Stuart J. Spechler

Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification

BACKGROUND Endoscopic oesophageal changes are diagnostically helpful and identify patients exposed to the risk of disease chronicity. However, there is a serious lack of agreement about how to describe and classify the appearance of reflux oesophagitis AIMS To examine the reliability of criteria that describe the circumferential extent of mucosal breaks and to evaluate the functional and clinical correlates of patients with reflux disease whose oesophagitis was graded according to the Los Angeles system. METHODS Forty six endoscopists from different countries used a detailed worksheet to evaluate endoscopic video recordings from 22 patients with the full range of severity of reflux oesophagitis. In separate studies, Los Angeles system gradings were correlated with 24 hour oesophageal pH monitoring (178 patients), and with clinical trials of omeprazole treatment (277 patients). RESULTS Evaluation of circumferential extent of oesophagitis by the criterion of whether mucosal breaks extended between the tops of mucosal folds, gave acceptable agreement (mean κ value 0.4) among observers. This approach is used in the Los Angeles system. An alternative approach of grouping the circumferential extent of mucosal breaks as occupying 0–25%, 26–50%, 51–75%, 76–99%, or 100% of the oesophageal circumference, gave unacceptably high interobserver variation (mean κ values 0–0.15) for all but the lowest category of extent (mean κ value 0.4). Severity of oesophageal acid exposure was significantly (p<0.001) related to the severity grade of oesophagitis. Preteatment oesophagitis grades A–C were related to heartburn severity (p<0.01), outcomes of omeprazole (10 mg daily) treatment (p<0.01), and the risk for symptom relapse off therapy over six months (p<0.05). CONCLUSIONS Results add further support to previous studies for the clinical utility of the Los Angeles system for endoscopic grading of oesophagitis.

Radiofrequency Ablation in Barrett's Esophagus with Dysplasia

BACKGROUND Barretts esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barretts esophagus and decrease the rate of neoplastic progression. METHODS In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barretts esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barretts esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. RESULTS In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P=0.03) and fewer cancers (1.2% vs. 9.3%, P=0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture. CONCLUSIONS In patients with dysplastic Barretts esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.)

Prevalence of metaplasia at the gastro-oesophageal junction

Specialised columnar epithelium (SCE), a form of intestinal metaplasia usually found in Barretts oesophagus, cannot be distinguished endoscopically from normal gastric epithelium. Endoscopists seldom obtain biopsy specimens from a normal-appearing gastro-oesophageal junction, and therefore short segments of SCE in this region may go unrecognised. We studied patients who had short segments of SCE at the gastro-oesophageal junction. All patients scheduled for elective endoscopic examinations in our general endoscopy unit, irrespective of indication, were questioned for symptoms of gastro-oesophageal reflux disease. At endoscopy, severity of oesophagitis was graded, and biopsy specimens obtained from the squamocolumnar junction, irrespective of its appearance or location in the oesophagus. Among 142 patients without endoscopically apparent Barretts oesophagus, 26 (18%) were found to have SCE. All patients with SCE were white, and the male/female ratio was 1.9. In contrast, non-whites accounted for 14% of the 114 patients without SCE and the male/female ratio was 0.8. The groups did not differ significantly in the frequency of symptoms and endoscopic signs of gastrooesophageal reflux. We conclude that adults frequently have unrecognised segments of SCE at the gastro-oesophageal junction; this may underlie the rising frequency of cancer of the gastrooesophageal junction in the USA and Europe.

Comparison of Medical and Surgical Therapy for Complicated Gastroesophageal Reflux Disease in Veterans

BACKGROUND Conventional medical treatment for gastroesophageal reflux disease involves life-style modifications and combination drug therapy, but few studies have included these features in their protocols. Antireflux surgery has seldom been studied prospectively, and there have been no trials comparing modern medical and surgical treatments for reflux disease. METHODS We conducted a long-term, randomized trial of medical therapy (lifestyle modifications and up to four medications) and surgical therapy (Nissen fundoplication) in 247 patients (243 men and 4 women) with peptic esophageal ulcer, stricture, erosive esophagitis, or Barretts esophagus. They received by random assignment either continuous medical therapy, medical therapy for symptoms only, or surgical therapy. Symptoms were assessed quarterly with a disease-activity index; esophagoscopy was performed at base line and each year for two years. The outcomes evaluated at one and two years included the activity index, and the endoscopic grade of esophagitis. RESULTS Follow-up data were available for 176 patients at one year and for 106 patients at two years. The mean (+/- SE) activity-index score (possible range, 74 to 172) decreased in one year from 108 +/- 3 to 87 +/- 2 in the group receiving continuous medical therapy, from 107 +/- 3 to 88 +/- 2 in the group receiving medical therapy for symptoms only, and from 109 +/- 3 to 78 +/- 2 in the surgical-therapy group (P less than 0.0001 for the change from base line, for all comparisons). The mean (+/- SE) grade of esophagitis (possible range, 1 to 4) decreased in the respective groups from 2.9 +/- 0.1 to 2.0 +/- 0.1, from 2.9 +/- 0.1 to 2.3 +/- 0.1, and from 2.9 +/- 0.1 to 1.4 +/- 0.1 (P less than 0.005 vs. base line, for all comparisons). The mean activity-index score and the grade of esophagitis were significantly better in the surgical-therapy group than in either medical-therapy group during the two years of follow-up (P less than 0.003). CONCLUSIONS In men with complicated gastroesophageal reflux disease, surgery is significantly more effective than medical therapy in improving the symptoms and endoscopic signs of esophagitis for up to two years, although medical treatment is also effective.

Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association

OBJECTIVE:Although a large body of information exists about the prevalence of gastroesophageal reflux disease (GERD) in general, available data specifically addressing nocturnal reflux are limited. Because nocturnal acid reflux is reported to be associated with more severe injuries such as esophagitis and stricture, as well as adenocarcinoma of the esophagus, a better understanding of the prevalence and impact of nighttime heartburn as a sign of nocturnal acid reflux events can have significant potential management implications. The aims of this study were to determine the prevalence of nighttime heartburn and reflux-attributed supraesophageal symptoms among patients with GERD; and the impact of nighttime heartburn on sleep and several activities of daily living that could affect quality of life.METHODS:A nationwide telephone survey of 1000 adults experiencing heartburn at least once a week was conducted by the Gallup Organization on behalf of the American Gastroenterological Association.RESULTS:Altogether, 79% of respondents reported experiencing heartburn at night. Among those, 75% reported that symptoms affected their sleep, 63% believed that heartburn negatively affected their ability to sleep well, and 40% believed that nocturnal heartburn impaired their ability to function the following day. Of the 791 respondents with nighttime heartburn, 71% reported taking over-the-counter medicine for it, but only 29% of these rated this approach extremely effective. Forty-one percent reported trying prescription medicines, and 49% of these rated this approach extremely effective.CONCLUSIONS:Nighttime heartburn occurs in a large majority of adults with GERD, resulting in sleeping difficulties and impaired next-day function. The expected result from implemented therapy for heartburn is not achieved by a sizable percentage of patients.

Early diagnosis of pancreatic infection by computed tomography-guided aspiration

We performed 92 computed tomography-guided percutaneous needle aspirations of pancreatic inflammatory masses in 60 patients suspected of harboring pancreatic infection. Thirty-six patients (60%) were found by Gram stain and culture to have a total of 41 separate episodes of pancreatic infection. Among 42 aspirates judged to be infected by computed tomography-guided aspiration, all but one were confirmed by surgery or indwelling catheter drainage. Among 50 aspirates judged to be sterile, no subsequent evidence of infection was found. All patients tolerated the procedure well and no complications were noted. As a result of this technique, we observed that pancreatic infection occurs earlier than has been previously appreciated (within 14 days of the onset of pancreatitis in 20 of the 36 patients) and that infection may recur during prolonged bouts of pancreatitis. We conclude that guided aspiration is a safe, accurate method for identifying infection of the pancreas at an early stage.

Durability of Radiofrequency Ablation in Barrett's Esophagus With Dysplasia

BACKGROUND & AIMS Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barretts esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

Thoughts on the Complex Relationship Between Gastroesophageal Reflux Disease and Eosinophilic Esophagitis

Recent data suggest that the interaction between gastroesophageal reflux disease (GERD) and eosinophilic esophagitis can be complex, and that the notion of establishing a clear distinction between the two disorders may be too simplistic. There are at least four situations in which GERD might be associated with esophageal eosinophils: (a) GERD causes esophageal injury that results in a mild eosinophilic infiltration, (b) GERD and eosinophilic esophagitis coexist but are unrelated, (c) eosinophilic esophagitis contributes to or causes GERD, or (d) GERD contributes to or causes eosinophilic esophagitis. The high frequency of GERD described in adult patients with eosinophilic esophagitis suggests that there may be more than a chance association between the two disorders. This report discusses potential mechanisms for the complex interaction between GERD and eosinophilic esophagitis. We hope that this information will serve as a conceptual basis for future studies on the relationship between the two disorders. Whereas there are a number of plausible mechanisms whereby GERD might contribute to the accumulation of eosinophils in the esophageal epithelium, it seems prudent to recommend a clinical trial of proton pump inhibitor (PPI) therapy even when the diagnosis of eosinophilic esophagitis seems clear-cut. Furthermore, we suggest that a favorable response to PPI therapy does not preclude a diagnosis of eosinophilic esophagitis.

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Gastroesophageal Reflux Might Cause Esophagitis Through a Cytokine-Mediated Mechanism Rather Than Caustic Acid Injury

BACKGROUND & AIMS Reflux esophagitis is believed to be caused by the caustic effects of refluxed gastric acid on esophageal epithelial cells. However, caustic chemical injuries develop rapidly whereas esophagitis might not appear until weeks after the induction of reflux in animal models. We studied early histologic events in the development of reflux esophagitis in a rat model and performed in vitro experiments to determine whether exposure to acidified bile salts causes esophageal epithelial cells to secrete chemokines that might contribute to inflammation. METHODS At various time points after esophagoduodenostomy, the rat esophagus was removed and inflammatory changes were analyzed by histologic analyses. Human esophageal squamous cell lines were exposed to acidified bile salts to evaluate their effects on cytokine production and immune-cell migration. RESULTS Reflux esophagitis started at postoperative day 3 with lymphocytic infiltration of the submucosa that progressed to the epithelial surface-these findings contradicted those expected from a caustic chemical injury. Basal cell and papillary hyperplasia preceded the development of surface erosions. Exposure of squamous cells to acidified bile salts significantly increased the secretion of interleukin-8 and interleukin-1beta; conditioned media from these cells caused significant increases in the migration rates of T cells and neutrophils. CONCLUSIONS These findings support, but do not prove, an alternative concept for the development of reflux esophagitis in which refluxed gastric juice does not directly damage the esophagus, but rather stimulates esophageal epithelial cells to secrete chemokines that mediate damage of esophageal tissue.