"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.
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 subjects (HS). Furthermore, intraduodenal infusion of lipid induces
greater symptoms in FD patients than in HS 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 afferent nerve endings (EPANs). 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 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. Likewise, in patients
with functional dyspepsia gastric mechanoperception may be enhanced by central
sensitisation as a consequence of enhanced stimulation of duodenal EPANs.
Furthermore, enhanced stimulation of duodenal EPANs 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 gastric mechanoperception
and duodenal chemoperception, by comparing duodenal mRNA expression of genes
and plasma and duodenal mucosal concentrations of proteins, involved in the
chylomicron-apoA-IV-CCK pathway, between FD patients and HS upon duodenal lipid
load.

Evaluate association between duodenal mRNA expression of genes and plasma and
duodenal mucosal concentrations of proteins, involved in the
chylomicron-apoA-IV-CCK pathway, upon duodenal lipid load and gastric
sensorimotor phenotype of FD patients.

On one day 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. Through the
nostril a manometric catheter will be introduced, via which lipid will be
infused 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.
On a separate day 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 until 9 is scored for abdominal discomfort/pain
or a volume of 1000 ml has been reached
Determination of gastric emptying rate by 13C octanoic breath test is part of
the standard workup of FD patients presenting at our department.

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 test patients will score upper abdominal sensations after
each distension step. The barostat test 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.