Alpha-Fetoprotein

Alpha-fetoprotein (AFP) is a glycoprotein produced mainly by the yolk sac, fetal liver, and gastrointestinal tract during pregnancy. 

In adults, AFP levels are typically low but can increase in various tumors of mesodermal or endodermal origin, such as liver, ovarian, and testicular cancers, making AFP a valuable tumor marker. 

Elevated AFP levels in adults can indicate hepatocellular carcinoma, germ cell tumors, and other malignancies. 

AFP exists in three glycoforms—L1, L2, and L3—with the L3 isoform particularly associated with malignant tumors and useful for identifying high-risk individuals for hepatocellular carcinoma. 

During pregnancy, AFP measurement is used to detect neural tube defects and chromosomal abnormalities, where elevated levels may indicate fetal abnormalities, and lower levels suggest potential chromosomal issues. 

AFP levels are monitored in various clinical settings to evaluate treatment efficacy and detect cancer recurrence, highlighting its importance in both oncology and prenatal care.

What is Alpha-fetoprotein (AFP)? [2., 3., 4.] 

Alpha-fetoprotein (AFP) is a glycoprotein produced mainly in the yolk sac, fetal liver, and gastrointestinal tract during pregnancy. 

In adults, AFP levels are typically low, but they can reappear in various tumors of mesodermal or endodermal origin. 

In nonpregnant adults AFP serves as a tumor marker, especially in liver, ovarian, and testicular cancers. [3.] 

Elevated AFP levels in adults can indicate hepatocellular carcinoma, germ cell tumors, and other malignancies. [2.] 

AFP can be divided into three glycoforms—L1, L2, and L3—using affinity electrophoresis. The L3 isoform is particularly associated with malignant tumors and can help identify individuals at high risk for hepatocellular carcinoma. [2.] 

AFP measurement is also crucial during pregnancy for detecting neural tube defects and aneuploidies. [2.] Elevated maternal serum AFP levels may indicate neural tube defects, while lower levels can suggest chromosomal abnormalities. AFP levels are monitored in various clinical settings to evaluate treatment efficacy and detect cancer recurrence.

AFP Production and Regulation

Alpha-fetoprotein (AFP) is a glycoprotein normally produced by the fetal yolk sac and liver during pregnancy. After birth, AFP levels decrease rapidly and remain low in healthy adults.

Normal Physiological Production in Pregnancy

During fetal development, AFP is synthesized by the yolk sac and later by the fetal liver. It plays a crucial role in regulating the transport of various molecules across the placenta, including bilirubin, fatty acids, heavy metals, dyes, pesticides, and steroids. [2.] 

AFP levels peak around the third trimester of pregnancy and then decline rapidly after birth. [2.] 

Regulation Mechanisms in Adults

In healthy, nonpregnant adults, AFP production is typically maintained at low levels. However, occasionally benign AFP elevations can be seen, which should be identified by the medical provider in order to avoid undue anxiety and diagnostic procedures for the patient. [8.] 

However, certain pathological conditions, such as liver cirrhosis, hepatocellular carcinoma (HCC), testicular cancer and germ cell tumors, can lead to the reactivation of AFP production, resulting in elevated serum levels. [2., 8.] 

Clinical Applications of AFP Testing

Alpha-fetoprotein (AFP) testing has several important clinical applications, primarily in the detection and monitoring of certain cancers and congenital abnormalities.

Screening for Liver Disease and Liver Cancer Including Hepatocellular Carcinoma (HCC) [2., 9.] 

Elevated serum AFP levels are commonly associated with hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer. 

AFP testing is widely used for HCC screening, particularly in high-risk populations, such as patients with chronic liver disease or cirrhosis. 

However, it is important to note that not all HCC cases exhibit elevated AFP levels, and other biomarkers may be used in combination for improved diagnostic accuracy.

AFP levels can also rise in non-cancerous liver conditions including hepatitis and liver cirrhosis. [2.] 

Monitoring Treatment Response in HCC [3.] 

In addition to its screening role, AFP levels are also monitored during the treatment of HCC to assess the effectiveness of therapy and detect potential recurrences. A decrease in AFP levels after treatment may indicate a positive response, while a persistent elevation or increase may suggest the need for further intervention.

Prenatal Screening for Neural Tube Defects and Congenital Abnormalities [2.]

AFP testing is an essential component of prenatal screening for neural tube defects, such as spina bifida and anencephaly, as well as other genetic defects or conditions in pregnancy. 

Elevated levels of AFP in the amniotic fluid or maternal serum can indicate the presence of congenital abnormalities, allowing for early detection and appropriate management.

Laboratory Testing for AFP

Test Information, Sample Collection and Preparation

The most common method for measuring AFP levels is through serum assays, which requires a blood draw.  Typically, no special preparation is required, although it is important to discuss any medications as well as the possibility of pregnancy prior to sample collection.  

It is recommended that individuals avoid biotin for 72 hours prior to sample collection. 

Interpretation of AFP Levels

Optimal Levels of AFP

It is important to interpret the context of an individual’s lab results within the context of his or her medical history.  

Elevations may normally be seen in pregnant people, and occasionally are seen in individuals who are otherwise healthy. [8.] Early identification of these individuals is important to avoid undue stress, anxiety, or diagnostic procedures.

Typically, in healthy, nonpregnant adults, the reference range for AFP is between 0-40 ng/mL. [2.] Some labs report AFP levels for nonpregnant adults as low as 0-10 ng/mL. [1.] 

What are Normal AFP Levels in Pregnancy?

Normal AFP levels in pregnancy depend on the gestational age of the fetus. Healthcare providers use specific charts to compare AFP levels to the expected range for a given week of pregnancy. Abnormal levels may indicate the need for further diagnostic testing to check for potential fetal abnormalities.

Levels of AFP are expected to climb in pregnancy and decline sharply following birth.  

One clinical guide gives the following levels for AFP in the second trimester, when AFP levels are expected to climb: [10.] 

Fetal blood (first trimester): Peak 200-400 mg/dL (2-4 g/L) 

Pregnancy (2nd trimester): 

• 14 weeks' gestation: Median 25.6 ng/mL (25.6 mcg/L)

• 15 weeks' gestation: Median 29.9 ng/mL (29.9 mcg/L)

• 16 weeks' gestation: Median 34.8 ng/mL (34.8 mcg/L)

• 17 weeks' gestation: Median 40.6 ng/mL (40.6 mcg/L)

• 18 weeks' gestation: Median 47.3 ng/mL (47.3 mcg/L)

• 19 weeks' gestation: Median 55.1 ng/mL (55.1 mcg/L)

• 20 weeks' gestation: Median 64.3 ng/mL (64.3 mcg/L)

• 21 weeks' gestation: Median 74.9 ng/mL (74.9 mcg/L)

Normal values for blacks or African Americans may be approximately 15% higher than for whites. [5.] 

Normal values are approximately 200% higher in women with twin pregnancy or multiple gestations. [5.] 

Clinical Significance of Elevated AFP Levels

Elevated AFP levels in pregnant women may be due to: [2.] 

• Neural tube defects (spina bifida, anencephaly): these defects expose fetal tissues, allowing more AFP to leak into the amniotic fluid and maternal circulation.

• Omphalocele: abdominal wall defect exposes internal organs, increasing AFP transfer to maternal blood.

• Gastroschisis: similar to omphalocele, this abdominal wall defect allows more AFP to enter maternal circulation.

• Sacrococcygeal teratoma: this tumor can produce additional AFP, elevating maternal serum levels.

• Placental abnormalities: compromised placental barrier may allow more AFP to cross into maternal blood.

• Cystic hygroma: associated with chromosomal abnormalities that can affect AFP production or transfer.

• Renal abnormalities: kidney defects may alter AFP metabolism or excretion, leading to elevated levels.

• Osteogenesis imperfecta: increased fetal tissue breakdown may release more AFP into circulation.

• Threatened abortion: placental damage can allow more AFP to enter maternal blood.

• Decreased maternal weight/intrauterine growth restriction: less maternal blood volume or smaller placenta can concentrate AFP levels.

Elevated AFP levels in nonpregnant adults may be due to: [2.] 

• Hepatocellular cancer: cancer cells in the liver can reactivate AFP gene expression, leading to increased production and secretion.

• Metastatic liver cancer: secondary liver tumors can stimulate AFP production in surrounding liver tissue or produce AFP themselves.

• Liver cirrhosis: chronic liver damage and regeneration can cause some hepatocytes to revert to a fetal-like state, increasing AFP production.

• Hepatitis: inflammation and regeneration of liver cells can trigger increased AFP synthesis as part of the healing process.

• Germ cell tumors: these tumors, particularly nonseminomatous types, can directly produce AFP as they contain cells similar to those in early embryonic development.

• Yolk sac tumor: this rare tumor type specifically produces AFP as it's derived from primitive germ cells that normally produce AFP during fetal development.

• Ataxia-telangiectasia: this genetic disorder affects DNA repair mechanisms, which may lead to increased AFP gene expression through complex cellular pathways.

• Incidental finding in healthy individuals [8.] 

What Can Cause a False Positive AFP Test?

False-positive AFP test results can be caused by: [2.] 

• Incorrect gestational age estimation in pregnancy

• Multiple pregnancies (e.g., twins or triplets)

• Certain benign liver tumors

• Recent Radiodiagnosis: High AFP levels can occur up to 2 weeks after radiodiagnosis involving radioactive tracers.

• Gestational Diabetes: This condition may lead to higher AFP levels.

• Cigarette Smoking: Smoking during pregnancy is associated with increased AFP levels.

• Race: AFP levels tend to be slightly higher in Black women and lower in women of Asian descent compared to White women.

• Weight Adjustments: AFP levels are adjusted for the mother's weight, which can affect the results.

• Contamination: Amniotic fluid specimens contaminated with fetal blood may show abnormally high AFP values, leading to misinterpretation.

• Mouse Monoclonal Antibodies: Patients who have received preparations of mouse monoclonal antibodies may have human anti-mouse antibodies, which can result in falsely high AFP readings.

• Rarely, other unknown reasons [8.] 

Clinical Significance of Decreased AFP

In pregnancy, a low level of AFP may signal need for additional assessment.  

Lower-than-expected levels of AFP in pregnancy can be due to: [2., 3., 7.]

• Down syndrome: fetuses with Down syndrome tend to produce less AFP, resulting in lower levels in maternal serum.

• Increased maternal weight: greater maternal blood volume can dilute AFP concentration, leading to lower measured levels.

• Fetal demise: AFP production stops when the fetus is no longer viable, causing levels to drop.

• Hydatidiform mole: this abnormal pregnancy produces little or no fetal tissue, resulting in minimal AFP production.

• Trisomy 18 (Edwards syndrome): similar to Down syndrome, fetuses with trisomy 18 often produce less AFP.

• Incorrect gestational age: AFP levels naturally rise during pregnancy, so if the fetus is younger than estimated, levels will appear lower than expected for the presumed gestational age.

FAQ: Understanding Alpha-Fetoprotein (AFP)

Alpha-Fetoprotein (AFP) is a protein produced primarily by the liver and yolk sac of a developing fetus. It is an important biomarker used in various medical contexts, including cancer diagnosis and monitoring during pregnancy. 

This FAQ section addresses common questions about AFP, AFP tests, and its significance.

What is AFP?

AFP stands for Alpha-Fetoprotein, a protein produced by the liver and yolk sac of a fetus. In adults, AFP levels are typically low, but elevated levels can indicate certain health conditions including liver disease and cancer.

What is the AFP Test?

The AFP test measures the level of Alpha-Fetoprotein in the blood. It is used as a screening tool in pregnancy and as a tumor marker to help diagnose and monitor certain types of cancer, particularly liver cancer.

What is AFP in Pregnancy?

During pregnancy, AFP is produced by the fetal liver and is present in the mother's blood. The AFP test is part of prenatal screening, used to detect potential birth defects such as neural tube defects (e.g., spina bifida) and abdominal wall defects in the developing baby.

When is the AFP Test Done?

The AFP test is typically done between the 15th and 20th weeks of pregnancy as part of the second trimester screening. It can also be done when liver cancer or other conditions that raise AFP levels are suspected.

What is the AFP Test Screening For?

The AFP test screens for:

• Neural tube defects and other abnormalities in a fetus during pregnancy

• Liver cancer (hepatocellular carcinoma)

• Germ cell tumors (testicular and ovarian cancers)

• Monitoring the effectiveness of cancer treatment

• Detecting potential recurrence of certain cancers

What are Normal AFP Levels in Pregnancy?

Normal AFP levels in pregnancy vary depending on the gestational age. The levels increase as the pregnancy progresses. 

Healthcare providers use gestational age-specific charts to interpret AFP levels. Abnormal levels can indicate potential fetal abnormalities and warrant further testing.

What Can Cause Elevated AFP Levels?

Elevated AFP levels can be caused by:

• Liver diseases such as hepatitis and cirrhosis

• Liver cancer (hepatocellular carcinoma)

• Germ cell tumors (testicular and ovarian cancers)

• Fetal abnormalities during pregnancy (neural tube defects, abdominal wall defects)

What Can Cause a False-Positive AFP Test?

False-positive AFP test results can be caused by: [2.] 

• Incorrect gestational age estimation in pregnancy

• Multiple pregnancies (e.g., twins or triplets)

• Certain benign liver tumors

• Recent Radiodiagnosis: High AFP levels can occur up to 2 weeks after radiodiagnosis involving radioactive tracers.

• Gestational Diabetes: This condition may lead to higher AFP levels.

• Cigarette Smoking: Smoking during pregnancy is associated with increased AFP levels.

• Race: AFP levels tend to be slightly higher in Black women and lower in women of Asian descent compared to White women.

• Weight Adjustments: AFP levels are adjusted for the mother's weight, which can affect the results.

• Contamination: Amniotic fluid specimens contaminated with fetal blood may show abnormally high AFP values, leading to misinterpretation.

• Mouse Monoclonal Antibodies: Patients who have received preparations of mouse monoclonal antibodies may have human anti-mouse antibodies, which can result in falsely high AFP readings.

• Rarely, other unknown reasons [8.]

How to Reduce AFP Levels Naturally?

There is no specific natural method to reduce AFP levels directly, but maintaining overall liver health can help. This includes:

• Eating a balanced diet rich in fruits, vegetables, and whole grains

• Avoiding excessive alcohol consumption

• Avoiding exposure to toxins and harmful chemicals

• Regular exercise

• Managing chronic conditions like diabetes and hypertension effectively

How is the AFP Level Chart Used for Liver Cancer?

The AFP level chart for liver cancer is used to compare individual AFP test results against established reference ranges to determine if AFP levels are elevated. 

Elevated AFP levels in nonpregnant adults can indicate liver cancer or other liver conditions. Monitoring changes in AFP levels over time helps assess the effectiveness of treatment and detect recurrence.

What are Normal AFP Levels in Pregnancy?

Normal AFP levels in pregnancy depend on the gestational age of the fetus. Healthcare providers use specific charts to compare AFP levels to the expected range for a given week of pregnancy. Abnormal levels may indicate the need for further diagnostic testing to check for potential fetal abnormalities.

Levels of AFP are expected to climb in pregnancy and decline sharply following birth.  

One clinical guide gives the following levels for AFP in the second trimester, when AFP levels are expected to climb: [10.]

Pregnancy (2nd trimester): 

• 14 weeks' gestation: Median 25.6 ng/mL (25.6 mcg/L)

• 15 weeks' gestation: Median 29.9 ng/mL (29.9 mcg/L)

• 16 weeks' gestation: Median 34.8 ng/mL (34.8 mcg/L)

• 17 weeks' gestation: Median 40.6 ng/mL (40.6 mcg/L)

• 18 weeks' gestation: Median 47.3 ng/mL (47.3 mcg/L)

• 19 weeks' gestation: Median 55.1 ng/mL (55.1 mcg/L)

• 20 weeks' gestation: Median 64.3 ng/mL (64.3 mcg/L)

• 21 weeks' gestation: Median 74.9 ng/mL (74.9 mcg/L)

Black or African American patients may have normal values approximately 15% higher than for whites. [5.]

Normal values are approximately 200% higher in women with multiple gestations. [5.]

When Should I Consult a Healthcare Provider About AFP Levels?

You should consult a healthcare provider if you have elevated AFP levels or if you have concerns about your AFP test results. This is particularly important if you are pregnant and have abnormal AFP levels, or if you have a condition such as liver disease or are being monitored for cancer.

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