other known risk factors (odds ratio, 1.49; 95% confidence interval, 1.16-1.91). This association was stronger in women than men. Results remained stable with sensitivity analyses. CONCLUSIONS In a large population-based case-control study, DM2 was a risk factor for BE, independent of obesity (as measured by BMI) and other risk factors (smoking and gastroesophageal reflux disease). These data suggest that metabolic pathways related to DM2 should be explored in BE pathogenesis and esophageal carcinogenesis.

Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett's Esophagus and Confirmed Low-Grade Dysplasia

BACKGROUND & AIMS Barretts esophagus (BE) with low-grade dysplasia (LGD) can progress to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been shown to be an effective treatment for LGD in clinical trials, but its effectiveness in clinical practice is unclear. We compared the rate of progression of LGD after RFA with endoscopic surveillance alone in routine clinical practice. METHODS We performed a retrospective study of patients who either underwent RFA (n = 45) or surveillance endoscopy (n = 125) for LGD, confirmed by at least 1 expert pathologist, from October 1992 through December 2013 at 3 medical centers in the United States. Cox regression analysis was used to assess the association between progression and RFA. RESULTS Data were collected over median follow-up periods of 889 days (interquartile range, 264-1623 days) after RFA and 848 days (interquartile range, 322-2355 days) after surveillance endoscopy (P = .32). The annual rates of progression to HGD or EAC were 6.6% in the surveillance group and 0.77% in the RFA group. The risk of progression to HGD or EAC was significantly lower among patients who underwent RFA than those who underwent surveillance (adjusted hazard ratio = 0.06; 95% confidence interval: 0.008-0.48). CONCLUSIONS Among patients with BE and confirmed LGD, rates of progression to a combined end point of HGD and EAC were lower among those treated with RFA than among untreated patients. Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for LGD.

Safety of endoscopic mucosal resection for Barrett's esophagus.

OBJECTIVES:Endoscopic mucosal resection (EMR) is an established technique for the management of Barretts esophagus (BE). Although EMR is generally perceived to be a relatively safe procedure, the published data regarding EMR-related complications are variable and the expertise of those performing EMR is often not disclosed. Our aim was to determine the complication rates in a large cohort of patients who underwent EMR at a specialized BE unit.METHODS:A prospectively maintained database was reviewed for patients with BE who underwent EMR from January 1995 to August 2008. EMR was performed in patients with neoplastic appearing lesions. Bleeding, stricture, and perforation related to EMR were reviewed as the main outcome measurements.RESULTS:In all, 681 patients (83% male; mean age 70 years old) underwent a total of 1,388 endoscopic procedures and 2,513 EMRs. Median length of BE was 3.0 cm (interquartile range (IQR) 1–7). A single experienced endoscopist performed 99% of the EMR procedures. EMR was performed using commercially available EMR kits in 95% (77% cap–snare and 18% band–snare) and a variceal band ligation device in 5% of cases. No EMR-related perforations occurred during the study period. The rate of post-EMR bleeding was 1.2% (8 patients). Seven patients were successfully treated endoscopically and one needed surgery. The rate for symptomatic strictures after EMR was 1.0% (7 cases), and all of the cases did not involve intervening ablation therapies. All strictures were successfully treated with endoscopic dilation.CONCLUSIONS:This is the largest series reported to date on EMR in BE. In this large retrospective study, EMR for BE was associated with a low rate of complications for selected patients when performed by experienced hands.