LAUSR

Due to the ever-increasing use of proton pump inhibitors (PPI), the therapeutic front line in gastroesophageal reflux disease (GERD) has changed. The successful healing of esophagitis, an elusive therapeutic target a mere 25 years ago, has been eclipsed by new considerations, with emphasis now being focused on symptom resolution, in particular, heartburn. Moreover, patients with heartburn are a heterogeneous group, including subpopulations with different mechanisms responsible for their symptoms. Patients with GERD symptoms such as heartburn either have increased esophageal acid exposure with (erosive esophagitis; EE) or without (non-erosive reflux disease; NERD) erosions, or with normal acid exposure with acid hypersensitivity (functional heartburn; FH) [1]. Although EE is readily diagnosed, the distinction between patients diagnosed with NERD and those with FH can be difficult despite being highly clinically relevant: the first group mostly benefits from pharmacological suppression of acid secretion or from surgical anti-reflux therapy, whereas in the second group, prolonged therapy with proton pump inhibitors (PPI) and anti-reflux surgery are unnecessary and possibly harmful and should thus be assiduously avoided. Until now, the missing piece in this puzzle has been the existence of a biomarker useful to differentiate patients with NERD from FH and to predict the response to PPI therapy. Patients with NERD have for long been considered poor responders to PPIs. Nonetheless, a meta-analysis emphasized that the previously reported low response rate in NERD was likely the result of biased studies that included patients with non-GERD-related upper gastrointestinal symptoms [2]. Twenty-four-hour esophageal pH monitoring is useful to define the etiology of heartburn symptoms. Recently, the addition of impedance, which recognizes fluid reflux, along with pH monitoring has enhanced the ability to detect patients with FH [3]. Nevertheless, these techniques have some intrinsic limitations: (a) esophageal acid exposure time presents a physiological day-to-day variability due to variations of dietary habits and physical activity; (b) symptoms reported during single-day monitoring are often absent or few, decreasing the reliability of reflux association indexes; and (c) patients are often uncomfortable and adopt a more sedentary lifestyle, reducing the frequency of reflux-provoking activities. These limitations could be particularly relevant to patients with NERD who frequently have weakly acidic (pH 4–7) reflux during 24-h pH monitoring, as opposed to patients with EE who generally have strongly acidic (pH < 4) reflux [4]. Ultrastructural studies [5–7] have demonstrated a widening of the intercellular junctions between cells in the esophageal epithelium in patients with NERD, with limited data supporting corresponding increased paracellular permeability to solutes, which was hypothesized to be due to acid damage to the intercellular junctional complex. Since the zonula adherens, a structure integral to maintaining the integrity of the tight junction between cells, is composed partly of cadherins, the presence of E-cadherin cleaved into carboxy (C)-terminal fragments (CTFs) and amino (N)-terminal fragments (NTFs) is likely associated with the increased junctional damage and increased paracellular permeability in patients with NERD [8]. In this issue of Digestive Diseases and Sciences, Jovov et al. [9] reported a study of twenty-nine NERD patients with heartburn occurring at least 3 days/week. Esophageal biopsies for western blot (WB) analysis of CTF expression were obtained at baseline, whereas blood samples for NTF analysis were acquired before and after a course of PPI therapy. * Carlo Calabrese [email protected]