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MOG 340204

REVIEW

CURRENT
OPINION Incidence of gallstone disease and complications
Daniel Mønsted Shabanzadeh

Purpose of review
The purpose of this review was to describe the epidemiology of gallstone disease in the era of ultrasound
screening and laparoscopic cholecystectomy.
Recent findings
Recent general population cohorts, including ultrasound screenings, have contributed to our understanding
of formation and clinical course of gallstone disease. Cohorts of symptomatic gallstone disease have been
informative about symptom recurrence and need of treatment. Preventive targets for gallstone formation
may include obesity and the associated metabolic changes. The presence of gallstone disease is best
described as a continuum from asymptomatic to symptomatic disease, with the latter including both pain
attacks and complicated disease. Symptomatic disease causes a persistent high risk of symptom recurrence
and need of cholecystectomy. The majority of gallstone carriers will remain asymptomatic and about one in
five will develop symptoms. Determinants of disease progression from asymptomatic to symptomatic disease
include sex, age, body mass index, and gallstone ultrasound characteristics.
Summary
Because of the absence of effective gallstone formation prevention, targets against the metabolic changes
in obesity should be further explored in randomized controlled trials. To optimize patient selection for
cholecystectomy, treatment algorithms including identified determinants of symptomatic disease in gallstone
carriers should be explored in prospective clinical trials.
Keywords
cholecystolithiasis, cholelithiasis, gallbladder diseases, gallstones, ultrasonography

INTRODUCTION loss of hepatic bile acids or the uptake of secondary

Gallstone disease is highly prevalent in general pop-
ulations and is a frequent cause of hospital admis-
sions, associated with high costs because of treatment
and morbidity [1]. Gallstone formation is multifac-
torial, including a complex interplay of sex-specific,
genetic, lifestyle, and comorbidity-associated factors.
The clinical course of gallstone disease ranges from
the asymptomatic carrier status, to uncomplicated
symptomatic disease with pain attacks, and to com-
plicated symptomatic disease including acute chole-
cystitis, common bile duct stones, pancreatitis,
cholangitis, and, rarely, bowel obstruction.
Based on their main constituents, gallstones can
be divided into cholesterol and pigment (bilirubin)
stones. The vast majority of symptomatic gallstone
disease in Western countries is caused by cholesterol
gallstones [2]. Cholesterol gallstone formation is
facilitated through mechanisms of increased bile
cholesterol saturation, either through endogenous
synthesis by the HMG Co-A reductase or bile cho-
lesterol excretion by the ABCG5/8 cholesterol trans-
porter; impaired gallbladder motor function; or
changes in the enterohepatic circulation, including
bile acids produced by colonic microbiota. Pigment
gallstone formation is caused by mechanisms of
hemolysis with elevated bile unconjugated bilirubin
excretion as a consequence [3]. The pathogenesis of
gallstones will be further discussed in another
review included in this issue. Mechanisms involved
in symptomatic gallstone disease are believed to
include gallstone migration through bile ducts,
causing obstruction and distention [4]. Whether
gallbladder motor function has an impact on symp-
tom development continues to be debated [5,6].
The study of gallstone disease epidemiology
and its clinical course have relied upon gallstone
identification directly through surgery, autopsy, or
Digestive Disease Center, Bispebjerg University Hospital, Copenhagen,
Denmark and Research Centre for Prevention and Health, Capital
Region of Denmark
Correspondence to Daniel Mønsted Shabanzadeh, Digestive Disease
Center, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400,
Copenhagen, Denmark. Tel: +45 3863 5062; fax +45 3863 9816;
e-mail: daniel.moensted.shabanzadeh.01@regionh.dk
Curr Opin Gastroenterol 2017, 33:000–000
DOI:10.1097/MOG.0000000000000418

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MOG 340204
Biliary Tract
KEY POINTS
 Cohort studies including gallstone ultrasound screening
and clinical studies performed during the laparoscopic
cholecystectomy era have contributed to the available
evidence on formation and the clinical course of
gallstone disease.
 Preventive determinants for gallstone formation may
include the metabolic changes in obesity, which should
be further explored in randomized controlled trials.
 The clinical course of gallstone disease is a continuum
ranging from asymptomatic to symptomatic disease
with the latter causing a persistent high risk for
symptom recurrence and need of cholecystectomy.
 The majority of gallstone disease carriers will remain
asymptomatic and about one out of five will develop
symptoms during long-term follow-up.
 Symptomatic disease development in gallstone carriers
is determined by sex, age, body mass index, and
ultrasound gallstone characteristics, which should be
further explored in treatment algorithms in prospective
clinical trials.
indirectly through x-ray. Variations in gallstone
disease detection modalities, populations studied,
and study designs have contributed to conflicting
views on the severity of gallstone disease through-
out the centuries. The idea of the innocent gallstone
has ranged from acceptance to myth. Real-time
ultrasound examination introduced a highly sensi-
tive, highly specific, noninvasive detection method
for gallstones without radiation exposure. Real-time
ultrasound examination has enabled gallstone dis-
ease screening in large unselected general popula-
tions. Decades have now passed since the first
screening studies were performed, enabling a longi-
tudinal exploration of determinants of gallstone
disease formation and clinical course. Furthermore,
the introduction of minimal-invasive laparoscopic
cholecystectomy in the 1990s has made the treat-
ment of gallstone disease more accessible and possi-
bly lowered the threshold for symptomatic gallstone
disease treatment.
The present review aimed to describe the epide-
miology of gallstone disease formation and its clini-
cal course in the era of ultrasound and laparoscopic
cholecystectomy.
INCIDENCE OF SCREEN-DETECTED
GALLSTONE DISEASE IN GENERAL
POPULATIONS
Cohort studies exploring the incidence of screen-
detected gallstone disease in unselected general
2 www.co-gastroenterology.com
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populations and, where baseline and follow-up
ultrasound examinations are performed, are supe-
rior for identifying the determinants of gallstone
formation. Most such studies are reported from
European populations and have identified screen-
detected gallstone disease incidence rates of 0.60–
1.39% per year (Table 1).
Gallstone formation is more likely at a higher
age [7–10] and for females [10]. Gallstone formation
is associated with number of childbirths [7,11] and a
consistent use of hormone replacement therapy has
also been identified as a risk factor [12]. Female
reproductive hormones stimulate gallstone forma-
tion through a stimulation of bile cholesterol excre-
tion and endogenous synthesis, which has been
identified through experimental animal studies
[13]. Recently, testosterone was also associated with
gallstone formation in males [12]. This possibly
suggests analogue effects of female and male repro-
ductive hormones on hepatic cholesterol metabo-
lism. With this knowledge, the higher incidence in
females then raises the hypothesis that, compared to
males, females have a higher cumulative exposure to
reproductive hormones throughout their lifetime,
possibly because of childbirths or hormone cycles,
as previously suggested [12]. Diabetes [7,8], nonal-
coholic fatty liver disease [9], and cirrhosis [8] have
also been associated with gallstone formation in
general populations.
The identification of specific symptoms asso-
ciated with gallstone disease has been challenging.
However, changes in symptoms associated with
newly formed gallstones have recently been
explored in a cohort unaware of gallstone status
[14]. An onset of abdominal pain with projection,
localized in the upper abdomen and of hours dura-
tion were associated with newly formed gallstones,
but the onset of unspecific abdominal pain or func-
tional symptoms, such as nausea, acid regurgitation,
or irritable bowel syndrome, were not found to be
associated with gallstone disease formation [14].
Pain in the epigastrium and right hypochondrium
at baseline have also been associated with incident
screen-detected gallstones disease in another cohort
study [8]. This identified pain complex shares simi-
larities with biliary colic, as previously described in
the historical literature [15].
Some potentially modifiable determinants of
gallstone formation have been identified, and sev-
eral studies have identified body mass index [7–11].
Alternative body fat tissue measures, such as waist-
to-hip circumference ratio or computed tomogra-
phy measured subcutaneous or visceral fat, have
recently also been independently associated with
&
gallstone disease prevalence [16,17 ]. Biomarkers of
the metabolic changes in obesity, such as fasting
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MOG 340204

Incidence of gallstone disease and complications Shabanzadeh

Table 1. Ultrasound screen-detected gallstone disease incidence rates in cohort studies

Participant baseline Participants (n), Follow-up Gallstone disease

Author and year Country characteristics participation (%) length incidence rate

General populations
Misciagna 1996[7] Italy MþF, 30–69 y 1962, 70.6% 7y 0.97% per year
Angelico 1997[11] Italy F, 20–69 y 253, 84.9% 10 y 0.63% per year
Festi 2008[8] Italy MþF, 30–79 y 9611, 86.5% 8y 0.67% per year
Halldestam 2009[20] Sweden MþF, 35–85 y 583, 81.0% 5y 1.39% per year
Chen 2014[9] Taiwan MþF, <40 to >60 y 1296, 57.3% 5y 0.63% per year
Shabanzadeh 2016[10] Denmark MþF, 30–60 y 2848, 83.8% 12 y 0.60% per year
Selected clinical morbid populations
Fornari 1994[23] Italy Alcoholic and nonalcoholic 165, NR 33 mo 4.7% per year
cirrhosis, MþF, 14–82 y
Benvegnú 1997[25] Italy Alcoholic and nonalcoholic 182, NR 40 mo 2% per year
cirrhosis, MþF, median 60
y
Del Olmo 1997[59] Spain Alcoholic and nonalcoholic 180, NR 56 mo 3.4% per year
cirrhosis, MþF, mean 53 y
Conte 1999[24] Italy Alcoholic and nonalcoholic 618, 62% 50 mo 5% per year
cirrhosis, MþF, mean 60 y
Tung 2006[26] Taiwan Type 2 diabetes, MþF, 40 y 281, 74.5% 1y 3.6% per year
and more
Parente 2007[27] Italy Inflammatory bowel disease, 600, 94.6% 5y Crohn’s disease
MþF, mean 35–39 y 1.44% per year
Ulcerative colitis
0.75% per year
Melmed 2010[29] Europe, USA, Acromegalic patients on 111, 89% 1y 26% per year
and China octreotide treatment, MþF,
mean 53.5 y (SD 13.9)

F, females; M, males; mo, months; NR, not reported; y, years.

&
insulin [18,19 ], fasting glucose, homeostasis model
assessment, the metabolic syndrome, systemic
inflammation, and genetic susceptibility for diabe-
&
tes and obesity [19 ], have been associated with
gallstone disease prevalence. A causal association
for obesity and gallstone formation is thereby sup-
ported through insulin resistance, which has been
shown to impair gallbladder motor function and
increase both cholesterol synthesis and bile choles-
terol excretion (mechanisms reviewed in [10]).
Blood cholesterol, especially non-high-density
lipoprotein cholesterol [10] and low-density lipo-
protein cholesterol [20], have been identified as
determinants of gallstone formation and this might
be explained through the mechanisms of choles-
terol transport. Blood cholesterol-lowering statins
have been inversely associated with cholecystec-
tomy, but their impact on gallstone formation
has not been explored in randomized controlled
trials [21,22].
Lifestyle variables have also been associated with
gallstone formation. Alcohol drinking, defined as the
amount of wine consumption per day [7], weekly
consumption [20], and increasing consumption
through long-term follow-up [12], are inverse deter-
minants of gallstone formation. The mechanisms of
alcohol drinking on cholesterol metabolism and
bowel transit support a causal inverse association
[3]. Although smoking has also been associated with
gallstone formation [7], the lack of knowledge about
the underlying biological mechanisms does currently
not support a strong causal association [3]. Coffee
consumption has been inversely associated with gall-
stone formation [7], but no association was identified
across studies in a meta-analysis [10]. A number of
dietary factors have also been associated with gall-
stone disease, but they have not been sufficiently
explored for incident screen-detected gallstones
disease.
INCIDENCE OF SCREEN-DETECTED
GALLSTONE DISEASE IN MORBID
POPULATIONS
Some studies have explored screen-detected gall-
stone disease incidence in clinical populations
with specific morbidities by performing ultrasound
screenings at regular clinical follow-up visits.

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MOG 340204

Biliary Tract

Cirrhosis of the liver is currently the most stud-
ied morbidity associated with gallstone formation,
with incidence rates of 2–5% per year, which is a
four-fold increase when compared to the general
populations (Table 1). Contrary to the cholesterol
gallstones frequently found in Western general pop-
ulations, cirrhosis causes pigment gallstone forma-
tion. Determinants of screen-detected gallstone
disease incidence in cirrhosis include alcoholic eti-
ology [23], a more severe cirrhosis (child stage)
[23,24], and longer cirrhosis duration [25]. Nonal-
coholic liver disease will be discussed in detail in
another review included in this issue.
Type 2 diabetes has also been associated with
gallstones, with high incidence rates of 3.6% per
year (Table 1), which is believed to be caused by
mechanisms of insulin resistance, as described
above. Identified determinants of gallstone forma-
tion in patients with diabetes include higher age,
higher waist circumference, and a higher level of
alanine aminotransferase [26].
Crohn’s disease has a gallstone incidence rate of
1.44% per year which is higher than in disease-free
controls [27] and general populations (see above).
Ulcerative colitis was not associated with a higher
incidence [27] (Table 1). Determinants of gallstone
formation in Crohn’s disease include age, disease
duration, number of total parenteral treatments,
high-dose steroid treatments, bowel resection
length, and other indicators of severe Crohn’s
disease. Suggested mechanisms include impaired
reabsorption of bile acids in the bowel because of
local inflammation or surgery which then causes
increased bile cholesterol saturation. Colectomy
was recently found to be associated with gallstone
disease admissions in patients with ulcerative colitis
[28], which supports this hypothesis. Alternatively,
an impaired gallbladder motor function has also
been identified in Crohn’s disease, which may con-
tribute to gallstone formation [27].
Gallstone formation is also high in acromegalic
patients undergoing treatment with somatostatin
analogues, as reported in the largest yet performed
randomized controlled trial [29] (Table 1). Suggested
mechanisms include prolonged bowel transit caus-
ing an altered enterohepatic circulation of bile acids
and an impaired gallbladder motor function because
of the somatostatin-induced inhibition of cholecys-
tokinin release, the hormone responsible for post-
prandial stimulation of gallbladder contractions
[30].
THE CLINICAL COURSE OF SCREEN-
DETECTED GALLSTONE DISEASE IN
GENERAL POPULATIONS
To identify determinants for incident symptomatic
gallstone disease, some general population ultra-
sound screening studies have performed long-term
follow-up of the subgroup with screen-detected gall-
stone disease. The majority of the gallstone disease
carriers from these studies are asymptomatic
at baseline (Table 2). The symptomatic disease
incidence is reported as higher (15.4–32.8% over
9–24 years) in studies using symptom question-
naires [11,31–33] than in studies using hospital
admission as symptomatic disease outcome (11.7–
&&
18.0% over 7–22 years) [34,35 ].
One study did not inform participants about the
presence of gallstone disease, and 90% of gallstone

Table 2. The clinical course of screen-detected gallstone disease carriers from general populations

Cumulative incidence of symptomatic disease

Study Baseline Participants (n), Total
Author and population symptom participation Follow-up symptomatic
year Country and design characteristics (%) length disease Complications Cholecystectomy

Attili 1995[31] Italy Cohort Asymptomatic 151, 93.8% 10 y 23.7% 3.0  1.8% 25.8  4.4%
Angelico 1997[11] Italy Cohort Asymptomatic 31, 88.5% 10 y 15.4% 0% 23.1%
Halldestam Sweden Cohort Symptomatic and 120, 97.6% 7y 11.7% 5.0% 8.3%
2004[34] asymptomatic
Festi 2010[32] Italy Cohort Asymptomatic 793, 92.6% 9y 21.9% 2.9% 13.7%
Schmidt 2011[33] Norway Cohort Asymptomatic 134, 87.0% 24 y 32.8% NR 6.2%
Inui 2016[38] Japan Cohort Symptomatic and 837, 86.0% 5y NR NR 7.6%
asymptomatic
Shabanzadeh Denmark Cohort 90% unaware of 664, 99.7% 20 y 18% 8% 7% (due to
&&
2016[35 ] gallstone disease uncomplicated
disease only)

F, females; M, males; NR, not reported; y, years.

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MOG 340204
Incidence of gallstone disease and complications Shabanzadeh
disease carriers were unaware of their gallstones at
baseline. The cumulative incidence proportion of
symptomatic disease was 18% over 20 years follow-
&&
up [35 ], which is the lowest reported across studies
(Table 2). Determinants of symptomatic disease
&&
included younger age [34,35 ], body mass index
[36], female sex, and awareness of gallstone disease
&&
[35 ]. Gallstone ultrasound characteristics also
determined symptomatic disease, including gall-
&&
stone multiplicity [35 ] and a gallstone size above
&&
10 or 15 mm [32,35 ]. A baseline presence of pain in
the epigastrium, of hours duration, of moderate to
extreme intensity and with the need of analgesics
have also been associated with incident symptom-
atic disease in unaware gallstone disease carriers
&
[37 ]. Functional symptoms, such as acid regurgita-
tion, nausea, or irritable bowel syndrome, were not
associated with symptomatic disease incidence in
&
gallstone carriers [37 ].
Complicated gallstone disease is reported with
low incidences of 8% or less depending on the
length of follow-up (Table 2). Complicated gallstone
disease is determined by diabetes [32], awareness of
&&
gallstone disease [35 ], a sedentary activity level
when compared to light or vigorous activity levels
& &
[36], pain at night, and need of analgesics [37 ].
Acute cholecystitis is associated with a gallstone size
greater than 10 mm and a gallstone age above 5
years. Common bile duct stones is associated with
&&
gallstone multiplicity [35 ].
Cholecystectomy rates among gallstone disease
patients vary across studies (Table 2). The highest
cholecystectomy incidence (25.8% over 10 years)
was reported in a study where participants were
referred to their family doctor after gallstone disease
was detected at ultrasound screening and prophy-
lactic cholecystectomies were also performed in
asymptomatic carriers [31]. Lower and comparable
cholecystectomy incidence rates of 8% or less are
&&
reported in studies from Scandinavia [33,34,35 ]
and Japan [38] (Table 2). The cholecystectomy inci-
dence for uncomplicated gallstone disease is associ-
ated with younger age, female sex, gallstone size
&&
greater than 10 mm, and gallstone awareness [35 ].
THE CLINICAL COURSE OF
SYMPTOMATIC GALLSTONE DISEASE IN
CLINICAL POPULATIONS
Symptomatic gallstone disease studies in clinical
populations where cholecystectomy is not per-
formed at initial presentation enable the explora-
tion of clinical recurrence. This selected group of
symptomatic gallstone disease patients is compara-
ble to the patients meet by clinicians. Recurrence of
symptomatic gallstone disease, complications, and
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cholecystectomy are assessed through hospital re-
admissions, which are explored in hospital records,
registers, and insurance claims databases.
Disease recurrence rates are reported to be
between nine to above 30% per year (Table 3).
Recurrence rates vary greatly between studies
because of differences in symptomatic gallstone
disease at presentation and lengths of follow-up.
However, disease recurrence in symptomatic gall-
stone disease is reported with much higher inci-
dence rates (Table 3) when compared to the
mostly asymptomatic course of gallstone disease
carriers in general populations (Table 2). If the
clinical course of gallstone disease is considered
a continuum ranging from asymptomatic to
symptomatic disease, this discrepancy might be
explained by selection of patients in the symptom-
atic part of the continuum, which then have a
persisting higher risk of symptom recurrence.
Determinants for re-admissions because of
symptomatic disease in general or for complicated
&
disease include older age, fewer comorbidities [39 ],
&
male sex [39 ,40] and longer waiting time to surgery
[41]. A symptomatic disease presentation including
&
complicated disease [39 ,42], emergency room visit
[39 ], or having no interventions performed [40] have
also been identified to determine re-admissions.
In patients presenting with acute cholecystitis, re-
admissions were determined by younger age, male
sex and were prevented by comorbidities including
valvular and neurological diseases [43]. In patients
presenting with acute pancreatitis, gallbladder stone
size of 5 mm or less and cholecystectomy performed
more than 14 days after the presentation were asso-
ciated with complicated recurrent disease in one
retrospective study [44].
Determinants for cholecystectomy have been
identified as younger age [42,45], female sex, fewer
comorbidities, and acute cholecystitis at presenta-
tion [45].
Only a few randomized controlled trials
have compared cholecystectomy to a conservative
approach in symptomatic gallstone disease (Table 3).
In patients with biliary colic randomized to urgent or
elective laparoscopic cholecystectomy, the elective
arm had a complicated gallstone disease recurrence
rate of 25.7% during the waiting time, a higher con-
version rate to open surgery, and a longer hospital stay
[46]. A high percentage of patients were excluded after
randomization, and that study, therefore, has a risk of
selection bias. The largest available randomized trial
performed in uncomplicated symptomatic gallstone
disease allocated patients to observation or cholecys-
tectomy. In the observation arm, 50.7% ultimately had
cholecystectomy performed, either because of persist-
ing pain or complicated disease during long-term
www.co-gastroenterology.com 5
 6
Table 3. The clinical course of symptomatic gallstone disease recurrence in symptomatic clinical populations

Cumulative incidence of symptomatic

disease recurrence
Biliary Tract

Baseline symptomatic Participants (n), Total

Study population gallstone disease participation Follow-up symptomatic
Author and year Country and design characteristics (%) length disease Complications Cholecystectomy

Clinical cohorts
Persson 1996[42] Sweden Hospital cohort Symptomatic disease 153, 100% 6y NR 15% (3.1% per 41%
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presented electively and year)

managed expectantly
Epari 2010[41] Australia Health-care register Symptomatic disease awaiting 4926, 93% 40 d 5% NR –
cohort cholecystectomy

www.co-gastroenterology.com
Riall 2010[43] USA Insurance claims Acute cholecystitis without 7451, 100% 2y NR 38% 28.5%
cohort, age cholecystectomy at
> 65 y presentation
Bergman 2015[40] Canada Retrospective Symptomatic disease 195, NR 1y 31.3% 10.3% emergency 29.7%
hospital cohort, managed expectantly surgery
age > 65 y
&
Parmar 2015[39 ] USA Insurance claims Symptomatic disease without 92436, 100% 2y NR 11.2% emergency 4% elective
cohort, age admission at presentation admission and/or cholecystectomy
MOG 340204

> 65 y surgery beyond 2.5 mo

Riall 2015[45] USA Insurance claims Symptomatic disease without 161568/ 2.5 mo / 2 y 18.6% within NR 22.3% within 2.5
cohort, age admission at presentation 125601, NR 2y mo
> 65 y
Williams 2015[60] USA Retrospective Symptomatic disease without 71, NR 2y 37.1% 12.9% (emergency 23.9%
hospital cohort surgery at presentation cholecystectomy)
Kim 2017[44] The Republic Retrospective Acute gallstone pancreatitis 290, NR 22 mo NR 19.3% –
of Korea hospital cohort awaiting cholecystectomy
Randomized controlled trials of cholecystectomy versus conservative treatment for symptomatic gallstone disease

Salman 2005[46] Turkey Randomized Biliary colic randomized to 75 (35 in 4 mo NR 25.7% –

controlled trial urgent and elective elective arm),
cholecystectomy 84.0%
Schmidt 2011[47] Norway Randomized Uncomplicated symptomatic 137 (69 in 14 y 30.4% 4% 50.7%
controlled trial disease randomized to observation
cholecystectomy and arm), 100%
observation
Schmidt 2011[48] Norway Randomized Acute cholecystitis randomized 64 (33 in 14 y 33.3% 30.3% 33.3%
controlled trial to cholecystectomy and observation
observation arm), 100%

d, days; F, females; M, males; mo, months; NR, not reported; we, weeks; y, years.

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Incidence of gallstone disease and complications Shabanzadeh

follow-up. Proportions of postcholecystectomy com-
plications or complicated disease during observation
did not differ in the two approaches. Although obser-
vation is a possible approach in uncomplicated symp-
tomatic gallstone disease, the study concluded that
cholecystectomy was the preferred treatment [47]. A
similar allocation was performed in patients with acute
cholecystitis with 33% of observed patients having
complicated recurrent disease during long-term fol-
low-up. Also in this trial, no difference in gallstone
disease or postcholecystectomy complications was
found between the two approaches, and no differences
in mortality [48].
THE CLINICAL COURSE OF GALLSTONE
DISEASE FROM CLINICAL POPULATIONS
Few studies have explored the clinical course of
gallstone disease discovered incidentally [49,50] or
believed to be asymptomatic at presentation [51] in
clinical cohorts and have found incident symptom-
atic disease in 10.8–31.5% during a maximum of
5 years follow-up [49–51]. The clinical course of
gallstone disease carriers in clinical cohorts with
comorbidities has also been explored [52,53]. Of
patients with diabetes, 25.7% were identified with
incident symptomatic disease during 5 years [52]
and of patients with spinal cord injury 6.3% were
identified to have incident cholecystectomy per
year follow-up [53]. The clinical course in these
clinical populations with apparently asymptomatic
gallstone disease or with comorbidities is with com-
parably high incidence rates for symptomatic dis-
ease as for symptomatic gallstone disease recurrence
as described above (Table 3). These high rates may be
explained by an increased health-care utilization in
these clinical and comorbid populations, which
most likely causes an increased symptomatic disease
detection and an increased risk of cholecystectomy
compared to the course in gallstone carriers from
general populations. Furthermore, the selection in
clinical cohorts (as described above) might also
contribute to the high risk reported in these studies.
EXTRA-BILIARY MORBIDITY OF
GALLSTONE DISEASE
Associations between gallstone disease and extra-
biliary manifestations have long been suspected and
observed in historical cohorts. Screen-detected gall-
stone diseases are associated with overall mortality
and especially mortality caused by cardiovascular
disease [54,55]. The association between gallstone
disease and cardiovascular disease might be because
of common risk factors, such as age, body mass
index, insulin resistance and mechanisms of
atherosclerosis. Recently, the association was also
identified in a cohort study with multivariable
adjustment for confounders in analyses [56] and
may, therefore, be caused by unidentified common
disease mechanisms. Some cancers have also been
associated with screen-detected gallstone disease
[54,57,58] and an association with incident right-
side colon cancer was recently confirmed. Suggested
mechanisms may involve the colonic microbiota,
which have been shown to produce secondary bile
acids. These are believed to be both carcinogenic
and to promote gallstone formation [58]. Possible
common disease mechanisms for gallstone disease,
cardiovascular disease, and cancer must be further
clarified with future research.
CONCLUSION
Cohort studies including ultrasound screening have
contributed to the available evidence on gallstone
disease formation and its clinical course. Preventive
and interventional targets for gallstone disease for-
mation have been suggested, such as the metabolic
changes associated with obesity. Because of the
current lack of effective preventive strategies for
gallstone formation, such targets should be further
explored in future randomized controlled trials.
When gallstone disease is present, its clinical course
is best described as a disease continuum from
asymptomatic to symptomatic disease. As soon as
symptoms such as a specific pain complex or com-
plicated disease has developed, a persistently high
risk of symptom recurrence and need of cholecys-
tectomy is present. The majority of gallstone disease
carriers will remain asymptomatic and about one in
five carriers will develop symptoms. Few objective
determinants of disease progression from asymp-
tomatic to symptomatic disease have been identi-
fied; those that have include sex, age, body mass
index, and gallstone ultrasound characteristics. To
optimize patient selection for cholecystectomy,
these objective determinants should be included
in treatment algorithms and explored in future
prospective clinical trials.
Acknowledgements
Thanks to professor Torben Jørgensen for his assistance
with the review.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.

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Biliary Tract
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