Overview of homocysteine

Overview of homocysteine
Overview of homocysteine
Robert S Rosenson, MD
David S Kang, MD, PhD
Section Editors
Robert H Fletcher, MD, MSc
Mason W Freeman, MD
Deputy Editor
Pracha Eamranond, MD, MPH
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Thu Oct 13 00:00:00 GMT 2011 (More)

INTRODUCTION — Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine. Homocystinuria or severe hyperhomocysteinemia is a rare autosomal recessive disorder characterized by severe elevations in plasma and urine homocysteine concentrations. Clinical manifestations of homocystinuria include developmental delay, osteoporosis, ocular abnormalities, thromboembolic disease, and severe premature atherosclerosis. Homocystinuria is not discussed further in this topic review.

Less marked elevations in plasma homocysteine are much more common, occurring in 5 to 7 percent of the population [1,2]. Although unassociated with the clinical stigmata of homocystinuria, mounting evidence suggests that moderate hyperhomocysteinemia is an independent risk factor for atherosclerotic vascular disease and for recurrent venous thromboembolism.

This topic will review the risks associated with elevated homocysteine levels, screening for hyperhomocysteinemia, and the evidence evaluating the use of vitamin supplements that lower homocysteine levels.

ETIOLOGY OF HYPERHOMOCYSTEINEMIA — Homocysteine is metabolized by one of two divergent pathways: transsulfuration and remethylation (figure 1). The transsulfuration of homocysteine to cysteine is catalyzed by cystathionine-ß-synthase, a process that requires pyridoxal phosphate (vitamin B6) as a cofactor. Remethylation of homocysteine produces methionine. This reaction is catalyzed either by methionine synthase or by betaine-homocysteine methyltransferase. Vitamin B12 (cobalamin) is the precursor of methylcobalamin, which is the cofactor for methionine synthase.

Elevations in the plasma homocysteine concentration can occur due to genetic defects in the enzymes involved in homocysteine metabolism, to nutritional deficiencies in vitamin cofactors, or to other factors including some chronic medical conditions and drugs (figure 1) [3-9]. Some drugs used in the treatment of hypercholesterolemia, such as fibrates and nicotinic acid, can raise homocysteine levels by approximately 30 percent; however, the clinical significance of this is uncertain [10-12]. Cigarette smoking also may elevate homocysteine levels [13]. Chronic kidney failure can increase homocysteine levels due to decreased renal removal and impaired metabolism. (See “Secondary prevention of cardiovascular disease in end-stage renal disease (dialysis)”, section on ‘Hyperhomocysteinemia’.)

Thermolabile variant of MTHFR — The most common form of genetic hyperhomocysteinemia results from production of a thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) with reduced enzymatic activity (T mutation) (figure 1) [14]. The gene encoding for this variant contains an alanine-to-valine substitution at amino acid 677 (C677T) [15].

The responsible gene is common, with a population frequency estimated between 5 to 14 percent [16,17]. Homozygosity for the thermolabile variant of MTHFR (TT genotype) is a relatively common cause of mildly elevated plasma homocysteine levels in the general population, often occurring in association with low serum folate levels [17-19]. As an example, one study of 625 men found that 11.5 percent were homozygous for the TT genotype [18]. However, for those in the top 5 and 10 percent of plasma homocysteine concentrations, the frequency rose to 48 and 36 percent, respectively. Homozygotes also had the lowest serum folate concentrations.

Vitamin deficiencies — Increased blood levels of homocysteine may reflect deficiency of folate, vitamin B6, and/or vitamin B12 [20-23]. Plasma folate and B12 levels, in particular, are strong determinants of the homocysteine concentration. Homocysteine levels are inversely related to folate consumption, reaching a stable baseline level when folate intake exceeds 400 µg/day [24,25]. Vitamin B6 is a weaker determinant [25].

The importance of vitamin deficiency in the pathogenesis of hyperhomocysteinemia was evaluated in a cohort of 1041 elderly subjects [24]. Two-thirds of patients with elevated homocysteine levels had a subnormal plasma concentration of folate, vitamin B12, or pyridoxal-5-phosphate (the coenzyme form of vitamin B6). The prevalence of low plasma B12 levels was higher in this cohort than in the younger participants in a European case-control study [25]. These data suggest that suboptimal B12 intake coupled with poorer absorption might play a greater role in elevating homocysteine and subsequent CHD risk in older adults than in younger patients. In contrast, folate intake low enough to raise plasma homocysteine may be relatively common in the general population, particularly in moderate consumers of alcohol.

Further evidence of the importance of vitamin deficiency comes from a report that assessed the results of the United States Food and Drug Administration regulation requiring all enriched grain products be fortified with folic acid. Patients who had blood tested following fortification had significantly higher blood folate concentrations and lower homocysteine concentrations [26]. In addition, the prevalence of a high homocysteine concentration (>13 µmol/L) decreased from 18.7 before fortification to 9.8 percent after fortification.

Additional support for the role of folic acid and perhaps vitamin B6 in hyperhomocysteinemia comes from a trial that randomly assigned 158 healthy siblings of 167 patients with premature atherothrombotic disease to folic acid (5 mg daily) and vitamin B6 (250 mg daily) or placebo; most of the siblings and all of the patients had postmethionine loading hyperhomocysteinemia [23]. After a two-year follow-up, fasting and postmethionine homocysteine levels significantly decreased with vitamin supplementation, from 14.7 to 7.4 µmol/L and 64.9 to 34.9 µmol/L respectively, while there were no changes with placebo therapy.

ATHEROTHROMBOTIC PROPERTIES OF HOMOCYSTEINE — Homocysteine has primary atherogenic and prothrombotic properties. Histopathologic hallmarks of homocysteine-induced vascular injury include intimal thickening, elastic lamina disruption, smooth muscle hypertrophy, marked platelet accumulation, and the formation of platelet-enriched occlusive thrombi [27-31]. These observations may help explain the association between hyperhomocysteinemia and cardiovascular disease described below.

There are multiple mechanisms by which homocysteine may induce vascular injury:

  • Homocysteine promotes leukocyte recruitment by upregulating monocyte chemoattractant protein-1 and interleukin-8 expression and secretion [32].
  • The thiolactone metabolite of homocysteine can combine with LDL-cholesterol to produce aggregates that are taken up by vascular macrophages in the arterial intima; these foam cells may then release the lipid into atherosclerotic plaques [2].
  • Homocysteine increases smooth muscle cell proliferation and enhances collagen production [33].
  • Prothrombotic effects of homocysteine, which have been demonstrated in patients with acute coronary syndromes [34], include attenuation of endothelial cell tissue plasminogen activator binding sites, activation of factor VIIa and V, inhibition of protein C and heparin sulfate, increased fibrinopeptide A and prothrombin fragments 1 and 2, increased blood viscosity, and decreased endothelial antithrombotic activity due to changes in thrombomodulin function [35-40]. (See “Overview of hemostasis”.)
  • Oxidative stress by free radicals formed during the oxidation of reduced homocysteine may directly injure endothelial cells [41,42].
  • Marked platelet accumulation may be secondary to direct proaggregatory effects of homocysteine or to an impairment in endothelium-mediated platelet inhibition [43,44].
  • Prolonged exposure of endothelial cells to homocysteine reduces the activity of dimethylarginine dimethylaminohydrolase, the enzyme that degrades asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase; this impairs the production of nitric oxide [43,45]. This may contribute to impaired endothelium-dependent vasodilation of both conduit and resistance vessels [46-48]. (See “Endothelial dysfunction”.)

Support for the role of homocysteine in endothelial dysfunction is derived from studies that found that folic acid supplementation both lowers the homocysteine concentration and improves measures of endothelial dysfunction [49-51].

An alternate view is that hyperhomocysteinemia is not directly harmful, but that it indirectly inhibits methyl fluxes during transmethylation of methionine; the resulting impairment of DNA methylation could then affect many physiologic processes [52]. A study in patients with uremia and hyperhomocysteinemia found increased levels of DNA hypomethylation and altered gene expression that were corrected by administration of folate [53].

LABORATORY DIAGNOSIS — Sensitive assays allow quantification of the total plasma homocysteine concentration; approximately 75 to 85 percent is protein-bound and 15 to 25 percent is in acid-soluble free forms [54]. Normal homocysteine concentrations range between 5 and 15 µmol/L. Hyperhomocysteinemia has been classified as follows [55]:

  • Moderate (15 to 30 µmol/L)
  • Intermediate (30 to 100 µmol/L)
  • Severe (>100 µmol/L)

An oral methionine challenge (100 mg/kg) can be given to patients suspected of hyperhomocysteinemia who have normal fasting homocysteine levels [56]. The oral methionine challenge is more useful for patients with cystathione-beta-synthase deficiency than for those MTHFR reductase deficiency [16]. The homocysteine concentration is measured on fasting samples before the methionine challenge and four and eight hours afterward. The patient is classified as having impaired homocysteine metabolism if the four hour post-methionine plasma homocysteine concentration exceeds the appropriate mean level by more than two standard deviations (table 1).

However, the prognostic significance of the oral methionine challenge is uncertain. In one series that included 24 of 163 subjects with homozygosity for the thermolabile variant, fasting but not postmethionine total homocysteine levels were associated with CHD status [16].

Homocysteine levels measured at the time of admission for acute myocardial infarction and unstable angina appear to be accurate [57]. In this small study, levels at admission were similar to those six months after the acute event, but there were minor variations in the homocysteine level during the first week after admission.


Hyperhomocysteinemia — Although early data on the relationship between elevated blood homocysteine concentrations and coronary heart disease (CHD) and stroke have been somewhat inconsistent [58-63], high homocysteine levels appear to be clearly associated with an increased risk of cardiovascular and cerebrovascular disease. However, homocysteine does not appear to be as important as other risk factors such as hypercholesterolemia, smoking, diabetes mellitus, and hypertension.

A meta-analysis that evaluated data from 30 prospective and retrospective studies, involving 5073 ischemic heart disease and 1113 stroke events, provides an analysis of the varied data [64]. Stronger associations between the blood homocysteine concentration and cardiovascular events were noted in retrospective compared with prospective studies. After adjustment for known cardiovascular risk factors, a 25 percent lower homocysteine concentration (about 3 µmol/L) in the prospective studies was associated with a lower risk of ischemic heart disease risk (odds ratio 0.89, 95% CI 0.83-0.86) and stroke (odds ratio 0.81, 95% CI 0.69-0.95).

These results are supported by a meta-analysis of 40 observational studies involving 11,162 patients who were homozygous for the thermolabile variant of MTHFR and 12,758 matched controls [65]. Patients with the MTHFR TT genotype had a 16 percent higher odds of coronary heart disease compared with controls (odds ratio 1.16, 95% CI 1.05-1.28). Additionally, the MTHFR TT genotype is associated with an increased risk of silent brain infarcts [66].

A meta-analysis performed for the US Preventive Services Task Force specifically examined the issue of whether homocysteine levels add predictive value for determining the risk of CHD in adults without known CHD [67]. The analysis found that, independent of Framingham risk factors, each increase in homocysteine level of 5 µmol/L increases the risk of CHD events by approximately 20 percent.

Hyperhomocysteinemia has been linked to the following vascular events:

  • Myocardial infarction, other acute coronary syndromes, and recurrent coronary events [34,68-74]
  • Premature coronary heart disease [71,75,76]
  • Cardiovascular and total mortality [74,77-79]
  • Adverse outcomes after angioplasty [80]
  • Carotid artery stenosis (figure 2) [81-83]
  • Stroke [84-88], recurrent stroke [89], and silent brain infarct [90]

Homocysteine levels have also been linked to the development of heart failure. A community-based cohort study found that higher homocysteine levels increased the risk of heart failure even after controlling for interim myocardial infarctions [91].

The issue of whether homocysteine plays a causal role in cardiovascular disease or whether there is a non-causal association has additionally been addressed by meta-analyses that have looked at both prospective studies and MTHFR mutation studies [92,93]. Similar odds ratios for cardiovascular disease were found in both types of studies. The consistent odds ratios across studies that should have had distinct sources of bias and error argue in favor of a causal role for homocysteine [94]. In contrast, a subsequent meta-analysis of MTHFR mutation studies found no evidence of a causal relationship between homocysteine and coronary heart disease in studies of North American, European, and Australian populations, but did find such evidence in studies of Middle Eastern and Asian populations [95]. The study found evidence of publication bias, and the authors felt the results could potentially be explained by such bias or by geographic variability in folate intake.

Vitamin status — Studies have also contributed to our knowledge regarding the complex relationship between the blood homocysteine concentration, vitamin status, and the risk of cardiovascular disease:

  • In a case-control study that evaluated 750 patients with documented vascular disease and 800 control subjects, low levels of folate and vitamin B6 were associated with an increased risk for atherosclerosis, independent of conventional risk factors [20]. The risk associated with folate was in part explained by increased serum homocysteine, while the relationship between vitamin B6 and atherosclerosis was independent of the homocysteine concentration.
  • The Nurses’ Health Study found a graded inverse association between higher dietary intakes of folate and vitamin B6 and CHD [21]. The lowest risk was seen in women in the highest quintile of intake for both folate and vitamin B6 (40 percent risk reduction). This lowest risk group had a dietary intake of folate above 545 micrograms/day and an average intake of vitamin B6 above 5.9 mg/day, which are well above the current RDAs (400 micrograms/day and 1.6 mg/day, respectively) (figure 3). The benefits of folate supplementation were greatest in women consuming the most alcohol, probably because alcohol increases folate metabolism and these women were relatively deficient to start. No association was observed between dietary vitamin B12 and CHD.
  • The Health Professional Follow-up Study of 43,732 men ages 40 to 75 who were free of cardiovascular disease and diabetes at baseline found in a multivariate analysis that compared with men in the lowest quintile of folate intake, men in the highest quintile had a relative risk of ischemic stroke of 0.71 (95% CI 0.52-0.96) [96]. No significant association was found between hemorrhagic stroke and folate intake. Intake of vitamin B12, but not vitamin B6, was also inversely associated with the risk of ischemic stroke.
  • An association between dietary folate and atherosclerosis was demonstrated in a prospective study of 1980 men, ages 42 to 60 years, who were followed for 10 years [22]. Those in the highest quintile of folate intake (>297 µg/day, mean intake 342.1 µg/day) had a relative risk of an acute coronary event of 0.45 compared to those in the lowest quintile (<211 µg/day, mean intake 187.7 µg/day); there was no association with B6 intake and only a weak association with the B12 intake.
  • In the meta-analysis of MTHFR mutations discussed above, there was significant heterogeneity between studies performed in European compared with North American populations, with a significant association between the TT genotype and coronary disease in the former but not the latter [65]. This heterogeneity may be explained by differences in folate status; the North American studies were performed after 1995, at a time when there was greater use of B vitamin supplements and folate fortification. Thus, adequate folate status appears to minimize the effect that the MTHFR TT genotype has on risk of cardiovascular disease. Another possible explanation is the difference in vitamin B2 (riboflavin) fortification in North America and Europe. A randomized trial found that vitamin B2 supplementation lowered homocysteine levels in patients with the MTHFR TT genotype but not in those with other genotypes [97].
  • Low levels of vitamin B6 may be independently associated with CHD [98]. After adjusting for other risk factors, higher plasma concentrations of pyridoxal 5′-phosphate were associated with a lower incidence of CHD; the relative risk for the highest versus lowest quintile was 0.28. This is supported by the data from a multicenter European study that showed that vitamin B6 was directly related to CHD risk independent of homocysteine levels [25]. Vitamin B6 may be more effective in counteracting the effects of methionine loading (simulating the fed state) on homocysteine levels, while folate may be more important in regulating plasma homocysteine in the fasting state [99,100].
SEE MORE:  Pathogenesis of the hypercoagulable state associated with malignancy

Data from studies are somewhat inconsistent, however. As an example, an Australian cohort study of 2950 people followed for 29 years that did not measure homocysteine concentration found no independent association of baseline serum folate, red cell folate, and serum vitamin B12 concentrations with mortality from cardiovascular disease after adjusting for age and other standard risk factors [101].

ROLE IN VENOUS THROMBOEMBOLISM — There is increasing evidence that hyperhomocysteinemia is a risk factor for venous thromboembolic disease (pulmonary embolism and deep vein thrombosis) [102-104]. Meta-analyses of case-control studies have found an odds ratio of 2.5 to 2.95 for venous thromboembolic disease in patients with homocysteine levels more than two standard deviations above the mean value of control groups [103,104].

Moderate hyperhomocysteinemia (15 to 30 µmol/L) may also be a risk factor for recurrent venous thrombosis. This was illustrated in a multicenter study in which patients with a single episode of idiopathic venous thromboembolism were prospectively followed after discontinuation of oral anticoagulants [105]. Recurrent venous thromboembolism was significantly more likely in the 66 patients with hyperhomocysteinemia than in the 198 with normal levels (18.2 percent versus 8.1 percent, respectively).

Some studies have suggested that the risk of thrombosis increases 10 to 50-fold in patients who have both homocysteinemia and an inherited thrombophilia (eg, factor V Leiden) [106,107]. (See “Activated protein C resistance and factor V Leiden”.) However, other studies have failed to confirm these findings [108]. These contradictory results may reflect statistical anomalies due to the small number of patients that have both defects. Further confusing the issue, most studies that have examined patients with the thermolabile variant of MTHFR have not found that this genotype increases the risk of venous thrombosis when found alone [109-111], or when associated with factor V Leiden or the prothrombin mutation [108,110].

Obstetric complications — The thermolabile variant of MTHFR has been linked to obstetric complications such as severe preeclampsia, abruptio placentae, fetal growth restriction, and stillbirth, which are associated with intervillous or spiral artery thrombosis and inadequate placental perfusion [112]. Women with an obstetric complication were significantly more likely to have the thermolabile variant of MTHFR. (See “Screening for inherited thrombophilia in asymptomatic populations”.)


Birth defects — Supplementation with folate reduces the risk of neural tube defects. (See “Vitamin supplementation in disease prevention”, section on ‘Folic acid’.) Homozygosity and heterozygosity for the thermolabile variant of MTHFR appear to be associated with an increased risk of neural tube defects [113].

Osteoporosis — Homocystinuria is associated with the early onset of osteoporosis. (See “The child with tall stature or abnormally rapid growth”.) High homocysteine levels in adults have been associated with osteoporotic fractures in some [114-117], but not all [118], studies.

Supplementation with folate and vitamin B12 in high risk groups may reduce the risk of fractures [119]. (See “Overview of the management of osteoporosis in postmenopausal women”, section on ‘Folate/vitamin B12’.)

It is not clear, however, whether high levels of homocysteine have a direct effect on bone or whether the effect is mediated through another factor, such as poor nutrition.

Dementia — There is conflicting evidence about whether homocysteine is an independent risk factor for dementia. (See “Risk factors for dementia”, section on ‘Homocysteine’.)

SCREENING FOR HYPERHOMOCYSTEINEMIA — The bulk of data suggest that hyperhomocysteinemia is an independent risk factor for cerebrovascular, peripheral vascular, and coronary heart disease, and for venous thromboembolic disease. However, this relationship alone does not provide a compelling argument for population screening [120]. The arguments against screening in the general population include the following:

 Identifying patients with the TT genotype of MTHFR is unlikely to be cost-effective. Combining the prevalence of the TT genotype (approximately 11 percent) and the relative risk, it is possible to estimate the population attributable risk (the proportion of coronary heart disease that would be eliminated from the population if the genetic variant did not exist) [121]. For the TT genotype, the population attributable risk is only 1 to 2 percent. In addition, adequate folic acid intake further reduces the impact of the genetic variant.

  • While screening for hyperhomocysteinemia itself is not difficult, a benefit from lowering the homocysteine concentration on cardiovascular and venous thromboembolic disease remains unproven [103,122]. (See ‘Treatment’ below.) Thus, even if we identify patients with an elevated homocysteine concentration it is not clear that acting on this information is of benefit.
  • Even if treatment of hyperhomocysteinemia is beneficial, it may be more cost effective to recommend that people take a daily multivitamin. (See “Vitamin supplementation in disease prevention”.)

Additionally, measurement variability of homocysteine is a significant problem in determining appropriate candidates for treatment [123].

Several randomized clinical trials are underway to address the effect of folate, B6, and B12 supplementation in primary prevention of cardiovascular disease.

Until the results of these studies are available, and given the negative results of using supplementation for secondary prevention, we recommend not screening for hyperhomocysteinemia. (See ‘Secondary prevention’ below.)

TREATMENT — There is no high quality evidence from trials with clinical endpoints to support treating patients who do not have severe hyperhomocysteinemia (homocystinuria).

The majority of hyperhomocysteinemia is caused by low levels of folate and vitamin B12 in patients with or without the thermolabile variant of MTHFR [124]. Correcting nutritional inadequacy of folic acid, vitamin B12, and choline (betaine) will lower homocysteine levels [124]. A diet rich in fruits, vegetables, and low-fat dairy products and low in saturated and total fat also can lower fasting serum homocysteine [125].

In patients who are treated beyond diet, the treatment varies with the underlying cause, but generally involves vitamin supplementation with folic acid, vitamin B12, and vitamin B6.

Lowering homocysteine levels — Vitamin supplementation with folate lowers homocysteine levels. In patients who are treated to lower homocysteine levels, we suggest treating with folic acid (1 mg/day), vitamin B6 (10 mg/day), and vitamin B12 (0.4 mg/day). All patients should receive a B complex vitamin to mitigate against peripheral neuropathy. Normalization of the homocysteine concentration has been reported within two weeks, but further lowering of homocysteine levels occurs by six weeks [126]. The dose of folic acid should be increased up to 5 mg/day as needed to lower the homocysteine concentration below 15 µmol/L. In patients with a homocysteine concentration >30 µmol/L or chronic renal failure the initial dose of folic acid is 5 mg/day.

The effect of dose and treatment duration was illustrated in a study in which 37 otherwise normal subjects with persistent hyperhomocysteinemia were treated with 0.2 mg/day of folic acid [17]. The plasma homocysteine concentration was reduced in almost all within seven weeks and fell to the normal range in 21 by seven months; most of the remaining subjects attained normal homocysteine concentrations on a higher folate dose of 5 mg/day.

Supplementation with folate has shown the following dose-response relationships in patients with CHD:

  • In a review of 75 patients, cereal providing 127 µg of folic acid daily increased plasma folic acid by 31 percent and reduced homocysteine by 3.7 percent [127]. Cereals providing 499 and 665 µg of folic acid per day raised plasma folic acid by 65 and 106 percent, respectively and lowered plasma homocysteine by 11 and 14 percent, respectively.
  • In the PACIFIC trial, 723 patients were randomly assigned to folic acid (2.0 or 0.2 mg/day) or placebo [128]. The fall in serum homocysteine was significantly greater at the higher dose (16 versus 11 percent, 1.8 versus 1.2 µmol/L).

Although the data are limited, in refractory cases we begin therapy with trimethylglycine (betaine) 750 mg twice daily and increase the dose as necessary.

Secondary prevention

Cardiovascular disease — Meta-analyses of randomized clinical trials for supplementation aimed at lowering homocysteine levels in patients with established cardiovascular disease demonstrated somewhat controversial results [129-133]. However, most studies have generally found no decrease in cardiovascular events or death.

In one of the largest trials included in these meta-analyses, the HOPE-2 trial, 5522 patients ages 55 and older with known vascular disease or diabetes were randomly assigned to receive supplementation with folic acid 2.5 mg daily, vitamin B6 50 mg daily, and vitamin B12 1 mg daily, or to receive placebo [134]. Mean homocysteine levels decreased by 2.4 µmol/L in patients in the supplement group and increased by 0.8 µmol/L in the placebo group. After a mean follow-up of five years, treatment with supplementation had no effect on the primary combined endpoint of cardiovascular death, myocardial infarction, and stroke (relative risk 0.95, 95% CI 0.84-1.07). There was also no benefit in patients with higher baseline homocysteine levels.

Although these results make it unlikely that reducing homocysteine levels with B-vitamin supplement is beneficial for the prevention of cardiovascular disease, it remains possible that design of the trials could have led to a benefit being missed. Most trials did not assess for overt homocysteinemia and adequate nutritional conditions, particularly folate and other B-vitamins. This limits the power of trials to detect benefits, particularly in populations that consume foods fortified with folate [54]. The above trials were performed in regions with a high folate concentration in the population and also included many patients without elevated homocysteine levels. In addition, control subjects received daily vitamin mixtures containing folic acid. It is noteworthy to find marked effects on homocysteine concentration due to the thermolabile MTHFR as well as in the probability for stroke in a population low in folate consumption, such as Asian countries, compared with areas in the folate fortification [135]. Trials performed in the future that target a specific homocysteine level in patients with baseline hyperhomocysteinemia, or that dose supplements to achieve specific serum folate or vitamin B12 levels, might be able to demonstrate clinical benefit.

In summary, the current trials found no benefits, even in the subsets of patients with elevated homocysteine levels at baseline. In the absence of demonstrable benefit and the absence of trials looking at subsets of patients with much more elevated homocysteine levels, we recommend not treating hyperhomocysteinemia for secondary prevention in patients with cardiovascular disease.

After PCI — In the specific case of supplementation after percutaneous coronary intervention (PCI), there is conflicting evidence:

  • A randomized trial of a daily combination supplement (folic acid 1 mg, vitamin B12 400 mcg, vitamin B6 10 mg) in 553 patients undergoing PCI found a decreased incidence of major adverse events after an average follow-up of 11 months [136]. The risk for a composite end point (death, nonfatal myocardial infarction, need for repeat revascularization) was significantly lower in patients receiving the supplement than in those receiving a placebo (15.4 percent versus 22.8 percent) primarily due to a reduced rate of target lesion revascularization (9.9 percent versus 16.0 percent). There was a trend toward fewer deaths (1.5 versus 2.8 percent, relative risk 0.54 [95% CI 0.16-1.70]) and toward fewer nonfatal myocardial infarctions (2.6 versus 4.3 percent, relative risk 0.60 [CI 0.24 to 1.51]). Only 29 percent of the patients had baseline elevated homocysteine levels (above 12 µmol/L) and none had severe hyperhomocysteinemia (above 100 µmol/L).
  • In contrast, a randomized trial of supplementation after coronary stent placement found that patients in the treatment group had higher rates of restenosis (34.5 versus 26.5 percent) and a higher percentage required target-vessel revascularization (15.8 versus 10.6 percent) [137]. Supplementation consisted of an initial intravenous bolus injection of folic acid 1 mg, vitamin B12 1 mg, and vitamin B6 5 mg, followed by daily oral administration of folic acid 1.2 mg, vitamin B12 60 mcg, and vitamin B6 48 mg. In subset analyses, there was a trend toward lower rates of restenosis in women, patients with diabetes, and patients with homocysteine levels of 15 µmol/L or more. The applicability of these results to patients who have received drug-eluting stents, which greatly reduce rates of stent restenosis, is unknown.
SEE MORE:  Asthma in children

The explanation for these conflicting results in PCI is uncertain; however, in the first study only about half the patients received stents. The authors of the second study suggest that supplementation may promote smooth muscle proliferation and matrix formation, which are important parts of restenosis after stenting. Lowering of homocysteine may play a protective role on the thrombus formation within intimal cracks and vascular remodeling that are important after balloon angioplasty [137]. Additionally, the second study used different doses of vitamins and gave an initial intravenous bolus, and in particular used much higher doses of vitamin B6. These higher doses of vitamin B6 could influence the metabolism of homocysteine with a potentially greater effect on the vitamin B6-dependent transsulfuration pathway than on the vitamin B12-dependent and folate-dependent remethylation pathways (figure 1) [138].

The various trials discussed above used differing doses of folate, vitamin B6, vitamin B12. One possible interpretation of the results is that high level supplementation with vitamin B6 and/or vitamin B12 is harmful while high dose folate supplementation might be beneficial. However, given the generally negative results in secondary prevention, the one trial showing a benefit may have found these results by random chance.

At this point, there is inadequate evidence for benefit. We do not recommend the use of vitamin supplements to lower homocysteine levels in patients with CHD including in patients who have recently undergone PCI.

Venous thrombosis — As discussed above, hyperhomocysteinemia is a risk factor for venous thromboembolic disease (VTE, pulmonary embolism and deep vein thrombosis). (See ‘Role in venous thromboembolism’ above.)

However, randomized trials have not found benefits on rates of VTE with vitamin therapy:

  • A randomized trial examined the role of homocysteine lowering with daily B vitamins (folic acid 5 mg, vitamin B6 50 mg, vitamin B12 0.4 mg) in 701 patients with a first episode of VTE [139]. There was no statistically significant reduction in recurrent VTE in patients treated with B vitamins (hazard ratio [HR] 0.84, 95% CI 0.56-1.26). There was also no reduction in recurrent VTE in the 360 patients with baseline homocysteine levels above the 75th percentile (HR 1.14, CI 0.65-1.98), or in the 341 patients with normal homocysteine levels (HR 0.58, CI 0.31-1.07).
  • A secondary analysis from the HOPE-2 trial, described above (see ‘Cardiovascular disease’ above), found no effect of vitamin therapy on rates of VTE (HR 1.01, CI 0.66-1.53) [140]. Vitamin therapy also did not appear to be effective in the 821 patients with a baseline homocysteine in the highest quartile in the study (>13.8 µmol/L), however, the confidence intervals were wide (HR 1.71, CI 0.48-6.06).

Based on these data, we suggest not screening for or treating hyperhomocysteinemia in patients with VTE.

SUPPLEMENTATION IN THE GENERAL POPULATION — Several large randomized clinical trials of vitamin B6, vitamin B12, and folate for the primary prevention of cardiovascular disease and stroke are underway [141]. These studies include large numbers of subjects and various doses and combinations of vitamins and will likely guide future recommendations for supplementation.

Until the results of these trials are available, decisions about the utility of supplementation in the general population must be based on extrapolation from observational data showing associations between homocysteine levels, vitamin levels, and vascular disease (see ‘Vitamin status’ above); from data from interventional trials showing the effects of supplementation on homocysteine levels; and from secondary prevention trials. It is uncertain whether relatively short-term trials of supplements in secondary prevention apply to long-term treatment for primary prevention, but with several other forms of therapy (eg, statins, hormone replacement) effects in primary prevention appear similar to those first demonstrated in secondary prevention.

A meta-analysis assessed the effects of supplementation in 12 trials with 1114 people [142]. Folic acid in a dose of 0.5 to 5.0 mg/day lowered serum homocysteine by 25 percent (95% CI 23-38 percent); vitamin B12 at 0.5 mg/day provided an additional reduction of 7 percent (95% CI 3-10 percent), while vitamin B6 had no additional effect (however, this study did not consider homocysteine levels after methionine loading). A similar effect of folic acid has been noted in subsequent clinical trials [127,128,143]. The effect would be expected to be less in patients with lower baseline serum homocysteine and higher baseline serum folate [128]. One report found that a folic acid dose of 0.8 mg/day was necessary to achieve the maximum reduction in serum homocysteine concentration [143].

In the absence of stronger evidence, and given the lack of benefit in secondary prevention trials, we do not recommend vitamin supplementation for the purpose of lowering homocysteine levels for primary prevention of cardiovascular disease. (See ‘Secondary prevention’ above.)

SUMMARY AND RECOMMENDATIONS — Hyperhomocysteinemia appears to be an independent risk factor for cerebrovascular, peripheral arterial, and coronary heart disease, and for venous thromboembolic disease. However, it does not appear to be as important as other cardiovascular risk factors such as hypercholesterolemia, smoking, diabetes mellitus, and hypertension.


  • We suggest not screening for hyperhomocysteinemia, including in patients with otherwise unexplained venous thrombosis (Grade 2B). (See ‘Screening for hyperhomocysteinemia’ above and ‘Venous thrombosis’ above.)
  • We recommend that patients with cardiovascular disease NOT be treated with vitamin supplementation aimed at lowering homocysteine levels (Grade 1B). (See ‘Secondary prevention’ above.)
  • We suggest that patients with venous thrombosis NOT be treated with vitamin supplementation aimed at lowering homocysteine levels (Grade 2B). (See ‘Venous thrombosis’ above.)
  • Given the negative results in secondary prevention, we suggest NOT administering vitamin supplementation for the purpose of lowering homocysteine levels for primary prevention (Grade 2B). (See ‘Supplementation in the general population’ above.)
Use of UpToDate is subject to the Subscription and License Agreement.


  1. Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med 1989; 114:473.
  2. McCully KS. Homocysteine and vascular disease. Nat Med 1996; 2:386.
  3. Kang SS. Critical points for determining moderate hyperhomocyst(e)inaemia. Eur J Clin Invest 1995; 25:806.
  4. Andersson A, Brattström L, Israelsson B, et al. Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest 1992; 22:79.
  5. Gaustadnes M, Rüdiger N, Rasmussen K, Ingerslev J. Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants. Thromb Haemost 2000; 83:554.
  6. D’Angelo A, Coppola A, Madonna P, et al. The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events. Thromb Haemost 2000; 83:563.
  7. Mezzano D, Muñoz X, Martínez C, et al. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine. Thromb Haemost 1999; 81:913.
  8. Refsum H, Ueland PM, Kvinnsland S. Acute and long-term effects of high-dose methotrexate treatment on homocysteine in plasma and urine. Cancer Res 1986; 46:5385.
  9. Smulders YM, de Man AM, Stehouwer CD, Slaats EH. Trimethoprim and fasting plasma homocysteine. Lancet 1998; 352:1827.
  10. Desouza C, Keebler M, McNamara DB, Fonseca V. Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs 2002; 62:605.
  11. Rosenson RS. Antiatherothrombotic effects of nicotinic acid. Atherosclerosis 2003; 171:87.
  12. Dierkes J, Westphal S, Luley C. The effect of fibrates and other lipid-lowering drugs on plasma homocysteine levels. Expert Opin Drug Saf 2004; 3:101.
  13. Bazzano LA, He J, Muntner P, et al. Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States. Ann Intern Med 2003; 138:891.
  14. Kang SS, Wong PW, Susmano A, et al. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 1991; 48:536.
  15. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10:111.
  16. Gallagher PM, Meleady R, Shields DC, et al. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation. Circulation 1996; 94:2154.
  17. Guttormsen AB, Ueland PM, Nesthus I, et al. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter). The Hordaland Homocysteine Study. J Clin Invest 1996; 98:2174.
  18. Harmon DL, Woodside JV, Yarnell JW, et al. The common ‘thermolabile’ variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM 1996; 89:571.
  19. Kluijtmans LA, Young IS, Boreham CA, et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood 2003; 101:2483.
  20. Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation 1998; 97:437.
  21. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998; 279:359.
  22. Voutilainen S, Rissanen TH, Virtanen J, et al. Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Risk Factor Study. Circulation 2001; 103:2674.
  23. Vermeulen EG, Stehouwer CD, Twisk JW, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet 2000; 355:517.
  24. Selhub J, Jacques PF, Wilson PW, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993; 270:2693.
  25. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr 1993; 57:47.
  26. Jacques PF, Selhub J, Bostom AG, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999; 340:1449.
  27. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56:111.
  28. Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976; 58:731.
  29. Harker LA, Slichter SJ, Scott CR, Ross R. Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med 1974; 291:537.
  30. Rolland PH, Friggi A, Barlatier A, et al. Hyperhomocysteinemia-induced vascular damage in the minipig. Captopril-hydrochlorothiazide combination prevents elastic alterations. Circulation 1995; 91:1161.
  31. Tsai JC, Perrella MA, Yoshizumi M, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci U S A 1994; 91:6369.
  32. Poddar R, Sivasubramanian N, DiBello PM, et al. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease. Circulation 2001; 103:2717.
  33. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease. Enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17:2074.
  34. Al-Obaidi MK, Philippou H, Stubbs PJ, et al. Relationships between homocysteine, factor VIIa, and thrombin generation in acute coronary syndromes. Circulation 2000; 101:372.
  35. Nappo F, De Rosa N, Marfella R, et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999; 281:2113.
  36. Hajjar KA. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 1993; 91:2873.
  37. Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986; 77:1909.
  38. Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991; 88:1906.
  39. Nishinaga M, Ozawa T, Shimada K. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 1993; 92:1381.
  40. Hayashi T, Honda G, Suzuki K. An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. Blood 1992; 79:2930.
  41. Mansoor MA, Bergmark C, Svardal AM, et al. Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Homocysteine and peripheral vascular disease. Arterioscler Thromb Vasc Biol 1995; 15:232.
  42. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986; 77:1370.
  43. Stamler JS, Osborne JA, Jaraki O, et al. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 1993; 91:308.
  44. McCully KS, Carvalho AC. Homocysteine thiolactone, N-homocysteine thiolactonyl retinamide, and platelet aggregation. Res Commun Chem Pathol Pharmacol 1987; 56:349.
  45. Stühlinger MC, Tsao PS, Her JH, et al. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001; 104:2569.
  46. Woo KS, Chook P, Lolin YI, et al. Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 1997; 96:2542.
  47. Kanani PM, Sinkey CA, Browning RL, et al. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 1999; 100:1161.
  48. Tawakol A, Omland T, Gerhard M, et al. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997; 95:1119.
  49. Title LM, Cummings PM, Giddens K, et al. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 2000; 36:758.
  50. Willems FF, Aengevaeren WR, Boers GH, et al. Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease. J Am Coll Cardiol 2002; 40:766.
  51. Thambyrajah J, Landray MJ, Jones HJ, et al. A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease. J Am Coll Cardiol 2001; 37:1858.
  52. van Guldener C, Stehouwer CD. Hyperhomocysteinaemia and vascular disease–a role for DNA hypomethylation? Lancet 2003; 361:1668.
  53. Ingrosso D, Cimmino A, Perna AF, et al. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 2003; 361:1693.
  54. Kang SS, Wong PW. Genetic and nongenetic factors for moderate hyperhomocyst(e)inemia. Atherosclerosis 1996; 119:135.
  55. Kang SS, Wong PW, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 1992; 12:279.
  56. Dudman NP, Wilcken DE, Wang J, et al. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology. Arterioscler Thromb 1993; 13:1253.
  57. Al-Obaidi MK, Stubbs PJ, Amersey R, Noble MI. Acute and convalescent changes in plasma homocysteine concentrations in acute coronary syndromes. Heart 2001; 85:380.
  58. Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern Med 2000; 160:422.
  59. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324:1149.
  60. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995; 274:1049.
  61. Cleophas TJ, Hornstra N, van Hoogstraten B, van der Meulen J. Homocysteine, a risk factor for coronary artery disease or not? A meta-analysis. Am J Cardiol 2000; 86:1005.
  62. Fallon UB, Ben-Shlomo Y, Elwood P, et al. Homocysteine and coronary heart disease in the Caerphilly cohort: a 10 year follow up. Heart 2001; 85:153.
  63. Knekt P, Reunanen A, Alfthan G, et al. Hyperhomocystinemia: a risk factor or a consequence of coronary heart disease? Arch Intern Med 2001; 161:1589.
  64. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288:2015.
  65. Klerk M, Verhoef P, Clarke R, et al. MTHFR 677C–>T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002; 288:2023.
  66. Kohara K, Fujisawa M, Ando F, et al. MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population: The NILS-LSA Study. Stroke 2003; 34:1130.
  67. Humphrey LL, Fu R, Rogers K, et al. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc 2008; 83:1203.
  68. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992; 268:877.
  69. Perry IJ, Refsum H, Morris RW, et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346:1395.
  70. Giles WH, Croft JB, Greenlund KJ, et al. Association between total homocyst(e)ine and the likelihood for a history of acute myocardial infarction by race and ethnicity: Results from the Third National Health and Nutrition Examination Survey. Am Heart J 2000; 139:446.
  71. Schwartz SM, Siscovick DS, Malinow MR, et al. Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation 1997; 96:412.
  72. Al-Obaidi MK, Stubbs PJ, Collinson P, et al. Elevated homocysteine levels are associated with increased ischemic myocardial injury in acute coronary syndromes. J Am Coll Cardiol 2000; 36:1217.
  73. Matetzky S, Freimark D, Ben-Ami S, et al. Association of elevated homocysteine levels with a higher risk of recurrent coronary events and mortality in patients with acute myocardial infarction. Arch Intern Med 2003; 163:1933.
  74. Soinio M, Marniemi J, Laakso M, et al. Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Ann Intern Med 2004; 140:94.
  75. Genest JJ Jr, McNamara JR, Upson B, et al. Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterioscler Thromb 1991; 11:1129.
  76. Pancharuniti N, Lewis CA, Sauberlich HE, et al. Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr 1994; 59:940.
  77. Nygård O, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337:230.
  78. Anderson JL, Muhlestein JB, Horne BD, et al. Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation 2000; 102:1227.
  79. Hoogeveen EK, Kostense PJ, Jakobs C, et al. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes : 5-year follow-up of the Hoorn Study. Circulation 2000; 101:1506.
  80. Schnyder G, Flammer Y, Roffi M, et al. Plasma homocysteine levels and late outcome after coronary angioplasty. J Am Coll Cardiol 2002; 40:1769.
  81. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332:286.
  82. Malinow MR, Nieto FJ, Szklo M, et al. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study. Circulation 1993; 87:1107.
  83. McQuillan BM, Beilby JP, Nidorf M, et al. Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Circulation 1999; 99:2383.
  84. Kelly PJ, Rosand J, Kistler JP, et al. Homocysteine, MTHFR 677C–>T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology 2002; 59:529.
  85. McIlroy SP, Dynan KB, Lawson JT, et al. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 2002; 33:2351.
  86. Tanne D, Haim M, Goldbourt U, et al. Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease. Stroke 2003; 34:632.
  87. Li Z, Sun L, Zhang H, et al. Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke: a Multicenter Case-Control Study in China. Stroke 2003; 34:2085.
  88. Iso H, Moriyama Y, Sato S, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation 2004; 109:2766.
  89. Boysen G, Brander T, Christensen H, et al. Homocysteine and risk of recurrent stroke. Stroke 2003; 34:1258.
  90. Kim NK, Choi BO, Jung WS, et al. Hyperhomocysteinemia as an independent risk factor for silent brain infarction. Neurology 2003; 61:1595.
  91. Vasan RS, Beiser A, D’Agostino RB, et al. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA 2003; 289:1251.
  92. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325:1202.
  93. Casas JP, Bautista LE, Smeeth L, et al. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 2005; 365:224.
  94. Hankey GJ, Eikelboom JW. Homocysteine and stroke. Lancet 2005; 365:194.
  95. Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ 2005; 331:1053.
  96. He K, Merchant A, Rimm EB, et al. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke 2004; 35:169.
  97. McNulty H, Dowey le RC, Strain JJ, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation 2006; 113:74.
  98. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1998; 98:204.
  99. Bostom AG, Jacques PF, Nadeau MR, et al. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis 1995; 116:147.
  100. Miller JW, Nadeau MR, Smith D, Selhub J. Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr 1994; 59:1033.
  101. Hung J, Beilby JP, Knuiman MW, Divitini M. Folate and vitamin B-12 and risk of fatal cardiovascular disease: cohort study from Busselton, Western Australia. BMJ 2003; 326:131.
  102. den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334:759.
  103. Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998; 158:2101.
  104. den Heijer M, Rosendaal FR, Blom HJ, et al. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998; 80:874.
  105. Eichinger S, Stümpflen A, Hirschl M, et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80:566.
  106. Margaglione M, D’Andrea G, d’Addedda M, et al. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation. Thromb Haemost 1998; 79:907.
  107. Ridker PM, Hennekens CH, Selhub J, et al. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997; 95:1777.
  108. De Stefano V, Casorelli I, Rossi E, et al. Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000; 26:305.
  109. Tsai AW, Cushman M, Tsai MY, et al. Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). Am J Hematol 2003; 72:192.
  110. Bezemer ID, Doggen CJ, Vos HL, Rosendaal FR. No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med 2007; 167:497.
  111. Naess IA, Christiansen SC, Romundstad PR, et al. Prospective study of homocysteine and MTHFR 677TT genotype and risk for venous thrombosis in a general population–results from the HUNT 2 study. Br J Haematol 2008; 141:529.
  112. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340:9.
  113. Kirke PN, Mills JL, Molloy AM, et al. Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ 2004; 328:1535.
  114. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004; 350:2033.
  115. McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004; 350:2042.
  116. Dhonukshe-Rutten RA, Pluijm SM, de Groot LC, et al. Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people. J Bone Miner Res 2005; 20:921.
  117. Sato Y, Iwamoto J, Kanoko T, Satoh K. Homocysteine as a predictive factor for hip fracture in elderly women with Parkinson’s disease. Am J Med 2005; 118:1250.
  118. Gerdhem P, Ivaska KK, Isaksson A, et al. Associations between homocysteine, bone turnover, BMD, mortality, and fracture risk in elderly women. J Bone Miner Res 2007; 22:127.
  119. Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA 2005; 293:1082.
  120. Smith SC Jr, Milani RV, Arnett DK, et al. Atherosclerotic Vascular Disease Conference: Writing Group II: risk factors. Circulation 2004; 109:2613.
  121. Wilson PW. Homocysteine and coronary heart disease: how great is the hazard? JAMA 2002; 288:2042.
  122. Stampfer MJ, Malinow MR. Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med 1995; 332:328.
  123. Rosenson RS, Tangney CC. Preanalytical sources of measurement error: the conundrum of the homocysteine hypothesis. Atherosclerosis 2007; 194:520.
  124. Kang SS. Treatment of hyperhomocyst(e)inemia: physiological basis. J Nutr 1996; 126:1273S.
  125. Appel LJ, Miller ER 3rd, Jee SH, et al. Effect of dietary patterns on serum homocysteine: results of a randomized, controlled feeding study. Circulation 2000; 102:852.
  126. Brattström L, Israelsson B, Norrving B, et al. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis 1990; 81:51.
  127. Malinow MR, Duell PB, Hess DL, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998; 338:1009.
  128. Neal B, MacMahon S, Ohkubo T, et al. Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. Eur Heart J 2002; 23:1509.
  129. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006; 296:2720.
  130. Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007; 369:1876.
  131. Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2009; :CD006612.
  132. Miller ER 3rd, Juraschek S, Pastor-Barriuso R, et al. Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. Am J Cardiol 2010; 106:517.
  133. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke 2010; 41:1205.
  134. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354:1567.
  135. Holmes MV, Newcombe P, Hubacek JA, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 2011; 378:584.
  136. Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002; 288:973.
  137. Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004; 350:2673.
  138. Herrmann HC. Prevention of cardiovascular events after percutaneous coronary intervention. N Engl J Med 2004; 350:2708.
  139. den Heijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial. Blood 2007; 109:139.
  140. Ray JG, Kearon C, Yi Q, et al. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Ann Intern Med 2007; 146:761.
  141. Eikelboom JW, Lonn E, Genest J Jr, et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999; 131:363.
  142. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 1998; 316:894.
  143. Wald DS, Bishop L, Wald NJ, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med 2001; 161:695.
SEE MORE:  Therapeutic use of heparin and low molecular weight heparin