Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by
nucleoside/
nucleotide analogues (
NAs) and increased sustained virologic response (SVR) rates by direct-acting
antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral
liver disease. Although viral
hepatitis remains the most common cause of HCC, non-
alcoholic liver disease (
NAFLD) with
metabolic syndrome and alcohol-associated
liver disease (ALD) are increasing. Effective and well-tolerated
NAs treatment can slow the
disease progression of chronic HBV
infection to
cirrhosis,
end-stage liver disease, and reduce HCC risk. Treatment with
NAs is also associated with significant improvement in the long-term survival of patients with HBV
infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated
liver cirrhosis and HCC. Similarly, DAA
therapy can reduce
disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV
infection with or without HCC. Meanwhile,
NAFLD is a rapidly increasing cause of HCC along with the epidemics of
obesity and
type 2 diabetes globally.
NAFLD-related HCC can occur in patients without
cirrhosis and is known to have a lower survival rate than viral
hepatitis-related HCC. Since there is currently no specific
pharmacotherapy effective for
NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the
COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.