Exploratory analyses of meal-induced heartburn identify distinct clinical phenotypes of gastroesophageal reflux disease.

Symptoms in symptomatic GERD patients result from esophageal acid exposure and are treated with agents that inhibit gastric acid secretion. We analyzed data from a clinical trial evaluating the effect of ranitidine plus antacid on heartburn severity in GERD patients. After 26 subjects ingested a standard meal and received either placebo or ranitidine-antacid, heartburn severity (assessed via a visual analog scale), esophageal pH, and gastric pH were measured at 15-min intervals. Two phenotypes emerged based on heartburn severity patterns: "Persistent Heartburn" (PH), characterized by sustained high severity, and "Non-persistent Heartburn" (NPH), where severity peaked and then declined. PH subjects had similar gastric acidity but higher overall heartburn severity and lower esophageal acid exposure than NPH subjects. Both phenotypes exhibited esophageal hyperalgesia, with significant heartburn even at esophageal pH above 4.0, and hyperalgesia was more pronounced in PH subjects. These findings suggest that esophageal sensitivity, rather than acid exposure alone, contributes to symptom severity. The differing responses to placebo and ranitidine-antacid highlight potential mechanisms underlying treatment failure in some GERD patients, emphasizing the need for tailored therapeutic approaches.