Changes in Liver Disease Etiology Support a Lower Alpha-Fetoprotein Threshold for Hepatocellular Carcinoma Screening

Serum alpha-fetoprotein (AFP) is a key component of hepatocellular carcinoma (HCC) screening, but its test characteristics are uncertain as alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) rates increase.

We evaluated AFP trends at HCC diagnosis and estimated its test performance for HCC screening in cirrhosis using Veterans Health Administration (VHA) and United Network for Organ Sharing data.

Among the 40,399 VHA patients diagnosed with HCC between 2001 and 2021, median AFP at HCC diagnosis declined over time and was highest in active-hepatitis C (HCV) (32.7 vs cured-HCV 8.3, ALD 9.0, MASLD 7.7 ng/mL). Among the 28,170 VHA patients with cirrhosis receiving care in 2019 (9.6% active-HCV, 43% cured-HCV, 24% ALD, 14% MASLD), 1,029 developed HCC in 2019. At AFP thresholds ≥20 and ≥10 ng/mL, the overall sensitivity/specificity for HCC screening was 31.7%/98.5% and 41.9%/94.1%, respectively. Lowering the AFP threshold to ≥10 ng/mL increased sensitivity with minimal reductions in specificity across all liver disease etiologies: active-HCV (sensitivity/specificity: 43.7% to 60.7%/92.6% to 83.0%), cured-HCV (32.5% to 41.5%/99.0% to 94.7%), ALD (22.8% to 32.3%/99.2% to 95.1%), and MASLD (21.7% to 29.9%/99.4% to 96.7%). Analysis of United Network for Organ Sharing (26,213 patients with HCC) resulted in similar increases in test sensitivity as the AFP threshold declined from ≥20 to ≥10 ng/mL (overall: 31.8% to 48.7%; active-HCV: 36.7% to 58.6%, cured-HCV: 21.4% to 36.4%, MASLD: 19.1% to 33.4%, and ALD: 15.9% to 27.1%).

For HCC screening in MASLD, ALD, and cured-HCV cirrhosis, reducing the AFP threshold to ≥10 ng/mL would substantially increase sensitivity while maintaining very high specificity.