human oesophagus integrity of distal exposed and proximal non-exposed Acid and weakly acidic solutions impair mucosal

Background Oesophageal mucosa dilated intercellular spaces (DIS) may be important for symptom perception in non-erosive reflux disease (NERD). Patients with NERD might have DIS even in the proximal oesophagus. We aimed to assess the effect of oesophageal perfusions with acid and weakly acidic solutions on ‘exposed’ and ‘non-exposed’ oesophageal mucosa and its relationship to symptoms in healthy subjects. Methods 14 healthy volunteers underwent upper gastrointestinal endoscopy with biopsies at 3 and 13 cm proximal to the oesophagogastric junction (OGJ). In following sessions, subjects received 30 min perfusions with neutral, weakly acidic, acidic and acidic-bile acid solutions at 5 cm above the EGJ (separated 4 weeks). Biopsies were taken 20 min after perfusions. Electron microscopy was used to measure DIS. Subjects scored heartburn during perfusions using a visual analogue scale. Results (1) Oesophageal perfusion with acid solutions, with or without bile acids, provoked DIS in the ‘exposed’ oesophageal mucosa; (2) oesophageal perfusion with weakly acidic solutions provoked identical changes to those observed after perfusion with acid solutions; (3) distal oesophageal perfusions not only provoked changes in the ‘exposed’ but also in the more proximal ‘nonexposed’ mucosa; and (4) in spite of the presence of perfusion-induced DIS, most healthy subjects did not perceive heartburn during the experiments. Conclusions The human oesophageal mucosa is very sensitive to continuous exposure with acidic and weakly acidic solutions. In spite of the presence of intraluminal acid and DIS, healthy subjects did not experience heartburn, suggesting that NERD patients should have other critical factors underlying their symptoms. INTRODUCTION The pathophysiology of symptoms in gastrooesophageal reflux disease (GORD) is not completely elucidated. In patients with oesophagitis, refluxed gastric content can reach sensory nerves endings through erosions in the oesophageal mucosa, leading to perception of heartburn. In patients with non-erosive reflux disease (NERD) the mechanism is not that obvious. In these patients, heartburn is thought to occur when acid and/or other components of the refluxed gastric content reach sensory nerve endings, through mucosal dilated intercellular spaces (DIS). The dilation of intercellular spaces is a marker of oesophageal mucosa cellular damage in these patients. Intra-epithelial nerve endings of spinal afferents are likely to be involved in the mediation of acid induced oesophageal symptoms. In vitro exposure of the rabbit oesophageal mucosa to acid provokes DIS and reduction of oesophageal acid exposure with proton pumps inhibitors (PPIs) in humans can reverse DIS suggesting that mucosal exposure to acid is critical in the development of DIS. However, NERD patients with normal oesophageal acid exposure and patients with well-controlled acid secretion but persistent symptoms in spite of PPI treatment may also have DIS suggesting that increased mucosal exposure to acid is not the only factor underlying this histological phenomenon. We recently showed that acute stress in rats and exposure of rabbit oesophageal mucosa to bile acids, can both provoke DIS. Interestingly, these two factors can be present in patients with NERD or refractory GORD. 13 The proximal extent of reflux is an important determinant for reflux perception, particularly in patients with NERD. This might be due to hypersensitivity to proximal oesophageal distension but also other mucosal factors might be involved. A recent study demonstrated that patients with NERD may have DIS not only in the distal but also in the proximal oesophageal epithelium which might contribute to enhance perception of proximal reflux. It is unknown whether proximal DIS occurs due to direct oesophageal mucosal contact with gastric contents or involves an indirect mechanism triggered by a stimulus at a more distal oesophageal site, ie, intrinsic afferent fibres, mast cells degranulation. 17 It has been proposed that intraluminal acid, in the presence of DIS, would provoke heartburn by activation of intra-epithelial nerve endings of spinal afferents. However, it is unknown whether these two conditions, in an otherwise healthy subject, would be enough to induce heartburn. The present study was designed to assess the effect of distal oesophageal perfusions with acid and weakly acidic solutions in healthy subjects. The aims of the study were (1) to test the hypothesis that exposure of the oesophageal mucosa, not only to acid but also to weakly acidic solutions, can provoke DIS in the distal oesophagus of healthy human subjects; (2) to assess the spread of perfusion-induced mucosal changes from the distal ‘exposed’ to the proximal ‘non exposed’ oesophagus; and (3) to assess the relationship between symptoms perception and presence or magnitude of DIS. Center for Gastroenterological Research, Catholic University Leuven, Belgium Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, (Ciberehd), Instituto de Salud Carlos III, Spain Department of Pathology, Institute of Pathology, Bayreuth Hospital, Bayreuth, Germany Department of Pathology, University Hospital Gasthuisberg, Catholic University Leuven, Belgium Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University Leuven, Belgium Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK Correspondence to Dr Daniel Sifrim, The Wingate Institute of Neurogastroenterology, 26 Ashfield Street, London E1 2AJ, UK; d.sifrim@qmul.ac. uk Revised 26 September 2009 Accepted 13 October 2009 Published Online First 1 November 2009 164 Gut 2010;59:164e169. doi:10.1136/gut.2009. 194191 Oesophagus group.bmj. com on March 6, 2010 Published by gut.bmj. com Downloaded from