Hepatocellular Carcinoma

Jorge A Marrero


Curr Opin Gastroenterol. 2005;21(3):308-312. 

In This Article

Risk Factors

It has been recognized that the most important risk factor for the development of HCC is cirrhosis.[9] HCV and hepatitis B (HBV) are the major etiological agents that lead to the development of HCC.[10,11] Familial clustering of HCC has been related to perinatal transmission of HBV. A recent study examined the route of HBV transmission and the risk of HCC development.[12] From 1992-1997 the relatives of individuals of with HBV-related HCC were screened prospectively with annual ultrasonography and alpha-fetoprotein. A total of 13,676 relatives in Taiwan from two generations were followed and higher rates of HCC were found in the index population than in the child generation. Furthermore, children of female index patients had higher rates of liver cancer mortality than children of male sex index patients. The authors concluded that perinatal transmission and maternal viral load are important risk factors in HBV carcinogenesis. HBV carriers have been thought to have a low incidence of HCC and complications of chronic liver disease. An Italian study followed a cohort of 296 blood donors excluded from donation 30 years ago (157 HBV-negative blood donors at the time were controls) when HBV surface antigen screening became mandatory.[13] There was no difference in HCC as the cause of death for HBV carriers (2/296; 0.6%) and controls (1/157; 0.6%). The authors confirmed that HBV carriers have a low rate of development of HCC. To summarize, attention to perinatal transmission (related to mother's viral load) is important and should be a target for the prevention of HBV infection and its consequences. The virological aspects of chronic HBV infection are very important for determining the risk of HCC. It has previously been shown that the presence of viral replication (positive e antigen) increases the risk of HCC 62-fold.[14] An assessment of viral replication is important to determine the risk of HCC in HBV infected individuals.

Besides etiology of liver disease, environmental risk factors have been shown to be important in the development of HCC. An association between diabetes mellitus and HCC has been reported,[15] but the temporal relation remains unknown. A recent study followed a cohort of patients discharged from the Department of Veterans Affairs medical system of the U.S. up to 2000.[16] The study identified 173,643 patients with diabetes, and the incidence rate for HCC was 2.39 in diabetics compared with 0.87 in nondiabetic patients ( P < 0.0001), with a hazard rate ratio of 2.16 for the development of HCC. This is the first population-based study that assesses the risk of HCC based on the presence of diabetes but this study needs to be replicated in a different population. Alcohol and tobacco have been shown to be important risk factors for the development of HCC. Another recent study evaluated the interaction of alcohol, tobacco, diabetes and viral hepatitis in the causation of HCC.[17] The authors studied 295 individuals with HCC and 435 age-, gender- and race-matched controls from Los Angeles, California. They found that alcohol, tobacco, diabetes and viral hepatitis were independent risk factors for HCC. A synergistic interaction on HCC risk was observed between alcohol consumption and diabetes (OR = 4.2; 95% CI: 2.6-5.8), alcohol and viral hepatitis (OR = 5.5; 95% CI: 3.9-7), diabetes and viral hepatitis (OR = 4.8; 95% CI: 2.7-6.9) but no synergy with tobacco smoking. Another study from the U.S. showed that male gender, advanced age and non-Caucasian background were independent risk factors for HCC.[18] These studies indicate that viral hepatitis, environmental (alcohol and tobacco), demographic (older age), diabetes, and familial risk factors interact to increase the risk of HCC. This is important because if these studies are reproduced in prospective cohort studies, we may be able to stratify the risk of HCC among individuals with cirrhosis, thereby targeting screening to those high-risk individuals.


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