"The role of fat in symptom generation in patients with functional dyspepsia"

Functional dyspepsia (FD) is a common condition, with an estimated prevalence
of 12% to 15% in developed countries. FD is characterized by chronic or
recurrent upper abdominal symptoms in the absence of organic, systemic, or
metabolic disease likely to explain these symptoms. Dyspeptic symptoms are
frequently induced or exacerbated by food ingestion.
In FD there is only a weak correlation between symptoms and upper
gastrointestinal motor abnormalities. More recently, visceral hypersensitivity
to mechanical and nutrient stimuli has been recognized as important in the
etiology of dyspeptic symptoms. A subgroup of FD patients have lower thresholds
for first perception and for discomfort or pain during distension of the
proximal stomach when compared with healthy volunteers. Furthermore,
intraduodenal infusion of lipid induces greater symptoms in FD patients than in
healthy subjects and exacerbates symptoms induced by concurrent gastric
distension. These findings show that gastric hypersensitivity to mechanical
stimuli and increased small intestinal chemosensitivity to lipid contribute to
symptoms in FD emerged.
The effect of duodenal lipid on the generation of dyspeptic symptoms and the
perception of 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. This signal transduction
route may also be involved in the CCK1-mediated generation of dyspeptic
symptoms during gastric distension upon duodenal lipid load, i.e. postprandial
symptoms.
Perception of esophageal stimuli is also enhanced by duodenal lipid. Recently
we found that genes implicated in lipid absorption are expressed at higher
levels in gastro-esofageal-reflux disease (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. As central sensitisation as a consequence of enhanced
stimulation of duodenal extrinsic primary afferents likely heightens the
perception of esophageal stimuli in GERD patients, in patients with functional
dyspepsia gastric mechanoperception may be enhanced in this way. Furthermore,
enhanced stimulation of duodenal extrinsic primary afferents by increased
release of CCK may underlie small intestinal chemosensitivity to lipid. Thus
the differences in gene expression identified may constitute the mechanism by
which fat contributes to symptom generation in FD.
FD is a heterogeneous disorder and it is unknown whether this putative
mechanism underlying small intestinal chemosensitivity to lipid correlates with
increased mechanosensitivity to gastric distension and/or delayed gastric
emptying.

Gain insight into the mechanism underlying enhanced mechanoperception of the
stomach and duodenal chemoperception in response to fat in patients with
functional dyspepsia.

In view of comparing components of the chylomicron-apoA-IV-CCK pathway between
FD patients and healthy subjects, intraduodenal lipid infusion followed by
upper GI endoscopy will be performed. A venous cannula will 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. During infusion,
patients will score upper abdominal sensations every 15 minutes. 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.
To assess the correlation of chylomicron-apoA-IV-CCK pathway components with
sensitivity to gastric distension, a gastric barostat test will be conducted. A
tube with an adherent small plastic bag will be introduced through the mouth.
The plastic bag will be inflated stepwise. During the distension protocol
patients will be asked to score upper abdominal sensations.
Determination of gastric emptying rate by 13C octanoic breath test is part of
the standard workup of FD patients presenting at our department.
Intraduodenal lipid infusion followed by upper GI endoscopy and the gastric
barostat test will be carried out in random order.

All participants will be asked to complete two questionnaires prior to the
study. During the intraduodenal lipid infusion patients will score upper
abdominal sensations every 15 minutes. Also 5 ml blood will be collected 6
times. In general a GI endoscopy is a safe procedure. The occurrence of
relative uncommon complications does not increase by taking duodenal biopsies.
During the barostat study patients will be asked to complete a questionnaire
after each distension step. The barostat study is a safe procedure. In the
extremely rare occasion that the balloon comes off the catheter, an endoscopy
will have to be performed to remove the balloon from the stomach.
Patients will be asked to discontinue any medication likely to affect
gastric-duodeno motility and sensitivity one week prior to both study days.