Relationship between symptom pattern, assessed by the PAGI-SYM© questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia

Abstract The patient assessment of upper gastrointestinal symptom severity index (PAGI‐SYM) questionnaire was recently developed and validated for the evaluation of therapeutic responsiveness in functional dyspepsia (FD). Functional dyspepsia is a heterogeneous disorder, with different pathophysiological mechanisms underlying the symptom pattern. The relationship between PAGI‐SYM scores and putative pathophysiological mechanisms has not been studied. The aim of this study was to evaluate the relationship between PAGI‐SYM subscales and gastric emptying, gastric sensitivity and gastric accommodation in FD. A total of 161 consecutive FD patients underwent Helicobacter pylori (HP), gastric barostat and standardized gastric emptying testing (n = 126), and completed the PAGI‐SYM questionnaire. Relationships between scores for the six subscales (heartburn/regurgitation, nausea/vomiting, fullness/satiety, bloating, upper abdominal pain, lower abdominal pain) and gastric function were analysed using Pearson’s linear correlation, multiple regression analysis, chi‐square and Student’s t‐tests. Gastric emptying was significantly correlated with scores for heartburn/regurgitation (r = 0.26), nausea/vomiting (r = 0.19), fullness/satiety (r = 0.20), bloating (r = 0.21) and lower abdominal pain (r = 0.22; all P < 0.05). Patients with delayed emptying had significantly higher scores for each of these subscales (all P < 0.05). Discomfort volume during gastric distension was significantly correlated with scores for fullness/satiety (r = ?0.27), bloating (r = ?0.23), heartburn/regurgitation (r = ?0.21), and upper abdominal pain (r = ?0.20). Patients with hypersensitivity to distension had significantly higher scores for fullness/satiety (P < 0.05). At different cut‐off levels of symptom severities, consistent associations were found between fullness/satiety and gastric discomfort volume, between preprandial volumes and upper abdominal pain, compliance and upper abdominal pain, and between bloating and gastric discomfort volume. Multiple regression analysis revealed that gastric emptying rate contributed significantly to models for the severity of these subscales. The importance of discomfort volume disappeared in favour of gender when sex was included in the model. No significant correlations were found with HP status or with gastric accommodation. PAGI‐SYM scores are mainly correlated with gastric emptying rate and with gastric hypersensitivity. Multivariate analysis suggests that the questionnaire may be useful in the evaluation of gastroprokinetics. Its role in the evaluation of drugs that alter gastric sensitivity is less clear.     

Influence of tegaserod on proximal gastric tone and on the perception of gastric distention in functional dyspepsia

Background Abnormalities in gastric sensorimotor function (hypersensitivity to distention and impaired meal accommodation) have been implicated in the pathophysiology of functional dyspepsia (FD). To study the effect of the 5‐HT₄ agonist tegaserod on sensitivity to gastric distention and gastric accommodation in FD. Methods Thirty FD patients (7 males, mean age 42 ± 2 years) underwent a gastric barostat study on two separate occasions, 2 weeks apart, after 5 days of pretreatment with placebo or tegaserod 6 mg b.i.d. in a double‐blind randomized order. After introduction of the barostat bag, graded isobaric distentions (2 mmHg increments/2 min) were performed to determine gastric compliance and sensitivity to distention. Subsequently, the pressure level was set at intra‐abdominal pressure [minimal distending pressure (MDP)] + 2 mmHg for 90 min, with administration of a liquid meal (200 mL; 300 kcal) after 30 min. Key Results Tegaserod had no influence on MDP (7.9 ± 0.4 vs 7.4 ± 0.4 mmHg) or fasting gastric compliance (44 ± 10 vs 61 ± 6 mL mmHg^?1) and on fasting thresholds for first perception (3.6 ± 0.4 vs 4.2 ± 0.2 mmHg above MDP) or discomfort (9.9 ± 0.7 vs 10.5 ± 0.5 mmHg above MDP). Tegaserod did not alter intra‐balloon volumes before and after the meal [respectively 146 ± 14 vs 120 ± 11 and 297 ± 28 vs 283 ± 29 mL, not significant (NS)], or the amplitude of the meal‐induced gastric relaxation (151 ± 23 vs 162 ± 23 mL, NS). In the subgroup with normal gastric emptying (n = 22), tegaserod significantly enhanced meal‐induced accommodation (126 ± 23 vs 175 ± 29 mL, anova P < 0.001). Conclusions & Inferences Tegaserod does not alter gastric sensorimotor function in FD patients as a group. In the subgroup with normal gastric emptying, tegaserod 6 mg b.i.d enhanced gastric accommodation.     

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.     

Distension-induced gastric accommodation in functional dyspepsia: effect of autonomic manipulation

Functional dyspepsia (FD) is associated with impaired gastric accommodation and autonomic dysregulation. The aim of this study was to investigate the effects of autonomic manipulation on distension-induced gastric accommodation in subjects with and without FD, using a newly developed gastric barostat paradigm. Twelve healthy subjects (HS) and 18 subjects with FD had four barostat examinations each: no intervention, intravenous atropine (1 mg), vagal stimulation (mental relaxation with deep breathing) and acute stress stimulation (serial subtraction task). Intrabag pressure increased from 1 to 15 mmHg in 5 min (ramp phase), and was maintained at 15 mmHg for 5 min (tonic phase). Volume responses were analysed using predefined parameters. There were no significant group differences in accommodation variables between HS and subjects with FD. The FD group could be subdivided into two distinct subgroups: subgroup 1 (n = 7, 38%) with low maximum volume and accommodation rate, and subgroup 2 with normal accommodation (n = 11). In subgroup 1, but not in subgroup 2 atropine increased maximum volume and accommodation rate substantially. Neither mental stress nor mental relaxation changed any of the accommodation variables. In a subgroup of subjects with FD, impairment of distension-induced gastric accommodation can be improved by cholinergic blockade, but not by acute physiological autonomic manipulation.     

Characterization of gastric volume responses and liquid emptying in functional dyspepsia and health by MRI or barostat and simultaneous 13C-acetate breath test

Abstract The assessment of gastric accommodation and emptying by different methodologies provides inconsistent results. We aimed to compare magnetic resonance imaging (MRI), barostat and ¹³C‐acetate breath test (BT) for the assessment of gastric volume responses and emptying in healthy controls (HC) and patients with functional dyspepsia (FD). Eight HC and eight FD patients underwent: (i) continuous BT with simultaneous MRI in the upright position after ingestion of isocaloric, 300 kcal, 200 and 800 mL meals, both labelled with 100 mg of ¹³C‐acetate; and (ii) BT with gastric barostat after ingestion of the 200 mL meal. MRI measured total gastric volume and gastric content volume (GCV) at baseline, after filling and during emptying. Meal emptying half‐times (T½) for MRI and BT were calculated (mean ± SD). We found: (i) Initial GCV was lower in FD than in HC (762 ± 22 vs 810 ± 52 mL, P < 0.04) after the 800 mL meal but not the 200 mL meal. T½_MRI was shorter for the 800 mL than the 200 mL meal (P < 0.001), but similar in HC and FD (200 mL: HC 117 ± 30 min vs FD 138 ± 42 min, ns; 800 mL: HC 71 ± 16 min vs FD 78 ± 27 min, ns). In contrast, T½_BT was similar between meals and groups (200 mL: HC 111 ± 11 min vs FD 116 ± 19 min; 800 mL: HC 114 ± 14 min vs FD: 113 ± 17 min). (ii) Barostat measurements showed similar postprandial volume increases between groups. We conclude that direct measurements by MRI provide a sensitive, non‐invasive assessment of gastric accommodation and emptying after a meal. In contrast to MRI, BT did not detect faster emptying of high‐volume compared to low‐volume liquid nutrient meals in HC or FD.     

Role of endogenous opioids in the control of gastric sensorimotor function

Abstract Endogenous opioids have been implicated not only in the process of feeding but also in the control of gastric sensitivity and gastric motor responses, and impairment of antinociceptive opioid pathways has been hypothesized to contribute to the pathogenesis of functional dyspepsia. Our aim was to study the effect of suppression of endogenous opioid action by naloxone on gastric sensorimotor function in healthy volunteers. During intravenous administration of saline or naloxone (0.4 mg intravenous bolus followed by continuous infusion 20 μg kg^?1 h^?1), sensitivity to gastric distension, gastric accommodation and fundic phasic contractility were evaluated by barostat in 15 subjects. Nutrient tolerance and meal‐related symptoms were assessed using a satiety drinking test (n = 13), and solid and liquid gastric emptying were evaluated by breath test (n = 14). Naloxone did not influence gastric compliance and sensitivity. No effect on preprandial gastric tone was found but meal‐induced accommodation was significantly inhibited by naloxone (P = 0.031). Subjects receiving naloxone demonstrated a higher motility index before (20.8 ± 2.4 vs 28.0 ± 1.9 mL s^?1, P = 0.007) and after (15.2 ± 2.0 vs 22.7 ± 1.5 mL s^?1, P = 0.0006) the meal. Naloxone significantly decreased the amount of food ingested at maximum satiety (715.4 ± 77.7 vs 617.3 ± 61.3 mL, P = 0.03). No effect of naloxone on gastric emptying was observed and intensity of postprandial symptoms was unchanged. These observations suggest that endogenous opioids are involved in the control of gastric accommodation and phasic contractility but not in the control of sensitivity to gastric distension or gastric emptying in healthy volunteers.     

Intersubject and intrasubject variability of gastric volumes in response to isocaloric liquid meals in functional dyspepsia and health.

Gastric emptying (GE) has a considerable variability, but data on reproducibility of gastric volume measurements are sparse. We aimed to study the reproducibility of postprandial gastric volume responses and GE using magnetic resonance imaging (MRI) in healthy controls (HC) and patients with functional dyspepsia (FD). Eight HC and eight FD patients underwent a MRI study on two occasions. MR images were acquired in seated position before and up to 120 min after liquid meal administration (200 mL, 300 kcal). Fasting (V0), initial postprandial stomach volumes (V1), volume changes (V1 - V0) and meal emptying half-times (T 1/2) were determined. Intersubject and intrasubject coefficients of variation (CV(inter), CV(intra)) and Pearson's correlation coefficients (r) were calculated. T 1/2 on both occasions were (mean +/- SD) 113 +/- 28 and 121 +/- 30 min in HC (ns) and 127 +/- 31 and 128 +/- 37 min in FD (ns), respectively. In HC, CV(inter), CV(intra), r were 31%, 23%, 0.49 for V0; 13%, 7%, 0.68 for V1; 10%, 4%, 0.71 for V1 - V0 and 25%, 7%, 0.90 for T 1/2. In FD these parameters were for V0: 42%, 41%, -0.06; for V1: 18%, 10%, 0.40; for V1 - V0: 20%, 14%, 0.74 and for T 1/2: 26%, 10%, 0.84. The stomach accommodates to a given meal volume, resulting in similar and reproducible postprandial volumes within- and between-subjects. MRI provides reproducible measurements of gastric volume responses in health and disease.     

Reproducibility and symptomatic predictors of a slow nutrient drinking test in health and in functional dyspepsia

Abstract  Impaired accommodation to a meal has been recognized as a pathophysiological mechanism in functional dyspepsia (FD). Based on observations in tertiary care patients, the drinking test has been proposed as a non-invasive tool to estimate accommodation. Our aim was to assess the reproducibility of the drinking test and its correlation with demographic, symptomatic and pathophysiological parameters in secondary care FD patients and healthy controls. Thirty-four healthy controls and 78 FD patients completed a drinking test (3 respectively 2 times), a gastric emptying study and an FD symptom questionnaire. Factors influencing maximal volume and gastric emptying were determined, and the reproducibility of the drinking test was investigated. The maximal satiety was reached at a lower volume in patients (489 ± 276 and 503 ± 248 mL for first and second test respectively vs 937 ± 428 and 1048 ± 421 mL, P  < 0.0001). The ingested amount depended on age, sex and baseline FD symptom score. Patients' sex, final satiety score, total score for stomach complaints at screening and total symptom score before test accounted for the total symptom score after the test. The slow nutrient drinking test confirms its possible role as an attractive non-invasive and reproducible tool for the diagnosis of impaired accommodation and for the assessment of treatment responsiveness.     

Influence of the 5‐HT3 receptor antagonist ondansetron on gastric sensorimotor function and nutrient tolerance in healthy volunteers

Background Serotonin is believed to be involved in the regulation of the gastric accommodation reflex in man however which receptor subtype(s) are involved remains to be elucidated. Methods Eleven healthy subjects (nine men, age 19–30) underwent a gastric barostat and a drinking test after treatment with either placebo or ondansetron (8 mg intravenously). During the barostat protocol an intragastric flaccid bag was stepwise distended (2 mmHg increments 2 min) to determine gastric compliance and sensitivity to distention. Subsequently, the pressure level was set at intra‐abdominal pressure +2 mmHg while volume was followed before and after administration of a liquid meal (200 mL; 300 kcal). During the drink test volunteers drank at a rate of 15 mL min^?1 until maximal satiation. Results (mean ± SEM) were compared using t‐tests and mixed model analysis. Key Results Gastric compliance was not significantly altered by ondansetron (51.5 ± 5.6 vs 49.2 ± 5.2 mL mmHg^?1), neither were the pressure thresholds for first perception or discomfort. Ondansetron treatment did not affect basal gastric tone (173 ± 14 vs 156 ± 12 mL), neither did it affect the amplitude of the meal‐induced relaxation (160 ± 52 vs 131 ± 43 mL) or the maximum volume increase after the meal (264 ± 54 mL vs 234 ± 51 mL). During the drinking test the amount of liquid meal ingested at maximum satiation was significantly increased by ondansetron (784 ± 74 vs 907 ± 64 mL, P < 0.05). Conclusions & Inferences These data suggest that 5‐HT acting at 5‐HT₃ receptors is not involved in the control of gastric sensorimotor function, but contributes to the regulation of hunger and satiation in man.     

Effect of mianserin on gastric sensorimotor function and gastric emptying: a randomized,placebo‐controlled,double‐blind,crossover study in healthy volunteers

Background Antidepressants such as mianserin can improve symptoms in some functional dyspeptic patients but their mechanism of action remains unclear. We aimed to assess the effects of mianserin on gastric sensorimotor function in man. Methods In this randomized, placebo‐controlled, double‐blind, crossover study 12 healthy subjects (six men) underwent a gastric barostat study and a gastric emptying breath test after 7 days pretreatment with placebo or mianserin (20 mg; p.o.). Graded isobaric and isovolumetric distentions were performed to determine gastric compliance and sensitivity. Subsequently, intrabag pressure was held constant and the volume increase after administration of a liquid meal (200 mL; 300 kcal) was studied. Breath was sampled before and after ingestion of a test meal and half‐emptying times for solids and liquids were determined from the breath samples. Mianserin was compared to placebo using t‐tests and mixed model analysis (mean ± SD). Key Results Mianserin did not affect pressures or volumes needed to induce first perception or discomfort. During isovolumetric distensions compliance was decreased after mianserin treatment (1.8 ± 0.4 vs 2.0 ± 0.3 mmHg 100 mL^?1; P < 0.05). Premeal volumes were comparable in both treatment arms (221 ± 99 vs 220 ± 88 mL), but meal‐induced relaxation during the first 30 min was significantly inhibited after mianserin treatment (F_6,40 = 2.58, P < 0.05). Mianserin did not affect either solid or liquid gastric emptying. Conclusions & Inferences Mianserin does not alter gastric emptying rate or sensitivity to gastric distension, but inhibits gastric accommodation to a meal in its early phase. These observations provide no explanation for the effects of mianserin in functional dyspeptic patients.     

Influence of gastric acid on gastric emptying and gastric distension-induced pain response in rats - effects of famotidine and mosapride

Background Gastroduodenal acidification has been reported to aggravate upper abdominal discomfort and pain that are symptoms suffered by functional dyspepsia (FD) patients. Delayed gastric emptying and hypersensitivity to gastric distension (GD) contribute importantly to the pathophysiology of FD. Methods In the present study, we determined the influence of pentagastrin‐stimulated endogenous gastric acid on gastric emptying and GD‐induced pain responses using rat model systems. Moreover, we evaluated the effects of famotidine and mosapride on changes in gastric emptying and the GD‐induced pain response to gastric acid hypersecretion. Gastric emptying was measured by excretion of glass beads that had been intragastrically administered with a liquid nutrient, and gastric pain response was evaluated by observing whether a GD‐induced increase in mean blood pressure occurred. Key Results Pentagastrin (2 mg kg^?1, s.c.) which markedly and continuously stimulated gastric acid secretion, significantly delayed and enhanced respectively, gastric emptying and pain compared with saline‐injected groups. Oral famotidine (0.1–3 mg kg^?1) and mosapride (0.3–3 mg kg^?1) administration in a dose‐dependent manner accelerated the delay of gastric emptying. Furthermore, famotidine (0.3–3 mg kg^?1) significantly alleviated the aggravation of the GD‐induced pain response, but mosapride (10 mg kg^?1) did not. Conclusions & Inferences We established rat models to evaluate the effect of gastric acid hypersecretion on gastric emptying and the GD‐induced pain response. In these models, acid hypersecretion delayed gastric emptying and aggravated the pain response. Furthermore, we showed that famotidine ameliorated both delayed gastric emptying and gastric hypersensitivity, whereas mosapride only improved delayed gastric emptying.     

Intragastric distribution of a standardized meal in health and functional dyspepsia: correlation with specific symptoms

In functional dyspepsia, abnormal intragastric distribution of a test meal has been identified but has never been correlated to any symptom pattern. The aim of this study was to compare the intragastric distribution of a meal between functional dyspepsia patients and controls, and to correlate distribution with symptom patterns, using scintigraphic gastric emptying studies. In forty patients with functional dyspepsia and 29 healthy volunteers, scintigraphic planar images were obtained immediately after ingestion of a mixed radiolabelled test meal and every 20 min for 2 h. The images of the stomach were divided into proximal and distal compartments. The mean intragastric distribution was similar in patients and controls. Over the whole test, 18 (45%) and 20 (50%) patients had a distal redistribution of the solid and liquid phase of the meal, respectively, while proximal retention of these phases was found in 13 (33%) and 9 (23%) patients. Early satiety was associated with early distal redistribution of the liquid phase and fullness was associated with late proximal retention. This study shows similar intragastric distribution of a test meal in health and functional dyspepsia. Within the patient group, an association between abnormal intragastric distribution patterns and symptom profiles was found, which might be related to different pathophysiological mechanisms.     

A dose-ranging, placebo-controlled, pilot trial of Acotiamide in patients with functional dyspepsia

Abstract  Impaired gastric accommodation, hypersensitivity to distension and delayed gastric emptying are major pathophysiological mechanisms in functional dyspepsia (FD). Acotiamide (Z-338) was well-tolerated in healthy volunteers. To determine the effect of three doses of Acotiamide on major pathophysiological mechanisms, symptoms, quality of life (QOL) and safety in functional dyspeptics. A phase IIa, randomized, double-blind, placebo-controlled study (14, 21 and 28 days, respectively, for run-in, study drug administration and follow-up). Gastric accommodation, sensitivity to distension and gastric emptying were assessed by barostat and ¹³C breath test, symptoms by daily diary cards and QOL by SF-36. A total of 71 patients were enrolled (62 evaluable). There was no effect on gastric emptying and sensitivity to distension. 300 mg was better than placebo for meal accommodation ( P  = 0.024). 100 mg was better than placebo at week 2 for upper abdominal bloating ( P  = 0.001) and overall symptom score ( P  = 0.022), and at week 3 for bloating ( P  = 0.008) and heartburn ( P  = 0.041). 100 mg was also better than placebo for QOL (physical function) ( P  = 0.003). Acotiamide was safe and well-tolerated in patients with FD. The involved mechanism could at least in part depend on an effect on meal-induced accommodation. 100 mg Acotiamide exhibited the potential to improve FD symptoms and QOL. Further studies are indicated.     

Assessment of gastric motor function in childhood functional dyspepsia and obesity

Background The aim was to compare gastric emptying rate and nutrient tolerance during a satiety drinking test in children with functional dyspepsia (FD) and obesity and to study the relationship between daily caloric intake and the satiety drinking test. Methods A total of 28 dyspeptic children (22 girls, mean age 12.5 ± 3.1 years) and 15 obese children (five girls, 13.3 ± 1.8 years) were studied. The patients underwent an octanoic acid gastric emptying breath test and a satiety drinking test. Prior to both tests, a dyspepsia questionnaire was filled out to calculate the mean calorie intake. Key Results The most prevalent dyspeptic symptoms were early satiety (96.4%), postprandial fullness (89.2%), and epigastric pain (78.6%), followed by nausea (50%). All dyspeptic and obese children (n = 43) started the satiety drinking test and 41 children completed the test until a score of 5 was reached. The maximum ingested volume in FD was significantly lower than in obesity or in age‐matched healthy controls (252 ± 85 vs 479 ± 199 and 359 ± 29 mL respectively, both P < 0.05). As a group, dyspeptic children had significantly slower gastric emptying than obese children (89.7 ± 54.8 min vs 72.5 ± 26.0 min, P = 0.05). Daily calorie intake was significantly higher in obese children than that in dyspeptic children (2325 ± 469 vs 1503 ± 272 cal, P < 0.0001). The endpoint of the satiety drinking test was significantly correlated with body weight or BMI (both R = 0.41, P = 0.04), but not with daily calorie intake, gastric emptying rate or age. Conclusions & Inferences The satiety drinking test is a potentially useful non‐invasive tool in the investigation of children with FD and obesity.     

Symptom pattern and pathophysiological correlates of weight loss in tertiary-referred functional dyspepsia

Abstract  In patients with gastrointestinal symptoms, weight loss is an alarm symptom, indicative of organic disease. Recent studies reported weight loss in subsets of functional dyspepsia (FD) patients. The aim of this study was to analyse symptom patterns associated with weight loss in tertiary care FD. Six hundred and thirty-six FD patients (67% female, mean age 43 years) completed a dyspepsia questionnaire, and underwent gastric emptying and gastric barostat studies. After identifying independent symptom domains through orthogonal factor analysis, patients were clustered on the basis of symptom profile. Clusters were compared in terms of their association with weight loss and gastric emptying or sensorimotor function. Weight loss (4.2 kg on average) correlated most strongly with early satiety followed by nausea and vomiting ( ρ respectively 0.38, 0.28 and 0.23, all P  < 0.0001). Factor analysis revealed three factors: Factor 1 characterized by nausea, vomiting and early satiety; factor 2 by early satiety, postprandial fullness and bloating; and factor 3 by pain, epigastric burning and belching. Subsequent cluster analysis revealed six patient clusters. The most severe cluster, which loaded high on all three factors, and a cluster dominated factor 2 were associated with the highest average weight loss (6.8 and 8.0 kg, respectively). The former cluster was also characterized by visceral hypersensitivity and delayed gastric emptying. The lowest weight loss occurred in the two clusters that had depressed scores for both early satiety associated factors (2.4 and 2.5 kg, respectively). In tertiary care FD, weight loss is strongly associated with two early satiety associated symptom clusters.