title: Hypersensitivity to acid is associated with impaired esophageal mucosal integrity in patients with gastroesophageal reflux disease with and without esophagitis.
abstract: Increased esophageal sensitivity and impaired mucosal integrity have both been described in patients with gastroesophageal reflux disease, but the relationship between hypersensitivity and mucosal integrity is unclear. The aim of the present study was to investigate acid sensitivity in patients with erosive and nonerosive reflux disease and control subjects to determine the relation with functional esophageal mucosal integrity changes as well as to investigate cellular mechanisms of impaired mucosal integrity in these patients. In this prospective experimental study, 12 patients with nonerosive reflux disease, 12 patients with esophagitis grade A or B, and 11 healthy control subjects underwent an acid perfusion test and upper endoscopy. Mucosal integrity was measured during endoscopy by electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance, transepithelial permeability and gene expression of tight junction proteins and filaggrin. Patients with nonerosive reflux disease and esophagitis were more sensitive to acid perfusion compared with control subjects, having a shorter time to perception of heartburn and higher perceived intensity of heartburn. In reflux patients, enhanced acid sensitivity was associated with impairment of in vivo and vitro esophageal mucosal integrity. Mucosal integrity was significantly impaired in patients with esophagitis, displaying higher transepithelial permeability and lower extracellular impedance. Although no significant differences in the expression of tight junction proteins were found in biopsies among patient groups, mucosal integrity parameters in reflux patients correlated negatively with the expression of filaggrin. In conclusion, sensitivity to acid is enhanced in patients with gastroesophageal reflux disease, irrespective of the presence of erosions, and is associated with impaired esophageal mucosal integrity. Mucosal integrity of the esophagus is associated with the expression of filaggrin.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Pim W
authors.initials: PW
authors.lastname: Weijenborg
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: André J P M
authors.initials: AJ
authors.lastname: Smout
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands;
authors.forename: Caroline
authors.initials: C
authors.lastname: Verseijden
authors.affiliation: Van Leeuwenhoek Center for Advanced Microscopy, Department of Cell Biology, Academic Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Henk A
authors.initials: HA
authors.lastname: van Veen
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands;
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; a.j.bredenoord@amc.uva.nl.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Bredenoord
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D017097:Electric Impedance; D050782:Esophageal pH Monitoring; D004941:Esophagitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004945:Esophagoscopy; D004947:Esophagus / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000091344:Filaggrin Proteins; D005764:Gastroesophageal Reflux / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006356:Heartburn / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D058748:Pain Perception; D011446:Prospective Studies; D012720:Severity of Illness Index; D013057:Spectrum Analysis; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins
keywords: esophageal sensitivity; gastroesophageal reflux; heartburn; mucosal integrity; nonerosive reflux disease