Risk factors associated with hepatocellular carcinoma (HCC) are well documented, but the synergisms between these risk factors are not well examined. We conducted a hospital-based, case-control study among 115 HCC patients and 230 non-liver cancer controls. Cases and controls were pathologically diagnosed at The University of Texas M. D. Anderson Cancer Center and were matched by 5-year age groups, sex, and year of diagnosis. Information on risk factors was collected by personal interview and medical records review. Blood samples were tested for the presence of antibodies to hepatitis C virus antigen (anti-HCV), hepatitis B surface antigen (HBsAg), and antibodies to hepatitis B core antigen (anti-HBc). Conditional logistic regression was used to determine odds ratios (ORs) by the maximum likelihood method. Multivariate ORs and 95% confidence intervals (CIs) were 15.3 (4.3-54.4), 12.6 (2.5-63.1), 4.5 (1.4-14.8), and 4.3 (1.9-9.9) for anti-HCV, HBsAg, heavy alcohol consumption (≥80 mL ethanol/d), and diabetes mellitus, respectively. Synergistic interactions on the additive model were observed between heavy alcohol consumption and chronic hepatitis virus infection (OR, 53.9; 95% CI, 7.0-415.7) and diabetes mellitus (OR, 9.9; 95% CI, 2.5-39.3). Independent of the effect of HCV, HBV, and diabetes mellitus, heavy alcohol consumption contributes to the majority of HCC cases (32%), whereas 22%, 16%, and 20% were explained by HCV, HBV, and diabetes mellitus, respectively. In conclusion, the significant synergy between heavy alcohol consumption, hepatitis virus infection, and diabetes mellitus may suggest a common pathway for hepatocarcinogenesis. Exploring the underlying mechanisms for such synergisms may indicate new HCC prevention strategies in high-risk individuals.

BACKGROUND: Despite the observed association between diabetes mellitus and hepatocellular carcinoma (HCC), little is known about the effect of diabetes duration before HCC diagnosis and whether some diabetes medications reduced the risk of HCC development. This objective of the current study was to determine the association between HCC risk and diabetes duration and type of diabetes treatment.METHODS: A total of 420 patients with HCC and 1104 healthy controls were enrolled in an ongoing hospital‐based case‐control study. Multivariate logistic regression models were used to adjust for HCC risk factors.RESULTS: The prevalence of diabetes mellitus was 33.3% in patients with HCC and 10.4% in the control group, yielding an adjusted odds ratio (AOR) of 4.2 (95% confidence interval [95% CI], 3.0‐5.9). In 87% of cases, diabetes was present before the diagnosis of HCC, yielding an AOR of 4.4 (95% CI, 3.0‐6.3). Compared with patients with a diabetes duration of 2 to 5 years, the estimated AORs for those with a diabetes duration of 6 to 10 years and those with a diabetes duration >10 years were 1.8 (95% CI, 0.8‐4.1) and 2.2 (95% CI, 1.2‐4.8), respectively. With respect to diabetes treatment, the AORs were 0.3 (95% CI, 0.2‐0.6), 0.3 (95% CI, 0.1‐0.7), 7.1 (95% CI, 2.9‐16.9), 1.9 (95% CI, 0.8‐4.6), and 7.8 (95% CI, 1.5‐40.0) for those treated with biguanides, thiazolidinediones, sulfonylureas, insulin, and dietary control, respectively.CONCLUSIONS: Diabetes appears to increase the risk of HCC, and such risk is correlated with a long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin were found to confer the highest magnitude of HCC risk, whereas treatment with biguanides or thiazolidinediones was associated with a 70% HCC risk reduction among diabetics. Cancer 2010. © 2010 American Cancer Society.

Carcinoids are rare neuroendocrine tumors (NETs); however, their incidence has significantly increased in the United States over the past 30 years. Little is known about the epidemiology of these cancers and their associated risk factors. We evaluated the independent effects of multiple risk factors associated with NETs arising at 5 disease sites (small intestine, stomach, lung, pancreas and rectum). We conducted a retrospective, hospital‐based, case–control study involving 740 patients with histologically confirmed NETs and 924 healthy controls. Information on different risk factors was collected, and unconditional logistic regression analysis was used to determine adjusted odds ratios (AORs) and 95% confidence interval (CI) by the maximum‐likelihood method. Smoking and alcohol consumption were not associated with NETs development in either men or women. However, a family history of cancer was a significant risk factor for all NETs. A long‐term history of diabetes mellitus was a significant risk factor for gastric NETs (AOR = 5.6; 95% CI, 2.1–14.5), particularly in women (AOR = 8.4; 95% CI, 1.9–38.1). Diabetes modified the risk among women with a positive family history of cancer for the development of gastric NETs (AOR = 52.2; 95% CI, 5.5–491.5). Our results suggest that the risk of NETs may mostly explained by genetic factors. The increased risk of gastric NETs in women with both diabetes and a positive family history of cancer suggest that women may have a greater genetic susceptibility to NETs than men.

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3-6.3). Restricted analyses among hepatitis virus–negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7-32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3-153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6-5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC. (Hepatology 2009;49:1563–1570.)