Ignite Creation Date:
2024-05-06 @ 12:31 AM
Last Modification Date:
2024-10-26 @ 10:50 AM
Study NCT ID:
NCT01591174
Status:
COMPLETED
Last Update Posted:
2019-05-20
First Post:
2012-05-02
Brief Title:
Ghrelin and Gastric Emptying in Children With Functional Dyspepsia
Sponsor:
Childrens Mercy Hospital Kansas City
Organization:
Childrens Mercy Hospital Kansas City
Study Overview
Official Title:
Evaluation of Liquid Gastric Emptying and Plasma Ghrelin in Children With Functional Dyspepsia
Status:
COMPLETED
Status Verified Date:
2019-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GHR
Brief 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 andor 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 eg 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
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 eg 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 eg inflammation mechanical or sensory dysfunction psychological eg anxiety depression somatization and social eg 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 ie 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
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 eg inflammation mechanical or sensory dysfunction psychological eg anxiety depression somatization and social eg 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 ie 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None