In the Journals

Reflux esophagitis may be caused by cytokine-mediated inflammation, not chemical injury

T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells was associated with proton pump inhibitor cessation among patients who had successfully treated their severe reflux esophagitis with proton pump inhibitors, according to the results of a preliminary study published in JAMA. These findings suggest the pathogenesis of reflux esophagitis may be caused by inflammatory cytokines rather than chemical injury.

“This study challenges some of the long-held beliefs about how gastroesophageal reflux damages the esophageal mucosa in patients with gastroesophageal reflux disease,” Kerry Dunbar, MD, PhD, associate professor of internal medicine and staff physician with the department of gastroenterology at the Dallas VA Medical Center, said in a press release.

The idea that reflux esophagitis is caused by an acid-peptic chemical injury has gone largely unchallenged since first proposed in a 1935 JAMA report, but a recent study in rats led to “an alternative concept for GERD pathogenesis ... in which refluxed gastric material did not damage esophageal epithelial cells directly, but stimulated them to secrete cytokines that attracted immune cells, which ultimately damaged the mucosa,” the researchers wrote.

Dunbar and colleagues therefore sought to study the pathogenesis of acute GERD by evaluating the histologic features of esophageal inflammatory changes in 11 men and one woman (mean age, 57.6 years) from the Dallas VA Medical Center who stopped taking PPIs for 2 weeks following previous successful PPI treatment of their reflux esophagitis. They evaluated the patients using esophageal manometry, 24-hour esophageal pH and impedance monitoring and esophagoscopy (using high-definition white light endoscopy and confocal laser endomicroscopy) with biopsies from noneroded areas of the distal esophagus at baseline, 1 and 2 weeks.

The primary outcome was change in esophageal inflammation at 2 weeks determined by changes in lymphocyte, eosinophil and neutrophil infiltrates in esophageal biopsies, which were scored on a 0 to 3-point scale. The researchers also evaluated changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure and mucosal impedance.

All patients had evidence of esophagitis at week 2. Esophageal acid exposure increased from a median of 1.2% at baseline to 17.8% at week 2 (P = .005), whereas mucosal impedance significantly decreased from baseline to week 2 (P = .001).

Biopsies showed significant increases in intraepithelial lymphocytes (mostly T cells) from a median histologic score of 0 at baseline to a median score of 1 at both weeks 1 (P = .005) and 2 (P = .002). There were few or no neutrophils or eosinophils. Biopsies also showed widening of intercellular spaces, which was confirmed by confocal laser endomicroscopy, and basal cell and papillary hyperplasia developed with no surface erosion.

“Although this radical change in the concept of how acid reflux damages the esophagus of GERD patients will not change our approach to its treatment with acid-suppressing medications in the near future, it could have substantial long-term implications,” Stuart Spechler, MD, professor of internal medicine at UT Southwestern and chief of the department of gastroenterology at the Dallas VA Medical Center, said in the press release.

This shift in the model of pathogenesis may help to explain other GERD phenotypes that have recently emerged, in particular the 1% to 5% of patients with hiatal hernia and a history of high-grade erosive esophagitis represented by this study cohort, as well as patients with PPI-responsive esophageal eosinophilia, Peter J. Kahrilas, MD, from Northwestern University, wrote in a related editorial.

“In all probability PPIs will remain the mainstay for treating esophagitis because of their unparalleled efficacy and safety for that condition. However, it is increasingly apparent that the pathogenesis of esophagitis is distinct from that of the spectrum of potential GERD symptoms ranging from heartburn to regurgitation, chest pain, dysphagia, laryngitis, and cough,” he wrote, adding that a “divide and conquer” mantra may be appropriate for treating refractory GERD based on these novel findings. – by Adam Leitenberger

Disclosure: Spechler reports consulting for Interpace, Ironwood and Takeda. Another researcher reports consulting for Interpace and Ironwood. Kahrilas reports no relevant financial disclosures.

T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells was associated with proton pump inhibitor cessation among patients who had successfully treated their severe reflux esophagitis with proton pump inhibitors, according to the results of a preliminary study published in JAMA. These findings suggest the pathogenesis of reflux esophagitis may be caused by inflammatory cytokines rather than chemical injury.

“This study challenges some of the long-held beliefs about how gastroesophageal reflux damages the esophageal mucosa in patients with gastroesophageal reflux disease,” Kerry Dunbar, MD, PhD, associate professor of internal medicine and staff physician with the department of gastroenterology at the Dallas VA Medical Center, said in a press release.

The idea that reflux esophagitis is caused by an acid-peptic chemical injury has gone largely unchallenged since first proposed in a 1935 JAMA report, but a recent study in rats led to “an alternative concept for GERD pathogenesis ... in which refluxed gastric material did not damage esophageal epithelial cells directly, but stimulated them to secrete cytokines that attracted immune cells, which ultimately damaged the mucosa,” the researchers wrote.

Dunbar and colleagues therefore sought to study the pathogenesis of acute GERD by evaluating the histologic features of esophageal inflammatory changes in 11 men and one woman (mean age, 57.6 years) from the Dallas VA Medical Center who stopped taking PPIs for 2 weeks following previous successful PPI treatment of their reflux esophagitis. They evaluated the patients using esophageal manometry, 24-hour esophageal pH and impedance monitoring and esophagoscopy (using high-definition white light endoscopy and confocal laser endomicroscopy) with biopsies from noneroded areas of the distal esophagus at baseline, 1 and 2 weeks.

The primary outcome was change in esophageal inflammation at 2 weeks determined by changes in lymphocyte, eosinophil and neutrophil infiltrates in esophageal biopsies, which were scored on a 0 to 3-point scale. The researchers also evaluated changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure and mucosal impedance.

All patients had evidence of esophagitis at week 2. Esophageal acid exposure increased from a median of 1.2% at baseline to 17.8% at week 2 (P = .005), whereas mucosal impedance significantly decreased from baseline to week 2 (P = .001).

Biopsies showed significant increases in intraepithelial lymphocytes (mostly T cells) from a median histologic score of 0 at baseline to a median score of 1 at both weeks 1 (P = .005) and 2 (P = .002). There were few or no neutrophils or eosinophils. Biopsies also showed widening of intercellular spaces, which was confirmed by confocal laser endomicroscopy, and basal cell and papillary hyperplasia developed with no surface erosion.

“Although this radical change in the concept of how acid reflux damages the esophagus of GERD patients will not change our approach to its treatment with acid-suppressing medications in the near future, it could have substantial long-term implications,” Stuart Spechler, MD, professor of internal medicine at UT Southwestern and chief of the department of gastroenterology at the Dallas VA Medical Center, said in the press release.

This shift in the model of pathogenesis may help to explain other GERD phenotypes that have recently emerged, in particular the 1% to 5% of patients with hiatal hernia and a history of high-grade erosive esophagitis represented by this study cohort, as well as patients with PPI-responsive esophageal eosinophilia, Peter J. Kahrilas, MD, from Northwestern University, wrote in a related editorial.

“In all probability PPIs will remain the mainstay for treating esophagitis because of their unparalleled efficacy and safety for that condition. However, it is increasingly apparent that the pathogenesis of esophagitis is distinct from that of the spectrum of potential GERD symptoms ranging from heartburn to regurgitation, chest pain, dysphagia, laryngitis, and cough,” he wrote, adding that a “divide and conquer” mantra may be appropriate for treating refractory GERD based on these novel findings. – by Adam Leitenberger

Disclosure: Spechler reports consulting for Interpace, Ironwood and Takeda. Another researcher reports consulting for Interpace and Ironwood. Kahrilas reports no relevant financial disclosures.