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Symptomatic gallstones and cholecystectomy are common and costly health problems in and of themselves. But a potential link between gallstones (lithic deposits of digestive fluid in the gallbladder), cholecystectomy, and kidney cancer makes them even more concerning. The genetic and possibly causal links, however, have been uncertain, so a group led by Justo Lorenzo Bermejo, PhD, of the Institute of Medical Biometry at Heidelberg University in Germany, recently investigated these links in a large two-part analysis, which was recently published in .

Bermejo discussed the findings in the following interview with the Reading Room.

What were the clinical and epidemiological backgrounds to this analysis?

Bermejo: About 700,000 gallstones are surgically removed each year in the U.S., 200,000 in Germany, and 60,000 in Chile. The risk of cancer, especially kidney cancer, in people who have had cholecystectomy is controversial. So we decided to comprehensively investigate the risk, drawing on data from large prospective cohorts using the statistical genetic method of This method uses measured variation in genes of known function to strengthen the causal effect of a modifiable exposure on disease in observational studies.

What were the study's design and participating cohorts?

Bermejo: In the first part of our study, we compared the risk of kidney cancer in cholecystectomized and non-cholecystectomized individuals -- more than 16 million persons -- from nationwide Swedish registries. The large sample size allowed us to take into account the age at cholecystectomy and the time between cholecystectomy and kidney cancer diagnosis. We next examined the possible causal effect of gallstones on kidney cancer risk based on data from more than 400,000 participants in the U.K. Biobank.

Did your findings surprise you?

Bermejo: Yes. We found the risk of developing kidney cancer was strongly increased by 279% in the first 6 months after gallbladder surgery, which is quite impressive.

We also found that patients who had cholecystectomy before the age of 40 had a 55% increased risk of developing kidney cancer compared with their non-cholecystectomized peers. In addition, our results showed that the risk of kidney cancer increases by almost 10% for every doubling of gallstone prevalence.

What is the mechanism by which gallstones might promote kidney cancer?

Bermejo: We can only hypothesize about the mechanisms linking gallstones and kidney cancer. One possibility is that cholecystectomy for the treatment of symptomatic gallstones could lead to increased excretion of bile acids, and the associated increased urinary excretion of bile acids could in turn lead to oxidative stress and damage to the kidneys, eventually leading to kidney cancer.

Another possible explanation is that excess bile acids lead to increased synthesis of secondary bile acids, which in turn can alter Wnt/β-catenin signaling and promote cancer. The regulates a huge array of cellular functions, including proliferation, differentiation, renewal, and apoptosis.

Interestingly, our results also suggest that type 2 diabetes and smoking partially mediate the effect of gallstones on kidney cancer. Cigarette smoke, for example, releases harmful chemicals that spread to the kidneys, damaging DNA and making it harder for kidney cells to repair renal DNA.

What is your best clinical recommendation to gastroenterologists?

Bermejo: Probably the most important message of our study is the compelling need to screen for and diagnostically rule out kidney cancer before and during gallbladder removal. It would also be important to inform patients undergoing cholecystectomy in their 30s about their increased risk of kidney cancer 25 to 30 years after surgery.

What's the next research step?

Bermejo: Further research into the underlying mechanisms linking gallstones and cancer development, and into cancer prevention after cholecystectomy, is urgently needed.

You can read the abstract of the study here, and about the clinical implications of the study here.