Oesophageal acid perception in patients with Barrett*s oesophagus.

Barrett*s oesophagus
Oesophageal adenocarcinoma is one of the fastest rising malignant diseases in
the western world, with a four-fold increase in the past few decades (1). A
premalignant condition associated with an increased risk of development of
adenocarcinoma is Barrett*s oesophagus (BO), defined as a replacement of the
normal squamous epithelium with columnar epithelium, or intestinal metaplasia
(2). The BO to adenocarcinoma pathway develops slowly through a well defined
sequence of intestinal metaplasia, low-grade intraepithelial neoplasia, high
grade intraepithelial neoplasia and finally early adenocarcinoma (3). The
disorder is thought to be a complication of longstanding chronic
gastro-oesophageal reflux disease (GORD) and it has been shown that there is
increased acid exposure in the oesophagus of Barrett patients compared to
healthy controls and symptomatic GORD patients (4). Approximately 10% of GORD
patients have shown to have a BO, however, recent studies suggest even higher
prevalence for short segment Barrett oesophagus, as defined as a segment of
Barrett epithelium < 3cm. A population based study in Sweden reports a total
prevalence of 1.6% (5).
Severity of oesophageal acid exposure is partly dependent on oesophageal acid
clearance, of which the main mechanism is pharyngeal swallowing (6). It has
been shown that the swallowing frequency increases in response to increased
oesophageal acid exposure in GORD patients (7). Furthermore, this increase is
most likely due to an increase in perception of reflux episodes (7). Patients
with BO are less sensitive to oesophageal acid exposure than GORD patients
(8,9). This could lead to decreased perception of reflux episodes and to a
decreased oesophageal clearance. Thereby it could contribute to the development
of intestinal metaplasia. Furthermore, a decreased sensitivity to oesophageal
acid could delay a physician consultation and delay adequate acid inhibition,
thereby leading to an excessive exposure of the oesophageal mucosa to acid and
the development of intestinal metaplasia.
A study currently performed at the Motility Centre in the AMC focuses on the
mechanisms of oesophageal acid sensitivity and permeability of oesophageal
tissue in GORD patients (MEC 10/275), with the hypothesis that oesophageal
permeability changes are thought to facilitate acid diffusion towards the
sensory nerves. In vivo measurements of tissue impedance (TIM) and ex vivo
Ussing experiments are performed to assess oesophageal permeability.
In the present study we hypothesize that oesophageal permeability changes
mediate the decreased acid sensitivity and perception in BO patients compared
to GORD patients and healthy volunteers.

Tissue impedance measurement (TIM)
Tissue impedance measurement is a new method to assess in vivo impedance of
tissue using an electrical current. It has previously been demonstrated that
with tissue impedance measurements is it possible to separate precancerous from
normal tissue in the cervix (10,11). In vitro work showed the possibility to
distinguish oesophageal squamous epithelium from metaplastic columnar
epithelium (12). The concept depends on inherent properties of the electrical
current, where high frequencies pass through the cells in the tissue while low
frequencies tend to pass between cells (13). By examining a range of
frequencies, the relative composition of the tissue can thus be examined. A new
probe designed to fit into the working canal of a gastroscope has been designed
in order to allow impedance evaluation of the distal oesophagus during routine
endoscopic examination. In animal experiments the probe has been demonstrated
to have an acceptable inter- and intraindividual variability of the main
parameters.

Key objective: the hypothesis that will be tested
Our hypothesis is that the decreased oesophageal acid sensitivity is mediated
by oesophageal permeability changes. Furthermore we hypothesize that the
electrical tissue impedance of oesophageal tissue in BO patients is altered
compared to normal oesophageal squamous epithelium, in both areas of intestinal
metaplasia and non-affected mucosa situated above these mucosal regions.

Aim
To investigate the oesophageal sensitivity to acid and the mechanism underlying
acid sensitivity changes in BO. Oesophageal permeability will be assessed
functionally by Ussing experiments on oesophageal biopsies and morphologically
by electron microscopy.

The study has an observational prospective design. One group of subjects will
be included, consisting of patients with BO without neoplastic changes.
The METC of the AMC Amsterdam has previously granted permission for the
inclusion of GORD patients and healthy volunteers in a similar protocol (MEC
10/275). While the analyses are similar, the healthy controls will serve as
control populations.

The risk of the performed procedures consists of the risk of oesophageal
biopsies, namely bleeding and perforation. The Bernstein test is a safe
procedure, only associated with discomfort during placement of the perfusion
catheter. There is no additional risk involved with the tissue impedance
measurements. The impedance measurements and obtaining 6 jumbo biopsies prolong
the time of a regular endoscopy with approximately 7 minutes. The study will
contribute to better understanding of the condition and possibly offer new
diagnostic tools.