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Gallstone disease is an important risk factor for the development of gallbladder cancer; however, not all individuals with gallstones will develop gallbladder cancer.

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Fig. 12. NCI mortality data for White women between 1970 and 1994 in the United States. (From National Cancer Institute. Available at: http://www.cancer.gov/.)

Moreover, having a history of benign gallbladder diseases increases the risk for developing gallbladder cancer, although some studies do not support this statement (Table 1). Most case-control studies strongly suggest a relationship, whereas cohort studies also support a link but with less strength.

A family history of gallbladder disease also increases the risk for developing gallbladder cancer, with case-control and cohort studies supporting this hypothesis. Studies have also shown that individuals who develop gallstones are four times (95% CI, 1.5-11) more likely to develop gallbladder cancer at a younger age. These patients are likely to present with gallbladder cancer an average of 6 years earlier than those with no gallstones.12

Obesity

Clearly, increasing body mass index (BMI), particularly in the overweight (BMI, 25.029.9) and obese (BMI, >30) range, increases risk for developing gallstones.3 Studies

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Fig. 13. NCI mortality data for African American men between 1970 and 1994 in the United States. (From National Cancer Institute. Available at: http://www.cancer.gov/.)

assessing increasing BMI as a risk factor for gallbladder cancer have reported conflicting findings (Table 2). A recent meta-analysis focusing on the potential relationship between excess body weight and risk for gallbladder cancer13 included three case-control and eight cohort studies in the final random-effects analysis, which had a total of 3288 cases of gallbladder cancer. No heterogeneity was reported among the studies. Compared with normal-weight subjects, individuals who were overweight or obese had a relative risk (RR) for developing gallbladder cancer of 1.15 (95% CI, 1.01-1.30) or 1.66 (95% CI, 1.47-1.88), respectively. Moreover, obese women (RR, 1.88; 95% CI, 1.66-2.13) were at greater risk than obese men (RR, 1.35; 95% CI, 1.09-1.68). In the United States, correlations between increasing rates of gallbladder disease and obesity have been made among Hispanics, who are more likely to be obese or overweight than non-Hispanic whites.14 This finding suggests that the effect of obesity may be mediated by other factors, such as ethnicity. Further research is needed to elucidate the mechanisms responsible.

Cancer mortality rates by state (age-ad jiated 1970 US population) Gallbladder: black females, 1970 to 19M, all aflea

Cancer mortality rates by state (age-ad jiated 1970 US population) Gallbladder: black females, 1970 to 19M, all aflea

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Fig. 14. NCI mortality data for African American women between 1970 and 1994 in the United States. (From National Cancer Institute. Available at: http://www.cancer.gov/.)

Reproductive Factors

Studies linking reproductive factors, such as increased parity and gravidity, to gallbladder cancer have provided conflicting results (Table 3). Previous research suggests an association between these reproductive factors and the development of gallstones. Other factors, such as oral contraceptives, have not been shown to increase the risk for gallbladder cancer. Furthermore, conflicting studies provide no clear picture of the potential link between menopause and hormone replacement therapy in relation to gallbladder cancer.

A prospective case-control study from India assessed lifestyle and reproductive factors in 78 incident cases of gallbladder cancer and 78 age- and gender-matched controls with gallstones.14 Almost two thirds of the cases and controls were women (68%), and the mean ages were 50 years for cases and 43 years for controls. Tobacco use (odds ratio [OR], 2.71; 95% CI, 1.22-6.02) and chewing tobacco (OR, 2.50; 95%

Mortality rate

Confidence interval

No. of deaths

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