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Host Immune Status and Incidence of Hepatocellular Carcinoma among Subjects Infected with Hepatitis C Virus: A Nested Case-Control Study in Japan

Departments of ¹ Epidemiology, ² Immunology and Infectious Diseases, and ³ Biostatistics, Harvard School of Public Health; ⁴ Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts; ⁵ Department of Internal Medicine II, University of Miyazaki Faculty of Medicine, Miyazaki, Japan; and ⁶ Digestive Disease and Life-style related Disease Health Research Human and Environmental Science, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, Japan

Requests for reprints: Robert Y. Suruki, GlaxoSmithKline, P. O. Box 13398, Five Moore Drive, Research Triangle Park, NC 27709. Phone: 919-483-7620; Fax: 919-315-8747. E-mail: suruki{at}post.harvard.edu

A nested case-control study was conducted to examine the association between host immune status, as characterized by serum immune marker levels, and the development of hepatocellular carcinoma (HCC) up to 8 years later in persons with chronic hepatitis C virus (HCV) infection. Cases (n = 39) and matched controls (n = 117) were selected from participants of the Town C HCV Study in Japan between 1996 and 2004 and matched on age at first available sample (±1 year), gender, and length of follow-up. Separate analyses were done for each of three serum immune markers: soluble tumor necrosis factor-receptor II (sTNF-R2) and soluble intercellular adhesion molecule-1 (sICAM-1), as indicators of type 1, cell-mediated immune response, and soluble CD30 (sCD30), as an indicator of type 2, humoral immune response. The median concentrations of sTNF-R2, sICAM-1, and sCD30 among controls were 3,170 pg/mL, 305 ng/mL, and 3.0 units/mL, respectively, and were higher among cases (3,870 pg/mL, 372 ng/mL, and 3.3 units/mL, respectively). The risk of developing HCC among subjects with immune marker concentrations above the median levels of the controls was >2-fold greater than among subjects with lower concentrations for all three markers [sTNF-R2: odds ratio (OR), 6.9; 95% confidence interval (95% CI), 2.4-20.5; sICAM-1: OR, 2.0; 95% CI, 0.9-4.1; and sCD30: OR, 2.1; 95% CI, 1.0-4.7]. Simultaneous adjustment for all three markers revealed only sTNF-R2 to be associated with HCC risk (OR, 6.4; 95% CI, 2.0-20.6). Adjustment for alcohol consumption and HCV serotype did not materially alter these associations. Results from this prospective, community-based study suggest that a dysregulation in both type 1–related and type 2–related host immunity contributes to the development of HCV-associated HCC. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2521–5)