In vivo evaluation of esophageal mucosal permeability in patients with non erosive reflux disease

Gastroesophageal reflux disease (GERD) is a very common disorder causing both
symptoms (heartburn, regurgitation) and damage of the esophagus (esophagitis).
In the majority of patients with reflux symptoms, upper gastrointestinal
endoscopy however reveals no abnormalities. Diagnosing GERD then occurs by
pH/impedance measurement. When this diagnosis can be made, patients are
referred to as having Non Erosive Reflux Disease (NERD). However, there are
patients with similar complaints who do not have a relation between their
complaints and esophageal reflux. These patients are referred to as having
functional heartburn. During endoscopy, there is no possibility to distinguish
these two.
Functional and histological analysis show various changes suggestive of reflux
induced damage in NERD patients. The basal cell layer is thickened and
intra-papillary capillary loops are elongated. More interestingly, in patients
with GERD the paracellular permeability of the esophageal mucosa for small
molecules is increased. In addition, the intercellular spaces are dilated in
NERD patients compared to healthy subjects. Due to these enlarged intercellular
spaces acid in the refluxate can reach the nerve endings in the epithelial
layer, giving rise to heartburn, one of the main symptoms of GERD. Dilated
intercellular spaces (DIS) were first seen in in vitro experiments, and later
proven as a persistent histopathological feature in patients with GERD.
Probably they are due to the proteolytic properties of pepsin and trypsin in
the refluxate on desmosomes and tight junctions. Both increased paracellular
permeability and DIS might prove to be a specific feature in the diagnosis of
NERD. Recent evidence suggest that the increase of paracellular permeability
precedes the occurrence of DIS.
The recent development of confocal endomicroscopy provides an opportunity to
obtain a 3-dimensional optical biopsy in vivo without physically disrupting
epithelial integrity.
By incorporating a miniaturized laser scanner with confocal imaging into a
conventional endoscope, confocal endomicroscopy can collect high-resolution
images from living human epithelium without fixation artefacts. Confocal
endomicroscopy has already shown dilated intercellular spaced in vivo. In this
study, fluoresceine was applied intravenously, where after it was taken up by
the esophageal mucosa.
When fluoresceine is sprayed into the esophageal lumen, this might show us the
permeability of the esophageal epithelium, as it diffuses through the
intercellular spaces. The aim of this study is to compare the esophageal
permeability in GERD patients to that of healthy volunteers, with a focus on
the permeability in patients with NERD.

We hypothesise that the increased permeability of the esophageal mucosa in GERD
patients can be shown using confocal laser scanning fluorescence microscopy.
This difference in esophageal permeability may prove a diagnosticum for
patients without other evidence of GERD at endoscopy, e.g. for patients with
non erosive reflux disease (NERD).

We will perform a prospective feasibility study comparing esophageal mucosal
permeability in patients with endoscopically confirmed GERD, patients with
esophageal complaints, to healthy subjects.

The risks of the study are limited to the risk of the endscopy and the
biopsies. The potential benefit for the group of patients can be that more
insight is acquired in pathophysiology of non erosive reflux disease.
Furthemore the study might lead to an endoscopic diagnosis of non erosive
reflux disease.