650998

research-article2016
SJS0010.1177/1457496916650998Gallstones and the risk of cardiovascular diseaseS. Upala, et al.

Meta-Analysis

Gallstone Disease and The Risk of Cardiovascular

Disease: A Systematic Review and Meta-Analysis of
Observational Studies

S. Upala1,2, A. Sanguankeo1,2, V. Jaruvongvanich3,4

1 Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians
and Surgeons, Cooperstown, NY, USA
2 Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University,

Bangkok, Thailand
3  Department of Internal Medicine, University of Hawaii, Honolulu, HI, USA
4  Department of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand

Abstract

Objectives: Gallstone disease shares certain risk factors with cardiovascular disease,
particularly metabolic risk factors. Patients with gallstone disease may be at increased risk
of cardiovascular disease. Several recent studies exploring the effect of gallstone disease
on cardiovascular disease outcomes demonstrated inconsistent results.
Design: We conducted a systematic review and meta-analysis of cohort, case–control,
and cross-sectional studies that compared the risk of developing cardiovascular disease
events in patients with gallstone disease versus non-gallstone disease controls. Data from
each study were combined using the random-effects, generic inverse variance method of
DerSimonian and Laird to calculate the pooled hazard ratio, odd ratio, and 95% confidence
interval.
Results: Data were extracted from six studies involving 176,734 cases and 803,714
controls. The pooled hazard ratio of cardiovascular events in patients with gallstone
disease was 1.28 (95% confidence interval: 1.23–1.33, I2 = 42%). The pooled odd ratio
of cardiovascular events in patients with gallstone disease was 1.82 (95% confidence
interval: 1.47–2.24, I2 = 68%).
Conclusions: Our study demonstrated a statistically significant increase in the risk of
cardiovascular disease among patients with gallstone disease.
Key words: Cardiovascular disease; gallstone disease; meta-analysis; myocardial infarction; stroke

Correspondence:
Veeravich Jaruvongvanich, M.D. Scandinavian Journal of Surgery
Department of Internal Medicine 1­–7
© The Finnish Surgical Society 2016
University of Hawaii Reprints and permissions:
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Email: veeravich_j@hotmail.com
2 S. Upala, et al.

Introduction http://sjs.sagepub.com. A manual search of refer-

ences of selected retrieved articles was also performed.
Gallstone disease (GD) is a common condition world-
wide. The prevalence of GD varies greatly by the eth-
nicity and geographic location ranging from 4%–73%, Study Selection
especially in the Western countries (1). A majority of Our inclusion criteria were (1) published observational
patients (up to 80%) will remain asymptomatic studies including cross-sectional, cohort, and case–
throughout their lifetimes (2). Although the mortality control studies assessing the risk of GD on CVD inci-
rate of GD is relatively low, this disease is one of the dence, prevalence and/or mortality, (2) participants
highest health care cost burdens of digestive diseases aged 18 years or older, (3) relative risks (RRs), odds
(3) and also the leading cause of hospitalization in the ratios (ORs), hazard ratios (HRs) or standardized inci-
United States (4). dence ratios with 95% confidence intervals (CIs) were
Cholesterol gallstone formation is the multifactorial provided, (4) participants without GD or participants
process involving a multitude of metabolic pathways. without CVD were used as a reference group. GD is
The hypersecretion of free cholesterol into bile is the defined as the presence of gallstones or history of chol-
primary pathogenic factor. Accelerated cholesterol ecystectomy. We excluded review articles, case reports,
crystallization, hypersecretion and accumulation of abstracts, and unpublished studies. CVD is defined as
mucin, high efficiency of intestinal cholesterol absorp- coronary heart disease, heart failure, and stroke.
tion, and impaired gallbladder and intestinal motility Two authors (SU and VJ) independently reviewed
are the secondary events involving in the pathogene- titles and abstracts of all citations that were identified.
sis of cholelithiasis (5, 6). The etiology is multifactorial After all abstracts were reviewed, data comparisons
with interaction of genetic and environmental factors. between the two investigators were conducted to
Intake of high energy, saturated fat, and simple sugar ensure completeness and reliability. The inclusion cri-
also favors gallstone formation (7). teria were independently applied to all identified
GD shares certain risk factors with cardiovascular studies. Differing decisions were resolved by consen-
disease (CVD), particularly age, obesity, diabetes mel- sus between the two authors.
litus, hypertension, hyperlipidemia, insulin resist-
ance, sedentary lifestyle, non-alcoholic fatty liver Data Extraction
disease, and metabolic syndrome (8–10). Additionally,
cholesterol is the main component of GD that is also Full-text versions of potentially relevant articles iden-
the main pathogenic factor for artherosclerotic plaque tified in the initial screening were retrieved. If multi-
formation that will further progress to several CVDs ple articles from the same study were found, only the
including stroke and coronary heart disease (11). In article with the most complete data was included.
light of sharing risk factors, patients with GD may be Data concerning author, year of publication, study
at increased risk of CVD. design, study location, participant characteristics,
Several recent studies exploring the effect of GD on diagnosis of GD, definition of CVD, confounder
CVD outcomes demonstrated contradictory results. adjustment, and quality assessment were indepen-
Thus, to further investigate this possible risk, we con- dently extracted by two authors. We contacted the
ducted a systematic review and meta-analysis of authors of the primary reports to request any unpub-
observational studies that compared the risk of CVD lished data. If the authors did not reply, we used the
in patients who had GD versus patients who did not available data for our analyses.
have GD.
Assessment of Quality

Methods A subjective assessment of methodological quality

for observational studies was evaluated by two
This systematic review and meta-analysis was con- authors (SU and VJ) using the Newcastle–Ottawa
ducted and reported according to the Meta-analysis Scale (NOS). The NOS is a quality assessment tool for
Of Observational Studies in Epidemiology statement non-randomized studies. It used a “star system”
(12) and was registered in PROSPERO (International based on three major perspectives: the selection of
Prospective Register of Systematic Reviews) (regis- the study groups (0–4 stars), the comparability of the
tration number: CRD42015030065). groups by controlling for first and second most rele-
vant factors (0–2 stars), and the ascertainment of out-
Data Sources and Search Strategy come of interest (0–3 stars). A total score of three or
less was considered poor, 4–6 was considered moder-
Two authors (Sikarin Upala (SU) and Veeravich ate, and 7–9 was deemed high quality (13). We
Jaruvongvanich (VJ)) independently searched pub- excluded poor quality studies in the sensitivity anal-
lished studies indexed in PubMed/MEDLINE and ysis. Discrepant opinions between authors were
EMBASE databases from the date of inception resolved by consensus.
to November 2015. References of all selected studies
were also examined. The following main search
Statistical Analysis
terms were used: Cardiovascular disease, stroke,
coronary heart disease, myocardial infarction, gall- We performed meta-analysis of the included studies
stones, cholelithiasis. The full search strategy is detailed using Comprehensive Meta-Analysis 3.3 software
in Item S1 in supplementary material, available at from Biostat, Inc. We calculated pooled effect estimates
 Gallstones and the risk of cardiovascular disease 3

(OR, HR, or RR) of CVD with 95% CIs comparing Publication Bias
between the groups of gallstones and non-gallstones To investigate potential publication bias, we examined
individuals using the random-effects model. We used the contour-enhanced funnel plot of the included
effect size (OR, HR, and RR) from the multivariate studies that assessed the ORs of CVD events (Fig. 3).
model with confounding factors adjusted in each The plot excludes bias since there is symmetrical dis-
study. We reported the pooled effect estimate of a tribution of studies on both sides of the mean.
change in outcome using a fixed effects model if Furthermore, Egger’s test was non-significant
I2 < 50% and a random effects model if I2 ≥ 50%. A fixed- (p = 0.91). Using the trim and fill methods in the ran-
effect meta-analysis is based on the assumption that dom-effects model, there was no difference of the
each study provides the same effect. While a random- imputed OR of 1.28 (95% CI 1.23–1.33).
effects meta-analysis model involves an assumption
that the effects being estimated in the different studies
are not identical, but follow some distribution. The het- Discussion
erogeneity of effect size estimates across these studies
In this systematic review and meta-analysis of approx-
was quantified using the Q statistic, its p value, and I2
imately 200,000 cases and 800,000 controls, we demon-
(p < 0.10 was considered significant). A value of I2 of
strate a significant increased risk of CVD events with
0%–25% indicates insignificant heterogeneity, 26%–
an overall 1.28-fold increased risk and 1.82-fold
50% low heterogeneity, 51%–75% moderate heteroge-
increased odds among patients with GD compared
neity, and 76%–100% high heterogeneity. Publication
with controls. We also demonstrated a 1.3-fold higher
bias was assessed using the funnel plot, Egger’s regres-
risk of coronary heart disease in patients with GD.
sion test, and its implications with the trim and fill
Several potential mechanisms may account for the
method. A funnel plot is a simple scatter plot of the
association between GD and CVD risk. First, the pres-
intervention effect estimates from individual studies
ence of GD was found to be related to many CVD risk
against some measure of each study’s size or precision.
factors including age, obesity, diabetes mellitus,
Egger’s regression test is a test for asymmetry of the
hypertension, hyperlipidemia, insulin resistance, sed-
funnel plot with a significance level at 0.10. The trim
entary lifestyle, and metabolic syndrome (8, 10, 20–22).
and fill method is a non-parametric data augmentation
However, in most of included studies, the risks were
technique used to estimate the number of studies miss-
adjusted to the common risk factors (e.g. hyperten-
ing from a meta-analysis due to publication bias.
sion, hyperlipidemia, obesity, and diabetes mellitus)
but the association of both conditions remained sig-
Results nificant in our analysis suggesting that other patho-
genic processes might play a role. Second, the
Description of Included Studies
abnormal regulation of hepatic cholesterol and bile
The initial search yielded 1933 articles; 1896 articles acid is the primary pathological process of stone for-
were excluded based on title and abstract review. A mation in the gall bladder (23). Gut microbiota are the
total of 37 articles underwent full-length review. A large number of healthy microorganisms residing
total of 31 articles were excluded (15 articles did not along the gastrointestinal tract, functioning to main-
report outcomes of interest, 10 articles did not study in tain the normal host physiology (24). They are able to
subjects of interest, 3 articles were letters, and 3 arti- regulate the composition of bile acid (25). The disrup-
cles were abstract). Data were extracted from six stud- tion of these organisms was found to be the potential
ies involving 176,734 patients with GD and 803,714 key process of gallstone formation (26). Moreover,
controls without GD. Item S2 in the supplementary several studies showed that the altered gut microbiota
material outlines the search methodology and selec- was found to increase not only the CVD but also car-
tion process. Table 1 describes the detailed characteris- diovascular risk factors including insulin resistance,
tics and quality assessment of included studies. diabetes mellitus, and obesity (26, 27). The association
of GD and CVD might be partly due this gut microbi-
ota dysbiosis. Third, inflammation could be a central
Meta-Analysis Results
pathogenic process of this association; since there was
Six studies (five cohort studies (14, 15, 17–19) and an increased oxidative stress in the gallbladder mucosa
one case–control study (16)) were included in the resulting in altered bile saturation and further pro-
meta-analysis. We analyzed the pooled HR and gress to gallstone (28). In the same manner, increased
pooled OR separately. The pooled HR of CVD events oxidative stress is the key factor of CVD development
in patients who had GD was 1.28 (95% CI: 1.23–1.33, as a result of lipid peroxidation and endothelial dys-
I2 = 42%) (four cohort studies (14, 15, 17, 19)) (Fig. 1). function (29). Physicians should be aware of this
There was also statistically significant higher odds of potential association and appropriately provide the
cardiovascular events in patients with GD with cardiovascular risk factor modifications to these
pooled OR of 1.82 (95% CI: 1.47–2.24, I2 = 68%) (one patients. Moreover, it is still unknown whether any
cohort study (18) and one case–control study (16)) intervention could modify the risk including anti-
(Fig. 2). In the subgroup analysis, the pooled HR of platelet medications. A prospective study is warranted
coronary heart disease in patients who had GD was to address this issue.
1.31 (95% CI: 1.14–1.51, I2 = 83%) (Item S3 in the sup- Even though most of the included studies have
plementary material) (two cohort studies (14, 19)). good quality, several limitations in this study should
 4

Table 1
Characteristics of included studies.

Lv et al. (14) Wei et al. (15) Jiang et al. (16) Wirth et al. (17) Bortnichak et al. (18) Olaiya et al. (19)

Country China Taiwan China Germany United States Taiwan

Year 2015 2014 2013 2015 1985 2013
Study design Prospective cohort Retrospective Case–control Prospective cohort Prospective cohort Retrospective cohort
cohort
Cases Population-based study National Health Patients underwent General population Framingham Heart Study National Health
Insurance Research coronary angiography registries Insurance Research
Database Database
Diagnosis of GD Interviewer-administered Diagnostic code Abdominal Computer-guided Imaging study and history Diagnostic code
standardized questionnaire ultrasonography interviews of cholecystectomy
Definition of CVD CHD Stroke CHD CHD and stroke CHD CHD, stroke and heart
failure
Diagnosis of CVD Diagnostic code, adjudicated by Diagnostic code Coronary angiography Self-report, contacting N/A Diagnostic code
medical record and cardiovascular patients’ physician,
specialist death certificate or
diagnostic code
No. of patients with 28,345 135,512 766 4828 302 6981
GD
No. of controls 459,028 271,024 504 41,658 4206 27,294
S. Upala, et al.

Mean age (years) N/A N/A Cases: 67 Cases: 54.2 N/A N/A
Controls: 62 Controls: 49.7
Female (%) 59.1 50.7 38.4 59 53.1 56.2
Average range of 7.2 N/A N/A 8.2 26 6
follow-up (years)
Confounder Age, sex, level of education, marital Age, sex, HTN, Age, gender, BMI, WC, Sex, age, study Age, sex, DM, left Age, gender, peripheral
adjustment status, alcoholism, smoking, physical DM, CHD, atrial TC, TG, LDL, HDL, center, educational ventricular hypertrophy, vascular disease, COPD,
activity, intake of red meat, fresh fruits, fibrillation, and fasting glucose, HTN, achievement, physical TC, length of follow-up, DM, HLD, HTN,
and vegetables, HTN, DM, family HLD DM, NAFLD, and activity, smoking, SBP, Framingham Relative alcoholism, chronic liver
history of heart attack, menopausal metabolic syndrome alcoholism, BMI, WC, Weight, smoking, and disease, and anemia
status, BMI, and history of digestive HTN, and HLD cholecystectomy
system disease
Quality assessment Selection: 4 Selection: 3 Selection: 4 Selection: 3 Selection: 3 Selection: 3
(NOS) Comparability: 2 Comparability: 2 Comparability: 2 Comparability: 2 Comparability: 2 Comparability: 2
Outcome: 3 Outcome: 2 Outcome: 2 Outcome: 2 Outcome: 3 Outcome: 2

BMI: body mass index; CHD: coronary heart disease; COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; HDL: high-density lipoprotein; HOMA: homeostasis model
assessment; HTN: hypertension; LDL: low-density lipoprotein; N/A: not applicable; NAFLD: non-alcoholic fatty liver disease; SBP: systolic blood pressure; TC: total cholesterol;
TG: triglyceride; WC: waist circumference; NOS: Newscastle–Ottawa scale; GD: gallstone disease; CVD, cardiovascular disease.
 Gallstones and the risk of cardiovascular disease 5

Fig. 1. Forest plot of the included studies comparing risk of cardiovascular disease in patients with gallstone disease and those without
gallstone disease; a diamond data marker represents the overall hazard ratios and 95% CI for the outcome of interest.

Fig. 2. Forest plot of the included studies comparing risk of cardiovascular disease in patients with gallstone disease and controls; a
diamond data marker represents the overall odds ratios and 95% CI for the outcome of interest.

be acknowledged. First, this is a meta-analysis of gallstone, black pigment gallstone, and brown pig-
observational studies so we can at best demonstrate ment gallstone were not separately analyzed for the
the association but not a causal relationship. A weak- risk of CVD in included studies. Since the pathogenic
ness inherent in observational studies is that they pathway of the stone formation in each subtype is dif-
may be subjected to confounding; therefore we can- ferent, it might contribute to the difference in CVD
not draw a conclusion that GD itself or other con- risk (30).
founders are the cause of the increased CVD risk.
Second, statistical heterogeneity presents in this
Conclusion
study. The possible sources of these heterogeneities
include the differences in the study design, methodol- Our meta-analysis demonstrates a significant elevated
ogy, and population. However, there was no signifi- risk of CVD among patients with GD. GD could be the
cant publication bias in our final analysis. Third, some risk factor for developing atherosclerosis. Further
of the included studies were conducted using medical studies are needed to identify the underlying mecha-
registry–based databases and so there is the possibil- nism and should assess this effect in patients with
ity of coding inaccuracy for both CVD and GD. different subtypes of GD (cholesterol gallstones, pig-
Fourth, the subtypes of stones including cholesterol mented gallstones, or mixed gallstones).
6 S. Upala, et al.

Fig. 3. Funnel plots showing publication bias in the studies reporting number of participants with cardiovascular disease in patients with
gallstone disease and controls. Circles represent observed published studies.

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9. Jaruvongvanich V, Sanguankeo A, Upala S: Significant associa-
Declaration of Conflicting Interests tion between gallstone disease and nonalcoholic fatty liver dis-
ease: A systematic review and meta-analysis. Dig Dis Sci. Epub
The author(s) declared no potential conflicts of interest with
ahead of print 18 March 2016. DOI: 10.1007/s10620-016-4125-2.
respect to the research, authorship, and/or publication of 10. Tsai CJ, Leitzmann MF, Willett WC et al: Prospective study of
this article. abdominal adiposity and gallstone disease in US men. Am J
Clin Nutr 2004;80(1):38–44.
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Ethical Approval artery disease. N Engl J Med 2005;352:1685–1695.
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