Alpha-fetoprotein explained

Alpha-fetoprotein (AFP,^[1] α-fetoprotein; also sometimes called alpha-1-fetoprotein, alpha-fetoglobulin, or alpha fetal protein) is a protein^{[2] [3]} that in humans is encoded by the AFP gene.^{[4] [5]} The AFP gene is located on the q arm of chromosome 4 (4q13.3).^[6] Maternal AFP serum level is used to screen for Down syndrome, neural tube defects, and other chromosomal abnormalities.^[7]

AFP is a major plasma protein produced by the yolk sac and the fetal liver during fetal development. It is thought to be the fetal analog of serum albumin. AFP binds to copper, nickel, fatty acids and bilirubin and is found in monomeric, dimeric and trimeric forms.

Structure

AFP is a glycoprotein of 591 amino acids^[8] and a carbohydrate moiety.^[9]

Function

The function of AFP in adult humans is unknown. AFP is the most abundant plasma protein found in the human fetus. In the fetus, AFP is produced by both the liver and the yolk sac. It is believed to function as a carrier protein (similar to albumin) that transports materials such as fatty acids to cells.^[10] Maternal plasma levels rise until the 32nd week of pregnancy, when they begin to decline.^[11] They decrease rapidly after birth. Normal adult levels in the newborn are usually reached by the age of 8 to 12 months. While the function in humans is unknown, in rodents it binds estradiol to prevent the transport of this hormone across the placenta to the fetus. The main function of this is to prevent the virilization of female fetuses. As human AFP does not bind estrogen, its function in humans is less clear.^[12] In human liver cancer, AFP is found to bind glypican-3 (GPC3), another oncofetal antigen.^[13]

The rodent AFP system can be overridden with massive injections of estrogen, which overwhelm the AFP system and will masculinize the fetus. The masculinizing effect of estrogens may seem counter-intuitive since estrogens are critical for the proper development of female secondary characteristics during puberty. However, this is not the case prenatally. Gonadal hormones from the testes, such as testosterone and anti-Müllerian hormone, are required to cause development of a phenotypic male. Without these hormones, the fetus will develop into a phenotypic female even if genetically XY. The conversion of testosterone into estradiol by aromatase in many tissues may be an important step in masculinization of that tissue.^{[14] [15]} Masculinization of the brain is thought to occur both by conversion of testosterone into estradiol by aromatase, but also by de novo synthesis of estrogens within the brain.^{[16] [17]} Thus, AFP may protect the fetus from maternal estradiol that would otherwise have a masculinizing effect on the fetus, but its exact role is still controversial.

Serum levels

See main article: Elevated alpha-fetoprotein.

Maternal

Fetal AFP levels can be monitored in the urine of pregnant women. Since AFP is quickly cleared from the mother's serum via her kidneys, maternal urine AFP correlates with fetal serum levels, although the maternal urine level is much lower than the fetal serum level. AFP levels rise until about week 32. Maternal serum alpha-fetoprotein (MSAFP) screening is performed at 16 to 18 weeks of gestation.^[18] If MSAFP levels indicate an anomaly, amniocentesis may be offered to the patient.

Infants

The normal range of AFP for adults and children is variously reported as under 50, under 10, or under 5 ng/mL.^{[19] [20]} At birth, normal infants have AFP levels four or more orders of magnitude above this normal range, that decreases to a normal range over the first year of life.^{[21] [22] [23] [24] [25] [26]}

During this time, the normal range of AFP levels spans approximately two 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), which results in the level being reported significantly lower than the actual concentration.^[27] This is important for analysis of a series of AFP tumor marker tests, e.g. in the context of post-treatment early surveillance of cancer survivors, where the rate of decrease of AFP has diagnostic value.

Clinical significance

See main article: Elevated alpha-fetoprotein. Measurement of AFP is generally used in two clinical contexts. First, it is measured in pregnant women through the analysis of maternal blood or amniotic fluid as a screening test for certain developmental abnormalities, such as aneuploidy. Second, serum AFP level is elevated in people with certain tumors, and so it is used as a biomarker to follow these diseases. Some of these diseases are listed below:

• Developmental birth defects associated with elevated AFP
  • Omphalocele^{[28] [29]}
  • Gastroschisis
  • Neural tube defects: elevated α-fetoprotein in amniotic fluid and maternal serum^[30]
• Tumors associated with elevated AFP
  • Hepatocellular carcinoma^{[31] [32]}
  • Metastatic disease affecting the liver
  • Nonseminomatous germ cell tumors
  • Yolk sac tumor
• Other conditions associated with elevated AFP
  • Ataxia telangiectasia: elevated AFP is used as one factor in diagnosis^[33]

A peptide derived from AFP that is referred to as AFPep is claimed to possess anti-cancer properties.^[34]

In the treatment of testicular cancer it is paramount to differentiate seminomatous and nonseminomatous tumors. This is typically done pathologically after removal of the testicle and confirmed by tumor markers. However, if the pathology is pure seminoma but the AFP is elevated, the tumor is treated as a nonseminomatous tumor because it contains yolk sac (nonseminomatous) components.^[35]

See also

• Tumor marker
• AFP-L3
• Triple test
• Advanced maternal age

Further reading

• Nahon JL . The regulation of albumin and alpha-fetoprotein gene expression in mammals . Biochimie . 69 . 5 . 445–459 . May 1987 . 2445387 . 10.1016/0300-9084(87)90082-4 .
• Tilghman SM . The structure and regulation of the alpha-fetoprotein and albumin genes . Oxford Surveys on Eukaryotic Genes . 2 . 160–206 . 1989 . 2474300 .
• Mizejewski GJ . Biological role of alpha-fetoprotein in cancer: prospects for anticancer therapy . Expert Review of Anticancer Therapy . 2 . 6 . 709–735 . Dec 2002 . 12503217 . 10.1586/14737140.2.6.709 . 8321005 .
• Yachnin S, Hsu R, Heinrikson RL, Miller JB . Studies on human alpha-fetoprotein. Isolation and characterization of monomeric and polymeric forms and amino-terminal sequence analysis . Biochimica et Biophysica Acta . 493 . 2 . 418–428 . Aug 1977 . 70228 . 10.1016/0005-2795(77)90198-2 .
• Aoyagi Y, Ikenaka T, Ichida F . Comparative chemical structures of human alpha-fetoproteins from fetal serum and from ascites fluid of a patient with hepatoma . Cancer Research . 37 . 10 . 3663–3667 . Oct 1977 . 71198 .
• Aoyagi Y, Ikenaka T, Ichida F . Copper(II)-binding ability of human alpha-fetoprotein . Cancer Research . 38 . 10 . 3483–3486 . Oct 1978 . 80265 .
• Aoyagi Y, Ikenaka T, Ichida F . alpha-Fetoprotein as a carrier protein in plasma and its bilirubin-binding ability . Cancer Research . 39 . 9 . 3571–3574 . Sep 1979 . 89900 .
• Torres JM, Anel A, Uriel J . Alpha-fetoprotein-mediated uptake of fatty acids by human T lymphocytes . Journal of Cellular Physiology . 150 . 3 . 456–462 . Mar 1992 . 1371512 . 10.1002/jcp.1041500305 . 32015210 .
• Greenberg F, Faucett A, Rose E, Bancalari L, Kardon NB, Mizejewski G, Haddow JE, Alpert E . Congenital deficiency of alpha-fetoprotein . American Journal of Obstetrics and Gynecology . 167 . 2 . 509–511 . Aug 1992 . 1379776 . 10.1016/S0002-9378(11)91441-0 .
• Bansal V, Kumari K, Dixit A, Sahib MK . Interaction of human alpha fetoprotein with bilirubin . Indian Journal of Experimental Biology . 28 . 7 . 697–698 . Jul 1990 . 1703124 .
• Pucci P, Siciliano R, Malorni A, Marino G, Tecce MF, Ceccarini C, Terrana B . Human alpha-fetoprotein primary structure: a mass spectrometric study . Biochemistry . 30 . 20 . 5061–5066 . May 1991 . 1709810 . 10.1021/bi00234a032 .
• Liu MC, Yu S, Sy J, Redman CM, Lipmann F . Tyrosine sulfation of proteins from the human hepatoma cell line HepG2 . Proceedings of the National Academy of Sciences of the United States of America . 82 . 21 . 7160–7164 . Nov 1985 . 2414772 . 390808 . 10.1073/pnas.82.21.7160 . 1985PNAS...82.7160L . free .
• Gibbs PE, Zielinski R, Boyd C, Dugaiczyk A . Structure, polymorphism, and novel repeated DNA elements revealed by a complete sequence of the human alpha-fetoprotein gene . Biochemistry . 26 . 5 . 1332–1343 . Mar 1987 . 2436661 . 10.1021/bi00379a020 .
• Sakai M, Morinaga T, Urano Y . The human alpha-fetoprotein gene. Sequence organization and the 5' flanking region . The Journal of Biological Chemistry . 260 . 8 . 5055–5060 . Apr 1985 . 2580830 . 10.1016/S0021-9258(18)89178-5 . free .
• Ruoslahti E, Pihko H, Vaheri A, Seppala M, Virolainen M, Konttinen A . Alpha fetoprotein: structure and expression in man and inbred mouse strains under normal conditions and liver injury . Johns Hopkins Medical Journal. Supplement . 3 . 249–255 . 1975 . 4138095 .
• Urano Y, Sakai M, Watanabe K, Tamaoki T . Tandem arrangement of the albumin and alpha-fetoprotein genes in the human genome . Gene . 32 . 3 . 255–261 . Dec 1984 . 6085063 . 10.1016/0378-1119(84)90001-5 .
• Beattie WG, Dugaiczyk A . Structure and evolution of human alpha-fetoprotein deduced from partial sequence of cloned cDNA . Gene . 20 . 3 . 415–422 . Dec 1982 . 6187626 . 10.1016/0378-1119(82)90210-4 .
• Morinaga T, Sakai M, Wegmann TG, Tamaoki T . Primary structures of human alpha-fetoprotein and its mRNA . Proceedings of the National Academy of Sciences of the United States of America . 80 . 15 . 4604–4608 . Aug 1983 . 6192439 . 384092 . 10.1073/pnas.80.15.4604 . 1983PNAS...80.4604M . free .

Notes and References

1. Encyclopedia: AFP . Henderson's Dictionary of Biological Terms . Lawrence . Eleanor . 10th . 1 . 0-470-21446-5.
2. Tomasi TB . Structure and function of alpha-fetoprotein . Annual Review of Medicine . 28 . 453–465 . 1977 . 67821 . 10.1146/annurev.me.28.020177.002321 .
3. Mizejewski GJ . Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants . Experimental Biology and Medicine . Maywood, N.J. . 226 . 5 . 377–408 . May 2001 . 11393167 . 10.1177/153537020122600503 . 23763069 . subscription .
4. Harper ME, Dugaiczyk A . 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 . 565–572 . July 1983 . 6192711 . 1685723 .
5. Web site: Entrez Gene: Alpha-fetoprotein .
6. Web site: Entry - *104150 - ALPHA-FETOPROTEIN; AFP - OMIM . 2023-06-12 . omim.org . en-us .
7. Book: Perry SE, Hockenberry MJ, Lowdermilk DL, Wilson D . 8: Nursing Care of the Family During Pregnancy . Maternal Child Nursing Care . St. Louis, Missouri . 2014 . Elsevier . 978-0-323-09610-2 . Fifth . 858005418 .
8. Pucci P, Siciliano R, Malorni A, Marino G, Tecce MF, Ceccarini C, Terrana B . Human alpha-fetoprotein primary structure: a mass spectrometric study . Biochemistry . 30 . 20 . 5061–5066 . May 1991 . 1709810 . 10.1021/bi00234a032 .
9. Seregni E, Botti C, Bombardieri E . Biochemical characteristics and clinical applications of alpha-fetoprotein isoforms . Anticancer Research . 15 . 4 . 1491–1499 . 1995 . 7544570 .
10. Chen H . Regulation and activities of alpha-fetoprotein . Critical Reviews in Eukaryotic Gene Expression . 7 . 1–2 . 11–41 . 1997 . 9034713 . 10.1615/critreveukargeneexpr.v7.i1-2.20 .
11. Mizejewski Gj (2003) Levels of Alpha-Fetoprotein During regnancy and Early Infancy in Normal and Disease States; Obs Gyn Survey 804-82658(12):
12. Book: Carter CS . JB B . Neuroendocrinology of sexual behavior in the female . Behavioral Endocrinology . Cambridge, Massachusetts . 88–89 . 2002 . MIT Press . 978-0-262-52321-9 . https://books.google.com/books?id=D6TnKbTRBJoC&q=AFP%20binds%20maternal%20estrogen&pg=PA88 .
13. Zhang YF, Lin S, Xiao Z, Ho M . A proteomic atlas of glypican-3 interacting partners: Identification of alpha-fetoprotein and other extracellular proteins as potential immunotherapy targets in liver cancer . Proteoglycan Research . 2 . 4 . October 2024 . 39822733 . 11737099 . 10.1002/pgr2.70004 . en . 2832-3556 . free .
14. Nef S, Parada LF . Hormones in male sexual development . Genes & Development . 14 . 24 . 3075–3086 . December 2000 . 11124800 . 10.1101/gad.843800 . free .
15. Elbrecht A, Smith RG . Aromatase enzyme activity and sex determination in chickens. . Science . New York, N.Y. . 255 . 5043 . 467–470 . Jan 1992 . 1734525 . 10.1126/science.1734525 . 1992Sci...255..467E .
16. Bakker J, Baum MJ . Role for estradiol in female-typical brain and behavioral sexual differentiation. . Frontiers in Neuroendocrinology . 29 . 1 . 1–16 . Jan 2008 . 17720235 . 2373265 . 10.1016/j.yfrne.2007.06.001 .
17. Harding CF . Hormonal modulation of singing: hormonal modulation of the songbird brain and singing behavior. . Annals of the New York Academy of Sciences . 1016 . 1 . 524–539 . Jun 2004 . 15313793 . 10.1196/annals.1298.030 . 2004NYASA1016..524H . 12457330 .
18. Book: Perry SE . Chapter 10: Assessment of High Risk Pregnancy . Maternal child nursing care : maternity pediatric . St. Louis, Missouri . 2018 . Elsevier . 978-0-323-54938-7 . Sixth . 999441854 . Shannon E. . Perry .
19. Ball D, Rose E, Alpert E . Alpha-fetoprotein levels in normal adults . The American Journal of the Medical Sciences . 303 . 3 . 157–159 . March 1992 . 1375809 . 10.1097/00000441-199203000-00004 .
20. Sizaret P, Martel N, Tuyns A, Reynaud S . Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups . Digestion . 15 . 2 . 97–103 . February 1977 . 65304 . 10.1159/000197990 .
21. Blohm ME, Vesterling-Hörner D, Calaminus G, Göbel U . Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age . Pediatric Hematology and Oncology . 15 . 2 . 135–142 . 1998 . 9592840 . 10.3109/08880019809167228 .
22. Ohama K, Nagase H, Ogino K, Tsuchida K, Tanaka M, Kubo M, Horita S, Kawakami K, Ohmori M . Alpha-fetoprotein (AFP) levels in normal children . European Journal of Pediatric Surgery . 7 . 5 . 267–269 . October 1997 . 9402482 . 10.1055/s-2008-1071168 . 260137699 .
23. Lee PI, Chang MH, Chen DS, Lee CY . Serum alpha-fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference . Journal of Pediatric Gastroenterology and Nutrition . 8 . 1 . 19–25 . January 1989 . 2471821 . 10.1097/00005176-198901000-00005 . Chang Mei-hwei . Ding-Shinn Chen . 21104946 . free .
24. Blair JI, Carachi R, Gupta R, Sim FG, McAllister EJ, Weston R . Plasma alpha fetoprotein reference ranges in infancy: effect of prematurity . Archives of Disease in Childhood . 62 . 4 . 362–369 . April 1987 . 2439023 . 1778344 . 10.1136/adc.62.4.362 .
25. Bader D, Riskin A, Vafsi O, Tamir A, Peskin B, Israel N, Merksamer R, Dar H, David M . Alpha-fetoprotein in the early neonatal period--a large study and review of the literature . Clinica Chimica Acta; International Journal of Clinical Chemistry . 349 . 1–2 . 15–23 . November 2004 . 15469851 . 10.1016/j.cccn.2004.06.020 .
26. Book: Wu JT, Roan Y, Knight JA . Mizejewski GJ, Porter I . Serum levels of AFP in normal infants: their clinical and physiological significance . Alfa-Fetoprotein and Congenital Disorders . New York . 111–122 . 1985 . Academic Press .
27. Jassam N, Jones CM, Briscoe T, Horner JH . The hook effect: a need for constant vigilance . Annals of Clinical Biochemistry . 43 . Pt 4 . 314–317 . July 2006 . 16824284 . 10.1258/000456306777695726 . free .
28. Szabó M, Veress L, Münnich A, Papp Z . [Alpha fetoprotein concentration in the amniotic fluid in normal pregnancy and in pregnancy complicated by fetal anomaly] . Orvosi Hetilap . 131 . 39 . 2139–2142 . September 1990 . 1699194 . hu .
29. Rosen T, D'Alton ME . Down syndrome screening in the first and second trimesters: what do the data show? . Seminars in Perinatology . 29 . 6 . 367–375 . December 2005 . 16533649 . 10.1053/j.semperi.2006.01.001 .
30. Bredaki FE, Poon LC, Birdir C, Escalante D, Nicolaides KH . First-trimester screening for neural tube defects using alpha-fetoprotein . Fetal Diagnosis and Therapy . 31 . 2 . 109–114 . 2012 . 22377693 . 10.1159/000335677 . 57465 .
31. Le, Tao. First Aid for the USMLE Step 1 2013. New York: McGraw-Hill Medical, 2013. Print.
32. Ertle J, Heider D, Wichert M, Keller B, Kueper R, Hilgard P, Gerken G, Schlaak J . A combination of α-fetoprotein and des-γ-carboxy prothrombin is superior in detection of hepatocellular carcinoma. . Digestion . 87 . 2 . 121–131 . 2013 . 23406785 . 10.1159/000346080 . 25266129 .
33. Taylor AM, Byrd PJ . Molecular pathology of ataxia telangiectasia . Journal of Clinical Pathology . 58 . 10 . 1009–1015 . October 2005 . 16189143 . 1770730 . 10.1136/jcp.2005.026062 .
34. Mesfin FB, Bennett JA, Jacobson HI, Zhu S, Andersen TT . Alpha-fetoprotein-derived antiestrotrophic octapeptide . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1501 . 1 . 33–43 . April 2000 . 10727847 . 10.1016/S0925-4439(00)00008-9 . free .
35. Schmoldt A, Benthe HF, Haberland G . Digitoxin metabolism by rat liver microsomes . Biochemical Pharmacology . 24 . 17 . 1639–1641 . September 1975 . 10 . 10.1016/0006-2952(75)90094-5 . 10033/333424 . free . subscription .