Ghrelin and Gastric Emptying in Children With Functional Dyspepsia

Functional Dyspepsia (FD) is defined as the presence of persistent or recurrent pain or
discomfort centered in the upper abdomen with no evidence of organic disease likely to
explain the symptoms.

This pain or discomfort must not be exclusively relieved by defecation or associated with
the onset of a change in stool frequency or stool form.

Initially, the FD classification criteria included 3 subtypes: ulcer-like, in which pain is
the predominant symptom; dysmotility-like, in which discomfort is the predominant symptom;
and, unspecified. In 2006, however, the criteria were revised by the Rome III committees. In
adults, the previous FD subtypes were eliminated and replaced by two new subtypes: (i)
postprandial distress syndrome (PDS), characterized by postprandial fullness or early
satiety; and, (ii) epigastric pain syndrome (EPS), characterized by epigastric pain or
burning unrelated to meals. In children, the Rome II subtypes were eliminated completely.
Although the Rome III subtypes have only been applied within adult criteria, there also
appear to be meaningful associations in children with FD which may support their adoption in
later revisions of the criteria. Specifically, both inflammation (reflected by mast cell
density) and self reported anxiety and depression appear to be uniquely associated with PDS
in children.

FD is a common disorder of the upper gastrointestinal (GI) tract, occurring in 26% to 34% of
the general population. FD is present in as many as 80% of children being evaluated for
chronic abdominal pain. FD is best explained by a biopsychological model with dysfunction
within the brain-gut axis. The model suggests that FD is as a result of interaction between
biological (e.g., inflammation, mechanical, or sensory dysfunction), psychological (e.g.,
anxiety, depression, somatization), and social (e.g., interactions with parents, teachers,
or peers) factors, which may be interactive with each other. Delayed gastric emptying is
one of the mechanical factors which have been implicated. Other mechanisms are visceral
hypersensitivity and impaired gastric fundic accommodation.

Delayed gastric emptying has been shown in up to 66% of children with FD. Most of previous
studies in children used solid GE as a measure to explain the function of pyloric emptying.
However, liquids GE is a good measure to predict the function of fundic accommodation,
visceral hypersensitivity as well as pyloric emptying, in which, all these mechanisms were
suggested in the mechanical pathophysiological model of FD specifically PDS subtypes. In
order to measure gastric emptying (GE), the 13C-acetate breath test (ABT) has the potential
to replace 99mtechnetium colloid-based scintigraphy which is the "gold standard" for
measuring GE. ABT has an advantage over scintigraphy in that it is a rapid, technically
simple, safe and inexpensive means to assess liquid GE in children. As such, it may be more
easily utilized as a diagnostic technique in standard clinical practice.

Gastric motility is mainly regulated by extrinsic autonomic nerves, intrinsic neurons of the
stomach, and GI hormones. It is hypothesized that these hormones strongly affect hunger and
energy expenditure and may be are altered in dyspeptic disorders affecting gastric motility.
Because altered gut-brain interactions may underlie symptom generation in FD and ghrelin is
an important gut peptide related to the gut-brain axis, plasma concentrations of ghrelin in
patients with FD have been investigated in several studies.

Ghrelin is a motilin-related peptide mainly synthesized and released by A-like cells in the
stomach. Ghrelin acts as an endogenous ligand of growth hormone secretagogue receptor
(GHSR). Ghrelin receptors are present in the anterior pituitary hypothalamus. There are two
forms of ghrelin. The first form is acyl ghrelin, comprising 28 amino acid residues with an
n-octanoyl ester at Ser3 that is essential for its biologic activity, which acts as an
endogenous ligand of growth hormone secretagogue receptor type 1a (GHS-R1a). Acyl ghrelin is
easily and rapidly degraded to the second form, desacyl ghrelin, or smaller fragments.

Functionally, ghrelin level progressively rises during fasting to peak just prior to a meal
and fall to its lowest level about an hour after eating. Ghrelin level again starts
increasing approximately 2 hours after eating to peak again before the next meal. A close
relationship has been documented between ghrelin and gastric motility in rats. In humans, it
has been demonstrated that ghrelin increases the gastric emptying rate in healthy, but not
in obese, controls. Ghrelin has a well-established role in increasing appetite and food
intake. These pieces of evidence have led to speculation that altered ghrelin function may
contribute to the disturbed gastric motility and appetite loss seen in FD. Moreover, ghrelin
agonist administration is found to have stimulatory effect on appetite in FD patients and
idiopathic gastroparesis.

Considering that most symptoms of FD are typically related to food intake, postprandial
ghrelin level has been investigated in several studies. It has been shown that fasting
ghrelin level, in general, is inversely related to gastric emptying time (i,e., lower
fasting ghrelin is associated with greater delay in GE). However, this relation is disrupted
in FD patients, as these patients do not demonstrate an increase in fasting ghrelin level.
Although results have been somewhat conflicting, some previous studies support a role for
ghrelin in FD in adults. Takamori et al. reported that fasting desacyl and total ghrelin
levels were significantly lower in FD patients than in controls. Further, fasting and
postprandial levels were not significantly different in FD, as compared to a significant
drop from fasting to postprandial level seen in controls, which suggests that fasting
ghrelin does not increase as expected during fasting in FD patients. Consistent with this,
Lee et al. showed that delayed GE has been reported in the majority of adults with FD where
abnormally low total pre-prandial ghrelin levels were observed. However, the relationship
between FD and ghrelin may differ by FD subtype. Shindo et al. reported that fasting acyl
ghrelin levels were significantly lower in PDS adult patients than in healthy volunteers.
Further, they demonstrated that Tmax value reflective of GE in PDS patients was
significantly higher than in healthy volunteers, as measured using the 13-C (carbon) acetate
breath test. These results suggested that acyl ghrelin is more biologically important and
might play a role in the pathophysiology of the PDS subtype of FD through its effect on
gastric emptying.

Collectively, previous studies suggest a relationship between plasma ghrelin concentration
and FD, or FD subtype, in adults. Further, it seems likely that this occurs through the
impact of ghrelin on gastric emptying in adults. However, to the best of our knowledge, the
role of ghrelin in pediatric FD and it its relation to gastric motility in children has not
been previously studied. There is a need to investigate the possible role of ghrelin in its
two different forms, as well as its relation to gastric motility, in children with FD as a
group and across possible subtypes in order to establish better understanding of the
pathophysiology of FD. This study may help to build a mechanical pathway model for FD
etiology, explore the pharmacokinetics of the ghrelin hormone, and establish its correlation
to liquid gastric emptying. If a relationship is established, future work can explore a
potential therapeutic role for ghrelin agonist in FD or specific FD subtypes.

Inclusion Criteria:

- All: Participants 8-17 years of age

- FD arms: Patients identified in CMH/Abdominal Pain Team Clinic with Functional
Dyspepsia who meet exclusion criteria.

- Control arm: healthy participants who meet exclusion criteria.

Exclusion Criteria:

- History of upper gastrointestinal surgery or intestinal obstruction.

- History of disease or symptoms suggestive of underlying malabsorption, Inflammatory
Bowel Disease (IBD), or Peptic Ulcer Disease (PUD).

- History or evidence of chronic illness requiring regular medical care such as
diabetes mellitis (DM), liver, heart, kidney, endocrine, or pulmonary disease and
asthma that precludes accurate exhalation into the study breath collection apparatus.

- Any patient with body Mass index (BMI) less than or equal to 10th percentile for age;
or equal to or greater than 90th percentile for age.

- Patient and/or parent not able to read English.

- Current pregnancy.

- History of milk allergy.

- Prokinetic or psychotropic medications used within the last 72 hour prior to study.

- Inability to exhale into study breath collection apparatus as directed.

- Recent acute illness that occurs prior to study visit.