Increased proximal reflux in a hypersensitive esophagus might explain symptoms resistant to proton pump inhibitors in patients with gastroesophageal reflux disease.

Approximately 30% of patients with gastroesophageal reflux disease have symptoms resistant to treatment with proton pump inhibitors (PPIs). Several mechanisms such as esophageal hypersensitivity, increased mucosal permeability, and possibly the position of the gastric acid pocket might underlie a partial response to PPIs. To what extent these mechanisms interact and contribute to PPI-resistant symptoms, however, has not been investigated previously. In 18 gastroesophageal reflux disease patients (9 PPI responders and 9 PPI partial responders), esophageal sensitivity, mucosal permeability, and postprandial reflux parameters were determined during PPI use. Esophageal sensitivity for distension was measured by gradual balloon inflation at 5 and 15 cm above the lower esophageal sphincter. The mucosal permeability of 4 esophageal biopsy specimens per patient was determined in Ussing chambers by measuring the transepithelial electrical resistance and transmucosal flux of fluorescein. Postprandial reflux parameters were determined using concurrent high-resolution manometry/pH impedance after a standardized meal. In addition, the acid pocket was visualized using scintigraphy. No difference in the rate of postprandial acid reflux, in the pH of the acid pocket (PPI responders 3.7 ± 0.7 vs PPI partial responders 4.2 ± 0.4; P = .54), or in the position of the acid pocket was observed in PPI partial responders compared with PPI responders. In addition, the permeability of the esophageal mucosa was similar in both groups, as shown by a similar transepithelial electrical resistance and flux of fluorescein. PPI partial responders had more reflux episodes with a higher mean proximal extent, compared with PPI responders, and were more sensitive to balloon distension, both in the upper and lower esophagus. PPI-resistant symptoms most likely are explained by increased proximal reflux in a hypersensitive esophagus and less likely by increased mucosal permeability or the position of the acid pocket.