What is Alpha-Fetoprotein (AFP)?
Alpha-fetoprotein (AFP) is an oncofetal glycoprotein synthesized initially by the yolk sac and later by the fetal liver during early human development, which normally becomes suppressed after birth but can re-emerge in adults with hepatocellular carcinoma, germ cell tumors, or various liver diseases. 1, 2
Biological Characteristics
AFP is an alpha globulin that serves as an important serum protein in early fetal life, passing from fetal bloodstream through the kidneys into urine and then into amniotic fluid. 1
After birth, AFP gene transcription is normally suppressed, with regulatory mechanisms shifting to maintain albumin production instead throughout adulthood. 2
AFP plays a critical role in immune regulation during pregnancy and fetal development, helping maintain immune balance. 2
In postnatal life, AFP expression can increase during hepatocyte injury, regeneration, and malignant transformation, making it the first discovered oncoprotein. 2, 3
AFP has a half-life of 5-7 days, which allows for reliable monitoring of tumor response to treatment. 4
Clinical Applications in Cancer Detection
Hepatocellular Carcinoma (HCC)
AFP is the most widely used tumor marker for HCC surveillance, typically combined with liver ultrasound every 6 months in high-risk patients with cirrhosis, chronic hepatitis B or C, and advanced NAFLD/NASH. 1, 5
Normal AFP range is 10-20 ng/mL, with levels >400 ng/mL typically considered diagnostic for HCC, though this threshold has very high specificity but extremely low sensitivity. 5
AFP has significant diagnostic limitations with sensitivity of only 39-65% and specificity of 76-97%, meaning it misses a substantial proportion of HCC cases. 5
Up to 35-46% of HCC patients have completely normal AFP levels even with large tumors, and two-thirds of HCCs less than 4 cm have AFP below 200 ng/mL. 5
A rising AFP over time, even below diagnostic thresholds, is highly suspicious for HCC and warrants shortened surveillance intervals and additional imaging. 5
Germ Cell Tumors
AFP is the definitive marker to distinguish nonseminoma from seminoma, as seminoma cells never produce AFP while nonseminomatous germ cell tumor cells do. 4
Any elevation of AFP above normal range indicates nonseminomatous elements with 100% specificity, even if histology appears to be "pure seminoma." 4
If AFP is elevated in a testicular tumor, diagnose and treat as nonseminoma regardless of histology. 4
Maternal-Fetal Medicine
AFP measured in maternal serum (MSAFP) is used for screening open neural tube defects during pregnancy, though this application requires careful quality control and gestational age determination. 1
Low MSAFP concentrations may be associated with chromosomal trisomies like Down syndrome, though this requires the same careful scrutiny as elevated levels. 1
False Positives and Other Causes of Elevation
False positive AFP elevations occur in active viral hepatitis, cirrhosis with regenerating nodules, pregnancy, and various non-hepatic cancers including intrahepatic cholangiocarcinoma, colon cancer metastases, lymphoma, and other germ cell tumors. 5
Elevated AFP is observed in patients with cirrhosis, nephrotic syndrome, gastritis, and during liver regeneration following partial hepatectomy or hepatotoxic injury, reflecting hepatocyte proliferation rather than malignancy. 6, 3
AFP elevation can occur as early as 1 week after exposure to hepatocarcinogens, even before detectable cell injury or morphological changes. 3
AFP Variants and Enhanced Testing
AFP-L3 (Lens culinaris agglutinin-reactive AFP) is a glycoform with increased specificity for HCC, and the GALAD score combining gender, age, AFP-L3, AFP, and des-gamma-carboxy prothrombin provides accurate HCC prediction. 1, 7
Combining AFP with other biomarkers like PIVKA-II (des-gamma-carboxy prothrombin) and GP73 significantly improves diagnostic accuracy, though these tests are not widely available or validated for routine use. 5, 8