Establishing alpha-fetoprotein reference ranges in patients with chronic liver disease and hepatocellular carcinoma

Alpha-fetoprotein (AFP) is the primary serum biomarker for hepatocellular carcinoma (HCC). However, the current diagnostic AFP thresholds for HCC are arbitrary and the definitive reference range has never been identified. Furthermore, some HCCs are AFP-negative, implying that these tumours do not synthesise AFP, making them difficult to characterise and diagnose.

By analysing AFP distribution in over 4500 patients with chronic liver disease (CLD) from Japan and UK with and without HCC, as well as in a population of healthy patients without CLD, we defined accurate AFP reference ranges for HCC and characterised a group of AFP-negative HCC patients.

We identified 40 ng/mL as the upper AFP limit for CLD patients without HCC, indicating that HCC can be accurately diagnosed above this threshold with minimal risk of false positives. Furthermore, the upper AFP limit for the healthy population was 5 ng/mL which was used to characterise AFP-negative HCC patients. By this definition, 15 % of HCC patients were AFP-negative. Those patients had significantly better survival after diagnosis compared to their AFP-positive counterparts irrespective of treatment.

Our established AFP reference ranges provide an accurate cutoff for HCC diagnosis and can also be used to identify AFP-negative HCCs.