Transient Gastric Pressure Elevation Synergizing With Impaired Esophagogastric Junction Barrier Function Plays a Pivotal Role in the Refractory Gastroesophageal Reflux Disease

Background/Aims: The pathophysiology of refractory gastroesophageal reflux disease (RGERD), which differs from proton pump inhibitor dependent gastroesophageal reflux disease (DGERD), remains incompletely elucidated.This study aims to compare esophageal motility patterns, transdiaphragmatic pressure gradients (TPG), and reflux profiles between RGERD and DGERD patients, and to delineate dynamic pressure gradient-esophagogastric junction (EGJ) interactions in these patients.Methods: In this retrospective study, 274 patients who underwent 24-hour impedance-pH monitoring and high-resolution manometry, along with an assessment of proton pump inhibitor responsiveness, were classified as RGERD (32.5%),DGERD (54.4%), or non-GERD (13.1%).Clinical characteristics, TPG, esophageal motility, and reflux metrics were compared between RGERD and DGERD patients.Subgroup analysis excluding hiatal hernia (HH) was conducted to investigate the pathophysiology of RGERD.Results: The RGERD group exhibited a significantly higher proportion of chest pain compared to the DGERD group.Regarding reflux profiles, RGERD patients without HH (RGERD HH-group) experienced increased weakly acidic reflux (P < 0.001) and prolonged bolus exposure (P = 0.006) compared to their counterparts (DGERD HH-group).Mechanistically, the RGERD HH-group showed reduced lower esophageal sphincter basal pressure (P = 0.010) and EGJ contractile integral (P = 0.005).Notably, following a wet-swallow, the RGERD HH-group experienced the significant elevation in gastric pressure and TPG.Correlation analyses revealed weakly acidic reflux and bolus exposure were positively correlated with gastric pressure variation, and inversely correlated with lower esophageal sphincter basal pressure.Conclusions: Transient gastric pressure elevation and compromised EGJ barrier function drive weakly acidic reflux and esophageal bolus exposure.This pressure gradient-barrier mismatch underpins the refractoriness of RGERD.