title: The role of cirrhosis in the etiology of hepatocellular carcinoma.
abstract: Abundant evidence supports the belief of a causal relationship between cirrhosis and hepatocellular carcinoma, but one that differs between high- and low-incidence regions of the tumor. In high-incidence regions, the cirrhosis is of the macronodular variety, is typically asymptomatic, and is caused predominantly by chronic hepatitis B virus infection, whereas in low-incidence regions, the cirrhosis, although usually macronodular, may be micronodular, is commonly symptomatic and of long-standing, and is caused by chronic hepatitis C virus infection, alcohol abuse over many years, the metabolic syndrome, or hereditary hemochromatosis. In a minority of patients, hepatocellular carcinoma develops in the absence of cirrhosis, supporting a direct hepatocarcinogenic effect of some of the causal agents. Cirrhosis is the major risk factor for tumor formation in patients with chronic hepatitis C virus infection. This virus does not integrate into cellular DNA, and malignant transformation results from increased liver cell turnover induced by recurring injury and regeneration of cells in the context of persisting inflammation, oxidative DNA damage, fibrosis, cirrhosis, and changes induced by the virus at a DNA level that have yet to be fully defined. Hepatitis B virus causes malignant transformation by both direct and indirect routes. The direct route results, in part, from integration of the viral DNA into host cellular DNA; transcriptional activation of host growth regulatory genes by hepatitis B virus-encoded proteins; and effects on apoptosis, cell signaling, and DNA repair. The direct route may share some similarities with that of hepatitis C virus infection. The metabolic syndrome may cause malignant transformation by production of oxidative stress and the induction of a variety of mutations, including some in the p53 gene.
authors.affiliation: Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa, Michael.Kew@uct.ac.za.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kew
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications*; D008113:Liver Neoplasms / Q000209:etiology*; D012307:Risk Factors