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HOMOCYSTEINE and MTHFR Polymorphisms
PROTEIN BUILDING BLOCK or THROMBOTIC RISK FACTOR or BOTH?
Homocysteine (Hcy) is an important intermediary in the metabolic pathways for both methionine and
cysteine1,2. At least four different enzyme systems regulate its concentration in body fluids via
synthesis and degradation pathways3. In the early 1960s, an autosomal recessive inherited disease
called homocystinuria was identified4. A severe deficiency of either of two enzymes, cystathionine -synthase or
methylenetetrahydrofola
te reductase (MTHFR), resulted in pronounced elevations of
homocysteine in the blood (200-400µM/L) and urine5,6. A striking presentation of homocystinuria
was severe vascular disease existing in early childhood with thromboembolic disease of vital organs
often occurring before the age of 305. In the late 1960s it was postulated that elevated homocysteine
levels might contribute to premature coronary artery disease in the general population as well4.
However, it is only within the last ten years that consistent data from at least 20 cross-sectional and
case controlled studies have supported the hypothesis that moderate homocysteinemia is associated
with vascular disease including peripheral vascular disease (both venous and arterial), coronary
disease, and cerebrovascular disease1,6-8. Mutations in the genes for either of these two enzymes can
cause increases in homocysteine
levels [see diagram], including
the C677T and A1298C
mutations in the MTHFR gene.
Research also suggests that
moderately elevated levels of
homocysteine may result from
defects in other enzyme systems
associated with homocysteine
metabolism as well as deficiencies of folate, vitamin B12, vitamin B6 and abnormal renal function2,9.
RISK ASSOCIATION:
It is now recognized that elevated plasma homocysteine levels are independently associated with
other risk factors for atherosclerotic disease - male sex, increasing age, high blood pressure, elevated
cholesterol, lack of exercise, and cigarette smoking6. It appears that the risk associated with
homocysteine rises with increased concentration, has no threshold, and is increased in women and the
elderly8,9. In addition it has been reported that patients who have the Factor V Leiden mutation as well
as homocysteinemia have an increased risk of thrombosis, greater than in either defect alone10.
BIOLOGICAL MECHANISMS:
There are several identified biological mechanisms of action of homocysteine. It is believed to
promote atherosclerosis by inducing endothelial cell damage, promoting platelet aggregation &
adhesion, and accelerating the proliferation of smooth muscle cells3,11. In vitro it has been shown to
activate clotting factors on the surface of endothelial cells, inhibit the activation of protein C, to
oxidize low density lipoproteins5,12, and increased binding of Lipoprotein (a) [Lp(a)] to fibrin as well
as other procoagulant activities 15.
THERAPY:
Vitamin supplementation lowers homocysteine concentrations in almost all subjects regardless of the
cause2,4,8-13. However, data is still not conclusive in determining if such supplementation is effective
in retarding or reversing the occlusive process2,4,11. Since simple, safe, and low cost therapy (folic acid
nutritional supplementation) has been shown to lower plasma levels of homocysteine, testing has been
recommended for individual patients with premature vascular occlusive disease. If future trials
demonstrate that lowering homocysteine levels decreases the development and progression of vascular
disease, testing for homocysteine may become as common as cholesterol testing in evaluating
cardiovascular risk4.
LABORATORY TESTING:
Serum homocysteine at HEMEX Laboratories: Hcy is measured by Fluorescence Polarization
Immunoassay (FPIA). Testing may be performed either with the patient fasting or following a
methionine load.5 There is no general agreement about the validity of methionine load testing,
although some researchers report that both test results should be measured to detect
hyperhomocysteinemia arising from different causes5. There is a risk gradient effect for both men
and women that extends into the reference range (5.0 to 15.0 umol/L), with >9.0 yielding some, >16
moderate, >30 intermediate, and >100 umol/L yielding the highest risk, respectively6,14.
Genetic studies at HEMEX Laboratories: Both MTHFR C677T and A1298C mutations are available for confirmation of a genetic defect in homocysteinemia. The C677T mutation should be ordered first, with follow-up testing of the A1298C mutation if the C677T is positive, due to added risk when both mutations are present. If the C677T is negative, the A1298C test is not necessary to evaluate hyperhomocysteinemia but may be helpful in family and at-risk studies.
Homocysteine: Two - 2 mL aliquots FROZEN serum. MTHFR: One 7 mL EDTA, ambient.
REFERENCES:
1. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395-98.
2. den Hiejer M, Blom HJ, Gerrits WBJ, Rosendaal FR, Haak HL, Wijermans PW, Bos GMJ. Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis? Lancet 1995;345:882-85.
3. Hathaway WE, Goodnight SH. Other potential causes of thrombosis. Disorders of Hemostasis and Thrombosis. 1993 McGraw-Hill.
4. Allen, RH, Stabler SP. Water soluble vitamins, hyperhomocysteinemia, and risk for vascular disease and thrombosis. CHR, November,1995.
5. Fermo I, Vigano'D'Angelo SV, Paroni R, Mazzola G, Calori G, D'Angelo AD. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Int Med 1995;123(10):747-753.
6. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, and Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. NEJM 1997; 337:230-6.
7. Amundsen T, Ueland PM, Waage A. Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler Thromb Vasc Biol 1995;15(9):1321-1323.
8. Robinson K, Mayer EL, Miller DP, Green R, van Lente F, Gupta A, Kottke-Marchant K, Savon SR, Selhub, Nissen SE, Kutner M, Topol EJ, Jacobsen DW. Hyperhomocysteinemia and low pyridoxal phosphate: common and independent risk factors for coronary artery disease. Circulation 1995;92:2825-30.
9. Den Heijer M, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. NEJM 1996;334(12):759-762.
10. Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocystinuria and factor V Leiden - effect on thrombosis. NEJM 1995;344(12):763-768.
11. van den Berg M, Stehouwer CDA, Bierdrager E, Rauwerda JA. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease. Arteriosclerosis, Thrombosis, and Vascular Biology 1996;16(1):165-171.
12. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. Higher plasma homocysteine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol 1995;15:1314-1320.
13. den Heijer M, Wijermans, PW, Brouwer IA, Bos GMJ, Blom HJ, Haak HL, Gerrits WBJ. Lowering of homocysteine blood levels by means of vitamin supplementation. Supplement 1 to Blood 1995;86(10):89a
14. Malinow, et al. Homocyst(e)ine, diet and cardiovascular diseases. AHA science advisory. Circulation 1999; 99: 178-82.
15. Foody JM, Milberg JA, Robinson, et al. Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vasc Biol 2000; 20: 493-499. R. 10/02