Naugler et al. found that estrogen-mediated inhibition of interleukin-6 production by Kupffer cells reduced the risk of liver cancer in females (36). Heavy consumption of alcohol is a well-known risk factor for liver cancer. Donato et al. found a positive linear relation between the risk of hepatocellular carcinoma (HCC) and alcohol intake, although these was no substantial relative risk differences between men and women (37). Further, risk of liver cancer is thought to be affected by synergistic interactions between HBV or HCV infection and alcohol (38). A systematic review of epidemiological

evidence #BEZ235 keyword# concluded that HBV infection, HCV infection and alcohol intake are major causes of HCC worldwide, and the three main risk factors together account for approximately 85% of the total HCC cases (39). Boffetta Inhibitors,research,lifescience,medical et al. found that DNA damage occurred after heavy alcohol consumption, and alcohol-associated liver cirrhosis was the most important risk factor for HCC in populations with low prevalence of infection from HBV and HCV, such as in the United States Inhibitors,research,lifescience,medical and northern Europe (40). Heavy alcohol consumption may cause DNA damage by reducing intake of nutrition; this could also explain the synergistic effect of alcohol and HBV and HCV infections (41). In addition,

other studies also reported a strong association

between obesity and liver cancer, although the mechanisms for this association remain unknown (42),(43). The metabolic abnormalities related to excess weight include high plasma triglyceride, glucose and insulin Inhibitors,research,lifescience,medical levels, as well as insulin resistance. Period effect identified by our age-period-cohort regression, though Inhibitors,research,lifescience,medical statistically significant only in women, is very likely due to an overall improvement in the quality of cancer registration data that took place in the 1970s and early 1980s in most Canadian provinces/territories, especially Quebec (21),(44). Changes to cancer diagnostic criteria and registration either methodology over that period were already documented by the Canadian Cancer Registry; however, its impact on the cancer trends was too small to be quantified by earlier studies (11),(44). In addition, the slight decrease in relative risks in the two most recent birth cohorts (Table 4) may indirectly indicate a likelihood that risks for liver cancer attributable to exposure to the risk factors identified above have yet to appear in younger generations. In summary, substantial increases in incidence and mortality from liver cancer have occurred over the last 3 decades, with increases in rates among men over twice that for women.