title: Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes.
abstract: OBJECTIVE
  The histologic changes associated with acute gastroesophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid.
  
  
  OBJECTIVE
  To evaluate histologic features of esophageal inflammation in acute GERD to study its pathogenesis.
  
  
  METHODS
  Patients from the Dallas Veterans Affairs Medical Center who had reflux esophagitis successfully treated with proton pump inhibitors (PPIs) began 24-hour esophageal pH and impedance monitoring and esophagoscopy (including confocal laser endomicroscopy [CLE]) with biopsies from noneroded areas of distal esophagus at baseline (taking PPIs) and at 1 week and 2 weeks after stopping the PPI medication. Enrollment began May 2013 and follow-up ended July 2015.
  
  
  METHODS
  PPIs stopped for 2 weeks.
  
  
  METHODS
  Twelve patients (men, 11; mean age, 57.6 year [SD, 13.1]) completed the study. Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0-3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity).
  
  
  RESULTS
  At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0-2) at baseline vs 1 (1-2) at both 1 week [P = .005] and 2 weeks [P = .002]); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased (median: 1.2% at baseline to 17.8% at 2 weeks; Δ, 16.2% [95% CI, 4.4%-26.5%], P = .005), mucosal impedance decreased (mean: 2671.3 Ω at baseline to 1508.4 Ω at 2 weeks; Δ, 1162.9 Ω [95% CI, 629.9-1695.9], P = .001), and all patients had evidence of esophagitis.
  
  
  CONCLUSIONS
  In this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01733810.
authors.affiliation: Esophageal Diseases Center, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas2Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical C.
authors.forename: Kerry B
authors.initials: KB
authors.lastname: Dunbar
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Agoston T
authors.initials: AT
authors.lastname: Agoston
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Odze
authors.affiliation: Esophageal Diseases Center, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas2Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical C.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Huo
authors.affiliation: Esophageal Diseases Center, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas4Department of Surgery, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Ce.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Pham
authors.affiliation: College of Nursing and Health Innovation, University of Texas at Arlington, Arlington.
authors.forename: Daisha J
authors.initials: DJ
authors.lastname: Cipher
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston.
authors.forename: Donald O
authors.initials: DO
authors.lastname: Castell
authors.affiliation: Esophageal Diseases Center, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas7Department of Pathology, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Genta
authors.affiliation: Esophageal Diseases Center, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas2Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical C.
authors.forename: Rhonda F
authors.initials: RF
authors.lastname: Souza
authors.affiliation: Esophageal Diseases Center, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas2Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical C.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Spechler
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000627:therapeutic use; D001706:Biopsy; D004804:Eosinophils / Q000473:pathology; D004942:Esophagitis, Peptic / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D004947:Esophagus / Q000473:pathology*; D005260:Female; D005764:Gastroesophageal Reflux / Q000150:complications / Q000473:pathology*; D006801:Humans; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology; D009853:Omeprazole / Q000627:therapeutic use; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000627:therapeutic use; D028761:Withholding Treatment
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D000077402:Pantoprazole; D009853:Omeprazole