Gallstones : a sentinel presentation of cardiometabolic disease

Gallstone disease is one of the most common surgically-managed conditions worldwide yet associations with other medical conditions outside of the biliary tree are poorly understood. Much like cardiovascular (CVD) and metabolic (cardiometabolic) disease (such as ischaemic heart disease, stroke, type 2 diabetes [T2DM] and non-alcoholic fatty liver disease [NAFLD]), gallstones are known to be more common in individuals who are overweight, do not exercise regularly and have a poor diet. Furthermore, gallstones, at least in populations with Western diets, are predominantly formed from cholesterol which is known to be a key determinant of cardiometabolic disease. It is therefore probable that individuals with gallstones are at higher risk of cardiometabolic disease than the general population. The relationship between gallstones and cardiometabolic disease (CVD, T2DM and NAFLD) was investigated. All three conditions were more common in individuals with gallstones than in gallstone-free controls and this increase in risk was not fully explained by established risk factors such as obesity, sedentary lifestyle or diet. Opportunistic identification of gallstones through radiology records was undertaken with natural language processing and similar increases in cardiometabolic disease identified. Gallstones are routinely managed by cholecystectomy and it was demonstrated that the apparent increase in risk of cardiometabolic disease was significantly attenuated compared to individuals who continued to live with their gallstones. This apparent reduction in risk was not explained by accounting for comorbidity or number of hospital attendances. Genetic analyses revealed a total of 75 genetic risk loci associated with gallstone formation (46 novel). These associations demonstrated heterogeneous effects on cardiometabolic disease outcomes and intermediate traits including lipids. A polygenic risk score was established with a six-fold increase in gallstone risk in the highest decile compared to the lowest. Genetic analysis of NAFLD was undertaken identifying 6 loci and confirming the suitability of electronic health records as a proxy to histological NAFLD evaluation in large cohorts. Mendelian randomisation (MR) was undertaken demonstrating a negative correlation between gallstones and CVD and no correlation between gallstones and either T2DM or NAFLD. After inclusion of additional variables in the model to account for pleiotropic pathways, the negative correlation with CVD was removed. Sensitivity analyses revealed that the negative association was driven primarily by a gain-of-function mutation in the ABCG8 gene which reduces serum cholesterol whilst simultaneously increasing biliary cholesterol saturation. Removing ABCG8 or adjusting for serum lipids both had the same effect of demonstrating no change in CVD risk in multivariable MR. These findings demonstrate a strong association between gallstones and other cardiometabolic disease outcomes that is not explained by established environmental risk factors or by shared genetic heritability. The additional risk may be explained by other, unknown or harder to measure environmental risk factors. This suggests that gallstones may act as a useful forewarning of cardiometabolic disease independent of established risk factors. Individuals with gallstones, and surgeons managing them, should be aware of their role as a sentinel presentation of cardiometabolic disease.