Mechanisms of reflux perception in gastroesophageal reflux disease: a review

Patients with reflux symptoms often do not have excessive esophageal acid exposure, and patients with severe gastroesophageal reflux often do not have reflux symptoms. Understanding why different types of reflux induce symptoms in different patients is vital for addressing therapeutic gaps in the treatment of gastroesophageal reflux disease (GERD). Here we review studies providing insight into how gastroesophageal reflux is perceived, with a focus on comparing reflux characteristics and esophageal sensitivity among subgroups of patients with GERD. The available studies indicate that patients with nonerosive reflux disease have fewer acid reflux episodes and thus less esophageal acid exposure than patients with reflux esophagitis but perceive less intense stimuli because of greater esophageal sensitivity. Reflux characteristics other than acidity, such as the presence of bile, pepsin, liquid, or gas in reflux, and the proximal extent or volume of reflux, may also contribute to symptom perception. Factors contributing to greater esophageal sensitivity may include impaired mucosal barrier function, peripherally mediated esophageal sensitivity (enhanced esophageal receptor signaling), and centrally mediated esophageal sensitivity (physiological stressors, sensitization of spinal sensory neurons). Further insight into mechanisms of reflux perception may require a shift toward studies aimed at understanding predisposing cellular, molecular, and genetic factors.