Elevated alpha-fetoprotein

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.

Maternal serum AFP (MSAFP) varies by orders of magnitude during the course of a normal pregnancy. MSAFP increases rapidly until about 32 weeks gestation, then decreases gradually. After the pregnancy ends it decreases rapidly, with a half-life of about 5 days.

Typically, MSAFP is measured in the beginning of the second trimester (14–16 weeks). It may be measured alone or as part of a package of routine prenatal screening tests, such as a triple test or quad test.

Because MSAFP test results must be interpreted according to the gestational age, they often are reported in terms of multiple of the median (MoM). Because the median is calculated from tests of other women's pregnancies at the same gestational age, in effect MoM is independent of gestational age, but depend on accurate gestational dating. A typical normal range is 0.5 to 2.0 or 2.5 MoM.

• MSAFP above normal is seen in multiple gestation, when there is placental abruption, as well as in a number of fetal abnormalities, such as neural tube defects including spina bifida and anencephaly, and abdominal wall defects. Other possibility is error in the date of the gestation. Mothers with Methylenetetrahydrofolate reductase genetic variant also have more frequent elevated MSAFP.[1] Rarely, high MSAFP is due to endodermal sinus tumor (EST) or another germ cell tumor containing EST. These tumors can occur in the pregnant woman (often as an ovarian tumor) or in the fetus.
• MSAFP below normal is associated with a smaller number of conditions, including Down syndrome and Trisomy 18. Diabetic patients also have lower levels.

Patients with abnormal MSAFP need to undergo detailed obstetric ultrasonography. The information is then used to decide whether to proceed with amniocentesis. Genetic counseling usually is offered when the screening test result is positive.

If a woman is already getting a Quad test for Down Syndrome screening, then the AFP-marker that is part of this test provides the screen result for neural-tube and abdominal wall defects. However, if a woman received a 1st Trimester Combined screen for Down Syndrome, which does not include AFP, then some physicians will specifically order an AFP-only test in the 2nd trimester to screen for neural tube/abdominal wall defects. However, because AFP-based screening only has an 80-85% sensitivity for neural tube and abdominal wall defects,[2] many maternal-fetal medicine specialists and some obstetricians do not bother ordering an AFP test and instead perform detailed "Level-II" ultrasounds on all of their patients, which, in competent hands, results in a 97% sensitivity for these defects. In fact, these physicians might disregard the AFP-related information on neural tube/abdominal wall defects and do the detailed ultrasound to look for these defects even if the patient has a "normal" AFP reading.

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

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).

In the context of evidence-based medicine, AFP is validated at the highest level as a tumor marker for use in patients with nonseminomatous germ cell tumors.[3][4]

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.

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.[5][6][7] 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.[8] When neonatal AFP is above normal (after adjustment for age), a low fraction of AFP-L3 is reassuring.[9]

For hepatocellular carcinoma (HCC), AFP cannot be considered to be specifically diagnostic of HCC, levels of AFP may be elevated in serum from patients with chronic disease; for example, research has indicated that AFP is not useful for screening in patients with cirrhosis[10] or Hepatitis C[11] and therefore elevated AFP in these patients may not be indicative, or be only suggestive, of HCC. AFP is considered a useful marker for post-treatment monitoring of HCC patients (e.g. for treatment efficacy or tumor recurrence). The value of such tests may be improved by parallel monitoring of other markers.[12][13]

AFP-L3, an isoform of AFP which binds Lens culinaris agglutinin, can be particularly useful in early identification of aggressive tumors associated with HCC.

Rare AFP-secreting tumor types include carcinoma in a mixed Müllerian tumor.[14] The Sertoli-Leydig cell tumor, which itself is rare, rarely secretes AFP.[15]

In Wilms tumor AFP is rarely elevated, but when it is elevated it may serve as a marker of disease progression or recurrence.[16]

Increased serum levels in adults are also seen in acute hepatitis, colitis and ataxia telangiectasia. Increased serum levels of alpha-fetoprotein are sometimes found in citrullinemia and argininosuccinate synthetase deficiency.[17]