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Preliminary Communication |

Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes

Kerry B. Dunbar, MD, PhD1,2; Agoston T. Agoston, MD, PhD3; Robert D. Odze, MD3; Xiaofang Huo, MD, PhD1,2; Thai H. Pham, MD1,4; Daisha J. Cipher, PhD5; Donald O. Castell, MD6; Robert M. Genta, MD1,7,8; Rhonda F. Souza, MD1,2,9; Stuart J. Spechler, MD1,2,9
[+] Author Affiliations
1Esophageal Diseases Center, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas
2Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas
3Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
4Department of Surgery, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas
5College of Nursing and Health Innovation, University of Texas at Arlington, Arlington
6Department of Medicine, Medical University of South Carolina, Charleston
7Department of Pathology, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas
8Miraca Life Sciences, Irving, Texas
9Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas
JAMA. 2016;315(19):2104-2112. doi:10.1001/jama.2016.5657.
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Importance  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.

Design, Setting, and Participants  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.

Interventions  PPIs stopped for 2 weeks.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT01733810.

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Figure 1.
Study Design

LA indicates Los Angeles; GERD-HRQL, Gastroesophageal Reflux Disease Health-Related Quality of Life; PPI, proton pump inhibitor.

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Figure 2.
Flow of Patients Through the Study

LA indicates Los Angeles; GERD, gastroesophageal reflux disease.

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Figure 3.
Representative Images of the Distal Esophagus From a Single Patient at Baseline and at 1 Week and 2 Weeks After Discontinuation of PPI Therapy

LA indicates Los Angeles; PPI, proton pump inhibitor. At baseline, HD-WLE showed an irregular tongue of columnar mucosa (Barrett esophagus) in the 12 o’clock position, but no esophagitis. At day 9, HD-WLE showed long linear mucosal breaks (4 and 6 o’clock positions) extending up the esophagus from the gastroesophageal junction (LA grade B esophagitis). At day 16, HD-WLE showed long mucosal breaks continuous between the tops of mucosal folds (LA grade C esophagitis). CLE revealed fluorescein within bright intraepithelial capillaries (yellow arrowheads), with fluorescein that leaked from blood vessels into intercellular spaces surrounding individual cells, creating a reticular appearance characteristic of squamous epithelium. CLE measurements revealed widened intercellular spaces with increased intercellular fluorescein at days 9 and 16. In the photomicrographs at day 9 and 16, black arrowheads indicate some of the numerous intraepithelial lymphocytes. Note the prominent lymphocytosis, basal cell hyperplasia, and papillary elongation at 2 weeks after discontinuation of PPI therapy. All photomicrographs are H&E stains, original magnification ×20. All images were modified in Photoshop to remove patient identification data, and to enhance clarity. Any adjustments in contrast, color balance, brightness or sharpness were applied to the entire image.

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