Hepatocellular carcinoma in the United States—HCV infection remains a threat, even as NAFLD increases

Hepatocellular carcinoma (HCC) is associated with high mortality—the 5-year survival rate (20%) among affected patients is second only to that associated with pancreatic cancer. Given that the incidence of HCC in the United States is projected to more than double from 43,000 cases in 2020 to 100,000 cases in 2040, improvements in risk recognition and reduction, early detection through improved surveillance, and advances in diagnostics and treatments will be required to reduce the burden of HCC.

Changing risk factors in the United States

HCV infection and NAFLD

The risk factors for cirrhosis and HCC have been changing over time. Although great progress was made with the introduction of antiviral drug therapies in the reduction of HCC cases attributed to HCV, current rates of HCV infection are increasing due to intravenous drug use. In light of the ongoing opioid abuse epidemic, it is predicted that HCV will continue to be a key cause of HCC.

Nonalcoholic fatty liver disease (NAFLD), which is driven primarily by obesity, can progress to nonalcoholic steatohepatitis (NASH), which may in turn lead to HCC, even in the absence of cirrhosis. Because of the sheer number of people who have obesity-related NAFLD, it is another important cause of HCC. Accordingly, the ongoing epidemics of opioid abuse and obesity are relevant contemporary risk factors contributing to the increase in HCC in the United States.

In this post, we consider two recent reports about the trends, challenges, and implications of the changing risk factors for HCC.

Implications of current trends and challenges in HCC risk factors

Current trends in cirrhosis risk factors and the risk of developing HCC

Kanwal and colleagues examined the etiologic risk factors for cirrhosis in two contemporary cohorts totaling 2733 patients who had cirrhosis. The cohorts comprised 2381 patients who were not undergoing surveillance for HCC and 352 patients who were undergoing active surveillance.     

The mean age of the combined cohorts was 60.1 years. Women comprised 31.3% of the total number of patients, who included 50.2% non-Hispanics whites, 27.4% Hispanics, and 19.5% non-Hispanic blacks.

• The study results revealed an overall annual HCC incidence of 1.87%
• Annual HCC incidence depended on etiology:
  • 2.73% among patients who had active HCV infection
  • 2.49% among patients who were cured of HCV infection
  • 1.28% among patients who had NAFLD

The authors concluded that “in this large prospective cohort, the annual overall HCC incidence among patients with cirrhosis was lower than previously reported. HCC risk was variable across etiologies, with higher risk in patients with active HCV cirrhosis and lower in those with NAFLD cirrhosis. Tobacco use increased HCC risk in patients with NAFLD cirrhosis.”

NAFLD-associated HCC in the absence of cirrhosis is a growing challenge

Mattos and colleagues acknowledge the increasing prevalence of NAFLD, which has been estimated at 25% globally, and its relevance to the increasing prevalence of NAFLD-associated HCC (with or without cirrhosis). It is in this context that the authors make a case for the possible role of genetic variants, related molecular events, and immune-mediated mechanisms that may help explain the progression of NAFLD to HCC in the absence of cirrhosis.

“Some of the mechanisms involved in hepatocarcinogenesis are particular to individuals with fatty liver, and they help explain why liver cancer develops even in patients without cirrhosis.”

With an incomplete understanding of the physiopathology of HCC in NAFLD in the absence of cirrhosis, determining whom to surveil is a challenge. The estimated annual incidence of HCC in patients who have NAFLD-related cirrhosis ranges from 0.5% to 2.6% in the western hemisphere. However, the annual incidence of HCC among patients with NAFLD who do not have cirrhosis is much lower than that reported for patients with cirrhosis.

This point is underscored by the results of a retrospective cohort study that included 296,707 patients who had NAFLD and a similar number of matched controls from the VA Health System database. In this study, patients who had NAFLD had a 7.6-fold higher risk of developing HCC than patients who did not have NAFLD. However, in the NAFLD-group, the annual incidence of HCC was 10.6/1000 person-years for individuals with cirrhosis and 0.08/1000 person-years for those without it, which was considered insufficient for a general recommendation of surveillance to be made for patients who do not have cirrhosis. In addition, the FIB-4 score was also evaluated; regardless of its association with the development of HCC, individuals with high FIB-4 scores (>2.67) but without a diagnosis of cirrhosis were still considered to have a low risk of developing HCC.

Recognizing 1) the increasing danger of NAFLD-associated HCC to public health, 2) that there are substantial subgroups of patients who have NAFLD and are at increased risk for HCC in the absence of cirrhosis, and 3) that stratification of these patients is not defined in current surveillance strategies, the authors state that “there is a profound necessity for the identification of better biomarkers to detect subgroups of patients that could benefit from surveillance aside from those with cirrhosis.”

Progress through research

Continuing research into the epidemiology and physiopathology of NAFLD-associated HCC is essential. It may provide knowledge that can help reduce known risks, enhance early detection through improved surveillance, and move diagnostics and treatments forward to one day reduce the burden of HCC.