We can improve hepatocellular carcinoma surveillance by understanding how risk factors are changing

The incidence, demographics, and risk factors associated with hepatocellular carcinoma (HCC) are evolving: Although the rise in the incidence of HCC associated with untreated hepatitis B and C virus infections may plateau, potential gains made may be reversed by worrying increases in HCC attributed to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

Changing incidence and demographic factors

The incidence of HCC has been increasing in the United States, with rates tripling over the last 4 decades, while related mortality has doubled. In addition, the incidence is as much as three times higher among men than women.

Hepatocellular carcinoma is characteristically diagnosed during the seventh decade of life, most commonly at 60 to 64 years of age among men and 65 to 69 years among women.

Twenty years ago, the rates of HCC in the United States were highest among Asian Americans and Pacific Islanders. Today they are highest among native Americans, including native Alaskans, followed by the Hispanic community and then by American Asians and Pacific Islanders, non-Hispanic Blacks, and non-Hispanic whites.

Risk factors are changing—what are the implications for surveillance?

The risk factors for HCC include chronic hepatitis B and C virus infections, chronic alcohol abuse, NAFLD, smoking, diabetes mellitus, obesity, and critically, cirrhosis. The changes occurring in the major risk factors for HCC and the potential implications for its surveillance in the United States are highlighted below.

Viral hepatitis

Chronic viral hepatitis is caused by infection with the hepatitis B virus (HBV) and/or the hepatitis C virus (HCV), which in turn can lead to cirrhosis and HCC. These infections are the most common risk factors for HCC throughout the world, although hepatitis C is much more common than hepatitis B in the United States, particularly among “baby boomers” born in 1945 through 1965.

The epidemiology of HCV infection is evolving

Most HCV infections are untreated; however, the use of direct-acting antiviral (DAA) treatment is increasing and has been shown to steadily decrease the risk of HCC in many patients who achieve sustained virologic response (SVR).

Despite the relative risk reduction of HCC observed in patients who achieve an SVR, the absolute risk of HCC remains elevated in patients who have cirrhosis at the time of SVR; therefore, all patients who have an HCV infection with cirrhosis will continue to benefit from HCC surveillance despite achieving SVR with DAA treatment.

Surveillance of HCC remains relevant in HBV infection

Antiviral treatments for HBV reduce viral load and improve liver function. Although antiviral drugs have been reported to reduce the risk of HCC, treatment may not eliminate the risk, which remains substantial in patients who have cirrhosis or are 50 or more years old.

• Patients who have chronic HBV infection and cirrhosis should undergo routine HCC surveillance. In the absence of cirrhosis, Asian men and women older than 40 and 50 years, respectively, and African and North American Blacks of any age should also undergo HCC surveillance.

Nonalcoholic fatty liver disease is a red alert

Nonalcoholic fatty liver disease occurs commonly among people who are obese; nearly 1 of every 3 adults in the United States is living with NAFLD. Among those who have NAFLD, 20% to 30% develop NASH, which can progress to cirrhosis in as many as 20% of cases.

“NAFLD is now a leading cause of cirrhosis, and NASH is the second leading cause of liver transplantation related to HCC in the United States.”
— McGlynn KA, et al. Hepatology. 2021.

The role of NAFLD in new cases of HCC in the absence of cirrhosis may be underappreciated in clinical practice: Fewer patients who have NAFLD-related HCC undergo surveillance for HCC than patients whose HCC is related to HCV infection. In this context, it is critical to recognize NAFLD/NASH as a red alert that triggers HCC surveillance in patients who have cirrhosis and possibly advanced fibrosis, too.

HCC surveillance in a changing world of risk factors

With the knowledge that early-stage HCC detection can improve patient outcomes, surveillance must be adapted to meet the evolving environment of risk factors. The current tools used to monitor patients are not sensitive enough to detect early HCC, and surveillance itself is often underutilized.

Red alert
Most guidelines recommend the use of ultrasonography for surveillance. Ultrasonography, however, has decreased accuracy in obese patients and those who have NAFLD/NASH and may fail to detect HCC in these patients.

Accordingly, surveillance for HCC must

• be highly accurate to detect the early stages of HCC in patients who are obese and who have various forms of chronic liver disease
• yield results that are easy to decipher
• be easy to use by physicians and convenient for patients
• include education for patients and support for healthcare providers to help improve adherence

Taken together, these approaches provide an opportunity to improve HCC surveillance in the coming years.