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Homocysteine testing has emerged from an obscure esoteric laboratory test, to one of the most important screening examinations for determining risk in atherosclerotic disease.


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For many years, HPLC was the standard, now, enzyme immunoassays are becoming increasingly popular

These EIA techniques are based upon similar techniques


Homocysteine oxidizes low density lipoprotein which may precipitate atherosclerosis and is toxic to the endothelium

Decreases expression of thombomodulin on the surface of endothelial cells-thrombomodulin interacts with protein C activation leading to inhibition of anticoagulant pathway, leading to thrombosis

Activates platelets and increases platelet aggregation

  Ann Intern Med 1999;131:363-375
Enhances smooth muscle cell proliferation, intimal-medial wall thickness, endothelial cell injury, thromboxane A2 formation, lipid abnormalities, LDL oxidation, and lipoprotein (a) binding to fibrin
  The reduced form is the most active form because of the sulfhydryl group

MTHFR 677C-->T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis.

Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG.

Wageningen Centre for Food Sciences and Division of Human Nutrition and Epidemiology, Wageningen University, PO Box 8129, 6700 EV Wageningen, the Netherlands.

JAMA 2002 Oct 23;288(16):2023-31 Abstract quote

CONTEXT: In observational studies, individuals with elevated levels of plasma homocysteine tend to have moderately increased risk of coronary heart disease (CHD). The MTHFR 677C-->T polymorphism is a genetic alteration in an enzyme involved in folate metabolism that causes elevated homocysteine concentrations, but its relevance to risk of CHD is uncertain.

OBJECTIVE: To assess the relation of MTHFR 677C-->T polymorphism and risk of CHD by conducting a meta-analysis of individual participant data from all case-control observational studies with data on this polymorphism and risk of CHD. DATA SOURCES: Studies were identified by searches of the electronic literature (MEDLINE and Current Contents) for relevant reports published before June 2001 (using the search terms MTHFR and coronary heart disease), hand searches of reference lists of original studies and review articles (including meta-analyses) on this topic, and contact with investigators in the field.

STUDY SELECTION: Studies were included if they had data on the MTHFR 677C-->T genotype and a case-control design (retrospective or nested case-control) and involved CHD as an end point. Data were obtained from 40 (34 published and 6 unpublished) observational studies involving a total of 11 162 cases and 12 758 controls.

DATA EXTRACTION: Data were collected on MTHFR 677C-->T genotype, case-control status, and plasma levels of homocysteine, folate, and other cardiovascular risk factors. Data were checked for consistency with the published article or with information provided by the investigators and converted into a standard format for incorporation into a central database. Combined odds ratios (ORs) for the association between the MTHFR 677C-->T polymorphism and CHD were assessed by logistic regression.

DATA SYNTHESIS: Individuals with the MTHFR 677 TT genotype had a 16% (OR, 1.16; 95% confidence interval [CI], 1.05-1.28) higher odds of CHD compared with individuals with the CC genotype. There was significant heterogeneity between the results obtained in European populations (OR, 1.14; 95% CI, 1.01-1.28) compared with North American populations (OR, 0.87; 95% CI, 0.73-1.05), which might largely be explained by interaction between the MTHFR 677C-->T polymorphism and folate status.

CONCLUSIONS: Individuals with the MTHFR 677 TT genotype had a significantly higher risk of CHD, particularly in the setting of low folate status. These results support the hypothesis that impaired folate metabolism, resulting in high homocysteine levels, is causally related to increased risk of CHD.


Homocysteine in whole blood is extremely unstable and if left at room temperature, the level may increase by 10% or more within one hour

If left for 24 hours, levels may rise 35-75%

Ideally should be centrifuged within 15 minutes of collection and stored on ice or stored on ice immediatly for later centrifugation


Ann Intern Med 1999;131:331-339
Although most laboratories use 15 umol/L as the cutoff between normal and abnormal, this recent study indicates that the reference range may be much lower

This study excluded patients with know risk factors for hyperhomocysteinemia including low vitamin B12 or folate intake, renal dysfunction, pregnant or postmenopausal women

MALE 4.3-9.9 umol/L 5.9-15.3 umol/L >/=11.4 umol/L
FEMALE 3.3-7.2 umol/L 4.9-11.6 umol/L >/=10.4 umol/L


Hyperhomocysteinemia measured by immunoassay: a valid measure of coronary artery atherosclerosis.

Stauffenberg MT, Lange RA, Hillis LD, Cigarroa J, Hsu RM, Devaraj S, Jialal I.

Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, USA.
Arch Pathol Lab Med. 2004 Nov;128(11):1263-6. Abstract quote  

CONTEXT: Homocysteine is emerging as a novel marker of atherothrombosis. Its role as an independent risk factor for cardiovascular disease is generally accepted. There is scanty data correlating homocysteine levels measured by immunoassay with cardiovascular disease. We previously validated a fluorescence polarization immunoassay for measuring homocysteine, which compared favorably with high performance liquid chromatography.

OBJECTIVE: To determine if homocysteine levels measured by immunoassay correlate with extent of atherosclerotic burden, as represented by degree of coronary artery stenosis determined by coronary angiography.

DESIGN: Fasting plasma samples were obtained from patients undergoing coronary angiography (N = 165). Homocysteine levels were measured by immunoassay and coronary artery stenosis was determined by coronary angiography.

RESULTS: Median coronary artery stenosis for the 3 homocysteine subgroups, less than 1.35, 1.35 to 6.75, and greater than 6.75 mg/L (<10, 10-15, and >15 micromol/L), was 75%, 90%, and 99%, respectively (P = .01 for trend). Also, folate and vitamin B12 levels decreased with increasing homocysteine levels (P = .01 and .04, respectively, for trend). Spearman's correlation showed a significant association between homocysteine level and coronary artery stenosis (r = 0.20; P = .009). When men and women were examined separately, the correlation was significant only for women (r = 0.30; P = .01).

CONCLUSION: Homocysteine levels, as measured by immunoassay, show a positive correlation with cardiovascular disease in women. Thus, this is a valid measure of atherosclerotic burden and, therefore, a reliable addition to the established laboratory repertoire for the assessment of cardiovascular disease.

Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.

Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M.

Stroke Research Center, Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
JAMA. 2004 Feb 4;291(5):565-75 Abstract quote.  

CONTEXT: In observational studies, elevated plasma total homocysteine levels have been positively associated with ischemic stroke risk. However the utility of homocysteine-lowering therapy to reduce that risk has not been confirmed by randomized trials.

OBJECTIVE: To determine whether high doses of folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12), given to lower total homocysteine levels, reduce the risk of recurrent stroke over a 2-year period compared with low doses of these vitamins. DESIGN: Double-blind randomized controlled trial (September 1996-May 2003).

SETTING AND PARTICIPANTS: 3680 adults with nondisabling cerebral infarction at 56 university-affiliated hospitals, community hospitals, private neurology practices, and Veterans Affairs medical centers across the United States, Canada, and Scotland.

INTERVENTIONS: All participants received best medical and surgical care plus a daily multivitamin containing the US Food and Drug Administration's reference daily intakes of other vitamins; patients were randomly assigned to receive once-daily doses of the high-dose formulation (n = 1827), containing 25 mg of pyridoxine, 0.4 mg of cobalamin, and 2.5 mg of folic acid; or the low-dose formulation (n = 1853), containing 200 microg of pyridoxine, 6 microg of cobalamin and 20 microg of folic acid.

MAIN OUTCOME MEASURES: Recurrent cerebral infarction (primary outcome); coronary heart disease (CHD) events and death (secondary outcomes).

RESULTS: Mean reduction of total homocysteine was 2 micromol/L greater in the high-dose group than in the low-dose group, but there was no treatment effect on any end point. The unadjusted risk ratio for any stroke, CHD event, or death was 1.0 (95% confidence interval [CI], 0.8-1.1), with chances of an event within 2 years of 18.0% in the high-dose group and 18.6% in the low-dose group. The risk of ischemic stroke within 2 years was 9.2% for the high-dose and 8.8% for the low-dose groups (risk ratio, 1.0; 95% CI, 0.8-1.3) (P =.80 by log-rank test of the primary hypothesis of difference in ischemic stroke between treatment groups). There was a persistent and graded association between baseline total homocysteine level and outcomes. A 3- micromol/L lower total homocysteine level was associated with a 10% lower risk of stroke (P =.05), a 26% lower risk of CHD events (P<.001), and a 16% lower risk of death (P =.001) in the low-dose group and a nonsignificantly lower risk in the high-dose group by 2% for stroke, 7% for CHD events, and 7% for death.

CONCLUSIONS: In this trial, moderate reduction of total homocysteine after nondisabling cerebral infarction had no effect on vascular outcomes during the 2 years of follow-up. However, the consistent findings of an association of total homocysteine with vascular risk suggests that further exploration of the hypothesis is warranted and longer trials in different populations with elevated total homocysteine may be necessary.
Mild to moderate elevation can increase risk of coronary artery disease by 2.5 times JAMA 1995;274:1049-1057
Lowering levels by 5 umol/L may reduce the death rate from coronary artery disease by 10%
Cardiac bypass patients with high baseline levels Circulation 2000;102:605-610
If these patients are not treated within 2.5 years, they have 2.6 x greater risk of recurring cardiac events

Homocysteine concentrations in a German cohort of 500 individuals: reference ranges and determinants of plasma levels in healthy children and their parents.

Rauh M, Verwied S, Knerr I, Dorr HG, Sonnichsen A, Koletzko B.

University Children's Hospital, Friedrich-Alexander-University, Erlanen-Nuermberg, Erlangen, Federal Republic of Germany.

Amino Acids 2001;20(4):409-18 Abstract quote

Elevated plasma homocysteine is a risk factor for cardiovascular disease and a sensitive marker of inadequate vitamin B12 and folate status.

We studied 257 pupils (120 boys, 137 girls, aged 6-17 years) and their parents (88 males, 172 females, aged 26-50 years). Our measurements were part of a national Bavarian health and nutrition examination survey evaluating cardiovascular risk factors. A mild hyperhomocysteinemia (Hcys >15 micromol/l) occurred in 7% of the adults, but in none of the children. Men had significantly higher Hcys levels than women (p<0.0001), boys and girls had comparable concentrations. For adults and children, Hcys correlated inversely with vitamin B12 and folate and positively with the lean body mass and creatinine in serum, but not with cystatin C. Genetic and nutritional factors are determinants of Hcys metabolism.

The correlation of Hcys and serum creatinine is dependent on the metabolic link between Hcys production and creatine synthesis.

Effect of homocysteine-lowering therapy with folic acid, vitamin B(12), and vitamin B(6) on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial.

Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM.

Division of Cardiology, Swiss Cardiovascular Center Bern, University Hospital, Switzerland.

JAMA 2002 Aug 28;288(8):973-9 Abstract quote

CONTEXT: Plasma homocysteine level has been recognized as an important cardiovascular risk factor that predicts adverse cardiac events in patients with established coronary atherosclerosis and influences restenosis rate after percutaneous coronary intervention.

OBJECTIVE: To evaluate the effect of homocysteine-lowering therapy on clinical outcome after percutaneous coronary intervention.

DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind placebo-controlled trial involving 553 patients referred to the University Hospital in Bern, Switzerland, from May 1998 to April 1999 and enrolled after successful angioplasty of at least 1 significant coronary stenosis (> or = 50%).

INTERVENTION: Participants were randomly assigned to receive a combination of folic acid (1 mg/d), vitamin B(12) (cyanocobalamin, 400 micro g/d), and vitamin B(6) (pyridoxine hydrochloride, 10 mg/d) (n = 272) or placebo (n = 281) for 6 months.

MAIN OUTCOME MEASURE: Composite end point of major adverse events defined as death, nonfatal myocardial infarction, and need for repeat revascularization, evaluated at 6 months and 1 year. RESULTS: After a mean (SD) follow-up of 11 (3) months, the composite end point was significantly lower at 1 year in patients treated with homocysteine-lowering therapy (15.4% vs 22.8%; relative risk [RR], 0.68; 95% confidence interval [CI], 0.48-0.96; P =.03), primarily due to a reduced rate of target lesion revascularization (9.9% vs 16.0%; RR, 0.62; 95% CI, 0.40-0.97; P =.03). A nonsignificant trend was seen toward fewer deaths (1.5% vs 2.8%; RR, 0.54; 95% CI, 0.16-1.70; P =.27) and nonfatal myocardial infarctions (2.6% vs 4.3%; RR, 0.60; 95% CI, 0.24-1.51; P =.27) with homocysteine-lowering therapy. These findings remained unchanged after adjustment for potential confounders.

CONCLUSION: Homocysteine-lowering therapy with folic acid, vitamin B(12), and vitamin B(6) significantly decreases the incidence of major adverse events after percutaneous coronary intervention.

Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.

Homocysteine Studies Collaboration.

JAMA 2002 Oct 23-30;288(16):2015-22 Abstract quote

CONTEXT: It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke.

OBJECTIVE: To assess the relationship of homocysteine concentrations with vascular disease risk.

DATA SOURCES: MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators.

STUDY SELECTION: Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete.

DATA EXTRACTION: Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression.

DATA SYNTHESIS: Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk.

CONCLUSIONS: This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.


Diabetes mellitus Circulation 2000;101:1506-1511
A 5 umol/L increase has been associated with a 60% increase in cardiovascular mortality versus a 17% increase in non-diabetics
Renal failure or dysfunction Elevation
Low vitamin B12 or folate intake Elevation
Pregnancy Elevation
Postmenopausal women Elevation
Hyperthyroidism Ann Intern Med 1999;131:348-351
Nonfasting Eating will cause elevation

Ann Intern Med 1999;131:331
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