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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Background : Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, is released from the stomach. Animal studies suggest that ghrelin stimulates gastrointestinal motor activity.

Aim : To investigate the influence of ghrelin on gastric emptying rate and meal-related symptoms in idiopathic gastroparesis.

Methods : In six patients with idiopathic gastroparesis, a breath test was used to measure gastric emptying rates (t1/2) for solids and liquids after administration of saline or ghrelin 40 μg/30 min in a double-blind, randomized fashion. At each breath sampling, the patient was asked to grade the intensity of six different symptoms (epigastric pain, bloating, postprandial fullness, nausea, belching and epigastric burning) and these were added to obtain meal-related symptom severity score.

Results : Ghrelin significantly enhanced liquid emptying (t1/2: 86 ± 7 vs. 53 ± 6 min, P = 0.02) and tended to enhance solid emptying (144 ± 45 vs. 98 ± 15 min, P = 0.06). Ghrelin pre-treatment significantly decreased cumulative meal-related symptom score (196 ± 30 vs. 136 ± 23, P = 0.04) and individual scores for fullness (55 ± 8 vs. 39 ± 8, P = 0.02), and for pain (40 ± 8 vs. 16 ± 5, P < 0.05).

Conclusions : In idiopathic gastroparesis, administration of ghrelin enhances gastric emptying and improves meal-related symptoms. These observations suggest a potential for ghrelin receptor agonists in the treatment of gastroparesis.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Delayed gastric emptying is considered a major pathophysiological mechanism underlying symptoms in functional dyspepsia and idiopathic gastroparesis.1–12 Several studies have investigated the relationship between delayed gastric emptying and symptom pattern and severity. Depending on the study, the percentage of dyspeptic patients with delayed gastric emptying is ranging from 25% to 50%.1–12 Most studies failed to find a relationship between delayed gastric emptying and symptom pattern,1–9 but recent large-scale studies showed that patients with delayed gastric emptying for solids are more likely to report postprandial fullness, nausea and vomiting.10–12

The relationship between symptom pattern and the presence of delayed emptying suggests a possible pathophysiological role for delayed gastric emptying in eliciting dyspeptic symptoms-like fullness, nausea and vomiting. Patients with delayed gastric emptying are usually treated with gastroprokinetic drugs such as metoclopramide, domperidone and previously also cisapride, although a relationship between improvement in gastric emptying rate and symptomatic benefit has not been proven.13–16 However, the gastroprokinetic effects of these drugs are limited. The findings of the strong gastrokinetic actions of motilin and of erythromycin, a macrolide antibiotic that acts as a motilin receptor agonist, were met with great enthusiasm17, 18 and several short-term studies reported beneficial effects of treatment with erythromycin in gastroparesis.13, 18–20 Different macrolide prokinetics, devoid of antibiotic properties, were developed and one of these, ABT-229, was studied in large clinical trials.21, 22 However, the outcomes of clinical trials with ABT-229 were unequivocally disappointing with regard to symptom improvement, both in dyspeptics and in patients with diabetic gastropathy with and without delayed emptying. However, there are strong indications of tachyphylaxis with macrolide prokinetics and especially with ABT-229, which has a long plasma half-life, and which was administered three times daily in the clinical trials.21–26 Hence, as measurement of gastric emptying was not repeated at the time of symptom assessment in the ABT-229 studies, the relationship between changes in gastric emptying rate and changes in symptom severity in gastroparesis has remained unclear.23

Ghrelin is a 28 amino acid motilin-related peptide that was first derived from rat stomach.27 It is the natural ligand for the growth hormone secretagogue receptor (GHSR). Ghrelin has a strong growth hormone-releasing activity and plays an important role in the control of food intake and energy balance.28, 29 Animal studies revealed that ghrelin has distinct effects on gastrointestinal motility, which can be mediated through GHSR on myenteric neurones and on the vagus nerve.30–39 Ghrelin was shown to enhance gastric motility and gastric emptying in rats and mice, to stimulate small intestine transit and to reverse post-operative gastric ileus.30–35 Recently, we confirmed a strong stimulatory effect of ghrelin on gastric interdigestive motility in humans.40

These observations suggest a potential gastroprokinetic activity of ghrelin in humans. The aim of the present study was to investigate the influence of ghrelin on gastric emptying rate and meal-induced dyspeptic symptoms in patients with idiopathic gastroparesis. We have previously shown the reproducibility of gastric emptying and meal-related symptom testing in patients with dyspepsia and gastroparesis.41

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Study subjects

Consecutive out-patients with established idiopathic gastroparesis were recruited for the study. The patients had presented to the motility out-patient clinic because of symptoms suggestive of gastroparesis, and all underwent careful history taking and clinical examination, routine biochemistry, upper gastrointestinal endoscopy, upper abdominal ultrasound and a gastric emptying breath test.8, 12, 39, 40 After the finding of delayed gastric emptying, a small bowel X-ray was also performed to rule out small bowel lesions or stenosis. Exclusion criteria were the presence of oesophagitis, gastric atrophy or erosive gastroduodenal lesions on endoscopy, the presence of lesions on small bowel X-ray, major abdominal surgery, underlying psychiatric illness and the use of non-steroidal anti-inflammatory drugs, steroids or drugs-affecting gastric acid secretion.

Each patient completed a symptom questionnaire as reported previously.12 The patient was asked to grade the intensity (0–3; 0 = absent, 1 = mild, 2 = relevant and 3 = severe, interfering with daily activities) of eight different symptoms (epigastric pain, bloating, postprandial fullness, early satiety, nausea, vomiting, belching and epigastric burning) over the last 3 months. Also, the amount of weight lost since the onset of the symptoms was noted.

All drugs potentially affecting gastrointestinal motility or sensitivity were discontinued at least 1 week prior to the gastric emptying studies. Informed consent was obtained from each participant. The protocol had been previously approved by the Ethics Committee of the University Hospital.

Gastric emptying breath test with assessment of meal-related symptoms

Gastric emptying rates for solids and liquids were determined using the 14C octanoic acid and 13C glycin breath test.8, 12, 42 The test meal consisted of 60 g of white bread, an egg, the yolk of which was doped with 74 kBq of 14C octanoid acid sodium salt (DuPont, NEN Research, Boston, MA, USA) and 300 mL of water in which 100 mg 13C glycin (99% enrichment; Isotec, Miamisburg, OH, USA) was dissolved. All meals were consumed within a 5-min period. The total caloric value of the test meal was 250 kcal. Breath samples were taken before the meal and at 15-min intervals for a period of 240 min postprandially. At each sampling point, the subject exhaled into two different containers for measuring exhaled 13C and 14C respectively. One was a liquid scintillation vial containing 2 mL of 1 m hyamine hydroxide and 2 mL of ethanol together with one drop of thymolphtalein solution. This amount of hyamine is neutralized by 2 mm of CO2. The end point of neutralization is indicated by decolouration of the indicator. After decolouration, 10 mL of scintillation cocktail (Hionic Fluor, Packard, Meriden, CT, USA) was added and radiation was determined by liquid scintillation counting (Packard Tri-Carb Liquid Scintillation Spectrometer, model 3375, Packard Instrument Company, Downers Grove, IL, USA). For 13C measurements breath was collected by blowing directly into a tube. The 13C breath content was determined by on-line gas chromatographic purification-isotope ratio mass spectrometry (ABCA, Europe Scientific, Crewe, UK).

At each breath sampling, the patient was asked to grade the intensity (0–3; 0 = absent, 1 = mild, 2 = relevant and 3 = severe) of six different symptoms (epigastric pain, bloating, postprandial fullness, nausea, belching and epigastric burning).

Study protocol

All patients underwent two gastric emptying breath tests with assessment of meal-related symptoms, approximately 1 week apart. At the start of the meal, when the subjects started eating, saline or ghrelin 40 μg (Ghrelin, Clinalfa, Läufelfingen, Switzerland) were infused intravenously over 30 min in a double-blind, randomized, crossover design. The dose of ghrelin was based on a previous study where ghrelin 20 μg intravenously over 30 min seemed to have little effect, whereas infusion of ghrelin 40 μg over 30 min had a consistent stimulatory effect on interdigestive gastrointestinal motility in healthy volunteers.40 The order of saline and ghrelin treatment was randomized by drawing cards from a box of cards determining the sequence. A study nurse who was otherwise not involved in the study administered the medication. Half of the subjects received saline first; the other half received ghrelin first.

Data analysis

Symptom scores were obtained before and for 4 h after the standardized meal. For each symptom, a meal-related severity score was obtained by adding scores at all time points. A cumulative meal-related symptom score was obtained by adding individual symptom severity scores.

The results of the 13CO2 and 14CO2 breath tests were expressed as the percentage 13CO2 and 14CO2 respectively, excreted per hour by calculating procedures described elsewhere.8, 12, 42, 43 For both carbon labels, CO2 production was assumed 300 mmol/m2 of body surface per hour. Gastric half emptying time (t1/2) was calculated from the 13CO2 and 14CO2 excretion curves as previously described.8, 12, 42, 43

Results are expressed as mean ± S.E.M. Student's t-test was used to compare results on different days or after different pre-treatments. A P-value of <0.05 was considered significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Patient characteristics

Six patients (five women, mean age 49 ± 6 years) with long-standing dyspeptic symptoms were recruited for the study. Previous studies had established delayed emptying for both solids and liquids. None of the patients had metabolic or organic disease that might explain the symptoms or the delayed gastric emptying. Table 1 summarizes the grading of dyspeptic symptoms in the patient group. Postprandial fullness, bloating and nausea were present in all patients. Epigastric pain (83%), early satiety (67%), belching (67%) and epigastric burning (67%) were also frequently reported. Vomiting was reported by 50% of the patients. Weight loss in excess of 5% was present in four patients (67%). All patients were Helicobacter pylori-negative.

Table 1.  Frequency of severity grading for each of eight dyspepsia symptoms in six patients with idiopathic gastroparesis
 0 (absent)1 (mild)2 (relevant)3 (severe)
  1. Values within parentheses represent percentages.

Postprandial fullness0 (0)0 (0)3 (50)3 (50)
Bloating0 (0)0 (0)3 (50)3 (50)
Epigastric pain1 (17)0 (0)3 (50)2 (33)
Early satiety2 (33)1 (17)1 (17)2 (33)
Nausea0 (0)0 (0)3 (50)3 (50)
Vomiting3 (50)0 (0)1 (17)2 (33)
Belching2 (33)1 (17)3 (50)0 (0)
Epigastric burning2 (33)2 (33)1 (17)1 (17)

Influence of ghrelin on gastric emptying and meal-related symptoms

After administration of saline, both solid and liquid gastric emptying were delayed (t1/2: 144 ± 45 and 86 ± 7 min respectively), as expected on the basis of the selection of patients (Figure 1). The cumulative and individual meal-related symptom severity scores are illustrated in Figures 2 and 3.

image

Figure 1. Influence of ghrelin 40 μg/30 min or saline intravenously (i.v.) in a double-blind, randomized crossover fashion at the start of the meal on solid and liquid half emptying times in idiopathic gastroparesis. * P < 0.05 and P = 0.06 compared with placebo. Upper limits of normal for solid and liquid half emptying times are indicated by the dotted lines.

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image

Figure 2. Influence of administration of ghrelin 40 μg/30 min or saline intravenously (i.v.) in a double-blind, randomized crossover fashion at the start of the meal on gastric emptying rate and on meal-related symptoms in six patients with idiopathic gastroparesis. Gastric emptying was assessed using the octanoic acid breath test. At each breath sampling, the patient was asked to grade the intensity (0–3; absent to severe) of six different symptoms (epigastric pain, bloating, postprandial fullness, nausea, belching and epigastric burning) and these were added to obtain meal-related symptom severity score. Treatment with ghrelin tended to enhance solid gastric half emptying time († P = 0.06) and significantly decreased cumulative meal-related symptom severity (* P < 0.05).

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image

Figure 3. Influence of administration of ghrelin 40 μg/30 min or saline intravenously (i.v.) in a double-blind, randomized crossover fashion at the start of the meal on the severity of meal-related symptoms in a 4-h postprandial window. At 15-min intervals, the patient was asked to grade the intensity (0–3; absent to severe) of six different symptoms (epigastric pain, bloating, postprandial fullness, nausea, belching and epigastric burning). Scores for each symptom were added to obtain meal-related symptom severity score. Administration of ghrelin significantly decreased the severity of postprandial fullness and pain. * P < 0.05 compared with placebo.

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After administration of ghrelin, liquid half emptying time was significantly enhanced liquids (t1/2: 86 ± 7 vs. 53 ± 6 min, P = 0.02) and solid half emptying time tended to be enhanced (t1/2: 144 ± 45 vs. 98 ± 15 min, P = 0.06; Figures 1 and 2).

Treatment with ghrelin significantly decreased the cumulative meal-related symptom score (196 ± 30 vs. 136 ± 23, P = 0.04). Individual symptom severity scores for fullness (55 ± 8 vs. 39 ± 8, P = 0.02), and for pain (40 ± 8 vs. 16 ± 5, P < 0.05) were improved by ghrelin (Figure 3). No significant correlation was found between changes in cumulative or individual meal-related symptom scores and changes in solid emptying times. The improvement in liquid emptying rate tended to be correlated to the improvement in bloating scores (R = 0.38, P = 0.06).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Traditionally, prokinetic agents, including metoclopramide, domperidone and cisapride, have been widely used in the treatment of functional dyspepsia13–15 and systematic analyses reported that prokinetics were more effective than placebo.44, 45 It is now evident that only a subset of patients with functional dyspepsia have delayed gastric emptying.6–12 As it seems logical to direct pharmacotherapeutic approaches towards the underlying pathophysiological disturbance, gastroprokinetic drugs are most likely to be beneficial to patients with delayed gastric emptying, and they should be most likely to improve the associated symptoms of postprandial fullness, nausea and vomiting.10–12, 46 However, currently available prokinetic drugs only modestly enhance gastric emptying and evidence that their symptomatic effect is related to enhancement of gastric emptying is actually lacking.1, 2, 41 Recent studies with the motilin agonist ABT-229 found no favourable effect, either in all patients or in those with established delayed gastric emptying only.21, 22 However, there are clear indications of tachyphylaxis with this compound, which may explain the negative outcome. In healthy volunteers, a single dose of ABT-229 increased gastric emptying after the first meal, but emptying of a second meal was not affected, although ABT-229 plasma levels were still high.24 Hence, there is a clear need for new therapeutic approaches for the treatment of gastroparesis.

In the present study, we evaluated the effect of ghrelin on gastric emptying rate and on meal-induced symptoms. We previously established the reproducibility of this test.41 We demonstrated that administration of ghrelin significantly enhances gastric emptying of liquids and tends to enhance solid emptying in idiopathic gastroparesis. These observations are in line with animal studies30–35 and with our recent observation of a stimulatory effect of the same dose of ghrelin on interdigestive motility in humans.40 The site and mechanism of action of ghrelin activating gastric emptying in humans cannot be determined from the present study. The prokinetic effects of ghrelin are reminiscent of those of motilin.17 Although there are sequence similarities between ghrelin and motilin, and between the GHSR and the motilin receptor,47, 48 there seems to be no cross-reactivity between both peptides.49, 50 In addition, we have previously shown that administration of the same dose of ghrelin does not induce an increase in plasma motilin levels in humans.40 Therefore, the prokinetic actions of ghrelin in the present study are mediated through GHSR activation.

The site of the involved ghrelin receptor is also unclear. In theory, these could be localized centrally, on vagal neurones, or on intrinsic neurones of the stomach. GHSRs have been demonstrated in the rat nodose ganglion and there is evidence that the gastric motor effects of ghrelin are vagally mediated.30, 51, 52 The vagus nerve is also involved in the control of fasting induced increases in plasma ghrelin levels and in ghrelin-induced feeding behaviour.51, 53 Studies in the rat suggest that under physiological conditions circulating ghrelin does not activate the myenteric plexus, but is able to do so following vagotomy.52 Certainly in vitro contractility and Ca2+-imaging studies provided evidence that the activity of ghrelin can also be mediated via the enteric nervous system.32, 33, 35, 36, 38 Finally, centrally administered ghrelin also accelerates gastric emptying and ghrelin changes the activity of neurones receiving ascending afferent signals from mechanoreceptors in the stomach.47, 52, 54

The present study also suggests a therapeutic potential for GHSR agonism, as we observed a significant improvement of meal-related symptoms and of fullness and pain after ghrelin pre-treatment. This is an unexpected finding, as the motilide prokinetic erythromycin failed to improve symptoms in a similar study design.41 It has been speculated that the lack of symptom improvement during erythromycin-induced enhancement of gastric emptying was attributed to its effect on the proximal stomach and induction of impaired accommodation.23, 41 However, at least in the fasting state in humans, ghrelin also induces a contraction of the proximal stomach.40 Further studies of the effect of ghrelin on postprandial gastric motor function seem warranted on the basis of this observation. Additional studies will also be needed to investigate whether the ghrelin receptor is a valid therapeutic target in gastroparesis. This would require establishing the absence of problems with desensitization and the availability of orally available agonists.

In conclusion, we have shown that acute administration of ghrelin in patients with idiopathic gastroparesis enhances gastric emptying and improves meal-induced symptoms. These observations suggest a potential for ghrelin receptor agonists in the treatment of gastroparesis, but further studies on the motor effects of acute and chronic stimulation of the GHSR will be required.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References
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