Gallbladder cancer has no single cause, but nearly all of its known risk factors share a common thread: chronic inflammation in the gallbladder. Long-lasting irritation damages cells over time, increasing the chance that DNA errors accumulate and a tumor develops. Gallstones are the most common driver of that inflammation, but infections, anatomical abnormalities, and certain medical conditions also play a role.
Gallstones and Chronic Inflammation
Up to 4 out of 5 people diagnosed with gallbladder cancer have gallstones at the time of diagnosis. Gallstones are hardened collections of cholesterol and other substances that sit inside the gallbladder, repeatedly irritating its lining. Over years or decades, this chronic inflammation can push cells through a progression from normal tissue to precancerous changes to cancer.
That said, gallstones are extremely common, and the vast majority of people who have them will never develop gallbladder cancer. The risk is higher with larger stones (generally over 3 centimeters) and with stones that have been present for many years. The connection is not that gallstones directly turn into cancer, but that the ongoing damage they cause creates an environment where cancerous changes become more likely.
Gallbladder Polyps
Small growths on the inner wall of the gallbladder, called polyps, are usually harmless. But size matters. Polyps larger than about 10 millimeters in diameter are more likely to be cancerous or to become cancerous over time. Those larger than 18 millimeters pose a significant risk of already being malignant. Most polyps are found incidentally on imaging done for other reasons, and doctors typically recommend removal of the gallbladder when polyps reach that 10-millimeter threshold.
Porcelain Gallbladder
When calcium deposits build up in the gallbladder wall, the organ stiffens and becomes visible on X-ray, a condition sometimes called porcelain gallbladder. Older estimates dramatically overstated the cancer risk, but more recent studies put the true incidence of gallbladder cancer in people with a calcified gallbladder wall at around 6%. That’s still high enough that surgical removal is often recommended, especially if the calcification is patchy rather than smooth and continuous.
Chronic Infections
Certain bacterial infections that settle in the gallbladder can sustain inflammation for years, even without obvious symptoms. The best-studied link involves the bacterium that causes typhoid fever. People who become chronic carriers of this bacterium, harboring it in their gallbladder long after their initial illness resolves, face roughly four to five times the usual risk of gallbladder cancer. A meta-analysis combining multiple studies found a summary relative risk of about 5.0 for people with confirmed bacterial presence in bile or stool cultures. This connection helps explain why gallbladder cancer rates are higher in parts of South Asia, South America, and other regions where typhoid is endemic.
Anatomical Abnormalities
Some people are born with structural differences in the ducts that connect the gallbladder, liver, and pancreas. One such condition involves cysts in the bile duct system. In a large review covering nearly 5,800 patients with these cysts, about 11.4% of adults developed a biliary tract cancer, with gallbladder cancer accounting for roughly one in four of those malignancies. The risk increases with each decade of life, and the median age at cancer diagnosis in this group is 42, younger than the typical gallbladder cancer patient.
An abnormal junction between the pancreatic duct and the bile duct is another structural issue. When these two ducts meet in an unusual way, pancreatic digestive juices can flow backward into the gallbladder, causing chemical irritation that promotes cancerous changes over time.
Primary Sclerosing Cholangitis
This autoimmune condition causes progressive scarring and inflammation of the bile ducts and is associated with an increased risk of gallbladder cancer. The risk is particularly notable when gallbladder polyps are also present. In patients with both conditions, one study found a cancer rate of 8.8 per 1,000 person-years among those with a detectable gallbladder polyp, a rate high enough that doctors monitor these patients closely with regular imaging.
Obesity and Body Size
Carrying excess weight raises gallbladder cancer risk through multiple pathways. Fat tissue produces hormones and inflammatory signals that affect the gallbladder, and obesity also makes gallstones more likely. A pooled analysis of 19 large prospective studies found that for every 5-point increase in BMI, the risk of gallbladder cancer rose by 24%. This means someone with a BMI of 35 faces a meaningfully higher risk than someone at 25, independent of other factors. The relationship is dose-dependent: the more excess weight, the greater the risk.
Gender, Age, and Ethnicity
Women develop gallbladder cancer at more than twice the rate of men. In the United States in 2016, there were 2,923 cases in women compared to 1,254 in men. This disparity likely reflects the fact that women are more prone to gallstones, partly due to the effects of estrogen on cholesterol metabolism in the gallbladder. Hormonal factors including pregnancy and hormone replacement therapy may further contribute.
The disease is rare before age 45 and becomes increasingly common in each subsequent decade. Ethnicity also plays a role. Native American and Hispanic populations in the United States have notably higher rates, as do populations in Chile, India, Pakistan, and parts of Eastern Europe. These geographic and ethnic patterns reflect a combination of genetic susceptibility, dietary habits, infection prevalence, and gallstone frequency.
Genetic Mutations in Tumor Cells
At the cellular level, gallbladder cancer involves the same types of DNA damage seen in many other cancers. Two of the most commonly altered genes are TP53, which normally acts as a brake on cell growth, and KRAS, which controls cell division signals. In one study of gallbladder adenocarcinoma patients, mutations in TP53 were found in 44% of tumors and KRAS mutations in 48%. These aren’t inherited mutations you’re born with. They’re acquired changes that accumulate in gallbladder cells over time, driven by the chronic inflammation and irritation described above. The mutations disable the cell’s ability to repair itself or stop dividing, allowing a tumor to form.
A small number of gallbladder cancers do cluster in families, suggesting that inherited genetic factors can increase susceptibility. But no single “gallbladder cancer gene” has been identified the way BRCA genes have for breast cancer. Family history raises risk modestly, likely by influencing gallstone formation and inflammatory responses rather than directly causing cancer.