CLINICALBILIARY
A Prediction Rule for Risk Stratication of Incidentally
Discovered Gallstones: Results From a Large Cohort Study
Daniel Mnsted Shabanzadeh,1,2 Lars Tue Srensen,1,3 and Torben Jrgensen2,4,5
1
Digestive Disease Center, Bispebjerg University Hospital, Copenhagen, Denmark; 2Research Centre for Prevention and
Health, Centre for Health, Capital Region of Copenhagen, Copenhagen, Denmark; 3Institute for Clinical Medicine, 4Department
of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Faculty of
Medicine, Aalborg University, Aalborg, Denmark
CLINICAL BILIARY
BACKGROUND & AIMS: No one knows exactly what proportion of gallstones cause clinical events among subjects
unaware of their gallstone status. We investigated the longterm occurrence of clinical events of gallstones and associations between ultrasound observations and clinical events.
METHODS: We analyzed data from 3 randomly selected
groups in the general population of urban Copenhagen (age,
3070 y) participating in an international study of cardiovascular risk factors (the Multinational mONItoring of trends
and determinants in CArdiovascular disease study). In this
study, participants (n 6037) were examined from 1982
through 1994, and underwent abdominal ultrasound examinations to detect gallstones. Our study population comprised
664 subjects with gallstones; subjects were not informed of
their gallstone status. Participants were followed up for clinical events through central registers until December 31, 2011.
Independent variables included ultrasound characteristics,
age, sex, comorbidity, and female-associated factors, which
were analyzed using Cox regression. RESULTS: Study participants were followed up for a median of 17.4 years (range,
0.129.1 y); 99.7% of participants completed the study. A total
of 19.6% participants developed events (8.0% complicated
and 11.6% uncomplicated). Ten percent had awareness of
their gallstones; awareness was associated with uncomplicated and complicated events. Stones larger than 10 mm were
associated with all events (hazard ratio [HR], 2.31; 95%
condence interval [CI], 1.453.69), acute cholecystitis (HR,
9.49; 95% CI, 2.0543.92), and uncomplicated events
(HR, 2.55; 95% CI, 1.384.71), including cholecystectomy
(HR, 2.69; 95% CI, 1.295.60). Multiple stones were associated with all events (HR, 1.68; 95% CI, 1.002.81), complicated events (HR, 2.52; 95% CI, 1.056.04), and common bile
duct stones (HR, 11.83; 95% CI, 1.5491). There was an association between gallstones more than 5 years old and acute
cholecystitis. Female sex was associated with all and uncomplicated events. We found a negative association between
participant age and all events, uncomplicated events, and
acute cholecystitis. Comorbidities and female-associated factors (intake of birth control pills or estrogens and number of
births) were not associated with events. Compared with men
with a single stone of 10 mm or smaller (reference), women
with multiple stones greater than 10 mm had the highest risk
for events (HR, 11.05; 95% CI, 3.7632.44; unadjusted
absolute risk, 0.0235 events/person-years). CONCLUSIONS:
Fewer than 20% of subjects with gallstones develop clinical
events. Larger, multiple, and older gallstones are associated
with events. Further studies are needed to conrm the prediction rules.
Abbreviations used in this paper: CI, condence interval; HR, hazard ratio;
MONICA, Multinational mONItoring of trends and determinants in
CArdiovascular disease.
Most current article
2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2015.09.002
Study
Gracie and
Ransohoff,4 1982,
United States
McSherry et al,5
1985,
United States
Friedman et al,6
1989,
United States
Attili et al,7
1995, Italy
Angelico et al,8
1997, Italy
Male faculty
members,
University
of Michigan
Health Insurance
Plan of
Greater
New York
subscribers
The Keiser
Permanente
Medical Care
Program,
Northern
California
Civil servants
in Rome.
Group for
Epidemiology
and Prevention
of Cholelithiasis
(GREPCO)
Random sample
of females
from electoral
rolls in one town
of rural central
Italy, GREPCO
Random sample
aged 3585
from one
municipality
Subjects with
gallstone
disease
followed
up, N
Gallstone
diagnosis
123
Oral cholecystography
1124
13%
biliary colic
2.4%
691
Oral
cholecystography,
surgery
Median,
5.2
22.3% change
in intensity
of pain
8.7%
467
Oral
cholecystography,
surgery
NA (maximum, 37)
21.2%
nonsevere
events
8.4%
19.7%
symptoms
and
prophylactic
151
Ultrasound
z10
18.5%
biliary colic
3.3%
7.3%
symptoms
9.9%
prophylactic
47
Ultrasound
z10
21.3%
biliary colic
123
Ultrasound
Median,
7.25 (range:
0.2512.2)
10.6%
developed
events
Follow-up
period, y
Symptom
development
Complicated
disease
0%
4.1%
8.9%
symptoms
24.4%
prophylactic
z21%
28%
14.9%
symptoms
NA
Halldestam
et al,9 2004,
Sweden
Population
Cholecystectomy
owing to
symptomatic
uncomplicated
disease or
prophylactic
in asymptomatic
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157
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CLINICAL BILIARY
158
Table 1. Continued
Population
Festi
et al,10 2010, Italy
Systematic
sampling
from
electoral
rolls in 10
Italian
regions,
Multicenter
Italian
Study on
Cholelithiasis
(MICOL)
Random
sample from
National
Peoples
Registry in Bergen
Schmidt,12
2011. Norway
Gallstone
diagnosis
Follow-up
period, y
Symptom
development
793
Ultrasound
Mean,
8.7
18.9%
developed
new
symptoms
of pain
225
Ultrasound
24
44%
interim or
present pain
Complicated
disease
4.5%
NA
Shabanzadeh et al
Study
Subjects with
gallstone
disease
followed
up, N
Cholecystectomy
owing to
symptomatic
uncomplicated
disease or
prophylactic
in asymptomatic
15.3%
symptoms
7.9%
prophylactic
NA
January 2016
Study Population
The 3 cohorts comprised 7847 persons. Of these, 6037
(76.9%) participated in the study and were examined by
ultrasound. Cholecystectomy was performed in 189 persons,
excluding them from the study population. A total of 664
persons had ultrasound-proven gallstones (Figure 1). Of these,
10% reported awareness of having gallstones.
Study Design
Data from the 664 individuals with gallstones were linked
to the Danish National Patient Registry by use of a unique
personal identication number for each participant. The National Patient Registry contains data on dates of contact with
hospitals and codes for diagnosis, treatments, and surgical
procedures, and has been validated several times.20 Entry in
this study was dened as the date gallstones were detected for
the rst time regardless if this was a baseline or follow-up
examination. All gallstone-positive individuals were followed
up until the date of a gallstone event, death, or emigration. The
follow-up evaluation was terminated on December 31, 2011
(Figure 1).
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160
Shabanzadeh et al
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Data Management
The primary author harmonized all variables in the 3 cohorts based on original questionnaires and the ultrasound information sheets. There was a discrepancy in the gallstone size
variable between the cohorts. Cohort 3 included it as a
continuous variable and the other 2 cohorts included it as a
Stone mobility
Gallstone age
(only cohort 1)
Awareness of
gallstone status
Diabetes
Hypertension
Birth control pills
Estrogen
Levels
Median [IQR]
Female
Male
Median [IQR]
2
1
10
>10
5
60.0 [50.065.0]
386 (58.1)a
278 (41.9)a
25.6 [23.129.2]
305 (51.9)a
283 (48.1)a
421 (67.0)a
207 (33.0)a
148 (80.4)a
76
>5
Not measured
Mobile
Nonmobile
>5 years
36 (19.6)a
480
566 (85.6)a
95 (14.4)a
216 (45.2)a
5 years
No re-examination
No
262 (54.8)a
186
595 (90.0)a
Yes
No
Yes
No
Yes
Ever used
Never used
Ever used
Never used
66
635
29
498
166
140
201
73
311
(10.0)a
(95.6)a
(4.4)a
(75.0)a
(25.0)a
(41.1)a
(58.9)a
(19.0)a
(81.0)a
36
45
2
Statistical Analysis
Descriptive analyses were reported as medians with interquartile ranges for continuous data and as counts and percentages for categoric data. Time-to-gallstone-event analyses
were performed as competing-risk analyses with cumulative
incidence proportions and death as competing outcomes for all
outcomes. In these, participants were right-censored when they
had a gallstone event, died, or emigrated, or they completed
follow-up evaluation until December 31, 2011. Separate analyses for prestudy awareness of gallstones were performed and
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161
Table 3.Counts of Gallstones Events During Complete Follow-Up Evaluation and Cumulated Incidence Proportions Over 20
Years
Event type
All
Complicated
Uncomplicated
Total
No awareness
Awareness
Total
Common bile duct stones
Pancreatitis
Endoscopic retrograde
cholangiopancreaticography
Endoscopic stent
Acute cholecystitis
Cholecystostomy
No awareness
Awareness
Total
Cholecystectomy
Clinical diagnosis
No awareness
Awareness
No events
Total
n (% of total)
130
99
30
53
26
3
3
(19.6)
(15.0)
(4.5)
(8.0)
(3.9)
(0.5)
(0.5)
1 (0.2)
19 (2.9)
1 (0.2)
43 (9.0)
9 (1.9)
77 (11.6)
44 (6.6)
33 (5.0)
56 (8.4)
21(3.2)
534 (80.4)
664 (100)
CIP20
a
years
0.18
0.15
0.42
0.08
P valueb
<.0001
0.07
0.16
0.113
.02
0.09c
0.32c
<.000
Results
Among the 664 subjects with gallstones, a total of 130
(19.6%) had gallstone events (Table 3). The median followup period was 17.4 years, with a range of 0.129.1 years,
comprising a total of 10,348 person-years at risk. At followup evaluation, 308 (46.4%) participants were alive, 354
(53.3%) had died, 1 had emigrated, and 1 had changed his
personal identication number (0.3%). Follow-up evaluation thus was 99.7% complete. No participants developed
gallbladder cancer.
All Events
The cumulative incidence proportion at 20 years was
18% (Table 3). The steepest curve with the most gallstone
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Shabanzadeh et al
CLINICAL BILIARY
Complicated Events
During follow-up evaluation, 8% of the participants
developed a complicated gallstone event. Of these, 5% had
common bile duct stones or pancreatitis and 3% had acute
cholecystitis. The cumulative incidence proportion at 20
years for complications was 8% (Table 3). Multiplicity of
stones had a signicant association with complicated events
in both unadjusted and age-adjusted models. Female sex or
participant age had no signicant associations with all
complicated events. Common bile duct stones were associated with multiple stones. Acute cholecystitis was
January 2016
163
All
Complicated
Uncomplicated
Variable
Participant age
Sex, female
Stone number 2
Largest stone size > 10 mm
Smallest stone size 5 mm
Stone mobility, mobile
Gallstone age 5 y
Gallstone awareness
Hypertension
Diabetes
Use of birth control pills
Use of estrogens
Number of births
All complicated events
Participant age
Sex, female
Stone number 2
Largest stone size > 10 mm
Smallest stone size 5 mm
Stone mobility, mobile
Gallstone age, 5 y
Gallstone awareness
Acute cholecystitise
Participant age
Sex, female
Stone number 2
Largest stone size > 10 mm
Stone mobility, mobile
Gallstone age, 5 y
Gallstone awareness
Common bile duct stonese
Participant age
Sex, female
Stone number 2
Largest stone size > 10 mm
Stone mobility, mobile
Gallstone age, 5 y
Gallstone awareness
All uncomplicated events
Participant age
Sex, female
Stone number 2
Largest stone size > 10 mm
Smallest stone size 5 mm
Stone mobility, mobile
Gallstone age, 5 y
Gallstone awareness
Cholecystectomy
Participant age
Sex, female
Stone number 2
Largest stone size > 10 mm
Stone mobility, mobile
Gallstone age, 5 y
Gallstone awareness
(0.960.99)
(1.343.85)
(1.002.81)
(1.453.69)
(0.323.94)
(0.421.40)
(0.401.14)
(2.567.05)
(0.501.52)
(0.152.52)
(0.672.02)
(0.371.66)
(0.871.23)
0.98
1.58
2.52
2.01
(0.951.01)
(0.753.34)
(1.056.04)
(0.974.17)
1.13 (0.403.23)
0.81 (0.351.86)
3.07 (1.327.13)
0.98
2.50
2.08
2.62
0.69
0.78
4.12
0.86
0.68
0.91
0.85
1.05
(0.951.00)a
(1.344.67)a
(1.213.59)a
(1.564.40)a
(0.331.43)a
(0.451.34)b
(2.466.90)b
(0.491.51)b
(0.162.82)b
(0.481.73)c
(0.401.81)c
(0.871.27)c
1.55 (0.733.27)d
2.74 (1.136.62)d
2.00 (0.974.15)d
1.12 (0.393.18)d
0.88 (0.382.06)d
3.22 (1.387.51)d
0.95
1.93
0.96
9.49
0.94
0.20
4.38
(0.900.99)
(0.517.28)
(0.283.32)
(2.0543.92)
(0.273.20)
(0.040.96)
(1.1316.97)
0.99
1.24
11.83
0.98
1.37
2.14
2.82
(0.961.03)
(0.493.14)
(1.5491)
(0.342.83)
(0.325.94)
(0.578.07)
(0.948.51)
0.97
3.12
1.31
2.55
0.91
0.61
0.60
5.25
(0.940.99)
(1.456.73)
(0.682.51)
(1.384.71)
(0.194.36)
(0.291.27)
(0.301.19)
(2.779.94)
0.97
3.00
1.53
2.44
0.95
2.86
0.91
2.69
1.05
0.59
5.37
(0.920.98)
(1.176.99)
(0.422.01)
(1.295.60)
(0.373.00)
(0.271.29)
(2.5111.48)
0.95 (0.930.98)g
0.94 (0.432.06)g
2.66 (1.285.53)g
1.13 (0.393.23)g
0.61 (0.281.32)g
4.82 (2.2510.35)g
Adjusted for age, sex, body mass index, stone number, largest stone size, and stone mobility.
Adjusted for age, sex, and body mass index.
c
Adjusted for age and body mass index.
d
Adjusted for age.
e
No adjustment owing to the low number of events.
f
Adjusted for age and sex.
g
Adjusted for sex.
b
(0.95 to <1.00)f
(1.396.48)f
(0.792.95)f
(1.324.52)f
0.65 (0.311.36)f
0.70 (0.341.41)f
5.28 (2.7510.11)f
CLINICAL BILIARY
Gallstone events
164
Shabanzadeh et al
Uncomplicated Events
Uncomplicated gallstone events occurred in 11.6% of the
participants during follow-up evaluation. Cholecystectomy
for uncomplicated events was performed in 6.6% of the
participants. The cumulative incidence proportion at 20
years was 11% (Table 3). Stone size greater than 10 mm
was associated with all uncomplicated events and with
cholecystectomy in both the unadjusted and adjusted
models. Female sex and younger age were associated with
uncomplicated events and cholecystectomy (Table 4).
CLINICAL BILIARY
Sensitivity Analysis
Five participants were categorized as having complicated events solely based on 1 treatment code for endoscopic retrograde cholangiopancreaticography, endoscopic
stent, or cholecystostomy without any diagnosis code to
conrm the type of clinical event (Table 3). For validation
purposes, a sensitivity analysis thus was performed after
these 5 cases were recategorized as uncomplicated events.
However, none of the HRs and 95% CIs were altered
signicantly in this analysis.
Discussion
This was a cohort study of the natural history of gallstones with a long-term follow-up evaluation of a population that was unaware of having gallstones. More than 4 of 5
participants with gallstones remained uneventful during the
20-year follow-up period. Determinants of clinical events
over a 10-year period were female sex, young age, awareness of gallstones, and large, multiple, and older stones. A
score for estimation of individual clinical prediction of
gallstone events has been suggested based on patient sex,
age, and gallstone size and number obtained through ultrasound. In this prediction score, the person who had the
highest risk for an event was the female with multiple and
large stones and she had an 11 times greater relative risk of
cholecystectomy or complications over 10 years when
compared with a male with a single gallstone of no more
than 10 mm in size.
This study had some methodologic advantages when
compared with other population-based cohort studies of
gallstone disease411 (Table 1). Many of the previous studies
selected populations with no random sampling.47 In addition, the reported follow-up data were not sufcient in some
studies to calculate the annual symptom or complication
rate and, therefore, only the total rates are reported in
Table 1. Contrary to all previous studies, the participants of
this study were not informed about gallstone status.
Consequently, comparisons between this study and others
should be made with caution. In previous studies, the
ndings of higher cholecystectomy rates for uncomplicated
disease suggested a more aggressive attitude toward cholecystectomy in uncomplicated symptomatic disease and
even in prophylactic surgery in asymptomatic patients when
the gallstone status is known. The most obvious explanation
is a pathologization of the gallstone condition and introduction of a protopathic bias, as Attili et al7 suggested.
Accordingly, 2 studies even referred participants to their
family doctor after gallstones were detected using ultrasound.7,8 In the present study, only 10% were aware of
having gallstones before entry into the study. This fraction
of the population had signicantly higher rates of all outcomes, especially uncomplicated events (Table 3). This
nding may reect a protopathic bias. It also may reect the
hypothesis that the participants who were aware of their
gallstones had suffered biliary colic attacks before entry into
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165
Table 5.Clinical Prediction Score of Gallstone Events (Cholecystectomy or Complicated Events) During 10 Years of Follow-Up
Evaluation
Male (1[1;1])
Female
(2.16 [1.10;4.25])
Largest stone
> 10 mm
(2.79 [1.57;4.96])
Multiple stones
(1.83 [1.02;3.30])
Rate of events, N
events/N persons in
prole categorya
Absolute risk, N
events/person years
in prole category
Prediction
HR (95% CI)
2/67
4/97
2/47
3/29
4/102
11/120
12/67
10/53
0,0032
0,0046
0,0048
0,0126
0,0041
0,0105
0,0211
0,0235
Reference
1.83 (1.023.30)
2.79 (1.574.96)
5.12 (2.1512.19)
2.16 (1.104.25)
3.96 (1.639.64)
6.02 (2.5314.33)
11.05 (3.7632.44)
NOTE. A multiple model was built including the 4 identied clinical relevant determinants of clinical events and each person
prole category prediction HR was calculated through the 3 dichotomous variables estimates from this model. The lowest-risk
person was chosen based on the estimate size and was identied as the male, with a single stone, and of a size no more than
10 mm. He served as the reference for the remaining person prole categories. The total rate of events, unadjusted absolute
risks, and prediction estimates are reported for each person prole category. The Largest stone size greater than 10 mm,
multiple stones, and sex were included as dichotomous variables and age was included as a continuous variable with a
linearity assumption. The age estimate (HR, 0.97 [0.95;0.99]) indicates that for each year older the risk is reduced by a factor of
0.97. An example of a prediction score HR calculation for a 60-year-old woman with the largest stone greater than 10 mm and
multiple stones was as follows: prediction score HR 11.05 * (0.97 60) 1.78. The values in parenthesis are hazard ratios
from the multiple model. The values in brackets are 95% condence intervals.
a
The total number of events was 48, the total sample size was 582.
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Shabanzadeh et al
CLINICAL BILIARY
Conclusions
In a random sample of the population that is unaware of
gallstone disease, less than 1 of 5 with gallstones will
develop clinical events, and less than half of the clinical
events will be complicated. Predictors of all gallstone events
were found to be female sex, younger age, and having
multiple older and larger stones. This knowledge has clinical
implications when it comes to advising patients with gallstones. Patients with no symptoms require no further
treatment. A clinical prediction score, such as suggested
here, shows that some gallstone carriers have higher risks of
clinical events compared with others based on the identied
risk factors. This score can be used to make assessments of
relative risks for future clinical events in patients with
gallstones. However, such a score requires validation in a
similar large population of subjects with gallstones. Future
research should focus on long-term modiable risk factors
for clinical events, how to predict complications, and the
long-term consequences of surgery for gallstone disease.
Supplementary Material
Note: To access the supplementary material accompanying
this article, visit the online version of Gastroenterology at
www.gastrojournal.org, and at http://dx.doi.org/10.1053/
j.gastro.2015.09.002.
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Shabanzadeh et al
Supplementary Table 1.Clustering of Diagnosis and Surgical Treatment Codes for the Denition of Complicated and Uncomplicated Gallstone Disease
Priority
1
Study outcome
Complicated gallstone disease
Included codes
Surgerya
Diagnosisb
Papillotomy
Stone extraction
Cholecystostomy
Endoscopic stent in bile duct
Endoscopic retrograde
cholangiopancreaticography
Acute cholecystitis
JKA10
JKE18
91050, UJK02
Combination surgery
and diagnosis
Pancreatitis
Cholecystectomy
Laparoscopic cholecystectomy
Chronic cholecystitis
cholecystectomy
Diagnosisb
Cholecystolithiasis, cholelithiasis
Uncomplicated gallstone
disease, cholecystectomy
Uncomplicated gallstone
disease, clinical diagnosis
Surgerya
Exclusion criteria