Alpha-fetoprotein (AFP)

Alpha-fetoprotein (AFP) Overview

Alpha-fetoprotein (AFP) is a glycoprotein, a type of protein normally produced primarily by the liver and yolk sac of a developing fetus. Its concentration in fetal serum peaks around 13 weeks of gestation and then gradually declines until birth. After birth, AFP levels drop rapidly, and in healthy adults (non-pregnant), AFP is present only in very low concentrations.

Measurement of AFP levels in blood (serum) serves two main clinical purposes: as a tumor marker for certain types of cancer and as part of prenatal screening for fetal abnormalities.

Indications for AFP Testing

Testing for alpha-fetoprotein (AFP) is indicated for several reasons:

1. Tumor Marker Monitoring:
   • Diagnosis, monitoring treatment effectiveness, and detecting recurrence of primary hepatocellular carcinoma (HCC), the most common type of liver cancer.
   • Diagnosis, monitoring treatment, and detecting recurrence of certain germ cell tumors, specifically yolk sac tumors (endodermal sinus tumors) and mixed germ cell tumors containing yolk sac elements, which can occur in the ovaries or testes.
2. Prenatal Screening: Measuring AFP in maternal serum (maternal serum AFP or MSAFP) or amniotic fluid, typically between 15 and 20 weeks of gestation, as part of screening for:
   • Open Neural Tube Defects (ONTDs): Such as spina bifida and anencephaly. Elevated AFP levels suggest an increased risk.
   • Abdominal Wall Defects: Such as gastroschisis and omphalocele. Elevated AFP levels suggest an increased risk.
   • Chromosomal Abnormalities: Abnormally low AFP levels (often combined with other markers like hCG and estriol in the "triple" or "quad" screen) suggest an increased risk for conditions like Down syndrome (Trisomy 21) and Edwards syndrome (Trisomy 18).
3. Monitoring Chronic Liver Disease: Sometimes used alongside imaging (like ultrasound) for HCC surveillance in high-risk patients (e.g., those with cirrhosis from chronic hepatitis B or C).

AFP Biology and Function

Alpha-fetoprotein has a molecular mass of approximately 70 kDa. Structurally and in its amino acid sequence, AFP shares similarities with albumin, another major serum protein. During electrophoresis, AFP migrates with the alpha-1 globulins.

In fetal development, AFP is believed to play several roles:

• Maintaining Osmotic Pressure: Similar to albumin, it helps maintain the colloid osmotic pressure of fetal blood.
• Immune Modulation: It may help protect the fetus from the mother's immune system.
• Transport/Binding: AFP binds certain substances, notably having a high binding capacity for estrogens, potentially regulating their effect on the fetus.
• Development: May participate in liver organogenesis (development).

Production shifts from the yolk sac early in gestation to primarily the fetal liver and gastrointestinal tract later on.

AFP in Pregnancy

AFP produced by the fetus crosses the placenta into the mother's bloodstream. Maternal serum AFP (MSAFP) levels rise during the second trimester and then decline.

• Elevated MSAFP: Significantly elevated levels for a given gestational age raise concern for open neural tube defects (where AFP leaks directly into the amniotic fluid and then maternal circulation), abdominal wall defects, multiple gestation (twins, triplets), or inaccurate dating of the pregnancy.
• Low MSAFP: Abnormally low levels, particularly after 10 weeks, are associated with an increased risk of chromosomal abnormalities like Down syndrome (Trisomy 21) and Edwards syndrome (Trisomy 18).

It is crucial to interpret MSAFP levels relative to the specific week of gestation, maternal weight, race, and diabetic status. AFP testing is a screening tool; abnormal results require further investigation with diagnostic tests like detailed ultrasound or amniocentesis.

AFP as a Tumor Marker

In non-pregnant adults, elevated AFP levels are strongly associated with certain cancers:

• Hepatocellular Carcinoma (HCC): Markedly elevated AFP levels (often > 400-500 ng/mL, sometimes > 1000 ng/mL) are found in a significant proportion (around 60-70%) of HCC patients. The level often correlates with tumor size and burden. AFP is used for diagnosis (in specific high-risk contexts), monitoring response to therapy, and detecting recurrence after treatment.
• Germ Cell Tumors (GCTs): AFP is significantly elevated in yolk sac tumors (endodermal sinus tumors) and embryonal carcinomas, whether occurring in the testes, ovaries, or extragonadal sites (like the mediastinum). It is NOT typically elevated in pure seminomas (testis) or dysgerminomas (ovary) or pure choriocarcinomas (which produce hCG). AFP, along with beta-hCG, is essential for staging, monitoring treatment, and detecting relapse in non-seminomatous GCTs.

A decrease in AFP concentration back to normal levels after tumor removal or successful treatment is a positive prognostic sign. A subsequent rise often indicates recurrence or metastasis.

Interpreting AFP Levels

Reference ranges vary slightly between laboratories, but generally:

• Normal Adult Level: Typically less than 10-15 ng/mL (or equivalent IU/mL).
• Pregnancy Levels: Must be interpreted based on gestational age using specific reference ranges (often expressed as Multiples of the Median, MoM).
• Tumor Marker Interpretation:
  • Very high levels (> 400-500 ng/mL) are highly suggestive of HCC or AFP-producing GCTs.
  • Moderately elevated levels (e.g., 20-400 ng/mL) can be seen in HCC or GCTs, but also in non-cancerous liver conditions.
  • Slight elevations may occur in various situations and need careful interpretation.

AFP in Other Conditions

Besides pregnancy and specific cancers, moderately elevated AFP levels (usually not exceeding 400-500 ng/mL) can sometimes be seen in non-cancerous conditions, particularly those involving liver regeneration or inflammation:

• Acute or chronic viral hepatitis (e.g., Hepatitis B, Hepatitis C)
• Cirrhosis
• Liver injury or recovery after liver surgery/transplant
• Ataxia-telangiectasia (rare genetic disorder)

In these benign conditions, the AFP elevation is usually transient or less pronounced than in HCC.

Slight elevations (e.g., up to 100 ng/mL, rarely up to 500 ng/mL) can also occur in patients with metastases to the liver from other cancers (like breast, lung, or colorectal cancer), particularly if liver involvement is extensive. However, in these cases, other tumor markers like Carcinoembryonic Antigen (CEA) are often very high. Measuring both AFP and CEA can sometimes help differentiate primary HCC (where AFP is often high and CEA normal/low) from metastatic disease (where CEA may be very high and AFP normal/slightly elevated).

AFP testing can be part of HCC screening protocols in high-risk groups (e.g., cirrhosis patients), often combined with liver ultrasound and liver enzyme monitoring (ALT, AST, GGT, ALP).

References

1. National Cancer Institute (NCI). (n.d.). Tumor Markers. NCI Dictionary of Cancer Terms. Retrieved from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/tumor-marker
2. American Cancer Society (ACS). (2023). Tumor Markers. Retrieved from https://www.cancer.org/cancer/diagnosis-staging/tests/tumor-markers.html
3. Mayo Clinic Laboratories. (n.d.). Test ID: AFP - Alpha-Fetoprotein (AFP), Tumor Marker, Serum. Test Catalog. Retrieved from https://www.mayocliniclabs.com/test-catalog/Overview/8391 (Example lab reference)
4. American College of Obstetricians and Gynecologists (ACOG). (2020). Practice Bulletin No. 226: Screening for Fetal Chromosomal Abnormalities. *Obstetrics & Gynecology*, 136(4), e48-e69.
5. European Association for the Study of the Liver (EASL). (2018). EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. *Journal of Hepatology*, 69(1), 182–236. https://doi.org/10.1016/j.jhep.2018.03.019