Alpha fetoprotein is a plasma glycoprotein found in humans.
It is the most abundant plasma protein synthesized by the human fetus. It is produced mainly by fetal liver and yolk sac during fetal development. Although synthesis drops markedly after birth, small amounts of alpha fetoprotein continue to be produced in the adult.
Alpha fetoprotein levels in serum, amniotic fluid and urine are used as a screening test for congenital defects, chromosomal abnormalities, as well as some adult tumors.
Structure and Function
Alpha fetoprotein is a glycoprotein having a single polypeptide chain of 591 amino acids and a carbohydrate moiety. It is encoded by the alpha fetoprotein gene on chromosome 4q25.
The function of alpha fetoprotein during development and later in adult life is largely unknown. Interest in this protein is based largely on the observation that it appears in increased quantity in the serum in adults in association with normal restorative processes (e.g. Liver regeneration) and malignant growth.
It is thought to be the fetal form of serum albumin. Similar to albumin, alpha fetoprotein binds and transports heavy metals, fatty acids, bilirubin, retinoids, steroids, etc.
The high affinity of alpha fetoprotein for estrogen could have important biological functions, although the significance of this binding has not yet been clearly understood.
Alpha fetoprotein is postulated to have immunoregulatory properties and may influence cell proliferation and growth. It is speculated to promote the development of tumors either by suppressing immune surveillance and/or immunity to oncogenic viruses.
Normal Levels of Alpha Fetoprotein
Men and non-pregnant women
0 ng/ml to 40 ng/ml.
Alpha fetoprotein concentration in maternal serum rises throughout pregnancy with a peak level at about 32 weeks of gestation. Thereafter, the levels start falling with a half-life of about 5 days. The level at 32 weeks gestation is 250 ng/ml. Between 15 and 20 weeks, levels usually range between 10 ng/ml to 150 ng/ml.
Alpha fetoprotein test results can also be reported as mom (multiple of the median, which measures how far an individual test result deviates from the median). If the median alpha fetoprotein at 16 weeks of gestation is 30 ng/ml and a pregnant woman’s alpha fetoprotein at same gestational age is 90 ng/ml, then her mom is equal to 90/30 = 3; which means, her alpha fetoprotein result is 3 times higher than median.
The normal range of alpha fetoprotein is 0.5 to 2.5 mom.
A higher than normal level may be seen in multiple gestation or in case of inaccurate dating of pregnancy.
Neonates have markedly elevated alpha fetoprotein levels (>100,000 ng/ml) that rapidly fall to below 100 ng/ml by 6 months and gradually return to normal over their first year.
Clinical Uses of Alpha Fetoprotein
To detect developmental birth defects
- Neural tube defects: such as spina bifida or anencephaly
- Abdominal wall defect such as omphalocele
The test is performed on pregnant women for screening certain fetal developmental abnormalities. Both maternal blood and amniotic fluid can be used to measure alpha fetoprotein levels.
To Diagnose Tumors
Serum alpha fetoprotein levels are increased in people with certain tumors. These include
- Hepatocellular carcinoma
- Pancreatic and gastro-intestinal malignancy
- Metastatic disease affecting the liver
- Nonseminomatous germ cell tumors of ovary and testes
- Yolk sac tumor
- Embryonal carcinoma
- Immature teratoma
Alpha fetoprotein level is used to support a clinical diagnosis of these malignancies. However, it is not recommended as a screening test to detect cancer in normal, healthy people.
To evaluate response to cancer treatment
Alpha fetoprotein may be used as a marker of response to treatment in patients with above-mentioned cancers and abnormal alpha fetoprotein levels. After surgical resection of the tumor, the elevated alpha fetoprotein level should fall to normal. If levels do not decrease and start increasing again, there is a greater likelihood of cancer recurrence.
Diagnostic support in certain diseases
- Benign liver disease (viral hepatitis, cirrhosis)- levels are only mildly elevated [In contrast to liver malignancies where it is markedly increased]
- Ataxia telangiectasia- elevated alpha fetoprotein is used to support the diagnosis
Method of Estimation
It is measured by immunoassay techniques. Most commonly chemiluminescent immunoassay is carried out for estimation.
Significance of Maternal Alpha fetoprotein Levels
The fetus normally excretes alpha fetoprotein into its urine, which goes into the amniotic fluid. From the amniotic fluid it reaches the maternal circulation through placenta. Thus it is found both in maternal serum and amniotic fluid. Maternal urine can also be used to measure alpha fetoprotein level but the values are lower.
Serum alpha fetoprotein
It forms part of the triple test (alpha fetoprotein, human chorionic gonadotropin and estriol) and quadruple test (inhibin A along with above three) which are prenatal screening tests carried out in the second trimester (14-16 weeks). These tests are used to screen for congenital abnormalities like Down syndrome, trisomy 18, neural tube defects, etc.
Low levels of alpha fetoprotein and abnormal levels of HCG, estriol or inhibin A may indicate Down syndrome, trisomy 18 or other chromosomal defect. Diabetic patients also have lower levels of alpha fetoprotein.
High levels of alpha fetoprotein are seen in neural tube defects like spina bifida, anencephaly, etc. Many patients with elevated maternal alpha fetoprotein do not develop birth defects, but there may be an increased risk of obstetric complications like premature rupture of membranes, placental abruption, placental accreta, etc.
Prenatal screening tests can be offered to all pregnant women but is essential in case of advanced maternal age or family history of previous births with chromosomal disorder or birth defects.
Read more about Genetic Inheritance: Modes and Significance
Abnormal levels only imply a significant risk and further evaluation and tests are usually required for definite confirmation.
Patients with abnormal levels of alpha fetoprotein should undergo detailed obstetric ultrasonography to look for fetal anomalies. Measurement of alpha fetoprotein in amniotic fluid obtained via amniocentesis can also be carried out. Genetic counseling is offered when the screening test result is positive.
Read more about Amniocentesis: Indications, Procedure, and Compilications
Read more about Level I and Level II Ultrasound in Pregnancy
Amniotic alpha fetoprotein
Amniotic fluid is obtained by inserting a hollow needle into the amniotic cavity through the abdominal wall under ultrasound guidance. This process is called amniocentesis.
Normal level of amniotic alpha fetoprotein is < or =2.0 multiples of median (mom)
Acetylcholinesterase (ache) analysis is an essential confirmatory test for all amniotic fluid specimens with positive alpha fetoprotein results. Combination of these two tests is able to detect 96% of all open spina bifida cases. False-positive result may occur from a bloody tap, which may cause both elevated alpha fetoprotein and ache levels.