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.     

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.     

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 placebo-controlled trial of an oral capsaicin load in patients with functional dyspepsia

Background The pathophysiology of functional dyspepsia is poorly understood. Visceral hypersensitivity may play a key role. We studied a previously validated test to assess chemical hypersensitivity in functional dyspepsia by applying an oral capsaicin load. Methods A total of 116 outpatients with upper gastrointestinal (GI) symptoms participated in this double‐blind, placebo‐controlled trial of which 73 patients received a final diagnosis of functional dyspepsia. Patients swallowed a capsule containing 0.75 mg capsaicin or placebo. A graded questionnaire evaluated the severity of nine upper GI symptoms before and after capsule ingestion and an aggregate symptom score was calculated. A final score of >9 was considered as a positive test. Key Results In functional dyspepsia, median perception scores were 10.8 (interquartile range: 4.5–18.8) after ingestion of capsaicin and 0.5 (0.0–2.5) after placebo (P < 0.001). Thirty‐seven functional dyspepsia patients (54%) had a positive test after capsaicin ingestion, whereas only four (11%) patients with upper GI symptoms but without functional dyspepsia were capsaicin positive [median perception score: 1.5 (0.0–5.0)]. After placebo, symptom scores were low and not significantly different among patient groups (P > 0.05). Clinical characteristics, age, and gender distribution was similar in capsaicin positive and capsaicin negative functional dyspepsia patients (P > 0.05). The value of patient blinding was good. Conclusions & Inferences Half of functional dyspepsia patients had chemical hypersensitivity, determined with an oral capsaicin load. Placebo response was negligible. The results of the capsaicin test were not associated with specific dyspepsia symptoms or Rome subgroups.     

Acotiamide hydrochloride (Z-338), a novel prokinetic agent, restores delayed gastric emptying and feeding inhibition induced by restraint stress in rats

Abstract  Acotiamide hydrochloride (Z-338) is a member of new class prokinetic agents currently being developed for the treatment of functional dyspepsia (FD). DNA microarray analysis showed that acotiamide altered the expressions of stress-related genes such as γ -aminobutyric acid (GABA) receptors, GABA transporters and neuromedin U (NmU) in the medulla oblongata or hypothalamus after administration of acotiamide. Therefore, effects of acotiamide on stress-related symptoms, delayed gastric emptying and feeding inhibition, in rats were examined. Acotiamide significantly improved both delayed gastric emptying and feeding inhibition in restraint stress-induced model, but did not affect both basal gastric emptying and feeding in intact rats, indicating that acotiamide exerted effects only on gastric emptying and feeding impaired by the stress. On the other hand, mosapride showed significant acceleration of gastric emptying in intact and restraint stress-induced model, and itopride showed no effect on restraint stress-induced delayed gastric emptying. In addition, gene expression of NmU increased by restraint stress was suppressed by administration of acotiamide, while acotiamide had no effect on delayed gastric emptying induced by an intracerebroventricular administration of NmU, suggesting that the suppressive effect of acotiamide on gene expression of NmU might be important to restore delayed gastric emptying or feeding inhibition induced by restraint stress. These findings suggest that acotiamide might play an important role in regulation of stress response. As stress is considered to be a major contributing factor in the development of FD, the observed effects may be relevant for symptom improvement in FD.     

A placebo‐controlled trial of the 5‐HT1A agonist R‐137696 on symptoms,visceral hypersensitivity and on impaired accommodation in functional dyspepsia

Abstract Acute studies suggested a therapeutic benefit for fundus‐relaxing drugs in functional dyspepsia (FD) with visceral hypersensitivity (VH) to gastric distention or impaired accommodation (IA), but long‐term studies are lacking. R‐137696 is a serotonin‐1A (5‐HT_1A) receptor agonist which relaxes the proximal stomach in man. Our aim was to investigate the influence of R‐137696 on symptoms in FD with VH or IA. Randomized, double‐blind, placebo‐controlled, parallel group study of 4 weeks R‐137696 2 mg t.i.d. in FD with VH or IA. Symptoms were assessed using the patient assessment of upper gastrointestinal symptom severity index (PAGI‐SYM) total score and individual symptom subscales. Barostat studies were performed before and after 4 weeks of treatment. Fifty‐three patients (33 VH and 20 IA), 18 men, mean age 40 ± 13 years were recruited. Twenty‐four received placebo and 29 received R‐137696. In VH patients, both placebo and R‐137696 improved total symptom scores, with a tendency for superiority of placebo (?1.12 vs?0.51, P = 0.07). Placebo was superior for the subscales of early satiety, bloating, fullness and discomfort (all P < 0.05). In IA, both placebo and R‐137696 had no significant influence on total or individual symptom scores (?0.08 and ?0.27). In VH, both placebo and R‐137696 increased the discomfort volume, without a statistical difference between both arms (+120 and +164 mL). In IA, both placebo and R‐137696 enhanced accommodation, without a statistical difference between both (+77 and +159 mL). Adverse events were similar for drug and placebo. A 4‐week administration of the fundus‐relaxing 5‐HT_1A agonist R‐137696 failed to significantly improve symptoms, VH or gastric accommodation compared to placebo.     

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.     

Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography

Background Improvement in subjective symptoms has been reported in functional dyspepsia (FD) patients administered with acotiamide. Improvement was confirmed in meal‐related symptoms, such as postprandial fullness, upper abdominal bloating, and early satiety. We examined the mechanism underlying the effects of acotiamide on gastric accommodation reflex (GAR) and gastroduodenal motility in FD patients. Methods Thirty‐four FD patients (mean age, 40.4 years) were examined ultrasonographically before and after 14–18 days of acotiamide (100 mg t.i.d.) or placebo administration. To assess GAR, expansion rate in cross‐sectional area of the proximal stomach was measured after every 100‐mL ingestion, using a straw, of up to 400 mL of a liquid meal (consommé soup, 13.1 kcal; 400 mL) in a supine position. Next, we measured gastric emptying rate (GER), motility index (MI, antral contractions), and reflux index (RI, duodenogastric reflux) to assess gastroduodenal motility. Patients also completed a survey based on the seven‐point Likert scale both before and after drug administration. Key Results Of the 37 cases, 19 and 18 were administered with acotiamide and placebo A respectively, significant difference was observed in GAR between the acotiamide and placebo groups (21.7%vs 4.4%) after 400 mL ingestion. GER significantly accelerated after treatment in the acotiamide group (P = 0.012), no significant differences were observed in MI and RI between the two groups. Improvement rates were 35.3 and 11.8% for the acotiamide and placebo groups. Conclusions & Inferences Acotiamide significantly enhances GAR and GER in FD patients. Acotiamide may have therapeutic potential for FD patients.     

Assessment of gastric sensorimotor function in paediatric patients with unexplained dyspeptic symptoms and poor weight gain

Recent studies indicate that impaired meal accommodation or hypersensitivity to distention are highly prevalent in adult functional dyspepsia (FD). Our aim was to investigate whether similar abnormalities also occur in paediatric FD. Sixteen FD patients (15 girls, 10-16 years) were studied. The severity (0-3; 0, absent; 3, severe) of eight dyspeptic symptoms (epigastric pain, fullness, bloating, early satiety, nausea, vomiting, belching and epigastric burning) and the amount of weight loss were determined by questionnaire. All children underwent a gastric barostat study after an overnight fast to determine sensitivity to distention and meal-induced accommodation, which were compared with normal values in young adults (18-22 years). On a separate day, all patients underwent a gastric emptying breath test. A mean weight loss of 4.8 +/- 0.9 kg was present in 14 children. Compared with controls, patients had lower discomfort thresholds to gastric distention (8.8 +/- 1.0 mmHg vs 13.9 +/- 1.9 mmHg, P < 0.02) and gastric accommodation (87 +/- 25 mL vs 154 +/- 20 mL P < 0.04). Hypersensitivity to distention and impaired accommodation were present in respectively nine (56%) and 11 (69%) patients. No relationship was found between barostat and gastric emptying, which was delayed in only three patients. The majority of children with unexplained epigastric symptoms have abnormalities of gastric sensorimotor function.     

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.     

Electroacupuncture for patients with refractory functional dyspepsia: A randomized controlled trial

Background

To test the efficacy of electroacupuncture for patients with refractory functional dyspepsia (FD).

Methods

A 24‐week, 2‐arm, single‐blind, randomized controlled trial was conducted at three hospitals in China. Patients with refractory FD were randomly assigned to receive 20 sessions of authentic or sham electroacupuncture in a treatment duration of 4 weeks. The primary outcome was complete absence of dyspeptic symptoms at 16 weeks after initiation of acupuncture (week 16). The secondary outcomes included adequate relief of dyspeptic symptoms, Leeds Dyspepsia Questionnaire (LDQ ), Nepean Dyspepsia Index (NDI ), and adverse events. Intention‐to‐treat analysis was performed.

Key Results

Two hundred patients were included, of which 196 (98%) completed follow‐up data at week 24. At week 16, 17 (17%) patients in the authentic electroacupuncture group vs 6 (6%) patients in the sham group achieved the primary outcome (P  = .014). Sixty‐two (62%) patients had adequate relief in the authentic electroacupuncture group, as compared to 22 (22%) in the sham group (P  = .001). The scores of LDQ and NDI were significantly improved in both groups at week 16, and patients in the authentic electroacupuncture group have more improvements (LDQ , mean difference, ?2.2, 95% confidence interval, ?2.3 to ?2.1, P  < .001; NDI , ?7.3, ?10.5 to ?4.2, P  < .001). Results were similar for all the outcomes assessed at week 24. No serious adverse events were reported in both groups.

Conclusion

Acupuncture efficaciously improves dyspeptic symptoms in patients with refractory FD.

     

Clinical trial: dose‐dependent therapeutic efficacy of acotiamide hydrochloride (Z‐338) in patients with functional dyspepsia – 100 mg t.i.d. is an optimal dosage

Background Acotiamide is a selective acetylcholinesterase inhibitor and enhances the actions of cholinergic neurons localized in the stomach. Methods The present two studies were conducted to examine the optimal dosage of acotiamide hydrochloride (Z‐338) in patients with functional dyspepsia (FD) in Japan. Key Results The improvement rate of ‘subjects global assessment of overall treatment efficacy (OTE)’ at the final evaluation was approximately 10% higher in the acotiamide 100 mg group than that in the placebo group with good reproducibility though there was no significant differences at primary endpoint. The elimination rate of postprandial fullness in the acotiamide 100 mg group was significantly higher compared to placebo group. In addition, the post hoc analysis showed that in patients whose main complaints are meal‐related symptoms such as postprandial fullness, upper abdominal bloating and/or early satiety, the improvement rate of ‘OTE’ at final evaluation in acotiamide 100 mg group was significantly superior to that in the placebo group. Conclusions & Inferences These results suggest that acotiamide possesses efficacy on FD and more specifically its meal‐related symptoms of FD.