Is nonalcoholic fatty liver disease driving the increased incidence of liver cancer?

Abstract

The latest Annual Report to the Nation demonstrates a significant increase in liver cancer (hepatocellular carcinoma [HCC]) incidence rates in the United States starting at age 55 years from 2008 through 2012.1 This is no surprise because, since the 1980s, there has been a consistently increased trend in liver cancer incidence rates noted in the United States, although the rates are nearly twice as high in men compared with women.2 Both hepatitis B virus (HBV) and hepatitis C virus (HCV) are important etiological factors in HCC, and HBV vaccination has been implemented in the United States since the early 1980s. Between 1982 and 2002, approximately 40 million infants and children and 30 million adults received an HBV vaccine.3 It is possible that vaccination in early life against HBV may result in a decline in liver cancer incidence rates in the coming years, but vaccination alone would not be adequate. In the United States, it has been estimated that 50% to 60% of patients with HCC are infected with HCV.4 In addition, an examination of the liver cancer incidence rates demonstrates substantial variability by sex and ethnicity, thereby indicating that different exposures are important in HCC etiology. Other keys factors in HCC etiology include heavy alcohol consumption and tobacco use. In the United States, heavy alcohol consumption patterns have been shown to have increased from 2002 to 2012.5 However, tobacco use has been declining since the 1960s.6 Overall, when all HCC risk factors are considered, an important contributor to HCC is nonalcoholic fatty liver disease (NAFLD). Based on ultrasonography data from 12,454 adults in the Third National Health and Nutrition Examination Survey (1988-1994), average prevalence rates of between 19% to 24% were found for NAFLD, but men, Mexican American individuals, and obese individuals were found to have a higher prevalence.7 Obese men have prevalence rates of NAFLD of between 24% to 59%.7 There also is an increasing prevalence of NAFLD noted among adolescents in the United States, where the condition currently affects approximately 11% of adolescents.8 NAFLD, which is the buildup of extra fat in the liver (steatosis), can lead to nonalcoholic steatohepatitis (NASH), inflammation, and eventually cirrhosis, with clinical consequences including liver failure.9 NASH is the second leading etiology of liver disease among US adults awaiting liver transplantation.10 There is growing evidence that NAFLD and NASH are linked to HCC etiology, but to my knowledge the magnitude of this relationship is not clear.11, 12 Although NAFLD and NASH are correlated with obesity and insulin resistance, NAFLD is also found in lean individuals,7 and there is evidence from longitudinal studies that NAFLD is a precursor of metabolic syndrome.13 In terms of HCC, other than HCV and HBV and heavy alcohol consumption, modifiable factors that affect the etiology of NAFLD and NASH would be important considerations in HCC prevention efforts. These factors include obesity, diabetes, sedentary lifestyle, a high-fat diet, low choline, a high-fructose diet, and excessive antibiotic use affecting the gut microbiome, all of which are high or increasing in the United States. Future research should investigate whether reductions in modifiable factors linked to the etiologies of NAFLD and NASH would reduce the risk and incidence of HCC. This information would be useful for primary liver cancer prevention efforts. No specific funding was disclosed. The authors made no disclosures. Somdat Mahabir, PhD, MPH Epidemiology and Genomics Research Program National Cancer Institute, National Institutes of Health Bethesda, Maryland