Alpha fetoprotein

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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.[1]

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[2][3][4][5][6][7] the normal range for adults,[8][9] 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.[10]

Elevated alphafetoprotein
Classification and external resources
ICD-10 R77.2, Z36.1
ICD-9 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 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.[11][12][13]. 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.[14]


Tests performed on cerebrospinal fluid (CSF)

In normal infants, AFP in CSF is[15]:

  • 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

Levels of AFP in CSF decline with gestational age in proportion to levels of AFP in serum[16]

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.

 

Sources 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 screening[17] but is somewhat useful for surveillance after treatment.[18]

Rare AFP-secreting tumor types include carcinoma in a malignant mixed Müllerian tumor.[19]

In Wilms tumor AFP is rarely elevated, but when it is elevated it may serve as a marker of disease progression or recurrence.[20]

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

  1. ^ LabCorp 2004 Annual Report
  2. ^ Blohm ME, Vesterling-Hörner D, Calaminus G, Göbel U (1998). "Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age.". Pediatric hematology and oncology 15 (2): 135-42. PMID 9592840. 
  3. ^ Ohama K, Nagase H, Ogino K, et al (1997). "Alpha-fetoprotein (AFP) levels in normal children.". European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift für Kinderchirurgie 7 (5): 267-9. PMID 9402482. 
  4. ^ Lee PI, Chang MH, Chen DS, Lee CY (1988). "Serum alpha-fetoprotein in normal Chinese infants.". Zhonghua Minguo xiao er ke yi xue hui za zhi [Journal]. Zhonghua Minguo xiao er ke yi xue hui 29 (3): 152-8. PMID 2483492. 
  5. ^ Blair JI, Carachi R, Gupta R, Sim FG, McAllister EJ, Weston R (1987). "Plasma alpha fetoprotein reference ranges in infancy: effect of prematurity.". Arch. Dis. Child. 62 (4): 362-9. PMID 2439023. 
  6. ^ Bader D, Riskin A, Vafsi O, et al (2004). "Alpha-fetoprotein in the early neonatal period--a large study and review of the literature". Clin. Chim. Acta 349 (1-2): 15-23. doi:10.1016/j.cccn.2004.06.020. PMID 15469851. 
  7. ^ Wu JT, Roan Y, Knight JA (1985). "Serum levels of AFP in normal infants: their clinical and physiological significance", Mizejewski GJ, Porter I: Alfa-Fetoprotein and Congenital Disorders. Academic Press, 111-122. 
  8. ^ Ball D, Rose E, Alpert E (1992). "Alpha-fetoprotein levels in normal adults". Am. J. Med. Sci. 303 (3): 157-9. doi:10.1097/00000441-199203000-00004. PMID 1375809. 
  9. ^ Sizaret P, Martel N, Tuyns A, Reynaud S (1977). "Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups". Digestion 15 (2): 97-103. PMID 65304. 
  10. ^ Jassam N, Jones CM, Briscoe T, Horner JH (2006). "The hook effect: a need for constant vigilance.". Ann. Clin. Biochem. 43 (Pt 4): 314-7. doi:10.1258/000456306777695726. PMID 16824284.  PubMed
  11. ^ Serum alpha fetoprotein (AFP) levels in normal infants
  12. ^ Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age
  13. ^ Alpha-fetoprotein in the early neonatal period--a large study and review of the literature
  14. ^ Serum alpha-fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference
  15. ^ 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. PubMed abstract
  16. ^ Alpha-fetoprotein in human fetal cerebrospinal fluid
  17. ^ Paul SB, Gulati MS, Sreenivas V, Madan K, Gupta AK, Mukhopadhyay S, Acharya SK (2007). "Evaluating patients with cirrhosis for hepatocellular carcinoma: value of clinical symptomatology, imaging and alpha-fetoprotein.". Oncology 72 Suppl 1: 117–23. doi:10.1159/000111717. PMID 18087192. 
  18. ^ Kim do Y, Paik YH, Ahn SH, Youn YJ, Choi JW, Kim JK, Lee KS, Chon CY, Han KH (2007). "PIVKA-II is a useful tumor marker for recurrent hepatocellular carcinoma after surgical resection.". Oncology 72 Suppl 1: 52–7. doi:10.1159/000111707. PMID 18087182. 
  19. ^ Rebischung C, Pautier P, Morice P, Lhomme C, Duvillard P (2000). "Alpha-fetoprotein production by a malignant mixed Müllerian tumor of the ovary.". Gynecol. Oncol. 77 (1): 203–5. doi:10.1006/gyno.1999.5653. PMID 10739713. 
  20. ^ Crocoli A, Madafferi S, Jenkner A, Zaccara A, Inserra A (2007). "Elevated serum alpha-fetoprotein in Wilms tumor may follow the same pattern of other fetal neoplasms after treatment: evidence from three cases.". Pediatr Surg Int: 499. doi:10.1007/s00383-007-2067-7. PMID 17987303. 

 

Further reading

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

 

See also

  • Tumor marker
  • AFP-L3

 

External links


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