Epidemiology of hepatocellular carcinoma in the United States: Where are we? Where do we go?

Abstract

The incidence of hepatocellular carcinoma (HCC) has almost tripled since the early 1980s in the United States, where it is the fastest rising cause of cancer-related deaths.1 According to population-based Surveillance Epidemiology and End Results registry data, the overall HCC age-adjusted incidence rates for liver and intrahepatic ducts cancer is as high as 8 per 100,000 underlying population in 2010 (Fig. 1) of which at least 6 per 100,000 are related to HCC. Men are at approximately three times higher risk than women. Asian men (i.e., Chinese, Korean, Filipino, and Japanese) have the highest age-adjusted incidence rates. However, the largest proportional increases have occurred among Hispanics followed by blacks and non-Hispanic whites, whereas the lowest proportional increases have occurred among Asians. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics.2 HCC incidence rates have increased in each successive birth cohort born between 1900 and 19593 (Fig. 2). In addition, the age distribution of HCC patients has shifted to younger ages, with the greatest proportional increases among individuals 45-60 years old (Fig. 2). There is a south to north gradient in the incidence and mortality of HCC; southern states, including Texas, Louisiana, and Mississippi, have some of the highest HCC incidence rates in the nation (Fig. 3). In one study, Texas Latinos and, especially, South Texas Latinos had the highest age-adjusted HCC incidence rates (as high as 10.6 per 100,000).4 Time trends (1975-2010) of population-based age-adjusted incidence and mortality rates for liver and intrahepatic bile ducts cancer in the United States. Both sexes and all races are included. State-specific population-based age-adjusted incidence rates for liver and intrahepatic bile ducts cancer. Both sexes and all races are included. Time-trends of HCC by age groups and birth cohorts in the United States. Source: Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27:1485-1491. Most HCC risk factors (chronic infection with hepatitis B [HBV] and/or C virus [HCV] and alcoholic liver disease [ALD]) operate by promoting the development of cirrhosis. Exceptions are rare in HCV-related HCC and mostly represent cases with at least bridging hepatic fibrosis.5 Whereas most cases of HBV-related HCC also occur in the background of cirrhosis (as high as 85% in some studies),6 HBV can cause HCC in the absence of advanced fibrosis or cirrhosis. Although there are several mechanisms for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD-NASH)-related HCC conceivably in the presence of mild or no fibrosis,7 there are no systematic studies to confirm or quantify this contention.8 Indirect measures of severity of hepatic fibrosis, such as degree of liver stiffness using elastography, is associated with risk of HCC.9 The risk of developing HCC in patients with cirrhosis varies with the underlying condition. The highest 5-year cumulative risks are observed in HCV cirrhosis (17% in the West and 30% in Japan), hemochromatosis (21%), HBV cirrhosis (10% in the West and 15% in Asia), alcoholic cirrhosis (8%-12%), and biliary cirrhosis (4%).10, 11 Most large studies and consistent data about the clinical course of HBV infection come from Asian countries, where HBV is endemic and vertical transmission is frequent. This pattern is different in areas that have low incidence of HCC (such as the United States), where HBV infection is mostly acquired in adulthood either through sexual or parenteral routes. There have been only a few adequate studies in Europe and North America that determined the incidence of HCC in hepatitis B surface antigen (HBsAg)-positive individuals—most included only small numbers of HBsAg-positive patients. Nevertheless, the summary HCC incidence rate in these regions is approximately 0.02 per 100 person-years in inactive carriers (HBsAg-positive, but with normal levels of alanine aminotransferase [ALT]), 0.3 in subjects with chronic HBV without cirrhosis, and 2.2 in subjects with HBV-related compensated cirrhosis. On the other hand, cohort studies estimated the incidence rates of HCC among subjects with chronic HBV infection in East Asian countries to be 0.2 per 100 person-years in inactive carriers, 0.6 per 100 person-years for those with chronic HBV infection without cirrhosis, and 3.7 per 100 person-years for those with compensated cirrhosis. Several demographic (male sex, older age, Asian or African ancestry, and family history of HCC), viral (higher levels of HBV replication, HBV genotype, longer duration of infection, coinfection with HCV, human immunodeficiency virus [HIV], or hepatitis D virus), and environmental factors (exposure to aflatoxin and heavy intake of alcohol or tobacco) increase HCC risk