Serum Levels of α-Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular Carcinoma

Clin Gastroenterol Hepatol. 2021 Jan;19(1):162-170.e4. doi: 10.1016/j.cgh.2020.04.084. Epub 2020 May 8.


Background & aims: Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC.

Methods: We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients).

Results: HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results.

Conclusions: We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.

Keywords: Biomarker; Liver Cancer; Prognostic Factor; Stratification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular* / diagnosis
  • Carcinoma, Hepatocellular* / epidemiology
  • Fetal Proteins
  • Humans
  • Liver Cirrhosis
  • Liver Neoplasms* / diagnosis
  • Liver Neoplasms* / epidemiology
  • alpha-Fetoproteins


  • Fetal Proteins
  • alpha-Fetoproteins