Spectrum of gastric emptying patterns in adult patients with cyclic vomiting syndrome

Background Cyclic vomiting syndrome (CVS) in adults is a disorder characterized by recurrent and stereotypic episodes of severe nausea, vomiting and abdominal pain separated by symptom‐free intervals. Both rapid and delayed gastric emptying (GE) have been observed but the reports involved small numbers of CVS patients. Methods We performed a retrospective study of 92 adult patients who met Rome Ш diagnostic criteria for CVS between 2003 and 2009 at the Kansas University Medical Center. Gastric emptying was measured by a standardized scintigraphic method involving a low fat (2%) isotope labeled egg white meal of 250 Kcal, with anterior and posterior gastric imaging in the standing position obtained at 0, 1, 2, 4 h after meal ingestion. Rapid GE was defined as <50% isotope retention at 1st h and/or <30% at 2nd h and delayed GE as >10% at 4 h. Key Results Ninety two patients were analyzed: 47 males and 45 females mean of age 37 ± 12 years (range: 20–68 years). There were 27 patients with a personal history of migraine headache, 30 with history of marijuana use, 12 had diabetes mellitus (DM) and 10 had irritable bowel syndrome (IBS) as an accompanying diagnosis. Fifty four patients (59%) met criteria for rapid GE, 25 (27%) had normal GE and 13 (14%) had slow GE. Eighty percent of patients with co‐existing IBS symptoms were identified as rapid. The subset with delayed emptying was often associated with narcotics use, DM and marijuana use (P < 0.05). Conclusions & Inferences (i) In adult CVS patients, GE is generally either rapid or normal. (ii) Cyclic vomiting syndrome is an important new etiology to explain the finding of rapid GE on a radionuclide test. (iii) The small subset of CVS patients (14%) whose GE was slow were explained by the role of narcotics and/or marijuana.     

Effect of peripheral obestatin on gastric emptying and intestinal contractility in rodents

Obestatin has recently been discovered in the rat stomach. It is encoded by the ghrelin gene and has been claimed to be a functional opponent of ghrelin and to be the natural ligand of the GPR39 receptor. The latter could not be confirmed by Holst et al. (Endocrinology, 2006). Yet, in GPR39 knockout mice, gastric emptying is accelerated. We verified the effects of obestatin on gastric emptying and intestinal contractility in rodents. Gastric emptying was measured with the (14)C octanoic breath test in mice. In vitro, the effect of obestatin was studied on electrically stimulated and non-stimulated strips from the fundus and small intestine of mice and rats. Obestatin (60, 125, 250 nmol kg(-1)) did not affect gastric emptying parameters (T(half) and T(lag)) and did not inhibit the prokinetic effects of ghrelin. Mouse and rat intestinal and fundic smooth muscle strips did not respond to obestatin either in the absence or in the presence of electrical field stimulation. Obestatin (125 nmol kg(-1)) did not inhibit fasting-induced hyperphagia. Our results suggest that peripheral obestatin is not a satiety signal that plays a role in the regulation of gastric emptying and do not support the concept that obestatin is a physiological opponent of ghrelin.     

Regional gastric emptying abnormalities in functional dyspepsia and gastro-oesophageal reflux disease

To characterize proximal and distal stomach emptying in functional dyspepsia (FD) and gastro-oesophageal reflux disease (GORD). Eighty-three patients underwent gastric emptying (GE) scintigraphy and symptom scoring for the evaluation of upper gastrointestinal symptoms and were divided into three groups: FD (n = 25), GORD (n = 20) and FD + GORD (n = 38). Total, proximal and distal gastric retention were determined scintigraphically and compared with normal controls. Delayed total GE was observed in each subgroup: FD (56%), GORD (45%) and FD + GORD (55%). Greater proximal gastric retention was observed after meal ingestion in GORD compared to FD. Greater distal gastric retention was observed in FD and FD + GORD but it was only mild in GORD. Nausea, vomiting, early satiety, distention and regurgitation were associated with proximal gastric retention whereas there was no symptom associated with distal gastric retention. Multiple regression demonstrated total gastric retention at 30 min and 1 h was positively correlated with regurgitation whereas early proximal gastric retention was positively correlated with regurgitation and negatively correlated with nausea. Selective abnormalities of proximal and distal stomach emptying were demonstrated in GORD and FD. GORD and FD symptoms were associated with proximal gastric retention suggesting that proximal stomach motor function may be important in the pathogenesis of symptoms associated with these disorders.     

Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Background Levodopa (l ‐dopa) is the most commonly used treatment for alleviating symptoms of Parkinson’s disease. However, l ‐dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents l ‐dopa action on gastric emptying and enhances circulating l ‐dopa in rats. Methods Gastric emptying of non‐nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) l ‐dopa, or intravenous (i.v.) ghrelin 10 min before orogastric l ‐dopa. Plasma l ‐dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 μg kg^?1) 10 min before i.p. l ‐dopa. Key Results Levodopa (5 and 15 mg kg^?1) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 μg kg^?1, i.v.) completely prevented l ‐dopa’s (15 mg kg^?1, orogastrically) inhibitory action on gastric emptying and enhanced plasma l ‐dopa and dopamine levels compared with vehicle 15 min after orogastric l ‐dopa. Levodopa (5 mg kg^?1) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg^?1, i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. Conclusions & Inferences Ghrelin counteracts l ‐dopa‐induced delayed gastric emptying but not Fos induction in the brain and enhances circulating l ‐dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson’s disease patients treated with l ‐dopa remain to be investigated.     

Endogenous and exogenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in mice

Abstract Ghrelin is an important orexigenic peptide that not only exerts gastroprokinetic but also immunoregulatory effects. This study aimed to assess the role of endogenous and exogenous ghrelin in the pathogenesis of colitis and in the disturbances of gastric emptying and colonic contractility during this process. Dextran sodium sulphate colitis was induced for 5 days in (i) ghrelin^+/+ and ghrelin^?/? mice and clinical and histological parameters were monitored at days 5, 10 and 26 and (ii) in Naval Medical Research Institute non‐inbred Swiss (NMRI) mice treated with ghrelin (100 nmol kg^?1) twice daily for 5 or 10 days. Neural contractility changes were measured in colonic smooth muscle strips, whereas gastric emptying was measured with the ¹⁴C octanoic acid breath test. Inflammation increased ghrelin plasma levels. Body weight loss, histological damage, myeloperoxidase activity and IL‐1β levels were attenuated in ghrelin^?/? mice. Whereas absence of ghrelin did not affect changes in colonic contractility, gastric emptying in the acute phase was accelerated in ghrelin^+/+ but not in ghrelin^?/? mice. In agreement with the studies in ghrelin knockout mice, 10 days treatment of NMRI mice with exogenous ghrelin enhanced the clinical disease activity and promoted infiltration of neutrophils and colonic IL‐1β levels. Unexpectedly, ghrelin treatment decreased excitatory and inhibitory neural responses in the colon of healthy but not of inflamed NMRI mice. Endogenous ghrelin enhances the course of the inflammatory process and is involved in the disturbances of gastric emptying associated with colitis. Treatment with exogenous ghrelin aggravates colitis, thereby limiting the potential therapeutic properties of ghrelin during intestinal inflammation.     

Association between changes in symptoms and gastric emptying in gastroparetic patients treated with gastric electrical stimulation

Abstract  To investigate whether there is an association between gastric emptying rate and symptom improvement in gastroparetic patients treated with gastric electrical stimulation (GES), we retrospectively reviewed 63 gastroparetic patients who received GES therapy for at least 1 year. Patient characteristics, seven upper gastrointestinal (GI) symptoms and 4-h standardized gastric emptying test (GET) were evaluated at baseline and at 1 year of GES. All symptoms were significantly reduced ( P  <   0.001). Mean gastric retention was reduced by 7% ( P  =   0.102) for measurement at 4 h. Of the 63 patients, 14 had their GET normalized and 49 remained delayed after 1 year. Normalized GET patients had a similar symptom improvement as those whose GET remained delayed. Of all upper GI symptoms, the improvements in vomiting ( P  =   0.04), nausea ( P  =   0.002) and epigastric pain ( P  =   0.001) were significantly correlated with reduction in 4-h gastric retention between baseline and 12 months of GES therapy for patients with normalized gastric emptying but there were no correlations with any symptoms and change in gastric emptying for those patients who remained delayed. In summary, overall gastric emptying is not significantly accelerated at 4 h after successful symptomatic improvement with GES but nausea, vomiting and epigastric pain can be correlated with normalization of GET in a subset of patients.     

Reversible autonomic dysfunction in hyperthyroid patients affects gastric myoelectrical activity and emptying

The autonomic nervous system (ANS) function in hyperthyroidism has been so far investigated mainly from the cardiovascular point of view. The aim of this study is to show that the ANS dysfunction in hyperthyroidism is also expressed in gastric myoelectrical activity disturbances and gastric emptying disorders and to search for a correlation between the severity of clinical manifestation and thyroid hormone levels and the degree of the ANS dysfunction. The analyzed group included 50 recently diagnosed patients with hyperthyroidism who were examined twice: before and after 3 months of thyrostatic treatment. Results were compared with those of a sex-, age- and BMI-matched control group of 50 healthy volunteers. The study included: heart rate variability analysis in time and frequency domain, at rest and during a deep-breathing test, surface electrogastrography in preprandial and postprandial periods measured simultaneously with the ultrasound assessment of gastric emptying time by Bolondi method. In patients with hyperthyroidism in comparison with the control group, the following significant differences were observed: a sharp reduction of the high-frequency component and a decrease of heart rate variability, a high incidence of dysrhythmia with dominant bradyarrhythmia, and a delay of gastric emptying. The degree of disorders related to the degree of clinical manifestation of hyperthyroidism's symptoms and free triiodothyronine serum concentration both. All the disorders were functional and disappeared in a stable euthyroidism. To conclude, the ANS dysfunction in hyperthyroidism results not only in with-drawal of vagal inhibitory effect on sinoatrial node, but in impaired mutual neuro-hormonal regulation (decrease of vagal influence) of gastric myoelectrical activity followed by delay of gastric emptying.     

Effects of gastric electrical field stimulation with long pulses on gastric emptying in dogs

The aim was to investigate the effects of electrical field stimulation (EFS) with long and short pulses on gastric emptying, gastric contractility and vagal activity in dogs. Sixteen dogs were equipped with a duodenal cannula, electrodes and strain gauges (10 dogs) in the stomach. Each dog was fed with Ensure and gastric effluent was collected from the cannula. Electrical stimulation was applied via two electrodes (about 12 cm apart, one in the corpus and the other in the antrum) with long pulses (a frequency of 6 cycles min-1, pulse amplitude of 6 mA and width of 100 ms) in 10 dogs and with short pulses (frequency of 30 Hz and pulse width of 300 micros) in six dogs. The electrocardiogram was also recorded and heart rate variability was derived to assess the vagal activity. It was found that: (i). EFS with long pulses did not alter gastric emptying during stimulation but increased gastric emptying during the 45 min immediately after stimulation; (ii). EFS with long pulses increased gastric contractility in both proximal and distal antrum during and after the stimulation; (iii). EFS with long pulses resulted in an increase in vagal tone during the 45 min immediately after stimulation. However, there is no difference during the 45 min period of stimulation; (iv). EFS with short pulses had no effect on gastric emptying. We concluded that long pulse gastric electrical field stimulation with one electrode in the corpus and the other electrode in the antrum has postponed effects on gastric emptying of liquid, gastric contractility and vagal activity.     

Gastric motor disturbances in patients with idiopathic rapid gastric emptying

Background The mechanisms of ‘idiopathic’ rapid gastric emptying, which are associated with functional dyspepsia and functional diarrhea, are not understood. Our hypotheses were that increased gastric motility and reduced postprandial gastric accommodation contribute to rapid gastric emptying. Methods Fasting and postprandial (300 kcal nutrient meal) gastric volumes were measured by magnetic resonance imaging (MRI) in 20 healthy people and 17 with functional dyspepsia; seven had normal and 10 had rapid gastric emptying. In 17 healthy people and patients, contractility was analyzed by spectral analysis of a time‐series of gastric cross‐sectional areas. Logistic regression models analyzed whether contractile parameters, fasting volume, and postprandial volume change could discriminate between health and patients with normal or rapid gastric emptying. Key Results While upper gastrointestinal symptoms were comparable, patients with rapid emptying had a higher (P = 0.002) body mass index than normal gastric emptying. MRI visualized propagating contractions at ～3 cpm in healthy people and patients. Compared with controls (0.32 ± 0.04, Mean ± SEM), the amplitude of gastric contractions in the entire stomach was higher (OR 4.1, 95% CI 1.2–14.0) in patients with rapid (0.48 ± 0.06), but not normal gastric emptying (0.20 ± 0.06). Similar differences were observed in the distal stomach. However, the propagation velocity, fasting gastric volume, and the postprandial volume change were not significantly different between patients and controls. Conclusions & Inferences MRI provides a non‐invasive and refined assessment of gastric volumes and contractility in humans. Increased gastric contractility may contribute to rapid gastric emptying in functional dyspepsia.     

Ghrelin does not stimulate gastrointestinal motility and gastric emptying: an experimental study of conscious dogs

Ghrelin is a peptide that was discovered in endocrine cells of the stomach. However, its action in regulating the fasted and fed motor activity of the digestive tract is not fully understood. In the present study, we examined the effects of an intravenous (i.v.) injection of canine ghrelin on the physiological fasted and fed motor activities in the stomach, duodenum, jejunum and colon of freely moving conscious dogs. An i.v. injection of canine ghrelin released growth hormone in a dose-dependent manner; however, it did not stimulate the motor activity of the digestive tract in either the fasted or the fed state. Moreover, an i.v. injection of high-dose canine ghrelin significantly reduced the motility index in the gastric body in the fasted state. Ghrelin did not accelerate gastric emptying, either. These results differ from previous reports dealing with rodents. It is significant that such results were obtained in research with dogs, which are larger animals.     

Cerebellar syndrome in adult celiac disease with vitamin E deficiency

We studied a woman with adult onset celiac disease complicated by a cerebellar syndrome that progressed despite the resolution of the malabsorption symptoms with a gluten free diet. The patient presented vitamin E deficiency and the cerebellar symptoms improved with vitamin E therapy. This case supports the possible role of this deficiency in the development of the neurological complications of celiac disease.     

Predictors of gastric emptying in Parkinson''s disease

Predictors of gastric emptying (GE) in patients with idiopathic Parkinson's disease (PD) of a solid and liquid meal are not well defined. For measurement of GE 80 patients with PD were randomly assigned to receive either a solid meal (250 kcal) containing 13C-octanoate (n = 40) or a liquid meal (315 kcal) with 13C-acetate (n = 40). All patient groups were off medication affecting motility and were matched for age, gender, body mass index, disease duration and severity, using Unified Parkinson's Disease Rating Scale (UPDRS). Gastric emptying was compared with a healthy control group (n = 40). Multiple regression analysis was used to determine predictors of gastric emptying. Exactly 88% and 38% of PD patients had delayed GE of solids and liquids respectively. Solid and liquid emptying was similar in women and men. There were no differences in GE in PD patients < 65 years of age when compared with patients > or = 65 years. Multiple regression analysis showed that motor handicaps such as rigour and action tremor are independent predictors of solid GE (r = 0.68, P < 0.001). The severity of motor impairment, but not any other neurological symptom, as assessed by UPDRS is associated with gastroparesis in PD and solid emptying is more likely to be delayed.     

Central administration of pan‐somatostatin agonist ODT8‐SST prevents abdominal surgery‐induced inhibition of circulating ghrelin,food intake and gastric emptying in rats

Background Activation of brain somatostatin receptors (sst_1–5) with the stable pan‐sst_1–5 somatostatin agonist, ODT8‐SST blocks acute stress and central corticotropin‐releasing factor (CRF)‐mediated activation of endocrine and adrenal sympathetic responses. Brain CRF signaling is involved in delaying gastric emptying (GE) immediately post surgery. We investigated whether activation of brain sst signaling pathways modulates surgical stress‐induced inhibition of gastric emptying and food intake. Methods Fasted rats were injected intracisternally (i.c.) with somatostatin agonists and underwent laparotomy and 1‐min cecal palpation. Gastric emptying of a non‐nutrient solution and circulating acyl and desacyl ghrelin levels were assessed 50 min post surgery. Food intake was monitored for 24 h. Key Results The abdominal surgery‐induced inhibition of GE (65%), food intake (73% at 2 h) and plasma acyl ghrelin levels (67%) was completely prevented by ODT8‐SST (1 μg per rat, i.c.). The selective sst₅ agonist, BIM‐23052 prevented surgery‐induced delayed GE, whereas selective sst₁, sst₂, or sst₄ agonists had no effect. However, the selective sst₂ agonist, S‐346‐011 (1 μg per rat, i.c.) counteracted the abdominal surgery‐induced inhibition of acyl ghrelin and food intake but not the delayed GE. The ghrelin receptor antagonist, [D‐Lys³]‐GHRP‐6 (0.93 mg kg^?1, intraperitoneal, i.p.) blocked i.p. ghrelin‐induced increased GE, while not influencing i.c. ODT8‐SST‐induced prevention of delayed GE and reduced food intake after surgery. Conclusions & Inferences ODT8‐SST acts in the brain to prevent surgery‐induced delayed GE likely via activating sst₅. ODT8‐SST and the sst₂ agonist prevent the abdominal surgery‐induced decrease in food intake and plasma acyl ghrelin indicating dissociation between brain somatostatin signaling involved in preventing surgery‐induced suppression of GE and feeding response.