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Anxiety Is Associated With Uninvestigated and Functional Dyspepsia (Rome III Criteria) in a Swedish Population-Based Study

      Background & Aims

      The Rome III criteria for functional dyspepsia have been changed to include 2 distinct syndromes: postprandial distress syndrome and epigastric pain syndrome. We investigated risk factors for functional dyspepsia among the functional dyspepsia subgroups defined by the Rome III criteria.

      Methods

      We performed a cross-sectional population-based study in a primary care setting (the Kalixanda study). A random sample (n = 2860) of the adult population from 2 northern Swedish municipalities (n = 21,610) was surveyed using a validated postal questionnaire to assess gastrointestinal symptoms (response rate, 74.2%; n = 2122). A randomly selected subgroup (n = 1001) of responders was invited to undergo an esophagogastroduodenoscopy (participation rate, 73.3%) including biopsy specimen collection, Helicobacter pylori culture and serology, and symptom assessments.

      Results

      Of the 1001 subjects examined by endoscopy, 202 (20.2%; 95% confidence interval [CI], 17.7–22.7) were classified as having uninvestigated dyspepsia and 157 (15.7%; 95% CI, 13.4–18.0) as having functional dyspepsia. Major anxiety (Hospital Anxiety and Depression Scale score ≥11) was associated with uninvestigated dyspepsia (odds ratio [OR], 3.01; 95% CI, 1.39–6.54), as was obesity (body mass index ≥30 kg/m2) (OR, 1.86; 95% CI, 1.15–3.01). Major anxiety was associated with functional dyspepsia and postprandial distress syndrome (OR of 2.56 [95% CI, 1.06–6.19] and 4.35 [95% CI, 1.81–10.46], respectively), as was use of nonsteroidal anti-inflammatory drugs (OR, 2.49 [95% CI, 1.29–4.78] and 2.75 [95% CI, 1.38–5.50], respectively). Depression was not associated with any dyspepsia group.

      Conclusions

      Anxiety but not depression is linked to uninvestigated dyspepsia, functional dyspepsia, and postprandial distress syndrome but not to epigastric pain syndrome.

      Abbreviations used in this paper:

      CI (confidence interval), HADS (Hospital Anxiety and Depression Scale), OR (odds ratio)
      See editorial on page 23.
      Dyspepsia broadly refers to one or more chronic or recurrent gastroduodenal symptoms, but most often no structural cause is identified by routine tests. Functional (or nonulcer) dyspepsia is a common problem in the community, but the underlying etiopathogenesis remains unclear. Only one fourth of individuals with dyspepsia seek medical consultation.
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      Dyspepsia and dyspepsia subgroups: a population-based study.
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      Epidemiology and health care seeking in the functional GI disorders: a population-based study.
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      Predictors of health care seeking for irritable bowel syndrome and non-ulcer dyspepsia: a critical review of the literature on symptom and psychosocial factors.
      The health care costs of dyspepsia for society are substantial due to health care seeking, medication, and sick leave costs.
      • Agréus L.
      • Borgquist L.
      The cost of gastro-oesophageal reflux disease, dyspepsia and peptic ulcer disease in Sweden.
      The reported prevalence of functional dyspepsia is high. Johnsen et al, in a Norwegian population-based survey, found the lifetime prevalence of functional dyspepsia to be 23% in men and 18% in women.
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      • Straume B.
      • Forde O.H.
      Peptic ulcer and non-ulcer dyspepsia—a disease and a disorder.
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      • Straume B.
      Non-ulcer dyspepsia and peptic ulcer: the distribution in a population and their relation to risk factors.
      In a study of employees in the United States, the prevalence rate of functional dyspepsia was 29%.
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      • El-Serag H.B.
      The prevalence and risk factors of functional dyspepsia in a multiethnic population in the United States.
      In a Taiwanese study, the prevalences of functional dyspepsia according to the Rome I and Rome II criteria were 24% and 12%, respectively.
      • Lu C.L.
      • Lang H.C.
      • Chang F.Y.
      • et al.
      Prevalence and health/social impacts of functional dyspepsia in Taiwan: a study based on the Rome criteria questionnaire survey assisted by endoscopic exclusion among a physical check-up population.
      The most frequently applied criteria for functional dyspepsia have been the Rome I
      • Drossman D.A.
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      The functional gastrointestinal disorders.
      and Rome II
      • Drossman D.A.
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      • Thompson W.G.
      • et al.
      Rome II The functional gastrointestinal disorders.
      definitions. Major changes were made in the Rome III criteria for functional dyspepsia where 2 distinct syndromes were postulated, namely postprandial distress syndrome (which includes one or more of bothersome postprandial fullness and early satiation) and epigastric pain syndrome (unexplained epigastric pain and/or epigastric burning); in all cases, there is no evidence of structural disease that is likely to explain the symptoms.
      • Tack J.
      • Talley N.J.
      • Camilleri M.
      • et al.
      Functional gastroduodenal disorders.
      However, little is known about the epidemiology of these newly defined syndromes and their very existence has not been established.
      The risk factors for functional dyspepsia, however defined, remain remarkably poorly documented. Stanghellini et al found that gastric emptying was more likely to be delayed in female patients with functional dyspepsia,
      • Stanghellini V.
      • Tosetti C.
      • Barbara G.
      • et al.
      Dyspeptic symptoms and gastric emptying in the irritable bowel syndrome.
      whereas a multicenter US study could not show any association.
      • Talley N.J.
      • Locke III, G.R.
      • Lahr B.D.
      • et al.
      Functional dyspepsia, delayed gastric emptying, and impaired quality of life.
      A link with Helicobacter pylori has been reported, but H pylori eradication therapy only has had a small, albeit statistically significant, effect in H pylori–positive functional dyspepsia and the trials all failed to randomize H pylori–negative cases.
      • Moayyedi P.
      • Soo S.
      • Deeks J.
      • et al.
      Eradication of H. pylori for non-ulcer dyspepsia.
      Koloski et al, in an Australian population-based study, found that psychological distress was linked to having persistent functional gastrointestinal symptoms and frequently seeking health care for them, but these subjects were not investigated for structural disease.
      • Koloski N.A.
      • Talley N.J.
      • Boyce P.M.
      Does psychological distress modulate functional gastrointestinal symptoms and health care seeking? A prospective, community cohort study.
      In a Finnish study, the risk of having mental distress was nearly 4-fold higher among patients with dyspepsia and functional dyspepsia than among controls, but nevertheless there was no difference between patients with functional dyspepsia or organic dyspepsia in the prevalence of mental distress.
      • Pajala M.
      • Heikkinen M.
      • Hintikka J.
      Mental distress in patients with functional or organic dyspepsia: a comparative study with a sample of the general population.
      Li et al, in a Chinese population-based study, found a link between functional dyspepsia and depression, poor socioeconomic conditions, use of alcohol, smoking, “bad dietary habits,” and a history of abuse,
      • Li Y.
      • Nie Y.
      • Sha W.
      • et al.
      The link between psychosocial factors and functional dyspepsia: an epidemiological study.
      but endoscopy was not performed. In a Norwegian population-based study, functional dyspepsia was confirmed by endoscopy and was associated with having a family history of dyspepsia, peptic ulcer in the family, both current and previous smoking, and the use of tranquilizers.
      • Bernersen B.
      • Johnsen R.
      • Straume B.
      Non-ulcer dyspepsia and peptic ulcer: the distribution in a population and their relation to risk factors.
      We have observed an association between duodenal eosinophilia and functional dyspepsia, but this finding needs to be confirmed.
      • Talley N.J.
      • Walker M.
      • Aro P.
      • et al.
      Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study.
      There have been no population-based endoscopic studies on risk factor associations with functional dyspepsia as defined by the Rome II or III criteria.
      Our aim was to explore potential risk factors in well-documented cases from a general population with functional dyspepsia and functional dyspepsia subgroups according to the Rome III definition. We hypothesized that psychological distress (anxiety and depression) would be an independent risk factor for functional dyspepsia.

      Subjects and Methods

       Setting and Participants

      The Kalixanda study setting consisted of 2 neighboring communities in northern Sweden (Kalix and Haparanda) with 28,988 inhabitants (as of December 1998). The distribution of age and sex was similar to the national average in Sweden in both communities, although unemployment status, income, and the proportion with a higher education were slightly lower.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.
      By using the computerized national population register, covering all citizens in the 2 communities by date of birth order, a representative stratified sample was generated. Every seventh adult (n = 3000) from the target population (20–80 years of age, n = 21,610 in September 1998) was drawn. The sampled subjects were given an identification number (1–3000) in random order.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.

       Study Design and Logistics

      The original study population (n = 3000) was invited by mail to take part. The invitation included information on the study design and the aims of the study as well as a validated questionnaire, the Abdominal Symptom Questionnaire, to be returned by mail.
      • Agréus L.
      • Svärdsudd K.
      • Nyrén O.
      • et al.
      Reproducibility and validity of a postal questionnaire The abdominal symptom study.
      Up to 2 reminders were sent when necessary. A total of 140 subjects were unavailable at the time for invitation; thus, 2860 of the original study population were eligible for inclusion.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.
      • Aro P.
      • Storskrubb T.
      • Ronkainen J.
      • et al.
      Peptic ulcer disease in a general adult population The Kalixanda study: a random population-based study.
      The overall response rate was 74.2% (n = 2122) of the eligible study population.
      The original study population was divided into 5 groups according to their given identification number; the study was completed in June 2001.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.
      In order to complete 1001 esophagogastroduodenoscopies, 1563 responders to the Abdominal Symptom Questionnaire had to be approached, of whom 364 declined, 74 had moved or could not be reached, and 124 were excluded according to the study protocol. Thus, the overall response rate for those eligible for the esophagogastroduodenoscopy was 73.3%.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.
      Biopsy specimens for H pylori culture and histologic analysis were available from 1000 subjects. At the visit for the esophagogastroduodenoscopy, the participants filled in a more comprehensive Abdominal Symptom Questionnaire, as described elsewhere.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.
      The study protocol was approved by the Umeå University Ethics Committee, and the study was conducted according to the Declaration of Helsinki. Oral informed consent was obtained from all participants.

       Assessments

      The Abdominal Symptom Questionnaire is a questionnaire assessing symptoms from the upper and lower part of the abdomen, and it has been found to be valid, reproducible, and reliable.
      • Agréus L.
      • Svärdsudd K.
      • Nyrén O.
      • et al.
      Reproducibility and validity of a postal questionnaire The abdominal symptom study.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Validation of the translation and cross-cultural adaptation into Finnish of the Abdominal Symptom Questionnaire, the Hospital Anxiety and Depression Scale and the Complaint Score Questionnaire.
      All participants were asked if they had been troubled by abdominal pain or discomfort at any location or by any of the listed 33 other gastrointestinal symptoms. A specific question on epigastric burning and 10 other pain or discomfort modalities in the abdomen was included. There was also a specific question about meal-related bothersome feelings of fullness and one question about meal-related early satiation.
      • Agréus L.
      • Svärdsudd K.
      • Nyrén O.
      • et al.
      Reproducibility and validity of a postal questionnaire The abdominal symptom study.
      The questionnaire was designed before the Rome III era but was updated to reflect all of the symptoms included in the Rome III definition of functional dyspepsia. The onset of symptoms was defined as 3 months before the endoscopy.
      • Agréus L.
      • Svärdsudd K.
      • Nyrén O.
      • et al.
      Reproducibility and validity of a postal questionnaire The abdominal symptom study.
      The extended Abdominal Symptom Questionnaire filled in at the esophagogastroduodenoscopy visit also included a grading of severity and the frequency of each symptom during the prior 3 months (monthly, weekly, or daily symptoms).
      A complete medical history was taken and recorded after the investigator-blinded research upper endoscopy; the endoscopist was unaware of the subject's symptomatic status. The doctor asked about the previous medical history and utilization of medical services after the upper endoscopy. The participants' medication use in the previous 3 months was also recorded.

       Demographic Data and History

      Demographic data were collected at the clinic visit (sex, age, height and weight, use of different tobacco products, use of alcohol, and use of medication). The subjects' level of education (low education = elementary, comprehensive, or secondary school; high education = upper secondary school or university) was recorded at the clinic visit. High alcohol consumption was defined as use of alcohol ≥100 g/wk. Current smokers were defined as individuals smoking cigarettes and having no other present or former tobacco use.

       Definition of Body Mass Index

      Body mass index was calculated and categorized according to World Health Organization recommendations.
      World Health Organization
      Obesity; preventing and managing the global epidemic Report of a WHO consultation on obesity, 3–5 June 1997, Geneva, Switzerland.

       Definitions of Symptom Groups

      Dyspepsia (uninvestigated dyspepsia) was defined based on the Rome III definition: weekly bothersome postprandial fullness or early satiation, or epigastric pain and/or epigastric burning (symptom onset 6 months before the survey was not asked about in the Abdominal Symptom Questionnaire). Pain and burning could not be relieved by defecation.
      • Tack J.
      • Talley N.J.
      • Camilleri M.
      • et al.
      Functional gastroduodenal disorders.
      Functional dyspepsia was defined as uninvestigated dyspepsia without findings of esophagitis, peptic ulcer, celiac disease, or cancer and no evidence of other structural disease at endoscopy that was likely to explain the symptoms. Further functional dyspepsia, according to the Rome III definition, was divided into the following: (1) postprandial distress syndrome, consisting of bothersome postprandial fullness and/or early satiation, and (2) epigastric pain syndrome, consisting of pain or burning localized to the epigastric area and not generalized or localized to other abdominal or chest regions and not relieved by defecation.
      • Tack J.
      • Talley N.J.
      • Camilleri M.
      • et al.
      Functional gastroduodenal disorders.
      Overlap between postprandial distress syndrome and epigastric pain syndrome was allowed according to the Rome III definition.
      No dyspepsia was defined as individuals not reporting any type of dyspeptic symptoms.
      Gastroesophageal reflux symptoms were defined as the presence of any troublesome heartburn and/or acid regurgitation over the past 3 months.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.
      • Ronkainen J.
      • Aro P.
      • Storskrubb T.
      • et al.
      High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda study report.
      Irritable bowel syndrome was defined as any troublesome abdominal pain located at any site plus concomitant bowel habit disturbances (constipation, diarrhea, or alternating constipation and diarrhea). This simple definition has been used previously and shown to produce results reasonably concordant with the Rome I criteria for irritable bowel syndrome in Sweden.
      • Agréus L.
      • Talley N.J.
      • Svärdsudd K.
      • et al.
      Identifying dyspepsia and irritable bowel syndrome: the value of pain or discomfort, and bowel habit descriptors.

       Definition of Anxiety and Depression

      The validated Hospital Anxiety and Depression Scale (HADS) was used to measure and define anxiety and depression. A HADS score from 8 to <11 was used to define suspected anxiety and depression, and 11 or more was used as a cutoff level for both clinically relevant (major) anxiety and depression.
      • Zigmond A.S.
      • Snaith R.P.
      The hospital anxiety and depression scale.

       Esophagogastroduodenoscopy

      The upper endoscopies were undertaken by 3 experienced endoscopists in the 2 clinics (Kalix and Haparanda) that gave sole medical coverage to the area. Internal validity was assessed by means of consensus sessions.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.
      • Ronkainen J.
      • Aro P.
      • Storskrubb T.
      • et al.
      Prevalence of Barrett's esophagus in the general population: an endoscopic study.
      The endoscopists had been participating in regular quality assessment programs over several years. The endoscopists were unaware of the symptoms of the subjects before endoscopy.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Valid symptom reporting at upper endoscopy in a random sample of the Swedish adult general population The Kalixanda study.

       Definition of Gastric and Duodenal Ulcer

      Peptic ulcer was defined as a mucosal break at least 3 mm in diameter, with or without a necrotic base in the middle of the lesion, in either the stomach or duodenum.
      • Aro P.
      • Storskrubb T.
      • Ronkainen J.
      • et al.
      Peptic ulcer disease in a general adult population The Kalixanda study: a random population-based study.

       Definition and Classification of Esophagitis

      At endoscopy, the subjects with mucosal breaks in the esophagus were classified as those with erosive esophagitis and graded according to the Los Angeles classification.
      • Armstrong D.
      • Bennett J.R.
      • Blum A.L.
      • et al.
      The endoscopic assessment of esophagitis: a progress report on observer agreement.
      • Lundell L.R.
      • Dent J.
      • Bennett J.R.
      • et al.
      Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification.

       H pylori

      Two experienced pathologists (M.V. and M. Stolte) who were unaware of the endoscopy findings evaluated the biopsy specimens and provided a common report. The biopsy specimens were stained with H&E. H pylori was histologically detected by Warthin–Starry silver staining.
      • Storskrubb T.
      • Aro P.
      • Ronkainen J.
      • et al.
      A negative H. pylori serology test is more reliable for exclusion of premalignant gastric conditions than a negative test for current Hp infection: a report on histology and H. pylori detection in the general adult population.
      Histologic parameters of the gastric mucosa were assessed by using the updated Sydney System score definitions.
      • Dixon M.F.
      • Genta R.M.
      • Yardley J.H.
      • et al.
      Classification and grading of gastritis The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994.
      Samples from the antrum and corpus were cultured and analyzed as described previously.
      • Storskrubb T.
      • Aro P.
      • Ronkainen J.
      • et al.
      A negative H. pylori serology test is more reliable for exclusion of premalignant gastric conditions than a negative test for current Hp infection: a report on histology and H. pylori detection in the general adult population.
      Current H pylori infection was defined as a positive culture or histology.
      • Storskrubb T.
      • Aro P.
      • Ronkainen J.
      • et al.
      A negative H. pylori serology test is more reliable for exclusion of premalignant gastric conditions than a negative test for current Hp infection: a report on histology and H. pylori detection in the general adult population.

       Statistical Analysis

      A 2-sided P value of <.05 was regarded as statistically significant. Fisher exact test was applied in appropriate analyses. The association of anxiety, depression, H pylori infection, use of aspirin, use of nonsteroidal anti-inflammatory drugs (NSAIDs), use of alcohol, smoking, use of moist snuff, use of proton pump inhibitors, use of histamine-2 receptor antagonists, and education level with uninvestigated dyspepsia, functional dyspepsia, epigastric pain syndrome, or postprandial distress syndrome was analyzed, applying multivariate logistic regression model adjusting for sex and age. Model improvement was applied when constructing the most suitable main effect logistic regression model, and all models adjusted for proton pump inhibitors, histamine-2 receptor antagonists, sex, and age. The results were controlled for possible statistical interactions.
      The results are presented as odds ratios (OR) with 95% confidence interval (CI). The goodness of fit of the models was judged from the Pearson χ2 test (acceptable model when P > .05). The Stata 8 program was used for the analyses.
      Stata Corporation
      The intercooled Stata 8 program.

       Study Power

      The power of the study was calculated post hoc to detect an association of anxiety with epigastric pain syndrome (n = 52) using nondyspeptic subjects (n = 799) as the reference group. The power value of this analysis was 77% at an α level of .05.

      Results

      Of the 1001 subjects who underwent endoscopy, 202 (20.2%; 95% CI, 17.7–22.7) were classified as having uninvestigated dyspepsia and 157 (15.7%; 95% CI, 13.4–18.0) as having functional dyspepsia. Of the subjects with functional dyspepsia, 52 (5.2% of all who underwent endoscopy; 95% CI, 3.8–6.6) had epigastric pain syndrome and 122 individuals (12.2% of all who underwent endoscopy; 95% CI, 10.2–14.2) had postprandial distress syndrome, while 17 of these had both epigastric pain syndrome and postprandial distress syndrome (1.7%; 95% CI, 0.9–2.5).
      The proportions of daily or weekly individual symptoms in postprandial distress and epigastric pain syndromes are shown in Table 1. Postprandial distress syndrome did overlap with bothersome weekly or daily reflux in 46.7% (95% CI, 37.8–55.6) of the cases and epigastric pain syndrome in 36.5% (95% CI, 23.4–49.6) of the cases.
      Table 1Proportion of Daily or Weekly Individual Symptoms in Postprandial Distress and Epigastric Pain Syndromes
      FullnessSatiationNauseaBelchingHeartburnEpigastric painEpigastric burning
      Postprandial distress syndrome (n = 122)10059.0 (50.3–67.7)23.0 (15.5–30.5)36.1 (27.6–44.6)36.9 (28.3–45.5)10.7 (5.2–16.2)3.3 (0.1–6.5)
      Epigastric pain syndrome (n = 52)21.2 (10.1–32.3)23.1 (11.6–34.6)23.1 (11.6–34.6)28.8 (16.5–41.1)32.7 (19.9–45.5)66.0 (53.1–78.9)34.0 (21.1–46.9)
      NOTE. All values are expressed as proportion (95% CI).
      Use of proton-pump inhibitors was reported by 12.4% (95% CI, 6.7–15.7) of subjects with uninvestigated dyspepsia, 13.4% (95% CI, 6.5–16.9) of subjects with functional dyspepsia, 17.3% (95% CI, 3.9–26.1) of subjects with epigastric pain syndrome, and 12.3% (95% CI, 6.4–18.0) of subjects with postprandial distress syndrome. In the nondyspeptic population (n = 799), proton pump inhibitors were taken by 24 subjects (3.0%; 95% CI, 1.8–4.2). Other demographic data are shown in Table 2. The mean HADS scores are presented in Table 3.
      Table 2Demographic Data of Different Dyspepsia Groups
      MaleH pylori infectionLow educationAspirin useNSAID useSmokingSnuff useAlcohol use ≥100 gUse of acid-reducing drugsMean age (y), SD
      No dyspepsia (n = 799)52.8 (49.3–56.3)33.7 (30.4–37.0)58.6 (55.2–62.0)11.3 (9.1–13.5)5.3 (3.7–6.9)15.0 (12.5–17.5)10.4 (8.3–12.5)13.3 (10.9–15.7)14.3 (11.9–16.7)54.8, 13.9
      Uninvestigated dyspepsia (n = 202)32.7 (26.2–39.2)34.6 (28.0–41.2)56.9 (50.1–63.7)8.4 (4.6–12.2)9.9 (5.8–14.0)22.3 (16.6–28.0)6.4 (3.0–9.8)10.9 (6.6–15.2)37.6 (30.9–44.3)51.2, 14.0
      Functional dyspepsia (n = 157)27.4 (20.4–34.4)33.3 (25.9–40.7)58.6 (50.9–66.3)7.0 (3.0–11.0)11.5 (6.5–16.5)19.1 (13.0–25.2)7.0 (3.0–11.0)8.9 (4.4–13.4)33.8 (26.4–41.2)51.2, 14.4
      Epigastric pain syndrome (n = 52)17.3 (0.1–13.9)32.7 (19.9–45.5)51.9 (38.3–65.5)11.5 (2.8–20.2)7.7 (0.5–14.9)21.2 (10.1–32.3)7.7 (0.5–14.9)7.7 (0.5–14.9)35.0 (22.0–48.0)51.5, 14.1
      Postprandial distress syndrome (n = 122)30.3 (22.1–38.5)33.6 (25.2–42.0)59.8 (51.1–68.5)5.7 (1.6–9.8)12.3 (6.5–18.1)18.0 (11.2–24.8)6.6 (2.2–11.0)8.2 (3.3–13.1)32.0 (23.7–40.3)50.7, 14.5
      NOTE. All values are expressed as proportion (95% CI) unless otherwise noted.
      Table 3Mean HADS Scores Among Different Dyspepsia Groups
      Mean HADS score for anxiety (SD)Mean HADS score for depression (SD)
      All individuals who underwent endoscopy (n = 1001)3.6 (3.2)2.8 (2.5)
      No dyspepsia (n = 799)3.2 (3.0)2.7 (2.5)
      Uninvestigated dyspepsia (n = 202)4.9 (3.7)3.2 (2.7)
      Functional dyspepsia (n = 157)4.8 (3.6)3.0 (2.6)
      Epigastric pain syndrome (n = 52)4.6 (3.5)2.6 (2.0)
      Postprandial distress syndrome (n = 122)5.1 (3.9)3.3 (2.8)

       Associations With Uninvestigated and Functional Dyspepsia

       Uninvestigated dyspepsia

      Suspected anxiety (HADS score ≥8 and <11) and major anxiety (HADS score ≥11) were independently associated with uninvestigated dyspepsia (OR, 1.93 [95% CI, 1.06–3.50] and 3.01 [95% CI, 1.39–6.54], respectively) but depression was not. Obesity (body mass index ≥30 kg/m2) (OR, 1.86; 95% CI, 1.15–3.01) was also associated with uninvestigated dyspepsia, as were the use of proton pump inhibitors and the use of histamine-2 receptor antagonists in the prior 3 months (OR, 4.81 [95% CI, 2.53–9.13] and 5.89 [95% CI, 2.65–13.07], respectively). H pylori infection, smoking, high consumption of alcohol, low education level, use of NSAIDs, and use of aspirin were not associated with uninvestigated dyspepsia.

       Functional dyspepsia

      Major anxiety was associated with functional dyspepsia (OR, 2.56; 95% CI, 1.06–6.19), but depression was not. Use of NSAIDs was also associated with functional dyspepsia (OR, 2.49; 95% CI, 1.29–4.78). Use of proton pump inhibitors and histamine-2 receptor antagonists was associated with functional dyspepsia (OR, 6.36 [95% CI, 3.09–13.09] and 7.18 [95% CI, 2.70–19.12], respectively), as was obesity (OR, 1.85; 95% CI, 1.05–3.27). Use of aspirin, high alcohol consumption, low education level, smoking, and H pylori infection were not associated with functional dyspepsia.

       Epigastric Pain Syndrome and Postprandial Distress Syndrome

       Epigastric pain syndrome

      Depression and anxiety were not associated with epigastric pain syndrome. The use of proton pump inhibitors and histamine-2 receptor antagonists was associated with epigastric pain syndrome (OR, 6.99 [95% CI, 2.81–17.41] and 15.41 [95% CI, 5.16–45.97], respectively), and the use of proton pump inhibitors was even more strongly associated with epigastric burning (OR, 9.75; 95% CI, 2.63–36.14). H pylori infection, high alcohol consumption, smoking, use of moist snuff, low education level, obesity, and use of aspirin or NSAIDs were not associated with epigastric pain syndrome.

       Postprandial distress syndrome

      Major anxiety was associated with postprandial distress syndrome (OR, 4.35; 95% CI, 1.81–10.46), as was use of NSAIDs (OR, 2.75; 95% CI, 1.38–5.50) and proton pump inhibitors (OR, 4.31; 95% CI, 2.01–9.20) and histamine-2 receptor antagonists (OR, 5.03; 95% CI, 1.90–13.28). Low education level was also associated with postprandial distress syndrome (OR, 1.73; 95% CI, 1.04–2.87).

      Discussion

      To our knowledge, this is the first population-based study in a randomly selected adult population to evaluate risk factors for functional dyspepsia using the Rome III definition with careful exclusion of organic disease by upper endoscopy. Our results show an association of anxiety both with uninvestigated and functional dyspepsia and the subgroup with postprandial distress syndrome but not with epigastric pain syndrome. There were no associations between H pylori infection, smoking, use of aspirin, education level, or high alcohol consumption and functional dyspepsia. Low education level was associated with postprandial distress syndrome.
      Whether psychological factors are causally linked to functional dyspepsia is controversial. A Swedish study observed that longstanding functional gastrointestinal disorders (functional dyspepsia and irritable bowel syndrome) were associated with psychological illness and with nongastrointestinal somatic complaints, and these symptoms were present regardless of whether the subjects had consulted a physician or not.
      • Ålander T.
      • Svärdsudd K.
      • Johansson S.E.
      • et al.
      Psychological illness is commonly associated with functional gastrointestinal disorders and is important to consider during patient consultation: a population-based study.
      Similarly, a population-based nonendoscopic survey in Australia found that neurotism, somatic distress, and anxiety were predictors for a functional gastrointestinal disorder diagnosis but psychological factors did not discriminate between consulters and nonconsulters.
      • Koloski N.A.
      • Talley N.J.
      • Boyce P.M.
      Epidemiology and health care seeking in the functional GI disorders: a population-based study.
      Pajala et al, in a prospective cohort study, observed no difference in mental distress or fear of serious illness in functional versus organic gastrointestinal disease, and notably gastrointestinal symptom reduction related to alleviation of mental distress only reached statistical significance in patients with organic disease.
      • Pajala M.
      • Heikkinen M.
      • Hintikka J.
      A prospective 1-year follow-up study in patients with functional or organic dyspepsia: changes in gastrointestinal symptoms, mental distress and fear of serious illness.
      Furthermore, the results from a randomized, double blind, placebo-controlled study in The Netherlands showed that treatment with venlafaxine was not more effective than placebo in patients with functional dyspepsia.
      • Van Kerkhoven L.A.
      • Laheij R.J.
      • Aparicio N.
      • et al.
      Effect of the antidepressant venlafaxine in functional dyspepsia: a randomized, double-blind, placebo-controlled trial.
      In contrast, a recent randomized double-blind trial reported that a combination of an anxiolytic and an antidepressant provided short-term improvement in functional dyspepsia symptoms applying the Rome III criteria.
      • Hashash J.G.
      • Abdul-Baki H.
      • Azar C.
      • et al.
      Clinical trial: a randomized controlled cross-over study of flupenthixol + melitracen in functional dyspepsia.
      Our results are consistent with the hypothesis that functional dyspepsia is causally linked to anxiety but not depression. We studied a community sample of nonconsulters, and thus our results should not be due to referral bias. However, it is also conceivable that having upper gastrointestinal symptoms drives increased anxiety. Alternatively, another factor such as a common genetic link could explain the coexistence of anxiety and dyspepsia in the population.
      Why meal-related symptoms (postprandial distress syndrome) are associated with anxiety and not with epigastric pain or burning (epigastric pain syndrome) needs further investigation. This observation does suggest that symptoms are unlikely to be driving the development of anxiety in functional dyspepsia, because it then would be expected that pain would induce more anxiety than discomfort. The underlying mechanisms of meal-related symptoms may include fundic disaccommodation and visceral hypersensitivity, but whether these abnormalities are centrally mediated (and hence modulated by anxiety) is uncertain. In a study of 201 tertiary care patients with functional dyspepsia, dyspepsia symptom severity was determined largely by somatization,
      • Van Oudenhove L.
      • Vandenberghe J.
      • Geeraerts B.
      • et al.
      Determinants of symptoms in functional dyspepsia: gastric sensorimotor function, psychosocial factors or somatization?.
      which may in turn be genetically driven.
      • Camilleri C.E.
      • Carlson P.J.
      • Camilleri M.
      • et al.
      A study of candidate genotypes associated with dyspepsia in a U.S. community.
      The search for common pathways that induce anxiety and dyspepsia now needs greater attention.
      We could not show any association of alcohol and smoking with functional dyspepsia, and these results are consistent with other data from both Australia
      • Nandurkar S.
      • Talley N.J.
      • Xia H.
      • et al.
      Dyspepsia in the community is linked to smoking and aspirin use but not to H. pylori infection.
      and the United States.
      • Talley N.J.
      • Zinsmeister A.R.
      • Schleck C.D.
      • et al.
      Smoking, alcohol, and analgesics in dyspepsia and among dyspepsia subgroups: lack of an association in a community.
      We did observe NSAID use to be associated both with functional dyspepsia and its subgroup postprandial distress syndrome, although aspirin was not. NSAIDs can induce dyspepsia in the absence of endoscopic findings, which may be relieved by proton pump inhibitors.
      • Hawkey C.
      • Talley N.J.
      • Yeomans N.D.
      • et al.
      Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors.
      We adjusted for acid suppression drugs in all of our analyses, so this should not have confounded our results.
      Obesity is strongly linked to gastroesophageal reflux disease.
      • Jacobson B.C.
      • Somers S.C.
      • Fuchs C.S.
      • et al.
      Body-mass index and symptoms of gastroesophageal reflux in women.
      We showed that obesity is associated with uninvestigated dyspepsia and with documented functional dyspepsia but not with the functional dyspepsia subgroups of epigastric pain syndrome and postprandial distress syndrome. Ford et al observed in a longitudinal follow-up study that higher body mass index was a significant risk factor for new-onset dyspepsia,
      • Ford A.C.
      • Forman D.
      • Bailey A.G.
      • et al.
      Initial poor quality of life and new onset of dyspepsia: results from a longitudinal 10-year follow-up study.
      and in a longitudinal birth cohort study of young adults in New Zealand an association between obesity and abdominal pain with nausea and vomiting was noted.
      • Talley N.J.
      • Howell S.
      • Poulton R.
      Obesity and chronic gastrointestinal tract symptoms in young adults: a birth cohort study.
      These findings may all reflect an association with gastroesophageal reflux disease rather than functional dyspepsia and further support separating unexplained dyspepsia from gastroesophageal reflux symptoms.
      The strength of our study is the population-based study design. The response rate to all parts of the study was high, suggesting that the results are likely to be reliable and representative. The Abdominal Symptom Questionnaire is valid, reliable, and reproducible.
      • Agréus L.
      • Svärdsudd K.
      • Nyrén O.
      • et al.
      Reproducibility and validity of a postal questionnaire The abdominal symptom study.
      • Aro P.
      • Ronkainen J.
      • Storskrubb T.
      • et al.
      Validation of the translation and cross-cultural adaptation into Finnish of the Abdominal Symptom Questionnaire, the Hospital Anxiety and Depression Scale and the Complaint Score Questionnaire.
      Psychological distress was assessed by the HADS, which has been widely used and is reliable and representative.
      • Zigmond A.S.
      • Snaith R.P.
      The hospital anxiety and depression scale.
      The weakness is that our study is a cross-sectional population-based study, and we cannot determine causal relations between our findings and functional dyspepsia. Another weakness is that we do not have any family history data on dyspepsia. Our study was not originally designed to evaluate risk factors in functional dyspepsia subgroups, but the power of the study was adequate, and therefore the lack of an association of anxiety with the smallest study group, epigastric pain syndrome, is probably not explained by a type II error. The Kalixanda study is, to our knowledge, the largest of its kind in this field. There is a need for a prospective follow-up study of a large random population sample to define the role of the possible causal associations we have identified.
      In conclusion, anxiety but not depression is linked to uninvestigated dyspepsia, functional dyspepsia, and postprandial distress syndrome but not to epigastric pain syndrome. Whether antianxiety agents have any role in management is unknown but worthy of testing. The different risk factor profiles support the current Rome III classification of functional dyspepsia and suggest that targeting therapy will need to be different in these entities.

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      Linked Article

      • New Epidemiologic Evidence on Functional Dyspepsia Subgroups and Their Relationship to Psychosocial Dysfunction
        GastroenterologyVol. 137Issue 1
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          Functional dyspepsia (FD) is a highly prevalent condition, characterized by symptoms suggested to be of gastroduodenal origin, in the absence of an organic cause that is likely to explain them.1,2 Most studies used the Rome II criteria, which defined FD as the presence of pain or discomfort in the epigastrium in the absence of underlying organic disease.1 In this approach, discomfort refers to a group of symptoms that includes postprandial fullness, early satiation, epigastric burning, belching, nausea, upper abdominal bloating, and vomiting.
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