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Alpha-fetoprotein (AFP) is the major protein of fetal serum but it is usually undetectable after birth. AFP is made by the yolk sac of the fetus, enters the amniotic fluid and crosses the placenta into the maternal circulation. See also the separate Tumour Markers article.
Conditions which may lead to raised levels of alpha-fetoprotein
- Hepatocellular carcinoma (HCC): AFP levels are abnormal in 40-60% of patients. The American Association for the Study of Liver Diseases recommends diagnosis of HCC in patients with cirrhosis in the presence of a mass in the liver if AFP is >200 ng/mL.
- Other gastrointestinal cancers:
- Gastric cancer: AFP-producing gastric cancer (AFP level >7 ng/mL) is rare but is associated with a poorer prognosis than non-AFP-producing gastric cancer.
- Biliary tract cancer.
- Pancreatic cancer.
- Nonseminomatous germ cell tumours: if suspected, AFP measurement is essential.
- AFP may also be raised in patients with metastatic lung cancer and (rarely) primary lung cancer.
- Cirrhosis: patients may have abnormal AFP values, although usually less than 500 ng/mL.
- Viral hepatitis.
- Ataxia with telangiectasia.
- Pregnancy is associated with elevated AFP levels, particularly if the pregnancy is complicated by a spinal cord defect or other abnormality:
- Maternal serum AFP test results, interpreted according to the gestational age, are often 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. A typical normal range is 0.5 to 2.0 or 2.5 MoM.
- Raised levels of maternal AFP at 16-18 weeks of gestation are found in fetal neural tube defects.
- Amniotic fluid AFP and acetylcholinesterase concentrations can be used to differentiate between open ventral wall defects (gastroschisis and omphalocele) and open neural tube defects.
- Where AFP levels are raised but there is no fetal abnormality, there may be greater risk of obstetric complications.
Uses of alpha-fetoprotein measurement
Screening for neural tube defects and trisomy
AFP screening is a simple maternal blood test, performed at around 15 weeks of gestation, that can detect increased risk to the fetus of certain genetic abnormalities such as:
- Open neural tube defects - eg, spina bifida.
- Down's syndrome.
- Other chromosomal abnormalities - eg, trisomy 18.
- Defects in the abdominal wall of the fetus - omphalocele.
However, midtrimester anomaly scanning may replace serum screening.A pregnant woman's AFP levels decrease soon after birth.
Diagnostic aid in premature rupture of membranes (PROM)
A study looking at prolactin, AFP and beta human chorionic gonadotrophin (beta-hCG) in vaginal fluid as markers for diagnosing PROM, showed that AFP had the greatest accuracy (94% sensitivity and specificity).Further studies have confirmed the reliability of cervicovaginal AFP for diagnosing PROM in equivocal cases.
Altered AFP levels, either too high or low compared with normal amounts, can also indicate increased risk of obstetric problems such as placenta accreta/increta/percreta when placenta praevia has been diagnosed.
Hepatocellular carcinoma (HCC)
Chronic hepatitis B and C infection may cause HCC. In conjunction with abdominal ultrasonography, AFP can be measured at six-monthly intervals in such patients who are at high risk of HCC (especially those with liver cirrhosis related to hepatitis B or C). However, a Cochrane review concluded that there is not enough evidence to know whether screening is worthwhile.A Health Technology Assessment concluded that the most effective surveillance strategy is to screen high-risk patients with both AFP assay and ultrasound imaging on a six-monthly basis. However, the addition of ultrasound is only cost-effective in those with blood AFP level >20 ng/mL.
Acute liver failure
Serum concentrations of AFP that are variably elevated during liver injury have been suggested to be of prognostic importance in acute liver failure, with higher values being associated with improved outcome. AFP values change dynamically during acute liver failure. In a large prospective study, higher absolute values of AFP did not predict a favourable outcome; however, a rising level of AFP over the first three hospital days frequently indicated survival.
Further reading and references
Beale G, Chattopadhyay D, Gray J, et al; AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease. BMC Cancer. 2008 Jul 188:200. doi: 10.1186/1471-2407-8-200.
Chun H, Kwon SJ; Clinicopathological characteristics of alpha-fetoprotein-producing gastric cancer. J Gastric Cancer. 2011 Mar11(1):23-30. doi: 10.5230/jgc.2011.11.1.23. Epub 2011 Mar 31.
Sturgeon CM, Lai LC, Duffy MJ; Serum tumour markers: how to order and interpret them. BMJ. 2009 Sep 22339:b3527. doi: 10.1136/bmj.b3527.
Kitada M, Ozawa K, Sato K, et al; Alpha-fetoprotein-producing primary lung carcinoma: a case report. World J Surg Oncol. 2011 May 99:47. doi: 10.1186/1477-7819-9-47.
Stray-Pedersen A, Borresen-Dale AL, Paus E, et al; Alpha fetoprotein is increasing with age in ataxia-telangiectasia. Eur J Paediatr Neurol. 2007 Nov11(6):375-80. Epub 2007 May 30.
Krantz DA, Hallahan TW, Sherwin JE; Screening for open neural tube defects. Clin Lab Med. 2010 Sep30(3):721-5. Epub 2010 Jun 15.
Loft AG, Hogdall E, Larsen SO, et al; A comparison of amniotic fluid alpha-fetoprotein and acetylcholinesterase in the prenatal diagnosis of open neural tube defects and anterior abdominal wall defects. Prenat Diagn. 1993 Feb13(2):93-109.
Chandra S, Scott H, Dodds L, et al; Unexplained elevated maternal serum alpha-fetoprotein and/or human chorionic gonadotropin and the risk of adverse outcomes. Am J Obstet Gynecol. 2003 Sep189(3):775-81.
Canick JA, MacRae AR; Second trimester serum markers. Semin Perinatol. 2005 Aug29(4):203-8.
Huang T, Alberman E, Wald N, et al; Triploidy identified through second-trimester serum screening. Prenat Diagn. 2005 Mar25(3):229-33.
Kooper AJ, de Bruijn D, van Ravenwaaij-Arts CM, et al; Fetal anomaly scan potentially will replace routine AFAFP assays for the detection of neural tube defects. Prenat Diagn. 2007 Jan27(1):29-33.
Shahin M, Raslan H; Comparative Study of Three Amniotic Fluid Markers in Premature Rupture of Membranes: Prolactin, Beta Subunit of Human Chorionic Gonadotropin, and Alpha-Fetoprotein. Gynecol Obstet Invest. 2006 Dec 763(4):195-199.
Singh CR, Bhat RG; Alpha-foetoprotein in the diagnosis of prelabour rupture of membranes. J Clin Diagn Res. 2014 Nov8(11):OC01-2. doi: 10.7860/JCDR/2014/8259.5093. Epub 2014 Nov 20.
Gagnon A, Wilson RD, Audibert F, et al; Obstetrical complications associated with abnormal maternal serum markers analytes. J Obstet Gynaecol Can. 2008 Oct30(10):918-49.
Aghoram R, Cai P, Dickinson JA; Alpha-foetoprotein and/or liver ultrasonography for screening of hepatocellular carcinoma in patients with chronic hepatitis B. Cochrane Database Syst Rev. 2012 Sep 129:CD002799. doi: 10.1002/14651858.CD002799.pub2.
Thompson Coon J, Rogers G, Hewson P, et al; Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis. Health Technol Assess. 2007 Sep11(34):1-206.
Schiodt FV, Ostapowicz G, Murray N, et al; Alpha-fetoprotein and prognosis in acute liver failure. Liver Transpl. 2006 Dec12(12):1776-81.
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