The reason for failure of on-demand PPI therapy in NERD patients.

To The Editors: We read with interest the paper by Wu et al (1) showing that concomitant irritable bowel syndrome, in addition to functional dyspepsia, is associated with failure of on-demand Proton Pump Inhibitors (PPI) therapy in reflux patients. The Authors performed a large study in which all patients underwent conventional manometry and pH monitoring in order to be characterized. They included in the group with non-erosive reflux disease (NERD) patients with abnormal acid exposure and those with normal acid and a strong correlation between symptoms and acid reflux events (SI>75%). They classified patients with negative symptoms association as having functional heartburn (FH) and excluded them from the study. The separation of FH from NERD represents a very important point, because the former sub-group is likely to be associated more frequently with other functional GI disorders and this can influence the therapeutic PPIs response. Indeed, in a recent study (2), we have shown that sub-grouping the complex population of endoscopy-negative reflux patients by means of impedance-pH testing led us to demonstrate that several dyspeptic symptoms, such as those pertaining to the postprandial distress syndrome (3), overlap significantly more with FH than with NERD. This sustains the concept that FH may be part of functional GI disorders, in which other factors (i.e. visceral hypersensitivity, psychological factors, etc.) rather than acid seem to play a major role. Therefore, the response to PPI therapy, given in whatever modality in these patients, is very poor. However, the fact that NERD patients had higher failure rate of on-demand PPI therapy than those with Erosive Esophagitis (EE), even after Wu et al had excluded FH from their study, may depend on additional factors. For instance, the use of traditional pH-metry alone allowed the Authors to detect only NERD patients with an esophagus hypersensitive to acid, while those with a positive symptom association with weakly acidic reflux were necessarily missed. The modern impedance-pH technique has the merit to distinguish acid from weakly acidic reflux events and this allowed us to demonstrate that there is a subgroup of endoscopy-negative patients who have a clear association between heartburn and weakly acidic reflux episodes (4). The presence of patients pertaining to this last subgroup among those with NERD and normal acid in their esophagus represents one of the main causes of non response to PPIs (5) and could explain why in the above study the failure rate to these drugs was higher in NERD than in EE.