Hepatocellular carcinoma (HCC) is the most common primary liver malignant neoplasm, with an increasing incidence and mortality in the US. The study by Qiu et al provides a thorough analysis of the evolving trends in HCC mortality. This study highlights the alarming rise in HCC deaths attributed to alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), with a concurrent decline in mortality from viral hepatitis. Specifically, Qiu et al found that the rates of HCC associated with ALD and MASLD in the US increased rapidly between 2006 and 2022. By 2026, ALD-related HCC is expected to become the leading cause, with MASLD-related HCC projected to be the second-leading cause by 2032. These are important insights into the changing etiologies driving the development of HCC, which highlights the future health care challenges in preventing and treating both these underlying conditions and HCC itself.

HCC has traditionally been associated with chronic viral hepatitis, particularly hepatitis B (HBV) and hepatitis C infection. However, with the advent of effective antiviral therapies and vaccination programs, the burden of viral hepatitis is steadily decreasing, making it a less significant driver of liver cirrhosis and HCC. In contrast, lifestyle-related factors such as alcohol consumption and metabolic syndrome are becoming increasingly prominent contributors to HCC. Qiu et al emphasize this shift, projecting that by 2032, ALD and MASLD will surpass viral hepatitis as the leading causes of HCC-related deaths.

These findings mirror previous research indicating the growing impact of ALD and MASLD across the spectrum of liver disease, including cirrhosis, HCC, and the need for liver transplantation. A population study examining the burden of cirrhosis and HCC between 2007 and 2016 found that mortality for ALD and MASLD cirrhosis and HCC increased while HBV-related mortality decreased during the study period. Another study examining the causes of liver disease among adults on the liver transplant waiting list in the US between 2014 and 2019 found that MASLD and ALD have emerged as the most common etiologies among registrants without HCC, with MASLD increasingly becoming a leading cause in patients with HCC. Although these trends are more prominent in the US, they appear to be present at a global level. This shift in the etiologic landscape of HCC underscores the need for a reevaluation of public health strategies. Current prevention efforts are largely focused on controlling viral hepatitis, and they must adapt to address the rising prevalence of ALD and MASLD. The increasing incidence of these conditions reflects broader societal trends, including the worsening obesity epidemic and changing alcohol consumption patterns. In addition, the study by Qiu et al projects statistically significant disparities in HCC mortality by race and ethnicity, with American Indian or Alaska Native, Black, and Hispanic populations expected to experience the most substantial increases.

The study by Qiu et al is particularly timely, given the ongoing research and drug development in MASLD, highlighted by the arrival of resmetirom, the first US Food and Drug Administration-approved treatment for MASLD, in 2024. Additional agents are expected to receive approval in the near future. However, it remains uncertain how effectively these treatments will stabilize or reverse the rising trend of MASLD-related liver disease. From a preventive standpoint, public health initiatives should focus on reducing alcohol consumption and promoting healthy lifestyles to mitigate the risk of ALD and MASLD. Although more medications are now available for obesity, the complex interplay among obesity, MASLD, and other components of metabolic syndrome raises questions about whether these new obesity treatments will significantly reduce the burden of liver disease.

In summary, the study by Qiu et al is part of a growing body of literature that demonstrates the increasing burden of ALD and MASLD, which have emerged as the dominant drivers of HCC mortality. Their study highlights the importance of addressing these conditions to decrease the burden of liver disease and liver disease mortality in the future. This will require a multifaceted approach, including early detection, lifestyle interventions, and the development of effective therapies.

Corresponding Author: Emad Qayed, MD, MPH, Division of Digestive Diseases, Emory University School of Medicine, 49 Jesse Hill Jr Dr, Atlanta, GA 30303 ([email protected]).