AFP-L3: a new generation of tumor marker for hepatocellular carcinoma

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Abstract

Background: Alpha-fetoprotein (AFP) from hepatocellular carcinoma (HCC) displays differential affinity to lectin Lens culinaris agglutinin (LCA) compared to that from chronic hepatitis/liver cirrhosis. According to their binding capability to LCA, total AFP can be separated into three different glycoforms, AFP-L1, AFP-L2, and AFP-L3. AFP-L1 is the non-LCA-bound fraction, which constitutes the major glycoform of AFP in serum of chronic hepatitis and liver cirrhosis. AFP-L3 is the LCA-bound fraction of AFP. It has been reported that malignant liver cells produce AFP-L3, even when HCC is at its early stages, and especially when the tumor mass is supplied by the hepatic artery. Clinical research has determined that AFP-L3 is a highly specific marker for HCC. 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 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. Combined sensitivity of AFP-L3 for HCC is 56%, with a specificity of >95%. Methods: Automated assay for measuring AFP-L3 has been developed and introduced in clinical use. The new automated method for measurement of ALP-L3 is based on liquid phase binding of the AFP-L3 glycoform with LCA and two specific monoclonal antibodies labeled with peroxidase and polysulfated tyrosine peptide, respectively. Conclusion: AFP-L3 is a new generation of tumor marker for HCC and yields useful information on HCC for clinical decision making.

Section snippets

Chronic hepatitis and hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has become a public health concern in recent years largely due to the worldwide epidemic of hepatitis B and hepatitis C. There is an estimated 1.25 million and 2.7 million individuals with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, respectively, in the United States [1]. Viral hepatitis in general, and chronic hepatitis C in particular, is the most common cause of chronic liver disease. There were 120,000 to 180,000 new cases of

α-Fetoprotein

Alpha-fetoprotein (AFP) has been used in clinical diagnosis for HCC. AFP is synthesized in large quantities during embryonic development by fetal yolk sac and by the liver [7]. AFP concentration decreases gradually after birth to <10 ng/ml in 12–18 months [7], [8]. AFP reappears in maternal serum during pregnancy. Pathologically, it is associated with HCC, gastric carcinoma, lung cancer, pancreatic and biliary tract cancer, and testicular carcinoma, etc. [8]. Although AFP can arise in many

Glycoforms of α-Fetoprotein

AFP is a glycoprotein with a single asparagine-linked complex-type carbohydrate chain on each molecule. Over the past decades, research have shown that total AFP is a collection of heterogeneous glycoproteins consisting of three different glycoforms. AFP from benign chronic liver diseases, such as chronic hepatitis and liver cirrhosis, and from HCC displayed differential affinities to lectin, Lens culinaris agglutinin (LCA). The total AFP can be separated into three subspecies, AFP-L1 to

Clinical significance of α-Fetoprotein glycoforms

Early diagnosis of HCC has been difficult, if not impossible, in a background of cirrhosis. Screening program exists in some hospitals in North America for chronic cirrhotic patients by abdominal ultrasonography and serum AFP [12], [13]. Early recognition of HCC is based on screening high-risk patients with long history of chronic liver disease. In prospective studies, the positive predictive value for HCC of serum AFP was 32% compared to 54% for abdominal ultrasonography [6], [14], [15].

Automated assay for AFP-L3

Laboratory assay for AFP-L3 used to be based on lectin affinity electrophoresis and Western blotting [27], [28]. These assays were tedious with long turnaround times. Recently, an automated assay for measuring the AFP-L3 has been developed and introduced for clinical use in Japan. The new automated method for measurement of AFP-L3 is an immunoassay based on the liquid phase binding of L3 subspecies of AFP with two specific monoclonal antibodies labeled with peroxidase and polysulfated tyrosine

Summary

Taken together, AFP-L3 is a new generation of tumor marker for measuring micro-heterogeneity in sugar chain in AFP for HCC. Its very high specificity is complementary to the total AFP assay, providing a cost-effective test useful for early tumor recognition, diagnosis, follow-up after treatment, and prognosis of HCC patients. Development of an automated assay has enabled testing in reference laboratories that have a high testing volume.

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