Medicine:Alpha-fetoprotein

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Short description: Fetal analogue of serum albumin


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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

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[4] and is found in monomeric, dimeric and trimeric forms.

Structure

AFP is a glycoprotein of 591 amino acids[7] and a carbohydrate moiety.[8]

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.[9] Maternal plasma levels peak near the end of the first trimester, and begin decreasing prenatally at that time, then 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.[10]

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.[11][12] 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.[13][14] 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

Maternal

In pregnant women, fetal AFP levels can be monitored in the urine of the pregnant woman. 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.[15] 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.[16][17] 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.[18][19][20][21][22][23]

During this time, the normal range of AFP levels spans approximately two orders of magnitude.[20] Correct evaluation of abnormal AFP levels in infants must take into account these normal patterns.[20]

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.[24] 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

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:

A peptide derived from AFP that is referred to as AFPep is claimed to possess anti-cancer properties.[31]

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, if the AFP is elevated, the tumor is treated as a nonseminomatous tumor because it contains yolk sac (nonseminomatous) components.[32]

See also

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

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 226 (5): 377–408. doi:10.1177/153537020122600503. PMID 11393167. http://www.ebmonline.org/cgi/content/abstract/226/5/377. 
  3. ↑ "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. July 1983. PMID 6192711. 
  4. ↑ 4.0 4.1 "Entrez Gene: Alpha-fetoprotein". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=174. 
  5. ↑ "Entry - *104150 - ALPHA-FETOPROTEIN; AFP - OMIM" (in en-us). https://omim.org/entry/104150?search=afp&highlight=afp. 
  6. ↑ Perry, Shannon E.; Hockenberry, Marilyn J.; Lowdermilk, Deitra Leonard; Wilson, David (2014). "8: Nursing Care of the Family During Pregnancy". Maternal Child Nursing Care (Fifth ed.). St. Louis, Missouri: Elsevier. ISBN 978-0-323-09610-2. OCLC 858005418. https://www.worldcat.org/oclc/858005418. 
  7. ↑ "Human alpha-fetoprotein primary structure: a mass spectrometric study". Biochemistry 30 (20): 5061–6. May 1991. doi:10.1021/bi00234a032. PMID 1709810. 
  8. ↑ "Biochemical characteristics and clinical applications of alpha-fetoprotein isoforms". Anticancer Research 15 (4): 1491–9. 1995. PMID 7544570. 
  9. ↑ Chen, H (1997). "Regulation and activities of alpha-fetoprotein". Crit Rev Eukaryot Gene Expr . 7 (1–2): 11–41. doi:10.1615/critreveukargeneexpr.v7.i1-2.20. PMID 9034713. 
  10. ↑ Carter CS (2002). "Neuroendocrinology of sexual behavior in the female". in Becker JB. Behavioral Endocrinology. Cambridge, Massachusetts: MIT Press. pp. 88–89. ISBN 978-0-262-52321-9. https://books.google.com/books?id=D6TnKbTRBJoC&q=AFP%20binds%20maternal%20estrogen&pg=PA88. 
  11. ↑ "Hormones in male sexual development". Genes & Development 14 (24): 3075–86. December 2000. doi:10.1101/gad.843800. PMID 11124800. 
  12. ↑ "Aromatase enzyme activity and sex determination in chickens.". Science 255 (5043): 467–70. 1992. doi:10.1126/science.1734525. PMID 1734525. Bibcode: 1992Sci...255..467E. 
  13. ↑ "Role for estradiol in female-typical brain and behavioral sexual differentiation.". Frontiers in Neuroendocrinology 29 (1): 1–16. 2008. doi:10.1016/j.yfrne.2007.06.001. PMID 17720235. 
  14. ↑ Harding CF (2004). "Hormonal modulation of singing: hormonal modulation of the songbird brain and singing behavior.". Annals of the New York Academy of Sciences 1016 (1): 524–39. doi:10.1196/annals.1298.030. PMID 15313793. Bibcode: 2004NYASA1016..524H. 
  15. ↑ Perry, Shannon E. (2018). "Chapter 10: Assessment of High Risk Pregnancy". Maternal child nursing care : maternity pediatric (Sixth ed.). St. Louis, Missouri: Elsevier. ISBN 978-0-323-54938-7. OCLC 999441854. https://www.worldcat.org/oclc/999441854. 
  16. ↑ "Alpha-fetoprotein levels in normal adults". The American Journal of the Medical Sciences 303 (3): 157–9. March 1992. doi:10.1097/00000441-199203000-00004. PMID 1375809. 
  17. ↑ "Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups". Digestion 15 (2): 97–103. February 1977. doi:10.1159/000197990. PMID 65304. 
  18. ↑ "Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age". Pediatric Hematology and Oncology 15 (2): 135–42. 1998. doi:10.3109/08880019809167228. PMID 9592840. 
  19. ↑ "Alpha-fetoprotein (AFP) levels in normal children". European Journal of Pediatric Surgery 7 (5): 267–9. October 1997. doi:10.1055/s-2008-1071168. PMID 9402482. 
  20. ↑ 20.0 20.1 20.2 "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. doi:10.1097/00005176-198901000-00005. PMID 2471821. 
  21. ↑ "Plasma alpha fetoprotein reference ranges in infancy: effect of prematurity". Archives of Disease in Childhood 62 (4): 362–9. April 1987. doi:10.1136/adc.62.4.362. PMID 2439023. 
  22. ↑ "Alpha-fetoprotein in the early neonatal period--a large study and review of the literature". Clinica Chimica Acta 349 (1–2): 15–23. November 2004. doi:10.1016/j.cccn.2004.06.020. PMID 15469851. 
  23. ↑ "Serum levels of AFP in normal infants: their clinical and physiological significance". Alfa-Fetoprotein and Congenital Disorders. New York: Academic Press. 1985. pp. 111–122. 
  24. ↑ "The hook effect: a need for constant vigilance". Annals of Clinical Biochemistry 43 (Pt 4): 314–7. July 2006. doi:10.1258/000456306777695726. PMID 16824284. 
  25. ↑ "[Alpha fetoprotein concentration in the amniotic fluid in normal pregnancy and in pregnancy complicated by fetal anomaly]" (in hu). Orvosi Hetilap 131 (39): 2139–42. September 1990. PMID 1699194. 
  26. ↑ "Down syndrome screening in the first and second trimesters: what do the data show?". Seminars in Perinatology 29 (6): 367–75. December 2005. doi:10.1053/j.semperi.2006.01.001. PMID 16533649. 
  27. ↑ 27.0 27.1 27.2 Le, Tao. First Aid for the USMLE Step 1 2013. New York: McGraw-Hill Medical, 2013. Print.
  28. ↑ "First-trimester screening for neural tube defects using alpha-fetoprotein". Fetal Diagnosis and Therapy 31 (2): 109–14. 2012. doi:10.1159/000335677. PMID 22377693. 
  29. ↑ Ertle, JM; Heider, D; Wichert, M; Keller, B; Kueper, R; Hilgard, P; Gerken, G; Schlaak, JF (2013). "A combination of α-fetoprotein and des-γ-carboxy prothrombin is superior in detection of hepatocellular carcinoma.". Digestion 87 (2): 121–31. doi:10.1159/000346080. PMID 23406785. 
  30. ↑ "Molecular pathology of ataxia telangiectasia". Journal of Clinical Pathology 58 (10): 1009–15. October 2005. doi:10.1136/jcp.2005.026062. PMID 16189143. 
  31. ↑ "Alpha-fetoprotein-derived antiestrotrophic octapeptide". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1501 (1): 33–43. April 2000. doi:10.1016/S0925-4439(00)00008-9. PMID 10727847. 
  32. ↑ "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol 24 (17): 1639–41. September 1975. doi:10.1016/0006-2952(75)90094-5. PMID 10. https://www.sciencedirect.com/science/article/abs/pii/0006295275900945. 

Further reading

External links

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



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