"The role of the duodenum in symptom generation in GERD"

"The role of the duodenum in symptom generation in GERD"

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder in
the western world where 15-20% of the population suffers from reflux symptoms
at least weekly. It is a disorder in which esophageal mucosal lesions and/or
symptoms occur as a consequence of reflux of gastric contents into the
esophagus.
In GERD there is a lack of association between symptom severity or frequency
and the presence or absence of esophageal mucosal inflammation or the extent of
esophageal mucosal injury. The presence of heartburn and acid regurgitation in
the absence of abnormal esophageal acid exposure but a close temporal
relationship between symptoms and acid reflux events (SAP >= 95%) suggests that
a subgroup of patients are sensitive to physiological amounts of acid.
Furthermore, GERD patients seem more sensitive to experimental esophageal
stimuli than healthy volunteers. Visceral hypersensitivity may therefore play a
role in the etiology of GERD symptoms.
GERD patients also frequently present with symptoms originating from other
gastrointestinal (GI) regions than the esophagus. In addition, it has been
shown that distal esophageal acid infusion lowers pain thresholds for
experimental stimuli in the proximal esophagus. These findings indicate that
central sensitisation contributes to visceral hypersensitivity in GERD patients.
Central sensitisation is an increase in excitability of central neurons induced
by heightened extrinsic primary afferent activation at a peripheral site. As
visceral afferents from different gastrointestinal regions converge at the
level of the central nervous system, the enhanced perception of reflux in the
esophagus may be caused by heightened afferent activation in another gut region.
Perception of esophageal and gastric stimuli is enhanced by duodenal lipid. The
effect of duodenal lipid on the perception of dyspeptic symptoms during gastric
distension is mediated by cholecystokinin (CCK)-1 receptors. For inhibition of
gastric emptying, another CCK1-mediated effect of duodenal lipid, it has been
demonstrated that apolipoprotein A-IV (apoA-IV) is an essential component of
the signal transduction pathway involved. ApoA-IV is a component of
chylomicrons and is released from enterocytes during lipid absorption. It has
been hypothesized that apoA-IV stimulates adjacent endocrine cells to release
CCK, which can activate CCK1 receptors on the peripheral terminals of duodenal
extrinsic primary afferents.
Recently we found that genes implicated in lipid absorption are expressed at
higher levels in GERD patients. This suggests that in GERD patients the
chylomicron-apoA-IV-CCK pathway generates more signals, which may induce
central sensitisation and thereby heighten the perception of esophageal stimuli.
It is conceivable that the differences in gene expression found between GERD
patients and healthy volunteers identified under fasting conditions may be more
prominent in the postprandial state, since GERD patients commonly report that
food ingestion, particularly fat, aggravates the symptoms.
The potentially increased signalling of the chylomicron-ApoA-IV-CCK pathway in
GERD patients will also be evaluated by comparing ApoA-IV and CCK
concentrations in plasma and mucosal biopsies of the duodenum with those of
healthy volunteers.

Gain insight into the role of the duodenum in symptom generation in GERD at the
mucosal level by comparing several components of the chylomicron-apoA-IV-CCK
pathway between GERD patients and healthy subjects upon duodenal lipid load.

A venous cannula wil be inserted in the arm for repeated sampling of blood in
which ApoA-IV and CCK concentrations will be measured. A manometric catheter
will be introduced through the nostril. Lipid will be infused through this
catheter into the duodenum. After removal of the catheter an upper GI endoscopy
will be performed and several biopsies of the duodenum will be collected, which
will be used for mRNA expression analysis and apoA-IV and CCK quantification.

5 ml blood will be collected 6 times. All participants will be asked to
complete two questionnaires. In general a GI endoscopy is a safe procedure. The
occurence of relative uncommon complications does not increase by taking
duodenal biopsies.