Multivariate analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis
Liver, Pancreas, and Biliary Tract
Received: 13 July 1995 Accepted: 26 January 1996 DOI:
10.1007/BF02355056 Cite this article as: Chiba, T., Matsuzaki, Y., Abei, M. et al. J Gastroenterol (1996) 31: 552. doi:10.1007/BF02355056 Abstract
To elucidate the risk factors for hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-related liver cirrhosis (LC), we examined 204 cirrhotic patients negative for hepatitis B surface antigen and positive for HCV antibodies. The independent influence of various clinical characteristics in these patients was analyzed by multiple logistic regression, and the risk factors for HCC were identified. Multiple logistic regression analysis identified and ranked the following four risk factors: male sex (
P<0.001), habitual heavy drinking ( P<0.005), hepatitis B virus antibody positivity (anti-HBs and/or anti-HBc, P<0.05), and age greater than 60 years ( P<0.05). The odds ratio of HCC was 4.20 (95% confidence interval; CI, 1.80–9.78) in male patients, 3.27 (95% CI, 1.46–7.30) in habitual heavy drinkers, 2.01 (95% CI, 1.01–3.99) in patients positive for hepatitis B virus antibodies, and 2.06 (95% CI, 1.00–4.23) in patients older than 60 years. The cumulative occurrence rates of HCC after blood transfusion were significantly higher in habitual heavy drinkers (4.8%, 49.4%, and 74.7% at 10, 20, and 30 years, respectively) than in non-drinkers (0%, 21.0%, and 23.3% at 10, 20, and 30 years, respectively, P<0.0003). The mean interval for progression to LC after blood transfusion was significantly shorter in the habitual heavy drinkers than in the non-drinkers (22.4±4.4 years vs 28.4±3.9 years; P<0.0003). This multivariate analysis revealed that habitual heavy drinking and hepatitis B virus antibody positivity are significant risk factors for HCC in HCV-related liver cirrhosis. Key words hepatocellular carcinoma hepatitis C virus hepatitis B virus alcohol drinking
This work was presented in preliminary form at the annual meeting of the American Association for Study of Liver Diseases, New Orleans, May 16, 1994 and published as an abstract in
Gastroenterology 14: A875, 1994. References
Parkin DM, Stjernsward J, Muir CS. Estimates of the worldwide frequency of 12 major cancers. Bull WHO 1984;62:162–182.
Linsell DA, Hibbinson J. The geographic pathology of liver cell cancer. In: Cameron HM, Linsell DA, Warwick GP (eds). Liver cell cancer. New York: Elsevier, 1976;1–16.
Beasley RP. Hepatitis B virus as the etiologic agent in hepatocellular carcinoma: Epidemiologic considerations. Hepatology 1982; 2(Suppl):21–26.
Kew M, Popper H. Relationship between hepatocellular carcinoma and cirrhosis. Semin Liver Dis 1984;4:136–146.
Beasley RP, Hwang LY. Hepatocellular carcinoma and hepatitis B virus. Semin Liver Dis 1984;4:113–121.
Sakuma K, Saitoh N, Kasai M, et al. Relative risks of death due to liver disease among Japanese male adults having various statuses for hepatitis B s and e antigen/antibody in serum: A prospective study. Hepatology 1988;8:1642–1646.
Bruix J, Calvet X, Costa J, et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989;II:1004–1006.
Columbo M, Kuo G, Choo QL, et al. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989;II:1004–1006.
Yu MC, Tong AJ, Cousaget P, et al. Prevalence of hepatitis B and C viral markers in black and white patients with hepatocellular carcinoma in the United States. J Natl Cancer Inst 1990;82:1038–1041.
Kiyosawa K, Sodeyama T, Tanaka E, et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: Analysis by detection of antibody to hepatitis C virus. Hepatology 1990;12:671–675.
Nishioka K, Watanabe J, Furuta, S, et al. A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan. Cancer 1991;67:429–433.
Tanaka K, Hirohata T, Koga S, et al. Hepatitis C and hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population. Cancer Res 1991;51:2842–2847.
Resnick RH, Koff R. Hepatitis C-related hepatocellular carcinoma: Prevalence and significance. Arch Int Med 1993;153:1672–1677.
Liver Cancer Study Group of Japan. Survey and follow-up study of primary liver cancer in Japan: Report 8 (in Japanese). Acta Hepatol Jap 1988;29:1619–1626.
Kalayci C, Johnson PJ, Davies SE, et al. Hepatitis B virus-related hepatocellular carcinoma in the non-cirrhotic liver. J Hepatol 1991;12:54–59.
Tanaka T, Miyamoto H, Hino O, et al. Primary hepatocellular carcinoma with hepatitis B virus-DNA integration in a 4-year-old boy. Hum Pathol 1986;17:202–204.
Chang MH, Chen PJ, Chen JY, et al. Hepatitis B virus integration in hepatitis B virus-related hepatocellular carcinoma in childhood. Hepatology 1991;13:316–320.
Ducreux M, Buffer C, Dussaix, et al. Antibody to hepatitis C virus in hepatocellular carcinoma. Lancet 1990;I:300–301.
Chiaramonte M, Farinati F, Faginoli S, et al. Antibody to hepatitis C virus in hepatocellular carcinoma. Lancet 1990;I:301–302.
Ikeda K, Saitoh S, Koida I, et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis: A prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993;18:47–53.
Cox DR. Regression models and life tables. J R Stat Soc 1972; 34:248–275.
Kaplan EL, Meier P. Nonparametric estimation for incomplete observation. J Am Stat Assoc 1958;53:457–481.
Simonetti RG, Camma C, Fiorello F, et al. Hepatocellular carcinoma: A worldwide problem and the major risk factors. Dig Dis Sci 1991;36:962–972.
Benvegnù, L, Fattovich G, Noventa F, et al. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. Cancer 1994;74:2442–2448.
Tanaka N, Chiba T, Matsuzaki Y, et al. High prevalence of Hepatitis B and C viral markers in Japanese patients with hepatocellular carcinoma. Gastroenterol Jpn 1993;28:547–553.
Galloway DA, McDougall JR. The oncogenic potential of
viruses: evidence for a “hit and run” mechanism. Nature 1983;302:21–24.
Paterlini P, Gerken G, Nakajima E, et al. Polymerase chain reaction to detect hepatitis B virus DNA and RNA sequences in primary liver cancers from patients negative for hepatitis B surface antigen. N Engl J Med 1990;323:80–85.
Kaneko S, Miller RH, Feinstone SM, et al. Detection of serum hepatitis B virus DNA in patients with chronic hepatitis using the polymerase chain reaction assay. Proc Natl Acad Sci USA 1989; 86:312–316.
Liang TJ, Baruch Y, Ben-Porath E, et al. Hepatitis B virus infection in patients with idiopathic liver disease. Hepatology 1991; 13:1044–1051.
Luo KX, Zhou R, He C, et al. Hepatitis B virus DNA in sera of virus carriers positive exclusively for antibodies to the hepatitis B core antigen. J Med Virol 1991;35:55–59.
Sheu JC, Huang GT, Shih LN, et al. Hepatitis C and B virus in hepatitis B surface antigen-negative hepatocellular carcinoma. Gastroenterology 1992;103:1322–1327.
Ruiz J, Sangro B, Cuende JI, et al. Hepatitis B and C viral infections in patients with hepatocellular carcinoma. Hepatology 1992;16:637–641.
Paterlini P, Driss F, Nalpas B, et al. Persistence of hepatitis B and hepatitis C viral genomes in primary liver cancers from HBsAg-negative patients: A study of a low-endemic area. Hepatology 1993;17:20–29.
Zhang YY, Hansson BG, Kuo LS, et al. Hepatitis B virus DNA in serum and liver is commonly found in Chinese patients with chronic liver disease despite the presence of antibodies to HBsAg. Hepatology 1993;17:538–544.
Nishioka K, Watanabe J, Furuta S, et al. Antibody to the hepatitis C virus in acute hepatitis and chronic liver diseases in Japan. Liver 1991;11:65–70.
Pares A, Barrera JM, Caballeria J, et al. Hepatitis C virus antibodies in chronic alcoholic patients: Association with severity of liver injury. Hepatology 1990;12:1295–1299.
Nalpas B, Driss F, Pol S, et al. Association between HCV and HBV infection in hepatocellular carcinoma and alcoholic liver disease. J Hepatol 1991;12:70–74.
Yamauchi M, Nakahara M, Maezawa Y, et al. Prevalence of hepatocellular carcinoma in patients with alcoholic cirrhosis and prior exposure to hepatitis C. Am J Gastroenterol 1993;88:39–43.
Takase S, Tsutsumi M, Kawahara H, et al. Alcohol-altered liver membrane antibody and hepatitis C virus infection in the progression of alcoholic liver disease. Hepatology 1993;17:9–13.
Takada A, Nei J, Takase S, et al. Effect of ethanol on experimental hepatocarcinogenesis. Hepatology 1986;6:65–72.
Schwarz M, Buchmann A, Wiesbeck G, et al. Effect of ethanol on early stages in nitrosamine carcinogenesis in rat liver. Cancer Lett 1983;20:305–312.
Paglialo L, Simonetti RG, Craxi A, et al. Alcohol and HBV infection as risk factors for hepatocellular carcinoma in Italy: A multicentric, controlled study. Hepato-Gastroenterol 1983;30:48–50.
Villa E, Baldini GM, Pasquinelli C, et al. Risk factors for hepatocellular carcinoma in Italy. Male sex, hepatitis B virus, non-A, non-B infection, and alcohol. Cancer 1988;62:611–615.
Ohnishi K, Iida S, Iwana S, et al. The effect of chronic alcohol intake on the development of liver cirrhosis and hepatocellular carcinoma: Relation to hepatitis B surface antigen carriage. Cancer 1982;49:672–677.