Alpha-fetoprotein

See also the separate Tumour markers article.

What is alpha-fetoprotein (AFP)?

Alpha-fetoprotein (AFP) is the major protein of foetal serum but it is usually undetectable after birth. AFP is made by the yolk sac of the foetus, enters the amniotic fluid and crosses the placenta into the maternal circulation. It is also produced by some cancers.

Alpha-fetoprotein is raised in some cancers and other medical conditions. It can therefore be used as a tumour marker. It is very important to recognise that 1) AFP is not recommended as a screening tool for the general population, and therefore should not be used for this purpose and 2) AFP is not available in general practice in many parts of the UK and therefore this test should not be considered as a primary care test.¹

• Hepatocellular carcinoma (HCC): AFP levels are abnormal in 40-60% of patients. It has limited specificity and sensitivity and therefore, whilst widely used for surveillance, it has significant limitations. It is not currently recommended for screening or diagnosis, at least alone. ² There appears to be a direct association with raised AFP levels and aggressive phenotypes so it can be used to predict clinical outcomes. ³

• Other gastrointestinal cancers:

  • Gastric cancer: AFP-producing gastric cancer (AFP level >7 ng/mL) is rare (accounting for between 1.3% and 15% of gastric cancers) but is associated with a highly malignant gastric cancer which has a poorer prognosis. ⁴

  • Biliary tract cancer. Very high AFP levels have been shown sporadically in patients with intrahepatic cholangiocarcinoma (ICC).⁵Enteroblastic cholangiocarcinoma also results in raised AFP levels.⁶

  • Pancreatic cancer. Pancreatic cancer rarely is AFP producing; as with the other AFP producing cancers this represents a highly malignant tumour with poorer prognosis. ⁷

• Nonseminomatous germ cell (testicular) tumours. These commonly produce AFP. AFP has limited use in monitoring and surveillance for relapse. ⁸

• Alpha-fetoprotein may also be raised in patients with metastatic lung cancer and primary lung cancer. AFP-producing tumours account for about 2% of all primary lung cancers. ⁹

• Cirrhosis: patients may have abnormal AFP values, although usually less than 500 ng/mL.

• Viral hepatitis.

• Ataxia with telangiectasia.¹⁰

• Pregnancy is associated with elevated AFP levels:

  • Maternal serum AFP test results can be interpreted according to the gestational age. Levels above those expected may be associated with foetal open neural tube defects. See also the articles on Prenatal diagnosis and Neural tube defects.¹¹¹²

  • There are other reasons for raised maternal serum AFP so AFP measurements alone are not diagnostic.

  • A raised maternal serum AFP is due to a neural tube defect between 2 and 4% of the time¹²and is used to determine who might benefit from further investigations.

  • Amniotic fluid AFP levels are also raised in open ventral wall defects (gastroschisis and omphalocele), congenital abnormalities of the nephron structures, epidermolysis bullosa simplex, porphyria, Hb Barts, Beckwith–Wiedemann Syndrome, and hepatic haemangioma. ¹³

  • Where there are high AFP levels but there is no foetal abnormality found, there is a greater risk of obstetric complications, including stillbirth, spontaneous abortion, and pre-term delivery. ¹⁴ Raised AFP levels in the second trimester have also been found to be associated with increased rates of intra-uterine growth retardation, low birthweight, premature rupture of membranes, and placenta praevia. They result more often in a male offspring. ¹⁵

  • Raised maternal AFP levels in the first trimester (unlike the second trimester) are not an independent risk factor for placenta-mediated complications. ¹⁶

Screening for neural tube defects and trisomy¹⁷

See also the separate Prenatal diagnosis and Prenatal screening for down's syndrome articles.

AFP screening is a maternal blood test, performed between 11 and 14 weeks gestation, that can detect increased rates of certain genetic abnormalities such as:

• Open neural tube defects - for example, spina bifida.

• Down's syndrome.

• Other chromosomal abnormalities - for example, trisomy 18.

• Defects in the abdominal wall of the foetus - omphalocele.

The AFP level is assessed, along with levels of beta-HCG, and measurements of the foetus during an ultrasound.

Hepatocellular carcinoma (HCC)

Chronic hepatitis B and C infection may cause HCC. In conjunction with abdominal ultrasonography, AFP measurement is sometimes offered 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). Whilst, historically, it has been unclear whether there is any benefit to screening these patients,¹⁸ more recent studies suggest that screening a risk-stratified group of patients may be of benefit. ¹⁹²⁰

UK recommendations are that patients with hepatitis B and significant fibrosis or cirrhosis (or without significant liver disease but with a family history of HCC), patients with both hepatitis B and D, patients with hepatitis C and advanced fibrosis, patients with haemochromatosis and advanced fibrosis, patients with other liver diseases causing a high risk of HCC, and patients with Child-Pugh²¹ score A or B (based on an individual assessment) or C (if awaiting liver transplantation), should be offered screening for HCC via a 6-monthly AFP blood test and ultrasound scan.²²

Acute liver failure