Alpha-fetoprotein 238706 225632747 2008-07-14T17:28:41Z 84.63.97.203 {{PBB|geneid=174}} '''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 tumor]]s. ==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 sac|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 [[United States|US]] clinical laboratory testing company, began offering AFP screening tests in the early 1980s.<ref>[http://www.labcorp.com/2004_annual_report/LabCorp_AR2004_1.pdf LabCorp 2004 Annual Report]</ref> ==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.<ref name="pmid1375809">{{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 }}</ref><ref name="pmid65304">{{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 = }}</ref> At birth, normal infants have AFP levels 4 or more [[Order of magnitude|orders of magnitude]] above this normal range, decreasing to within it over the first 1–2 years of life.<ref name="pmid9592840">{{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 = }}</ref><ref name="pmid9402482">{{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 = }}</ref><ref name="pmid2471821">{{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 = }}</ref><ref name="pmid2439023">{{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 = }}</ref><ref name="pmid15469851">{{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 }}</ref><ref name="Wu+1985">{{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 }}</ref> During this time, the normal range of AFP levels spans approximately 2 orders of magnitude.<ref name="pmid2471821"/> 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.<ref name="Jassam+2006">{{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}}</ref> 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 [[blood plasma|serum (blood plasma)]], and tests performed on [[amniotic sac|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 [[blood plasma|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 birth|multiple gestation]] as well as in a number of fetal abnormalities, such as [[neural tube defect]]s including [[spina bifida]] and [[anencephaly]], and [[abdominal wall defect]]s. 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, [[Human chorionic gonadotropin|hCG]] and [[estriol]] * '''Quad test''': AFP, [[Human chorionic gonadotropin|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 [[Lentil|''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 [[Human chorionic gonadotropin|HCG]]) used to monitor [[testicular cancer]], [[ovarian cancer]], and [[teratoma|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.<ref>[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]</ref><ref>[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]</ref><ref>[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]</ref>. 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.<ref>[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]</ref> <!-- === Tests performed on [[amniotic sac|amniotic fluid]]=== --> === Tests performed on [[cerebrospinal fluid]] (CSF) === In normal infants, AFP in CSF is<ref>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]</ref>: * 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<ref>[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]</ref> ==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 [[tumor]]s 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<ref name="pmid18087192">{{cite 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 }}</ref> but is somewhat useful for surveillance after treatment.<ref name="pmid18087182">{{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 }}</ref> Rare AFP-secreting tumor types include [[carcinoma]] in a [[malignant mixed Müllerian tumor]].<ref name="pmid10739713">{{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 }}</ref> In [[Wilms tumor]] AFP is rarely elevated, but when it is elevated it may serve as a marker of disease progression or recurrence.<ref name="pmid17987303">{{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 }}</ref> There are [[case report]]s of elevated AFP associated with [[teratoma]]. However, some of these case reports involve [[infant]]s but do not correct for the normal elevation of AFP in infants, while others ignore the likelihood that teratoma (and other [[germ cell tumor]]s) 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== {{reflist|2}} ==Further reading== {{refbegin | 2}} {{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}} }} {{refend}} ==See also== *[[Tumor marker]] *[[AFP-L3]] ==External links== * {{MeshName|alpha-Fetoproteins}} {{Tumor markers}} [[Category:Glycoproteins]] [[Category:Tumor markers]] [[Category:Obstetrics]] [[Category:Oncology]] [[ar:الفا فيتو بروتين]] [[de:Alpha-1-Fetoprotein]] [[es:Alfa-fetoproteína]] [[fr:Alpha-fœtoprotéine]] [[it:Alfa-feto proteina]] [[pl:Αlfa-fetoproteina]] [[pt:Alfa feto proteína]] [[ru:Альфа-фетопротеин]] [[fi:Alfafetoproteiini]] [[zh:Α-胎兒蛋白]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = yes | update_citations = yes }}