What are the risk factors for gallbladder cancer?

Risk Factors for Gallbladder Cancer

Gallstones represent the strongest and most well-established risk factor for gallbladder cancer, with a pooled relative risk of 4.9, and the risk correlates directly with stone size. 1

Major Established Risk Factors

Gallstone Disease

• Cholelithiasis is the primary risk factor, present in the majority of gallbladder cancer cases and associated with chronic inflammation that drives carcinogenesis through persistent immune activation and oxidative stress 2, 3
• Larger gallstones confer greater risk than smaller stones, suggesting a dose-response relationship 4, 3
• The mechanism involves chronic inflammation leading to metaplastic changes in the gallbladder epithelium, which may progress to dysplasia and carcinoma 3
• However, coexisting gallstones should not influence risk stratification of gallbladder polyps specifically, given their ubiquity 5

Gallbladder Polyps

• Polyps >1 cm in size that are solitary, sessile, and echopenic carry the highest malignancy risk 4, 3
• These characteristics warrant close ultrasonic follow-up or cholecystectomy depending on clinical context 4

Biliary Tract Abnormalities

• Anomalous pancreaticobiliary duct junction (AJPBD), especially without choledochal cyst, significantly increases gallbladder cancer risk 4, 3
• Over 90% of patients with choledochal cysts have AJPBD, with cholangiocarcinoma incidence of 7.0% and gallbladder cancer incidence of 13.4% in these cases 6
• Chronic reflux of pancreatic juice causes intestinal metaplasia, hyperplasia, and dysplasia with p53 and K-ras mutations 3
• Choledochal cysts (particularly Types I and IV) require complete excision with Roux-en-Y hepaticojejunostomy to prevent malignant transformation 6

Porcelain Gallbladder

• Porcelain gallbladder is an established risk factor warranting prophylactic cholecystectomy in operative candidates 4
• The causal relationship, while recognized, remains incompletely understood mechanistically 3

Primary Sclerosing Cholangitis (PSC)

• PSC is associated with gallbladder polyps and gallbladder cancer secondary to biliary epithelium field defects 5
• Gallbladder lesions in PSC patients show 18-50% association with gallbladder cancer and 25-35% with premalignant lesions, though surgical referral bias may affect these figures 5
• Standard gallbladder polyp guidelines should NOT be applied to PSC patients; specialty gastroenterology guidelines should be consulted instead 5

Demographic and Metabolic Risk Factors

Sex and Age

• Gallbladder cancer occurs 2-6 times more frequently in women than men 5
• Choledochal cysts occur 3-8 times more frequently in females 6
• Risk increases with age, with 65% of patients over 65 years old 5
• However, advancing age alone should not alter management of gallbladder polyps due to lack of evidence and increased surgical risks in elderly patients 5

Obesity and Metabolic Factors

• Obesity increases gallbladder cancer risk with a relative risk of 1.31, with premenopausal women showing the greatest obesity-associated risk 5
• Diabetes mellitus confers a relative risk of 1.97 5
• High body mass index, high total energy intake, and high carbohydrate intake are associated with increased risk 7
• These factors likely operate through increased gallstone formation 7

Infectious Risk Factors

Chronic Bacterial Infections

• Chronic Salmonella typhi and S. paratyphi infections carry a pooled relative risk of 4.8 for gallbladder cancer 1
• Chronic typhoid carriers have a sixfold increased risk of all hepatobiliary malignancy 5
• Helicobacter bilis and H. pylori infections confer a pooled relative risk of 4.3 1
• Chronic bacterial infections of the gallbladder contribute to the inflammatory milieu driving carcinogenesis 4

Parasitic Infections

• Liver fluke infections (Opisthorchis viverrini and Clonorchis sinensis) are recognized risk factors, particularly in Southeast Asia 5

Lifestyle and Environmental Factors

Tobacco and Alcohol

• Smoking increases gallbladder cancer risk with a relative risk of 1.25 5
• Smoking shows increased risk particularly in association with PSC 5
• Alcohol consumption is a potential risk factor requiring further study 5

Occupational and Environmental Exposures

• Certain occupational and environmental carcinogens have been associated with gallbladder cancer, though specific agents require further characterization 4

Geographic and Genetic Factors

High-Risk Populations

• Highest incidence rates worldwide occur in Delhi, India (21.5/100,000 women), South Karachi, Pakistan (13.8/100,000), and Quito, Ecuador (12.9/100,000) 1
• High incidence is also found in Korea, Japan, and central/eastern European countries 1
• Native Americans and Chileans show extremely high prevalence 4
• Geographic and genetic factors may increase polyp risk stratification to the low-risk category when known 5

Genetic Susceptibility

• Familial risk of gallbladder cancer is largely mediated through family history of gallstones in Chinese populations 5
• Maternal transmission patterns have been suggested 5

Additional Considerations

Multiparity

• Multiple pregnancies show consistent association with increased gallbladder cancer risk 1
• Hormonal changes in women are recognized as contributing factors 4

Chronic Diarrhea

• Chronic diarrhea is associated with increased gallbladder cancer risk, likely through mechanisms related to gallstone disease 7

Clinical Implications

The presence of gallbladder symptoms requiring medical attention (such as biliary obstruction) represents a major risk factor with an odds ratio of 4.4, and this association persists even when symptoms first appeared more than 20 years prior (OR 6.2). 7 This underscores the importance of long-term inflammatory processes in gallbladder carcinogenesis and supports consideration of prophylactic cholecystectomy in high-risk populations with symptomatic gallstone disease, porcelain gallbladder, or AJPBD, provided patients are suitable operative candidates 4.