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Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia

      Abstract

      Background & Aims: Hypersensitivity to gastric distention has been reported in functional dyspepsia, but its characteristics and relevance to symptoms remain unclear. The aim of this study was to define hypersensitivity to gastric distention and its association to specific symptoms in functional dyspepsia. Methods: We used a gastric barostat to study sensitivity to gastric distention in 80 healthy subjects and in 160 functional dyspepsia patients. Demographic characteristics, gastric emptying, Helicobacter pylori status, gastric accommodation, and a dyspepsia symptom score were obtained from all patients and the relationship with visceral sensitivity was assessed using univariate and multivariate analysis. Results: The increase of intra-balloon pressure over intra-abdominal pressure needed to induce discomfort or pain is the most appropriate expression of sensitivity to gastric distention because it yields a meaningful lower range of normal and it is independent from age and body mass index. Hypersensitivity to gastric distention was found in 34% of the patients, who did not differ from the other patients in demographic and other pathophysiological characteristics. Hypersensitivity to distention was associated with a higher prevalence of postprandial pain, belching, and weight loss. Conclusions: Hypersensitivity to gastric distention is present in a subset of functional dyspepsia patients. It is associated with symptoms of postprandial epigastric pain, belching, and weight loss.
      GASTROENTEROLOGY 2001;121:526-535

      Abbreviations:

      CI (confidence interval), MDP (minimal distending pressure), OR (odds ratio), (half emptying time)
      Functional dyspepsia is a clinical syndrome defined by chronic or recurrent upper abdominal symptoms without identifiable cause by conventional diagnostic means.
      • Talley NJ
      • Stanghellini V
      • Heading RC
      • Koch KL
      • Malagelada J-R
      • Tytgat GJN
      Functional gastroduodenal disorders.
      The symptom complex is often related to feeding and includes epigastric pain, bloating, early satiety, fullness, epigastric burning, belching, nausea, and vomiting.
      • Talley NJ
      • Stanghellini V
      • Heading RC
      • Koch KL
      • Malagelada J-R
      • Tytgat GJN
      Functional gastroduodenal disorders.
      The pathophysiology of functional dyspepsia is unknown, but a number of mechanisms have been suggested. Dyspeptic symptoms could originate from delayed gastric emptying, impaired gastric accommodation to a meal, visceral hypersensitivity to distention, abnormal duodenojejunal motility, Helicobacter pylori gastritis, or central nervous system dysfunction.
      • Stanghellini V
      • Tosetti C
      • Paternico A
      • Barbara G
      • Morselli-Labate AM
      • Monetti N
      • Mrengo M
      • Corinaldesi R
      Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      • Wilmer A
      • Van Cutsem E
      • Andrioli A
      • Tack J
      • Coremans G
      • Janssens J
      Prolonged ambulatory gastrojejunal manometry in severe motility-like dyspepsia: lack of correlation between dysmotility, symptoms and gastric emptying.
      • Bradette M
      • Pare P
      • Douville P
      • Morin A
      Visceral perception in health and functional dyspepsia. Crossover study of gastric distensions with placebo and domperidone.
      • Mearin F
      • Cucala M
      • Azpiroz F
      • Malagelada JR
      The origin of symptoms on the brain-gut axis in functional dyspepsia.
      • Danesh J
      • Lawrence M
      • Murphy M
      • Roberts S
      • Collins R
      Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia.
      During the last decade, it has been suggested that visceral hypersensitivity might be a major pathophysiological mechanism in functional gastrointestinal diseases such as functional dyspepsia and irritable bowel syndrome.
      • Mayer EA
      • Gebhart FG
      Basic and clinical aspects of visceral hyperalgesia.
      • Camilleri M
      • Coulie B
      • Tack J
      Visceral hypersensitivity: facts, speculations and challenges.
      Gastric barostat studies have confirmed that, as a group, patients with functional dyspepsia have lower thresholds for first perception and for discomfort or pain during balloon distention of the proximal stomach.
      • Bradette M
      • Pare P
      • Douville P
      • Morin A
      Visceral perception in health and functional dyspepsia. Crossover study of gastric distensions with placebo and domperidone.
      • Mearin F
      • Cucala M
      • Azpiroz F
      • Malagelada JR
      The origin of symptoms on the brain-gut axis in functional dyspepsia.
      Hypersensitivity to gastric distention, defined as perception or discomfort thresholds outside the normal range, is found in a subset of patients with functional dyspepsia, but not in patients with organic causes of dyspepsia.
      • Mertz H
      • Fullerton S
      • Naliboff B
      • Mayer EA
      Symptoms and visceral perception in severe functional and organic dyspepsia.
      Unlike defective gastric accommodation, it is unclear whether hypersensitivity to gastric distention is associated with specific current or recent symptoms in functional dyspepsia patients. Moreover, there are still some methodological discrepancies between different studies because of different approaches to calculate sensitivity to distention and to determine the range of normality.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      • Bradette M
      • Pare P
      • Douville P
      • Morin A
      Visceral perception in health and functional dyspepsia. Crossover study of gastric distensions with placebo and domperidone.
      • Mearin F
      • Cucala M
      • Azpiroz F
      • Malagelada JR
      The origin of symptoms on the brain-gut axis in functional dyspepsia.
      • Mertz H
      • Fullerton S
      • Naliboff B
      • Mayer EA
      Symptoms and visceral perception in severe functional and organic dyspepsia.
      • Holtmann G
      • Gschossmann J
      • Neufang-Huber J
      • Gerken G
      • Talley NJ
      Differences in gastric mechanosensory function after repeated ramp distensions in non-consulters with dyspepsia and healthy controls.
      Thresholds to gastric distention obtained from barostat studies have been expressed as the intra-balloon pressure, as the increase of the intra-balloon pressure over intra-abdominal pressure, and as the intra-balloon volume needed to induce first perception or discomfort.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      • Bradette M
      • Pare P
      • Douville P
      • Morin A
      Visceral perception in health and functional dyspepsia. Crossover study of gastric distensions with placebo and domperidone.
      • Mearin F
      • Cucala M
      • Azpiroz F
      • Malagelada JR
      The origin of symptoms on the brain-gut axis in functional dyspepsia.
      • Mertz H
      • Fullerton S
      • Naliboff B
      • Mayer EA
      Symptoms and visceral perception in severe functional and organic dyspepsia.
      • Holtmann G
      • Gschossmann J
      • Neufang-Huber J
      • Gerken G
      • Talley NJ
      Differences in gastric mechanosensory function after repeated ramp distensions in non-consulters with dyspepsia and healthy controls.
      To define the range of normality, both the mean −2 SD and the mean −1.5 SD from healthy control studies have been used.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      • Mertz H
      • Fullerton S
      • Naliboff B
      • Mayer EA
      Symptoms and visceral perception in severe functional and organic dyspepsia.
      • Holtmann G
      • Gschossmann J
      • Neufang-Huber J
      • Gerken G
      • Talley NJ
      Differences in gastric mechanosensory function after repeated ramp distensions in non-consulters with dyspepsia and healthy controls.
      It is unclear whether these methodological differences influence the prevalence of and the symptoms associated with hypersensitivity to gastric distention.
      The aim of the present study was first to better define hypersensitivity to gastric distention and to determine the most relevant parameters. Our second aim was to study the sensitivity to gastric distention in a group of patients with functional dyspepsia, and to investigate whether the presence of visceral hypersensitivity is correlated with specific dyspeptic symptoms or with any of the other putative pathophysiological mechanisms in functional dyspepsia.

      Materials and methods

       Study subjects

      Eighty healthy controls (52 men; age, 19–31 years; mean age, 24.7 ± 2.3 years) and 160 patients with functional dyspepsia (51 men; age, 16–79 years; mean age, 40.1 ± 13.9 years) participated in this study. None of the healthy subjects had symptoms or a history of gastrointestinal disease or drug allergies, nor were they taking any medication.
      The patients presented to the outpatient clinic because of meal-related epigastric symptoms, and all underwent careful history taking and clinical examination, upper gastrointestinal endoscopy, routine biochemistry, and upper abdominal ultrasonography. Inclusion criteria were the presence of dyspeptic symptoms for at least 12 weeks in the last 12 months, in the absence of organic, systemic, or metabolic disease. Dyspeptic symptoms had to be present at least 3 days per week, with 2 or more symptoms scored as relevant or severe on the symptom questionnaire. Exclusion criteria were the presence of esophagitis, gastric atrophy, or erosive gastroduodenal lesions on endoscopy; heartburn as a predominant symptom; a history of peptic ulcer, major abdominal surgery, or underlying psychiatric illness; and the use of nonsteroidal anti-inflammatory drugs, steroids, or drugs affecting gastric acid secretion. During upper gastrointestinal endoscopy, biopsy specimens were taken from the antrum and the corpus to stain with cresyl violet for the presence of Helicobacter pylori. In patients with relevant or severe epigastric burning on the symptom questionnaire (n = 57), a 24-hour esophageal pH monitoring was performed and found to be normal (<4% of time; pH, <4). A psychiatrist ruled out anorexia nervosa in patients with weight loss in excess of 5% of the initial body weight. All drugs potentially affecting gastrointestinal motility were discontinued at least 1 week before the barostat and gastric emptying studies. Informed consent was obtained from each participant. The protocol had been previously approved by the Ethics Committee of the University Hospital.

       Symptom questionnaire

      Before the barostat studies, each patient completed a dyspepsia questionnaire as reported previously.
      • Stanghellini V
      • Tosetti C
      • Paternico A
      • Barbara G
      • Morselli-Labate AM
      • Monetti N
      • Mrengo M
      • Corinaldesi R
      Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      The patient was asked to grade the intensity (0–3; 0 = absent, 1 = mild, 2 = relevant, and 3 = severe, interfering with daily activities) of 8 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.

       Barostat studies

      After an overnight fast of at least 12 hours, a double lumen polyvinyl tube (Salem sump tube 14 Ch; Sherwood Medical, Petit Rechain, Belgium) with an adherent plastic bag (1200 mL capacity; 17 cm maximal diameter), finely folded, was introduced through the mouth and secured to the subject's chin with adhesive tape. The position of the bag in the gastric fundus was checked fluoroscopically.
      The polyvinyl tube was then connected to a programmable barostat device (Synectics Visceral Stimulator, Stockholm, Sweden). To unfold the bag, it was inflated with a fixed volume of 300 mL of air for 2 minutes with the study subject in a recumbent position, and again deflated completely. The subjects were then positioned in a comfortable sitting position with the knees bent (80°) and the trunk upright in a specifically designed bed.
      After a 30-minute adaptation period, minimal distending pressure (MDP) was first determined by increasing intrabag pressure by 1 mm Hg every 3 minutes until a volume of 30 mL or more was reached.
      • Notivol R
      • Coffin B
      • Azpiroz F
      • Mearin F
      • Serra J
      • Malagelada JR
      Gastric tone determines the sensitivity of the stomach to distention.
      This pressure level equilibrates the intra-abdominal pressure. Subsequently, isobaric distentions were performed in stepwise increments of 2 mm Hg starting from MDP, each lasting for 2 minutes, while the corresponding intragastric volume was recorded. Subjects were instructed to score their perception of upper abdominal sensations at the end of every distending step, using a graphic rating scale that combined verbal descriptors on a scale graded 0–6.
      • Notivol R
      • Coffin B
      • Azpiroz F
      • Mearin F
      • Serra J
      • Malagelada JR
      Gastric tone determines the sensitivity of the stomach to distention.
      The end point of each sequence of distentions was established at an intrabag volume of 1000 mL, or when the subjects reported discomfort or pain (score 5 or 6). We previously established that more complex distending protocols yield similar results.
      • Sarnelli G
      • Vos R
      • Cuomo R
      • Janssens J
      • Tack J
      Reproducibility of gastric barostat studies in healthy controls and in dyspeptic patients.
      In all healthy controls and in all patients, after a 30-minute adaptation period with the bag completely deflated, the pressure level was set at MDP + 2 mm Hg during at least 90 minutes. After 30 minutes, a standardized liquid meal (200 mL, 300 kcal, 13% proteins, 48% carbohydrates, 39% lipids; Nutridrink; Nutricia, Bornem, Belgium) was administered to 147 patients. Gastric tone measurement was continued for at least 60 minutes after the meal. For 13 patients who received a different meal, data on gastric accommodation were omitted from the analysis.

       Gastric emptying studies

      Gastric emptying for solids was measured in all patients, using the previously validated 14C octanoic acid breath test.
      • Ghoos YF
      • Maes BD
      • Geypens BJ
      • Hiele MI
      • Rutgeerts PJ
      • Vantrappen G
      Measurement of gastric emptying rate of solids by means of a carbon labeled octanoic acid breath test.
      Briefly, all studies were carried out in the morning after an overnight fast. The test meal consisted of 60 g of white bread, 1 egg, the yolk of which was doped with 74 kBq of 14C octanoic acid sodium salt, and 300 mL of water. Breath samples were taken before the meal and at 15-minute intervals for a period of 240 minutes postprandially. Gastric half emptying time (t½) was calculated as previously described.
      • Ghoos YF
      • Maes BD
      • Geypens BJ
      • Hiele MI
      • Rutgeerts PJ
      • Vantrappen G
      Measurement of gastric emptying rate of solids by means of a carbon labeled octanoic acid breath test.
      Delayed emptying was defined as t½ above the 95% confidence interval (CI) in healthy volunteers.
      • Maes BD
      • Ghoos YF
      • Hiele MI
      • Rutgeerts PJ
      Gastric emptying rate of solids in patients with nonulcer dyspepsia.

       Data analysis

      Primary end points were the thresholds for perception and discomfort during gastric distention. Secondary end points were the rate of gastric emptying, gastric accommodation to a meal, and Helicobacter pylori status.
      For each 2-minute distending period, the intragastric volume was calculated by averaging the recording. Perception threshold was defined as the first level of pressure and the corresponding volume that evoked a perception score of 1 or more. Discomfort threshold was defined as the first level of pressure and the corresponding volume that provoked a score of 5 or more. Pressure thresholds were expressed both as pressures relative to MDP and as absolute pressures. The gastric wall tension at the threshold for first perception and for discomfort was calculated using Laplace's law.
      • Distrutti E
      • Azpiroz F
      • Soldevilla A
      • Malagelada J-R
      Gastric wall tension determines perception of gastric distention.
      Pressure-volume and pressure-perception curves were obtained from the stepwise distentions. Different curve models (including linear, parabolic, sigmoid, hyperbolic, and power exponential models) were evaluated for goodness of fit of the individual pressure-volume and pressure-perception curves. As reported previously, a linear regression model provided the best fit.
      • Tack J
      • Coulie B
      • Wilmer A
      • Andrioli A
      • Janssens J
      Effect of sumatriptan on gastric fundus tone and on the perception of gastric distension in man.
      Gastric compliance was calculated as the slope and the intercept of the pressure-volume curve obtained during the first 3 steps of isobaric distentions.
      Gastric tone before and after administration of the meal was measured by calculation of the mean balloon volume for consecutive 5-minute intervals. The meal-induced gastric relaxation was quantified as the difference between the average volumes during 30 minutes before and 60 minutes after the administration of the meal.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.

       Statistical analysis

      Demographic characteristics of healthy subjects and patients were compared by the Student t test. The intercepts and slopes, obtained by linear regression analysis of pressure-volume curves and pressure-perception curves in healthy subjects and in patients, were compared by the Student t test. The normal range (mean ± 2 SD) for sensitivity to gastric distention was calculated from the healthy volunteers' data. Subsequently, patients were divided into those with normal sensitivity and those with hypersensitivity to gastric distention. Age, body weight, gastric compliance, accommodation to a meal, and t½ for solid gastric emptying in both patient groups were compared using the Student t test. Furthermore, individual dyspeptic symptoms were analyzed using 3 possible cutoffs (≥1 vs. 0; ≥2 vs. ≤1; and 3 vs. ≤2). The prevalence of dyspeptic symptoms, the prevalence of delayed gastric emptying, the prevalence of impaired accommodation, sex distribution, and the presence of H. pylori infection in both patient groups were compared by χ2 testing.
      Stepwise multiple logistic regression analysis was used to identify the association between the risk of hypersensitivity to gastric distention, the presence of dyspeptic symptoms, and patient variables. P values of 0.05 and 0.1 were chosen as cutoff points to enter and exit the stepwise procedure. Odds ratios (ORs) with 95% CI were computed.
      Differences were considered to be significant at the 5% level. All data are given as mean ± SD. Statistical evaluations were performed using specialized software (SAS; SAS Institute, Cary, NC).

      Results

       Characteristics of patients with functional dyspepsia

      Patients were significantly older than healthy subjects, and a higher proportion of the patients were female (P < 0.01). Dyspeptic symptoms were present for 21 ± 7 months. Table 1 summarizes the grading of dyspeptic symptoms in the patient group.
      Table 1Frequency of severity grading for each of 6 dyspepsia symptoms in 160 patients with functional dyspepsia
      0 (Absent)1 (Mild)2 (Relevant)3 (Severe)
      Postprandial fullness16 (10)10 (6)43 (27)91 (57)
      Bloating31 (19)9 (6)48 (30)72 (45)
      Epigastric pain49 (31)11 (7)40 (25)60 (37)
      Early satiety54 (34)14 (9)37 (23)55 (34)
      Nausea52 (32)13 (8)48 (30)47 (30)
      Vomiting108 (68)2 (1)13 (8)37 (23)
      Belching67 (42)20 (13)50 (31)23 (14)
      Epigastric burning77 (48)26 (16)34 (22)23 (14)
      NOTE. Numbers in parentheses represent row percentages.
      Postprandial fullness and bloating were the most prevalent symptoms, present in 90% and 81%, respectively, of the patients. Epigastric pain (69%), early satiety (66%), nausea (68%), and belching (58%) were also frequently reported. Vomiting and epigastric burning sensation were present in 33% and 52%, respectively, of the patients. Weight loss in excess of 5% was present in 70 patients (44%). H. pylori was demonstrated on gastric biopsy specimens in 27 patients (17%). Thirty-seven patients (23%) had delayed gastric emptying of solids (t½ > 119 minutes).

       Sensitivity to gastric distention in healthy subjects

      The results of gastric barostat studies in healthy subjects are summarized in Table 2. MDP did not differ between both sexes, but a significant correlation between MDP and body mass index was present (R = 0.47; P < 0.001). Mean pressure-volume relationships and mean pressure-perception curves in healthy subjects are shown in Figures 1 and 2, respectively.
      Figure thumbnail gr1
      Fig. 1Pressure-volume relationship obtained by gradually increasing isobaric gastric distentions in 80 healthy controls and 160 patients with functional dyspepsia. Linear model fitting revealed no significant differences between both groups.
      Figure thumbnail gr2
      Fig. 2Pressure-perception relationship obtained by gradually increasing isobaric gastric distentions in 80 healthy controls and 160 patients with functional dyspepsia. Linear model fitting revealed a shift towards higher perceptions for the same distending pressures in patients.
      Table 2Results of barostat studies in 80 healthy controls and 160 dyspeptic patients
      Healthy controlsDyspeptic patientsP
      MDP (mm Hg)7.2 ± 1.96.6 ± 2.3NS
      Y-intercept of pressure-volume curve (mL)34 ± 11420 ± 65NS
      Slope of pressure-volume curve (mL/mm Hg)53 ± 3458 ± 21NS
      X-intercept of pressure-perception curves (mm Hg)1.0 ± 1.91.0 ± 3.9NS
      Slope of pressure-perception curves (mm Hg−1)0.44 ± 0.190.52 ± 0.32<0.05
      Relative pressure at perception threshold (mm Hg above MDP)3.5 ± 1.83.8 ± 3.1NS
      Relative pressure at discomfort threshold (mm Hg above MDP)12.0 ± 2.79.0 ± 4.2<0.001
      Absolute pressure at perception threshold (mm Hg)10.7 ± 2.710.3 ± 0.3NS
      Absolute pressure at discomfort threshold (mm Hg)19.2 ± 3.215.6 ± 0.4<0.001
      Volume at first perception threshold (mL)249 ± 124270 ± 190NS
      Volume at discomfort threshold (mL)647 ± 193550 ± 206<0.001
      Wall tension at perception threshold (cm/mm Hg)15.4 ± 10.017.4 ± 19.0NS
      Wall tension at discomfort threshold (cm/mm Hg)70.7 ± 20.251.4 ± 28.3<0.001
      The absolute pressures at first perception and at discomfort (R = 0.57; P < 0.001 and R = 0.33; P = 0.02, respectively) were significantly correlated to the body mass index, but not the relative pressures or the corresponding volumes and the calculated wall tensions (all R values < 0.28, all P values > 0.05). The absolute pressures at first perception and at discomfort, the relative pressures at first perception and at discomfort, and the corresponding volumes and calculated wall tensions were not significantly correlated to the age of the subjects (all R values < 0.05, all P values > 0.05).
      The lower range of normal (mean −2 SD) for the distending pressure inducing discomfort was 6.6 mm Hg above MDP (“relative pressure cut-off”) or an absolute pressure of 12.8 mm Hg (“absolute pressure cut-off”), with a corresponding volume of 261 mL (“volume cut-off”) and a calculated wall tension of 30.3 cm/mm Hg. A meaningful lower range of normal for the distending pressure and volume and the calculated wall tension inducing first perception could not be determined because this value was below MDP or below 0 mm Hg or 0 mL, respectively.

       Sensitivity to gastric distention in dyspeptic patients

      The results of gastric barostat studies in patients with functional dyspepsia are summarized in Table 2. A significant correlation between MDP and body mass index was present (R = 0.42; P < 0.001). The y-intercepts and slopes, obtained by linear regression analysis of pressure-volume curves, were 20 ± 65 mL and 58 ± 21 mL/mm Hg, respectively (NS compared with controls). Gastric compliance did not differ between controls and dyspeptic patients (Figure 1 and Table 2). However, at similar distending pressures, perception scores were significantly higher in patients with functional dyspepsia (Figure 2 and Table 2). Pressures, intra-balloon volumes, and calculated wall tension at first perception did not differ significantly between healthy controls and patients with functional dyspepsia. Relative pressures, absolute pressures, intra-balloon volumes, and calculated wall tension at discomfort threshold were significantly lower in patients (Table 2), without a correlation with the duration of dyspeptic symptoms (all R values < 0.05; all P values > 0.05). The absolute pressures at first perception and at discomfort (R = 0.34, P < 0.001 and R = 0.36, P < 0.001, respectively), the relative pressures at discomfort (R = 0.22, P < 0.01), the corresponding volumes (R = 0.18, P < 0.02 and R = 0.22, P < 0.005, respectively), and the calculated wall tensions (R = 0.24, P < 0.005) were all significantly correlated to the body mass index. The absolute pressures at first perception and at discomfort (R = 0.34, P < 0.001 and R = 0.33, P < 0.001, respectively), the relative pressures at first perception and at discomfort (R = 0.21, P = 0.02 and R = 0.24, P = 0.002, respectively), calculated wall tension at first perception and at discomfort (R = 0.21, P < 0.01 and R = 0.24, P < 0.005, respectively), and the corresponding volume at first perception (R = 0.20, P = 0.01), but not the corresponding volume at discomfort (R = 0.14, NS), were significantly correlated to the age of the patient.

       Gastric accommodation in healthy subjects and in patients

      Before administration of a meal, mean intragastric volume at MDP + 2 mm Hg was similar in healthy subjects and in patients (194 ± 129 mL and 201 ± 105 mL, NS). During the first 60 minutes after the meal, intragastric volume was significantly higher in healthy subjects compared with patients (392 ± 163 mL vs. 308 ± 161 mL, P < 0.005). Accommodation to a meal, expressed as the average increase in intragastric volume during the first postprandial hour, was significantly lower in patients than in healthy volunteers (108 ± 134 mL vs. 198 ± 135 mL; P < 0.001). Using the lower range of normal in healthy volunteers (64 mL) as a cut-off, 59 of 147 patients (40%) had an impaired gastric accommodation.

       Univariate analysis of pathophysiological and symptomatic correlates of abnormal sensitivity to gastric distention (using relative pressure cut-off)

      Using the lower range of relative pressure threshold as a cut-off (mean −2 SD), 55 patients (34%) had hypersensitivity to gastric distention (Figure 3).
      Figure thumbnail gr3
      Fig. 3Number of healthy subjects or functional dyspepsia patients that reported discomfort at a given distending pressure, expressed as the increase of the intra-balloon pressure over intra-abdominal pressure needed to induce discomfort or pain. The shaded area indicates the normal range (mean ± 2 SD). Hypersensitivity to gastric distention is present in 34% of the patients. A small subset of patients (9%) with thresholds above the mean + 2 SD of the control group are less sensitive to gastric distention.
      The result was identical when the mean −1.5 SD was used as a cut-off. There was no significant difference in sex distribution, body mass index, or age between patients with hypersensitivity and with normal sensitivity to gastric distention (13/55 vs. 38/105 men, 20.9 ± 4.3 vs. 21.9 ± 3.9 kg/m2, and 38 ± 12 vs. 41 ± 15 years, respectively, all NS). The prevalence of Helicobacter infection also did not differ significantly (6/55 vs. 21/105, NS). There was no difference in t½ for solids between both groups (111 ± 65 vs. 97 ± 53 minutes, NS), nor did the prevalence of delayed emptying for solids differ (13/55 and 24/115, NS). Gastric compliance (y-intercept 11 ± 63 vs. 25 ± 66 mL, NS, and slope 63 ± 23 vs. 56 ± 20 mL/mm Hg, NS), accommodation to a meal (102 ± 127 vs. 111 ± 138 mL, NS) and the prevalence of impaired accommodation (22/50 and 37/97, NS) were comparable in both groups (Figure 4).
      Figure thumbnail gr4
      Fig. 4Mean intragastric volume at 5-minute intervals as measured by a gastric barostat in healthy volunteers, in dyspeptic patients with normal sensitivity to gastric distention, and in dyspeptic patients with hypersensitivity to gastric distention, before and after administration of a mixed liquid meal (time = 0). Ingestion of the meal induces a rapid and sustained increase in intragastric volume, reflecting a relaxation of the gastric fundus. The relaxation is significantly larger in controls than in dyspeptic patients, regardless of their sensitivity to gastric distention.
      Figure 5 shows the percentage of patients grading individual symptoms as relevant or severe and the presence of weight loss in the subgroups with hypersensitivity and with normal sensitivity to gastric distention.
      Figure thumbnail gr5
      Fig. 5Dyspepsia symptoms in 160 patients with functional dyspepsia. The figure depicts the number of patients grading individual symptoms as relevant or severe (score ≥ 2) in the subgroups with normal sensitivity or hypersensitivity to gastric distention. Postprandial pain, belching, and weight loss exceeding 5% of the initial body weight were significantly more prevalent in patients with hypersensitivity to gastric distention.
      Weight loss exceeding 5% of the initial body weight was significantly more prevalent in patients with hypersensitivity to gastric distention (33/55 vs. 37/105, P < 0.005). The association between individual symptom grading and hypersensitivity to gastric distention was investigated. The presence of relevant or severe (score ≥ 2) postprandial pain (45/55 vs. 55/105, P < 0.001) and of relevant or severe belching (36/55 vs. 37/105, P < 0.001) were significantly more prevalent in patients with hypersensitivity to gastric distention.
      Similarly, the presence (score ≥ 1) of postprandial pain (48/55 vs. 63/105, P < 0.001) and of belching (40/55 vs. 53/105, P < 0.01) was significantly more prevalent in patients with hypersensitivity to gastric distention. Severe (score ≥ 3) postprandial pain (29/55 vs. 31/105; P < 0.001) and severe belching (12/55 and 11/105, P = 0.05) were also significantly more prevalent in patients with hypersensitivity to gastric distention.
      Nine patients (6%) had decreased sensitivity to gastric distention (discomfort threshold above mean + 2 SD) (Figure 3). Their demographic, symptomatic, and other pathophysiological features did not differ from the other patients.

       Univariate analysis of pathophysiological and symptomatic correlates of abnormal sensitivity to gastric distention (using absolute pressure or volume or wall tension cut-off)

      When the absolute pressure threshold cut-off was used, the number of patients with hypersensitivity to gastric distention was 47 (29%). Patients with hypersensitivity to gastric distention were younger and had a lower body mass index than patients with normal sensitivity to gastric distention (35 ± 13 vs. 42 ± 14 years and 19.8 ± 2.9 vs. 22.4 ± 4.3 kg/m2, respectively, both P < 0.005). There was no difference in sex distribution (10/47 vs. 41/113) or in the prevalence of Helicobacter infection (5/47 vs. 22/113) between both groups. Patients with hypersensitivity to gastric distention had a higher t½ for solid gastric emptying (118 ± 71 vs. 95 ± 50 minutes; P < 0.05), but the prevalence of delayed emptying for solids did not differ between both groups (13/47 and 24/113, NS). Accommodation to a meal (121 ± 144 vs. 102 ± 130 mL, NS), the prevalence of impaired accommodation (18/43 and 41/104, NS), and gastric compliance (y-intercept 20 ± 65 vs. 20 ± 66 mL, NS, and slope 64 ± 24 vs. 56 ± 19 mL/mm Hg, NS) were comparable in both groups.
      Weight loss exceeding 5% of the initial body weight was significantly more prevalent in patients with hypersensitivity to gastric distention based on the absolute pressure cut-off (31/47 vs. 39/113, P < 0.001). The prevalence of relevant or severe (score ≥ 2) postprandial pain (37/47 vs. 63/113, P < 0.01) and of relevant or severe belching (31/47 vs. 42/113, P < 0.001) was significantly higher in patients with hypersensitivity to gastric distention based on the absolute pressure cut-off. Similarly, the presence of (score ≥ 1) postprandial pain (38/47 vs. 73/113; P < 0.05), belching (35/47 vs. 58/113; P < 0.01), vomiting (21/47 vs. 31/113; P < 0.05), and nausea (37/47 vs. 71/113; P = 0.05) were all significantly more prevalent in patients with hypersensitivity to gastric distention. Severe (score ≥ 3) postprandial pain (28/47 vs. 32/113, P < 0.001), severe belching (11/47 and 12/113; P < 0.05), and severe early satiety (23/47 vs. 32/113; P < 0.05) were also significantly more prevalent in patients with hypersensitivity to gastric distention based on the absolute pressure cut-off.
      Eight patients (5%) had decreased sensitivity to gastric distention (discomfort threshold above mean + 2 SD). Their demographic, symptomatic, and other pathophysiological features were not different from the other patients.
      When the calculated wall tension at discomfort threshold was used as a cut-off, the number of patients with hypersensitivity to gastric distention was only 38 (24%), and these were a subgroup of the patients identified using a pressure cut-off. Their demographic and other pathophysiological features were not different from the other patients. Postprandial pain was the only symptom whose prevalence was higher in these patients, regardless of the cut-off. Six patients had a calculated wall tension at discomfort level above the normal range. Their demographic, symptomatic, and other pathophysiological features were not different from the other patients.
      When the volume threshold inducing discomfort was used, the number of patients with hypersensitivity to gastric distention was only 11 (7%), and these were a subgroup of the patients identified using a pressure cut-off. Their demographic and other pathophysiological features were not different from the other patients. Postprandial pain was the only symptom whose prevalence was higher in these patients, regardless of the cut-off. No patients had a volume discomfort threshold above the normal range.

       Multivariate analysis of pathophysiological and symptomatic correlates of hypersensitivity to gastric distention

      Stepwise multiple logistic regression analysis was used to identify the association between the risk of hypersensitivity to gastric distention and patient demographic characteristics and symptoms. In a first set of analyses, the relative pressure cut-off was used to define hypersensitivity to gastric distention (Table 3).
      Table 3Factors associated with hypersensitivity to gastric distention, using the relative pressure cut-off
      Symptom cut-offSymptomOR95% CIP value
      Present (>0)Weight loss >5%3.141.46–6.770.004
      Postprandial pain8.012.78–23.070.001
      Belching2.791.28–6.100.01
      Fullness4.361.03–18.400.04
      Relevant or severe (>1)Postprandial pain6.572.68–16.090.0001
      Belching3.511.21–5.430.001
      Severe (>2)Postprandial pain2.981.48–5.980.002
      In that case, age, sex, and body mass index did not influence the risk of hypersensitivity to gastric distention. The presence of weight loss in excess of 5% of original body weight was significantly associated with the risk of hypersensitivity to gastric distention (OR, 3.14; 95% CI, 1.46–6.77; P = 0.004). When symptoms coded as relevant or severe symptoms (score ≥ 2) were considered, both postprandial pain (OR, 6.57; 95% CI, 2.68–16.09; P = 0.0001) and belching (OR, 3.51; 95% CI, 1.66–7.43; P = 0.001) were independently associated with hypersensitivity to gastric distention. When the presence of symptoms (score ≥ 1) was considered, postprandial pain (OR, 8.01; 95% CI, 2.78–23.07; P = 0.0001), belching (OR, 2.79; 95% CI, 1.28–6.10; P = 0.01), and postprandial fullness (OR, 4.36; 95% CI, 1.03–18.40; P = 0.04) were independently associated with hypersensitivity to gastric distention. When the presence of severe symptoms (score ≥ 3) was considered, only postprandial pain was significantly associated with hypersensitivity to gastric distention (OR, 2.98; 95% CI, 1.48–5.98; P = 0.002). All other symptoms and patient demographic variables were not independent factors in the multiple logistic regression.
      Similar statistics were performed using the absolute pressure cut-off to define hypersensitivity to gastric distention. In this case, body mass index was inversely correlated with the risk of hypersensitivity to gastric distention (OR, 0.808; 95% CI, 0.708–0.923; P = 0.001). Analysis of the association between symptom pattern and hypersensitivity yielded similar symptoms as obtained with relative pressures (summarized in Table 4).
      Table 4Factors associated with hypersensitivity to gastric distention, using the absolute pressure cut-off
      Type of factor (cut-off)FactorOR95% CIP value
      Demographic variableBMI0.810.71–0.920.002
      Symptom present (>0)Weight loss >5%2.521.10–5.800.03
      Postprandial pain3.861.42–10.450.008
      Belching3.421.43–8.170.006
      Fullness7.431.38–40.080.02
      Symptom relevant or severe (>1)Postprandial pain5.362.06–13.970.0006
      Belching3.851.64–9.010.002
      Symptom severe (>2)Postprandial pain3.721.70–8.120.001
      When the volume cut-off or the calculated wall tension cut-off was used to define hypersensitivity to gastric distention, only the presence of relevant or severe pain or the presence of severe pain were associated with the risk of hypersensitivity to gastric distention.

      Discussion

      Visceral hypersensitivity has been put forward as a unifying pathophysiological concept that may underlie several functional gastrointestinal disorders.
      • Mayer EA
      • Gebhart FG
      Basic and clinical aspects of visceral hyperalgesia.
      • Camilleri M
      • Coulie B
      • Tack J
      Visceral hypersensitivity: facts, speculations and challenges.
      Several studies have clearly established that, as a group, patients with functional dyspepsia display enhanced sensitivity to gastric distention.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      • Bradette M
      • Pare P
      • Douville P
      • Morin A
      Visceral perception in health and functional dyspepsia. Crossover study of gastric distensions with placebo and domperidone.
      • Mearin F
      • Cucala M
      • Azpiroz F
      • Malagelada JR
      The origin of symptoms on the brain-gut axis in functional dyspepsia.
      • Mertz H
      • Fullerton S
      • Naliboff B
      • Mayer EA
      Symptoms and visceral perception in severe functional and organic dyspepsia.
      • Holtmann G
      • Gschossmann J
      • Neufang-Huber J
      • Gerken G
      • Talley NJ
      Differences in gastric mechanosensory function after repeated ramp distensions in non-consulters with dyspepsia and healthy controls.
      However, in these studies, different approaches to calculate sensitivity to gastric distention and to determine the range of normality have been used.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      • Bradette M
      • Pare P
      • Douville P
      • Morin A
      Visceral perception in health and functional dyspepsia. Crossover study of gastric distensions with placebo and domperidone.
      • Mearin F
      • Cucala M
      • Azpiroz F
      • Malagelada JR
      The origin of symptoms on the brain-gut axis in functional dyspepsia.
      • Mertz H
      • Fullerton S
      • Naliboff B
      • Mayer EA
      Symptoms and visceral perception in severe functional and organic dyspepsia.
      • Holtmann G
      • Gschossmann J
      • Neufang-Huber J
      • Gerken G
      • Talley NJ
      Differences in gastric mechanosensory function after repeated ramp distensions in non-consulters with dyspepsia and healthy controls.
      By consequence, the prevalence of hypersensitivity to gastric distention and its relationship to symptoms in functional dyspepsia have not been clearly established. Using a gastric barostat, we studied the sensitivity to distention of the proximal stomach in 80 healthy controls and in 160 consecutive dyspeptic patients. Our analysis suggests that the increase of the intra-balloon pressure over intra-abdominal pressure needed to induce discomfort or pain is the most appropriate expression of sensitivity to gastric distention because it is independent from age and body mass index. In contrast, the absolute intra-balloon pressure (or the volume) needed to induce discomfort or pain is strongly influenced by body mass index in both univariate and in multivariate analysis. The absolute intra-balloon pressure (or the volume) needed to induce discomfort or pain is also influenced by age in univariate analysis, but not in multivariate analysis, suggesting that the influence of age on these thresholds might occur secondarily to the age-related increase in body mass index. Unlike thresholds inducing discomfort or pain, thresholds inducing first sensation did not allow to determine a meaningful range of normality.
      Although barostat studies generally use pressure increments as a driving stimulus, recent studies have shown that activation of gastric tension receptors is required to generate perception.
      • Distrutti E
      • Azpiroz F
      • Soldevilla A
      • Malagelada J-R
      Gastric wall tension determines perception of gastric distention.
      • Piessevaux H
      • Tack J
      • Wilmer A
      • Coulie B
      • Geubel A
      • Janssens J
      Perception of changes in wall tension of the proximal stomach in man.
      Only intra-balloon pressures higher than the intra-abdominal pressure (called the MDP) will be able to distend the stomach, and hence to activate tension receptors. The MDP is probably generated both by the parietal characteristics of the stomach and by the organs and fat deposits around the stomach. The most adequate way to quantify perception thresholds, therefore, is to express them as relative pressure increments above intra-abdominal pressure. Absolute pressure thresholds are comprised of both the MDP and the relative perception threshold. Because the MDP is directly related to the body mass index, it is not surprising that variations of body mass index accounted for up to half of the variations in absolute pressure thresholds in healthy subjects in the present study. The multivariate analysis confirmed the close correlation between body mass index and absolute pressure thresholds inducing discomfort.
      Using the relative pressure needed to induce discomfort as a marker, we showed that hypersensitivity to gastric distention is found in 37% of patients with functional dyspepsia. No correlation was present between hypersensitivity to gastric distention and other pathophysiological mechanisms, such as impaired accommodation, delayed gastric emptying, or the presence of H. pylori infection. Based on the present study, visceral hypersensitivity is not the unifying pathophysiological mechanism underlying functional dyspepsia; only a subset of patients with functional dyspepsia has increased sensitivity to gastric distention, and in some dyspeptic patients, diminished sensitivity to gastric distention can be found. Because dyspeptic symptoms are usually triggered by meal ingestion, sensitivity to gastric distention in the postprandial period might be involved in symptom generation. However, sensitivity to gastric distention after a meal is likely to be determined by the interaction of several mechanisms such as the accommodation of the stomach to a meal, the rate of gastric emptying of a meal, and the fasting sensitivity to gastric distention.
      If gastric wall tension seems to be an important element in the transduction of mechanical stimuli, it would be tempting to calculate absolute values for this parameter. Circumferential wall tension during gastric balloon distention has been approximated using the simplified law of Laplace.
      • Distrutti E
      • Azpiroz F
      • Soldevilla A
      • Malagelada J-R
      Gastric wall tension determines perception of gastric distention.
      • Tack J
      • Coulie B
      • Wilmer A
      • Andrioli A
      • Janssens J
      Effect of sumatriptan on gastric fundus tone and on the perception of gastric distension in man.
      Applying this formula to the gastric wall requires a number of assumptions that are not necessarily fulfilled: the stomach has a spherical shape, the gastric wall is infinitely thin, and no active contractile activity occurs.
      • Camilleri M
      • Coulie B
      • Tack J
      Visceral hypersensitivity: facts, speculations and challenges.
      In the present study, wall tensions calculated with the simplified law of Laplace in healthy controls displayed large variability. When the calculated wall tension was used as a cut-off, only a small group of patients with hypersensitivity to gastric distention were identified, and they were a subset of the patients identified when the relative pressure threshold was used as a cut-off. Moreover, defining hypersensitivity to gastric distention based on calculated wall tensions yielded a poorer correlation with the dyspepsia symptom pattern. There seems to be little advantage, therefore, in expressing thresholds to gastric distention as calculated wall tensions.
      In univariate and in multivariate analysis, gastric hypersensitivity was significantly and consistently associated with symptoms of postprandial pain, belching, and weight loss. Studies that assess distention-induced pain or discomfort as a marker for functional dyspepsia are sensitive to pain reporting bias. Hence, we cannot exclude the possibility that patients who are reporting pain during fasting gastric distentions are potentially more prone to report postprandial pain on a symptom questionnaire. For the symptom of belching, also associated with hypersensitivity to gastric distention, reporting bias is unlikely to play a similar role. Excessive belching is usually considered a symptom associated with gastroesophageal reflux disease or aerophagia.
      • Talley NJ
      • Stanghellini V
      • Heading RC
      • Koch KL
      • Malagelada J-R
      • Tytgat GJN
      Functional gastroduodenal disorders.
      • Wienbeck M
      • Berges W
      Esophageal disorders in the etiology and pathophysiology of dyspepsia.
      The association of belching with hypersensitivity to gastric distention indicates that this symptom may also be considered a manifestation of hypersensitivity, perhaps triggered by the physiological amounts of air normally present in the stomach. Hypersensitivity to gastric distention was also associated with a higher prevalence of weight loss in dyspeptic patients. We recently reported that this symptom may occur secondarily to early satiety in functional dyspepsia patients with impaired accommodation.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      In the present study, weight loss was an independent variable associated with hypersensitivity to distention. The nature of this association remains to be established. It is conceivable that the occurrence of severe postprandial symptoms in patients with hypersensitivity to gastric distention leads to decreased food intake, thus resulting in weight loss. Additional studies, including quantification of calorie intake, will be required to further clarify this issue.
      The current study adds further evidence that functional dyspepsia is a heterogeneous disorder, in which different underlying pathophysiological disturbances are associated with specific symptom patterns. Previously, we and others showed that delayed gastric emptying is associated with postprandial fullness and vomiting
      • Stanghellini V
      • Tosetti C
      • Paternico A
      • Barbara G
      • Morselli-Labate AM
      • Monetti N
      • Mrengo M
      • Corinaldesi R
      Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Geypens B
      • Caenepeel P
      • Ghoos Y
      • Janssens J
      Symptom pattern and gastric emptying rate assessed by the octanoic acid breath test in functional dyspepsia (abstr).
      and that impaired accommodation to a meal is associated with early satiety.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Caenepeel P
      • Janssens J
      Role of impaired gastric accommodation to a meal in functional dyspepsia.
      The findings of the current study may have implications for the design of therapeutic trials that evaluate drugs, which decrease visceral sensitivity in functional dyspepsia.
      • Fraitag B
      • Homerin M
      • Hecketsweiler P
      Double-blind dose-response multicenter comparison of fedotozine and placebo in treatment of nonulcer dyspepsia.
      • Read NW
      • Abitbol JL
      • Bardhan KD
      • Whorwell PJ
      • Fraitag B
      Efficacy and safety of the peripheral kappa agonist fedotozine versus placebo in the treatment of functional dyspepsia.
      First, hypersensitivity to gastric distention is present in only a subset of patients with functional dyspepsia; identification and selective recruitment of this subgroup may yield the best efficacy of a drug that decreases visceral sensitivity. Second, symptoms that are statistically associated with hypersensitivity such as postprandial pain and belching may more readily respond to this type of therapy than other dyspepsia symptoms and should preferably be taken into consideration.
      In conclusion, our study showed that the increase of the intra-balloon pressure over intra-abdominal pressure needed to induce discomfort or pain is the most appropriate expression of sensitivity to gastric distention. Hypersensitivity to gastric distention is present in a subset of patients with functional dyspepsia; a very small number of patients have decreased sensitivity to distention. Demographic factors, gastric emptying rate, accommodation to a meal, and H. pylori status do not differ between patients with normal or with increased sensitivity to gastric distention. Hypersensitivity to gastric distention is associated with symptoms of postprandial pain, belching, and weight loss. Our data support the hypothesis that functional dyspepsia is a heterogeneous disorder in which different underlying pathophysiological mechanisms are associated with different symptom profiles.

      References

        • Talley NJ
        • Stanghellini V
        • Heading RC
        • Koch KL
        • Malagelada J-R
        • Tytgat GJN
        Functional gastroduodenal disorders.
        Gut. 1999; 45: 37-42
        • Stanghellini V
        • Tosetti C
        • Paternico A
        • Barbara G
        • Morselli-Labate AM
        • Monetti N
        • Mrengo M
        • Corinaldesi R
        Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia.
        Gastroenterology. 1996; 110: 1036-1042
        • Tack J
        • Piessevaux H
        • Coulie B
        • Caenepeel P
        • Janssens J
        Role of impaired gastric accommodation to a meal in functional dyspepsia.
        Gastroenterology. 1998; 115: 1346-1352
        • Wilmer A
        • Van Cutsem E
        • Andrioli A
        • Tack J
        • Coremans G
        • Janssens J
        Prolonged ambulatory gastrojejunal manometry in severe motility-like dyspepsia: lack of correlation between dysmotility, symptoms and gastric emptying.
        Gut. 1998; 42: 36-41
        • Bradette M
        • Pare P
        • Douville P
        • Morin A
        Visceral perception in health and functional dyspepsia. Crossover study of gastric distensions with placebo and domperidone.
        Dig Dis Sci. 1991; 36: 52-58
        • Mearin F
        • Cucala M
        • Azpiroz F
        • Malagelada JR
        The origin of symptoms on the brain-gut axis in functional dyspepsia.
        Gastroenterology. 1991; 101: 999-1006
        • Danesh J
        • Lawrence M
        • Murphy M
        • Roberts S
        • Collins R
        Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia.
        Arch Intern Med. 2000; 160: 1192-1198
        • Mayer EA
        • Gebhart FG
        Basic and clinical aspects of visceral hyperalgesia.
        Gastroenterology. 1994; 107: 271-293
        • Camilleri M
        • Coulie B
        • Tack J
        Visceral hypersensitivity: facts, speculations and challenges.
        Gut. 2001; 48: 125-131
        • Mertz H
        • Fullerton S
        • Naliboff B
        • Mayer EA
        Symptoms and visceral perception in severe functional and organic dyspepsia.
        Gut. 1998; 42: 814-822
        • Holtmann G
        • Gschossmann J
        • Neufang-Huber J
        • Gerken G
        • Talley NJ
        Differences in gastric mechanosensory function after repeated ramp distensions in non-consulters with dyspepsia and healthy controls.
        Gut. 2000; 47: 332-336
        • Notivol R
        • Coffin B
        • Azpiroz F
        • Mearin F
        • Serra J
        • Malagelada JR
        Gastric tone determines the sensitivity of the stomach to distention.
        Gastroenterology. 1995; 108: 330-336
        • Sarnelli G
        • Vos R
        • Cuomo R
        • Janssens J
        • Tack J
        Reproducibility of gastric barostat studies in healthy controls and in dyspeptic patients.
        Am J Gastroenterol. 2001; 96: 1047-1055
        • Ghoos YF
        • Maes BD
        • Geypens BJ
        • Hiele MI
        • Rutgeerts PJ
        • Vantrappen G
        Measurement of gastric emptying rate of solids by means of a carbon labeled octanoic acid breath test.
        Gastroenterology. 1993; 104: 1640-1647
        • Maes BD
        • Ghoos YF
        • Hiele MI
        • Rutgeerts PJ
        Gastric emptying rate of solids in patients with nonulcer dyspepsia.
        Dig Dis Sci. 1997; 42: 1158-1162
        • Distrutti E
        • Azpiroz F
        • Soldevilla A
        • Malagelada J-R
        Gastric wall tension determines perception of gastric distention.
        Gastroenterology. 1999; 116: 1035-1042
        • Tack J
        • Coulie B
        • Wilmer A
        • Andrioli A
        • Janssens J
        Effect of sumatriptan on gastric fundus tone and on the perception of gastric distension in man.
        Gut. 2000; 46: 468-473
        • Piessevaux H
        • Tack J
        • Wilmer A
        • Coulie B
        • Geubel A
        • Janssens J
        Perception of changes in wall tension of the proximal stomach in man.
        Gut. 2001; 49: 203-208
        • Wienbeck M
        • Berges W
        Esophageal disorders in the etiology and pathophysiology of dyspepsia.
        Scand J Gastroenterol Suppl. 1985; 109: 133-143
        • Tack J
        • Piessevaux H
        • Coulie B
        • Geypens B
        • Caenepeel P
        • Ghoos Y
        • Janssens J
        Symptom pattern and gastric emptying rate assessed by the octanoic acid breath test in functional dyspepsia (abstr).
        Gastroenterology. 1998; 114: G1233
        • Fraitag B
        • Homerin M
        • Hecketsweiler P
        Double-blind dose-response multicenter comparison of fedotozine and placebo in treatment of nonulcer dyspepsia.
        Dig Dis Sci. 1994; 39: 1072-1077
        • Read NW
        • Abitbol JL
        • Bardhan KD
        • Whorwell PJ
        • Fraitag B
        Efficacy and safety of the peripheral kappa agonist fedotozine versus placebo in the treatment of functional dyspepsia.
        Gut. 1997; 41: 664-668