Developing a diagnostic understanding of GERD phenotypes through the analysis of levels of mucosal injury, immune activation, and psychological comorbidity

Patients with gastroesophageal reflux disease (GERD) can present with typical or atypical symptoms. The aim of this study is to explore the underlying physiological and psychological mechanisms that lead to different symptomatic manifestations of GERD. A total of 238 patients diagnosed with GERD underwent gastroscopy, 24 h multichannel intraluminal impedance-pH (MII-pH) monitoring, and psychological assessment with questionnaires. Patient symptoms were used to classify GERD into phenotypes of typical reflux syndrome (TRS, n = 87), reflux chest pain syndrome (RCS, n = 98), and extraesophageal syndromes (EES, n = 53). 38 healthy volunteers served as controls. Reflux parameters and baseline impedance values (BIVs) were acquired from MII-pH monitoring results. A subset of subjects were biopsied from the lower esophagus; certain immune cells were stained with immunohistochemistry. BIVs in GERD patients (TRS, RCS, and EES) were significantly lower than in healthy controls and TRS patients exhibited the lowest BIVs (all P < 0.01). This indicated that the extent of mucosal injury differed across groups. TRS patients had higher acid exposure time (AET) compared to RCS, EES and controls (all P < 0.05). RCS patients had more intraepithelial T lymphocyte (IEL) and mast cell (MC) infiltration, and higher psychometric scores compared to TRS patients and controls (all P < 0.05), suggesting a possible stress-related esophageal hypersensitivity basis. TRS patients are characterized by acid reflux and correlated mucosal injury, which explains their typical reflux symptoms. RCS patients exhibit less acid-related injury but possible psychological stress-related esophageal hypersensitivity, which could be the main cause of their esophageal pain.