Hepatocellular carcinoma: Possible etiologies in patients without serologic evidence of hepatitis B virus infection

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Abstract
Although hepatitis B virus (HBV) has been closely associated with the development of hepatocellular carcinoma (HCC), no serologic markers of HBV can be found in up to 11% of HCC patients in developing countries and up to 68% of HCC patients in industrialized countries. Despite the absence of HBV serologic markers in these HCC patients, HBV DNA sequences have been found to be integrated into HCC DNA in 13–100% of these patients, indicating a possible role of HBV in the etiology of their HCC. Although six patients with chronic non‐A, non‐B hepatitis virus infection who were followed have been documented to develop HCC, it is not known whether the non‐A, non‐B hepatitis viruses cause or contribute to the development of HCC in some HCC patients without HBV serologic markers. Ethanol, cigarette smoking, oral contraceptives, and aflatoxin also have been suggested as possible etiologies and should be studied further. Suggested etiologies that are not supported by the published data include alpha‐1‐antitrypsin deficiency and schistosomiasis.