A Population-Based Study of IGF Axis Polymorphisms and the Esophageal Inflammation, Metaplasia, Adenocarcinoma Sequence

BACKGROUND & AIMS: Insulin-like growth factor (IGF) axis plays a key role in cell development, proliferation, and survival and is implicated in the etiology of several cancers. Few studies have examined the relationship between genetic variation of this axis and esophageal adenocarcinoma (EAC) or its precursors. METHODS: In a population-based case-control study, we investigated the association of common polymorphisms of IGF-1, IGF-2, IGF-1 receptor, IGF binding protein -3, growth hormones (GH) 1 and GH2, and GH receptor with reflux esophagitis (RE), Barrett esophagus (BE), and EAC. Two hundred and thirty RE, 224 BE, 227 EAC cases, and 260 controls were studied. Gene polymorphisms were identified using publicly available online resources; 102 IGF axis tag and putatively functional single-nucleotide polymorphisms (SNPs) were analyzed using MassARRAY iPLEX and Taqman assays. Results were analyzed using Haploview.
RESULTS: Three polymorphisms were disease-associated. IGF1 SNP rs6214 was associated with BE (adjusted P = .039). Using GG genotype as reference, odds ratio for BE in AA (wild-type) was 0.43 (95% confidence interval [CI], 0.24-0.75). GH receptor SNP rs6898743 was associated with EAC (adjusted P = .0112). With GG as reference, odds ratio for EAC in CC (wildtype) genotype was 0.42 (95% CI, 0.23-0.76). IGF1 (CA)(17) 185-bp allele was associated with RE (adjusted P = .0116). Using IGF1(non17) as reference, odds ratio for RE in IGF1(17) carriers was 7.29 (95% CI, 1.57-46.7).
CONCLUSIONS: In this study, 3 polymorphisms of IGF genes were associated with EAC or its precursors. These polymorphisms may be markers of disease risk; independent validation of our findings is required. These results suggest the IGF pathway is involved in EAC development.

Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence

Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett's esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammation-metaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett's esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett's esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence.

Resultados do tratamento cirúrgico da doença do refluxo gastroesofágico em crianças com e sem afecções neurológicas concomitantes

RACIONAL: Crianças portadoras de distúrbios neurológicos têm maior incidência de refluxo e, em geral, não apresentam melhora da sintomatologia com tratamento clínico, necessitando de intervenção cirúrgica. OBJETIVO: Comparar os resultados da operação antirefluxo em crianças normais e com comprometimento neurológico, identificando as principais complicações e causas de reoperação. MÉTODOS: Cento e vinte crianças portadores de refluxo foram distribuídas em dois grupos de estudo: Grupo I - 60 crianças normais; Grupo II - 60 crianças com comprometimento neurológico. Exame contrastado do esôfago, estômago e duodeno, endoscopia digestiva alta com biópsia, pHmetria esofágica de 24 horas e cintilografia foram os exames utilizados no diagnóstico e na avaliação da eficácia da operação antirefluxo. Todos os pacientes operados eram refratários ao tratamento clínico. O procedimento cirúrgico antirefluxo realizado foi predominantemente a fundoplicatura de Lind, sendo associada à gastrostomia em 55% dos pacientes do Grupo II. RESULTADOS: No Grupo II a indicação cirúrgica foi significantemente mais precoce que no Grupo I. A principal causa de indicação cirúrgica entre neuropatas foi o alto comprometimento do desenvolvimento neuropsíquico-motor e as pneumonias de repetição. O tempo de internação, as reoperações e a necessidade de dilatações esofágicas no pós-operatório foi maior no Grupo II (p<0,01). Ocorreram três óbitos no pós-operatório tardio no Grupo II (sepse e infecção respiratória grave). CONCLUSÃO: O tratamento cirúrgico adotado foi satisfatório para o tratamento cirúrgico do refluxo nos dois grupos de pacientes. Porém, torna-se necessário o aprofundamento dos estudos acerca da população de crianças neuropatas portadoras de refluxo, uma vez que estas respondem de forma menos favorável ao procedimento cirúrgico, principalmente no que se refere às taxas de mortalidade, recorrência dos sintomas respiratórios, índice de reoperações e gravidade das complicações pós-operatórias.

Avaliação dos danos do DNA na mucosa esofágica e sangue periférico de portadores da doença do refluxo gastroesofágico

RACIONAL: A doença do refluxo gastroesofágico é a afecção digestiva de maior prevalência. Os portadores podem apresentar na evolução algumas complicações, sendo o esôfago de Barrett a de maior importância, tendo em vista seu potencial de malignidade. Todavia os processos inflamatórios do trato gastrointestinal podem apresentar degeneração maligna. OBJETIVOS: Avaliar os possíveis danos do DNA em portadores de esofagite de refluxo gastroesofágico de vários graus e verificar a aplicação do ensaio Cometa na detecção dos mesmos. MÉTODOS: Foram estudados 25 pacientes distribuídos em quatro grupos: controle (n=5), esofagite leve (n=8), esofagite severa (n=5) e câncer (n=7). O ensaio Cometa foi realizado no sangue periférico (linfócitos) e biópsia do terço distal do esôfago. RESULTADOS: O ensaio Cometa detectou danos no DNA nos pacientes com esofagite leve e severa (sangue periférico e biópsia), sendo que na esofagite severa a intensidade dos danos foi maior (p<0,05). Os danos do DNA dos pacientes com esofagite severa e câncer não mostraram diferença significativa e a intensidade dos mesmos corresponde ao ensaio Cometa classe 4 (maior que 95% de danos). CONCLUSÕES: 1) As frequências de quebras do DNA da mucosa esofágica e linfócitos estão diretamente relacionadas ao grau de inflamação; 2) a esofagite severa apresenta praticamente a mesma frequência de danos no DNA do câncer esofágico; 3) o ensaio Cometa mostrou-se muito sensível para a detecção dos danos do DNA.

Associação entre o achado de cárdia incompetente à endoscopia digestiva alta e presença de esofagite de refluxo

Incompetent cardia (IC) or loose cardia is not uncommon at endoscopic examination but its meaning is not clear. Such incompetence could facilitate gastroesophageal reflux and the appearance of esophagitis as a consequence. The aim of this study is to investigate if there is an association between IC and reflux esophagitis (RE). A review was made of 395 consecutive endoscopic reports of adult males and females performed at the Botucatu Clinics Hospital, of the Unesp - University of the State of São Paulo. Diagnosis of IC is defined by the endoscopic image in which the cardia is partially opened and/or involves the endoscope in a loose manner. Esophagitis characterization was based in the Los Angeles classification. The statistical analysis showed a significant association between CI and RE (p < 0.0001). Although there is not a clear explanation for this association, some hypotheses could be suggested involving hypotonic LES, diaphragmatic crura ineffectiveness and TLESR disorders as conditions able not only to keep the cardia relaxed but also to the reflux followed by esophagitis.

Pólipos hiperplásicos da junção gastro-esofágica em idade pediátrica

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Characteristics of Reflux Episodes and Symptom Association in Patients With Erosive Esophagitis and Nonerosive Reflux Disease: Study Using Combined Impedance–pH Off Therapy

We sought to compare reflux and symptom association patterns in patients with nonerosive reflux disease (NERD), erosive esophagitis (EE), and in healthy volunteers (HVs).

Characteristics of gastro-esophageal reflux episodes in Barrett's esophagus, erosive esophagitis and healthy volunteers

Gastro-esophageal reflux is considered a major culprit in the pathogenesis of Barrett's esophagus (BE). Still, there is controversy on the role of weakly acidic and weakly alkaline reflux in BE. To compare characteristics of reflux episodes patients with BE, erosive esophagitis (EE), and healthy volunteers (HV).

Dichotomy of food and inhalant allergen sensitization in eosinophilic esophagitis

Background: Eosinophilic esophagitis (EE) is an emerging condition where patients commonly present with symptoms of gastroesophageal reflux disease and fail to respond adequately to anti-reflux therapy. Food allergy is currently recognized as the main immunological cause of EE; recent evidence suggests an etiological role for inhalant allergens. The presence of EE appears to be associated with other atopic illnesses. Objectives: To report the sensitization profile of both food and inhalant allergens in our EE patient cohort in relation to age, and to profile the prevalence of other allergic conditions in patients with EE. Method: The study prospectively analyzed allergen sensitization profiles using skin prick tests to common food allergens and inhalant allergens in 45 children with EE. Patch testing to common food allergens was performed on 33 patients in the same cohort. Comorbidity of atopic eczema, asthma, allergic rhinitis and anaphylaxis were obtained from patient history. Results: Younger patients with EE showed more IgE and patch sensitization to foods while older patients showed greater IgE sensitization to inhalant allergens. The prevalence of atopic eczema, allergic rhinitis and asthma was significantly increased in our EE cohort compared with the general Australian population. A total of 24% of our cohort of patients with EE had a history of anaphylaxis. Conclusion: In children with EE, the sensitization to inhalant allergens increases with age, particularly after 4 years. Also, specific enquiry about severe food reactions in patients presenting with EE is strongly recommended as it appears this patient group has a high incidence of anaphylaxis. © 2007 The Authors.

The pathophysiology of eosinophilic esophagitis: Altered mechanisms of antigen detection in the esophagus

Recently, a chronic idiopathic disease of the esophagus has emerged, which is now known as eosinophilic esophagitis (EoE). Incomplete knowledge regarding the pathogenesis of EoE has limited treatment options. EoE is known to be a Th2-type immune-mediated disorder. Based on previous studies in both patients and experimental models, it is possible that an abnormal reaction to antigen mediates the pathophysiology of EoE. In this thesis, symptoms and signs unique to EoE were identified by an age-matched, case-controlled study of 326 patients with EoE and gastroesophageal reflux disease. The molecular mechanisms involved in antigen detection in the esophagus, in relation to EoE were then investigated. Esophageal epithelial cells were found, for the first time, to be capable of acting as non-professional antigen presenting cells, with the ability to engulf, process and present antigen on MHC class II to T helper lymphocytes. Antigen presentation by esophageal epithelial cells was induced by interferon-γ, which is increased in biopsies from patients with EoE. Next, it was discovered that esophageal epithelial cell lines expressed functional toll-like receptor (TLR) 2 and TLR3, but in esophageal mucosal biopsies only infiltrating immune cells (including eosinophils) expressed TLR2 and TLR3. Finally, the potential involvement of IgE in the pathogenesis of esophageal inflammation was investigated. IgE in the esophagus was found to be present on mast cells, which are increased in density in the esophageal mucosae of patients with EoE and especially those with a history of atopy. Mechanisms of antigen detection may mediate the pathophysiology of EoE in the esophagus through antigen presentation by epithelial cells, detection by TLRs on immune cells and detection through IgE on mucosal mast cells. Together, these findings demonstrate that mechanisms of antigen detection may actually contribute to the pathophysiology of EoE. Through increased understanding of the mechanisms of EoE, the results of this thesis may contribute to future therapy.

Brazilian consensus on gastroesophageal reflux disease: Proposals for assessment, classification, and management

The Brazilian Consensus on Gastroesophageal Reflux Disease considers gastroesophageal reflux disease to be a chronic disorder related to the retrograde flow of gastroduodenal contents into the esophagus and/or adjacent organs, resulting in a variable spectrum of symptoms, with or without tissue damage. Considering the limitations of classifications currently in use, a new classification is proposed that combines three criteria - clinical, endoscopic, and pH-metric - providing a comprehensive and more complete characterization of the disease. The diagnosis begins with the presence of heartburn, acid regurgitation, and alarm manifestations (dysphagia, odynophagia, weight loss, GI bleeding, nausea and/or vomiting, and family history of cancer). Also, atypical esophageal, pulmonary, otorhinolaryngological, and oral symptoms may occur. Endoscopy is the first approach, particularly in patients over 40 yr of age and in those with alarm symptoms. Other exams are considered in particular cases, such as contrast radiological examination, scyntigraphy, manometry, and prolonged pH measurement. The clinical treatment encompasses behavioral modifications in lifestyle and pharmacological measures. Proton pump inhibitors in manufacturers' recommended doses are indicated, with doubling of the dose in more severe cases of esophagitis. The minimum time of administration is 6 wk. Patients who do not respond to medical treatment, including those with atypical manifestations, should be considered for surgical treatment. Of the complications of gastroesophageal reflux disease, Barrett's esophagus presents a potential development of adenocarcinoma; biopsies should be performed, independent of Barrett's esophagus extent or location. In this regard the designation short Barrett's is not important in terms of management and prognosis. © 2002 by Am. Coll. of Gastroenterology.

Severe distal cytomegalovirus esophagitis with aerodigestive symptoms in an immunocompetent infant

We report a case of an immunocompetent infant, with no evidence of neurological disorders, which developed clinical manifestation of recurrent crisis of choking, dysphagia, laryngeal stridor and sub costal retractions since the first day of life. Direct laryngoscopy was unremarkable. Upper gastrointestinal series showed a dilated tortuous esophagus with severe peristalsis impairment and reflux episodes till the proximal third of the esophagus. An upper gastrointestinal endoscopy showed a moderately dilated esophagus with erosive lesions in the distal esophagus. Esophageal biopsy specimens revealed CMV inclusion bodies associated to moderate inflammation and immunohistochemistry was positive for CMV early antigen. Prolonged 24 h esophageal pH metry was within normal limits. Antiviral therapy with intravenous ganciclovir was introduced and was associated with rapid improvement of the symptoms. Child gradually increased oral intake and weight gain, and there were no side effects related to therapy. Thus, the respiratory symptoms could have been a supra esophageal manifestation of a non-acid reflux disease related to the CMV esophagitis.

Pediatric and adult eosinophilic esophagitis: similarities and differences

Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil-predominant infiltration, thereby conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis (EoE) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that EoE represents a T-helper (Th)2-type inflammatory disease. Remodeling of the esophagus is a hallmark of EoE, leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single-nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the EoE population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, EoE seems to be primarily a food antigen-driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for EoE include the 3Ds: drugs, diet, and dilation. The crucial question of whether adult and pediatric EoE are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between EoE in adults and children.

Immunopathogenesis of eosinophilic esophagitis

Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with dysphagia in adults and refractory reflux syndromes in children. Methods: Immunological and genetic approaches have been used to better understand the pathophysiology of the underlying inflammation. Results and Conclusions: Evidence has accumulated that EoE represents a T-helper (Th) 2-type inflammatory disease, in which allergens play a role in triggering the disease. The majority of the patients suffer from concurrent allergic rhinitis, asthma, and eczema, and have a history of atopy. The chronic inflammatory response in EoE is associated with tissue damage and remodeling, both of which lead to esophageal dysfunction and bolus impaction. The new insights into the pathophysiology have resulted in the development of the first pharmacological therapies of EoE.

Prevalence of gastro esophageal reflux disease following the Montreal Consensus and its association with Helicobacter pylori infection and obesity in a random sample of adults of Ciudad Juarez, Mexico, 2004.

Gastroesophageal reflux disease is a common condition affecting 25 to 40% of the population and causes significant morbidity in the U.S., accounting for at least 9 million office visits to physicians with estimated annual costs of $10 billion. Previous research has not clearly established whether infection with Helicobacter pylori, a known cause of peptic ulcer, atrophic gastritis and non cardia adenocarcinoma of the stomach, is associated with gastroesophageal reflux disease. This study is a secondary analysis of data collected in a cross-sectional study of a random sample of adult residents of Ciudad Juarez, Mexico, that was conducted in 2004 (Prevalence and Determinants of Chronic Atrophic Gastritis Study or CAG study, Dr. Victor M. Cardenas, Principal Investigator). In this study, the presence of gastroesophageal reflux disease was based on responses to the previously validated Spanish Language Dyspepsia Questionnaire. Responses to this questionnaire indicating the presence of gastroesophageal reflux symptoms and disease were compared with the presence of H. pylori infection as measured by culture, histology and rapid urease test, and with findings of upper endoscopy (i.e., hiatus hernia and erosive and atrophic esophagitis). The prevalence ratio was calculated using bivariate, stratified and multivariate negative binomial logistic regression analyses in order to assess the relation between active H. pylori infection and the prevalence of gastroesophageal reflux typical syndrome and disease, while controlling for known risk factors of gastroesophageal reflux disease such as obesity. In a random sample of 174 adults 48 (27.6%) of the study participants had typical reflux syndrome and only 5% (or 9/174) had gastroesophageal reflux disease per se according to the Montreal consensus, which defines reflux syndromes and disease based on whether the symptoms are perceived as troublesome by the subject. There was no association between H. pylori infection and typical reflux syndrome or gastroesophageal reflux disease. However, we found that in this Northern Mexican population, there was a moderate association (Prevalence Ratio=2.5; 95% CI=1.3, 4.7) between obesity (≥30 kg/m2) and typical reflux syndrome. Management and prevention of obesity will significantly curb the growing numbers of persons affected by gastroesophageal reflux symptoms and disease in Northern Mexico. ^