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.