SUPERFICIAL ESOPHAGEAL MUCOSAL AFFERENT NERVES IN THE PROXIMAL ESOPHAGUS MAY CONTRIBUTE TO SEVERITY OF ESOPHAGEAL SYMPTOMS IN PATIENTS WITH ACHALASIA

Objectives:
Dysphagia and chest pain are the common symptoms in achalasia. The mechanisms underlying such symptoms are not completely understood. The two symptoms can be triggered by mechanical stimulation via the sensory vagal and spinal afferent nerve fibers. We previously reported that superficial nociceptive mucosal afferent nerves (i.e. calcitonin gene-related peptide-immunoreactive (CGRP-IR) nerves) might contribute to acid hypersensitivity in non-erosive reflux disease. The mucosal nerves can also detect mechanical deformation of the mucosa apart from chemical stimulation. Therefore, the aim of this study was to investigate the association between the severity of esophageal symptoms in achalasia patients and the characteristics of mucosal afferent nerve innervation.

Methods:
This was a muti-center prospective study involving six tertiary centers. Patients with predominant dysphagia and/or chest pain referred to the centers were recruited if they underwent upper endoscopy and high-resolution manometry for the examination of their symptoms. Esophageal motility was diagnosed on the basis of Chicago classification ver 4.0. The severity of dysphagia and chest pain were evaluated using Brief Esophageal Dysphagia Questionnaire (BEDQ) and a self-reported chest pain questionnaire respectively. Biopsies were taken from the proximal and distal esophagus for assessment of CGRP-IR mucosal nerves. The position of such nerves was expressed as cell layers from the esophageal luminal surface. We used a historical cohort of 8 asymptomatic healthy volunteers for comparison with the patients.

Results:
Overall, 61 patients with achalasia (n=57) or EGJ outflow obstruction (n=4) were included (median age, 56 years; 24 female (39%)). All the patients had dysphagia with the median of BEDQ score of 19 (11-26), and 39% of them had concomitant strong chest pain. The mucosal afferent nerves were located significantly closer to the lumen in the patients than in HVs (8 vs 11 cell layers, p=0.046 in the proximal, 9 vs 24 cell layers, p<0.001 in the distal). The position of mucosal afferent nerve negatively correlated to BEDQ score both in the proximal (rho=-0.567, p<0.001) and distal esophagus (rho=-0.317, p=0.021). The patients with strong chest pain showed more superficial mucosal afferent in the proximal esophagus (7 cell layers (4-9)) than those with weak chest pain (9 cell layers (7-14), p=0.022). Multivariate analysis found that the position of the afferent nerves in the proximal esophagus were independently and inversely associated with BEDQ score (-0.013 (-0.020, -0.006), <0.001) and chest pain (-0.054 (-0.101, -0.007), p=0.044). However, there was not such relationship in the distal esophagus.

Conclusions:
The superficial afferent nerves in the proximal, not distal esophagus, were associated with severe dysphagia and chest pain.