Superficial Esophageal Mucosal Afferent Nerves May Contribute to Reflux Hypersensitivity in Nonerosive Reflux Disease

Gastroenterology. 2017 Nov;153(5):1230-1239. doi: 10.1053/j.gastro.2017.07.017. Epub 2017 Jul 20.


Background & aims: Little is known about the causes of heartburn in patients with gastro-esophageal reflux disease. Visible epithelial damage is seldom associated with symptom severity, evidenced by the significant symptom burden in patients with nonerosive reflux disease (NERD) compared with patients with erosive reflux disease (ERD) or Barrett's esophagus (BE). We studied the distribution of mucosal nerve fibers in patients with NERD, ERD, and BE, and compared the results with those of healthy subjects.

Methods: We performed a prospective study of 13 patients with NERD, 11 patients with ERD, and 16 patients with BE undergoing endoscopic evaluation in the United Kingdom or Greece. Biopsies were obtained from the proximal and distal esophageal mucosa of patients with NERD, from the distal esophageal mucosa of patients with ERD, and the distal-most squamous epithelium of patients with BE. These were examined for the presence and location of nerve fibers that reacted with a labeled antibody against calcitonin gene-related peptide (CGRP), a marker of nociceptive sensory nerves. The results were compared with those from 10 healthy volunteers (controls).

Results: The distribution of CGRP-positive nerves did not differ significantly between the distal esophageal mucosa of controls (median, 25.5 cell layers to surface; interquartile range [IQR], 21.4-28.8) vs patients with ERD (median, 23 cell layers to surface; IQR, 16-27.5), or patients with BE (median, 21.5 cell layers to surface; IQR, 16.1-27.5). However, CGRP-positive nerves were significantly more superficial in mucosa from patients with NERD-both distal (median, 9.5 cell layers to surface; IQR, 1.5-13.3; P < .0001 vs ERD, BE, and controls) and proximal (median, 5.0 cell layers to surface; IQR, 2.5-9.3 vs median 10.4 cell layers to surface; IQR, 8.0-16.9; P = .0098 vs controls).

Conclusions: Proximal and distal esophageal mucosa of patients with NERD have more superficial afferent nerves compared with controls or patients with ERD or BE. Acid hypersensitivity in patients with NERD might be partially explained by the increased proximity of their afferent nerves to the esophageal lumen, and therefore greater exposure to noxious substances in refluxate.

Keywords: Barrett’s; Esophagitis; GERD; NERD.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Barrett Esophagus / pathology*
  • Barrett Esophagus / physiopathology
  • Biomarkers / analysis
  • Biopsy
  • Calcitonin Gene-Related Peptide / analysis
  • Case-Control Studies
  • Esophageal Mucosa / innervation*
  • Female
  • Gastroesophageal Reflux / pathology*
  • Gastroesophageal Reflux / physiopathology
  • Greece
  • Heartburn / pathology*
  • Heartburn / physiopathology
  • Humans
  • Hyperalgesia / pathology*
  • Hyperalgesia / physiopathology
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Prospective Studies
  • Sensory Receptor Cells / chemistry
  • Sensory Receptor Cells / pathology*
  • United Kingdom
  • Young Adult


  • Biomarkers
  • Calcitonin Gene-Related Peptide