GASTROENTEROLOGY 2009;137:94 100
Anxiety Is Associated With Uninvestigated and Functional Dyspepsia
(Rome III Criteria) in a Swedish Population-Based Study
ALIMENTARY TRACT
PERTTI ARO,* NICHOLAS J. TALLEY,, JUKKA RONKAINEN,* TOM STORSKRUBB,* MICHAEL VIETH,
CLINICAL
SVENERIK JOHANSSON,* ELISABETH BOLLINGSTERNEVALD,*,# and LARS AGRUS*
*Care Sciences and Society, Department of Neurobiology, Center for Family and Community Medicine, Karolinska Institutet, Stockholm, Sweden; Department of
Internal Medicine, Mayo Clinic College of Medicine, Jacksonville, Florida; Department of Medicine, University of Sydney, Sydney, Australia; Institute of Pathology,
Bayreuth, Germany; and #AstraZeneca R&D, Mlndal, Sweden
See editorial on page 23.
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 north-
ern Swedish municipalities (n 21,610) was surveyed
using a validated postal questionnaire to assess gastroin-
testinal 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 col-
lection, Helicobacter pylori culture and serology, and
symptom assessments. RESULTS: Of the 1001 subjects
examined by endoscopy, 202 (20.2%; 95% confidence in-
terval [CI], 17.722.7) were classified as having uninves-
tigated 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, 1.153.01). 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, 1.8110.46], 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 dys-
pepsia, and postprandial distress syndrome but not
to epigastric pain syndrome.
D yspepsia broadly refers to one or more chronic or
recurrent gastroduodenal symptoms, but most of-
ten 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.13 The health care
costs of dyspepsia for society are substantial due to
health care seeking, medication, and sick leave costs.4
The reported prevalence of functional dyspepsia is
high. Johnsen et al, in a Norwegian population-based
survey, found the lifetime prevalence of functional dys-
pepsia to be 23% in men and 18% in women.5,6 In a study
of employees in the United States, the prevalence rate of
functional dyspepsia was 29%.7 In a Taiwanese study, the
prevalences of functional dyspepsia according to the
Rome I and Rome II criteria were 24% and 12%, respec-
tively.8
The most frequently applied criteria for functional
dyspepsia have been the Rome I9 and Rome II10 defini-
tions. 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.11 However, little is
known about the epidemiology of these newly defined
syndromes and their very existence has not been estab-
lished.
The risk factors for functional dyspepsia, however de-
fined, remain remarkably poorly documented. Stang-
hellini et al found that gastric emptying was more likely
to be delayed in female patients with functional dyspep-
sia,12 whereas a multicenter US study could not show any
association.13 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
Abbreviations used in this paper: CI, condence interval; HADS,
Hospital Anxiety and Depression Scale; OR, odds ratio.
2009 by the AGA Institute
0016-5085/09/$36.00
doi:10.1053/j.gastro.2009.03.039
July 2009
randomize H pylorinegative cases.14 Koloski et al, in an
Australian population-based study, found that psycho-
logical 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.15 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 be-
tween patients with functional dyspepsia or organic dys-
pepsia in the prevalence of mental distress.16 Li et al, in a
Chinese population-based study, found a link between
functional dyspepsia and depression, poor socioeco-
nomic conditions, use of alcohol, smoking, bad dietary
habits, and a history of abuse,17 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.6 We have observed
an association between duodenal eosinophilia and func-
tional dyspepsia, but this finding needs to be con-
firmed.18 There have been no population-based endo-
scopic 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 func-
tional dyspepsia and functional dyspepsia subgroups ac-
cording 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 neigh-
boring 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, al-
though unemployment status, income, and the propor-
tion with a higher education were slightly lower.19 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 popula-
tion (20 80 years of age, n 21,610 in September 1998)
was drawn. The sampled subjects were given an identifi-
cation number (13000) in random order.19
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.20 Up to
ASSOCIATIONS WITH FUNCTIONAL DYSPEPSIA 95
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.19,21 The overall response rate was 74.2% (n
2122) of the eligible study population.
ALIMENTARY TRACT
The original study population was divided into 5
groups according to their given identification number;
CLINICAL
the study was completed in June 2001.19 In order to
complete 1001 esophagogastroduodenoscopies, 1563 re-
sponders 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 accord-
ing to the study protocol. Thus, the overall response rate
for those eligible for the esophagogastroduodenoscopy
was 73.3%.19 Biopsy specimens for H pylori culture and
histologic analysis were available from 1000 subjects. At
the visit for the esophagogastroduodenoscopy, the par-
ticipants filled in a more comprehensive Abdominal
Symptom Questionnaire, as described elsewhere.19
The study protocol was approved by the Ume Univer-
sity 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.20,22 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 epigas-
tric 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 full-
ness and one question about meal-related early satia-
tion.20 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 dyspep-
sia. The onset of symptoms was defined as 3 months
before the endoscopy.20 The extended Abdominal Symp-
tom Questionnaire filled in at the esophagogastroduode-
noscopy 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 subjects symptom-
atic status. The doctor asked about the previous medical
history and utilization of medical services after the upper
endoscopy. The participants medication use in the pre-
vious 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
 96 ARO ET AL
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
ALIMENTARY TRACT
of alcohol 100 g/wk. Current smokers were defined as
individuals smoking cigarettes and having no other
CLINICAL
present or former tobacco use.
Definition of Body Mass Index
Body mass index was calculated and categorized
according to World Health Organization recommenda-
tions.23
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.11
Functional dyspepsia was defined as uninvestigated
dyspepsia without findings of esophagitis, peptic ulcer,
celiac disease, or cancer and no evidence of other struc-
tural 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 bother-
some 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.11 Overlap between postprandial
distress syndrome and epigastric pain syndrome was al-
lowed 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 re-
gurgitation over the past 3 months.19,24
Irritable bowel syndrome was defined as any trouble-
some abdominal pain located at any site plus concomi-
tant bowel habit disturbances (constipation, diarrhea, or
alternating constipation and diarrhea). This simple defi-
nition has been used previously and shown to produce
results reasonably concordant with the Rome I criteria
for irritable bowel syndrome in Sweden.25
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.26
GASTROENTEROLOGY Vol. 137, No. 1
Esophagogastroduodenoscopy
The upper endoscopies were undertaken by 3 ex-
perienced 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.19,27 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.19
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.21
Definition and Classification of Esophagitis
At endoscopy, the subjects with mucosal breaks in
the esophagus were classified as those with erosive esoph-
agitis and graded according to the Los Angeles classifi-
cation.28,29
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 WarthinStarry silver
staining.30 Histologic parameters of the gastric mucosa
were assessed by using the updated Sydney System score
definitions.31
Samples from the antrum and corpus were cultured
and analyzed as described previously.30 Current H pylori
infection was defined as a positive culture or histology.30
Statistical Analysis
A 2-sided P value of .05 was regarded as statis-
tically significant. Fisher exact test was applied in appro-
priate 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, epi-
gastric 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 antago-
nists, sex, and age. The results were controlled for possi-
ble statistical interactions.
The results are presented as odds ratios (OR) with 95%
confidence interval (CI). The goodness of fit of the mod-
els was judged from the Pearson 2 test (acceptable model
when P .05). The Stata 8 program was used for the
analyses.32
July 2009
Table 1. Proportion of Daily or Weekly Individual Symptoms in Postprandial Distress and Epigastric Pain Syndromes
Fullness Satiation Nausea
Postprandial 100 59.0 (50.367.7) 23.0 (15.530.5)
distress
syndrome
(n 122)
Epigastric pain 21.2 (10.132.3) 23.1 (11.634.6) 23.1 (11.634.6)
syndrome
(n 52)
NOTE. All values are expressed as proportion (95% CI).
Study Power
The power of the study was calculated post hoc to
detect an association of anxiety with epigastric pain syn-
drome (n 52) using nondyspeptic subjects (n 799) as
the reference group. The power value of this analysis was
77% at an level of .05.
Results
Of the 1001 subjects who underwent endoscopy,
202 (20.2%; 95% CI, 17.722.7) 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 syn-
drome and 122 individuals (12.2% of all who underwent
endoscopy; 95% CI, 10.214.2) 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 over-
lap 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.
Use of proton-pump inhibitors was reported by 12.4%
(95% CI, 6.715.7) of subjects with uninvestigated dys-
pepsia, 13.4% (95% CI, 6.516.9) of subjects with func-
tional 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.
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 dys-
pepsia (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,
ASSOCIATIONS WITH FUNCTIONAL DYSPEPSIA 97
Belching Heartburn Epigastric pain Epigastric burning
36.1 (27.644.6) 36.9 (28.345.5) 10.7 (5.216.2) 3.3 (0.16.5)
ALIMENTARY TRACT
28.8 (16.541.1) 32.7 (19.945.5) 66.0 (53.178.9) 34.0 (21.146.9)
CLINICAL
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, 2.539.13] 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 associ-
ated 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 hista-
mine-2 receptor antagonists was associated with func-
tional 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, 1.053.27). 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 anxi-
ety 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, 2.8117.41] 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, 2.6336.14). 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, 1.8110.46), as was use of NSAIDs (OR,
2.75; 95% CI, 1.38 5.50) and proton pump inhibitors
(OR, 4.31; 95% CI, 2.019.20) and histamine-2 receptor
antagonists (OR, 5.03; 95% CI, 1.90 13.28). Low educa-
tion 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
 98 ARO ET AL GASTROENTEROLOGY Vol. 137, No. 1

Table 3. Mean HADS Scores Among Different Dyspepsia

54.8, 13.9

51.2, 14.0

51.2, 14.4

51.5, 14.1

50.7, 14.5
Mean age
(y), SD
Groups
Mean HADS Mean HADS
score for score for
14.3 (11.916.7)

37.6 (30.944.3)

33.8 (26.441.2)

35.0 (22.048.0)

32.0 (23.740.3)
reducing drugs
anxiety (SD) depression (SD)
Use of acid-
ALIMENTARY TRACT

All individuals who underwent 3.6 (3.2) 2.8 (2.5)

endoscopy (n 1001)
CLINICAL

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)
13.3 (10.915.7)

10.9 (6.615.2)

8.9 (4.413.4)

7.7 (0.514.9)

8.2 (3.313.1)
Epigastric pain syndrome (n 52) 4.6 (3.5) 2.6 (2.0)
Alcohol use
100 g

Postprandial distress syndrome 5.1 (3.9) 3.3 (2.8)

(n 122)
10.4 (8.312.5)

7.0 (3.011.0)

7.7 (0.514.9)

6.6 (2.211.0)

evaluate risk factors for functional dyspepsia using the

6.4 (3.09.8)
Snuff use

Rome III definition with careful exclusion of organic

disease by upper endoscopy. Our results show an associ-
ation of anxiety both with uninvestigated and functional
dyspepsia and the subgroup with postprandial distress
15.0 (12.517.5)

22.3 (16.628.0)

19.1 (13.025.2)

21.2 (10.132.3)

18.0 (11.224.8)

syndrome but not with epigastric pain syndrome. There

Smoking

were no associations between H pylori infection, smoking,

use of aspirin, education level, or high alcohol consump-
tion and functional dyspepsia. Low education level was
associated with postprandial distress syndrome.
9.9 (5.814.0)

11.5 (6.516.5)

7.7 (0.514.9)

12.3 (6.518.1)

Whether psychological factors are causally linked to

5.3 (3.76.9)
NSAID use

functional dyspepsia is controversial. A Swedish study

observed that longstanding functional gastrointestinal
disorders (functional dyspepsia and irritable bowel syn-
drome) were associated with psychological illness and
11.3 (9.113.5)

8.4 (4.612.2)

7.0 (3.011.0)

11.5 (2.820.2)

5.7 (1.69.8)

with nongastrointestinal somatic complaints, and these

Aspirin use

symptoms were present regardless of whether the sub-

jects had consulted a physician or not.33 Similarly, a
population-based nonendoscopic survey in Australia
found that neurotism, somatic distress, and anxiety were
58.6 (55.262.0)

56.9 (50.163.7)

58.6 (50.966.3)

51.9 (38.365.5)

59.8 (51.168.5)
Low education

predictors for a functional gastrointestinal disorder di-

agnosis but psychological factors did not discriminate
NOTE. All values are expressed as proportion (95% CI) unless otherwise noted.

between consulters and nonconsulters.2 Pajala et al, in a

Table 2. Demographic Data of Different Dyspepsia Groups

prospective cohort study, observed no difference in men-

tal distress or fear of serious illness in functional versus
33.7 (30.437.0)

34.6 (28.041.2)

33.3 (25.940.7)

32.7 (19.945.5)

33.6 (25.242.0)
H pylori infection

organic gastrointestinal disease, and notably gastrointes-

tinal symptom reduction related to alleviation of mental
distress only reached statistical significance in patients
with organic disease.34 Furthermore, the results from a
randomized, double blind, placebo-controlled study in
52.8 (49.356.3)

32.7 (26.239.2)

27.4 (20.434.4)

30.3 (22.138.5)

The Netherlands showed that treatment with venlafaxine

17.3 (0.113.9)

was not more effective than placebo in patients with

Male

functional dyspepsia.35 In contrast, a recent randomized

double-blind trial reported that a combination of an
anxiolytic and an antidepressant provided short-term im-
provement in functional dyspepsia symptoms applying
Uninvestigated dyspepsia

Epigastric pain syndrome

No dyspepsia (n 799)

syndrome (n 122)

the Rome III criteria.36 Our results are consistent with the
Postprandial distress
Functional dyspepsia

hypothesis that functional dyspepsia is causally linked to

anxiety but not depression. We studied a community
(n 202)

(n 157)

(n 52)

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
July 2009
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 epi-
gastric 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 dis-
comfort. 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,37 which may in turn
be genetically driven.38 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 Australia39 and the
United States.40 We did observe NSAID use to be associ-
ated 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.41 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.42 We showed that obesity is associated with un-
investigated dyspepsia and with documented functional
dyspepsia but not with the functional dyspepsia sub-
groups 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 sig-
nificant risk factor for new-onset dyspepsia,43 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.44 These find-
ings may all reflect an association with gastroesophageal
reflux disease rather than functional dyspepsia and fur-
ther support separating unexplained dyspepsia from gas-
troesophageal 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.20,22 Psy-
chological distress was assessed by the HADS, which has
been widely used and is reliable and representative.26 The
weakness is that our study is a cross-sectional popula-
tion-based study, and we cannot determine causal rela-
tions between our findings and functional dyspepsia.
ASSOCIATIONS WITH FUNCTIONAL DYSPEPSIA 99
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
ALIMENTARY TRACT
smallest study group, epigastric pain syndrome, is prob-
ably not explained by a type II error. The Kalixanda study
CLINICAL
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 post-
prandial 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 enti-
ties.
References
1. Talley NJ, Zinsmeister AR, Schleck CD, et al. Dyspepsia and
dyspepsia subgroups: a population-based study. Gastroenterol-
ogy 1992;102:1259 1268.
2. Koloski NA, Talley NJ, Boyce PM. Epidemiology and health care
seeking in the functional GI disorders: a population-based study.
Am J Gastroenterol 2002;97:2290 2299.
3. Koloski NA, Talley NJ, Boyce PM. Predictors of health care seek-
ing for irritable bowel syndrome and non-ulcer dyspepsia: a criti-
cal review of the literature on symptom and psychosocial factors.
Am J Gastroenterol 2001;96:1340 1349.
4. Agrus L, Borgquist L. The cost of gastro-oesophageal reflux
disease, dyspepsia and peptic ulcer disease in Sweden [pub-
lished correction appears in Pharmacoeconomics 2003;21:148].
Pharmacoeconomics 2002;20:347355.
5. Johnsen R, Straume B, Forde OH. Peptic ulcer and non-ulcer
dyspepsiaa disease and a disorder. Scand J Prim Health Care
1988;6:239 243.
6. Bernersen B, Johnsen R, Straume B. Non-ulcer dyspepsia and
peptic ulcer: the distribution in a population and their relation to
risk factors. Gut 1996;38:822 825.
7. Shaib Y, El-Serag HB. The prevalence and risk factors of func-
tional dyspepsia in a multiethnic population in the United States.
Am J Gastroenterol 2004;99:2210 2216.
8. Lu CL, Lang HC, Chang FY, et al. Prevalence and health/social
impacts of functional dyspepsia in Taiwan: a study based on the
Rome criteria questionnaire survey assisted by endoscopic exclu-
sion among a physical check-up population. Scand J Gastroen-
terol 2005;40:402 411.
9. Drossman DA, Richter JE, Talley NJ, et al. The functional gastro-
intestinal disorders. 1st ed. Boston, MA: Little, Brown and Com-
pany, 1994.
10. Drossman DA, Corazziari E, Thompson WG, et al. Rome II. The
functional gastrointestinal disorders. 2nd ed. McLean, VA: Deg-
non Associates, 2000.
11. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal
disorders. Gastroenterology 2006;130:1466 1479.
12. Stanghellini V, Tosetti C, Barbara G, et al. Dyspeptic symptoms
and gastric emptying in the irritable bowel syndrome. Am J Gas-
troenterol 2002;97:2738 2743.
 100 ARO ET AL
13. Talley NJ, Locke GR III, Lahr BD, et al. Functional dyspepsia,
delayed gastric emptying, and impaired quality of life. Gut 2006;
55:933939.
14. Moayyedi P, Soo S, Deeks J, et al. Eradication of H. pylori for
non-ulcer dyspepsia. Cochrane Database Syst Rev 2006(2):
CD002096.
ALIMENTARY TRACT
15. Koloski NA, Talley NJ, Boyce PM. Does psychological distress
modulate functional gastrointestinal symptoms and health care
CLINICAL
seeking? A prospective, community cohort study. Am J Gastroen-
terol 2003;98:789 797.
16. 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. Aliment Pharmacol Ther 2005;
21:277281.
17. Li Y, Nie Y, Sha W, et al. The link between psychosocial factors
and functional dyspepsia: an epidemiological study. Chin Med J
(Engl) 2002;115:10821084.
18. Talley NJ, Walker M, Aro P, et al. Non-ulcer dyspepsia and duo-
denal eosinophilia: an adult endoscopic population-based case-
control study. Clin Gastroenterol Hepatol 2007;5:11751183.
19. 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. Scand J Gastroenterol
2004;39:1280 1288.
20. Agrus L, Svrdsudd K, Nyrn O, et al. Reproducibility and validity
of a postal questionnaire. The abdominal symptom study. Scand
J Prim Health Care 1993;11:252262.
21. Aro P, Storskrubb T, Ronkainen J, et al. Peptic ulcer disease in a
general adult population. The Kalixanda study: a random popu-
lation-based study. Am J Epidemiol 2006;163:10251034.
22. Aro P, Ronkainen J, Storskrubb T, et al. Validation of the trans-
lation and cross-cultural adaptation into Finnish of the Abdominal
Symptom Questionnaire, the Hospital Anxiety and Depression
Scale and the Complaint Score Questionnaire. Scand J Gastro-
enterol 2004;39:12011208.
23. World Health Organization. Obesity; preventing and managing the
global epidemic. Report of a WHO consultation on obesity, 35
June 1997, Geneva, Switzerland. Available at: www.who.int/nut/
documents/obesity_executive_summary.pdf.
24. Ronkainen J, Aro P, Storskrubb T, et al. High prevalence of
gastroesophageal reflux symptoms and esophagitis with or with-
out symptoms in the general adult Swedish population: a Kalix-
anda study report. Scand J Gastroenterol 2005;40:275285.
25. Agrus L, Talley NJ, Svrdsudd K, et al. Identifying dyspepsia and
irritable bowel syndrome: the value of pain or discomfort, and
bowel habit descriptors. Scand J Gastroenterol 2000;35:142
151.
26. Zigmond AS, Snaith RP. The hospital anxiety and depression
scale. Acta Psychiatr Scand 1983;67:361370.
27. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barretts
esophagus in the general population: an endoscopic study. Gas-
troenterology 2005;129:18251831.
28. Armstrong D, Bennett JR, Blum AL, et al. The endoscopic assess-
ment of esophagitis: a progress report on observer agreement.
Gastroenterology 1996;111:8592.
29. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of
oesophagitis: clinical and functional correlates and further vali-
dation of the Los Angeles classification. Gut 1999;45:172180.
30. Storskrubb T, Aro P, Ronkainen J, et al. A negative H. pylori
serology test is more reliable for exclusion of premalignant gas-
tric conditions than a negative test for current Hp infection: a
report on histology and H. pylori detection in the general adult
population. Scand J Gastroenterol 2005;40:302311.
31. Dixon MF, Genta RM, Yardley JH, et al. Classification and grading
of gastritis. The updated Sydney System. International Workshop
GASTROENTEROLOGY Vol. 137, No. 1
on the Histopathology of Gastritis, Houston 1994. Am J Surg
Pathol 1996;20:11611181.
32. Stata Corporation. The intercooled Stata 8 program. College
Station, TX: StataCorp, 2003.
33. lander T, Svrdsudd K, Johansson SE, et al. Psychological
illness is commonly associated with functional gastrointestinal
disorders and is important to consider during patient consulta-
tion: a population-based study. BMC Med 2005;3:8.
34. 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. Aliment Pharmacol Ther 2006;24:12411246.
35. Van Kerkhoven LA, Laheij RJ, Aparicio N, et al. Effect of the
antidepressant venlafaxine in functional dyspepsia: a random-
ized, double-blind, placebo-controlled trial. Clin Gastroenterol
Hepatol 2008;6:746 752.
36. Hashash JG, Abdul-Baki H, Azar C, et al. Clinical trial: a random-
ized controlled cross-over study of flupenthixol melitracen in
functional dyspepsia. Aliment Pharmacol Ther 2008;27:1148
1155.
37. Van Oudenhove L, Vandenberghe J, Geeraerts B, et al. Determi-
nants of symptoms in functional dyspepsia: gastric sensorimotor
function, psychosocial factors or somatization? Gut 2008;57:
1666 1673.
38. Camilleri CE, Carlson PJ, Camilleri M, et al. A study of candidate
genotypes associated with dyspepsia in a U.S. community. Am J
Gastroenterol 2006;101:581592.
39. Nandurkar S, Talley NJ, Xia H, et al. Dyspepsia in the community
is linked to smoking and aspirin use but not to H. pylori infection.
Arch Intern Med 1998;158:14271433.
40. Talley NJ, Zinsmeister AR, Schleck CD, et al. Smoking, alcohol,
and analgesics in dyspepsia and among dyspepsia subgroups:
lack of an association in a community. Gut 1994;35:619 624.
41. Hawkey C, Talley NJ, Yeomans ND, et al. Improvements with
esomeprazole in patients with upper gastrointestinal symptoms
taking non-steroidal anti-inflammatory drugs, including selective
COX-2 inhibitors. Am J Gastroenterol 2005;100:1028 1036.
42. Jacobson BC, Somers SC, Fuchs CS, et al. Body-mass index and
symptoms of gastroesophageal reflux in women. N Engl J Med
2006;354:2340 2348.
43. Ford AC, Forman D, Bailey AG, et al. Initial poor quality of life and
new onset of dyspepsia: results from a longitudinal 10-year
follow-up study. Gut 2007;56:321327.
44. Talley NJ, Howell S, Poulton R. Obesity and chronic gastrointes-
tinal tract symptoms in young adults: a birth cohort study. Am J
Gastroenterol 2004;99:18071814.
Received August 19, 2008. Accepted March 17, 2009.
Reprint requests
Address requests for reprints to: Pertti Aro, MD, PhD, Center for
Family and Community Medicine, Karolinska Institutet, Alfred
Nobels all 12, S-141 52 Huddinge, Sweden. e-mail: pertti.aro@
mnet.; fax: (358) 30 633 8802.
Conicts of interest
The authors disclose the following: E.B.-S. is an employee of
AstraZeneca. The remaining authors disclose no conicts.
Funding
Supported in part by the Swedish Research Council, the Swedish
Society of Medicine (Stockholm, Sweden), Mag-Tarm Sjukas Frbund
(Stockholm, Sweden), the Norrbotten County Council, Sweden, and
AstraZeneca R&D (Mlndal, Sweden). The study sponsors had no
role in the study design or in the collection, analysis, and
interpretation of data.