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Alpha-fetoprotein
Identifiers
Symbols AFP; FETA; HPAFP
External IDs OMIM: 104150 MGI: 87951 HomoloGene: 36278 GeneCards: AFP Gene
RNA expression pattern
PBB GE AFP 204694 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 174 11576
Ensembl ENSG00000081051 ENSMUSG00000054932
UniProt P02771 Q3TGA3
RefSeq (mRNA) NM_001134 NM_007423
RefSeq (protein) NP_001125 NP_031449
Location (UCSC) Chr 4:
74.52 - 74.54 Mb		 Chr 5:
91.57 - 91.58 Mb
PubMed search [1] [2]

Alpha-fetoprotein (AFP, α-fetoprotein) is a protein[1][2] that in humans is encoded by the AFP gene.[3][4]

This gene encodes alpha-fetoprotein, a major plasma protein produced by the yolk sac and the liver during fetal life. The protein is thought to be the fetal counterpart of serum albumin, and the alpha-fetoprotein and albumin genes are present in tandem on chromosome 4. Alpha-fetoprotein is found in monomeric as well as dimeric and trimeric forms, and binds copper, nickel, fatty acids and bilirubin.[4]

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 healthy 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: it is principally increased in open neural tube defects and omphalocoele & decreased in Down syndrome. It is also measured in non-pregnant women, other adults, and children, serving as a biomarker to detect a subset of tumors. In adults, levels over 500 nanograms/milliliter of AFP are seen in only three situations: Hepatocellular carcinoma, Germ cell tumors, and metastatic cancer in the liver originating from other primary tumors elsewhere.

In rats, AFP binds maternal estrogen, preventing its passage through the placenta. The main function of this is to prevent the masculinization of female fetuses. The system can be overridden with massive injections of estrogen, which swamp the AFP system and masculinize female fetuses.

Contents

Structure and levels

AFP is a glycoprotein of 591 amino acids and a carbohydrate moiety. Many functions have been proposed for AFP such as 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.[5]

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.[6][7] 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.[8][9][10][11][12][13] During this time, the normal range of AFP levels spans approximately 2 orders of magnitude.[10] 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.[14] 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.

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 (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 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.

If a women 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[15], 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[citation needed]. 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[citation needed].

Tumor marker

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.[16][17]

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 and HCG are the main tumor markers used to monitor adult and pediatric germ cell tumors, including testicular, ovarian and extragonadal germ cell tumors as well as malignant teratoma in any location: values of AFP and HCG can have significant effects 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.[8][12][18] 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.[10] When neonatal AFP is above normal (after adjustment for age), a low fraction of AFP-L3 is reassuring.[19]

Tests performed on cerebrospinal fluid (CSF)

In normal infants, AFP in CSF is:[20]

  • 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[21]

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 cannot be considered to be specifically diagnostic of HCC, as levels of AFP may be elevated in serum from patients with chronic liver disease; for example, research has indicated that AFP is not useful for screening in patients suffering from cirrhosis[22] or Hepatitis C[23] 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.[24][25]

Rare AFP-secreting tumor types include carcinoma in a mixed Müllerian tumor.[26] The Sertoli-Leydig cell tumor, which itself is rare, rarely secretes AFP.[27]

In Wilms tumor AFP is rarely elevated, but when it is elevated it may serve as a marker of disease progression or recurrence.[28]

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. Increased serum levels of [alpha-fetoprotein] are sometimes found in Citrullinemia and Argininosuccinate synthetase deficiency. [29]

See also

References

  1. ^ Tomasi TB (1977). "Structure and function of alpha-fetoprotein". Annual review of medicine 28: 453–65. doi:10.1146/annurev.me.28.020177.002321. PMID 67821. 
  2. ^ Mizejewski GJ (May 2001). "Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants". Experimental biology and medicine (Maywood, N.J.) 226 (5): 377–408. PMID 11393167. http://www.ebmonline.org/cgi/content/abstract/226/5/377. 
  3. ^ Harper ME, Dugaiczyk A (July 1983). "Linkage of the evolutionarily-related serum albumin and alpha-fetoprotein genes within q11-22 of human chromosome 4". American journal of human genetics 35 (4): 565–72. PMID 6192711. 
  4. ^ a b "Entrez Gene: Alpha-fetoprotein". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=174. 
  5. ^ LabCorp 2004 Annual Report
  6. ^ 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. 
  7. ^ 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. doi:10.1159/000197990. PMID 65304. 
  8. ^ a b 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. 
  9. ^ 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. 
  10. ^ a b c Lee PI, Chang MH, Chen DS, Lee CY (January 1989). "Serum alpha-fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference". J. Pediatr. Gastroenterol. Nutr. 8 (1): 19–25. PMID 2471821. 
  11. ^ 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. doi:10.1136/adc.62.4.362. PMID 2439023. 
  12. ^ a b 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. 
  13. ^ Wu JT, Roan Y, Knight JA (1985). "Serum levels of AFP in normal infants: their clinical and physiological significance". in Mizejewski GJ, Porter I. Alfa-Fetoprotein and Congenital Disorders. Academic Press. pp. 111–122. 
  14. ^ 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
  15. ^ http://www.cdph.ca.gov/programs/pns/Documents/Provider%20Handbook%20%202009%20WEB.pdf
  16. ^ Duffy MJ (September 2004). "Evidence for the clinical use of tumour markers". Ann. Clin. Biochem. 41 (Pt 5): 370–7. doi:10.1258/0004563041731529. PMID 15333188. 
  17. ^ Duffy MJ, Crown J (November 2008). "A personalized approach to cancer treatment: how biomarkers can help". Clin. Chem. 54 (11): 1770–9. doi:10.1373/clinchem.2008.110056. PMID 18801934. 
  18. ^ Wu JT, Book L, Sudar K (January 1981). "Serum alpha fetoprotein (AFP) levels in normal infants". Pediatric research 15 (1): 50–2. doi:10.1203/00006450-198101000-00012. PMID 6163129. 
  19. ^ Kinoshita Y, Tajiri T, Souzaki R, Tatsuta K, Higashi M, Izaki T, Takahashi Y, Taguchi T (June 2008). "Diagnostic value of lectin reactive alpha-fetoprotein for neoinfantile hepatic tumors and malignant germ cell tumors: preliminary study". J. Pediatr. Hematol. Oncol. 30 (6): 447–50. doi:10.1097/MPH.0b013e31816916ad. PMID 18525461. 
  20. ^ Coakley J, Kellie SJ, Nath C, Munas A, Cooke-Yarborough C (January 2005). "Interpretation of alpha-fetoprotein concentrations in cerebrospinal fluid of infants". Annals of clinical biochemistry 42 (Pt 1): 24–9. doi:10.1258/0004563053026763. PMID 15802029. 
  21. ^ Christiansen M, Høgdall CK, Høgdall EV (January 2000). "Alpha-fetoprotein in human fetal cerebrospinal fluid". Clinica chimica acta; international journal of clinical chemistry 291 (1): 35–41. doi:10.1016/S0009-8981(99)00195-3. PMID 10612715. 
  22. ^ 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. 
  23. ^ Samir Gupta, MD; Stephen Bent, MD; and Jeffrey Kohlwes, MD, MPH (2003). "Test Characteristics of {alpha}-Fetoprotein for Detecting Hepatocellular Carcinoma in Patients with Hepatitis C: A Systematic Review and Critical Analysis". Annals of Internal Medicine 139 (1): 46–50. PMID 12834318. 
  24. ^ 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. 
  25. ^ Zhou L, Liu J, Luo F (2006). "Serum tumor markers for detection of hepatocellular carcinoma". World J Gastroenterol 12 (8): 1175–1181. PMID 16534867. 
  26. ^ 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. 
  27. ^ Watanabe T, Yamada H, Morimura Y, Abe M, Motoyama T, Sato A (June 2008). "Ovarian Sertoli-Leydig cell tumor with heterologous gastrointestinal epithelium as a source of alpha-fetoprotein: a case report". J. Obstet. Gynaecol. Res. 34 (3): 418–21. doi:10.1111/j.1447-0756.2008.00730.x. PMID 18588618. 
  28. ^ 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 24: 499. doi:10.1007/s00383-007-2067-7. PMID 17987303. 
  29. ^ http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=citrin

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. doi:10.1016/0378-1119(84)90001-5. 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. doi:10.1016/0378-1119(82)90210-4. 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. 

External links

Tumor markers
Blood
Endocrine
Nervous system
Cardiovascular/
respiratory
Digestive
Alpha-fetoprotein/AFP-L3
Reproductive/
urinary/
breast
βhCG · Alpha-fetoprotein/AFP-L3 · CD30
General histology
Musculoskeletal
Note: all are peptide except normetanephrine and PCA3.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.








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