Perception of reflux and mucosal integrity in the proximal oesophagus

Gastro-oesophageal reflux disease
Approximately 15-20% of the general population experiences heartburn
and/or regurgitation at least weekly (1). Although it is generally accepted
that gastro-oesophageal reflux causes these symptoms, the mechanism through
which this occurs has not been clarified. In the minority of patients mucosal
abnormalities such as oesophagitis can be found during upper endoscopy, these
patients suffer from erosive reflux disease (ERD). However, the vast majority
of patients has no mucosal abnormalities during upper endoscopy and thus
suffers from so-called non-erosive reflux disease (NERD). Regardless of the
presence of distal erosions all GORD patients seem more sensitive during
oesophageal acid infusion compared to asymptomatic controls (2,3). The cause of
this hypersensitivity to acid is unclear.

Proximal extent of reflux and proximal oesophageal sensitivity to acid
Several studies have demonstrated that patients with reflux disease
have more proximal reflux episodes than healthy controls.(2,4) Furthermore,
reflux that reached the proximal oesophagus more often generated typical reflux
symptoms than reflux that only reached the distal oesophagus.(5) Also, in
patients with reflux symptoms despite PPI therapy reflux episodes reaching the
proximal oesophagus were more often associated with symptoms than reflux
reaching only the distal part of the oesophagus.(6,7) A study using multiple
pH-impedance sensors at different oesophageal levels showed that the proportion
of both acidic and weakly acidic reflux episodes that become symptomatic is
significantly higher in the proximal oesophagus than in the distal
oesophagus.(8) These data suggest that the proximal oesophagus is more
sensitive to acid than the distal oesophagus.
Oesophageal sensitivity to acid can be measured using an acid perfusion test.
A neutral and an acidic solution are perfused in the oesophagus in a random
order while the patient is blinded to the nature of the solution. Subsequently,
the time to heartburn perception and the intensity of perceived heartburn is
scored. Our group recently showed that patients with non-erosive reflux disease
are more sensitive to distal acid perfusion than healthy subjects. (Weijenborg
et al., UEGW 2012) However, the sensitivity of the proximal oesophagus measured
with an acid perfusion test has not been separately assessed.

Oesophageal mucosal integrity
The oesophageal mucosa is characterized by the presence of a
non-keratinised squamous epithelium, forming an effective barrier against
noxious substances during the reflux of gastric contents. The integrity of this
barrier is impaired in patients with reflux disease, demonstrated by the
presence of dilated intercellular spaces and increased transepithelial flux of
small molecules.(9,10) Recently our group demonstrated that these mucosal
integrity parameters were related to acid hypersensitivity measured by an acid
perfusion test. (Weijenborg, UEGW 2012). Patients with an impairment of mucosal
integrity are characterized by an increase in esophageal sensitivity to acid.
In the present study we will evaluate the sensitivity of different
regions of the oesophagus. We will investigate whether the proximal oesophagus
is more sensitive to acid by separate infusions of these regions during an acid
perfusion test. We will also investigate whether mucosal integrity changes
underlie these changes in sensitivity by doing in vivo and in vitro mucosal
integrity measurements.

Key objective: the hypothesis that will be tested:
Our hypothesis is that the proximal oesophagus of patients with GORD is more
sensitive to acid than the distal oesophagus, which is due to more pronounced
mucosal integrity changes in the proximal oesophagus.
This can be further specified:
• Lag time to heartburn perception is shorter after proximal acid perfusion
compared to distal acid perfusion.
• Heartburn intensity is higher after proximal acid perfusion compared to
distal acid perfusion.
• Impairment of the mucosal barrier after acid perfusion is larger in the
proximal esophagus than in the distal esophagus, which is characterized by a:
o Lower in vivo impedance of tissue
o Lower in vitro transepithelial electrical resistance
o Higher in vitro transepithelial permeability of small molecules
o Larger intercellular spaces
• A positive relation between acid perception and mucosal barrier impairment

Aim
To investigate the segmental sensitivity to acid of the oesophagus in patients
with GORD and its underlying mechanism.

The study has a prospective observational design and the protocol consists of a
single acid perfusion test and obtaining electrical tissue impedance
measurements and mucosal biopsies during a routinely planned gastroscopy.
The MEC of the AMC Amsterdam has previously granted permission for the
inclusion of GORD patients and healthy volunteers in a similar protocol
(MEC10/275).

The risk of the performed procedures consists of the risk related to obtaining
oesophagal biopsies. Oesophageal biopsies are taken regularly during upper
endoscopy. A very rare but potentially severe risk of a biopsy is a
perforation. In the vast majority of cases perforation can be treated
expectative or endoscopically. In a minority of cases, surgery has to be
performed to close the perforation. Another very rare risk of an oesophageal
biopsy is bleeding, which can be treated endoscopically.
The acid perfusion test is a safe procedure, only associated with discomfort
during placement of the perfusion cathether. There is no additional risk
involved with the tissue impedance measurements. The extra procedures during
endoscopy will proong the time of a regular endosocpy with 3-4 minutes. The
study will contribute to better understanding of the condition and possibly
offer new targets of treatment.