Alpha-fetoprotein

Overview
Alpha-fetoprotein (AFP) is a molecule produced in the developing embryo and fetus. In humans, AFP levels decrease gradually after birth, reaching adult levels by 8 to 12 months. Normal adult AFP levels are low, but detectable; however, AFP has no known function in normal adults. In normal fetuses, AFP binds the hormone estradiol. AFP is measured in pregnant women, using maternal blood or amniotic fluid, as a screening test for a subset developmental abnormalities, principally open neural tube defects. It is also measured in pregnant women, other adults, and children, serving as a biomarker to detect a subset of tumors, principally hepatocellular carcinoma and endodermal sinus tumors.

Structure and levels
AFP is a glycoprotein of 590 amino acids and a carbohydrate moiety. Many functions have been proposed for AFP; an anti-cancer active site peptide has been identified and is referred to as AFPep. AFP is normally produced by the fetal yolk sac, the fetal gastrointestinal tract, and eventually by the fetal liver. Levels of AFP in fetal serum rise until the end of the first trimester of gestation and then fall. Because the fetus excretes AFP into its urine, amniotic fluid levels of AFP tend to mirror fetal serum levels. In contrast, maternal serum levels of fetal AFP are much lower but continue to rise until about week 32.

History
LabCorp, a large US clinical laboratory testing company, began offering AFP screening tests in the early 1980s.

AFP in normal infants
The normal range of AFP for adults is variously reported as under 50, under 10, and under 5. At birth, normal infants have AFP levels 4 or more magnitudes above     the normal range for adults,  decreasing to adult levels over the first year of life. Correct evaluation of abnormal AFP levels in infants must take into account this normal pattern.

Very high AFP levels may be subject to hooking, resulting in a false low level.

AFP tests
There are two categories of AFP tests: tests performed on serum (blood plasma), and tests performed on amniotic fluid. Tests performed on serum are further categorized by the reason for performing the test: maternal serum, adult tumor marker, and pediatric tumor marker.

Tests performed on serum
The standard is a quantitative test, reporting a measured concentration of AFP in the sample, but there is also a less expensive qualitative test, reporting only that the concentration is normal or high. The qualitative test is appropriate only in some circumstances.

The resulting test report should specify the assay method and equipment used, and the report of a quantitative test should also provide a reference range for the test result. Many laboratories report reference ranges that are based on all other samples tested in that laboratory, necessarily including samples with abnormal AFP concentrations due to disease. Superior reference ranges are produced by research on healthy subjects.

Maternal serum
Maternal serum AFP tests need to be interpreted according to the gestational age, as levels rise until about 32 weeks gestation. Typically, such measurements are done in the middle of the second trimester (14-16 weeks). Elevated levels are seen in multiple gestation as well as in a number of fetal abnormalities, such as neural tube defects including spina bifida and anencephaly, and abdominal wall defects. Other possibilities are errors in the date of the gestation or fetal demise. In contrast, low levels of maternal serum AFP are associated with Down syndrome and Trisomy 18. Diabetic patients also have lower levels. Patients with abnormal levels need to undergo detailed obstetric ultrasonography. The information is then used to decide whether to proceed with amniocentesis.

Maternal serum AFP may be measured as part of a routine prenatal screening test:
 * Triple test: AFP, hCG and estriol
 * Quad test: AFP, hCG, estriol, and Inhibin
 * Genetic counseling usually is offered when the screening test result is positive.

Tumor marker
Like any elevated tumor marker, elevated AFP by itself is not diagnostic, only suggestive. Tumor markers are used primarily to monitor the result of a treatment (e.g. chemotherapy). If levels of AFP go down after treatment, the tumor is not growing. In the case of babies, after treatment AFP should go down faster than it would normally. A temporary increase in AFP immediately following chemotherapy may indicate not that the tumor is growing but rather that it is shrinking (and releasing AFP as the tumor cells die). AFP-L3, an isoform of AFP which binds Lens culinaris agglutinin, can be particularly useful in early identification of aggressive tumors associated with hepatocellular carcinoma (HCC).

AFP is the main tumor marker (sometimes with HCG) used to monitor testicular cancer, ovarian cancer, and malignant teratoma in any location: values of AFP over time can have significant effect on the treatment plan.

AFP is normally elevated in infants, and because teratoma is the single most common kind of tumor in infants, several studies have provided reference ranges for AFP in normal infants. . Perhaps the most useful is this equation:  log Y = 7.397 - 2.622.log (X + 10), where X = age in days and Y = AFP level in nanograms per milliliter.

Tests performed on cerebrospinal fluid (CSF)
In normal infants, AFP in CSF is : Levels of AFP in CSF decline with gestational age in proportion to levels of AFP in serum
 * median 61 kIU/L (5th-95th centile: 2-889 kIU/L) in infants -69 to 31 days old
 * median 1.2 kIU/L (5th-95th centile: 0.1-12.5 kIU/L) in infants 32 to 110 days old

Interpretation of AFP test results
AFP test results often are reported as either ng/ml or MoM (multiple of the median, where the median is calculated for an appropriate reference population).

Maternal serum
Abnormally elevated AFP in the serum of a pregnant woman can have one or more of these sources:


 * a problem with the fetus
 * a problem with the placenta
 * a tumor or liver disease in the woman
 * a normally elevated AFP in the fetus or woman (some people naturally have very high AFP)

Usual follow-up steps include (1) a prenatal ultrasound exam to look for fetal abnormalities and/or (2) measurement of AFP in amniotic fluid obtained via amniocentesis.

Amniotic fluid
AFP in amniotic fluid has one or two sources. The fetus normally excretes AFP into its urine, hence into the amniotic fluid. A fetus with one of three broad categories of defects also releases AFP by other means. These categories are open neural tube defect, open abdominal wall defect, and skin disease or other failure of the interior or exterior body surface.

Abnormally elevated AFP in amniotic fluid can have one or more of many different causes:


 * normal elevation. 75% of AF AFP test results in the range 2.0 to 4.9 MoM are false positives:  the baby is normal.
 * open neural tube defect
 * open abdominal wall defect
 * congenital nephrosis
 * others

Sources of AFP: Normal
Serum alpha-fetoprotein is a fetal serum protein produced by the yolk sac and liver.

Tumors
Principal tumors that secrete AFP are endodermal sinus tumor (yolk sac carcinoma), neuroblastoma, hepatoblastoma, and hepatocellular carcinoma.

With regard to hepatocellular carcinoma, AFP is not useful for screening but is somewhat useful for surveillance after treatment.

Rare AFP-secreting tumor types include carcinoma in a malignant mixed Müllerian tumor.

In Wilms tumor AFP is rarely elevated, but when it is elevated it may serve as a marker of disease progression or recurrence.

There are case reports of elevated AFP associated with teratoma. However, some of these case reports involve infants but do not correct for the normal elevation of AFP in infants, while others ignore the likelihood that teratoma (and other germ cell tumors) may in fact be mixed tumors containing elements of endodermal sinus tumor.

In patients with AFP-secreting tumors, serum levels of AFP often correlate with tumor size. Resection is usually associated with a fall in serum levels. Serum levels are useful in assessing response to treatment.

Other
Increased serum levels in adults are also seen in acute hepatitis, colitis and ataxia telangiectasia.