Elevated alpha-fetoprotein

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Elevated alphafetoprotein
Specialty Laboratory medicine

Elevated alpha-fetoprotein refers to a state where alpha-fetoprotein levels are outside of the reference range.

Contents

There are two categories of AFP tests: tests performed on serum (blood plasma), and tests performed on 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.

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.[ citation needed ]

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.[ citation needed ]

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 testing for fetal screening

Abnormally elevated AFP in the serum of a pregnant woman can have one or more of these sources:[ citation needed ]

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.

Maternal serum AFP (MSAFP) varies by orders of magnitude during the course of a normal pregnancy. MSAFP increases rapidly until about 32 weeks gestation, then decreases gradually. After the pregnancy ends it decreases rapidly, with a half-life of about 5 days.

Typically, MSAFP is measured in the beginning of the second trimester (14–16 weeks). It may be measured alone or as part of a package of routine prenatal screening tests, such as a triple test or quad test.

Because MSAFP test results must be interpreted according to the gestational age, they often are 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, but depend on accurate gestational dating. A typical normal range is 0.5 to 2.0 or 2.5 MoM.

Patients with abnormal MSAFP need to undergo detailed obstetric ultrasonography. The information is then used to decide whether to proceed with amniocentesis. Genetic counseling usually is offered when the screening test result is positive.[ citation needed ]

If a woman is already getting a Quad test for Down Syndrome screening, then the AFP-marker that is part of this test provides the screen result for neural-tube and abdominal wall defects. However, if a woman received a 1st Trimester Combined screen for Down Syndrome, which does not include AFP, then some physicians will specifically order an AFP-only test in the 2nd trimester to screen for neural tube/abdominal wall defects. However, because AFP-based screening only has an 80-85% sensitivity for neural tube and abdominal wall defects, [2] many maternal-fetal medicine specialists and some obstetricians do not bother ordering an AFP test and instead perform detailed "Level-II" ultrasounds on all of their patients, which, in competent hands, results in a 97% sensitivity for these defects[ citation needed ]. In fact, these physicians might disregard the AFP-related information on neural tube/abdominal wall defects and do the detailed ultrasound to look for these defects even if the patient has a "normal" AFP reading[ citation needed ].

Tumor marker

Principal tumors that secrete AFP are endodermal sinus tumor (yolk sac carcinoma), hepatoblastoma, and hepatocellular carcinoma.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.[ citation needed ]

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).[ citation needed ]

Nonseminomatous germ cell tumor

In the context of evidence-based medicine, AFP is validated at the highest level as a tumor marker for use in patients with nonseminomatous germ cell tumors. [3] [4]

There are case reports of elevated AFP associated with teratoma. However, some of these case reports involve infants but do not correct for the normal elevation of AFP in infants, while others ignore the likelihood that teratoma (and other germ cell tumors) may in fact be mixed tumors containing elements of endodermal sinus tumor.

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. [5] [6] [7] 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. [8] When neonatal AFP is above normal (after adjustment for age), a low fraction of AFP-L3 is reassuring. [9]

Hepatocellular carcinoma

For hepatocellular carcinoma (HCC), AFP cannot be considered to be specifically diagnostic of HCC, levels of AFP may be elevated in serum from patients with chronic disease; for example, research has indicated that AFP is not useful for screening in patients with cirrhosis [10] or Hepatitis C [11] and therefore elevated AFP in these patients may not be indicative, or be only suggestive, of HCC. AFP is considered a useful marker for post-treatment monitoring of HCC patients (e.g. for treatment efficacy or tumor recurrence). The value of such tests may be improved by parallel monitoring of other markers. [12] [13]

AFP-L3, an isoform of AFP which binds Lens culinaris agglutinin, can be particularly useful in early identification of aggressive tumors associated with HCC.

Other tumor

Rare AFP-secreting tumor types include carcinoma in a mixed Müllerian tumor. [14] The Sertoli-Leydig cell tumor, which itself is rare, rarely secretes AFP. [15]

In Wilms tumor AFP is rarely elevated, but when it is elevated it may serve as a marker of disease progression or recurrence. [16]

Other

Increased serum levels in adults are also seen in acute hepatitis, colitis and ataxia telangiectasia. Increased serum levels of alpha-fetoprotein are sometimes found in citrullinemia and argininosuccinate synthetase deficiency. [17]

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.[ citation needed ]

Abnormally elevated AFP in amniotic fluid can have one or more of many different causes:[ citation needed ]

CSF

In normal infants, AFP in CSF is: [18]

Levels of AFP in CSF decline with gestational age in proportion to levels of AFP in serum [19]

Related Research Articles

<span class="mw-page-title-main">Hepatocellular carcinoma</span> Medical condition

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.

<span class="mw-page-title-main">Alpha-fetoprotein</span> Fetal analogue of serum albumin

Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene. The AFP gene is located on the q arm of chromosome 4 (4q13.3). Maternal AFP serum level is used to screen for Down syndrome, neural tube defects, and other chromosomal abnormalities.

Liver tumors are abnormal growth of liver cells on or in the liver. Several distinct types of tumors can develop in the liver because the liver is made up of various cell types. Liver tumors can be classified as benign (non-cancerous) or malignant (cancerous) growths. They may be discovered on medical imaging, and the diagnosis is often confirmed with liver biopsy. Signs and symptoms of liver masses vary from being asymptomatic to patients presenting with an abdominal mass, hepatomegaly, abdominal pain, jaundice, or some other liver dysfunction. Treatment varies and is highly specific to the type of liver tumor.

<span class="mw-page-title-main">Prenatal testing</span> Testing for diseases or conditions in a fetus

Prenatal testing is a tool that can be used to detect some of these abnormalities at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts or as early in gestation as practicable. Screening can detect problems such as neural tube defects, chromosome abnormalities, and gene mutations that would lead to genetic disorders and birth defects, such as spina bifida, cleft palate, Down syndrome, Tay–Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Some tests are designed to discover problems which primarily affect the health of the mother, such as PAPP-A to detect pre-eclampsia or glucose tolerance tests to diagnose gestational diabetes. Screening can also detect anatomical defects such as hydrocephalus, anencephaly, heart defects, and amniotic band syndrome.

<span class="mw-page-title-main">Polyhydramnios</span> Excess of amniotic fluid in the amniotic sac

Polyhydramnios is a medical condition describing an excess of amniotic fluid in the amniotic sac. It is seen in about 1% of pregnancies. It is typically diagnosed when the amniotic fluid index (AFI) is greater than 24 cm. There are two clinical varieties of polyhydramnios: chronic polyhydramnios where excess amniotic fluid accumulates gradually, and acute polyhydramnios where excess amniotic fluid collects rapidly.

Oligohydramnios is a medical condition in pregnancy characterized by a deficiency of amniotic fluid, the fluid that surrounds the fetus in the abdomen, in the amniotic sac. It is typically diagnosed by ultrasound when the amniotic fluid index (AFI) measures less than 5 cm or when the single deepest pocket (SDP) of amniotic fluid measures less than 2 cm. Amniotic fluid is necessary to allow for normal fetal movement, lung development, and cushioning from uterine compression. Low amniotic fluid can be attributed to a maternal, fetal, placental or idiopathic cause and can result in poor fetal outcomes including death. The prognosis of the fetus is dependent on the etiology, gestational age at diagnosis, and the severity of the oligohydramnios.

The triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy in the second trimester to classify a patient as either high-risk or low-risk for chromosomal abnormalities.

<span class="mw-page-title-main">Hepatoblastoma</span> Liver cancer occurring in infants and children

Hepatoblastoma is a malignant liver cancer occurring in infants and children and composed of tissue resembling fetal liver cells, mature liver cells, or bile duct cells. They usually present with an abdominal mass. The disease is most commonly diagnosed during a child's first three years of life. Alpha-fetoprotein (AFP) levels are commonly elevated, but when AFP is not elevated at diagnosis the prognosis is poor.

<span class="mw-page-title-main">Embryonal carcinoma</span> Relatively uncommon type of germ cell tumour

Embryonal carcinoma is a relatively uncommon type of germ cell tumour that occurs in the ovaries and testes.

A blastoma is a type of cancer, more common in children, that is caused by malignancies in precursor cells, often called blasts. Examples are nephroblastoma, medulloblastoma, and retinoblastoma. The suffix -blastoma is used to imply a tumor of primitive, incompletely differentiated cells, e.g., chondroblastoma is composed of cells resembling the precursor of chondrocytes.

<span class="mw-page-title-main">Neural tube defect</span> Group of birth defects of the brain or spinal cord

Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo begin to change shape and form the neural tube. When the neural tube does not close completely, an NTD develops.

In oncology, AFP-L3 is an isoform of alpha-fetoprotein (AFP), a substance typically used in the triple test during pregnancy and for screening chronic liver disease patients for hepatocellular carcinoma (HCC). AFP can be fractionated by affinity electrophoresis into three glycoforms: L1, L2, and L3 based on the reactivity with the lectin Lens culinaris agglutinin (LCA). AFP-L3 binds strongly to LCA via an additional α 1-6 fucose residue attached at the reducing terminus of N-acetylglucosamine; this is in contrast to the L1 isoform. It is the L1 isoform which is typically associated with non-HCC inflammation of liver disease condition. The L3 isoform is specific to malignant tumors and its detected presence can serve to identify patients whom need increased monitoring for the development of HCC in high risk populations. AFP-L3% is now being considered as a tumor marker for the North American demographic.

<span class="mw-page-title-main">Simpson–Golabi–Behmel syndrome</span> Congenital disorder

Simpson–Golabi–Behmel syndrome (SGBS), is a rare inherited congenital disorder that can cause craniofacial, skeletal, vascular, cardiac, and renal abnormalities. There is a high prevalence of cancer associated in those with sgbs which includes wilms tumors, neuroblastoma, tumors of the adrenal gland, liver, lungs and abdominal organs. The syndrome is inherited in an X-linked recessive manner. Females that possess one copy of the mutation are considered to be carriers of the syndrome but may still express varying degrees of the phenotype, suffering mild to severe malady. Males experience a higher likelihood of fetal death.

<span class="mw-page-title-main">Triploid syndrome</span> Chromosomal disorder in which there are three copies of every chromosome

Triploid syndrome, also called triploidy, is a chromosomal disorder in which a fetus has three copies of every chromosome instead of the normal two. If this occurs in only some cells, it is called mosaic triploidy and is less severe.

Des-gamma carboxyprothrombin (DCP), also known as protein induced by vitamin K absence/antagonist-II (PIVKA-II), is an abnormal form of the coagulation protein, prothrombin. Normally, the prothrombin precursor undergoes post-translational carboxylation by gamma-glutamyl carboxylase in the liver prior to secretion into plasma. DCP/PIVKA-II may be detected in people with deficiency of vitamin K and in those taking warfarin or other medication that inhibits the action of vitamin K.

<span class="mw-page-title-main">Fetal protein</span>

Fetal proteins are high levels of proteins present during the fetal stage of development. Often related proteins assume similar roles after birth or in the embryo, in which case the fetal varieties are called fetal isoforms. Sometimes, the genes coding fetal isoforms occur adjacent to their adult homologues in the genome, and in those cases a locus control region often coordinates the transition from fetal to adult forms. In other cases fetal isoforms can be produced by alternate splicing using fetal exons to produce proteins that differ in only a portion of their amino acid sequence. In some situations the continuing expression of fetal forms can reveal the presence of a disease condition or serve as a treatment for diseases such as sickle cell anemia. Some well known examples include:

A multiple of the median (MoM) is a measure of how far an individual test result deviates from the median. MoM is commonly used to report the results of medical screening tests, particularly where the results of the individual tests are highly variable.

<span class="mw-page-title-main">Fibrolamellar hepatocellular carcinoma</span> Medical condition

Fibrolamellar carcinoma (FLC) is a rare form of carcinoma that typically affects young adults and is characterized, under the microscope, by laminated fibrous layers interspersed between the tumor cells. It has been estimated that 200 new cases are diagnosed worldwide each year. However, in light of recent advances in our molecular understanding, this has recently been revised to suggest it may be at least ten times more common. FLC, also known as fibrolamellar hepatocellular carcinoma, is different from the more common hepatocellular carcinoma (HCC) in that it afflicts young people with normal liver function and no known risk factors.

The MOMS Trial was a clinical trial that studied treatment of a birth defect called myelomeningocele, which is the most severe form of spina bifida. The study looked at prenatal and postnatal surgery to repair this defect. The first major phase concluded that prenatal surgery had strong, long-term benefits and some risks.

<span class="mw-page-title-main">Endodermal sinus tumor</span> Medical condition

Endodermal sinus tumor (EST) is a member of the germ cell tumor group of cancers. It is the most common testicular tumor in children under three, and is also known as infantile embryonal carcinoma. This age group has a very good prognosis. In contrast to the pure form typical of infants, adult endodermal sinus tumors are often found in combination with other kinds of germ cell tumor, particularly teratoma and embryonal carcinoma. While pure teratoma is usually benign, endodermal sinus tumor is malignant.

References

  1. ↑ Björklund NK, Evans JA, Greenberg CR, Seargeant LE, Schneider CE, Chodirker BN (Sep 2004). "The C677T methylenetetrahydrofolate reductase variant and third trimester obstetrical complications in women with unexplained elevations of maternal serum alpha-fetoprotein". Reprod Biol Endocrinol. 2: 65. doi: 10.1186/1477-7827-2-65 . PMC   520832 . PMID   15352998.
  2. ↑ "Archived copy" (PDF). Archived from the original (PDF) on 2017-02-12. Retrieved 2010-04-11.{{cite web}}: CS1 maint: archived copy as title (link)
  3. ↑ Duffy MJ (September 2004). "Evidence for the clinical use of tumour markers". Ann. Clin. Biochem. 41 (Pt 5): 370–7. doi: 10.1258/0004563041731529 . PMID   15333188.
  4. ↑ Duffy MJ, Crown J (November 2008). "A personalized approach to cancer treatment: how biomarkers can help". Clin. Chem. 54 (11): 1770–9. doi: 10.1373/clinchem.2008.110056 . PMID   18801934.
  5. ↑ Blohm ME, Vesterling-Hörner D, Calaminus G, Göbel U (1998). "Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age". Pediatr Hematol Oncol. 15 (2): 135–42. doi:10.3109/08880019809167228. PMID   9592840.
  6. ↑ Bader D, Riskin A, Vafsi O, et al. (November 2004). "Alpha-fetoprotein in the early neonatal period--a large study and review of the literature". Clin. Chim. Acta. 349 (1–2): 15–23. doi:10.1016/j.cccn.2004.06.020. PMID   15469851.
  7. ↑ Wu JT, Book L, Sudar K (January 1981). "Serum alpha fetoprotein (AFP) levels in normal infants". Pediatric Research. 15 (1): 50–2. doi: 10.1203/00006450-198101000-00012 . PMID   6163129.
  8. ↑ Lee PI, Chang MH, Chen DS, Lee CY (January 1989). "Serum alpha-fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference". J. Pediatr. Gastroenterol. Nutr. 8 (1): 19–25. doi: 10.1097/00005176-198901000-00005 . PMID   2471821. S2CID   21104946.
  9. ↑ Kinoshita Y, Tajiri T, Souzaki R, Tatsuta K, Higashi M, Izaki T, Takahashi Y, Taguchi T (June 2008). "Diagnostic value of lectin reactive alpha-fetoprotein for neoinfantile hepatic tumors and malignant germ cell tumors: preliminary study". J. Pediatr. Hematol. Oncol. 30 (6): 447–50. doi:10.1097/MPH.0b013e31816916ad. PMID   18525461. S2CID   21701227.
  10. ↑ Paul SB, Gulati MS, Sreenivas V, Madan K, Gupta AK, Mukhopadhyay S, Acharya SK (2007). "Evaluating patients with cirrhosis for hepatocellular carcinoma: value of clinical symptomatology, imaging and alpha-fetoprotein". Oncology. 72 (Suppl 1): 117–23. doi:10.1159/000111717. PMID   18087192. S2CID   23948726.
  11. ↑ Samir Gupta, MD; Stephen Bent, MD; Jeffrey Kohlwes, MD, MPH (2003). "Test Characteristics of {alpha}-Fetoprotein for Detecting Hepatocellular Carcinoma in Patients with Hepatitis C: A Systematic Review and Critical Analysis". Annals of Internal Medicine. 139 (1): 46–50. doi:10.7326/0003-4819-139-1-200307010-00012. PMID   12834318. S2CID   53088047.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ↑ Kim do Y, Paik YH, Ahn SH, Youn YJ, Choi JW, Kim JK, Lee KS, Chon CY, Han KH (2007). "PIVKA-II is a useful tumor marker for recurrent hepatocellular carcinoma after surgical resection". Oncology. 72 (Suppl 1): 52–7. doi:10.1159/000111707. PMID   18087182. S2CID   38198282.
  13. ↑ Zhou L, Liu J, Luo F (2006). "Serum tumor markers for detection of hepatocellular carcinoma". World J Gastroenterol. 12 (8): 1175–1181. doi: 10.3748/wjg.v12.i8.1175 . PMC   4124425 . PMID   16534867.
  14. ↑ Rebischung C, Pautier P, Morice P, Lhomme C, Duvillard P (2000). "Alpha-fetoprotein production by a malignant mixed Müllerian tumor of the ovary". Gynecol. Oncol. 77 (1): 203–5. doi:10.1006/gyno.1999.5653. PMID   10739713.
  15. ↑ Watanabe T, Yamada H, Morimura Y, Abe M, Motoyama T, Sato A (June 2008). "Ovarian Sertoli-Leydig cell tumor with heterologous gastrointestinal epithelium as a source of alpha-fetoprotein: a case report". J. Obstet. Gynaecol. Res. 34 (3): 418–21. doi: 10.1111/j.1447-0756.2008.00730.x . PMID   18588618. S2CID   41408152.
  16. ↑ Crocoli A, Madafferi S, Jenkner A, Zaccara A, Inserra A (2007). "Elevated serum alpha-fetoprotein in Wilms tumor may follow the same pattern of other fetal neoplasms after treatment: evidence from three cases". Pediatr Surg Int. 24 (4): 499–502. doi:10.1007/s00383-007-2067-7. PMID   17987303. S2CID   11572139.
  17. ↑ Saheki, T.; Song, Y. Z.; Adam, M. P.; Everman, D. B.; Mirzaa, G. M.; Pagon, R. A.; Wallace, S. E.; Bean LJH; Gripp, K. W.; Amemiya, A. (1993). "Citrin Deficiency". GeneReviews®. University of Washington, Seattle. PMID   20301360.
  18. ↑ Coakley J, Kellie SJ, Nath C, Munas A, Cooke-Yarborough C (January 2005). "Interpretation of alpha-fetoprotein concentrations in cerebrospinal fluid of infants". Annals of Clinical Biochemistry. 42 (Pt 1): 24–9. doi: 10.1258/0004563053026763 . PMID   15802029.
  19. ↑ Christiansen M, Høgdall CK, Høgdall EV (January 2000). "Alpha-fetoprotein in human fetal cerebrospinal fluid". Clinica Chimica Acta. 291 (1): 35–41. doi:10.1016/S0009-8981(99)00195-3. PMID   10612715.
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