Elevated plasma homocyst(e)ine concentrations are associated with atherosclerotic cardiovascular disease. Increased concentration may result from decreased renal function and from some drug therapies (eg phenytoin). Hyperhomocysteinaemia may also result from folate and/or vitamin B12 deficiency, which leads to decreased remethylation of homocysteine to methionine; and from deficiency of vitamin B6 which is an essential cofactor for cystathione beta-synthase in the trans-sulphuration pathway.
Genetic defects of homocysteine metabolism also increase homocysteine concentrations. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, has a prevalence of 20% in Asians, 12% in Caucasions and less than 2% in Africans. TT homozygotes have plasma homocyst(e)ine concentrations approximately 25% higher than the wild CC genotype.
The rarer cystathione beta-synthase deficiency, a genetic defect affecting the trans-sulphuration pathway, has an incidence of less than 1 in 25000 in the general population. It is associated with homocystinuria, hyperhomocysteinaemia (homocysteine > 100µmol/L), adolescent age strokes and transient ischemic attacks.
Vitamin B6 deficiency, causes only a minimal increase in plasma homocysteine, but can be unmasked by an oral methionine load.
Homocysteine is thought to exert its toxicity by damaging vascular endothelial cells, preventing normal endothelium-mediated vasodilatation. Auto-oxidation of homocysteine by trace metal ions produces reactive oxygen species (superoxide anion, hydrogen peroxide, hydroxyl and thiol free radicals) which oxidise LDL, potentiating its deleterious effects. Homocysteine may also interact with growth factors and cytokines in atherosclerotic lesions to induce proliferation of smooth muscle cells during atherogenesis.
Elevated homocysteine appears to be an independent risk factor, conferring an additive effect on other risk factors. A rise of 5µmol/L in homocysteine is considered equivalent in terms of cardiovascular risk to an increase of 0.5mmol/L cholesterol.
The finding of a high homocysteine should prompt investigation of renal function and of folate and vitamin B12 status. Supplementation with folate reduces plasma homocysteine concentration, and prospective trials are underway to evaluate its benefits. Further investigation of a high plasma homocysteine concentration may include demonstration of the presence or absence of the thermo-labile MTHFR gene mutation.
In addition to being a risk factor for cardiovascular disease and thrombosis, an elevated plasma homocysteine concentration has also been implicated as a risk factor for neural tube defects and psychogeriatric illness (eg Alzheimers disease).
Premature cardiovascular disease
Risk assessment should be based on major risk determinants. A high plasma homocysteine concentration may prompt more aggressive treatment of other risk factors.
Approximate Reference range:
5 – 15µmol/L (Adult)
5 – 20µmol/L (Adult >70y)
Mild elevation: 16-30µmol/L
Moderate elevation: 31-100µmol/L
Severe elevation: >100µmol/L
(see individual laboratory report)
An overnight fast is required. Blood samples for B12 and folate and for renal function should be taken at the same time. Due to circadian rhythm, values are lowest in the morning. Values are increased by a high protein diet, during pregnancy, the follicular phase and post-menopause, and by some drugs (eg phenytoin).
EDTA plasma – separated within 30 minutes (10% increase per hour). min. vol. 0.5ml.
Stable 4 days at 4°C, >1year at -20°C
Transport – First Class Post (avoid weekends)
Age,sex, NHS/Hospital No.
Rasmussen K, Moller J. Total homocysteine measurement in clinical practice. Ann Clin Biochem 2000; 37: 627-648