Obesity and metabolic syndrome are recognized risk factors for development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC). Dysregulation of adipokines, particularly the decreased secretion of adiponectin, appears to play a key role. To investigate the association between adiponectin and hepatocarcinogenesis, we conducted a large-scale retrospective cohort study. We enrolled 325 patients with CHC (146 men, 179 women; mean age 58.0 ± 10.3 years) whose serum samples were collected between January 1994 and December 2002. Subjects were divided into two groups according to their serum adiponectin levels. We evaluated the association between adiponectin level and the risk of subsequent HCC development using univariate and multivariate Cox proportional hazard regression. Because average serum adiponectin level was higher in females than males, each gender was analyzed separately. Patients with CHC had significantly higher adiponectin levels than healthy controls. During the follow-up period (mean: 9.0 years), HCC developed in 122 subjects. Unexpectedly, subjects with higher serum adiponectin levels had a higher incidence of HCC (males: p = 0.032; females: p = 0.01; log-rank test). Multivariate analysis revealed that a high serum adiponectin level was independently associated with HCC development (hazard ratio [HR] = 2.07; p = 0.031 in females and HR = 1.82; p = 0.05 in males). Isoform analysis revealed that middle- and low-molecular-weight isoforms contributed to the risk of HCC. In conclusion, Patients who had CHC with high serum adiponectin levels had a higher risk of liver cancer development. Adiponectin may thus be tumorigenic or indicate a liver disease state independently of other clinical parameters.
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