Alpha-fetoprotein

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 increased in open neural tube defects & decreased in Down syndrome. 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.

tructure 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. [ [http://www.labcorp.com/2004_annual_report/LabCorp_AR2004_1.pdf LabCorp 2004 Annual Report] ]

AFP in normal infants

The normal range of AFP for adults and children is variously reported as under 50, under 10, and under 5 ng/mL.cite journal
author = Ball D, Rose E, Alpert E
title = Alpha-fetoprotein levels in normal adults
journal = Am. J. Med. Sci.
volume = 303
issue = 3
pages = 157–9
year = 1992
pmid = 1375809
doi = 10.1097/00000441-199203000-00004 ] cite journal
author = Sizaret P, Martel N, Tuyns A, Reynaud S
title = Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups
journal = Digestion
volume = 15
issue = 2
pages = 97–103
year = 1977
pmid = 65304
doi =
issn = ] At birth, normal infants have AFP levels 4 or more orders of magnitude above this normal range, decreasing to within it over the first 1–2 years of life.cite journal
author = Blohm ME, Vesterling-Hörner D, Calaminus G, Göbel U
title = Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age.
journal = Pediatric hematology and oncology
volume = 15
issue = 2
pages = 135–42
year = 1998
pmid = 9592840
doi =
issn = ] cite journal
author = Ohama K, Nagase H, Ogino K, "et al"
title = Alpha-fetoprotein (AFP) levels in normal children.
journal = European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift für Kinderchirurgie
volume = 7
issue = 5
pages = 267–9
year = 1997
pmid = 9402482
doi =
issn = ] cite journal
author = Lee PI, Chang MH, Chen DS, Lee CY
title = Serum alpha-fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference
journal = J. Pediatr. Gastroenterol. Nutr.
volume = 8
issue = 1
pages = 19–25
year = 1989
month = January
pmid = 2471821
doi =
url =
issn = ] cite journal
author = Blair JI, Carachi R, Gupta R, Sim FG, McAllister EJ, Weston R
title = Plasma alpha fetoprotein reference ranges in infancy: effect of prematurity.
journal = Arch. Dis. Child.
volume = 62
issue = 4
pages = 362–9
year = 1987
pmid = 2439023
doi =
issn = ] cite journal
author = Bader D, Riskin A, Vafsi O, "et al"
title = Alpha-fetoprotein in the early neonatal period--a large study and review of the literature
journal = Clin. Chim. Acta
volume = 349
issue = 1-2
pages = 15–23
year = 2004
pmid = 15469851
doi = 10.1016/j.cccn.2004.06.020 ] cite book
author = Wu JT, Roan Y, Knight JA
chapter = Serum levels of AFP in normal infants: their clinical and physiological significance
title = Alfa-Fetoprotein and Congenital Disorders
editor = Mizejewski GJ, Porter I
year = 1985
pages = 111-122
publisher = Academic Press
address = New York] During this time, the normal range of AFP levels spans approximately 2 orders of magnitude. Correct evaluation of "abnormal" AFP levels in infants must take into account these normal patterns.

Very high AFP levels may be subject to hooking (see Tumor marker), resulting in a reported high level that is nonetheless significantly lower than the actual level.cite journal
author = Jassam N, Jones CM, Briscoe T, Horner JH
title = The hook effect: a need for constant vigilance.
journal = Ann. Clin. Biochem.
volume = 43
issue = Pt 4
pages = 314–7
year = 2006
pmid = 16824284
doi = 10.1258/000456306777695726 PMID|16824284] This is important for analysis of a series of AFP tumor marker tests, eg in the context of post-treatment early surveillance of cancer survivors, where the rate of decrease of AFP has diagnostic value.

DiseaseDisorder infobox
Name = Elevated alphafetoprotein
ICD10 = R77.2, Z36.1
ICD9 = ICD9|V28.1

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 (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. 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 possibilities are errors in the date of the gestation or fetal demise. 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.

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. [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=6163129 Serum alpha fetoprotein (AFP) levels in normal infants] ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=9592840 Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age] ] [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=15469851 Alpha-fetoprotein in the early neonatal period--a large study and review of the literature] ] . 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. [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=2471821 Serum alpha-fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference] ]

Tests performed on cerebrospinal fluid (CSF)

In normal infants, AFP in CSF is [Coakley J, Kellie SJ, Nath C, Munas A, Cooke-Yarborough C. Interpretation of alpha-fetoprotein concentrations in cerebrospinal fluid of infants. Ann Clin Biochem. 2005 Jan;42(Pt 1):24-9. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15802029 PubMed abstract] ] :
* 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 oldLevels of AFP in CSF decline with gestational age in proportion to levels of AFP in serum [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=10612715 Alpha-fetoprotein in human fetal cerebrospinal fluid] ]

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

ources of AFP: Normal

Serum alpha-fetoprotein is a fetal serum protein produced by the yolk sac and liver.

ources of AFP: Abnormal

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 screeningcite journal
author = Paul SB, Gulati MS, Sreenivas V, Madan K, Gupta AK, Mukhopadhyay S, Acharya SK
title = Evaluating patients with cirrhosis for hepatocellular carcinoma: value of clinical symptomatology, imaging and alpha-fetoprotein.
journal = Oncology
volume = 72 Suppl 1
issue =
pages = 117–23
year = 2007
pmid = 18087192
doi = 10.1159/000111717 ] but is somewhat useful for surveillance after treatment.cite journal
author = Kim do Y, Paik YH, Ahn SH, Youn YJ, Choi JW, Kim JK, Lee KS, Chon CY, Han KH
title = PIVKA-II is a useful tumor marker for recurrent hepatocellular carcinoma after surgical resection.
journal = Oncology
volume = 72 Suppl 1
issue =
pages = 52–7
year = 2007
pmid = 18087182
doi = 10.1159/000111707 ]

Rare AFP-secreting tumor types include carcinoma in a malignant mixed Müllerian tumor.cite journal
author = Rebischung C, Pautier P, Morice P, Lhomme C, Duvillard P
title = Alpha-fetoprotein production by a malignant mixed Müllerian tumor of the ovary.
journal = Gynecol. Oncol.
volume = 77
issue = 1
pages = 203–5
year = 2000
pmid = 10739713
doi = 10.1006/gyno.1999.5653 ]

In Wilms tumor AFP is rarely elevated, but when it is elevated it may serve as a marker of disease progression or recurrence.cite journal
author = Crocoli A, Madafferi S, Jenkner A, Zaccara A, Inserra A
title = Elevated serum alpha-fetoprotein in Wilms tumor may follow the same pattern of other fetal neoplasms after treatment: evidence from three cases.
journal = Pediatr Surg Int
volume = 24
issue =
pages = 499
year = 2007
pmid = 17987303
doi = 10.1007/s00383-007-2067-7 ]

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.

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Nahon JL |title=The regulation of albumin and alpha-fetoprotein gene expression in mammals. |journal=Biochimie |volume=69 |issue= 5 |pages= 445–59 |year= 1987 |pmid= 2445387 |doi=
*cite journal | author=Tilghman SM |title=The structure and regulation of the alpha-fetoprotein and albumin genes. |journal=Oxf. Surv. Eukaryot. Genes |volume=2 |issue= |pages= 160–206 |year= 1989 |pmid= 2474300 |doi=
*cite journal | author=Mizejewski GJ |title=Biological role of alpha-fetoprotein in cancer: prospects for anticancer therapy. |journal=Expert Rev Anticancer Ther |volume=2 |issue= 6 |pages= 709–35 |year= 2003 |pmid= 12503217 |doi= 10.1586/14737140.2.6.709
*cite journal | author=Yachnin S, Hsu R, Heinrikson RL, Miller JB |title=Studies on human alpha-fetoprotein. Isolation and characterization of monomeric and polymeric forms and amino-terminal sequence analysis. |journal=Biochim. Biophys. Acta |volume=493 |issue= 2 |pages= 418–28 |year= 1977 |pmid= 70228 |doi=
*cite journal | author=Aoyagi Y, Ikenaka T, Ichida F |title=Comparative chemical structures of human alpha-fetoproteins from fetal serum and from ascites fluid of a patient with hepatoma. |journal=Cancer Res. |volume=37 |issue= 10 |pages= 3663–7 |year= 1977 |pmid= 71198 |doi=
*cite journal | author=Aoyagi Y, Ikenaka T, Ichida F |title=Copper(II)-binding ability of human alpha-fetoprotein. |journal=Cancer Res. |volume=38 |issue= 10 |pages= 3483–6 |year= 1978 |pmid= 80265 |doi=
*cite journal | author=Aoyagi Y, Ikenaka T, Ichida F |title=alpha-Fetoprotein as a carrier protein in plasma and its bilirubin-binding ability. |journal=Cancer Res. |volume=39 |issue= 9 |pages= 3571–4 |year= 1979 |pmid= 89900 |doi=
*cite journal | author=Torres JM, Anel A, Uriel J |title=Alpha-fetoprotein-mediated uptake of fatty acids by human T lymphocytes. |journal=J. Cell. Physiol. |volume=150 |issue= 3 |pages= 456–62 |year= 1992 |pmid= 1371512 |doi= 10.1002/jcp.1041500305
*cite journal | author=Greenberg F, Faucett A, Rose E, "et al." |title=Congenital deficiency of alpha-fetoprotein. |journal=Am. J. Obstet. Gynecol. |volume=167 |issue= 2 |pages= 509–11 |year= 1992 |pmid= 1379776 |doi=
*cite journal | author=Bansal V, Kumari K, Dixit A, Sahib MK |title=Interaction of human alpha fetoprotein with bilirubin. |journal=Indian J. Exp. Biol. |volume=28 |issue= 7 |pages= 697–8 |year= 1991 |pmid= 1703124 |doi=
*cite journal | author=Pucci P, Siciliano R, Malorni A, "et al." |title=Human alpha-fetoprotein primary structure: a mass spectrometric study. |journal=Biochemistry |volume=30 |issue= 20 |pages= 5061–6 |year= 1991 |pmid= 1709810| doi=10.1021/bi00234a032
*cite journal | author=Liu MC, Yu S, Sy J, "et al." |title=Tyrosine sulfation of proteins from the human hepatoma cell line HepG2. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=82 |issue= 21 |pages= 7160–4 |year= 1985 |pmid= 2414772| doi=10.1073/pnas.82.21.7160
*cite journal | author=Gibbs PE, Zielinski R, Boyd C, Dugaiczyk A |title=Structure, polymorphism, and novel repeated DNA elements revealed by a complete sequence of the human alpha-fetoprotein gene. |journal=Biochemistry |volume=26 |issue= 5 |pages= 1332–43 |year= 1987 |pmid= 2436661| doi=10.1021/bi00379a020
*cite journal | author=Sakai M, Morinaga T, Urano Y, "et al." |title=The human alpha-fetoprotein gene. Sequence organization and the 5' flanking region. |journal=J. Biol. Chem. |volume=260 |issue= 8 |pages= 5055–60 |year= 1985 |pmid= 2580830 |doi=
*cite journal | author=Ruoslahti E, Pihko H, Vaheri A, "et al." |title=Alpha fetoprotein: structure and expression in man and inbred mouse strains under normal conditions and liver injury. |journal=Johns Hopkins Med. J. Suppl. |volume=3 |issue= |pages= 249–55 |year= 1975 |pmid= 4138095 |doi=
*cite journal | author=Urano Y, Sakai M, Watanabe K, Tamaoki T |title=Tandem arrangement of the albumin and alpha-fetoprotein genes in the human genome. |journal=Gene |volume=32 |issue= 3 |pages= 255–61 |year= 1985 |pmid= 6085063 |doi=
*cite journal | author=Beattie WG, Dugaiczyk A |title=Structure and evolution of human alpha-fetoprotein deduced from partial sequence of cloned cDNA. |journal=Gene |volume=20 |issue= 3 |pages= 415–22 |year= 1983 |pmid= 6187626 |doi=
*cite journal | author=Morinaga T, Sakai M, Wegmann TG, Tamaoki T |title=Primary structures of human alpha-fetoprotein and its mRNA. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=80 |issue= 15 |pages= 4604–8 |year= 1983 |pmid= 6192439| doi=10.1073/pnas.80.15.4604

ee also

*Tumor marker
*AFP-L3

External links

*

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