Ghrelin and Gastric Emptying in Children With Functional Dyspepsia
Condition: Functional Dyspepsia
MeSH terms: Dyspepsia
Study type: Observational

Summary: 
      The purpose of this research is to see if there are differences between children who have FD
      and children without FD in the ability of the stomach to empty food and/or in ghrelin hormone
      levels before and after eating.

      Chronic abdominal pain is the most common persistent pain condition in children and
      adolescents. One of the most often diagnosed types of abdominal pain is functional dyspepsia
      (FD). FD is abdominal pain or discomfort (e.g., nausea, bloating) in the upper abdomen that
      does not get better by having a bowel movement.

      One possible explanation for having FD is a delay in the emptying of food from the stomach,
      or delayed gastric (stomach) emptying. Failing to empty the stomach quickly enough may result
      in the feeling of being full and cause symptoms of bloating, nausea, vomiting and pain.
      Further, hormonal changes occur before, during, or after eating food that appear to impact
      stomach emptying.

      One of the hormones that changes with meals is called ghrelin. The relationship between
      ghrelin and stomach emptying needs to be explored more in children with FD. Better
      understanding of what causes FD symptoms may help us to improve treatment for this condition.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        All FD patients will be recruited from the Section of Gastroenterology at the Children's
        Mercy Hospital and Clinics. The control group will be recruited by advertisement within
        Children's Mercy Hospital.
      
Biospecimen description: 
      breath specimen blood plasma
    
Keywords: Functional Dyspepsia; Postprandial Distress Syndrome; ghrelin; C-13 acetate