J Gastrointest Surg (2017) 21:831839

DOI 10.1007/s11605-016-3349-y

ORIGINAL ARTICLE

Which Abdominal Symptoms are Associated with Clinical Events

in a Population Unaware of Their Gallstones? a Cohort Study
Daniel Mnsted Shabanzadeh 1,2 & Lars Tue Srensen 1,3 & Torben Jrgensen 1,2,4,5

Received: 15 November 2016 / Accepted: 30 December 2016 / Published online: 12 January 2017
# 2017 The Society for Surgery of the Alimentary Tract

Abstract
Background High rates of persistent symptoms are found following cholecystectomy in patients with gallstones. The aim of this
population based cohort study was to determine which symptoms were associated with the development of clinical gallstone
events in a population unaware of their gallstones.
Material and Methods Three random population samples from Copenhagen (N = 6037) were examined with ultrasound during
19821994. Participants were not informed about gallstone status. Abdominal symptoms were assessed at baseline through a
questionnaire. Follow-up for clinical events was performed through central registers until 2011. Multivariable Cox regression
analyses were performed.
Results Participants unaware of their gallstones (N = 595) were followed for median 17.5 years. A total of 16.6% participants
developed clinical events. Both uncomplicated and complicated events were associated with high pain intensity at baseline.
Complicated events were also associated with pain at night. Uncomplicated events were associated with pain localized in the
epigastrium, of longer duration, and in need of pain medication. No associations were identified for dyspepsia or irritable bowel
syndrome.
Conclusions In a population of unaware gallstone carriers, it was possible to identify abdominal symptoms associated with later
clinical detection of the gallstones. These finding may contribute to a better selection of patients for surgery.

Keywords Cholelithiasis . Gallbladder diseases . Signs and Introduction

symptoms . Ultrasonography
* Daniel Mnsted Shabanzadeh
daniel.moensted.shabanzadeh.01@regionh.dk
1
Digestive Disease Center, Bispebjerg University Hospital,
Bispebjerg Bakke 23, DK-2400 Copenhagen, Denmark
2
Research Centre for Prevention and Health, Capital Region of
Denmark, Copenhagen, Denmark
3
Department of Clinical Medicine, Faculty of Health and Medical
Sciences, University of Copenhagen, Copenhagen, Denmark
4
Department of Public Health, Faculty of Health and Medical
Sciences, University of Copenhagen, Copenhagen, Denmark
5
The Faculty of Medicine, Aalborg University, Aalborg, Denmark
Only few gallstone carriers will progress to clinical events.1
When treated surgically, up till 1043% experience persisting
symptoms.28 A rational selection of patients for cholecystec-
tomy is hampered by an incomplete knowledge of specific
symptoms associated with gallstones.
Classical Bbiliary colic^ includes pain attacks localized in the
upper right abdominal quadrant or epigastrium, of longer dura-
tion, of higher intensity, and with possible pain projection to the
right abdomen or back.9 The association between these and
similar symptoms to gallstones have been shown in some ob-
servational studies in both clinical and general populations,10,11
but not in all.12 Also some studies have indicated an association
between gallstones and a number of functional abdominal
symptoms.10,11 In a recent analysis, it was shown that newly
formed gallstones were associated with a symptom complex
including pain in the whole upper abdomen with projection
832
and of longer duration, but no associations to a debut in
functional symptoms were identified.13
The prediction of clinical events or disease progression in
gallstone carriers has been studied in populations aware1418
and unaware1,19 of their gallstones. Identified determinants
include female sex,1,14,15 younger age,1,14,18 obesity or higher
body mass index,15,19 larger gallstones,1,17 multiple gall-
stones, gallstone age above 5 years,1 vocational training, and
a sedentary physical activity level.19 Knowledge about specif-
ic symptoms caused by gallstones is needed in order to im-
prove identification of patients that will benefit from surgery
and, thereby, improve post-cholecystectomy outcome. This
has never been investigated in a population unaware of their
gallstones.
The aim of this cohort study was to determine which symp-
toms were associated with the development of clinical gall-
stone events in a general population sample unaware of their
gallstones.
Material and Methods
The data in this study comprised three random samples of the
general population aged 3070 years, living in 11 municipal-
ities in the western part of the urban area of Copenhagen, and
drawn by computer from the Civil Registration System. The
cohorts were part of an international collaboration multina-
tional monitoring of trends and determinants in cardiovascular
disease (MONICA) with the aim to examine cardiovascular
risk factors in the general population and it included
MONICA 1 examined in 19821994, the 1914 cohort exam-
ined in 1984, and MONICA 3 examined in 19911992. All
were invited by letter and non-responders were re-invited and
contacted by telephone. Free transportation and examinations
that took place outside of office working hours were offered if
necessary. Participants appeared after 12 h of fasting and
underwent a general health examination, including a question-
naire about abdominal symptoms and medical history, and had
an abdominal ultrasound examination in order to assess gall-
stone status. Gallstones were defined as acoustic shadows that
moved with gravity in a gallbladder lumen. Exceptions from
the mobility criteria included if a stone was wedged in the
infundibulum of the gallbladder or otherwise impeded by size,
septae, or folds.20 Informed consent was obtained from all
participants before enrolment. Participants were not informed
about gallstone status or of other benign gallbladder condi-
tions identified by ultrasound examination. This was accepted
by the local research ethics committee to avoid unnecessary
treatment and worrying of participants.21 Studies on gallstone
prevalence, incidence, mortality, gallstone characteristics,
and other determinants of clinical events have been
published before.1,1924
J Gastrointest Surg (2017) 21:831839
This study population was followed by linkage to the
National Patient Registry and The Civil Registration System
using the unique personal registration number. Entrance into
the study was defined as the day gallstones were detected by
ultrasound. Participants were followed until clinical event,
death, emigration, or censoring on December 31, 2011,
whichever came first. Causes of death were explored in post
hoc analyses by linkage to the Danish Register of Causes of
Death, which contains death certificates including one under-
lying cause of death with a number contributory causes.
Clinical events were defined as hospital contact, where the
gallstones were detected. Events were reported as total gall-
stone events and as subgroups complicated and uncomplicat-
ed events. Complicated events were defined as acute chole-
cystitis, common bile duct stones, or pancreatitis and uncom-
plicated events as a cholecystectomy or having a clinical di-
agnosis of gallstone disease without any treatment
(cholecystolithiasis or cholelithiasis). Diagnose and treatment
according to the International Classification of Disease (ICD 8
or ICD 10ICD 9 was never used in Denmark) and the
Nordic Classification of Surgical Procedures, either as single
codes or in combination.
The presence of abdominal symptoms experienced by
the participants within the past 12 months was assessed by
a questionnaire at the baseline examination. Symptoms in-
cluded pain localization in the upper abdomen (under right
rib, epigastrium, or whole upper abdomen), pain from same
localizations with projection to the right shoulder or back,
and specific pain characteristics (frequency, duration, inten-
sity, use of pain medication, and pain at night). Frequency,
duration, and intensity were included as categorical vari-
ables with levels ranging from no pain to the worst level,
frequency ranging from pain occurring once until daily, du-
ration from seconds to days, and intensity from mild to ex-
treme. Pain characteristics were dichotomized with the cut
points at weekly for frequency, at hours for duration, and at
moderate for intensity. Only estimates from dichotomized
variables were reported. Categorical variables were ex-
plored for linear trends and were reported if significant.
Use of pain medication was originally a categorical variable
ranging from never to every time and was dichotomized at
often. Functional gastrointestinal symptoms were included
as symptom complexes, which had been identified through
symptom cluster analyses in the same cohort.25 They in-
cluded two types of dyspepsia defined by upper abdominal
pain with either nausea or acid regurgitation and irritable
bowel syndrome defined by abdominal pain and distension
with additional borborygmi, altering stool consistency, or
both.
Other variables included body mass index (kg/m2), stone
size above 10 mm at ultrasound examination, and number of
visits to general practitioner within the past year prior to
examination.
J Gastrointest Surg (2017) 21:831839
Statistical Analyses
Medians with interquartile range (IQR) were reported for con-
tinuous variables and numbers with percentages were reported
for categorical variables. For total events, proportions of
events and years of follow-up were reported. Cox regression
was performed for statistical analyses. Hazard ratios (HR)
with 95% CI were reported and significant associations were
defined by a confidence interval not including 1. Scaled
Schoenfelds residuals were used to test goodness of fit for
the most adjusted estimate.26 A time-dependent change in
hazards of some variables was expected due to the long
follow-up available. Estimates for pain localized in the whole
upper abdomen and the irritable bowel syndrome did not ful-
fill goodness of fit when complete follow-up period was
included and analyses for these variables, therefore, only
included the first 10 years of follow-up. Principles for
choosing variables for each model were a minimum of 10
outcome events per parameter and goodness of fit.
Multivariable models were built in order to adjust for possible
confounding by factors associated with clinical events.1,19 A
multivariable model 1 was built by adjusting for the covariates
age (years) and sex. Model 2 was further adjusted for body
mass index and these analyses were considered the primary.
Model 3 was built for total events only and further included
stone size above 10 mm and number of visits to general prac-
titioner. The latter variable was included in order to explore a
possible detection bias and was considered a mediator in the
causal pathway between symptoms and gallstone events. All
statistical analyses were performed with the BR Studio^
software (RStudio Inc, Boston, MA) and the Bsurvival^ pack-
age. Reporting was performed according to the STROBE
Statement.27
Fig. 1 Participant flow and study
design
833
Results
Of invited persons (N = 7847), 77% (N = 6037) participated in
the study. A total of 853 had or had had gallstones. Of these,
189 had a former cholecystectomy and 69 were aware of their
gallstones, leaving 595 persons unaware of their ultrasound-
proven gallstones for analyses (Fig. 1). Missing observations
were higher for pain projection due to only being examined in
one cohort and for pain medication and duration due to only
being examined in two of the three cohorts. Missing observa-
tions due to erroneous or non-response in questionnaires did
not exceed 4.5%. Distributions of baseline characteristics
were reported in Table 1 and distribution of baseline symp-
toms were reported in Table 3.
The study population was followed median 17.5 years (IQR
(10.0; 20.8)) of which participants with clinical events were
followed median 9.70 years (IQR (5.60; 12.7)) and participants
with no events were followed 17.9 years (IQR (12.1; 21.4)). At
follow-up, 283 participants were alive, 311 had died, and one
participant was lost due to emigration and follow-up was thus
99.8% complete. Clinical events occurred in 99 (16.6%) and of
these, 43 (7.2%) were complicated and 56 (9.4%) were uncom-
plicated events based on codes for diagnoses and treatments
(Fig. 1). A detailed description of occurring clinical events in
the study population is reported in Table 2. None of the partic-
ipants had developed gallbladder cancer during follow-up.
When exploring causes of death in the entire gallstone disease
population (N = 853) as a post hoc analysis, a total of three
study participants had gallstone disease registered. Of these,
one had a common bile duct stone and one had a gallbladder
perforation registered as the underlying cause of death, and the
third had died of a myocardial infarction but had gallstone
disease registered as a contributing cause of death.
834 J Gastrointest Surg (2017) 21:831839

Table 1 Baseline characteristics

of study population including 595 Unit n (%)/median (interquartile range)
unaware gallstone carriers
examined in 19821994 Age Years 60.0 (50.0; 65.0)
Sex Female 338 (56.8)
Male 257 (43.2)
Body mass index kg/m2 25.5 (23.0; 28.9)
Visits to the general practitioner the past yeara 2.00 (0.00; 3.00)
Stone sizea 10 mm 392 (69.0)
>10 mm 176 (31.0)
a
Missing data in 27 participants

Total events were associated with abdominal pain localized
in the epigastrium, of duration more than hours, of moderate
to severe intensity, occurring at night, and in need of pain
medications in all analyses. Dyspepsia nausea type was asso-
ciated in the sex and age adjusted model 1 but not when
adjusted for body mass index (model 2). No associations were
found for pain localization under the right rib or in the whole
upper abdomen, pain projection, frequency, or functional
symptoms. Estimates did not change significantly with the
addition of stone size or visits to general practitioner in model
3. When pain characteristics were explored as categorical var-
iables with levels ranging from no pain to the worst category,
significant trends were found for pain frequency, duration, and
intensity (Table 3).
Complicated events were significantly associated with pain
at night in Model 1 and with moderate to severe intensity in
Model 2. When pain characteristics were explored as categor-
ical variables, a significant trend for complications and inten-
sity was identified (Table 4). Uncomplicated events were sig-
nificantly associated with pain localized in the epigastrium, of
duration more than hours, of moderate to severe intensity, and
in need of pain medication in all analyses. When pain charac-
teristics were explored as categorical variables, significant
trends for uncomplicated events and pain frequency, duration,
and intensity were found (Table 4).
Discussion
Clinical events in unaware gallstone carriers were associated
with pain localized in the epigastrium, of duration more than
hours, of moderate to severe intensity, of higher frequency,
occurring at night, and in need of pain medication. Moderate
to severe pain intensity was associated with both complicated
and uncomplicated events. Complicated events were also as-
sociated with pain at night. Uncomplicated events were asso-
ciated with a symptom complex of pain localized in the
epigastrium, of duration more than hours, and of higher fre-
quency and a need of pain medication. No significant associ-
ations with clinical events were identified for dyspepsia or
irritable bowel syndrome.
No associations for dyspepsia nausea type and all events
were identified when adjusted for body mass index indicating
possible confounding by body mass index or other associated
factors. Estimates were not changed significantly by the inclu-
sion of the larger gallstones or by number of visits to the
general practitioner. When explored separately, complicated
events were few and associations could not be fully adjusted
in multiple models. Generally, not many symptoms were iden-
tified to predict complicated events. Not all three cohorts were
examined for pain projection, duration, or medication.
This present study confirms, that the Bbiliary colic^ of pain
localized in the epigastrium, of longer duration, of higher in-
tensity, of higher frequency, occurring at night, and in need of
pain medication is associated with gallstones911 and that this
symptom complex bring gallstone carriers from the general
population to seek medical help during long-term follow-up.
Pooled observational clinical studies and a randomized trial
report relief from Bbiliary colic^ in 9092% of patients
Table 2 Number of gallstones events in 595 unaware gallstone carriers
during follow-up (1982December 31, 2011)
N (%)
Total events 99 (16.6)
Complicated events 43 (7.2)
Common bile duct stonesa 28 (4.7)
Acute cholecystitisb 15 (2.5)
Uncomplicated events 56 (9.4)
Cholecystectomyc 31 (5.2)
Clinical diagnosis (cholecystolithiasis or cholelithiasis)d 25 (4.2)
No events 496 (83.4)
a
Included diagnose codes for common bile duct stones and pancreatitis,
and treatment codes for endoscopic retrograde cholangiography
b
Included diagnose codes for acute cholecystitis and one participant had a
treatment code for cholecystostomy
c
Included treatment codes for cholecystectomy or laparoscopic cholecys-
tectomy without concomitant treatment codes or diagnose codes for bil-
iary disease or gastrointestinal cancers
d
Included codes for cholecystolithiasis or cholelithiasis without concom-
itant treatment codes or diagnose codes for biliary disease, treatment, or
gastrointestinal cancers
Table 3 Cox regression analyses of abdominal symptoms and total gallstone events during follow-up (1982December 31, 2011)

Events/total Median years follow-up Model 1 HR (95% CI)e Model 2 HR (95% CI)f Model 3 HR (95% CI)g
(interquartile range)

Pain localization Under right rib No 92/571 17.5 (10.0; 20.8) Reference Reference Reference
Yes 7/24 17.2 (11.3; 20.3) 1.70 (0.78; 3.72) 1.55 (0.70; 3.41) 1.42 (0.61; 3.35)
Under right rib + projection No 73/439 17.8 (11.5; 23.2) Reference Reference Reference
Yes 1/3 14.2 (14.0; 16.2) 1.49 (0.20; 10.8) 0.99 (0.14; 7.29) 1.65 (0.22; 12.5)
Epigastrium No 76/508 17.5 (10.2; 20.8) Reference Reference Reference
Yes 23/87 17.4 (7.90; 20.7) 1.62 (1.01; 2.61) 1.66 (1.03; 2.67) 1.68 (1.03; 2.75)
J Gastrointest Surg (2017) 21:831839

Epigastrium + projection No 68/428 17.8 (11.7; 23.2) Reference Reference Reference

Yes 6/14 16.5 (6.00; 25.3) 2.32 (0.99; 5.41) 2.08 (0.89; 4.86) 2.35 (0.98; 5.64)
Whole upper abdomena No 85/553 17.5 (10.0; 20.8) Reference Reference Reference
Yes 14/42 15.2 (11.3; 20.4) 0.76 (0.28; 2.06) 0.75 (0.28; 2.06) 0.42 (0.10; 1.71)
Whole upper abdomena + projection No 73/439 17.8 (11.7; 23.2) Reference Reference Reference
Yes 1/3 11.3 (8.50; 19.9) 1.44 (0.19; 10.9) 1.61 (0.22; 11.8) 2.18 (0.28; 16.8)
Pain characteristics Frequency No pain/monthly 83/538 17.5 (10.1; 20.7) Reference Reference Reference
Weekly/daily 16/57 17.3 (8.00; 21.9) 1.52 (0.87; 2.63) 1.52 (0.88; 2.64) 1.42 (0.80; 2.51)h
Duration No pain/minutes 65/435 17.8 (11.1; 21.2) Reference Reference Reference
Hours/days 28/90 17.3 (10.0; 20.7) 2.10 (1.34; 3.30) 2.03 (1.29; 3.19) 1.98 (1.24; 3.16)h
Intensity No pain/mild pain 69/472 17.6 (10.9; 20.8) Reference Reference Reference
Moderate/extreme 28/105 16.3 (7.40; 20.4) 1.88 (1.21; 2.94) 1.95 (1.24; 3.04) 1.88 (1.17; 3.01)h
Pain at night No 59/393 17.8 (11.7; 23.3) Reference Reference Reference
Yes 15/49 17.7 (9.20; 21.9) 2.06 (1.17; 3.66) 2.09 (1.18; 3.70) 2.32 (1.31; 4.13)
Pain medication No/sometimes 74/485 17.6 (10.9; 22.7) Reference Reference Reference
Often/every time 4/10 7.6 (5.70; 9.60) 7.06 (2.51; 19.9) 7.71 (2.75; 21.6) 8.42 (2.97; 23.9)
Functional symptoms Dyspepsia nausea typeb No 85/564 17.5 (10.2; 20.8) Reference Reference Reference
Yes 3/7 16.2 (3.60; 18.0) 3.24 (1.02; 10.3) 2.98 (0.94; 9.50) 2.81 (0.85; 9.34)
Dyspepsia regurgitation typec No 95/580 17.6 (10.0; 20.8) Reference Reference Reference
Yes 4/14 13.8 (7.20; 17.8) 2.09 (0.77; 5.70) 2.15 (0.79; 5.87) 2.56 (0.93; 7.05)
Irritable bowel syndromea, d No 87/558 17.5 (10.2; 20.8) Reference Reference Reference
Yes 7/26 17.7 (7.30; 23.0) 1.38 (0.44; 4.40) 1.36 (0.43; 4.33) 1.43 (0.45; 4.58)

a
Follow-up was restricted to first 10 years in order to obtain goodness of fit
b
Abdominal pain with nausea
c
Abdominal pain with acid regurgitation or heartburn
d
Abdominal pain and distension with either borborygmi, change in stool consistency, or both
e
Model 1 includes age (years) and sex
f
Model 2 includes age (years), sex, and body mass index (kg/m2 )
g
Model 3 includes age (years), sex, body mass index (kg/m2 ), stone size >10 mm, and number of visits to general practitioner the past year
h
When explored as categorical variables ranging from no pain to worst category, significant trends were found for frequency (P = 0.02), duration (P = 0.002), and intensity (P = 0.0001)
835
836 J Gastrointest Surg (2017) 21:831839

Table 4 Cox regression analyses of abdominal symptoms, complicated, and uncomplicated events during follow-up (1982 - December 31st 2011)

Complicated events Uncomplicated events

Model 1 HR (95% Model 2 HR (95% Model 1 HR (95% Model 2 HR (95%

CI)e CI)f CI)e CI)f

Pain localization Under right rib No Reference Reference Reference Reference

Yes 1.17 (0.28; 4.92) 1.04 (0.24; 4.41) 2.07 (0.81; 5.30) 1.92 (0.74; 4.96)
Under right rib + projection No Reference Reference Reference Reference
Yes 2.44 (0.33; 18.0) 1.61 (0.21; 12.2)
Epigastrium No Reference Reference Reference Reference
Yes 1.27 (0.58; 2.77) 1.31 (0.60; 2.87) 1.91 (1.04; 3.48) 1.94 (1.06; 3.54)
Epigastrium + projection No Reference Reference Reference Reference
Yes 1.97 (0.46; 8.41) 2.52 (0.89; 7.18) 2.28 (0.80; 6.51)
Whole upper abdomena No Reference Reference Reference Reference
Yes 1.08 (0.53; 2.22) 1.08 (0.53; 2.22) 0.87 (0.38; 1.98) 0.87 (0.38; 1.97)
Whole upper No Reference Reference
abdomena + projection Yes 2.24 (0.30; 16.9) 2.59 (0.35; 19.3)
Pain Frequency No pain/monthly Reference Reference Reference Reference
characteristics Weekly/daily 1.63 (0.70; 3.77) 1.65 (0.71; 3.80) 1.44 (0.69; 2.99) 1.44 (0.70; 3.00)h
Duration No pain/minutes Reference Reference Reference Reference
Hours/days 1.65 (0.80; 3.40) 1.59 (0.77; 3.28) 2.49 (1.39; 4.46) 2.42 (1.35; 4.34)h
Intensity No pain/mild pain Reference Reference Reference Reference
Moderate/extreme 1.91 (0.97; 3.78) 2.00 (1.01; 3.97)g 1.87 (1.04; 3.37) 1.91 (1.06; 3.46)h
Pain at night No Reference Reference Reference
Yes 2.40 (1.03; 5.60) 1.83 (0.84; 3.97) 1.88 (0.87; 4.07)
Pain medication No/sometimes Reference Reference Reference
Often/every time 3.96 (0.52; 29.8) 9.58 (2.84; 32.3) 10.3 (3.08; 34.7)
Functional Dyspepsia nausea typeb No Reference Reference Reference
symptoms Yes 2.59 (0.35; 19.1) 3.70 (0.89; 15.3) 3.37 (0.81; 14.0)
Dyspepsia regurgitation No Reference Reference Reference Reference
typec Yes 2.45 (0.59; 10.2) 2.53 (0.61; 10.5) 1.83 (0.45; 7.52) 1.87 (0.46; 7.70)
Irritable bowel syndromea, d No Reference Reference Reference Reference
Yes 1.74 (0.76; 3.98) 1.75 (0.76; 4.02) 2.01 (0.88; 4.61) 2.02 (0.88; 4.64)
a
Follow-up was restricted to first 10 years in order to obtain goodness of fit
b
Abdominal pain with nausea
c
Abdominal pain with acid regurgitation or heartburn
d
Abdominal pain and distension with either borborygmi, change in stool consistency, or both
e
Model 1 includes age (years) and sex
f
Model 2 includes age (years), sex, and body mass index (kg/m2 )
g
When explored as categorical variables ranging from no pain to extreme pain, a significant trend was found (P = 0.005)
h
When explored as categorical variables from no pain to worst category, significant trends were found for frequency (P = 0.02), duration (P = 0.003), and
intensity (P = 0.002)

following cholecystectomy47,28 further strengthening the
identified associations. Newly formed gallstones have recent-
ly been associated with pain in the whole upper abdomen and
not to specific sites in the upper abdomen.13 The discrepancy
between these findings may indicate that clinical disease with
pain localized in epigastrium is caused by gallstones of older
age as suggested in a recent cohort study.1 The mechanisms of
Bbiliary colic^ are not identified completely. They are
suggested to involve the migration of a stone through the
cystic duct or the impaction of gallstone in the cystic duct or
ampulla of Vater causing a distension of the gallbladder and
biliary tract, which then activates the visceral sensory
neurons.9,29,30 In vitro gallbladder smooth muscle contractility
has been associated with pain in gallstone carriers as well.31
The association between gallstones and functional gastroin-
testinal symptoms is controversial. Most cross-sectional studies
J Gastrointest Surg (2017) 21:831839
have, just like the present study, found no association between
gallstones and functional symptoms such as heartburn, acid
regurgitation, or heterogeneously defined Bdyspepsia^10,13,32
while other studies have found associations with nausea and
vomiting.10,32 Experimental research has shown that persons
with gallstones compared to gallstone-free controls have signif-
icantly more and longer periods of an acidic environment in the
esophagus indicating an increased gastro-esophageal reflux.33
In addition, patients with gallstones have also been identified to
have an increased duodeno-gastric reflux, an increased amount
of bile acids in gastric content, and gastritis when compared to
controls.3439 Clinical studies examining patients before and
after cholecystectomy have disclosed increased duodeno-
gastric reflux of bile and histopathological gastritis following
cholecystectomy.4042 As gallstone patients have higher risk of
both gastro-esophageal and duodeno-gastric reflux, cholecys-
tectomy will increase the duodeno-gastric bile reflux even fur-
ther. The very poor dyspepsia relief following cholecystectomy
might be explained by these mechanisms.24,28,4345
The irritable bowel syndrome has been shown to be prev-
alent in gallstone carriers but unlikely associated with incident
gallstones.13 Contrary to this present study, other studies have
found an association between the irritable bowel syndrome
and cholecystectomy or gallstone events.46,47 Clinical studies
show poor outcomes for the irritable bowel syndrome follow-
ing cholecystectomy as well.8,48 There might be common risk
factors between gallstones and functional symptoms, but they
do not seem to be similar diseases and should, therefore, not
be treated with cholecystectomy.
The methodological strength of this study was that the pop-
ulation was unaware of having gallstones. Gallstone aware-
ness has been shown to overestimate clinical events in cohort
studies and to introduce protopathic bias.1 Since the partici-
pants were derived from the general population, this study
enables conclusions to be drawn about the true natural history
of gallstones in an unselect population. The follow-up was
long and free of attrition bias. Multiple adjusted models in-
cluding variables associated with gallstone events were used
to minimizing possible confounding by known factors for
clinical gallstone events. The limitations of this study include
the use of data from registries. A risk of non-differential mis-
classification causing estimations toward the null might there-
fore be present. This risk must be outweighed by the advan-
tage of the comprehensive follow-up. A risk of detection bias
exists through the selection of patients for cholecystectomy
based on physicians suspicion of gallstone related pain. An
attempt to control for this was made by adjusting for number
of annual visits to the general practitioner. Although this ad-
justment did not change estimates, detection bias cannot be
adjusted for completely. Complicated events were few and
pain projection, duration, and medication was not assessed
in all three cohorts and, thereby, a risk of type II error on the
estimates of these specific associations.
837
Clinical implications of this studies result include a better
patient selection for surgery based on specific patient centered
gallstone symptoms. Since this study does not examine reso-
lution of abdominal symptoms following surgery, future pro-
spective studies should examine abdominal symptoms before
and after surgery.
Conclusion
In unaware gallstone carriers, clinical events were associated
with pain localized in the epigastrium, of duration more than
hours, of moderate to severe intensity, of higher frequency,
occurring at night, and in need of pain medication.
Functional symptoms were not associated with clinical events.
Gallstone carriers should be referred to surgery in the presence
of the identified symptoms and not when the major complaints
are functional symptoms or other unspecified abdominal
symptoms.
Acknowledgements We would like to thank Anja Lykke Madsen for
data management.
Grant Support This study was financially supported by the Faculty of
Health and Medical Sciences at the University of Copenhagen
Author Contributions Daniel Mnsted Shabanzadeh: design, data
analysis, interpretation of data, drafting of manuscript, and approval of
final manuscript. Lars Tue Srensen: design, interpretation of data, criti-
cal revision of manuscript, and approval of final manuscript. Torben
Jrgensen: design, acquisition of data, interpretation of data, critical revi-
sion of manuscript, and approval of final manuscript.
Compliance with Ethical Standards Informed consent was obtained
from all participants before enrollment into the study.
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