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This report explores two hypotheses regarding eosinophilic esophagitis (EoE): (1) that the use of proton pump inhibitors (PPIs) might contribute to the pathogenesis of EoE by preventing peptic digestion of food allergens, by increasing gastric mucosal permeability to enable gastric absorption of those undegraded food allergens, and by causing microbial dysbiosis, and (2) that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms, and that the muscle-predominant form of EoE might cause a variety of esophageal motility disorders including achalasia.

The prevalence of eosinophilic esophagitis, a manifestation of food allergy, has increased in recent years for reasons that are not clear. The gastrointestinal mucosa is regularly exposed to food antigens with the potential to evoke immunological reactions. Studies have shown that some food allergens that ordinarily would be degraded by peptic digestion are not degraded when the pH of gastric fluid is raised to levels commonly found in the stomachs of patients treated with proton pump inhibitors (PPIs). Other studies have shown that PPIs increase gastrointestinal mucosal permeability, which might facilitate the uptake of undegraded peptide allergens. Mice treated with antisecretory medications while being fed a diet of caviar have been found to develop caviar-specific immunoglobulin E (IgE) antibodies, T-cell reactivity, and gastric eosinophilia. Adult patients treated with antisecretory medications for 3 months have been found to develop a rise in their IgE antibody levels and new, food-specific IgE antibodies. These data establish a plausible mechanism whereby acid-suppressive medications, by interfering with the peptic digestion of food allergens and increasing mucosal permeability, might lead to the development of food allergy. The time course of the introduction and subsequent widespread usage of PPIs with the emergence of eosinophilic esophagitis fits well with the hypothesis that PPIs may play an etiological role. Although the mere demonstration of a plausible association does not establish cause and effect, further studies on the role of acid suppression in the development of eosinophilic esophagitis clearly are warranted.

Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the varied presentations of GERD, enhancements in diagnostic testing, and approach to patient management have evolved. During this time, scrutiny of proton pump inhibitors (PPIs) has increased considerably. Although PPIs remain the medical treatment of choice for GERD, multiple publications have raised questions about adverse events, raising doubts about the safety of long-term use and increasing concern about overprescribing of PPIs. New data regarding the potential for surgical and endoscopic interventions have emerged. In this new document, we provide updated, evidence-based recommendations and practical guidance for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to evaluate the evidence and the strength of recommendations. Key concepts and suggestions that as of this writing do not have sufficient evidence to grade are also provided.

Eosinophilic esophagitis (EoE), a disorder identified by its esophageal mucosal features, often is associated with esophageal motility abnormalities, which are manifestations of esophageal muscle dysfunction. Those motility abnormalities sometimes normalize with treatments that reduce esophageal eosinophilia, suggesting that eosinophils can cause reversible esophageal motility disturbances, perhaps by releasing myoactive and neuroactive eosinophil products. Although achalasia uncommonly is associated with EoE as currently defined, most achalasia patients have evidence of an abnormal accumulation of eosinophils and/or their degranulation products in the esophageal muscularis propria, a location inaccessible to routine endoscopic evaluation. Achalasia is an idiopathic condition resulting from destruction of neurons in the myenteric plexus of the esophagus, and degranulating eosinophils release toxic proteins capable of destroying those neurons, thereby causing the irreversible motility abnormalities of achalasia. This report reviews data on the association of esophageal eosinophilia with achalasia and other esophageal motility abnormalities. Based on this review, we propose that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms with different clinical manifestations. A muscle-predominant form of EoE could underlie a variety of reversible and irreversible esophageal motility disorders, including achalasia. The concept that esophageal motility abnormalities might develop from a muscle-predominant form of EoE warrants serious consideration and further investigation.

Endoscopic ablation of Barrett's esophagus can bury metaplastic glands under a layer of neosquamous epithelium. To explore the frequency and importance of buried metaplasia, we have conducted a systematic review of reports on endoscopic ablation. We performed computerized and manual searches for articles on the results of photodynamic therapy (PDT) and radiofrequency ablation (RFA) for Barrett's esophagus. We extracted information on the number of patients treated, biopsy protocol, biopsy depth, and frequency of buried metaplasia. We found 9 articles describing 34 patients with neoplasia appearing in buried metaplasia (31 after PDT). We found five articles describing a baseline prevalence of buried metaplasia (before ablation) ranging from 0% to 28%. In 22 reports on PDT for 953 patients, buried metaplasia was found in 135 (14.2%); in 18 reports on RFA for 1,004 patients, buried metaplasia was found in only 9 (0.9%). A major problem limiting the conclusions that can be drawn from these reports is that they do not describe specifically how frequently biopsy specimens contained sufficient subepithelial lamina propria to be informative for buried metaplasia. Endoscopic ablation can bury metaplastic glands with neoplastic potential but, even without ablation, buried metaplasia often is found in areas where Barrett's epithelium abuts squamous epithelium. Buried metaplasia is reported less frequently after RFA than after PDT. However, available reports do not provide crucial information on the adequacy of biopsy specimens and, therefore, the frequency and importance of buried metaplasia after endoscopic ablation remain unclear.

Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, and are widely regarded as the agents of choice for the treatment of acid-peptic disorders. For patients with upper gastrointestinal symptoms of uncertain etiology, improvement with PPI therapy is considered prima facie evidence of a pathogenetic role for acid-peptic disease. In addition to anti-secretory effects, however, PPIs have been found to have anti-oxidant properties and direct effects on neutrophils, monocytes, endothelial, and epithelial cells that might prevent inflammation. Those anti-inflammatory effects of the PPIs might influence a variety of inflammatory disorders, both peptic and non-peptic, within and outside of the gastrointestinal tract. The purpose of this report is to review the mechanisms whereby PPIs might exert anti-inflammatory effects exclusive of gastric acid inhibition, to discuss the clinical implications of those effects, and to emphasize that a clinical response to PPIs should not be construed as proof for an underlying acid-peptic disorder.

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.

Barrett esophagus develops when metaplastic columnar epithelium predisposed to develop adenocarcinoma replaces esophageal squamous epithelium damaged by gastroesophageal reflux disease. Although several types of columnar metaplasia have been described in Barrett esophagus, intestinal metaplasia with goblet cells currently is required for a definitive diagnosis in the United States. Studies indicate that the risk of adenocarcinoma for patients with nondysplastic Barrett esophagus is only 0.12% to 0.38% per year, which is substantially lower than previous studies had suggested. Nevertheless, the incidence of esophageal adenocarcinoma continues to rise at an alarming rate. Regular endoscopic surveillance for dysplasia is the currently recommended cancer prevention strategy for Barrett esophagus, but a high-quality study has found no benefit of surveillance in preventing deaths from esophageal cancer. Medical societies currently recommend endoscopic screening for Barrett esophagus in patients with multiple risk factors for esophageal adenocarcinoma, including chronic gastroesophageal reflux disease, age of 50 years or older, male sex, white race, hiatal hernia, and intra-abdominal body fat distribution. However, because the goal of screening is to identify patients with Barrett esophagus who will benefit from endoscopic surveillance and because such surveillance may not be beneficial, the rationale for screening might be made on the basis of faulty assumptions. Endoscopic ablation of dysplastic Barrett metaplasia has been reported to prevent its progression to cancer, but the efficacy of endoscopic eradication of nondysplastic Barrett metaplasia as a cancer preventive procedure is highly questionable. This review discusses some of these controversies that affect the physicians and surgeons who treat patients with Barrett esophagus. Studies relevant to controversial issues in Barrett esophagus were identified using PubMed and relevant search terms, including Barrett esophagus, ablation, dysplasia, radiofrequency ablation, and endoscopic mucosal resection.

Ideally, an animal model of Barrett's esophagus should recapitulate the human disease histologically and immunohistochemically, and be readily susceptible to genetic manipulation. We have developed such a model using a strain of mice commonly used for transgenic and knockout manipulations. We induced reflux by esophagojejunostomy (EJ) in 20 C57Bl/6 mice. At defined time points, sections of the esophagus were stained with H&E and Alcian blue, and immunohistochemical staining was performed for Sox9 (a transcription factor in Barrett's metaplasia), cytokeratin (CK) 8/18 (a columnar marker) and CK14 (a squamous marker). Procedural mortality was 40% for the first ten animals, 20% for the next 10. Reflux esophagitis developed by 13 weeks, and intestinal metaplasia with goblet cells developed by 34 weeks. The metaplasia expressed CK8/18, but not CK14, and exhibited nuclear immunostaining for Sox9. Nuclear Sox9 was also seen in scattered basal cells of squamous epithelium close to the EJ anastomosis. EJ can be performed successfully in C57Bl/6 mice, resulting in reflux esophagitis and intestinal metaplasia that exhibits phenotypic and molecular features of human Barrett's metaplasia. This surgical model in a mouse strain that is easy to manipulate genetically should be a valuable tool for studying the pathogenesis of Barrett's esophagus.

Endoscopic eradication therapy is used to treat mucosal neoplasms in Barrett's esophagus, but cannot cure cancers that have metastasized to lymph nodes. The risk of such metastases has been proposed as a reason to consider esophagectomy rather than endoscopic therapy for esophageal mucosal neoplasia. The objective of our study was to determine the frequency of lymph-node metastases in patients with high-grade dysplasia (HGD) and intramucosal carcinoma in Barrett's esophagus. We performed a systematic review using the PRISMA guidelines to identify studies that included patients who had esophagectomy for HGD or intramucosal carcinoma in Barrett's esophagus, and that reported final pathology results after examination of esophagectomy specimens. We identified 70 relevant reports that included 1,874 patients who had esophagectomy performed for HGD or intramucosal carcinoma in Barrett's esophagus. Lymph-node metastases were found in 26 patients (1.39 % , 95 % CI 0.86 – 1.92). No metastases were found in the 524 patients who had a final pathology diagnosis of HGD, whereas 26 (1.93 % , 95 % CI 1.19 – 2.66 %) of the 1,350 patients with a final pathology diagnosis of intramucosal carcinoma had positive lymph nodes. The risk of unexpected lymph-node metastases for patients with mucosal neoplasms in Barrett's esophagus is in the range of 1 – 2 %. Esophagectomy has a mortality rate that often exceeds 2 %, with substantial morbidity and no guarantee of curing metastatic disease. Therefore, the risk of lymph node metastases alone does not warrant the choice of esophagectomy over endoscopic therapy for HGD and intramucosal carcinoma in Barrett's esophagus.