Original article
Alimentary tract
Increased Proximal Reflux in a Hypersensitive Esophagus Might Explain Symptoms Resistant to Proton Pump Inhibitors in Patients With Gastroesophageal Reflux Disease

https://doi.org/10.1016/j.cgh.2013.10.026Get rights and content

Background & Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Section snippets

Patients

We included 18 patients with GERD, of whom 9 patients were PPI responders (5 men; age, 59 y), and 9 patients experienced refractory symptoms on PPI (2 men; age, 52 y). The latter category of patients was classified as partial PPI responders. A diagnosis of GERD was based on the observation of esophagitis during endoscopy and/or a pathologic acid exposure, both in combination with typical reflux symptoms off PPI. In GERD patients with complete response, typical reflux symptoms were absent during

Patients

In all 18 patients esophageal sensitivity measurements and the postprandial reflux protocol were completed. In 2 patients (1 responder, 1 partial responder) endoscopy could not be performed, such that no biopsy specimens were available for Ussing experiments.

No significant differences were found in ages or sex between complete and partial responders (age, 59 ± 4.9 vs 52 ± 6.4 y, P = .39; sex, 5 males vs 2 males, P = .34). The PPIs used were omeprazole, pantoprazole, and esomeprazole (8, 5, and

Discussion

Visceral hypersensitivity, impaired mucosal integrity, and differences in acidity and position of the acid pocket have been hypothesized to contribute to PPI-resistant symptoms in GERD patients. In the current study we showed that mucosal permeability and the position of the acid pocket are similar in PPI partial responders and responders and are therefore less likely to explain persistent symptoms. In contrast, esophageal sensitivity to distension and the number of reflux episodes with a

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      Although our cohort size was small, our results are supported by another study13 demonstrating no difference in the degree of esophageal reflux exposure between patients who failed to respond and those who achieved symptom resolution while taking once-daily PPI. Furthermore, a study conducted by Rohof et al25 showed that partial responders to PPI are most likely explained by increased proximal reflux in a hypersensitive esophagus, as opposed to number of reflux events, increased mucosal permeability, or the position of the acid pocket. In summary, our study is the first to demonstrate that reflux characteristics, using impedance pH, were not significantly different between patients who responded to those who failed PPI once daily.

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    Conflicts of interest The authors disclose no conflicts.

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