Version May 2024
INTRODUCTION — Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine (figure 1). Homocystinuria is a rare autosomal recessive disorder characterized by severe elevations in plasma and urine homocysteine concentrations. Clinical manifestations of homocystinuria include developmental delay, Marfanoid appearance, osteoporosis, ocular abnormalities, thromboembolic disease, and severe premature atherosclerosis.
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, moderate hyperhomocysteinemia was considered an independent risk marker for atherosclerotic vascular disease and for venous thromboembolism (VTE). However, associations between plasma homocysteine and vascular complications, particularly VTE, may have been due to failure to take into account confounding risk factors. (See 'Disease associations' below.)
This topic will review hyperhomocysteinemia as a risk marker for vascular disease and whether or not to test for or treat elevated homocysteine levels.
ETIOLOGY OF HYPERHOMOCYSTEINEMIA — Homocysteine is metabolized by one of two pathways: transsulfuration and remethylation (figure 1). Vitamins are necessary in the metabolism of homocysteine. The transsulfuration of homocysteine to cysteine is catalyzed by cystathionine-beta-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 plasma homocysteine levels can result from:
●Genetic factors – 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) [3]. The responsible gene is common; in the United States, approximately 30 percent of the population is heterozygous for the thermolabile variant of MTHFR and 10 percent is homozygous [4]. Homozygosity for the thermolabile variant of MTHFR (TT genotype) is a relatively common cause of elevated plasma homocysteine levels in the general population, often occurring in association with low serum folate levels [5-7]. At any given level of folate intake, TT homozygotes have lower plasma folate levels than nonhomozygotes [8].
●Vitamin deficiencies – Increased blood levels of homocysteine may reflect deficiency of folate, vitamin B6, or vitamin B12 [9-12]. 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 microg/day [13-15]. Vitamin B6 is a weaker determinant of homocysteine levels [14].
The importance of vitamin deficiency in the pathogenesis of hyperhomocysteinemia was evaluated in a cohort of 1041 older adults [13]. 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 a European case-control study with younger patients [14]. These data suggest that suboptimal B12 intake coupled with decreased absorption might play a greater role in elevating homocysteine and subsequent coronary heart disease (CHD) risk in older adults than in younger patients. By 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 US Food and Drug Administration (FDA) 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 [16]. In addition, the prevalence of a high homocysteine concentration (>13 micromol/L) decreased from 18.7 percent before fortification to 9.8 percent after fortification.
●Chronic kidney disease – Chronic kidney disease can increase homocysteine levels due to decreased renal removal and impaired metabolism. (See "Secondary prevention of cardiovascular disease in end-stage kidney disease (dialysis)", section on 'Hyperhomocysteinemia'.)
●Drugs – 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 [17-19]. Metformin has also been associated with increases in homocysteine levels [20], as has methotrexate [17].
●Smoking – Cigarette smoking may elevate homocysteine levels [21].
DISEASE ASSOCIATIONS — Markedly elevated levels of homocysteine in the blood have primary atherogenic and prothrombotic properties [2,22-38]. 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 [39-43]. These observations were presumed to explain the association between mild hyperhomocysteinemia and the diseases described below.
Vascular disease — Elevated homocysteine levels have been associated with an increased risk of cardiovascular and cerebrovascular disease. However, unlike modifiable risk factors such as hypertension, hypercholesterolemia, smoking, and diabetes, it has not been shown that lowering homocysteine prevents cardiovascular events [44]. (See 'Patients with cardiovascular disease or venous thromboembolism' below and "Overview of established risk factors for cardiovascular disease".)
The association of elevated homocysteine with cardiovascular disease and stroke was illustrated by a meta-analysis that evaluated data from 12 prospective studies, involving 1855 coronary heart disease (CHD) events and 463 stroke events [45]. After adjustment for known cardiovascular risk factors, a 25 percent lower homocysteine level (approximately 3 micromol/L) was associated with a lower risk of ischemic heart disease risk (odds ratio [OR] 0.89, 95% CI 0.83-0.86) and stroke (OR 0.81, 95% CI 0.69-0.95). Another meta-analysis performed for the US Preventive Services Task Force (USPSTF) specifically examined the issue of whether or not homocysteine levels add predictive value when estimating the risk of new-onset CHD [46]. The analysis found that, independent of Framingham risk factors, each 5 micromol/L higher homocysteine level was associated with a 20 percent greater risk of CHD. Hyperhomocysteinemia has also been associated with lower-extremity peripheral arterial disease and heart failure [47,48].
Genetic studies, whereby individuals with genetically determined elevations in plasma homocysteine are examined, have reported inconsistent findings about risk for cardiovascular disease [49-51]. As an example, in one meta-analysis of 40 observational studies involving 11,162 patients who were homozygous for the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR, which produces higher homocysteine levels) and 12,758 matched controls, the MTHFR TT genotype was associated with a higher risk for CHD (OR 1.16, 95% CI 1.05-1.28) [49]. However, a subsequent meta-analysis of genome-wide association studies including 31,400 cases and 92,927 controls found no association between a genetic risk score of homocysteine-regulating genes and CHD, although plasma homocysteine levels were lacking in most individuals [51].
Venous thromboembolism — Hyperhomocysteinemia has been associated with venous thromboembolism (VTE) in some but not all studies [52-58].
Meta-analyses of case-control studies have found an odds ratio of 2.5 to 3.0 for VTE in patients with markedly elevated homocysteine levels of more than two standard deviations above the mean value of control groups [53,54]. Moderate hyperhomocysteinemia (15 to 30 micromol/L) may also be a risk marker for recurrent VTE. This was reported in a multicenter study in which patients with a single episode of idiopathic VTE were prospectively followed after discontinuation of oral anticoagulants [55]. Recurrent VTE was significantly more likely in the 66 patients with hyperhomocysteinemia than in the 198 patients with normal homocysteine levels (18.2 versus 8.1 percent).
Additional research, however, has concluded that perceived associations between mild hyperhomocysteinemia and VTE may have been due to confounding [56-58]. In a large case-control study of over 3000 individuals, for example, mild hyperhomocysteinemia was associated with venous thrombosis in models adjusted for age and sex but not after also controlling for body mass index (BMI) and smoking status [58].
Obstetric complications — An early report linked the thermolabile variant of MTHFR to obstetric complications such as severe preeclampsia, abruptio placentae, fetal growth restriction, neural tube defects, and stillbirth [59,60]. However, a 2006 meta-analysis of 26 studies of 2120 women with unexplained recurrent pregnancy loss and 2949 controls did not find that the MTHFR C677T genotype was a risk factor for this outcome, except in a Chinese population [61].
Other — Hyperhomocysteinemia is also associated with other disorders:
●Osteoporosis – High homocysteine levels in adults have been associated with osteoporotic fractures in some [62-64], but not all [65], studies.
In a trial of homocysteine-lowering therapy with folate and B12 in adults at high risk for cardiovascular disease, there was no reduction in vertebral or nonvertebral fractures, although baseline homocysteine levels were not elevated in the study population [66]. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)
●Dementia – Hyperhomocysteinemia is associated with higher rates of dementia [67]; however, there is no convincing evidence that lowering homocysteine levels prevents or treats dementia [68]. (See "Risk factors for cognitive decline and dementia", section on 'Homocysteine'.)
●Several studies report an association of elevated homocysteine with cognitive impairment in Parkinson disease [69,70].
DECISION TO TEST — In general, we only measure serum homocysteine in patients suspected of having homocystinuria but not in other clinical settings.
Patients with suspected homocystinuria — We measure homocysteine levels in patients with suspected homocystinuria and in first-degree relatives of patients with homocystinuria.
Homocystinuria is suspected in children and adolescents with characteristic physical findings, developmental delay, or cardiovascular disease or thromboembolism. It is occasionally diagnosed in young adults [71]. Patients with homocystinuria have markedly elevated serum and urine homocysteine.
Homocystinuria is a rare autosomal recessive disorder. Clinical manifestations of homocystinuria include developmental delay, Marfanoid appearance, osteoporosis, ocular abnormalities (ectopia lentis), thromboembolic disease, and severe premature atherosclerosis. Routine newborn screening can detect homocystinuria but is not universally available.
Patients with cardiovascular disease or venous thromboembolism — Interventions to lower homocysteine have not been shown to prevent cardiovascular disease or venous thromboembolism (VTE) [44,72-77]. In addition, as outlined above, the association between mild hyperhomocysteinemia and VTE may be due to confounding. Accordingly, we generally do not measure homocysteine levels in patients with vascular disease or VTE. Our approach is based upon trial evidence that lowering homocysteine levels with vitamin supplementation does not improve clinical outcomes. However, these trials were conducted in countries with folic acid fortification of the food supply and primarily among participants who were not required to have elevated plasma homocysteine at baseline. In addition, these trials were designed to lower homocysteine concentrations with folic acid, but participants with normal folic acid levels were not excluded [15].
Lowering homocysteine levels has not been shown to prevent future cardiovascular events, with the possible exception of stroke [44,72,74]. The best data come from a meta-analysis of 15 randomized trials including 71,422 participants which found that, compared with placebo, homocysteine-lowering therapy (folate, vitamin B12, and/or vitamin B6) failed to reduce the risk of myocardial infarction (7.1 versus 6.0 percent), all-cause mortality (11.7 versus 12.3 percent), or serious adverse events (8.3 versus 8.5 percent) [44]. Homocysteine-lowering therapy modestly reduced the incidence of stroke compared with placebo (4.3 versus 5.1 percent), although this finding was largely influenced by a single Chinese study [78].
As with cardiovascular disease, lowering homocysteine has not been shown to reduce rates of recurrent VTE. The best data come from a randomized trial 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 [76]. 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, 95% CI 0.65-1.98), or in the 341 patients with normal homocysteine levels (HR 0.58, 95% CI 0.31-1.07). A post hoc subgroup analysis of a second trial reached similar conclusions [77].
Patients without known vascular disease — Patients without known vascular disease may ask to have their homocysteine levels checked as part of risk stratification for cardiovascular disease. Given the lack of evidence for benefit from lowering elevated homocysteine levels in patients with established cardiovascular disease, we do not measure homocysteine levels in patients without known vascular disease.
LABORATORY MEASUREMENT OF HOMOCYSTEINE — Sensitive assays allow quantification of the total homocysteine concentration; approximately 75 to 85 percent is protein-bound and 15 to 25 percent is in acid-soluble free forms [79]. Processing of specimens for homocysteine measurement requires cooling the specimen in wet ice and prompt transfer to the laboratory to minimize delays in processing. Delays in processing contribute to falsely elevated homocysteine levels [80].
Normal homocysteine concentrations range between 5 and 15 micromol/L. Hyperhomocysteinemia has been classified as follows [81]:
●Moderate (15 to 30 micromol/L)
●Intermediate (30 to 100 micromol/L)
●Severe (>100 micromol/L)
TREATMENT — As described above, the available evidence suggests not testing for or treating hyperhomocysteinemia unless homocystinuria is suspected or confirmed. In the rare patient with severe hyperhomocysteinemia associated with homocystinuria, we recommend referral to both a specialist in metabolic diseases and a nutritionist. (See 'Decision to test' above.)
The majority of hyperhomocysteinemia is caused by low levels of folate and vitamin B12 in patients with or without the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR). (See 'Etiology of hyperhomocysteinemia' above.)
Correcting nutritional inadequacy of folic acid and vitamin B12 will lower homocysteine levels in most patients [82]. A diet rich in fruits, vegetables, and low-fat dairy products and low in saturated and total fat can also lower serum homocysteine when compared with a diet relatively low in fruits, vegetables and dairy products, with a fat content typical of United States consumption [83].
In many countries, grains are fortified with folic acid, which leads to higher folate levels across the population. As an example, mandatory folic acid fortification of cereal grains in the United States led to a more than twofold increase in mean serum folate levels in a nationally representative survey [84].
SUMMARY AND RECOMMENDATIONS
●Definition – Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine. Elevations in plasma homocysteine are common, occurring in 5 to 7 percent of the population. (See 'Introduction' above.)
●Etiology of hyperhomocysteinemia – Homocysteine is metabolized by one of two pathways: transsulfuration and remethylation (figure 1). Vitamins are necessary in the metabolism of homocysteine. Elevations in plasma homocysteine levels can result from genetic factors, most commonly a thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) with reduced enzymatic activity (T mutation); vitamin deficiencies, specifically deficiency of folate, vitamin B6, or vitamin B12; chronic kidney disease, which can increase homocysteine levels due to decreased renal removal and impaired metabolism; certain drugs, including fibrates, nicotinic acid, metformin, and methotrexate; and cigarette smoking. (See 'Etiology of hyperhomocysteinemia' above.)
●Decision to test – In general, we only measure serum homocysteine in patients suspected of having homocystinuria but not in other clinical settings. (See 'Decision to test' above and 'Laboratory measurement of homocysteine' above.)
●Homocystinuria – Homocystinuria, a rare condition detected by newborn screening in many regions, presents in children and adolescents with developmental delay, Marfanoid appearance, osteoporosis, ocular abnormalities (ectopia lentis), thromboembolic disease, severe premature atherosclerosis, and extreme elevations in plasma homocysteine. In the rare patient with severe hyperhomocysteinemia associated with homocystinuria, we recommend referral to both a specialist in metabolic diseases and a nutritionist. (See 'Decision to test' above and 'Treatment' above.)
●Disease associations – Moderately elevated homocysteine levels have been associated with an increased risk of cardiovascular and cerebrovascular disease, venous thromboembolic disease, and obstetric complications. In experimental studies, homocysteine has primary atherogenic and prothrombotic properties, suggesting a possible mechanism for these associations. (See 'Disease associations' above.)
●Limited role for treatment – Despite some limitations, clinical trials have generally found that reducing levels of homocysteine with B vitamin supplementation does not prevent cardiovascular disease or reduce the incidence of recurrent venous thromboembolism (VTE) or arterial thrombosis. Thus, we suggest not testing for or treating hyperhomocysteinemia (Grade 2B), unless homocystinuria is suspected or confirmed. (See 'Patients with cardiovascular disease or venous thromboembolism' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Kang, MD, PhD, who contributed to an earlier version of this topic review.
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