Portal de Periódicos da CAPES

Contributions From Gastroenterology: Acid Peptic Disorders, Barrett’s Esophagus and Eosinophilic Esophagitis

2018; Elsevier BV; Volume: 154; Issue: 5 Linguagem: Inglês

10.1053/j.gastro.2017.12.023

1528-0012

Rhonda F. Souza, Joel H. Rubenstein, John Y. Kao, Ikuo Hirano,

Eosinophilic Disorders and Syndromes

Over the past three-quarters of a century, manuscripts published in Gastroenterology have had a substantial impact on our clinical recognition, understanding, and management of peptic ulcer disease (PUD), Helicobacter pylori, gastroesophageal reflux disease (GERD), Barrett’s esophagus, and eosinophilic esophagitis (EoE). This article highlights selected, highly cited works with overlapping themes of acid injury, chronic mucosal inflammation, and H pylori infection that are historically contextualized in Figures 1 and 2.Figure 2Timeline of historical context for key gastroenterology publications on eosinophilic esophagitis and Helicobacter pylori.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The understanding of acid-related diseases as they relate to GERD have been shaped by several landmark studies published in Gastroenterology. Significant pre-H pylori advances include effective managements of acid using proton pump inhibitors (PPIs) as well as highly selective vagotomy. Although the impact of H pylori on gastroduodenal ulcers and gastric neoplasia is well-known, the impact of H pylori on GERD was more controversial, because positive associations of GERD symptoms were linked with factors contributing more severe gastritis, whereas H pylori was linked to reduced esophageal cancer risk. Before the discovery of effective antisecretory therapies, surgery was the only option to effectively manage PUD and its complications. However, the standard surgical vagotomy combined with antrectomy impairs motor functions of the antrum and pylorus. Highly selective vagotomy is the first operation for PUD, which both avoids gastric resection and keeps the antral and pyloric sphincter intact. A sentinel report was published in Gastroenterology by Amdrup and Jensen1Amdrup E. Jensen H.E. Selective vagotomy of the parietal cell mass preserving innervation of the undrained antrum. A preliminary report of results in patients with duodenal ulcer.Gastroenterology. 1970; 59: 522-527Abstract Full Text PDF PubMed Google Scholar showing superior clinical outcomes (eg, early dumping, diarrhea, and bilious vomiting) of highly selective vagotomy compared with traditional approaches. With the availability of histamine-2 receptor antagonists, Collen et al2Collen M.J. Lewis J.H. Benjamin S.B. Gastric acid hypersecretion in refractory gastroesophageal reflux disease.Gastroenterology. 1990; 98: 654-661Abstract Full Text PDF PubMed Scopus (148) Google Scholar identified that patients with GERD failing therapy had gastric acid hypersecretion and require increased doses of histamine-2 receptor antagonists. Subsequently, Smith et al3Smith P.M. Kerr G.D. Cockel R. et al.A comparison of omeprazole and ranitidine in the prevention of recurrence of benign esophageal stricture. Restore Investigator Group.Gastroenterology. 1994; 107: 1312-1318Abstract Full Text PDF PubMed Scopus (200) Google Scholar demonstrated superior efficacy of PPI compared with histamine-2 receptor antagonists in the management of benign peptic strictures. The discovery of H pylori the a single most important etiologic factor for gastroduodenal ulcers prompted the speculation that H pylori might also lead to GERD. Vicari et al4Vicari J.J. Peek R.M. Falk G.W. et al.The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease.Gastroenterology. 1998; 115: 50-57Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar demonstrated an increased prevalence of CagA+ H pylori strains in the spectrum of GERD, and particularly in individuals with interleukin (IL)-1β and IL-1RN polymorphism,5Queiroz D.M. Guerra J.B. Rocha G.A. et al.IL1B and IL1RN polymorphic genes and Helicobacter pylori cagA strains decrease the risk of reflux esophagitis.Gastroenterology. 2004; 127: 73-79Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar risk alleles predictive of more severe H pylori gastritis clinical outcome. However, several studies reported the negative association between H pylori and GERD,6Holtmann G. Cain C. Malfertheiner P. Gastric Helicobacter pylori infection accelerates healing of reflux esophagitis during treatment with the proton pump inhibitor pantoprazole.Gastroenterology. 1999; 117: 11-16Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 7Labenz J. Blum A.L. Bayerdörffer E. et al.Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis.Gastroenterology. 1997; 112: 1442-1447Abstract Full Text PDF PubMed Scopus (698) Google Scholar thus raising the question as to whether H pylori is positively or negatively correlated with GERD. The answer may depend on the location of infection. Corpus-predominant pangastritis is associated with more profound hypochlorhydria and thus reduced GERD symptoms as opposed to antral-predominant gastritis.8El-Omar E.M. Oien K. El-Nujumi A. et al.Helicobacter pylori infection and chronic gastric acid hyposecretion.Gastroenterology. 1997; 113: 15-24Abstract Full Text PDF PubMed Scopus (569) Google Scholar The first study to identify how common GERD is in the United States was reported by Locke et al9Locke 3rd, G.R. Talley N.J. Fett S.L. et al.Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota.Gastroenterology. 1997; 112: 1448-1456Abstract Full Text PDF PubMed Scopus (1898) Google Scholar in Gastroenterology in 1997. The population-based survey study based in Olmsted County, Minnesota, demonstrated that 19.8% experienced typical GERD symptoms (heartburn or acid regurgitation) at least weekly for >5 years.9Locke 3rd, G.R. Talley N.J. Fett S.L. et al.Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota.Gastroenterology. 1997; 112: 1448-1456Abstract Full Text PDF PubMed Scopus (1898) Google Scholar Furthermore, patients related that their typical reflux symptoms also were associated with atypical symptoms like noncardiac chest pain, dysphagia, and dyspepsia. Approximately 30% of patients with typical GERD symptoms have endoscopically visible reflux esophagitis, which can result in esophageal complications like strictures and Barrett’s esophagus. The endoscopic classification system of reflux disease (Los Angeles grade) was reported in Gastroenterology in 1996, providing a standardized and reproducible assessment of GERD and its complications.10Armstrong D. Bennett J.R. Blum A.L. et al.The endoscopic assessment of esophagitis: a progress report on observer agreement.Gastroenterology. 1996; 111: 85-92Abstract Full Text Full Text PDF PubMed Scopus (915) Google Scholar Reflux esophagitis was regarded as an acid-peptic injury, but studies reported by Champion et al11Champion G. Richter J.E. Vaezi M.F. et al.Duodenogastroesophageal reflux: relationship to pH and importance in Barrett's esophagus.Gastroenterology. 1994; 107: 747-754Abstract Full Text PDF PubMed Scopus (429) Google Scholar and others in Gastroenterology have demonstrated the injurious nature of bile as well. Traditionally, reflux esophagitis was viewed as a “burn” that started at the esophageal mucosal surface with squamous cells succumbing to the caustic chemical effects of refluxed acid and bile. The death of surface cells was assumed to stimulate basal cell hyperplasia, a characteristic histologic feature of GERD. This concept of reflux esophagitis pathogenesis had gone largely unchallenged until 2009, when Souza et al12Souza R.F. Huo X. Mittal V. et al.Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury.Gastroenterology. 2009; 137: 1776-1784Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar reported in Gastroenterology a study on the histologic progression of GERD in rats with reflux induced by esophagoduodenostomy. Surprisingly, esophageal inflammation in these rats did not start with granulocytes infiltrating the mucosa, but rather began with lymphocytes infiltrating the submucosa. Surface cell injury did not appear until weeks later, and basal cell hyperplasia developed while esophageal surface cells were still intact. Accompanying in vitro studies demonstrated that human esophageal epithelial cells exposed to acid and bile salts secrete proinflammatory and proproliferative cytokines. Thus, an alternative concept for GERD pathogenesis was proposed in which esophagitis develops as a cytokine-mediated inflammatory injury. Subsequently, these investigators showed that they could induce acute reflux esophagitis by interrupting PPI therapy in patients who had severe reflux esophagitis that had been healed by PPIs.13Dunbar K.B. Agoston A.T. Odze R.D. et al.Association of acute gastroesophageal reflux disease with esophageal histologic changes.JAMA. 2016; 315: 2104-2112Crossref PubMed Scopus (121) Google Scholar Esophageal biopsies from those patients confirmed that, as in the rat model, acute reflux esophagitis in humans develops as a lymphocyte-predominant form of inflammation that seems to be cytokine mediated. These studies have refuted decades-old dogma on GERD pathogenesis. Other studies reported in Gastroenterology have shown that GERD can cause esophageal motor abnormalities through cytokine-mediated processes. For example, Rieder et al14Rieder F. Cheng L. Harnett K.M. et al.Gastroesophageal reflux disease-associated esophagitis induces endogenous cytokine production leading to motor abnormalities.Gastroenterology. 2007; 132: 154-165Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar reported that motor disorders of the esophagus might result from esophageal mucosal production of proinflammatory cytokines. Using a combination of patient-derived esophageal mucosal biopsies, human cell lines, human gastric juice, and feline circular smooth muscle strips, these investigators found that (1) mucosal biopsies from patients with reflux esophagitis produced proinflammatory cytokines including IL-1β and IL-6, which can reduce esophageal muscle contractility, (2) esophageal squamous cells, fibroblasts, and muscle cells secrete cytokines upon exposure to inflammatory stimuli in vitro, (3) human gastric juice can induce cytokine production by esophageal squamous cells, and (4) cytokines secreted by esophageal squamous cells from patients with reflux esophagitis diminish contraction in esophageal circular smooth muscle. Thus, these studies establish a functional link between GERD-induced cytokine production by esophageal squamous cells and esophageal motor abnormalities. What we now call Barrett’s esophagus was actually first described by Tileston in 1906. Norman Barrett proposed that the condition was a congenital intrathoracic segment of stomach rather than the modern generally accepted position that it is a metaplastic tissue.15Spechler S.J. Goyal R.K. The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett.Gastroenterology. 1996; 110: 614-621Abstract Full Text PDF PubMed Scopus (433) Google Scholar By the 1980s, the association between Barrett’s esophagus and esophageal adenocarcinoma had been recognized. In 1995 Cameron et al16Cameron A.J. Lomboy C.T. Pera M. et al.Adenocarcinoma of the esophagogastric junction and Barrett's esophagus.Gastroenterology. 1995; 109: 1541-1546Abstract Full Text PDF PubMed Scopus (401) Google Scholar inferred from a study of esophagectomy specimens that all esophageal adenocarcinomas and most esophagogastric junction adenocarcinomas arose from Barrett’s esophagus. The cancers without Barrett’s esophagus had larger tumors, suggesting that the Barrett’s mucosa had been overgrown by the tumors. At that time, some cohort studies had suggested an annual incidence of esophageal adenocarcinoma among patients with Barrett’s esophagus upwards of 2%. It was not until 2000 that Shaheen et al17Shaheen N.J. Crosby M.A. Bozymski E.M. et al.Is there publication bias in the reporting of cancer risk in Barrett's esophagus?.Gastroenterology. 2000; 119: 333-338Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar published a systematic review in Gastroenterology estimating that the true annual incidence of cancer in Barrett’s esophagus was around 0.5%. The study was one of the first within the field of gastroenterology to apply the relatively new technique of funnel plot analysis to assess for the presence of dissemination bias in which small studies with positive outcomes are more likely to be published than small studies with negative outcomes. A number of subsequent large cohort studies have suggested annual incidences as low as 0.1%. The recognition of the precancerous potential of Barrett’s esophagus, and of the association of GERD symptoms with both Barrett’s esophagus and esophageal adenocarcinoma, led to extensive efforts of endoscopic screening of patients with GERD symptoms and surveillance of those with Barrett’s esophagus. Nonetheless, Dulai et al18Dulai G.S. Guha S. Kahn K.L. et al.Preoperative prevalence of Barrett's esophagus in esophageal adenocarcinoma: a systematic review.Gastroenterology. 2002; 122: 26-33Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar noted in 2002 from a meta-analysis of cohort studies that only 5% of patients undergoing esophagectomy for esophageal adenocarcinoma had been diagnosed with Barrett’s esophagus before their diagnosis of the cancer, a statistic that has remained frustratingly low in subsequent studies within large administrative datasets such as Medicare. One of the reasons for the low proportion is that most patients with the cancer deny substantial prior GERD symptoms. That same year, Gerson et al19Gerson L.B. Shetler K. Triadafilopoulos G. Prevalence of Barrett's esophagus in asymptomatic individuals.Gastroenterology. 2002; 123: 461-467Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar also reported in Gastroenterology that 25% of patients without GERD symptoms undergoing colorectal cancer screening and volunteered for upper endoscopy were found to have Barrett’s esophagus. The observation was met with skepticism bordering on derision. However, multiple subsequent studies demonstrated substantial, if not quite as high, prevalences of Barrett’s esophagus in asymptomatic individuals, particularly among older obese white American men. Owing to the substantial morbidity and mortality associated with esophagectomy, there was great interest in developing endoscopic treatments for early esophageal adenocarcinoma or dysplastic Barrett’s esophagus. Studies of photodynamic therapy demonstrated good efficacy, but were limited by toxicities of skin photosensitivity and esophageal strictures. In 2000, Ell et al20Ell C. May A. Gossner L. et al.Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett's esophagus.Gastroenterology. 2000; 118: 670-677Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar reported in Gastroenterology their experience of endoscopic mucosal resection in 64 patients with high-grade dysplasia or T1 cancers. Their article led toward the technique ultimately being recommended as the standard of care for early neoplastic Barrett’s esophagus with visible lesions. Finally, in 2006 an international working group published the Prague criteria for documenting the endoscopic length of Barrett’s esophagus.21Sharma P. Dent J. Armstrong D. et al.The development and validation of an endoscopic grading system for Barrett's esophagus: the Prague C & M criteria.Gastroenterology. 2006; 131: 1392-1399Abstract Full Text Full Text PDF PubMed Scopus (808) Google Scholar The first reported case of EoE was published in Gastroenterology in 1977 by Dobbins and Behar. The patient was a 51-year-old man with asthma and allergic rhinitis who presented with dysphagia. Esophageal biopsies demonstrated elongated papillae and basal zone hyperplasia typical for GERD, but also prominent eosinophilic infiltration of the squamous epithelium, lamina propria, and muscularis mucosae. Manometry demonstrated repetitive, simultaneous esophageal contractions while pH testing was normal. A second report by Landres in Gastroenterology in 1978 reported a similar case with manometry consistent with achalasia. In 1982, Winter published a highly cited pediatric study that associated low-grade, intraepithelial eosinophils with abnormal acid clearance. For the next 2 decades, esophageal eosinophils were widely viewed as a biomarker for GERD. The initial characterization of EoE as it is currently recognized was elucidated by Atwood and Straumann in case series from 1993 and 1994, but the disease remained underappreciated for the ensuing decade, with the exception of growing number of studies from a handful of pediatric centers in the United States. Although initial progress was slow, Kelly et al22Kelly K.J. Lazenby A.J. Rowe P.C. et al.Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.Gastroenterology. 1995; 109: 1503-1512Abstract Full Text PDF PubMed Scopus (880) Google Scholar reported a groundbreaking case series in Gastroenterology in 1995 that introduced the concept that EoE might be a form of food allergy. The study demonstrated symptom and histologic response to elemental formula in a series of 10 children who had failed to respond to medical or surgical antireflux therapies. The therapeutic role of dietary elimination of putative food allergens was substantiated in the first prospective study of the 6-food elimination diet by Gonsalves et al in 2012.23Gonsalves N. Yang G.Y. Doerfler B. et al.Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors.Gastroenterology. 2012; 142 (quiz e14–15): 1451-1459 e1Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar Subsequent studies have confirmed the effectiveness of the elimination diet, leading to its use as a primary therapy for EoE in adults and children. One of the most influential and highly cited papers in the field of EoE was a consensus recommendation paper by Furuta et al in Gastroenterology in 2007.24Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Abstract Full Text Full Text PDF PubMed Scopus (1371) Google Scholar This article brought together an international panel of pediatric and adult gastroenterologists, pathologists, basic scientists, allergists, and investigators to establish diagnostic criteria as well as summarize a growing body of literature on EoE. Additional highly influential studies included natural history studies by Straumann et al published in Gastroenterology that identified the chronic nature of the disease and proclivity for progression to severe fibrostenosis when unrecognized25Straumann A. Spichtin H.P. Grize L. et al.Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years.Gastroenterology. 2003; 125: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar, 26Schoepfer A.M. Safroneeva E. Bussmann C. et al.Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.Gastroenterology. 2013; 145 (e1–2): 1230-1236Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar and a cross-sectional study by Dellon et al that found an inverse association between esophageal eosinophilia and H pylori infection.27Dellon E.S. Peery A.F. Shaheen N.J. et al.Inverse association of esophageal eosinophilia with Helicobacter pylori based on analysis of a US pathology database.Gastroenterology. 2011; 141: 1586-1592Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar From a therapeutic perspective, several innovative trials of medical therapies for EoE have been published in Gastroenterology. These include the first prospective trial and first randomized controlled trial of topical steroids for EoE by Teitelbaum and Konikoff respectively, the first randomized controlled trials of budesonide by Straumann and Aceves, and the first randomized controlled trial of budesonide suspension to demonstrate efficacy using validated endpoints by Dellon et al. Furthermore, murine models of EoE and translational studies by Mishra and Rothenberg in Gastroenterology have demonstrated the importance of TH-2 and allergic pathways in the pathogenesis of EoE, specifically identifying IL-5, IL-13, and IL-15 as potential targets. These fundamental observations have led to the development of novel biologic therapies with recent publications describing the efficacy of this targeted approach in EoE patients.