Mid-esophageal mucosal impedance reflects mucosal integrity and phenotypes refractory reflux-like symptoms

BACKGROUND: Refractory reflux-like symptoms (rRLS) are frequently encountered in clinical practice and often reflect heterogeneous underlying mechanisms beyond acid exposure alone. Esophageal mucosal impedance has emerged as a marker of mucosal integrity, yet its role in phenotyping rRLS remains incompletely defined. METHODS: In this retrospective study, adult patients with reflux-like symptoms who underwent multichannel intraluminal impedance-pH monitoring and high-resolution manometry were enrolled. Patients exhibiting persistent reflux-like symptoms despite ≥ 8 weeks of double-dose PPI therapy were defined as having rRLS. Baseline impedance (BI) and mean nocturnal baseline impedance (MNBI) were assessed at three esophageal levels, with particular focus on the mid-esophagus (9 cm above the lower esophageal sphincter). Among patients with refractory symptoms, final diagnoses were established using clinical evaluation, endoscopy, impedance-pH monitoring, and manometry, allowing classification into refractory gastroesophageal reflux disease (GERD), functional heartburn/reflux hypersensitivity (FH/FES) and esophageal structural or functional abnormalities (ESFA). RESULTS: Among 165 patients, 73 (44.2%) exhibited rRLS. BI at the mid-esophageal level was significantly lower in refractory compared with non-refractory patients, whereas impedance values at proximal and distal levels showed no significant differences. In refractory patients, MNBI at the mid-esophagus differed significantly across diagnostic phenotypes. Lower MNBI values were associated with esophageal structural or functional abnormalities, while higher values were more frequently observed in functional heartburn or reflux hypersensitivity. CONCLUSIONS: Mid-esophageal mucosal impedance reflects impairment of mucosal integrity and may contribute to the physiological phenotyping of patients with rRLS. Location-specific impedance assessment could serve as a complementary tool to conventional reflux testing, aiding in mechanism-based classification. However, it should not be used in isolation to guide therapeutic decisions.