The positive association between gallstones and CVD has recently received much attention because of the increasing role of inflammation in the development of CVD and gallstones. In addition to the subclinical inflammatory process, acute bacterial infections associated with gallstones may accelerate atherosclerosis in the vasculature. We carried out a risk analysis to investigate the CVD risk in the GSI or non-GSI groups treated by cholecystectomy. In this study, we demonstrated that CVD risks and risk changes due to treatment are determined by the presence or absence of GSI. The GSI group had greater risks of MI or CI and higher risk reduction by cholecystectomy than the non-GSI group. To the best of our knowledge, this is the first study to demonstrate that CVD risk is strongly associated with GSI and is partially reduced by cholecystectomy in patients with gallstones.
The role of inflammation in CVD risk has been emphasized in recent years. Control of the inflammatory reaction is targeted as a strategy for atheroprotection.24 We hypothesized that CVD risk among gallstone patients increases under GSI conditions. Gram-negative bacteremia frequently occurs in patients with GSI, which produces LPS or circulating endotoxins. These inflammatory mediators accelerate atherosclerosis or vasculopathy via cytokines from human vascular endothelial and smooth muscle cells.25 In this study, the risk of MI or CI increased by 32% and 24%, respectively, in the GSI group compared to controls, while they were nearly equal to controls in the non-GSI group. Studies regarding CVD risk in GSI and non-GSI groups have reported mixed results.5,17,18 In one study, risk of ischemic stroke increased by 7% in symptomatic gallstones compared with asymptomatic gallstones, while hemorrhagic stroke showed similar results.17 On the other hand, CVD risk was similar between severe and non-severe gallstone patients in another study.18 They defined symptomatic gallstones as acute cholecystitis, acute cholangitis, biliary pancreatitis, or those treated by surgery or endoscopic intervention.18 Moreover, recent meta-analysis5 reported that CVD risk was higher in screen-detected gallstones than in symptomatic gallstones with 35% and 21% increased risk, respectively, with reference to controls. These unmatched results may be caused by incomplete adjustment of other risk factors such as obesity, physical inactivity, high blood pressure, high blood glucose level, alcohol drinking or smoking.
In the present study, cholecystectomy had a greater effect on the CVD risk in the GSI group than in the non-GSI group. Cholecystectomy partially reduced the increased risk of CVD in the GSI group. Attenuation of systemic inflammation by cholecystectomy may have a role in reducing CVD risk.17 Risk reduction by cholecystectomy was greater in CI than in MI in the GSI group, with 16.1% and 11.4%, respectively. However, the original risk of CVD and the risk reduction by cholecystectomy were negligible in the non-GSI group. Studies regarding cholecystectomy and CVD risk factors are rare and have reported mixed results. A population-based study in Taiwan revealed that stroke risk decreased in gallstone patients who underwent cholecystectomy compared with those who did not. Risk reduction rates were 46% and 25% for symptomatic gallstones and asymptomatic gallstones, respectively.17 However, several studies have reported that cholecystectomy for gallstones did not influence CVD risks.19–21 Moreover, CVD risk was higher in case of gallstones treated by cholecystectomy compared to screening-detected gallstones19 or gallstones treated conservatively.20 However, they did not compare CVD risks separately in GSI and non-GSI groups nor adjustment by severity of inflammation. Cholecystectomy is usually indicated for biliary pain and gallstone-related complications. Therefore, patients who require cholecystectomy may have more complicated gallstones. Therefore, the increased CVD risk in the cholecystectomy group was not due to cholecystectomy itself but due to confounding variables related to high CVD risk.
In the present study, CVD risk among gallstone patients was higher in younger than in older patients. This finding was consistent with a recent meta-analysis.7 Because younger people had a low prevalence of gallstones and fewer other CVD risks, the effect of gallstones or cholecystectomy seemed to be stronger in the younger group.18 Theses findings suggested that younger patients with gallstones should be given more attention for the prevention of CVD. In addition, the risk of MI was higher in females than in males, whereas the risk of CI was similar between the sexes. These findings were consistent with those of previous studies, where CVD risks were higher in females than in males among gallstone patients.5,7,18,26,27 The explanation for these results is not clear, but we speculate that gallstones or cholecystectomy seemed to have a stronger risk of MI in females because of fewer other risk factors and a lower incidence of MI compared to males. No previous studies have performed subgroup analysis for the effect of cholecystectomy in terms of sex or age. This is the first study to demonstrate that risk reduction by cholecystectomy was higher in younger patients and females compared to older patients and males.
Our data were compatible with previous studies showing that obesity,28,29 hyperlipidemia,21 diabetes mellitus, hypertension,30 smoking31,32 and long sedentary periods33 are associated with gallstones and CVD.34 These cardiometabolic factors were revealed as dose-responsive predictors of both MI and CI, with a slight difference between them. As in a previous study,35 hypertension was associated with a higher risk of CI than MI, whereas cholesterol and smoking showed the opposite effect. In this study, the adjusted risk (aHR) of gallstones for CVD development was lower than crude risk (IRR). CVD risk among gallstone patients was usually lower with complete adjustment of confounding factors, longer follow-up, and a larger study compared to their counterparts.26 Therefore, adjustment of other risk factors is needed to evaluate the effects of gallstones on CVD development.
Disease patterns of CVD are slightly different in Eastern and Western populations. Coronary heart disease is prevalent in Western people, while stroke is prevalent in Eastern people.35,36 This study of Korean people revealed that CI incidence was 2-fold higher than MI and the risk reduction rate by cholecystectomy was higher for CI than MI. These differences between MI and CI could be explained by regional or racial variations with regards to the risk factors of MI or CI. Therefore, our results are limited to Asian populations and further studies are needed including patients with other ethnicities.
We selected controls by matching age, sex, and visit frequency as outpatients. Matched clinic visit frequency is important to reduce selection bias in terms of economic status, interest in health, and detection bias. Using this method, we selected a control group to investigate the real effects of gallstones or cholecystectomy on the risk of MI or CI.
We identified patients diagnosed with MI or CI using the International Classification of Disease (ICD)-10 codes. A recent population-based large cohort study using the KNHI demonstrated that the ICD-10 code for CVD is valid.37 In this study, we defined GSI group as patients diagnosed with acute cholecystitis or acute cholangitis among gallstones using ICD-10 codes. Because the proportion of acute biliary pancreatitis was less than 1% and was not related to bacterial infection, we excluded acute biliary pancreatitis in the GSI group. The ICD-10 code for gallstones has been validated in our previous study.38
This study has several limitations. First, GSI was identified using the ICD-10 code, not by clinical findings or pathology results. Detailed information regarding patient symptoms or pathological findings could not be obtained from the KNHI data. However, our data are consistent with the previous results. The proportion of GSI cases among cholecystectomy cases was 31% in this study, consistent with that of Taiwan’s study.39 In addition, the proportion of GSI among gallstones was 17% in this study, which was compatible with 7%-26% of gallstone-related complications among gallstone patients.40 Therefore, our study population represents a real clinical setting. Second, there were unadjusted risk factors for CVD and gallstones, such as insulin resistance, lipid-lowering drugs, inflammatory mediators, nonalcoholic fatty liver disease,41,42 and the gut microbiota. Despite these limitations, this is the first study to extensively evaluate the effects of cholecystectomy on the risk of MI or CI by adjusting for confounding factors in a large population-based cohort.
In conclusion, cholecystectomy for GSI reduces the risk of MI or CI independent of other risk factors, and it was greater in females and younger patients. However, it had minimal effect on CVD in the non-GSI group. Among patients with GSI, younger people and females who have risk factors for CVD need close monitoring for CVD development. Cholecystectomy should be recommended in patients with prior or current biliary tract infection to reduce the risk of ischemic CVD and recurrence of biliary complications.