Association of acute gastroesophageal reflux disease with esophageal histologic changes

Kerry B. Dunbar, Agoston T. Agoston, Robert D. Odze, Xiaofang Huo, Thai H. Pham, Daisha J. Cipher, Donald O. Castell, Robert M. Genta, Rhonda F. Souza, Stuart J. Spechler

Research output: Contribution to journalArticle

Abstract

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 1508.4ω at 2 weeks;Δ 1162.9ω [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.

Original languageEnglish (US)
Pages (from-to)2104-2112
Number of pages9
JournalJournal of the American Medical Association
Volume315
Issue number19
DOIs
StatePublished - May 17 2016
Externally publishedYes

Fingerprint

Proton Pump Inhibitors
Gastroesophageal Reflux
Peptic Esophagitis
Electric Impedance
Hyperplasia
Biopsy
Esophagitis
Extracellular Space
Inflammation
Eosinophils
Acids
Lasers
Neutrophils
Epithelial Cells
Lymphocytes
Esophageal pH Monitoring
Esophagoscopy
T-Lymphocytes
Wounds and Injuries
Veterans

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dunbar, K. B., Agoston, A. T., Odze, R. D., Huo, X., Pham, T. H., Cipher, D. J., ... Spechler, S. J. (2016). Association of acute gastroesophageal reflux disease with esophageal histologic changes. Journal of the American Medical Association, 315(19), 2104-2112. https://doi.org/10.1001/jama.2016.5657

Association of acute gastroesophageal reflux disease with esophageal histologic changes. / Dunbar, Kerry B.; Agoston, Agoston T.; Odze, Robert D.; Huo, Xiaofang; Pham, Thai H.; Cipher, Daisha J.; Castell, Donald O.; Genta, Robert M.; Souza, Rhonda F.; Spechler, Stuart J.

In: Journal of the American Medical Association, Vol. 315, No. 19, 17.05.2016, p. 2104-2112.

Research output: Contribution to journalArticle

Dunbar, KB, Agoston, AT, Odze, RD, Huo, X, Pham, TH, Cipher, DJ, Castell, DO, Genta, RM, Souza, RF & Spechler, SJ 2016, 'Association of acute gastroesophageal reflux disease with esophageal histologic changes', Journal of the American Medical Association, vol. 315, no. 19, pp. 2104-2112. https://doi.org/10.1001/jama.2016.5657
Dunbar, Kerry B. ; Agoston, Agoston T. ; Odze, Robert D. ; Huo, Xiaofang ; Pham, Thai H. ; Cipher, Daisha J. ; Castell, Donald O. ; Genta, Robert M. ; Souza, Rhonda F. ; Spechler, Stuart J. / Association of acute gastroesophageal reflux disease with esophageal histologic changes. In: Journal of the American Medical Association. 2016 ; Vol. 315, No. 19. pp. 2104-2112.
@article{4b9c2e2a2e02404da063adae6ae3800b,
title = "Association of acute gastroesophageal reflux disease with esophageal histologic changes",
abstract = "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 1508.4ω at 2 weeks;Δ 1162.9ω [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.",
author = "Dunbar, {Kerry B.} and Agoston, {Agoston T.} and Odze, {Robert D.} and Xiaofang Huo and Pham, {Thai H.} and Cipher, {Daisha J.} and Castell, {Donald O.} and Genta, {Robert M.} and Souza, {Rhonda F.} and Spechler, {Stuart J.}",
year = "2016",
month = "5",
day = "17",
doi = "10.1001/jama.2016.5657",
language = "English (US)",
volume = "315",
pages = "2104--2112",
journal = "JAMA - Journal of the American Medical Association",
issn = "0098-7484",
publisher = "American Medical Association",
number = "19",

}

TY - JOUR

T1 - Association of acute gastroesophageal reflux disease with esophageal histologic changes

AU - Dunbar, Kerry B.

AU - Agoston, Agoston T.

AU - Odze, Robert D.

AU - Huo, Xiaofang

AU - Pham, Thai H.

AU - Cipher, Daisha J.

AU - Castell, Donald O.

AU - Genta, Robert M.

AU - Souza, Rhonda F.

AU - Spechler, Stuart J.

PY - 2016/5/17

Y1 - 2016/5/17

N2 - 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 1508.4ω at 2 weeks;Δ 1162.9ω [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.

AB - 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 1508.4ω at 2 weeks;Δ 1162.9ω [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.

UR - http://www.scopus.com/inward/record.url?scp=84969180418&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969180418&partnerID=8YFLogxK

U2 - 10.1001/jama.2016.5657

DO - 10.1001/jama.2016.5657

M3 - Article

VL - 315

SP - 2104

EP - 2112

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0098-7484

IS - 19

ER -