RESUMEN
Gastroesophageal reflux disease (GERD) is a condition that occurs when reflux of gastric contents into the esophagus causes symptoms and/or complications. The prevalence of GERD in Western societies has been estimated at 30%, making it one of the most commonly encountered disorders in primary care. The spectrum of GERD includes typical symptoms of esophageal reflux (heartburn and/or regurgitation); esophageal injury (erosive esophagitis; stricture; Barrett esophagus; and, rarely, adenocarcinoma); and extraesophageal symptoms, such as hoarseness and chronic cough. Proper diagnosis and treatment of GERD includes symptom control, exclusion of other disorders, avoiding overuse of medications and invasive testing, and minimizing complications.
Asunto(s)
Reflujo Gastroesofágico , Humanos , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/complicaciones , Inhibidores de la Bomba de Protones/uso terapéutico , Esófago de Barrett/diagnóstico , Esófago de Barrett/complicaciones , Factores de RiesgoRESUMEN
INTRODUCTION: Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett's cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett's oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids. METHODS: 15 BO patients had endoscopy with biopsies of Barrett's metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1α was knocked down with siRNA or shRNA. RESULTS: At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1α, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1α activation, which decreased miR-200a&b while increasing VEGF, ZEB1 and motility; HIF-1α knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1α, increased VEGF and decreased miR-200a&b. CONCLUSIONS: In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1α signalling in Barrett's metaplasia. In Barrett's cells, ABS trigger EMP via HIF-1α signalling. Thus, HIF-1α appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO. TRIAL REGISTRATION NUMBER: NCT02579460.
Asunto(s)
Esófago de Barrett , Transición Epitelial-Mesenquimal , Subunidad alfa del Factor 1 Inducible por Hipoxia , Inhibidores de la Bomba de Protones , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esófago de Barrett/patología , Esófago de Barrett/metabolismo , Esófago de Barrett/genética , Movimiento Celular , Esofagitis Péptica/patología , Esofagitis Péptica/metabolismo , Esofagitis Péptica/etiología , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genéticaRESUMEN
BACKGROUND & AIMS: Brain-gut behavior therapies (BGBT) are increasingly recognized as effective therapeutic interventions for functional heartburn. However, recommendations regarding candidacy for treatment, initial treatment selection, and navigating treatment non-response have not been established for functional heartburn specifically. The aim of this study was to establish expert-based recommendations for behavioral treatment in patients with functional heartburn. METHODS: The validated RAND/University of California, Los Angeles Appropriateness Method was applied to develop recommendations. A 15-member panel composed of 10 gastrointestinal psychologists and 5 esophageal specialists ranked the appropriateness of a series of statements on a 9-point interval scale over 2 ranking periods. Statements were within the following domains: pre-therapy evaluation, candidacy criteria for BGBT, selection of initial BGBT, role of additional therapy for initial non-response to BGBT, and role of pharmacologic neuromodulation. The primary outcome was appropriateness of each intervention based on the recommendation statements. RESULTS: Recommendations for psychosocial assessment (eg, hypervigilance, symptom-specific anxiety, health-related quality of life), candidacy criteria (eg, motivated for BGBT, acknowledges the role of stress in symptoms), and treatment were established. Gut-directed hypnotherapy or cognitive behavioral therapy were considered appropriate BGBT for functional heartburn. Neuromodulation and/or additional BGBT were considered appropriate in the context of non-response. CONCLUSIONS: Gut-directed hypnotherapy and/or cognitive behavioral therapy are recommended as appropriate behavioral interventions for heartburn symptoms, depending on clinical indication, specific gut-brain targets, and preferred treatment modality (pharmacologic vs non-pharmacologic). Pre-therapy evaluation of psychosocial processes and candidacy for BGBT are important to determine eligibility for referral to psychogastroenterology services.
Asunto(s)
Terapia Conductista , Pirosis , Humanos , Terapia Conductista/métodos , Pirosis/terapiaRESUMEN
The pathogenesis of subsquamous intestinal metaplasia (SSIM), in which glands of Barrett's esophagus (BE) are buried under esophageal squamous epithelium, is unknown. In a rat model of reflux esophagitis, we found that columnar-lined esophagus developed via a wound-healing process involving epithelial-mesenchymal plasticity (EMP) that buried glands under ulcerated squamous epithelium. To explore a role for reflux-induced EMP in BE, we established and characterized human Barrett's organoids and sought evidence of EMP after treatment with acidic bile salts (AB). We optimized media to grow human BE organoids from immortalized human Barrett's cells and from BE biopsies from seven patients, and we characterized histological, morphological, and molecular features of organoid development. Features and markers of EMP were explored following organoid exposure to AB, with and without a collagen I (COL1) matrix to simulate a wound-healing environment. All media successfully initiated organoid growth, but advanced DMEM/F12 (aDMEM) was best at sustaining organoid viability. Using aDMEM, organoids comprising nongoblet and goblet columnar cells that expressed gastric and intestinal cell markers were generated from BE biopsies of all seven patients. After AB treatment, early-stage Barrett's organoids exhibited EMP with loss of membranous E-cadherin and increased protrusive cell migration, events significantly enhanced by COL1. Using human BE biopsies, we have established Barrett's organoids that recapitulate key histological and molecular features of BE to serve as high-fidelity BE models. Our findings suggest that reflux can induce EMP in human BE, potentially enabling Barrett's cells to migrate under adjacent squamous epithelium to form SSIM.NEW & NOTEWORTHY Using Barrett's esophagus (BE) biopsies, we established organoids recapitulating key BE features. During early stages of organoid development, a GERD-like wound environment-induced features of epithelial-mesenchymal plasticity (EMP) in Barrett's progenitor cells, suggesting that reflux-induced EMP can enable Barrett's cells to migrate underneath squamous epithelium to form subsquamous intestinal metaplasia, a condition that may underlie Barrett's cancers that escape detection by endoscopic surveillance, and recurrences of Barrett's metaplasia following endoscopic eradication therapy.
Asunto(s)
Esófago de Barrett , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Esofagitis Péptica , Reflujo Gastroesofágico , Animales , Esófago de Barrett/patología , Ácidos y Sales Biliares/farmacología , Carcinoma de Células Escamosas/complicaciones , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/patología , Reflujo Gastroesofágico/complicaciones , Humanos , Metaplasia , Organoides/patología , RatasRESUMEN
BACKGROUND: Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine). METHODS: Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)-Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year. RESULTS: A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P = 0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, -5 to 38; P = 0.17). CONCLUSIONS: Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.).
Asunto(s)
Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/cirugía , Pirosis/tratamiento farmacológico , Omeprazol/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Adulto , Baclofeno/uso terapéutico , Desipramina/uso terapéutico , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Fundoplicación , Reflujo Gastroesofágico/complicaciones , Pirosis/etiología , Pirosis/cirugía , Humanos , Masculino , Persona de Mediana Edad , Relajantes Musculares Centrales/uso terapéutico , Calidad de Vida , Encuestas y Cuestionarios , VeteranosRESUMEN
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.
Asunto(s)
Manejo de la Enfermedad , Endoscopía del Sistema Digestivo/métodos , Reflujo Gastroesofágico/diagnóstico , Inhibidores de la Bomba de Protones/uso terapéutico , Reflujo Gastroesofágico/terapia , HumanosRESUMEN
INTRODUCTION: Radiofrequency ablation (RFA) of Barrett's esophagus (BE) inflicts a wound spanning 3 epithelial types (stratified squamous, Barrett's metaplasia, gastric epithelium), yet the esophageal injury heals almost completely with squamous epithelium. Knowledge of how this unique wound heals might elucidate mechanisms underlying esophageal metaplasia. We aimed to prospectively and systematically characterize the early endoscopic and histologic features of RFA wound healing. METHODS: Patients with nondysplastic BE had endoscopy with systematic esophageal photographic mapping, biopsy, and volumetric laser endomicroscopy performed before and at 1, 2, and 4 weeks after RFA. RESULTS: Seven patients (6 men; mean age 56.1 ± 10.9 years) completed this study. Squamous re-epithelialization of RFA wounds did not only progress exclusively through squamous cells extending from the proximal wound edge but also progressed through islands of squamous epithelium sprouting throughout the ablated segment. Volumetric laser endomicroscopy revealed significant post-RFA increases in subepithelial glandular structures associated with the squamous islands. In 2 patients, biopsies of such islands revealed newly forming squamous epithelium contiguous with immature-appearing squamous cells arising from esophageal submucosal gland ducts. Subsquamous intestinal metaplasia (SSIM) was found in biopsies at 2 and/or 4 weeks after RFA in 6 of 7 patients. DISCUSSION: RFA wounds in BE are re-epithelialized, not just by squamous cells from the proximal wound margin but by scattered squamous islands in which esophageal submucosal gland duct cells seem to redifferentiate into the squamous progenitors that fuel squamous re-epithelialization. SSIM can be found in most patients during the healing process. We speculate that this SSIM might underlie Barrett's recurrences after apparently successful eradication.
Asunto(s)
Esófago de Barrett , Carcinoma de Células Escamosas , Ablación por Catéter , Neoplasias Esofágicas , Anciano , Esófago de Barrett/patología , Carcinoma de Células Escamosas/cirugía , Neoplasias Esofágicas/patología , Esofagoscopía , Humanos , Masculino , Metaplasia/complicaciones , Persona de Mediana Edad , Cicatrización de HeridasRESUMEN
BACKGROUND AND AIMS: After EMR, prophylactic clipping is often performed to prevent clinically significant post-EMR bleeding (CSPEB) and other adverse events (AEs). Prior evidence syntheses have lacked sufficient power to assess clipping in relevant subgroups or in nonbleeding AEs. We performed a meta-analysis of individual patient data (IPD) from randomized trials assessing the efficacy of clipping to prevent AEs after EMR of proximal large nonpedunculated colorectal polyps (LNPCPs) ≥20 mm. METHODS: We searched EMBASE, MEDLINE, Cochrane Central Registry of Controlled Trials, and PubMed from inception to May 19, 2021. Two reviewers screened citations in duplicate. Corresponding authors of eligible studies were invited to contribute IPD. A random-effects 1-stage model was specified for estimating pooled effects, adjusting for patient sex and age and for lesion location and size, whereas a fixed-effects model was used for traditional meta-analyses. RESULTS: From 3145 citations, 4 trials were included, representing 1248 patients with proximal LNPCPs. The overall rate of CSPEB was 3.5% and 9.0% in clipped and unclipped patients, respectively. IPD were available for 1150 patients, in which prophylactic clipping prevented CSPEB with an odds ratio (OR) of .31 (95% confidence interval [CI], .17-.54). Clipping was not associated with perforation or abdominal pain, with ORs of .78 (95% CI, .17-3.54) and .67 (95% CI, .20-2.22), respectively. CONCLUSIONS: Prophylactic clipping is efficacious in preventing CSPEB after EMR of proximal LNPCPs. Therefore, clip closure should be considered a standard component of EMR of LNPCPs in the proximal colon.
Asunto(s)
Pólipos del Colon , Resección Endoscópica de la Mucosa , Humanos , Pólipos del Colon/patología , Resección Endoscópica de la Mucosa/efectos adversos , Hemorragia Gastrointestinal/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Instrumentos QuirúrgicosRESUMEN
BACKGROUND: Optimal timing for anticoagulation resumption after polypectomy is unclear. We explored the association between timing of anticoagulation resumption and occurrence of delayed post-polypectomy bleeding (PPB) and thromboembolic (TE) events. METHODS: We performed a post-hoc analysis of patients in an earlier study whose anticoagulants were interrupted for polypectomy. We compared rates of clinically important delayed PPB and TE events in relationship to timing of anticoagulant resumption. Late resumption was defined as > 2 days after polypectomy. RESULTS: Among 437 patients, 351 had early and 86 late resumption. Compared to early resumers, late resumers had greater polypectomy complexity. PPB rate was higher (but not significantly) in the late versus early resumers (2.3% vs. 0.9%, 1.47% greater, 95% CI [- 2.58 to 5.52], p = 0.26). TE events were more frequent in late versus early resumers [0% vs. 1.2% at 30 days, 0% vs. 2.3%, 95% CI 0.3-8, (p = 0.04) at 90 days]. On multivariate analysis, timing of restarting anticoagulation was not a significant predictor of PPB (OR 0.97, 95% CI 0.61-1.44, p = 0.897). Significant predictors were number of polyps ≥ 1 cm (OR 4.14, 95% CI 1.27-13.66, p = 0.014) and use of fulguration (OR 11.43, 95% CI 1.35-80.80, p = 0.014). CONCLUSIONS: Physicians delayed anticoagulation resumption more commonly after complex polypectomies. The timing of restarting anticoagulation was not a significant risk factor for PPB and late resumers had significantly higher rates of TE events within 90 days. Considering the potentially catastrophic consequences of TE events and the generally benign outcome of PPBs, clinicians should be cautious about delaying resumption of anticoagulation after polypectomy.
Asunto(s)
Pólipos del Colon , Tromboembolia , Anticoagulantes/efectos adversos , Pólipos del Colon/cirugía , Colonoscopía/efectos adversos , Hemorragia , Humanos , Estudios Retrospectivos , Tromboembolia/epidemiología , Tromboembolia/etiología , Tromboembolia/prevención & controlRESUMEN
The frequency of esophageal adenocarcinoma is rising despite widespread use of proton pump inhibitors (PPIs), which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett's esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett's cells. Because p53 is inactivated frequently in Barrett's esophagus and p38 can assume p53 functions, we explored p38's role in DNA damage response and repair. We exposed Barrett's cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38 dependent. We also measured phospho-p38 in biopsies of Barrett's metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced bromodeoxyuridine incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease I (Ref-1/APE1). Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All of these effects were observed in p53-intact and p53-deficient Barrett's cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett's metaplasia. WABM exposure generates ROS, causing oxidative DNA damage in Barrett's cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett's esophagus.NEW & NOTEWORTHY We found that weakly acidic bile salt solutions, with compositions similar to the refluxed gastric juice of gastroesophageal reflux disease patients on proton pump inhibitors, cause oxidative DNA damage in Barrett's metaplasia that could contribute to the development of esophageal adenocarcinoma. We also have elucidated a critical role for p38 in Barrett's metaplasia in its response to and repair of oxidative DNA damage, suggesting a potential chemopreventive role for agents like ursodeoxycholic acid that increase p38 activity in Barrett's esophagus.
Asunto(s)
Esófago de Barrett/enzimología , Daño del ADN , Reparación del ADN , Ácido Desoxicólico/toxicidad , Células Epiteliales/efectos de los fármacos , Mucosa Esofágica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Esófago de Barrett/genética , Esófago de Barrett/patología , Línea Celular Transformada , Proliferación Celular/efectos de los fármacos , Células Epiteliales/enzimología , Células Epiteliales/patología , Mucosa Esofágica/enzimología , Mucosa Esofágica/patología , Femenino , Histonas/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Masculino , Fosforilación , Cultivo Primario de Células , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ácido Ursodesoxicólico/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
BACKGROUND & AIMS: The efficacy of prophylactic placement of hemoclips to prevent delayed bleeding after removal of large colonic polyps has not been established. We conducted a randomized equivalence study to determine whether prophylactic placement of hemoclips affects incidence of delayed post-polypectomy bleeding (PPB). METHODS: During elective colonoscopy performed at 4 Veterans Affairs Medical Centers, 1098 patients who had polyps ≥1 cm removed were randomly assigned to groups that received prophylactic hemoclips (n = 547) or no hemoclips (n = 551), from September 2011 through September 2018. Data on PPB (rectal bleeding resulting in hemoglobin decreases ≥2 g/dL, hemodynamic instability, colonoscopy, angiography, or surgery) within 30 days of colonoscopy (called delayed PPB) were collected during telephone interviews or hospital visits 7 and 30 days after colonoscopy. The primary outcome was the incidence of important post-polypectomy bleeding. RESULTS: Twelve patients in the hemoclip group (2.3%) and 15 patients in the no hemoclip group (2.9%) had important delayed PPB. There were no deaths, and no patients in either group required angiography or surgery. In intention-to-treat analysis, two 1-sided test's lower and upper confidence interval limits were -2.07 and 1.01, indicating that the data approached but did not meet equivalence criteria. On multiple logistic regression analysis, significant predictors of PPB included use of warfarin with bridging, thienopyridines, polyp size, and polyp location, but hemoclip placement did not associate with important delayed PPB. CONCLUSIONS: In a randomized trial, we found that prophylactic placement of hemoclips after removal of large colon polyps does not affect the proportion of important delayed PPB events, compared with no hemoclip placement. These findings call into question the widespread, expensive practice of routinely placing prophylactic hemoclips after polypectomy. ClinicalTrials.gov ID: NCT01647581.
Asunto(s)
Colectomía/efectos adversos , Pólipos del Colon/cirugía , Colonoscopía/efectos adversos , Técnicas Hemostáticas/instrumentación , Hemorragia Posoperatoria/prevención & control , Instrumentos Quirúrgicos , Colectomía/métodos , Pólipos del Colon/patología , Diseño de Equipo , Femenino , Técnicas Hemostáticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Hemorragia Posoperatoria/etiología , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , United States Department of Veterans AffairsRESUMEN
BACKGROUND: The Los Angeles (LA) grade of reflux esophagitis (A to D) is assumed to reflect severity of the underlying gastroesophageal reflux disease (GERD). Thus, LA-D esophagitis patients might be expected to have the most conditions predisposing to GERD (eg, obesity, hiatal hernia), and the highest frequency of GERD symptoms. GOALS: The main goal of this study is to compare clinical features of patients with the most severe (LA-D) and mildest (LA-A) grades of esophagitis. STUDY: For this comparative study, we searched our endoscopy database for patients diagnosed with LA-D or LA-A esophagitis, reviewed their endoscopic images, and reviewed medical records of the first 100 we confirmed to have LA-D or LA-A esophagitis. RESULTS: Compared with LA-A patients, LA-D patients were older (mean age, 65±13.4 vs. 56±13.4 y; P<0.001), had lower body mass index (25.9±5.6 vs. 29.4±5.3; P<0.001), were more frequently hospitalized (70% vs. 3%; P<0.001), and in the intensive care unit (15% vs. 0%; P<0.001), and had significantly more serious cardiopulmonary disorders and gastrointestinal bleeding. Conversely, a GERD history was more common in LA-A than LA-D patients (67% vs. 45%; P=0.002). Hiatal hernia was more frequent in LA-A patients than LA-D patients, but not significantly (48% vs. 36%; P=0.09). CONCLUSIONS: LA-D esophagitis primarily affects hospitalized, older, nonobese patients who often have serious comorbidities, and no history of GERD or hiatal hernia. In contrast, LA-A patients are generally younger, obese outpatients who often have a history of GERD and hiatal hernia without serious comorbidities. These profound differences between LA-A and LA-D patients suggest that factors other than typical GERD contribute to LA-D esophagitis pathogenesis.
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Esofagitis Péptica/fisiopatología , Reflujo Gastroesofágico/fisiopatología , Hernia Hiatal/complicaciones , Obesidad/complicaciones , Adulto , Anciano , Índice de Masa Corporal , Endoscopía/métodos , Esofagitis Péptica/etiología , Femenino , Reflujo Gastroesofágico/complicaciones , Hernia Hiatal/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. DESIGN: We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression. RESULTS: In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. CONCLUSIONS: Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Esófago de Barrett , Ácidos y Sales Biliares/metabolismo , Factor de Transcripción CDX2/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , FN-kappa B/efectos de los fármacos , Factor de Transcripción CDX2/metabolismo , Células Epiteliales/metabolismo , Humanos , FN-kappa B/metabolismoRESUMEN
OBJECTIVE: In an earlier study wherein we induced acute reflux by interrupting proton pump inhibitor (PPI) therapy in patients with reflux oesophagitis (RO) healed by PPIs, we refuted the traditional concept that RO develops as an acid burn. The present study explored our alternative hypothesis that RO results from reflux-stimulated production of pro-inflammatory molecules mediated by hypoxia-inducible factors (HIFs). DESIGN: Using oesophageal biopsies taken from patients in our earlier study at baseline and at 1 and 2â weeks off PPIs, we immunostained for HIF-1α, HIF-2α and phospho-p65, and measured pro-inflammatory molecule mRNAs. We exposed human oesophageal squamous cell lines to acidic bile salts, and evaluated effects on HIF activation, p65 function, pro-inflammatory molecule production and immune cell migration. RESULTS: In patient biopsies, increased immunostaining for HIF-2α and phospho-p65, and increased pro-inflammatory molecule mRNA levels were seen when RO redeveloped 1 or 2â weeks after stopping PPIs. In oesophageal cells, exposure to acidic bile salts increased intracellular reactive oxygen species, which decreased prolyl hydroxylase function and stabilised HIF-2α, causing a p65-dependent increase in pro-inflammatory molecules; conditioned media from these cells increased T cell migration rates. HIF-2α inhibition by small hairpin RNA or selective small molecule antagonist blocked the increases in pro-inflammatory molecule expression and T cell migration induced by acidic bile salts. CONCLUSIONS: In patients developing RO, increases in oesophageal HIF-2α correlate with increased pro-inflammatory molecule expression. In oesophageal epithelial cells, acidic bile salts stabilise HIF-2α, which mediates expression of pro-inflammatory molecules. HIF-2α appears to have a role in RO pathogenesis. TRIAL REGISTRATION NUMBER: NCT01733810; Results.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Epiteliales/metabolismo , Esofagitis Péptica/metabolismo , Reflujo Gastroesofágico/metabolismo , Hipoxia/metabolismo , Línea Celular , Movimiento Celular/fisiología , Esofagitis Péptica/etiología , Esofagitis Péptica/patología , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/patología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Estadística como AsuntoRESUMEN
BACKGROUND & AIMS: Quality esophageal high-resolution manometry (HRM) studies require competent interpretation of data. However, there is little understanding of learning curves, training requirements, or measures of competency for HRM. We aimed to develop and use a competency assessment system to examine learning curves for interpretation of HRM data. METHODS: We conducted a prospective multicenter study of 20 gastroenterology trainees with no experience in HRM, from 8 centers, over an 8-month period (May through December 2015). We designed a web-based HRM training and competency assessment system. After reviewing the training module, participants interpreted 50 HRM studies and received answer keys at the fifth and then at every second interpretation. A cumulative sum procedure produced individual learning curves with preset acceptable failure rates of 10%; we classified competency status as competency not achieved, competency achieved, or competency likely achieved. RESULTS: Five (25%) participants achieved competence, 4 (20%) likely achieved competence, and 11 (55%) failed to achieve competence. A minimum case volume to achieve competency was not identified. There was no significant agreement between diagnostic accuracy and accuracy for individual HRM skills. CONCLUSIONS: We developed a competency assessment system for HRM interpretation; using this system, we found significant variation in learning curves for HRM diagnosis and individual skills. Our system effectively distinguished trainee competency levels for HRM interpretation and contrary to current recommendations, found that competency for HRM is not case-volume specific.
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Competencia Clínica , Gastroenterología/educación , Reflujo Gastroesofágico/diagnóstico , Personal de Salud , Curva de Aprendizaje , Manometría/métodos , Adulto , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
PURPOSE OF REVIEW: Lymphocytic esophagitis (LE) is an unusual esophageal condition defined by an increased number of lymphocytes in the esophageal epithelium. With few published studies of LE available, it is unclear whether LE is a truly distinct clinical entity or a histological manifestation of other known gastrointestinal disorders. This review summarizes recent studies of lymphocytic esophagitis. RECENT FINDINGS: Studies have suggested that LE may be related to eosinophilic esophagitis (EoE) or a manifestation of gastroesophageal reflux disease (GERD). There is an association between LE and Crohn's disease in children, but not in adults. Patients with LE frequently report symptoms of dysphagia and GERD. Treatment options for LE are limited and involve symptom management similar to treatment of EoE or GERD, including proton pump inhibitors (PPI), swallowed topical steroids, and endoscopic dilation. With no formal definition and a variety of clinical presentations and endoscopic findings, diagnosis and management of symptomatic LE patients is challenging for clinicians.
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Esofagitis , Linfocitosis , Factores de Edad , Enfermedad de Crohn/complicaciones , Trastornos de Deglución/etiología , Dilatación , Esofagitis Eosinofílica/patología , Esofagitis/etiología , Esofagitis/patología , Reflujo Gastroesofágico/complicaciones , Humanos , Linfocitosis/etiología , Linfocitosis/patología , Linfocitosis/terapia , Inhibidores de la Bomba de Protones/uso terapéuticoRESUMEN
OBJECTIVE: Barrett's metaplasia might develop if GORD causes oesophageal squamous cells to convert into columnar cells. Acid and bile exposures upregulate columnar differentiation genes like CDX2 in oesophageal squamous cells, but it is not known if such exposures downregulate squamous differentiation genes like SOX2. In addition to acid and bile, patients with GORD also have high oesophageal concentrations of nitric oxide (NO). This study aims to determine how acid, bile salts and NO affect genes that influence oesophageal cell phenotype. DESIGN: Oesophageal squamous cells from patients with Barrett's oesophagus were exposed to acidic bile salts or NOC-9 (an NO donor). SOX2, p63 (squamous transcription factor) and CDX2 mRNAs were measured by quantitative RT-PCR. SOX2 and its regulatory Akt pathway proteins were evaluated by western blotting. S-nitrosylation by NO was blocked by dithiothreitol. Immunohistochemistry for SOX2 was performed on the oesophagus of rats with surgically induced GORD which were fed diets with and without nitrite supplementation. RESULTS: In oesophageal squamous cells, NO profoundly decreased SOX2 protein and caused a significantly greater decrease in SOX2 mRNA than did acidic bile salts. NO also decreased p63 and increased CDX2 expression. NO caused S-nitrosylation of Akt, blocking its phosphorylation. Akt pathway inhibition by LY294002 or Akt siRNA reduced SOX2 mRNA. Rats fed with nitrite-supplemented diets exhibited weaker SOX2 oesophageal staining than rats fed with normal diets. CONCLUSIONS: In oesophageal squamous cells, NO blocks SOX2 expression through Akt S-nitrosylation. NO also increases CDX2 and decreases p63 expression. By triggering molecular events preventing squamous differentiation while promoting intestinal differentiation, NO might contribute to Barrett's pathogenesis.
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Esófago de Barrett , Factor de Transcripción CDX2/metabolismo , Células Epiteliales , Reflujo Gastroesofágico , Óxido Nítrico/metabolismo , Factores de Transcripción SOXB1/metabolismo , Triazenos/metabolismo , Animales , Esófago de Barrett/etiología , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Ácidos y Sales Biliares/metabolismo , Diferenciación Celular , Línea Celular , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Esófago/patología , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/patología , Humanos , Masculino , ARN Mensajero/metabolismo , Ratas , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND & AIMS: Esophageal manometry is the standard for the diagnosis of esophageal motility disorders. Variations in the performance and interpretation of esophageal manometry result in discrepant diagnoses and unnecessary repeated procedures, and could have negative effects on patient outcomes. We need a method to benchmark the procedural quality of esophageal manometry; as such, our objective was to formally develop quality measures for the performance and interpretation of data from esophageal manometry. METHODS: We used the RAND University of California Los Angeles Appropriateness Method (RAM) to develop validated quality measures for performing and interpreting esophageal manometry. The research team identified potential quality measures through a literature search and interviews with experts. Fourteen experts in esophageal manometry ranked the proposed quality measures for appropriateness via a 2-round process on the basis of RAM. RESULTS: The experts considered a total of 29 measures; 17 were ranked as appropriate and were as follows: related to competency (2), assessment before the esophageal manometry procedure (2), the esophageal manometry procedure itself (3), and interpretation of data (10). The data interpretation measures were integrated into a single composite measure. Eight measures therefore were found to be appropriate quality measures for esophageal manometry . Five other factors also were endorsed by the experts, although these were not ranked as appropriate quality measures. CONCLUSIONS: We identified 8 formally validated quality measures for the performance and interpretation of data from esophageal manometry on the basis of RAM. These measures represent key aspects of a high-quality esophageal manometry study and should be adopted uniformly. These measures should be evaluated in clinical practice to determine how they affect patient outcomes.
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Trastornos de la Motilidad Esofágica/diagnóstico , Manometría/métodos , Manometría/normas , Calidad de la Atención de Salud , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Gastric intestinal metaplasia (GIM) is an accepted pathologic precursor to gastric adenocarcinoma (GAC). While surveillance of GIM in Europe and Asia is common, only limited recommendations related to endoscopic surveillance of GIM exist in the United States. AIM: To understand the clinical practice patterns of US gastroenterologists in the management and endoscopic surveillance of GIM. METHODS: A 23 item survey was developed to explore endoscopists' opinions regarding the surveillance of GIM and knowledge of current guidelines. Eight clinical vignettes were developed to address specific clinical scenarios where endoscopic surveillance of GIM might be considered. RESULTS: There were 227 respondents, with 60 % working primarily in the private sector and 40 % in academic medicine. While 68 % of the respondents refer to major society guidelines for guidance in patient management, almost 78 % of endoscopist responders believe that there are no specific US guidelines pertaining to surveillance of GIM. Only two-thirds of respondents believe that based on current data, patients at increased risk of GAC should be a part of an endoscopic surveillance program, while 15 % believe all patients with GIM should receive endoscopic surveillance. Respondents use a wide range of biopsy techniques and surveillance intervals for patients with GIM, with no consistent pattern of practice identified. CONCLUSIONS: There is variability in the knowledge and practice patterns of US endoscopists related to surveillance of gastric intestinal metaplasia. In the absence of detailed US GI society guidelines, many endoscopists perform surveillance endoscopy on patients with GIM using variable biopsy techniques and surveillance intervals.