Alpha-fetoprotein, type L3 measurement is used to assess the risk of hepatocellular carcinoma, diagnose hepatocellular carcinoma, assess the prognosis for individuals with hepatocellular carcinoma, and monitor hepatocellular carcinoma therapy.
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of mortality worldwide. There are many risk factors for hepatocellular carcinoma, including alcohol, obesity, and diabetes, but HBV and HCV infections account for the majority of hepatocellular carcinoma worldwide. Globally, 53% of hepatocellular carcinoma is attributed to hepatitis B virus (HBV) and 25% to hepatitis C virus (HCV). The disease burden is highest in endemic regions of HBV infection.
For patients at high risk for hepatocellular carcinoma, surveillance by abdominal ultrasound (US) is used as the first-line modality, followed by dynamic computed tomography (CT) or magnetic resonance imaging (MRI). Imaging studies should be performed every six months (or three months if indicated) to detect hepatocellular carcinoma. Most guidelines recommend imaging with concomitant alpha-fetoprotein (AFP) level for hepatocellular carcinoma surveillance. However, AFP can be elevated not only in HCC but also in other conditions such as pregnancy, chronic liver inflammation, and ALT flare. In recent years, AFP-L3 has been used as the specific tumor marker for HCC.
AFP is an alpha1-globulin-containing glycoprotein whose level increases during pregnancy due to production by the fetal liver. Elevated AFP levels disappear from serum within three weeks after childbirth.
Furthermore, elevated AFP during acute liver injury indicates active regeneration of liver cells. Serum studies before and after partial hepatectomy experiments in animals have indicated that hepatocyte proliferation is related to alpha-fetoprotein production.
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AFP is a glycosylated protein and based on its binding capability to lectin Lens Culinaris Agglutinin (LCA), and total AFP can be separated into three different glycoforms, AFP-L1, AFP-L2, and AFP-L3. AFP-L1 does not bind LCA, and it is the major glycoform produced by nonmalignant hepatocytes in patients with chronic hepatitis B (CHB) infection or cirrhosis. AFP-L2 has an intermediate binding affinity to LCA, produced by yolk sac tumors, and can be detected in the maternal serum during normal pregnancy. AFP-L3 does bind LCA and is produced by malignant hepatocytes. The current cut-off value for L3% is 10%. Patients with AFP-L3 > 10% are consistent with hepatocellular carcinoma. They could be defined as more aggressive cancers, as HCC cells producing more AFP-L3 have been found to tend to early vascular invasion and intra-hepatic metastasis.
The AFP-L3 can be detected in the serum of approximately 35% of the patients with small HCC (< 2 cm). The AFP-L3-positive HCC has the potential for rapid growth and early metastasis. Compared to imaging techniques, it has been shown to have 9–12 months of lead time in early HCC recognition. The combined sensitivity of AFP-L3 for HCC is 56%, with a specificity of >95%.
AFP-L3 should be used as an adjunct to other diagnostic tests, such as ultrasound, CT scans, or MRI, to help diagnose liver cancer and monitor its progression or response to treatment.
Interpretation
Individuals with an increased AFP-L3 in serum are at increased risk of developing hepatocellular carcinoma. AFP and AFP-L3 levels decline to normal levels with effective therapy; rising levels suggest disease progression or recurrence.
Cautions
- Not all hepatic cancers secrete AFP or AFP-L3. These biomarkers may be elevated in individuals with germ cell tumors and other cancers, including those of the gastric and biliary tract, lung, pancreas, and testes.
- AFP may also be elevated in individuals with viral infections or liver diseases other than HCC, individuals who are pregnant, and children less than 18 months of age.
- Results should be interpreted in conjunction with other laboratory and clinical findings.
