Proton Pump Inhibitor–Unresponsive Gastroesophageal Reflux Disease: A Prospective Cohort Study to Uncover Motility Disorder Masquerade

Background: A significant proportion of patients with gastroesophageal reflux disease (GERD) remain symptomatic despite adequate proton pump inhibitor (PPI) therapy, constituting PPI-unresponsive GERD. Esophageal motility abnormalities are increasingly recognized as contributors to symptom persistence. High-resolution manometry (HRM) interpreted using Chicago Classification version 4.0 (CCv4.0) provides improved diagnostic precision and clinical relevance. Aim: The aim of this study was to evaluate esophageal motility patterns in patients with PPI-unresponsive GERD using HRM interpreted according to CCv4.0. Methodology: Adult patients with persistent GERD symptoms despite at least 8 weeks of PPI therapy underwent HRM using a solid-state catheter system. Studies were analyzed strictly according to CCv4.0 criteria. Demographic data, HRM findings, and pathological acid exposure were analyzed. Results: A total of 201 patients were included (mean age 62.7 ± 7.6 years; 17.4% male). Esophageal motility abnormalities were identified in 55%–65% of patients. Minor motility disorders predominated, with ineffective esophageal motility in 30%–35%. Major motility disorders were present in 10%–15%. Application of CCv4.0 led to diagnostic reclassification in 20%–25%. Pathological acid exposure was observed in 23.4%, whereas 76.6% had normal acid exposure despite persistent symptoms. Conclusion: Esophageal motility abnormalities are common in PPI-unresponsive GERD. HRM interpreted using CCv4.0 enhances diagnostic accuracy and supports individualized management.