The main finding of the present study was that the patients using statins did not have worse outcomes after cholecystectomy than the non-users, although the statin users were older, had polypharmacy and demonstrated more comorbidities than the non-users. Statin therapy was also associated with a shorter laparoscopic operation time. There was also a trend of other benefits from statin use for surgical outcomes, such as less bleeding. These findings are of clinical importance, as one would anticipate that statin users would have more post-surgical complications than non-users. A well-conducted prospective randomized study to show the possible benefits of statins in cholecystectomy is warranted.
The risk of developing symptoms or complications related to gallstones is approximately 1–4% per year [12, 13]. The known risk factors for gallstones are female gender, increasing age, obesity, metabolic syndrome, rapid weight loss and gallbladder stasis [14, 15]. The most important complications of the gallstone disease are biliary pancreatitis, cholecystitis and cholangitis. Festi et al. showed that during follow-up, approximately 80% of gallstones remain asymptomatic, 10% develop mild symptoms, and 10% develop severe symptoms leading to cholecystectomy . The development of the symptomatic gallstones is associated with obesity and alcohol use, likely because of their effects on serum lipids . It is presently unknown whether statin therapy would transform asymptomatic cholelithiasis to symptomatic.
The use of statins and other lipid-lowering drugs has been greatly increasing in Finland in recent years . This increase has occurred particularly among elderly patients with hypercholesterolemia . Prior to beginning our study, we anticipated that statin users would have less severe acute gallbladder inflammation, fewer stones in the common bile duct and more frequent laparoscopic cholecystectomy than non-users; this hypothesis proved wrong. Statins reduce the bile cholesterol content, which may theoretically reduce the risk of developing micro-gallstones or sludge. In the present study, the 1-year incidence of symptomatic cholelithiasis was approximately 0.22% among statin users and 0.14% among non-statin users (these calculations are based on reimbursement register data, data not shown).
Bodmer et al. performed a case control study using a UK-based database of approximately 5 million patients to investigate statins and the reduced risk of gallstone disease. In this large observational study, a lower incidence of cholecystectomy was noted in patients taking statins . In addition, Tsai et al. performed a large retrospective cohort study among 2479 American women who had histories of gallstones. The authors found that statin use was associated with a reduced risk of cholecystectomy . Smith et al. observed that simvastatin (20 mg/day) decreased plasma and biliary cholesterol levels by reducing cholesterol synthesis after 3 weeks of medication . A long-term study in prairie dogs found that lovastatin alters biliary lipid composition and dissolves gallstones . However, most human studies did not find that statin monotherapy would lead to the complete dissolution of gallstones . In accordance with this finding, the need of surgery of any type or the cholelithiasis outcomes did not differ between the statin and non-statin groups, which contrasted with some previous studies. In a Taiwanese study, the investigators did not find a beneficial association between statin use and gallstone disease . However, in East Asia, there is a lower prevalence of gallstones, and the stones primarily have a brown pigment, which indicates that they are comprised mainly of calcium .
Statins were not associated with a lower total serum bilirubin level in our study. In 2011, Ong et al. published a contrasting finding. They investigated whether statins in routine use increase the total bilirubin levels in subjects at high cardiovascular risk; but unexpectedly, the authors found that statin use was associated with lower total bilirubin levels. They suggested that this result could be explained, at least partially, by the effect of statins on glycemia and LDL cholesterol .
The clinical outcomes did not differ significantly between the study groups, except for the laparoscopic operation time. A shorter laparoscopic operation time was unexpected, as these patients more often have heart disease or hypertension. Conversely, the patients with cardiac disorders used more medications, thereby affecting the bleeding cascade, which would predispose them to bleeding complications. On average, more bleeding was observed among non-users compared with users during laparoscopic operations, but the difference remained statistically insignificant with a p value of 0.07. However, this finding is in line with the shorter operation time among statin users. Possible mechanisms behind these findings may include smaller size of cholesterol particles and gallstones. More research with larger sample sizes is warranted to confirm these findings. The two-year mortality rate (the study time mortality) was also similar among the statin users and non-users. Four patients died in the hospital. Longer observation time mortality was not studied in this study.
The mechanism by which statins might shorten the operation time or diminish bleeding remains unknown and requires further study. There were no differences in the perioperative procedures between the groups, and the same surgical team was in charge of their treatment. There is evidence that statins might have relevant anti-inflammatory effects independent of their lipid lowering ability .
The factors that contribute to supersaturating cholesterol in bile and to the formation of cholesterol gallstones are multifactor. Major sources of cholesterol for biliary secretion are the intestine, liver hepatocytes and circulating lipoproteins. Gallbladder hypomotility, destabilization of bile by kinetic protein factors, abnormal mucins and genetic factors also play roles in cholesterol gallstone disease . Many other factors are associated with cholesterol gallstones formation, such as dietary and life style factors and associated conditions (obesity, estrogen therapy, metabolic syndrome, etc.).
Our study had some limitations. Because this study was a retrospective analysis, we could not determine whether the gallstone formation developed before the statin medication was administered. Gallstone formation occurs over a long time period. Furthermore, we do not have accurate data on the patients’ adherence to statin use nor on the duration of the statin treatment in individual patients. Most gallstones are asymptomatic, and the patient does not require a cholecystectomy or hospital admission . In this study, all patients were hospitalized because they had gallstone-related symptoms or complications. We do not have data from the patients with asymptomatic gallstone disease.