Relationship between Symptoms and Gastric Emptying of Solids in Functional Dyspepsia

Abstract

Objective:

Functional dyspepsia is a heterogeneous disorder and different pathophysiological mechanisms underlie its symptom patterns. This study investigated the relationship between dyspepsia symptoms and overall and proximal gastric emptying in patients with functional dyspepsia.

Methods:

A total of 93 patients with functional dyspepsia and 32 healthy subjects were enrolled in this cross-sectional study. Prevalence and severity of eight dyspepsia symptoms were recorded. Gastric emptying was measured using single photon emission computed tomography scanning.

Results:

Overall and proximal gastric emptying were delayed in 47.3% (44/93) and 46.2% (43/93) of the patients, respectively. Logistic regression analyses showed that presence of nausea was associated with delayed proximal gastric emptying (odds ratio 4.951; 95% confidence interval 1.321, 18.558). There were no significant differences between normal and delayed overall gastric emptying according to presence of symptoms.

Conclusions:

Presence of nausea might indicate delayed gastric emptying of the proximal stomach. Promotion of proximal gastric emptying may constitute an effective therapy for patients with functional dyspepsia who report nausea as the dominant symptom.

Keywords

Functional dyspepsia Gastric emptying Proximal Single photon emission computed tomography Symptoms

Introduction

According to the Rome III criteria, functional dyspepsia is defined as the presence of at least one of the following, in the absence of organic disease that is likely to explain the symptoms: bothersome postprandial fullness; early satiation; epigastric pain; epigastric burning.¹ Symptoms must be present for the 3 months preceding diagnosis and have an onset ≥ 6 months before diagnosis. Research has shown that the incidence of functional dyspepsia is 16%,² and that it accounts for ∼ 40% of the total outpatient population of gastroenterology departments.³ Functional dyspepsia does not shorten life expectancy, but it seriously affects health-related quality of life and consumes extensive medical resources.⁴

Functional dyspepsia is a heterogeneous disease with an unclear pathophysiology. Different symptom patterns may be associated with variable disease mechanisms. Delayed gastric emptying occurs in about 23 – 59% of patients with functional dyspepsia.⁵ Some research has shown that delayed gastric emptying may be related to postprandial fullness and vomiting, with these symptoms being more frequently found in female patients than in males.^6–8 Other studies have failed to confirm any difference in the occurrence of functional dyspepsia symptoms between patients with normal or delayed gastric emptying.^9,10 It is clinically important to confirm the presence of delayed gastric emptying in symptomatic patients so that they can receive the most appropriate treatment.

The relationship between symptoms and gastric solid emptying in patients with functional dyspepsia has not been studied in detail and there have been few studies in Asian populations. Given the paucity of data, the purpose of the present study was to determine the proportion of patients with functional dyspepsia who also have delayed gastric emptying (overall or proximal stomach) using scintigraphy, the gold-standard method for assessing gastric solid emptying function. This study also investigated the relationship between delayed gastric emptying (overall or proximal stomach) and symptom patterns of functional dyspepsia.

Patients and methods

Study Population

This was a cross-sectional study conducted in the Department of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health (a tertiary referral centre), Beijing, China, between October 2009 and November 2011. Consecutive adult patients with dyspepsia symptoms, presenting to outpatient gastroenterology clinics, were invited to participate in this study. All recruited patients received a physical examination, performed by experienced gastroenterologists (S-K.Y ., Y-L.Z.). Medical histories were documented and patients were subjected to endoscopy of the alimentary tract using the Olympus CV-260SL video processor (Olympus Medical Systems, Tokyo, Japan), routine blood biochemistry tests and abdominal ultrasound using the Phillips iU22 system (Royal Phillips Electronics, Amsterdam, the Netherlands). Medications that might affect gastrointestinal (GI) function (including antidepressants) were discontinued for  1 week prior to any examination.

All patients fulfilled the Rome III criteria after assessment;¹ they reported one or more of four symptoms including postprandial fullness, early satiety, epigastric pain or epigastric burning. Symptoms must have been present for the 3 months preceding diagnosis and have occurred for  6 months before diagnosis. Patients presented no evidence of organic disease that could be responsible for these symptoms. Exclusion criteria included: oesophagitis; atrophic gastritis or gastro-oesophageal erosion diagnosed by endoscopy; mental disorder; history of alimentary tract ulceration; abdominal surgery; administration of nonsteroidal anti-inflammatory drugs, hormones or other medications that can affect gastric acid secretion within 6 months of study entry.

During upper GI endoscopy, tissue biopsies were taken from the antrum and the corpus, and immediately fixed in 10% neutral-buffered formalin for 24 h at room temperature. Tissues were then dehydrated in ethanol, cleared in xylene and embedded in paraffin wax. Representative sections (4-μm thick) were cut and mounted onto poly-L-lysine-coated slides. Specimens were then stained with cresyl violet to detect the presence of Helicobacter pylori.

Healthy (control) subjects were recruited by advertisements in the hospital, and consisted of volunteers from local colleges and companies; none of these volunteers were patients attending another hospital clinic. All healthy subjects were required to have no symptoms of functional dyspepsia and no history of alimentary tract diseases or drug allergy. They were subjected to upper GI endoscopy, routine biochemistry panels and abdominal ultrasound as undertaken for patients with functional dyspepsia, to exclude alimentary tract diseases.

The study was approved by the Ethics Committee of the China-Japan Friendship Hospital, and written informed consent was obtained from all study participants.

Dyspepsia Symptom Questionnaire

Demographic data and dyspepsia symptoms in recruited patients with functional dyspepsia were collected by means of the validated Rome III questionnaire.¹¹ On the questionnaire, the intensity of functional dyspepsia symptoms (including postprandial fullness, early satiety, epigastric pain, burning, bloating, nausea, vomiting or belching) was divided into four grades: no symptoms, 0; mild symptoms, 1 (only felt when attention was paid to them); moderate symptoms, 2 (tolerable, but sometimes affecting normal life and work); serious symptoms, 3 (intolerable, significantly affecting normal life and work). Due to the relatively small number of patients included in the present study, prevalence of dyspepsia symptoms was not presented by severity. Patients with functional dyspepsia were required to complete the symptom questionnaire based on their condition in the previous 3 months. They were also asked about changes in their body weight since the onset of disease.

Gastric Emptying Studies

Gastric emptying was assessed in patients with functional dyspepsia and healthy subjects at the Department of Nuclear Medicine, China-Japan Friendship Hospital. After an overnight fast of  10 h, participants arrived at the hospital in the morning and were asked to ingest a standard meal that consisted of 50 g scrambled egg and 400 ml of noodle soup, labelled with 2 mCi ^99mtechnetium-labelled diethylene-triamine-pentacetate (^99mTc-DTPA). The meal had a calorific value of 500 kcal (nutritional composition: 14 g protein, 21 g fat, 64 g carbohydrate), was prepared immediately before the test and was consumed by each participant within 10 min. Immediately after meal intake, patients laid supine on the examination bed, to reduce overlapping of the stomach and small intestines. Image acquisition was initiated immediately after completion of the meal (0 min); subsequent images were obtained every 15 min for 120 min, using a double transducer single-photon emission computed tomography scanner (Millennium VG Hawkeye; GE Healthcare Biosciences, Piscataway, NJ, USA); nine images were acquired. In each time period, 1-min anterior and posterior images were collected. Radioactivity calibration and anterior–posterior calibration were performed.¹² Scintigraphic images were obtained with a large field-of-view gamma camera (Millennium VG Hawkeye, GE Healthcare Biosciences) using a low-energy all-purpose collimator with a 20% energy window setting centred at 140 keV. During the interval between two image acquisitions, participants rested in a sitting position. Females were not examined during a menstrual period in order to avoid the effect of hormone levels on rates of gastric emptying.

A nuclear medicine physician (L-J.Y.) and a gastroenterologist (Y-L.Z.) analysed and processed the acquired data, and delineated the region of interest (ROI) on each image. A radioactive count of the ROI was calculated, and standard gastric emptying curves were obtained after radioactive decay correction and anterior–posterior calibration. Measurement of proximal stomach emptying was achieved by drawing a horizontal ROI from the incisura angularis of the stomach that was extended around the stomach orad to this line. In order to identify the incisura angularis, initial or subsequent scans that identified the angle of the stomach were carefully studied, such that the same ROI could then applied to all subsequent gastric images to determine proximal stomach emptying.¹³

Observation parameters included the overall gastric emptying half-time (time [min] needed for half emptying of a standard meal in the total stomach [overall GE t_1/2]) and the proximal gastric emptying half-time (time [min] needed for half emptying of a standard meal in the proximal stomach [proximal GE t_1/2]).

Statistical Analyses

The overall GE t_1/2 was calculated using standard gastric emptying curves. Using the upper limit of the overall GE t_1/2 (95% confidence interval [CI]) in healthy subjects as a definition of normality, patients with functional dyspepsia were divided into two groups: normal overall gastric emptying and delayed overall gastric emptying. Similarly, according to the upper limit of the proximal GE t_1/2 (95% CI), patients with functional dyspepsia were classified as having normal or delayed proximal gastric emptying.

All statistical analyses were performed using the SPSS^® statistical package, version 15.0 (SPSS Inc., Chicago, IL, USA) for Windows^®. All data were presented as mean ± SD. Age and body mass index (BMI) in both patient subgroups (normal versus delayed emptying) were compared using the Student's t-test. Prevalence of dyspepsia symptoms, sex distribution and presence of H. pylori infection were compared across patient subgroups using the χ²-test. Logistic regression analysis was used to identify any association between the risk of delayed gastric emptying of solids (overall or proximal), presence of dyspepsia symptoms and demographic characteristics. P-values of 0.05 and 0.1 were chosen as cut-off points to enter and exit, respectively, the stepwise procedure. The odds ratio (OR) and 95% CI were calculated. A P-value of < 0.05 was considered to be statistically significant.

Results

A total of 93 consecutive adult patients with dyspepsia symptoms participated in this study: 38 were male and 55 were female (mean ± SD age, 39.59 ± 12.50 years). A total of 32 healthy subjects also participated in the study; 15 were male and 17 were female (mean ± SD age, 27.34 ± 7.47 years). The mean age of the healthy subjects was significantly lower than that of the patients with functional dyspepsia (P < 0.01), but the difference in sex distribution was not significant. Fig. 1 summarizes the prevalence of eight dyspepsia symptoms in patients with functional dyspepsia: postprandial fullness and belching were the most prevalent symptoms, whereas epigastric burning and vomiting had the lowest prevalence. Eight patients refused biopsies during upper GI endoscopy; of the 85 patients subjected to testing for H. pylori infection, 22 (25.9%) were H. pylori-positive.

FIGURE 1:

Prevalence of eight dyspepsia symptoms in patients diagnosed with functional dyspepsia (n = 93)

The mean ± SD overall GE t_1/2 in healthy subjects was 110.41 ± 15.99 min. Compared with healthy subjects (GE t_1/2 above the 95% CI for overall gastric emptying in healthy subjects, 116.62 min), 49 out of 93 patients (52.7%) with functional dyspepsia had normal gastric solid emptying of the overall stomach and 44 out of 93 patients (47.3%) had delayed gastric solid emptying of the overall stomach. The mean ± SD proximal GE t_1/2 in healthy subjects was 93.28 ± 14.65 min. Compared with healthy subjects (GE t_1/2 above the 95% CI of proximal gastric emptying in healthy subjects, 98.96 min), 50 out of 93 patients (53.8%) with functional dyspepsia had normal gastric solid emptying of the proximal stomach and 43 out of 93 patients (46.2%) had delayed gastric solid emptying of the proximal stomach.

There were no significant differences in age, sex distribution, BMI or prevalence of H. pylori infection between patients with functional dyspepsia with normal or delayed overall gastric emptying, or between patients with normal or delayed proximal gastric emptying (Table 1). The prevalence of eight dyspepsia symptoms was also not significantly different in patients with functional dyspepsia with normal overall gastric emptying, compared with those with delayed overall gastric emptying (Fig. 2). Of the eight dyspepsia symptoms, only the prevalence rates of nausea and belching were significantly different between those with functional dyspepsia, with either normal or delayed proximal gastric emptying (P = 0.003 and P = 0.043, respectively; Fig. 3). Logistic regression analysis demonstrated that the risk of delayed overall or proximal gastric emptying was not influenced by age, sex, BMI or H. pylori status. Consistent with the results of the single-factor analysis, none of the functional dyspepsia symptoms were found to be independent factors in the logistic regression analysis for overall gastric emptying. Only nausea (OR 4.951; 95% CI 1.321, 18.558; P = 0.018) was consistently and independently associated with the risk of delayed gastric solid emptying of the proximal stomach. All other symptoms and patient demographic characteristics were not independent factors in the logistic regression analysis.

FIGURE 2:

Comparison of the prevalence of eight dyspepsia symptoms in patients with functional dyspepsia with either normal (n = 49) or delayed overall gastric emptying (GE, n = 44). There were no statistically significant differences in symptom prevalence between patients with functional dyspepsia with normal or delayed overall GE using the χ²-test

FIGURE 3:

Comparison of the prevalence of eight dyspepsia symptoms in patients with functional dyspepsia with either normal (n = 50) or delayed proximal gastric emptying (GE, n = 43). ^aP < 0.003, ^bP < 0.043 compared with patients with normal proximal GE using the χ²-test

TABLE 1:

Comparison of demographic characteristics of patients with functional dyspepsia (n = 93) with normal or delayed overall or proximal gastric emptying (GE)

	Overall GE		Proximal GE
Characteristic	Normal n = 49	Delayed n = 44	Normal n = 50	Delayed n = 43
Age, years	39.0 ± 12.1	40.3 ± 13.1	39.5 ± 13.1	36.7 ± 11.9
Sex, male	24	14	25	13
Body mass index, kg/m²	20.7 ± 2.6	21.6 ± 3.1	20.8 ± 2.8	21.5 ± 3.0
Helicobacter pylori,^a positive/negative	10/37	12/26	11/36	11/27

Data presented as mean ± SD or n patients.

85/93 patients received a test for H. pylori infection.

No statistically significant between-group differences (P  0.05). Age and body mass index compared using

Student's t-test; sex distribution and presence of H. pylori infection compared using the χ²-test.

Discussion

Research into the mechanisms involved in functional dyspepsia has focused on abnormal gastric emptying function, visceral hypersensitivity, decreased compliance, abnormal autonomic nervous function, H. pylori infection, increased sensitivity of the duodenum to fat or acids, abnormal duodenal motility, or psychological and social factors.^14–23 As the relationship between the mechanisms and symptoms is not fully understood, empirical treatment is the main method of managing functional dyspepsia, including promotion of gastric motility and digestion, and inhibition of gastric acid secretion.¹ Empirical treatment can theoretically result in poor therapeutic effects and high recurrence after discontinuation of medication.⁵

Delayed gastric emptying is generally considered to be one of the most important pathogenic factors in functional dyspepsia, but no consensus has been reached regarding the relationship between symptoms and gastric emptying. Sarnelli et al.¹⁷ found that the prevalence of postprandial fullness, nausea and vomiting was higher in patients with delayed gastric solid emptying of the overall stomach than in patients with normal emptying. Multifactorial analysis showed that only postprandial fullness and vomiting were related to delayed gastric solid emptying of the overall stomach.¹⁷ Another study showed that female sex, relevant and severe postprandial fullness, and severe vomiting were independently associated with delayed gastric emptying of solids in patients with functional dyspepsia.⁶ In a study of 864 patients with functional dyspepsia, postprandial fullness was independently associated with delayed gastric emptying, but the association was weak (OR 1.98; 95% CI 1.02, 3.86; P = 0.04).⁸ Other investigations have, however, failed to identify a relationship between delayed gastric emptying and functional dyspepsia symptoms. For example, Karamanolis et al.²⁴ found no correlation between symptoms and severely delayed gastric emptying, although this study demonstrated that impaired accommodation was significantly related to early satiety and weight loss. Correlations were also found between visceral hypersensitivity of the proximal stomach to mechanical distension and epigastric pain, early satiety and weight loss.²⁴ The study concluded that the pattern of functional dyspepsia symptoms was determined by sensitivity and accommodation of the proximal stomach, rather than by the severity of delayed gastric emptying.²⁴ Inconsistencies among previous studies^6,8,17,24 might be due to differences in the inclusion criteria, the number of subjects studied, cultural and language factors, eating habits, methods used to measure gastric emptying and the use of questionable statistical analyses.

Gastric emptying scintigraphy is the gold-standard method for testing gastric solid emptying function.²⁵ The present study utilized gastric emptying scintigraphy to demonstrate that nearly half (47.3%) of the patients with functional dyspepsia who were studied had delayed overall gastric emptying. No significant differences were observed, however, between patients with normal or delayed overall gastric emptying in terms of the prevalence of functional dyspepsia symptoms. Postprandial fullness was not found to be related to delayed gastric emptying; the majority of patients with functional dyspepsia reported this symptom (97.8%, 91/93) and there was no significant difference in the prevalence of postprandial fullness between patients with normal or delayed overall gastric emptying (95.9% versus 100% of patients, respectively). It is possible that differences may become apparent if the sample size was increased or if functional dyspepsia symptoms were staged according to severity.

Previous reports have mainly concentrated on the relationship between gastric solid emptying of the overall stomach and functional dyspepsia symptoms.^6,8,17,24,26 Few studies have dealt with the relationship between gastric solid emptying of the proximal stomach and symptoms. In a study that compared food distribution in the stomachs of healthy subjects and patients with functional dyspepsia, postprandial fullness was found to be related to food retention in the proximal stomach late after meal ingestion.²⁷ The present study attempted to clarify the relationship between the gastric solid emptying function of the proximal stomach and functional dyspepsia symptoms. Delayed proximal gastric emptying occurred in almost half of the patients (46.2%) with functional dyspepsia, which was consistent with the rate of delayed overall gastric emptying. Single-factor analysis revealed that the prevalence of nausea and belching were both significantly higher in the delayed proximal gastric emptying group compared with the normal group. When age, sex, BMI, H. pylori status and functional dyspepsia symptoms were used as independent variables in logistic regression analysis, only nausea was shown to be related to delayed proximal gastric emptying. These observations suggest that the presence of nausea might indicate delayed gastric emptying of the proximal stomach.

The findings of the present study suggest that assessment of gastric emptying in patients with functional dyspepsia should also include an examination of proximal gastric emptying, in addition to the measurement of overall gastric emptying. These results are clinically important in terms of the diagnosis and treatment of functional dyspepsia, because the pathogenesis of symptoms can be easily determined in patients who report nausea as the dominant symptom, according to the correlation between nausea and delayed proximal gastric emptying. Functional dyspepsia symptoms could be alleviated with the use of prokinetic agents without the need to undertake GI function tests. Based on symptomatology, patients with functional dyspepsia could be specifically treated according to the correlation between symptoms and pathogenesis. As such, the present findings might be useful in the study of drugs that promote gastric motility. The relationship between improvement of gastric emptying and alleviation of functional dyspepsia symptoms is unclear; in fact, some investigations have reached the opposite to the conclusions presented herein:^28,29 a discrepancy that might be related to participant selection. Findings of the present study suggest that, in patients diagnosed with delayed gastric emptying of the proximal stomach according to the symptom of nausea or determined by gastric emptying function tests, the use of medications that promote gastric motility may alleviate the symptoms.

Major limitations of the present study were the relatively low number of patients with functional dyspepsia analysed and the fact that it was a cross-sectional study, which permits the drawing of conclusions about associations, but not about causal or temporal relationships between variables studied or directionality of the associations found. In addition, the patients with functional dyspepsia were consecutively recruited from a tertiary care centre, which limits the generalizability of the results towards other populations of patients with the disease. Furthermore, the patients with functional dyspepsia were significantly older than the healthy subjects studied.

In conclusion, delayed gastric emptying of the overall or proximal stomach occurs in approximately half of all patients with functional dyspepsia. The presence of nausea was found to be related to delayed gastric emptying of the proximal stomach. Promotion of proximal gastric emptying function may, therefore, constitute an effective therapy for patients with functional dyspepsia who report nausea as the dominant symptom.

Footnotes

Acknowledgements

This study was supported by grant number 2007BAI20B0901 from the National Key Technology R&D Programme in the 11th 5-Year Plan of China.

The authors had no conflicts of interest to declare in relation to this article.

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