Hyperhomocysteinemia …

Nikolaos Papamitsakis MD

Stroke & Vascular Disorders

Updated 07.21.2021
Released 04.13.1998
Expires For CME 07.21.2024

Hyperhomocysteinemia

Author: Nikolaos Papamitsakis MD

See Contributor Disclosures

Editor: Steven R Levine MD

Hyperhomocysteinemia

In This Article

Quick Link

Introduction

Overview

In this article, the author discusses hyperhomocysteinemia and reviews developments in the understanding of its relationship with cerebrovascular disease and dementia. Although folic acid, vitamin B12, and vitamin B6 lower homocysteine levels, many recent randomized, controlled trials suggest that treatment with these vitamins does not clearly lower the risk of vascular disease.

Key points

	• Severe hyperhomocysteinemia (homocysteine level > 100 µM, also reported as homocysteinuria) is associated with congenital manifestation of ectopia lentis, myopia, marfanoid features, livedo reticularis, malar rash, intellectual disability, seizures, and also with arterial and venous vascular occlusions/thromboembolism.
	• Homocystinuria occurs as the result of inborn errors of metabolism that impair enzyme systems important for methionine metabolism, including cystathionine beta-synthase (CBS).
	• Moderate hyperhomocysteinemia (homocysteine level 15 µM - 100 µM) is associated with increased risk of cerebrovascular disease and cognitive dysfunction.
	• Vitamin B complex (folic acid, pyridoxine, cobalamin) can lower homocysteine levels and has been a main treatment for severe hyperhomocysteinemia.
	• In moderate hyperhomocysteinemia, the effectiveness of vitamin B complex therapy in order to prevent stroke or dementia is not well established.

Historical note and terminology

Hyperhomocysteinemia is defined as elevation, typically 20-fold or higher, of plasma total concentration of homocysteine and disulfide addition products of homocysteine (homocystine, cysteine-homocysteine), collectively termed "homocyst(e)ine" (Hcy) or "total homocysteine."

The hypothesis that hyperhomocysteinemia is a risk factor for vascular disease was proposed in 1969 by Dr. Kilmer S McCully, who observed advanced atherosclerosis in children with rare inherited disorders causing markedly elevated levels of total plasma homocysteine (35). The persons homozygous for cystathionine beta-synthase deficiency, leading to homozygous homocystinuria, frequently develop premature atherosclerosis and thrombotic complications as stroke (40). There has been a resurgence of interest in hyperhomocysteinemia because of the recognition that even moderately elevated concentrations of total plasma homocysteine are associated with increased risk of stroke, cardiovascular disease, and venous thrombosis (07; 46; 11).

Categorizing homocysteine levels into severe, moderate, and normal ranges is useful. Severe hyperhomocysteinemia is defined as a fasting total plasma homocysteine concentration greater than 100 µM. Moderate hyperhomocysteinemia is defined as a fasting total plasma homocysteine concentration between 15 µM and 100 µM. Mean fasting concentrations of total plasma homocysteine are usually less than or equal to 10 µM, with the 95th percentile at approximately 15 µM.

Clinical manifestations

Presentation and course

Severe hyperhomocystenemia. Severe hyperhomocysteinemia is often caused by deficiency of the cystathionine beta-synthase enzyme and other enzyme systems in the metabolism of methionine (52). Excessive homocysteine in serum is excreted through the kidney, thus high homocysteine level is often detected in urine as well (homocysteinuria). Clinical manifestations associated with severe hyperhomocysteinemia are shown in Table 1 and include skeletal, ocular, vascular, and nervous system abnormalities, although some individuals exhibit none of these phenotypic characteristics.

The age of onset and severity of clinical features vary widely among affected individuals. However, approximately 50% of patients with severe hyperhomocysteinemia develop stroke, myocardial infarction, or pulmonary embolism prior to 30 years of age (41).

Table 1. Clinical Features Associated with Severe Hyperhomocysteinemia

Skeletal abnormalities
	• Increased length of long bones (marfanoid habitus), with arm span longer than body height • Osteoporosis • Scoliosis • Pes cavus • Codfish vertebra
Ocular abnormalities
	• Ectopia lentis (lens deviated to downward/“setting sun” lenticular dislocation) • Myopia • Retinal detachment • Glaucoma • Cataracts • Corneal abnormalities
Vascular abnormalities
	• Ischemic stroke and transient ischemic attack • Cerebral venous thrombosis • Myocardial infarction • Peripheral vascular disease • Deep venous thrombosis • Pulmonary embolism
Neurologic abnormalities
	• Intellectual disability • Seizures • Psychiatric disorders
Other abnormalities
	• Fatty infiltration of liver • (Livedo reticularis) • Endocrine abnormalities • Myopathy • Malar flash

Moderate hyperhomocysteinemia. Moderate hyperhomocysteinemia is a risk factor for stroke, peripheral vascular disease, myocardial infarction, and venous thromboembolism. It could rarely cause a priapism (24). An odds ratio of 2.5 for cerebrovascular disease was estimated in patients with moderate hyperhomocysteinemia in a metaanalysis of 11 studies (04). Coexistence of moderate hyperhomocysteinemia in conjunction with other risk factors for thrombosis, such as the factor V Leiden mutation, may produce a greater risk for thrombotic vascular disease (45).

Moderate hyperhomocysteinemia has been associated with an increased risk of the development of dementia. Due to the well-studied relationship of homocysteine with stroke, an association with vascular dementia would not be surprising. However, some studies have suggested Alzheimer disease, in particular, to be associated with hyperhomocysteinemia (05; 49). A metaanalysis of prospective studies confirms an association between homocysteine and dementia (55).

A study of centenarians with and without dementia found that higher homocysteine level is 1 of the factors predicting dementia. Other factors were poorer nutritional status, lower blood pressure, and higher inflammatory activities (10). An observational study of 543 patients found the association between 3 measures (hyperhomocysteinemia, low folate level, low vitamin D level) and dementia more pronounced in subcortical vascular dementia than in Alzheimer disease (38).

Hyperhomocysteinemia is significantly associated with cognitive dysfunction in Parkinson disease (31). This may need to be considered in choosing therapeutic options for Parkinson disease because levodopa, the most commonly used medication in Parkinson disease, is known to induce hyperhomocysteinemia (18).

Hyperhomocysteinemia may be associated with progression of multiple sclerosis. In a study of 180 multiple sclerosis patients, homocysteine levels were higher in progressive forms than in relapsing-remitting multiple sclerosis independent of sex and age (43).

Prognosis and complications

In a large international survey of patients with severe hyperhomocysteinemia due to cystathionine β-synthase deficiency, mortality by 20 years of age was approximately 5% in pyridoxine-responsive patients and 20% in those resistant to pyridoxine (41). The major causes of death were stroke, myocardial infarction, and pulmonary embolism.

Moderate hyperhomocysteinemia has been known to be a strong predictor of mortality in patients with coronary artery disease (42). A study of 644 elderly patients (mean age 80.3, SD 8.7) with acute ischemic infarction showed that moderate hyperhomocysteinemia on admission was related to poor functional outcome on discharge from stroke unit, but not related to mortality (15).

Clinical vignette

A 40-year-old man without a history of classic vascular risk factors (eg, hypertension, diabetes, dyslipidemia, smoking) presented with acute onset of expressive aphasia and weakness of the right face and arm. MRI of the brain showed an acute left frontal lobe infarct. Carotid duplex, transcranial Doppler ultrasonography, and transthoracic and transesophageal echocardiography did not reveal any abnormalities.

He was started on aspirin 162 mg daily. A fasting total plasma homocysteine level was found to be elevated at 22 µM. His folate and vitamin B12 levels were normal. He was treated with a multivitamin daily. After 1 month, the fasting total plasma homocysteine had decreased to 15 µM. He was started on folic acid 1 mg each day. After 1 month, his homocysteine decreased to 9 µM.

Biological basis

Etiology and pathogenesis

Factors associated with hyperhomocysteinemia are shown in Table 2. Severe hyperhomocysteinemia is often caused by homozygous enzyme deficiencies. Moderate hyperhomocysteinemia can be caused by heterozygous enzyme deficiencies or any other factors in the table.

Apart from genetic etiologies and predispositions, individuals can develop hyperhomocysteinemia due to acquired defects of the metabolism of methionine via abnormalities in folate-, cobalamin- or betaine-dependent pathways. There is a well-documented inverse relationship between plasma levels of vitamin B12 and folic acid and plasma levels of homocysteine.

Table 2. Factors Associated with Hyperhomocysteinemia

Enzyme deficiency
	• Cystathionin β-synthetase • Methylenetetrahydrofolate reductase (MTHFR) • Methionine synthase • Homozygous deficiency commonly causes severe disease, whereas heterozygous deficiency often causes moderate disease.
Vitamin deficiency
	• Folic acid • Vitamin B6 (pyridoxine) • Vitamin B12 (cobalamine)
Medications
	• Fibrates • Statins • Niacin • Antihypertensive agents • Metformin • Methotrexate • Sulfasalazine • Anticonvulsants • Levodopa • Theophylline
Demographic characteristics
	• Advanced age • Male gender
Clinical characteristics
	• Smoking • Systemic lupus erythematosus • Hypothyroidism • Renal insufficiency

Homocysteine metabolism

Homocysteine is converted to methionine by receiving a methyl group from 5-methyltetrahydrofolate (active form of folate; betaine). Irreversible removal of homocysteine occurs via the transsulphuration pathway, which combines H...

Hyperhomocysteinemia often results from a dysfunction in homocysteine metabolic pathway to methionine or cystathionine. The 2 most commonly defected enzymes are methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthetase.

A mutation in MTHFR in the folic acid pathway has been correlated with an increase in plasma Hcy concentrations and can possibly be a risk factor for cerebrovascular disease (26). The most common mutation occurs in a C-to-T point mutation at the nucleotide C677T (switching alanine to valine), leading to reduction of the basal activity of the enzyme (16). It is estimated that the heterozygotes with this mutation are 40% to 50% and the homozygotes 5% to 15% in several populations. This mutation leads to elevated plasma Hcy levels, without clear association with increased stroke risk, especially in adults (08).

Many of the key enzymes involved in homocysteine metabolism require vitamin cofactors, such as folic acid, vitamin B6, and vitamin B12. Therefore, deficiency of these vitamins can also lead to hyperhomocysteinemia. Deficiency of folic acid or vitamin B12 is more common than deficiency of vitamin B6.

Decreased renal clearance of homocysteine in patients with chronic renal failure may contribute to hyperhomocysteinemia.

High serum homocysteine has been shown to have detrimental effects on neural cells, vascular endothelial cells, osteoblasts, and osteoclasts. Homocysteine is also known to increase oxidative stress, disrupt cross-linking of collagen molecules, and increase levels of advanced glycation end products, which results in reduced bone strength (47).

Studies have investigated effects of homocysteine on blood vessels (02). In vitro and animal studies have led to the hypothesis that homocysteine may induce endothelial dysfunction by altering normal antithrombotic process, perhaps through a reactive oxygen species-involved mechanism (32; 12). Endothelial dysfunction has been observed in human volunteers as well during acute hyperhomocysteinemia (25).

Endothelial dysfunction may contribute to early development of atherosclerosis, and this is a potential pathophysiology of increased vascular accident risk in hyperhomocysteinemia. There have been some animal studies suggesting that hyperhomocysteinemia may accelerate the development of atherosclerosis (19; 57).

A more recent paper from France suggests that hyperhomocysteinemia worsens cardiovascular disease by increasing the production of hydrogen sulfide, in turn decreasing the expression of adenosine A2 receptors on the surface of cardiovascular and immune cells, leading to ischemia and inflammation (44).

Epidemiology

Severe hyperhomocysteinemia is a rare disorder, with an estimated prevalence of 1 in 50,000 to 1 in 300,000 (40).

The estimated incidence of homocystinuria is 1 in 332,000 newborns, although 0.3% to 1.5% of the general population may be heterozygous for cystathionine beta-synthase deficiency, and in those individuals the cystathionine beta-synthase activity can be reduced by 50%.

The most frequent cause of severe hyperhomocysteinemia is a deficiency of cystathionine β-synthase. In a review of data from several countries, cystathionine β-synthase deficiency was detected by screening for hypermethioninemia in 1 in 344,000 newborns (40). However, because this screening test has limited sensitivity for hyperhomocysteinemia, this frequency probably underestimates the true prevalence of cystathionine β-synthase deficiency.

Moderate hyperhomocysteinemia is more common than severe hyperhomocysteinemia.

Moderate hyperhomocysteinemia due to deficiency of cystathionine β-synthase has a prevalence of 0.5% to 1.0% in North American and European populations. The C677T mutation in methylenetetrahydrofolate reductase is more prevalent, occurring in up to 15% of the general population. This mutation produces a thermo-labile enzyme that predisposes to moderate hyperhomocysteinemia, especially in folate-deficient patients.

The most common causes of moderate hyperhomocysteinemia are nutritional deficiencies of folic acid or vitamin B12. It is estimated that up to 30% of the elderly population may have moderate hyperhomocysteinemia due to a deficiency of folic acid (06). Before 1996, 90% of Americans did not ingest the minimum 400 mcg/day of folic acid. A regulation by the Food and Drug Administration mandated that, after 1998, all bread, pasta, rice, cornmeal, and grain products are required to contain 140 mcg folic acid per 100 gr of flour, with the goal to increase folic acid intake in women of child-bearing age, reducing the neural tube effects in their children (34). Only modest reductions of Hcy levels have been since then noted, after vitamin supplementation.

An association between total homocysteine levels and white matter hyperintensity volume on the fluid-attenuated inversion recovery (FLAIR) brain MRI sequence was suggested in a substudy of the Northern Manhattan Stroke Study (NOMASS) (56).

A cohort study of 1226 middle-aged and older patients in Shanghai, China with a 17-year follow-up suggested significant association between elevated Hcy levels (> 10 mmol / L) and the risk of stroke, cerebrovascular disease, and new onset hypertension (13).

In a study of 356 Chinese patients with brain arteriovenous malformations, the level of homocysteine was a protective factor for developing hemorrhage or rupture in arteriovenous malformations patients (60).

Diagnostic workup

The diagnosis of hyperhomocysteinemia is based on the results of laboratory measurement of total plasma homocysteine. Fasting total plasma homocysteine is the most common and convenient test to perform.

Although a number of different methods have been developed for this purpose, a specific technique utilizing liquid chromatography-tandem mass spectrometry provides several advantages in terms of speed, sensitivity, and specificity (59).

One must know that total plasma homocysteine levels can be erroneously altered depending on handling of the sample. If plasma is not separated from blood cells within 30 minutes, homocysteine levels increase at a rate of 10% per hour. This elevation may be delayed by 6 hours if the sample is placed on ice.

Total plasma homocysteine increases after protein meals or methionine loading. This provides the basis for the "post-methionine loading" test for hyperhomocysteinemia. In this test, total plasma homocysteine is measured 2 hours after oral administration of methionine (0.1 g/kg). This test may have greater sensitivity than measurement of fasting total plasma homocysteine for detecting moderate hyperhomocysteinemia caused by abnormalities of homocysteine transsulfuration (06).

Specialized tests for detection of specific DNA mutations in cystathionine β-synthase or methylenetetrahydrofolate reductase are available in reference laboratories.

If the homocysteine is elevated, levels of folate, vitamin B12, and vitamin B6 could also be measured because they may be helpful in determining whether specific supplementation with 1 of these vitamins may be most efficacious. Additionally, further work-up for an etiology of these deficiencies may be warranted, especially vitamin B12 deficiency.

Management

Mainstay of therapy to lower the plasma homocysteine levels is the vitamin B complex, comprising pyridoxine (B6), cobalamine (B12), and folic acid.

Severe hyperhomocysteinemia. Management of patients with severe hyperhomocysteinemia is directed toward lowering the total plasma homocysteine level with vitamin B complex supplementation.

Initial therapy for severe homocysteinemia consists of oral administration of large doses of pyridoxine (250 to 1200 mg daily). Supplementation with folic acid and vitamin B12 are often added because about 50% of patients with cystathionine β-synthase deficiency do not respond to pyridoxine.

Additional therapeutic measures may also be helpful, such as dietary methionine restriction and administration of methyl donor betaine.

Moderate hyperhomocysteinemia. Homocysteine lowering therapy for patients with moderate hyperhomocysteinemia remains controversial.

Most trials of patients with established vascular disease or cognitive dysfunction have found no benefit of homocysteine lowering by B vitamin complex therapy.

In the Vitamin Intervention for Stroke Prevention (VISP) trial, high-dose vitamin B complex therapy did not affect the risk of recurrent ischemic stroke, compared with a low-dose therapy (53).

In the Vitamins to Prevent Stroke Study (VITATOPS) trial, 8164 patients with recent stroke or transient ischemic attack were randomized to vitamin B complex versus placebo. After a median of 3.4 years of follow-up, the study found no effect of vitamin B complex supplementation on risk of stroke (54). However, as noted in the editorial accompanying the article, there is still place for further trials of homocysteine lowering treatments if the intervention can achieve and sustain large reduction in homocysteine levels (48).

In the SU.FOL.OM3 trial, patients with history of heart disease or ischemic stroke were randomized to vitamin B complex and/or omega-3 versus placebo. No effect of vitamin B therapy on reducing risk of primary outcome was found (17).

In the HOPE2 trial in patients with established vascular disease or diabetes mellitus, vitamin B complex therapy did reduce homocysteine levels, but did not affect the composite end-point of cardiovascular death, myocardial infarction, or stroke (20).

However, the investigators in the China Stroke Primary Prevention Trial (CSPPT) showed that folic acid supplementation significantly reduced the risk of stroke in China, where folate fortification has not been implemented (21), eventually suggesting that serum levels of Hcy and vitamin B12 should be measured in patients with stroke and elevated Hcy should be treated with B vitamins (51).

Another study of ischemic stroke patients with elevated homocysteine levels in China showed that the TT genotype of the C677T allele of the methylenetetrahydrofolate (MTHFR) gene was common in this population and an independent risk factor for poor efficacy of Hcy lowering treatment (09).

A metaanalysis of folic acid supplementation in 26 randomized trials found no effect on the risk of cardiovascular disease (58).

Another metaanalysis of folic acid supplementation in 30 randomized trials found 10% reduction of stroke risk and 4% reduction of overall cardiovascular disease risk. A greater benefit was observed among the participants with lower plasma folate levels and without preexisting cardiovascular disease. Folic acid supplementation had no significant effect on risk of coronary heart disease (30).

An analysis based on Mendelian randomization and genetic testing associated with various stroke subtypes revealed that Hcy and folate levels are associated with the small vessel disease subtype (29).

Several randomized controlled trials of vitamin B complex therapy for cognitive decline have been studied, yet most of them have been inconclusive (36; 01; 14; 28). One randomized trial of vitamin B complex therapy in patients with mild cognitive decline showed a reduced rate of brain atrophy, but the therapeutic effect to cognitive function was not tested (50). A metaanalysis of 4 randomized trials of vitamin B supplement on elderly patients with cognitive disorders found an effective reduction of homocysteine level. However, it did not translate into cognitive improvement (61).

The 2014 American Heart Association guideline for primary stroke prevention recommended that vitamins B complex might be considered for the prevention of ischemic stroke in patients with hyperhomocysteinemia, but its effectiveness is not well established (37).

The ineffectiveness of homocysteine lowering therapy may suggest that hyperhomocysteinemia is a marker for vascular disease or cognitive decline, but not a cause of them.

References

01: Aisen PS, Schneider LS, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease. JAMA 2008;300:1774-83. PMID 18854539
02: Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell death and differentiation 2004;11:S56-64. PMID 15243582
03: Badner NH, Drader K, Freeman D, et al. The use of intraoperative nitrous oxide leads to postoperative increases in plasma homocysteine. Anesth Analg 1998;87:711-3. PMID 9728858
04: Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57. PMID 7563456
05: Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449-55. PMID 9823829
06: D'Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood 1997;90:1-11. PMID 9207431
07: den Heijer M, Rosendaal FR, Blom HJ, et al. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998;80:874-7. PMID 9869152
08: Djordjevic V, Stankovic M, Brankovic-Sreckovic V, Rakicevic L, Radojkovic D. Genetic risk factors for arterial ischemic stroke in children: a possible MTHFR and eNOS gene-gene interplay? J Child Neurol 2009;24(7):823-7. PMID 19372095
09: Du X, Xiao L, Sun R, et al. A prospective cohort study of MTHFR C677T gene polymorphism and its influence on the therapeutic effect of homocysteine in stroke patients with hyperhomocysteinemia. BMC Neurol 2020;20(1):128. PMID 32278343
10: Duarte PO, Duarte MGF, Pelichek A, et al. Cardiovascular risk factors and inflammatory activity among centenarians with and without dementia. Aging Clin Exp Res 2017;29(3):411-7. PMID 27377066
11: 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;131:363-75. PMID 10475890
12: Faraci FM, Lentz SR. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke 2004;35:345-7. PMID 14757874
13: Feng Y, Kang K, Xue Q, Chen Y, Wang W, Cao J. Value of plasma homocysteine to predict stroke, cardiovascular diseases, and new-onset hypertension: a retrospective cohort study. Medicine (Baltimore) 2020;99(34):e21541. PMID 32846763
14: Ford AH, Flicker L, Alfonso H, et al. Vitamins B(12), B(6), and folic acid for cognition in older men. Neurology 2010;75(17):1540-7. PMID 20861451
15: Forti P, Maioli F, Arnone G, et al. Homocysteinemia and early outcome of acute ischemic stroke in elderly patients. Brain Behav 2016;6(5):e00460. PMID 27096104
16: 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(1):111-3. PMID 7647779
17: Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomized placebo controlled trial. BMJ 2010;341:c6273. PMID 21115589
18: Guo G, Xu S, Cao LD, et al. The effect of levodopa benserazide hydrochloride on homocysteinemia levels in patients with Parkinson's disease and treatment of hyperhomocysteinemia. Eur Rev Med Pharmacol Sci 2016;20(11):2409-12. PMID 27338068
19: Hoffmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 2001;107:675-83. PMID 11254667
20: HOPE 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567-77. PMID 16531613
21: Huo Y, Li J, Qin X, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA 2015;313(13):1325-35. PMID 25771069
22: Jacobsen DW. Determinants of hyperhomocysteinemia: a matter of nature and nurture. Am J Clin Nutr 1996;64:641-2. PMID 8839513
23: 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;340:1449-54. PMID 10320382
24: Kalathia J, Agrawal S, Chipde SS, Agrawal R. Homocysteinemia: a rare cause of priapism. Urol Ann 2016;8(1):118-21. PMID 26834419
25: 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;100:1161-8. PMID 10484535
26: Kang SS, Passen EL, Ruggie N, Wong PW, Sora H. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1993;88(4 Pt 1):1463-9. PMID 8403293
27: Kharb S, Aggarwal D, Bala J, Nanda S. Evaluation of homocysteine, vitamin b12 and folic acid levels during all the trimesters in pregnant and preeclamptic women. Curr Hypertens Rev 2016;12(3):234-8. PMID 27748186
28: Kwok T, Lee J, Law CB, et al. A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. Clinical Nutrition 2011;30:297-302. PMID 21216507
29: Larsson SC, Traylor M, Markus HS. Homocysteine and small vessel stroke: a mendelian randomization analysis. Ann Neurol 2019;85(4):495-501. PMID 30785218
30: Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB. Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J Am Heart Assoc 2016;5(8). PMID 27528407
31: Licking N, Murchison C, Cholerton B, et al. Homocysteine and cognitive function in Parkinson's disease. Parkinsonism Relat Disord 2017;44:1-5. PMID 28807493
32: Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 1996;98:5-7. PMID 8690803
33: Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178-82. PMID 9884399
34: 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;338:1009-15. PMID 9535664
35: McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969;56:111-28. PMID 5792556
36: McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 2006; 354:2764-72. PMID 16807413
37: Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45(12):3754-832. PMID 25355838
38: Moretti R, Caruso P, Dal Ben M, Conti C, Gazzin S, Tiribelli C. Vitamin D, homocysteine, and folate in subcortical vascular dementia and Alzheimer dementia. Front Aging Neurosci 2017;9:169. PMID 28611659
39: Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet 1996;58:17-20. PMID 8554053
40: Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. 7th edition. New York: McGraw-Hill, Inc., 1995:1279-327.
41: Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985;37:1-31. PMID 3872065
42: Nygard O, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6. PMID 9227928
43: Oliveira SR, Flauzino T, Sabino BS, et al. Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis. Metab Brain Dis 2018;33(5):1393-9. PMID 29797117
44: Paganelli F, Mottola G, Fromonot J, et al. Hyperhomocysteinemia and cardiovascular disease: is the adenosinergic system the missing link? Int J Mol Sci 2021;22(4):1690. PMID 33567540
45: Ridker PM, Hennekens CH, Selhub J, et al. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997;95:1777-82. PMID 9107163
46: Sacco RL, Roberts JK, Jacobs BS. Homocysteine as a risk factor for ischemic stroke: an epidemiological story in evolution. Neuroepidemiology 1998;17:167-73. PMID 9701830
47: Saito M, Marumo K. The effects of homocysteine on the skeleton. Curr Osteoporos Rep 2018;16(5):554-60. PMID 30116976
48: Sandercock P. Vitamin B supplements for prevention of stroke. Lancet Neurol 2010;9(9):842-3. PMID 20688573
49: Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002;346:476-83. PMID 11844848
50: Smith AD, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS ONE 2010;5(9):e12244. PMID 20838622
51: Spence JD. Homocysteine lowering for stroke prevention: unravelling the complexity of the evidence. Int J Stroke 2016;11(7):744-7. PMID 27462097
52: Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders. Arch Neurol 2010;67(2):148-53. PMID 20142522
53: Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. JAMA 2004;291:565-75. PMID 14762035
54: VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol 2010;9(9):855-65. PMID 20688574
55: Wald DS, Kasturiratne A, Simmonds M, et al. Serum homocysteine and dementia: meta-analysis of eight cohort studies including 8669 participants. Alzhemiers Dement 2011;7:412-7. PMID 21784352
56: Wright CB, Paik MC, Brown TR, et al. Total homocysteine is associated with white matter hyperintensity volume: the Northern Manhattan Study. Stroke 2005;36(6):1207-11. PMID 15879345
57: Zhou J, Moller J, Danielsen CC, et al. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in apoE-deficient mice. Arterioscler Thromb Vasc Biol 2001;21:1470-6. PMID 11557674
58: Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL. Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med 2012;23(8):745-54. PMID 22884409
59: Yuan L, Sharer JD. Quantitative analysis of total plasma homocysteine by LC-MS/MS. Curr Protoc Hum Genet 2016;89:17.21.1-17.21.10. PMID 27037487
60: Zeng C, Lin F, Ge P, Zhang D, Wang S, Zhao J. Homocysteine level and risk of hemorrhage in brain arteriovenous malformations. Dis Markers 2021;2021:8862299. PMID 33859768
61: Zhang DM, Ye JX, Mu JS, Cui XP. Efficacy of vitamin B supplementation on cognition in elderly patients with cognitive-related diseases. J Geriatr Psychiatry Neurol 2017;30(1):50-9. PMID 28248558

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Nikolaos Papamitsakis MD

Dr. Papamitsakis of SUNY Downstate Health Sciences Center has no relevant financial relationships to disclose.
See Profile

Editor

Steven R Levine MD

Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.
See Profile

Former Authors

Yongwoo Kim MD
Steven R Lentz MD PhD (original author), Bradley S Jacobs MD, and Yongwoo Kim MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Sulfur-bearing amino-acid metabolism disorder: 270.4
ICD-10: Disorders of sulfur-bearing amino-acid metabolism, unspecified: E72.10

Homocystinuria: E72.11

Methylenetetrahydrofolate reductase deficiency: E72.12

Other disorders of sulfur-bearing amino-acid metabolism: E72.19
OMIM: Homocystinuria: #236200

5,10-Methylenetetrahydrofolate reductase: *607903

Vitamin B12 metabolic defect with methylmalonic acidemia and homocystinuria: #277400

Vitamin B12 metabolic defect, type 2: #277410

Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism: #236270

Methylcobalamin deficiency, cbl G type: #250940

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Hyperhomocysteinemia

Associated Disorders

Deep venous thrombosis
Pulmonary embolism
Myocardial infarction
Ischemic stroke
Cerebral venous thrombosis
- Peripheral vascular disease
- Neural tube defects

Differential Diagnosis

elevated homocysteine levels may result from acute stroke
stroke in childhood
Fabry disease
methylmalonic acidemia
propionic acidemia
- myopia, lens abnormalities, body habitus
- Marfan syndrome
- arterial dissections
- hypercoagulable status
- vasculitis

Also Relevant

Cephaloceles
Folate deficiency
Homocystinuria due to cystathionine beta-synthase deficiency
Hypercoagulable states and cerebrovascular disease
Ischemic stroke
- Lacunar infarction
- Primary prevention of stroke
- Vitamin B12 deficiency

Stroke in childhood
	• Fabry disease • Methylmalonic acidemia • Propionic acidemia
Myopia, lens abnormalities, body habitus
	• Marfan syndrome

Hyperhomocysteinemia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Clinical Features Associated with Severe Hyperhomocysteinemia

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 2. Factors Associated with Hyperhomocysteinemia

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Zika virus: neurologic complications

CNS germinoma

Vein of Galen malformations

Hemorrhagic transformation of ischemic stroke

Thalamic hemorrhage

Infective endocarditis

Cerebellar astrocytoma

Rare brain embryonal tumors in infancy and early childhood

This is an article preview.
Start a Free Account
to access the full version.