The greatest increase in US cancer deaths from 1995–2004 was in those caused by cancers of the liver and bile duct, of which HCC comprised about 76%. This might be attributed to the increasing incidence of HCV-related HCC because rates for HBVrelated and alcohol-related HCC have remained stable during recent years. The incidence of HCV-related HCC in the United States is projected to peak in 2019 at 14,000 cases/year. In a large US database, the proportion of HCV-related cases of HCC among HCC patients aged =65 years doubled from 11% in 1993–1996 to 21% in 1996–1999. During the past decade, the fastest increase in HCC incidence has affected Hispanics and whites. In multivariate analysis HCV infection was an independent predictor for the development of HCC. Furthermore, maintenance therapy with peginterferon did not reduce the 5-year incidence of HCC in the HALT-C cohort.

Comparisons of US and Japanese HCV strains suggest that the US HCV epidemic began about 2 to 3 decades after that in Japan. This has led to speculation that the burden of HCC in the United States might eventually equal that currently seen in Japan as HCV-infected individuals age and their infection duration increases. In Japan, HCV-related HCC accounts for 80% of all HCC cases, and the rate of HCC among HCV-infected men has risen from 17.4/100,000 in 1972–1976 (32,335 deaths) to 27.4/100,000 in 1992–1996 (109,365 deaths).

A recent Italian study of 214 HCV-infected patients with Child–Pugh class A cirrhosis showed that HCC developed at a rate of almost 4%/year. HCC was the first complication to occur in 55 (27%) patients; after 17 years, HCC had developed in 68 (32%) patients. In another cohort of 416 patients with uncomplicated Child–Pugh class A HCV-related cirrhosis, the incidence of HCC was 13.4% at 5 years, and the 5-year HCC death rate was 15.3%, with the hazard rate of HCC tending to increase over time.

Several factors influence the risk of HCC in patients with HCV-related cirrhosis. Generally, HCC risk is increased in patients aged >50 years or those infected when aged >50 years, patients with longer duration of infection, men, overweight or diabetic patients, and patients with advanced cirrhosis or elevated alpha-fetoprotein. Other possible risk factors include the presence of steatosis, HCV genotype 1b, Asian/African American race, and occult HBV infection. As for hepatic fibrosis, an association between cigarette smoking and HCV-related HCC has been suggested in some studies but not others.

Chronic HCV-related inflammation might increase HCC risk by shifting hepatocytic transforming growth factor– beta signaling from tumor suppression to fibrogenesis. HCC generally develops after cirrhosis is established, signifying the likely importance of long-standing necrosis and regeneration, an environment of extensive scarring, in its pathogenesis. HCV might influence hepatocarcinogenesis through the oncogenic effects of its core protein, which might augment oxidative stress. It might also alter the signaling cascade of mitogen-activated protein kinase and activating factor 1, thereby activating cellcycle control. Liver angiogenesis and the neovascular response, plus genomic changes that deregulate components of the Jak/STAT pathway in early carcinogenesis, might also promote HCV-related hepatocarcinogenesis. Additional mechanisms have also been proposed.