Esophageal Reflux Hypersensitivity: A Comprehensive Review

Abstract

Reflux hypersensitivity (RH) is one of the phenotypes of gastroesophageal reflux disease. The latest Rome IV defines RH as a condition with typical reflux symptoms and positive reflux-symptom association despite normal acid exposure. Subsequently, the Lyon consensus proposed detailed cutoff values for the criteria on the basis of experts' consensus. Rome IV brought a clear-cut perspective into the pathophysiology of gastroesophageal reflux disease and the importance of esophageal hypersensitivity. This perspective can be supported by the fact that other functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia often overlap with RH. Although several possible pathophysiological mechanisms of esophageal hypersensitivity have been identified, there is still unmet medical needs in terms of treatment for this condition. This review summarizes the current knowledge regarding RH.

Keywords: Behavioral disorders; Functional esophageal disorders; Gastroesophageal reflux disease; Impedance-pH monitoring; Reflux hypersensitivity.

Fig. 1

Prevalence of each reflux phenotype in all patients with heartburn (A) and in endoscopy-negative patients with heartburn and/or regurgitation (B). The patients in both studies were phenotyped after at least a 14-day discontinuation of acid suppressive therapy. Only pH monitoring was used in (A), while impedance-pH monitoring was used in (B) so that the reflux-symptom association could be calculated for both acid and nonacid reflux episodes. NERD, nonerosive reflux disease; RH, reflux hypersensitivity; FH, functional heartburn.

Fig. 2

Diagnostic algorithm of PPI/PCAB refractory reflux patients. PPI, proton pump inhibitor; PCAB, potassium-competitive acid blocker; SGB, supragastric belching; RS, rumination syndrome; EGD, esophagogastricduodenoscopy; HRM, high-resolution manometry; HRIM, high-resolution impedance manometry; RS, rumination syndrome; EoE, eosinophilic esophagitis; GERD, gastroesophageal reflux disease; LA, Los Angeles classification; LSBE, long segment Barrett’s esophagus; AET, acid exposure time.

Fig. 3

Mechanism underlying esophageal reflux hypersensitivity. Exogenous stimuli perceived by the esophageal sensory nerves are transmitted to the central nervous system via two ways; vagal afferent nerves via the nodose ganglion and spinal nerves via dorsal root ganglion. Several factors contribute to reflux hypersensitivity influencing peripheral sensors in the esophagus or the central nervous system. Some mechanisms such as mucosal integrity, cytokines and prostaglandin E2, sensory receptors (TRPV1 and ASIC3) and superficial mucosal afferent nerves are associated with peripheral hypersensitivity. Other mechanisms such as esophageal hypervigilance along with anxiety and sleep disturbance mainly affect the processing of the conveyed stimuli in the central nervous system, which results in amplification of the sensation. These factors also might enhance peripheral sensitivity by impairing the mucosal integrity. TRPV1, transient receptor potential vanilloid receptor-1; ASIC3, acid-sensing ion channel 3.