NERD: an umbrella term including heterogeneous subpopulations.

Nonerosive reflux disease (NERD) represents the more common phenotypic presentation of GERD and comprises patients who have typical symptoms without any mucosal breaks at endoscopy. However, these patients are markedly heterogeneous from a pathophysiological point of view and should be correctly classified by means of 24 h impedance-pH testing, which enables detection of both acidic and weakly acidic reflux and correlation with symptoms. This technique is able to identify two subsets of NERD (that is, patients with an excess of acid or with a hypersensitive oesophagus to both acid and weakly acidic reflux) and patients with functional heartburn (who do not have any kind of reflux underlying their symptoms and must be excluded from the realm of GERD). The mechanisms of symptom generation are not clear in patients with NERD, but the presence of microscopic oesophagitis, including the dilation of intercellular spaces, seems to have a relevant role. Patients with NERD in whom acid is the main pathogenetic factor respond successfully to PPI therapy, while those with hypersensitive oesophagus to weakly acidic reflux need to be treated with reflux inhibitors or surgery, although the experience in this field is very scant. Patients with functional heartburn should undergo therapy with pain modulators, but large placebo-controlled trials are necessary.