Hepatitis B and C
The two most important etiological factors contributing to hepatocelluar carcinoma are hepatitis B and hepatitis C (Figure 5). In parts of China and Taiwan, 80% of hepatocellular carcinoma is due to hepatitis B. In the United States and Europe, hepatitis C and hepatitis B contribute equally to disease cases. In Japan, where the prevalence of hepatitis B and hepatitis C is similar, the incidence of hepatocellular carcinoma is higher in patients with hepatitis C compared to hepatitis B (10.4% vs. 3.9%). The pathogenesis of hepatocellular carcinoma in the presence of hepatitis B virus may be due to increased cell turnover from chronic liver disease, or a combination of processes specific to the hepatitis B virus. These may include integration of the hepatitis B DNA genome into the host genome, thereby disrupting the regulatory elements of cell cycling, or via transactivation of host oncogenes by either HBx protein or a truncated protein derived from pre-S2/S region of hepatitis B genome. The pathogenesis of hepatocellular carcinoma in hepatitis C is less understood. It is possible that some of these patients had previous exposure to hepatitis B virus.
Cirrhosis
Cirrhosis, irrespective of its etiology , is a risk factor for the development of hepatocellular carcinoma. The risk is 3–4 times higher in patients with cirrhosis compared to those with chronic hepatitis in a given population. An increase in hepatocellular proliferation may lead to the activation of oncogenes and mutation of tumor suppressor genes. These changes, in turn, may initiate hepatocarcinogeneses . In low-incidence areas, more than 90% of patients with hepatocellular carcinoma have underlying cirrhosis. However, the presence of cirrhosis is less (approximately 80%) in high-incidence areas, which is probably related to vertical transmission of hepatitis B virus in these areas (Figure 5).
Other Factors
Other etiological factors affecting disease incidence include aflatoxins, alcohol, hemochromatosis , and anabolic steroid use (Figure 5). Exposure to dietary carcinogenic aflatoxins, produced by Aspergillus parasiticus and Aspergillus flavus, is common in certain regions of Southeast Asia and sub-Saharan Africa. Hepatitis B is also common in these areas. The relative contribution of aflatoxins and the hepatitis B virus to the pathogenesis of hepatocellular carcinoma in these parts of the world are poorly understood. In patients with hepatitis C viral infection, alcohol has been found to be another contributing factor. Whether this is related to a more aggressive disease due to a combination of hepatitis C virus and alcohol, or whether alcohol is an independent factor remains unknown. The incidence of hepatocellular carcinoma in patients with hemochromatosis can be as high as 45%, and often the tumor is multifocal.
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