The NO/cGMP pathway in duodenal motor, mechano- and chemosensory responses to acid: A randomized, placebo-controlled study with sildenafil in healthy volunteers.

BACKGROUND: Altered duodenal sensorimotor responses to acid have been reported in a subset of patients with functional dyspepsia. To investigate whether NO is involved in these abnormalities, the effect of sildenafil (activates the NO pathway) on duodenal motor and sensory responses to acid in healthy humans was evaluated. METHODS: A barostat-manometry catheter including an infusion tube was positioned in the duodenum of 12 healthy volunteers. Duodenal motility and dyspeptic symptoms were evaluated during the whole study. A first series of stepwise isobaric distensions was performed while participants scored their perception of upper abdominal sensations at the end of every distension step. Next, the duodenum was infused with sildenafil 50 mg or saline, followed by duodenal acid infusion. During duodenal acidification, a second sequence of stepwise isobaric distensions with the assessment of sensations was repeated. KEY RESULTS: Acid infusion did not induce dyspeptic symptoms with both placebo and sildenafil pretreatment. Duodenal motility decreased after sildenafil infusion, whereas it was not affected by placebo. Acid-induced increase in motility was, however, observed in both conditions, and no difference between the conditions was found. Duodenal acidification decreased thresholds for discomfort and increased perception scores during duodenal distensions in both groups, but again no difference was observed between placebo and sildenafil pretreatment. CONCLUSIONS AND INFERENCES: Sildenafil does not affect duodenal motor, mechanosensory, and chemosensory responses to acid in healthy controls. Therefore, it is less likely that the NO pathway plays a role in the altered response to acid in functional dyspepsia patients.

Pathophysiological Abnormalities in Functional Dyspepsia Subgroups According to the Rome III Criteria.

OBJECTIVES: The Rome III criteria proposed to subdivide functional dyspepsia (FD) into a postprandial distress syndrome (PDS) group, characterized by the presence of postprandial fullness and/or early satiety, and an epigastric pain syndrome (EPS) group, characterized by the presence of epigastric pain and/or epigastric burning. It has been suggested that different pathophysiological mechanisms underlie the symptom presentations in these subgroups that might determine treatment choices. The aim of this study was to investigate the prevalence of gastric sensorimotor dysfunction in the PDS, EPS, and overlap groups and to evaluate potential differential associations with dyspeptic symptom scores. METHODS: Consecutive FD patients fulfilling Rome III criteria were recruited and they scored frequency of dyspeptic symptoms (postprandial fullness, early satiety, nausea, bloating, epigastric pain, and epigastric burning) over the past 3 months (0-5; 1=once a month or less, 2=two or three times a month, 3=once a week, 4=several times a week, 5=every day). The cumulative symptom score was calculated by adding up the score of these dyspeptic symptoms. Based on these symptom scores, the patients were subdivided into subgroups according to the Rome III consensus: (i) PDS, characterized by postprandial fullness and/or early satiety at least several times a week, (ii) EPS, characterized by epigastric pain and/or epigastric burning at least once a week, and (iii) overlap, fulfilling the criteria for both PDS and EPS. Gastric sensitivity and gastric accommodation were measured using barostat testing, and solid gastric emptying was determined using the [14C]octanoate breath test. RESULTS: A total of 560 FD patients (165 men, age 41.8±0.7 years) were classified into PDS (n=131), EPS (n=50), and overlap (n=379) groups. The prevalence of gastric hypersensitivity, impaired gastric accommodation, and delayed gastric emptying were 37%, 37%, and 23%, respectively, without any differential distribution in Rome III subgroups (P=0.16, P=0.27, and P=0.39 respectively). Comparing the physiological parameters for these gastric sensorimotor functions, there was only a significant difference in the gastric half emptying time between subgroups, with the overlap group having a higher t1/2 (P<0.05) compared with the EPS group. In the overlap group, gastric hypersensitivity was associated with the severity of PDS symptoms (P=0.03), EPS symptoms (P=0.02), and the cumulative symptom score (P=0.02), whereas delayed gastric emptying was associated with nausea (P=0.02) and the cumulative symptom score (P=0.02). CONCLUSIONS: Except for gastric emptying in the overlap group, FD subgroups as defined by the Rome III criteria are not differentially associated with putative pathophysiological mechanisms. These observations question the utility of this classification for guiding therapeutic choices in clinical practice.

The use of pictograms improves symptom evaluation by patients with functional dyspepsia.

BACKGROUND: No validated patient-reported outcome (PRO) measure exists for functional dyspepsia (FD) assessment. Verbal descriptions of different upper abdominal symptoms may be poorly distinguishable to patients. AIM: To investigate whether understanding of FD symptoms is enhanced by pictograms symbolising the nature of the symptoms, besides verbal descriptors. METHODS: Consecutive FD patients were randomised to fill out a questionnaire assessing nineupper gastrointestinal symptoms (post-prandial fullness, early satiation, epigastric pain, epigastric burning, bloating centred in the upper abdomen, nausea, vomiting, heartburn, regurgitation) with or without accompanying pictograms. Symptoms were rated for frequency and severity (0-5), and patients also identified the most bothersome symptom. Subsequently, in-depth history was taken by an expert clinician, who filled out the same symptom ratings. Concordance between patient and clinician ratings was quantified using chi-square and kappa statistics. RESULTS: Content validity of pictograms was first confirmed by 15 FD patients. Next, 76 patients (52 women, age 42.2 ± 1.9) were randomised to questionnaires with or without pictograms. The concordance with clinician's assessment as gold standard rose from 36 without to 48% for questions with pictograms (P < 0.0001). Considering the Rome III subdivision, benefit in concordance with pictograms was present for post-prandial distress, epigastric pain syndrome and reflux symptoms. Kappa statistics confirmed these gains (weighted kappa values for concordance of symptom frequency ratings rose from 0.214 to 0.446 with pictograms), and also showed better concordance of the most bothersome symptom with pictograms. CONCLUSION: Pictograms accompanying verbal descriptors significantly improve concordance of functional dyspepsia symptom ratings by patients with evaluation by their physicians.

Therapeutic options for functional dyspepsia.

Functional dyspepsia (FD) is defined by the presence of chronic gastroduodenal symptoms in the absence of organic or systemic disease that explains them, and a negative upper endoscopy. According to the Rome III consensus, FD can be subdivided into PDS (postprandial distress syndrome) and EPS (epigastric pain syndrome). In patients with mild symptoms, reassurance and lifestyle adjustments are often sufficient. Pharmacotherapy, for those with more severe or persisting symptoms, includes the use of proton pump inhibitors (PPIs), prokinetics and psychotropic agents. In those diagnosed with Helicobacter pylori infection, eradication is recommended, although the symptom impact is often limited. PPIs are the initial therapy of choice for EPS, while prokinetics can be used in PDS. Tricyclic antidepressants can be used for refractory symptoms, especially in EPS. Emerging therapies include the novel gastroprokinetic agent acotiamide for PDS, fundus-relaxing 5-HT(1A) agonists in patients with PDS/early satiation and mirtazapine for FD with weight loss.

Postprandial symptoms originating from the stomach in functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is characterized by chronic epigastric symptoms. The stomach has been held responsible for the generation of symptoms, but the latest reports have pointed out that also the duodenum can be implicated in the pathophysiology. The aim of this study was to elucidate which dyspeptic symptoms originate from the stomach and/or from the small intestine after a meal. METHODS: Two hundred eighty-four FD patients underwent a gastric emptying breath test. Breath samples were taken and the intensity of six dyspeptic symptoms (fullness, bloating, belching, nausea, epigastric burning, and epigastric pain) was scored before a meal and at 15 min intervals for a period of 240 min postprandially. Time curves of each symptom were analyzed and severity scores during the gastric and the intestinal phase were compared. KEY RESULTS: Time curves of fullness, bloating, belching, and nausea displayed a significant negative slope, while symptom severity of epigastric burning and epigastric pain did not decrease over time. Numerical analysis revealed that scores for fullness, bloating, and belching were higher during the gastric phase compared with the intestinal phase. On the other hand, intensities of nausea, epigastric burning, and epigastric pain were similar during both phases. CONCLUSIONS & INFERENCES: Intensities of fullness, bloating, and belching decrease with food moving from the stomach to the small intestine indicating that the stomach plays a crucial role in the generation of these symptoms. In contrast, the symptom severity of epigastric burning and epigastric pain persists with progression of food to the small intestine.