Skip to main content
NCBI home page
Scientific Reports logoLink to Scientific Reports
. 2019 Apr 9;9:5830. doi: 10.1038/s41598-019-42327-2

Gallstone Disease and the Risk of Cardiovascular Disease

Cameron J Fairfield 1,✉, Stephen J Wigmore 1, Ewen M Harrison 1
PMCID: PMC6456597  PMID: 30967586

Abstract

Gallstone disease (GD) is one of the most common presentations to surgical units worldwide and shares several risk factors with cardiovascular disease (CVD). CVD remains the most common cause of death worldwide and results in considerable economic burden. Recent observational studies have demonstrated an association between GD and CVD with some studies demonstrating a stronger association with cholecystectomy. We present the findings of a meta-analysis assessing the relationship between GD and CVD. A total of fourteen cohort studies with over 1.2 million participants were included. The pooled hazard ratio (HR, 95% confidence interval [CI]) for association with GD from a random-effects model is 1.23 (95%CI: 1.16–1.30) for fatal and non-fatal CVD events. The association was present in females and males. Three studies report the relationship between cholecystectomy and CVD with a pooled HR of 1.41 (95%CI: 1.21–1.64) which compares to a HR of 1.30 (95%CI: 1.07–1.58) when cholecystectomy is excluded although confounding may influence this result. Our meta-analysis demonstrates a significant relationship between GD and CVD events which is present in both sexes. Further research is needed to assess the influence of cholecystectomy on this association.

Introduction

Cardiovascular disease (CVD) remains the most common cause of death worldwide1–3. Despite significant advances in the prevention and treatment of CVD, the societal and economic burden is considerable and continues to rise4. CVD is preventable and it is cost-effective to promote risk factor modification in those at risk of CVD5. Early identification of at-risk populations may allow these changes to be implemented at a time when they are most effective.

Gallstone disease (GD) forms one of the most common presentations to surgical units worldwide6–8 and patients with gallstones have a higher prevalence of risk factors for cardiovascular disease including obesity and elements of the metabolic syndrome9,10. The presence of gallstones is associated with atherosclerosis11 and patients with gallstones may be at high risk of progression to symptomatic CVD.

Several observational studies have been published reporting a link between GD and CVD although some studies have found no difference12–22. While recent meta-analyses have demonstrated an association between GD and CVD, there is significant variation in the effect size of contributing studies. No meta-analysis to date has adequately accounted for confounding and the heterogeneity remains unexplained21,23,24. Further uncertainty is present over the role of cholecystectomy in modifying the risk of CVD with some authors concluding that cholecystectomy may directly cause CVD24. Analyses of cholecystectomy and CVD have not sufficiently accounted for the presence of confounding variables such as gallstone severity and inflammation. It is likely that these factors account for any apparent association between cholecystectomy and CVD. An additional cohort study examining the relationship between screen-detected GD and CVD has also been published with assessment of the impact of cholecystectomy on CVD22.

We therefore undertook a systematic review with meta-analysis of longitudinal studies assessing the impact of GD on CVD. We performed additional analyses assessing the impact of cholecystectomy on this association.

Results

Search Results

The search identified 5497 references of which 984 were duplicates. Searching of bibliographies identified six other potentially relevant references. Following screening of titles and abstracts, 118 articles remained for full text review. After exclusion of 93 articles (not longitudinal studies, not including GD or not including CVD), a total of 25 citations referring to fourteen cohort studies were included in this systematic review (Fig. 1). One publication reported two cohort studies14 and one publication reported three separate cohort studies as well as a meta-analysis21. Two cohort studies included participants recruited from the same National Health Insurance Research Database (Taiwan) and recruited controls from overlapping inclusion periods17,18. To prevent bias in our meta-analysis we conducted all analyses twice: first using the larger of the two studies18 and second using the smaller study17. We present results from the first set of analyses and describe any differences from the second set of analyses.

Figure 1.

Figure 1

Open in a new tab

Flow chart of study selection process

Study Characteristics

There were 14 prospective and retrospective cohort studies reported in eleven primary publications and reported in a further fourteen duplicate publications including conference abstracts. The characteristics of the studies are reported in Table 1. Two studies reported CVD mortality, seven studies reported coronary heart disease (CHD), one study reported cerebrovascular disease and four studies reported multiple CVD outcomes. Four studies relied on baseline ultrasound for diagnosis of GD, one study used cholecystography, two studies used International Classification of Disease (ICD) database records of GD verified in hospital records, five studies used self-reported GD at baseline with four of these verifying reports through hospital records and two studies do not report on ascertainment of exposure to GD and define exposure as “gallbladder disease” rather than GD. Both of the studies which consider “gallbladder disease” do not provide adequate numeric data to be incorporated into a meta-analysis and are therefore considered only in the qualitative analysis. It was felt that “gallbladder disease” was most likely to represent gallstones in these studies given the relative rarity of other gallbladder pathologies although caution is needed when considering the findings of these two studies. All of the remaining studies define exposure as “gallstone disease”. Three studies report separate outcomes for participants with GD who do not undergo cholecystectomy compared to controls and participants who undergo cholecystectomy compared to controls. Five studies report the rate of cholecystectomy which varied from approximately 31% to 73%. Four studies included only females and three studies included only males. Length of follow-up varied from 4.5 to 32 years with a median of 20 years.

Table 1.

Characteristics of Included Studies.

Author Paul Petitti Bortnichak Bortnichak Grimaldi Ruhl Olaiya Wei Lv Wirth Zheng Zheng Zheng Shabanzdeh
Year 1963 1979 1985 1985 1993 2011 2013 2014 2015 2015 2016 2016 2016 2017
Sex Male Female Male Female Both Both Both Both Both Both Female Female Male Both
Country United States United States United States United States United States United States Taiwan Taiwan China Germany United States United States United States Denmark
Design Prospective cohort Prospective cohort Prospective cohort Prospective cohort Prospective cohort Prospective cohort Retrospective cohort Retrospective cohort Prospective cohort Prospective cohort Prospective cohort Prospective cohort Prospective cohort Prospective cohort
Case ascertainment Employees of WEC WCCDS FHS FHS GRIC NHANES NHIRD NHIRD CKB EPIC-Germany NHS NHSII HPFS MONICA - Danish
GD diagnosis Not stated Not stated Baseline US Baseline US Cholecystography Baseline US Inpatient insurance claims for GD Inpatient HR Self-reported GD at baseline Self-reported GD at baseline Self-reported GD at baseline Self-reported GD at baseline Self-reported GD at baseline Baseline US
CVD diagnosis Planned follow-up examination Self-reported outcome verified in HR HR HR Review of DC Review of DC National database linkage (ICD-9) National database linkage (ICD-9) Linkage to DC registry and insurance registry, active follow-up, verification of HR and DC by cardiologist Postal questionnaire, HR or DC HR and DC HR and DC HR and DC National database linkage (ICD8 and ICD10)
CVD definition CHD CHD, cerebro-vascular disease, VTE CHD, coronary insufficiency, sudden death, (not angina pectoris) CHD, coronary insufficiency, sudden death, (not angina pectoris) Death due to CVD Death due to CVD CHD, cerebrovascular disease, coronary insufficiency Cerebrovascular disease CHD CHD, cerebrovascular disease CHD CHD CHD CHD, cerebro-vascular disease, VTE
No. Cases Not stated Not stated 180* 322* 222 2018 6981 135512 28345 4828 8796 5227 1449 504
No. Control Not stated Not stated 2028 2178 161 12210 27924 271024 459028 41658 103724 107692 42252 4992
Follow-up (years) 4.5 6.5 26 26 20 14.7 6 7–10 7.2 8.2 30 22 25 32
Con-founder adjust-ment Not stated Smoking, age, obesity, current OC use, previous OC use, hypertension, hypercholesterolaemia, alcohol consumption Age, smoking, obesity, hypertension, hypercholesterolaemia, diabetes mellitus, LVH Age, smoking, obesity, hypertension, hypercholesterolaemia, diabetes mellitus, LVH Age, sex, diabetes mellitus, BMI, serum cholesterol Age, sex, ethnicity, education, BMI, WHR, diabetes mellitus, HbA1c > 6.5%, serum cholesterol, smoking, alcohol consumption, caffeine consumption, CRP protein, SBP, DBP Age, sex, PVD, hyperlipidaemia, diabetes mellitus, hypertension, COPD, alcoholism, CLD, HHA, AHA Age, sex, hypertension, diabetes mellitus, IHD, AF, hyperlipidaemia Age, sex, education, marital status, alcohol consumption, smoking, physical activity, red meat intake, fruit intake, vegetable intake, hypertension, diabetes mellitus, family history IHD, menopausal status, BMI, chronic hepatitis, cirrhosis, PUD Age, sex, study centre, educational achievement, physical activity, smoking, alcohol intake, BMI, waist circumference, hypertension, hyperlipidaemia Age, ethnicity, family history IHD, marital status, smoking, BMI, physical activity, diabetes mellitus, hypertension, hyperchole-sterolaemia, aspirin-use, alcohol intake, energy-adjusted cholesterol-intake, energy intake, menopausal status, HRT, OC use Age, ethnicity, family history IHD, marital status, smoking, BMI, physical activity, diabetes mellitus, hypertension, hyperchole-sterolaemia, aspirin-use, alcohol intake, energy-adjusted cholesterol-intake, energy intake, menopausal status, HRT, OC use Age, ethnicity, family history IHD, marital status, smoking, BMI, physical activity, diabetes mellitus, hypertension, hyperchole-sterolaemia, aspirin-use, alcohol intake, energy-adjusted cholesterol-intake, energy intake Age, sex, cohort, BMI, SBP, DBP, non-HDL cholesterol, HDL, smoking, alcohol consumption, diet, physical activity, social group
Quality assessment (NOS) Selection: 2 Comp-arability: 0 Outcome: 2 Selection: 2 Comp-arability: 1 Outcome: 2 Selection: 3 Comparability: 2 Outcome: 3 Selection: 3 Comp-arability: 2 Outcome: 3 Selection: 2 Comp-arability: 1 Outcome: 3 Selection: 3 Comp-arability: 2 Outcome: 3 Selection: 4 Comparability: 2 Outcome: 1 Selection: 4 Comparability: 1 Outcome: 1 Selection: 4 Comparability: 1 Outcome: 2 Selection: 2 Comparability: 2 Outcome: 1 Selection: 3 Comparability: 2 Outcome: 2 Selection: 3 Comparability: 2 Outcome: 2 Selection: 3 Comp-arability: 2 Outcome: 2 Selection: 4 Comp-arability: 2 Outcome: 3
Open in a new tab

GD: gallstone disease; CVD: cardiovascular disease; NOS: Newcastle-Ottawa Scale; US: ultrasound; WEC: Hawthorne Works of the Western Electrical Company (Chicago); WCCDS: Walnut Creek Contraceptive Drug Study; FHS: Framingham Heart Study; GRIC: Gila River Indian Community; NHANES: National Health and Nutrition Examination Survey; NHIRD: National Health Insurance Research Database; CKD: China Kadoorie Biobank; EPIC-Germany: European Prospective Investigation into Cancer and Nutrition, German cohorts; NHS: Nurses’ Health Study; NHSII: Nurses’ Health Study II; HPFS: Health Professionals Follow-up Study; MONICA: Multinational mONItoring of trends and determinants in CArdiovascular disease, Danish cohorts only), HR: hospital records; DC: death certificates; ICD-9-CM: International Classification of Diseases, 9th Revision, Clinical Modification; IHD: ischaemic heart disease; VTE: venous thromboembolism; MI: myocardial infarction; PVD: peripheral vascular disease; OC: oral contraceptive; LVH: left ventricular hypertrophy; BMI: body mass index; WHR: waist-to-hip ratio; CRP: C-reactive protein; SBP: systolic blood pressure; DBP: diastolic blood pressure; COPD: chronic obstructive pulmonary disease; CLD: chronic liver disease; HHA: hereditary haemolytic anaemia; AHA: acquired haemolytic anaemia; AF: atrial fibrillation; PUD: peptic ulcer disease; HRT: hormone-replacement therapy without cholecystectomy excluded from analysis, number of cases remaining in analysis not stated.

Nine studies report adjusted HR of which eight are included in the main analysis (one includes duplication of controls from the same database). Two studies reported in the same publication report odds ratio (OR) and are considered in the qualitative analysis. Two studies report relative risk (RR) of which one does not report a sample size and the studies were therefore considered qualitatively. One study does not report numeric data. Overall this review includes over 1,269,137 participants (number of participants not provided in two studies). The quantitative meta-analysis included 1,229,171 participants (186,589 cases and 1,042,582 controls).

Gallstone Disease and the risk of Cardiovascular Disease

Ten of the fourteen studies reported a statistically significant increase in CVD due to GD. Three studies report non-statistically significant findings of which two demonstrate a trend towards an increase in CVD with GD and one reports a trend towards reduced CHD with GD in a female-only cohort. The study reporting no numeric data examined CHD and states: “There was no significant relationship with a history of gallbladder disease”.

All Cardiovascular Disease

After controlling for confounding variables participants with GD had a 23% increased risk of CVD compared to controls (95% CI = 1.16–1.30, Fig. 2). We identified considerable heterogeneity (I2 = 76.3%, p = 0.0001).

Figure 2.

Figure 2

Open in a new tab

Forest plot demonstrating relationship between GD and CVD. Squares and horizontal lines represent individual studies with 95% confidence intervals. Area of squares is proportional to study weighting in random effects meta-analysis. Diamond (blue) represents pooled HR from meta-analysis with 95% CI. Reference line (black) represents hazard ratio of 1.00 (no association between GD and CVD). Summary line (red) represents summary estimate and demonstrates increased risk of CVD with GD (23%).

Coronary Heart Disease

Seven studies reported CHD as a separate outcome including 843,312 participants (56,040 cases and 787,272 controls). Participants with GD had a 24% increased risk of CHD compared to controls (95% CI = 1.16–1.32). We identified considerable heterogeneity when CHD was considered (I2 = 70.7%, p = 0.0023).

Cerebrovascular Disease

Four studies reported cerebrovascular disease as a separate outcome although two studies used controls from the same database. Three studies were pooled by meta-analysis including 458,518 participants (140,844 cases and 317,674 controls). Participants with GD had a 29% increased risk of cerebrovascular disease compared to controls (95% CI = 1.26–1.32). We did not identify heterogeneity when cerebrovascular disease was considered (I2 = 0.00%, p = 0.76).

Subgroup Analyses and Sensitivity Analyses

We performed subgroup analyses for male-only participants, female-only participants, non-diabetic participants, diabetic participants, screen-detected GD and symptomatic GD (Table 2). We identified a statistically significant association between GD and CVD in all subgroups. One study which reported RR reported a summary estimate <1.00 but was not statistically significant and included only 322 cases compared to 103,562 cases included in our meta-analysis. We therefore demonstrate that the relationship between GD and CVD is present in both men and women (Fig. 3). The difference between diabetic and non-diabetic participants is not statistically significant although a trend towards a stronger effect suggests that GD may have a greater relative importance as a predictor of CVD in non-diabetic participants. CVD was significantly more common in both screen-detected and symptomatic GD. Heterogeneity remained moderate to substantial in all subgroup analyses other than cerebrovascular disease, screen-detected GD and cholecystectomy-only.

Table 2.

Subgroup Analyses for relationship between GD and CVD.

Subgroup HR (95% CI) P (Cochran Q test) I2 P (Wald-type test) Studies
Sex
Female 1.24 (1.17–1.32) 0.000 77.9% 0.428 5*
Male 1.18 (1.04–1.33) 0.000 90.5% 4*
Diabetes
Diabetic 1.13 (1.06–1.20) NA NA 0.075 1
Non-diabetic 1.23 (1.15–1.32) 0.000 91.3% 6**
Detection of GD
Screen-detected 1.35 (1.17–1.57) 0.847 0.00% 0.183 2
Symptomatic 1.21 (1.15–1.29) 0.000 82.4% 6*
Open in a new tab

Studies which included duplicated participants report subgroup results for male and female participants and symptomatic GD, we therefore conducted two separate analyses which produced similar results. studies reported in one publication are pooled by meta-analysis and both studies which included duplicated participants report subgroup analyses for non-diabetic participants and we therefore conducted four separate analyses (with and without inclusion of the pooled result and with and without each study using duplicated participants) which produced similar results.

Figure 3.

Figure 3

Open in a new tab

Forest plot demonstrating relationship between GD and CVD stratified by sex. Blue diamonds represent pooled summary estimate with 95% CI for each subgroup and overall pooled estimate for both groups combined.

Two studies from the same database report similar increases in CVD with GD for normotenstive and hypertensive participants. One study reports similar increases in CVD with GD for hyperlipidemic and non-hyperlipidemic participants. Three studies from the same publication were pooled in a meta-analysis for non-obese participants and for non-smokers revealing similar results in both analyses to the overall cohorts. Two studies from the same database report HRs for comorbidity-free participants as well as age-stratified subgroups for which results are similar to the overall cohorts except in the study assessing effect of GD on cerebrovascular where younger and comorbidity-free participants appear to have relatively greater burden of CVD risk. One study stratified participants according to GD duration at baseline and found no difference between groups.

We performed sensitivity analyses by iteratively excluding one study from the analysis to detect its impact on heterogeneity. Heterogeneity remained substantial for all sensitivity analyses with one study removed. Heterogeneity was noted to fall (I2 = 49%) when both Taiwanese studies using data from the same database were excluded.

We performed a meta-regression which did not detect any significant effect of follow-up, year of publication, quality assessment score, degree of adjustment for confounding variables or variance (p > 0.4 in all cases). In addition, none of the explanatory variables accounted for heterogeneity (pseudo-R2 = 0.00%, I2 = 70.4%).

Effect of Cholecystectomy on risk of Cardiovascular Disease

Three studies report separate data for cholecystectomy compared to controls and for GD without cholecystectomy compared to controls. One study reports a separate analysis of cholecystectomy versus GD without cholecystectomy. Pooled adjusted HR for cholecystectomy compared to controls was 1.41 (95%CI: 1.21–1.64) with insignificant heterogeneity (p = 0.250, I2 = 27.8%). Pooled adjusted HR for GD without cholecystectomy compared to controls was 1.30 (95%CI:1.07–1.58) with moderate heterogeneity (p = 0.161, I2 = 45.3%). The study compared cholecystectomy to GD without cholecystectomy directly found no statistically significant difference (HR 1.24, 95%CI: 0.85–1.81). One study also reported mild GD (cholelithiasis or choledocholithiasis excluding definition of severe GD) and severe GD (acute calculous cholecystitis, calculous pancreatitis, cholangitis, surgical procedure for GD or endoscopic procedure for GD) and reported a stronger association in mild gallstone disease (HR 1.34, 95%CI: 1.24–1.46 for non-severe GD versus HR 1.20, 95%CI: 1.02–1.40 for severe GD).

One report including three cohort studies limited exposure to cholecystectomy only and stated: “CHD risk was similar to when our definition of gallstone disease included both history of gallstones and cholecystectomy” although does not provide numeric data for this subgroup21. One report including two cohort studies states: “Cholecystectomy status proved to be superior to gallstone disease diagnosis in discriminating between those individuals who went on to develop coronary disease and those who did not”. This report did not provide data for GD with and without cholecystectomy14.

Overall four studies favour a stronger relationship between GD and CVD when cholecystectomy alone is considered and six studies favour a weaker relationship or no difference. No studies report a statistically significant difference between the two groups. Only one study16 adjusted for inflammatory markers (C-reactive protein) and found a non-significant trend towards lower risk of CVD in patients undergoing cholecystectomy compared to those with gallstones who did not undergo cholecystectomy.

Publication Bias

We did not detect publication bias through visual inspection of the funnel plot or by Egger’s regression test (p = 0.51, Fig. 4).

Figure 4.

Figure 4

Open in a new tab

Funnel plot with pseudo-95% confidence limits. Circles represent identified studies. Log-transformed adjusted HR plotted against inverse standard error of log-transformed HR.

Discussion

This systematic review with meta-analysis includes over 1.2 million participants and demonstrates a significant association between GD and CVD with an increase of 23% between cases and controls following adjustment for confounding variables. The association with GD is present for CHD, cerebrovascular disease and PVD as well as for men and women. There is trend towards a relatively stronger association in young and otherwise healthy individuals although no subgroup differences were statistically significant. The review highlights a scarcity of high quality evidence for the association between cholecystectomy and CVD.

Three separate meta-analyses investigating the relationship between GD and CVD have been published and report similar findings to our review with a statistically significant increase in CVD with GD which is present in several subgroups21,23,24.

Possible mechanisms linking GD and CVD include dyslipidemia, chronic inflammation and abnormalities in the ABCG8 cholesterol transporter gene25–27. Patients with the D19H and T400k polymorphisms of the ABCG8 gene have been demonstrated to have elevated risk of both CVD and GD suggesting a shared aetiology through aberrant cholesterol metabolism28,29. The presence of gallstones is known to be associated with inflammation of the gallbladder mucosa7. The presence of inflammation is already known to promote formation of atherosclerotic plaques even at distant sites and it is possible that low-grade inflammation associated with gallstones triggers a similar response30,31. GD is also associated with obesity, hyperlipidemia, diabetes mellitus and hypertension10,32 which is responsible in part for an increase in CVD. Adjustment of the reported HR for these confounding variables results in a reduction of CVD risk although, in all but two studies the association remains statistically significant. Other aetiological mechanisms such as altered gut microbiota and reduced levels of serum insulin-like growth factor are implicated in gallstone development and development of atherosclerotic plaques that have not been accounted for in any existing studies33–36.

In another meta-analysis, Fan et al. conclude that cholecystectomy is likely to be responsible for increased risk of CVD compared to GD without cholecystectomy. They cite evidence of altered serum lipid levels post-cholecystectomy in animal models, protective effects of biliary hormones on lipid and glucose metabolism and post-cholecystectomy alteration in gut microbiota. We do not feel that the evidence is sufficient to support this hypothesis. Only one cohort study makes direct comparison between cholecystectomy and GD without cholecystectomy and finds no significant difference. Changing the definition of exposure from GD to cholecystectomy is reported to have no significant impact in three studies although numeric data is not provided. Two studies report a trend towards higher rates of CVD following cholecystectomy and one publication reporting two studies only published data for cholecystectomy as this was found to be a stronger predictor of CVD than GD as a whole. Three studies found a trend towards a weaker association between GD and CVD when cholecystectomy only was considered. Of the studies which find cholecystectomy to be a weaker predictor of CVD than GD as a whole, one of these studies16 adjusts for C-reactive protein suggesting that inflammation may be responsible for any apparent increase in CVD in the cholecystectomy group. None of the studies which demonstrate a trend towards higher rates of CVD in the cholecystectomy group, compared to those with gallstones who do not require cholecystectomy, adjust for inflammatory markers. Symptoms arising from inflammation of the gallbladder are a key determinant of the need for cholecystectomy, meaning that patients who require cholecystectomy may have suffered from more extensive systemic inflammation. For these reasons we do not feel that cholecystectomy contributes directly to increased risk of CVD and is, instead, more likely to represent those patients who have a greater burden from other CVD risk factors.

Our meta-analysis identified substantial heterogeneity for which we did not identify the likely cause. It is possible that additional confounding variables at participant- or study-level have not been recorded or reported. A total of five studies reported having additional data available, which we were unable to obtain, relating to differences between rate of CVD following cholecystectomy compared to GD without cholecystectomy. This suggests that the review may be subject to selective reporting bias with only those articles finding a difference between the two comparisons publishing the results. Our review identified a persistent direction of effect in all but one study and included data from three studies not previously considered in any other review on the same topic. The findings are consistent in several populations and subgroups but do not demonstrate a causal link between GD or cholecystectomy and CVD.

Our review has confirmed the significant association between GD and CVD and highlights the importance of recognizing GD as a risk factor for CVD. We have demonstrated that risk of CVD is elevated in GD for both males and females. We have demonstrated that cholecystectomy may not increase the risk of CVD as previously thought. Our review identifies the need for further research into the impact of chronic inflammation on the risk of CVD in patients with GD and in particular whether this accounts for any apparent increase in CVD with cholecystectomy.

Methods

A systematic review with meta-analysis was undertaken in accordance with the Meta-analysis of Observation Studies in Epidemiology (MOOSE) statement37 and the PRISMA statement38.

Search Strategy

In October 2017 we ran searches in MEDLINE, EMBASE, Science Citation Index and Social Sciences Citation Index Expanded and Literatura Latino-americana e do Caribe em Ciências da Saúde (LILACS) from earliest date possible. The search strategies are shown in Supplementary Table S1. We combined terms into three categories (GD; CVD; and observational studies) using the OR operator before combining the three categories using the AND operator.

Study Selection

We included studies meeting the following criteria:

  • Longitudinal cohort study

  • Assessing the relationship between GD and CVD

We included cholecystectomy as well as GD without cholecystectomy, we also included screen-detected as well as symptomatic GD. Studies which reported “gallbladder disease” and were thought to represent gallstones rather than rarer gallbladder pathology were considered only in the qualitative analysis. We included fatal and non-fatal CVD events and considered CHD, cerebrovascular disease and peripheral vascular disease (PVD). Each subgroup of CVD was considered separately in subanalyses where possible as well as combined into one single composite outcome of CVD. No relevant non-English language articles were identified. When identified studies were reported in multiple publications we extracted unique data from each publication.

Data Extraction

We extracted the following data from each study: authors, publication year, study population, baseline characteristics, sample size, study design, country, ascertainment of exposure, detection of CVD events, definition of CVD, follow-up duration, confounding variable adjustment, rate of cholecystectomy and adjusted effect measures (hazard ratio [HR], relative risk [RR] or odds ratio [OR]) with 95% confidence interval. We assessed each study according to the Newcastle-Ottawa Quality Assessment Scale (NOS)39. Prior to data extraction we defined an appropriate follow-up period of at least 10 years to allow for CVD events to occur and a follow-up rate of >90%. We contacted authors to request additional data when required.

Data Analysis

We assimilated data using DerSimonian-Laird random effects meta-analysis40. We used fully adjusted (multivariable) effect measures from each study when available. We did not transform each unique effect measures into one single effect measure and as such studies reporting HR, RR or OR are considered in three distinct groups. All effect measures were log-transformed for purposes of data analysis prior to back-transformation for presentation of results.

Subgroup analyses were performed for the following groups:

  • Male-only participants

  • Female-only participants

  • Diabetic participants

  • Non-diabetic participants

  • Screen-detected GD

  • Symptomatic GD

  • Gallstones (not including cholecystectomy) versus controls

  • Cholecystectomy only versus controls

Discrete subgroups were compared using a Wald-type test with p value significance set at <0.01. We assessed influences of moderator variables by meta-regression using a mixed effects model and the Knapp and Hartung adjustment41. For the mixed effects model and meta-regression we included length of follow-up, year of publication, degree of adjustment for confounding variables, variance and NOS score.

We assessed for presence of heterogeneity using Cochran’s Q test with p value significance set at <0.1 and quantified heterogeneity with the I2 statistic42,43. We assessed for the presence of publication bias by visual inspection of funnel plots and Egger’s regression test with p value significance set at <0.144.

All analyses were undertaken in R version 3.3.1 using the “metafor” package45,46. All data is available in original manuscripts.

Supplementary information

Supplementary Information (426.2KB, pdf)

Acknowledgements

This research was undertaken as part of the third year of the MSc in Surgical Sciences (The University of Edinburgh).

Author Contributions

S.J.W. developed the research question, C.J.F. collected the data, C.J.F. and E.M.H. analysed the data. All authors reviewed the manuscript.

Competing Interests

The authors declare no competing interests.

Footnotes

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information accompanies this paper at 10.1038/s41598-019-42327-2.

References

  • 1.World Health Organisation. World Health Statistics 2017: Monitoring Health for the SDGs, Sustainable Development Goals. Tech. Rep., World Health Organisation, Geneva (2017).
  • 2.Lozano R, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet. 2012;380:2095–2128. doi: 10.1016/S0140-6736(12)61728-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Office for National Statistics. Deaths registered in England and Wales - Office for National Statistics. Bulletin, Office for National Statistics (2017).
  • 4.American Heart Association & American Stroke Association. A.S.A Cardiovascular disease: a costly burden for America, projections through 2035 (2017). Tech. Rep., The American Heart Association, Connecticut (2017).
  • 5.Gaziano TA. Cardiovascular Disease in the Developing World and Its Cost-Effective Management. Circulation. 2005;112:3547–3553. doi: 10.1161/CIRCULATIONAHA.105.591792. [DOI] [PubMed] [Google Scholar]
  • 6.Harrison EM, et al. Hospital volume and patient outcomes after cholecystectomy in Scotland: retrospective, national population based study. BMJ. 2012;344:e3330. doi: 10.1136/bmj.e3330. [DOI] [PubMed] [Google Scholar]
  • 7.Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. The Lancet. 2006;368:230–239. doi: 10.1016/S0140-6736(06)69044-2. [DOI] [PubMed] [Google Scholar]
  • 8.Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999;117:632–639. doi: 10.1016/S0016-5085(99)70456-7. [DOI] [PubMed] [Google Scholar]
  • 9.Chavez-Tapia NC, et al. Association between cholecystectomy for gallstone disease and risk factors for cardiovascular disease. Annals Hepatol. 2012;11:85–89. [PubMed] [Google Scholar]
  • 10.Chen L-Y, et al. Metabolic syndrome and gallstone disease. World J. Gastroenterol.: WJG. 2012;18:4215–4220. doi: 10.3748/wjg.v18.i31.4215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Jiang Z-Y, et al. Gallbladder Gallstone Disease Is Associated with Newly Diagnosed Coronary Artery Atherosclerotic Disease: A Cross-Sectional Study. PLOS ONE. 2013;8:e75400. doi: 10.1371/journal.pone.0075400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Paul O, et al. A Longitudinal Study of Coronary Heart Disease. Circulation. 1963;28:20–31. doi: 10.1161/01.CIR.28.1.20. [DOI] [PubMed] [Google Scholar]
  • 13.Petitti DB, Wingerd J, Pellegrin F, Ramcharan S. Risk of Vascular Disease inWomen: Smoking, Oral Contraceptives, Noncontraceptive Estrogens, and Other Factors. JAMA. 1979;242:1150–1154. doi: 10.1001/jama.1979.03300110022020. [DOI] [PubMed] [Google Scholar]
  • 14.Bortnichak EA, et al. The Association Between Cholesterol Cholelithiasis and Coronary Heart Disease in Framingham, Massachusetts. Am. J. Epidemiol. 1985;121:19–30. doi: 10.1093/oxfordjournals.aje.a113978. [DOI] [PubMed] [Google Scholar]
  • 15.Grimaldi CH. Increased Mortality with Gallstone Disease: Results of a 20-Year Population-Based Survey in Pima Indians. Annals Intern. Medicine. 1993;118:185. doi: 10.7326/0003-4819-118-3-199302010-00005. [DOI] [PubMed] [Google Scholar]
  • 16.Ruhl CE, Everhart JE. Gallstone Disease is Associated with Increased Mortality in the United States. Gastroenterology. 2011;140:508–516. doi: 10.1053/j.gastro.2010.10.060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Olaiya MT, Chiou H-Y, Jeng J-S, Lien L-M, Hsieh F-I. Significantly Increased Risk of Cardiovascular Disease among Patients with Gallstone Disease: A Population-Based Cohort Study. PLOS ONE. 2013;8:e76448. doi: 10.1371/journal.pone.0076448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Wei C-Y, et al. Gallstone Disease and the Risk of Stroke: A Nationwide Population-based Study. J. Stroke Cerebrovasc. Dis. 2014;23:1813–1820. doi: 10.1016/j.jstrokecerebrovasdis.2014.04.024. [DOI] [PubMed] [Google Scholar]
  • 19.Lv J, et al. Gallstone Disease and the Risk of Ischemic Heart Disease. Arter. Thromb. Vasc. Biol. 2015;35:2232–2237. doi: 10.1161/ATVBAHA.115.306043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Wirth J, et al. Presence of gallstones and the risk of cardiovascular diseases: The EPIC-Germany cohort study. Eur. J. Prev. Cardiol. 2015;22:326–334. doi: 10.1177/2047487313512218. [DOI] [PubMed] [Google Scholar]
  • 21.Zheng, Y. et al. Gallstones and Risk of Coronary Heart Disease: Prospective Analysis of 270 000 Men and Women From 3 US Cohorts and Meta-Analysis. Arter. Thromb. Vasc. Biol. ATVBAHA. 116.307507 (2016). [DOI] [PMC free article] [PubMed]
  • 22.Shabanzadeh DM, Skaaby T, Sorensen LT, Jorgensen T. Screen-detected gallstone disease and cardiovascular disease. Eur. journal epidemiology. 2017;32:501–510. doi: 10.1007/s10654-017-0263-x. [DOI] [PubMed] [Google Scholar]
  • 23.Upala S, Sanguankeo A, Jaruvongvanich V. Gallstone Disease and the Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Observational Studies. Scand. J. Surg. 2017;106:21–27. doi: 10.1177/1457496916650998. [DOI] [PubMed] [Google Scholar]
  • 24.Fan Ll, Chen BH, Dai ZJ. The relation between gallstone disease and cardiovascular disease. Sci. Reports. 2017;7:15104. doi: 10.1038/s41598-017-15430-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat. Rev. Cardiol. 2009;6:399–409. doi: 10.1038/nrcardio.2009.55. [DOI] [PubMed] [Google Scholar]
  • 26.Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J. Intern. Medicine. 2015;278:483–493. doi: 10.1111/joim.12406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Buch S, et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat. Genet. 2007;39:995–999. doi: 10.1038/ng2101. [DOI] [PubMed] [Google Scholar]
  • 28.Rudkowska I, Jones PJH. Polymorphisms in ABCG5/G8 transporters linked to hypercholesterolemia and gallstone disease. Nutr. Rev. 2008;66:343–348. doi: 10.1111/j.1753-4887.2008.00042.x. [DOI] [PubMed] [Google Scholar]
  • 29.Koeijvoets KCMC, et al. ABCG8 gene polymorphisms, plasma cholesterol concentrations, and risk of cardiovascular disease in familial hypercholesterolemia. Atherosclerosis. 2009;204:453–458. doi: 10.1016/j.atherosclerosis.2008.09.018. [DOI] [PubMed] [Google Scholar]
  • 30.Beukers NGFM, Heijden GJMG. v. d., Wijk, A. J. v. & Loos, B. G. Periodontitis is an independent risk indicator for atherosclerotic cardiovascular diseases among 60 174 participants in a large dental school in the Netherlands. J Epidemiol Community Heal. 2017;71:37–42. doi: 10.1136/jech-2015-206745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circ. Res. 2016;118:145–156. doi: 10.1161/CIRCRESAHA.115.306656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Zhu Q, et al. The association between gallstones and metabolic syndrome in urban Han Chinese: a longitudinal cohort study. Sci. Reports. 2016;6:29937. doi: 10.1038/srep29937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Wu T, et al. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC genomics. 2013;14:669. doi: 10.1186/1471-2164-14-669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Miele L, et al. Impact of Gut Microbiota on Obesity. Diabetes, and Cardiovascular Disease Risk. Curr. Cardiol. Reports. 2015;17:120. doi: 10.1007/s11886-015-0671-z. [DOI] [PubMed] [Google Scholar]
  • 35.Moschetta A, et al. Effects of growth hormone deficiency and recombinant growth hormone therapy on postprandial gallbladder motility and cholecystokinin release. Dig. Dis. Sci. 2004;49:529–534. doi: 10.1023/B:DDAS.0000020515.75879.2f. [DOI] [PubMed] [Google Scholar]
  • 36.Juul A, Scheike T, Davidsen M, Gyllenborg J, Jørgensen T. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002;106:939–944. doi: 10.1161/01.CIR.0000027563.44593.CC. [DOI] [PubMed] [Google Scholar]
  • 37.Stroup DF, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012. doi: 10.1001/jama.283.15.2008. [DOI] [PubMed] [Google Scholar]
  • 38.Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLOS Medicine. 2009;6:e1000097. doi: 10.1371/journal.pmed.1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur. J. Epidemiol. 2010;25:603–605. doi: 10.1007/s10654-010-9491-z. [DOI] [PubMed] [Google Scholar]
  • 40.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control. Clin. Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
  • 41.Knapp G, Joachim H. Improved tests for a random effects meta-regression with a single covariate. Stat. Medicine. 2003;22:2693–2710. doi: 10.1002/sim.1482. [DOI] [PubMed] [Google Scholar]
  • 42.Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ: Br. Med. J. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat. Medicine. 2002;21:1539–1558. doi: 10.1002/sim.1186. [DOI] [PubMed] [Google Scholar]
  • 44.Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634. doi: 10.1136/bmj.315.7109.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.R Core Team. R: A Language and Environment for Statistical Computing (2017).
  • 46.Viechtbauer W. Conducting Meta-Analyses in R with the metafor Package. J. Stat. Softw. 2010;36:1–48. doi: 10.18637/jss.v036.i03. [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information (426.2KB, pdf)

Articles from Scientific Reports are provided here courtesy of Nature Publishing Group

RESOURCES