Hyperhomocysteinemia …

Stroke & Vascular Disorders

Updated 03.31.2025
Released 04.13.1998
Expires For CME 03.31.2028

Hyperhomocysteinemia

Authors: Bradley S Jacobs MD, Stephen Fuqua DO

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Editor: Steven R Levine MD

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Hyperhomocysteinemia

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Introduction

Overview

Hyperhomocysteinemia has been recognized as an independent risk factor for cardiovascular disease, stroke, and dementia. Vitamin supplementation has inconsistently demonstrated benefit in preventing these diseases. Hyperhomocysteinemia continues to be a topic of ongoing research.

Key points

	• Severe hyperhomocysteinemia (homocysteine level > 100 µM) is most commonly due to homocystinuria, an inborn error of metabolism that impairs an enzyme important for methionine metabolism (most commonly cystathionine beta-synthase). Symptoms include arterial and venous thromboses, intellectual disability, seizures, marfanoid features, and livedo reticularis.
	• Moderate hyperhomocysteinemia (homocysteine level 15 to 100 µM) in the adult population is usually not related to inborn metabolic error and is an independent risk factor for cerebrovascular disease and cognitive dysfunction.
	• Folic acid, vitamin B6, and vitamin B12 can lower homocysteine levels. Homocysteine-lowering therapies have shown a mild benefit in secondary stroke prevention and little to no benefit in the reduction of cardiovascular disease and myocardial infarction.
	• Increasing evidence suggests that hyperhomocysteinemia is an independent risk factor for developing dementias. Higher levels of homocysteine are correlated with increased severity of cognitive deficits.

Historical note and terminology

Homocysteine is a non-essential amino acid produced during metabolism of methionine. Homocysteine can be converted back to methionine in an enzymatic reaction requiring folate and vitamin B12. Hyperhomocysteinemia is defined as elevation of plasma total concentration of homocysteine and metabolic products of homocysteine (homocysteine, cysteine-homocysteine). These are collectively termed "homocyst(e)ine" 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 (34). Those homozygous for cystathionine beta-synthase deficiency, termed “homozygous homocystinuria,” frequently develop premature atherosclerosis and thrombotic complications, including stroke (38). Through the end of the 20th century, hyperhomocysteinemia became a topic of research and discussion because of the recognition that even moderately elevated concentrations of homocysteine are associated with an increased risk of stroke, cardiovascular disease, and venous thrombosis (43).

Mean fasting concentrations of total plasma homocysteine are usually less than or equal to 10 µM, with the 95th percentile at approximately 15 µM. Some have categorized hyperhomocysteinemia as moderate if between 15 and 100 µM and severe if greater than 100 µM.

Clinical manifestations

Presentation and course

	• Homocystinuria is a congenital metabolic disorder causing intellectual disability, thrombotic events, and marfanoid features.
	• Severe hyperhomocysteinemia is most commonly due to congenital homocystinuria and can lead to thrombosis, neurologic abnormalities, ocular abnormalities, and skeletal abnormalities.
	• Moderate hyperhomocysteinemia is an acquired disorder linked to venous and arterial thromboses and neurodegenerative dementias.

Severe hyperhomocystenemia. Severe hyperhomocysteinemia is often caused by deficiency of the cystathionine beta-synthase enzyme and other enzyme systems in the metabolism of methionine (50). Excessive homocysteine in serum is excreted through the kidney, thus, high homocysteine level is often detected in urine as well (homocystinuria). Clinical manifestations associated with severe hyperhomocysteinemia are shown in Table 1, 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 vascular abnormalities, such as stroke, myocardial infarction, or pulmonary embolism prior to 30 years of age (39).

Table 1. Clinical Features Associated with Severe Hyperhomocysteinemia

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

Moderate hyperhomocysteinemia. Moderate hyperhomocysteinemia is a risk factor for ischemic stroke, peripheral vascular disease, myocardial infarction, and venous thromboembolism (26). In a meta-analysis of 11 studies, people with moderate hyperhomocysteinemia had an odds ratio of 2.5 to develop cerebrovascular disease (04). A cohort study of 1226 middle-aged and older patients in Shanghai, China, with a 17-year follow-up suggested a significant association between elevated homocysteine levels (> 10 mmol/L) and the risk of ischemic stroke, cerebrovascular disease, and new-onset hypertension (11). 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 (44).

An association between hyperhomocysteinemia and dementia has been proposed for several decades (06), and increasing evidence points towards hyperhomocysteinemia as an independent risk factor to develop vascular and Alzheimer dementias (05). A meta-analysis examining hyperhomocysteinemia and the risk of developing Alzheimer dementia found that for every 5 umol/L increase, the relative risk of Alzheimer dementia linearly increased by 15% (58).

Homocysteine levels are increased relative to the severity of cognitive impairment. Homocysteine levels over 10 umol/L were associated with a higher severity of cognitive impairment, increased functional impairment, and increased neuropsychiatric symptom severity when compared with levels under 10 umol/L (27). Hyperhomocysteinemia is significantly associated with cognitive dysfunction in Parkinson disease (28). This may need to be considered in choosing therapeutic options for Parkinson disease because levodopa, the most commonly used medication in Parkinson disease, has been shown to induce hyperhomocysteinemia (16).

Similarly, homocysteine has been found to be elevated in people with intracranial hemorrhage, with levels similar to those with ischemic stroke (59). Interestingly, several small studies have indicated that increased homocysteine levels are a protective factor against rupture in patients with arteriovenous malformations (55).

Hyperhomocysteinemia may be associated with progression of multiple sclerosis. In a study of 180 patients with multiple sclerosis, homocysteine levels were higher in progressive forms than in relapsing multiple sclerosis independent of sex and age (41), and patients with both progressive and relapsing multiple sclerosis have higher homocysteine levels than subjects without multiple sclerosis (36).

Prognosis and complications

In a large international survey of patients with severe hyperhomocysteinemia due to cystathionine beta-synthase deficiency, mortality by 20 years of age was approximately 5% in pyridoxine-responsive patients and 20% in those resistant to pyridoxine (39). 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 (40). A study of 644 elderly patients (mean age 80.3) with acute ischemic stroke showed that moderate hyperhomocysteinemia on admission was related to poor functional outcome on discharge from stroke unit but not related to mortality (13). An additional study demonstrated that high folate levels were associated with lower risks of death and major disability among Chinese patients with ischemic stroke (47). Homocysteine at least partly mediated this effect and hypothetically worsened neuronal damage.

The CHANCE-2 study compared ticagrelor and aspirin versus clopidogrel and aspirin for stroke prevention among Chinese patients with minor ischemic stroke or transient ischemic attack and the CYP2C19 loss-of-function allele (53). The combination of ticagrelor and aspirin showed benefit in these patients in the primary study. Interestingly, this benefit was noted more so in patients with elevated homocysteine levels hypothetically related to prothrombotic effects of homocysteine counteracted by better antithrombotic effects of ticagrelor and aspirin in this population.

Clinical vignette

A 40-year-old man without a significant past medical history 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. CTA of the head and neck and transthoracic and transesophageal echocardiography did not reveal any abnormalities.

He was started on aspirin 81 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 started on folic acid 1 mg each day. After 1 month, his homocysteine decreased to 9 µM.

Biological basis

Etiology and pathogenesis

	• Hyperhomocysteinemia has many causes, including inborn enzyme deficiencies, nutritional vitamin deficiencies, medications, and medical comorbidities, including smoking.
	• Hyperhomocysteinemia causes symptoms through multiple mechanisms, including endothelial dysfunction, induction of pro-inflammatory states, and oxidative stress.

Severe hyperhomocysteinemia is often caused by homozygous enzyme deficiencies, whereas moderate hyperhomocysteinemia can be caused by heterozygous enzyme deficiencies.

There is a well-documented inverse relationship between plasma levels of cobalamin and folic acid and plasma levels of homocysteine. There are many other causes of moderate hyperhomocysteinemia as listed in Table 2.

Table 2. Factors Associated with Hyperhomocysteinemia

Enzyme deficiency
	• Cystathionine beta-synthetase • Methylenetetrahydrofolate reductase (MTHFR) • Methionine synthase
Vitamin deficiency
	• Folate • Vitamin B6 • Vitamin B12
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 the homocysteine metabolic pathway to methionine or cystathionine. The two most commonly defective enzymes are methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthetase.

Mutations affecting MTHFR in the folic acid pathway have been correlated with an increase in plasma homocysteine concentrations and may be a risk factor for cerebrovascular disease (22). The most common MTHFR mutation is a C-to-T point mutation at the nucleotide C677T (switching alanine to valine), which leads to reduction of the basal enzyme activity (14). This mutation is quite common, with heterozygotes representing 40% to 50% of some populations and homozygotes representing 5% to 15%.

The key enzymes involved in homocysteine metabolism require vitamin cofactors, such as folate, vitamin B6, or vitamin B12. Therefore, deficiency of these vitamins can also lead to hyperhomocysteinemia. Deficiency of folate 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 (45).

Studies have investigated the 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 (29; 10). Endothelial dysfunction has been observed in human volunteers as well during acute hyperhomocysteinemia (21). Endothelial dysfunction may contribute to early development of atherosclerosis. There have been some animal studies suggesting that hyperhomocysteinemia may accelerate the development of atherosclerosis (17; 57).

A 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 (42).

Epidemiology

	• Homocystinuria is a relatively rare disorder but may be underdiagnosed due to insensitive newborn screenings.
	• Moderate hyperhomocysteinemia is very common in the general population, affecting up to 30% of adults.

Homocystinuria has classically been described as a rare diagnosis, affecting about 1 in 100,000 to 200,000 people in the United States (1 in 200,000 to 335,000 worldwide). Some studies have raised concerns about the sensitivity of newborn screenings, and when patients who are diagnosed later in life are included, the prevalence may be closer to 1 in 10,000 (46). Severe hyperhomocysteinemia is a rare disorder, with an estimated prevalence of 1 in 50,000 to 1 in 300,000 (38).

Hyperhomocysteinemia due to deficiency of cystathionine beta-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 people to moderate hyperhomocysteinemia, especially in folate-deficient patients.

Moderate hyperhomocysteinemia is more common than severe hyperhomocysteinemia. 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 (08). Before 1996, 90% of Americans did not ingest the minimum 400 mcg/day of folic acid. Since 1998, a regulation by the Food and Drug Administration mandated that 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 (31).

Management

	• The management of hyperhomocysteinemia is controversial.
	• The primary method of lowering hyperhomocysteinemia is folate and other B vitamin supplementation.
	• Homocysteine lowering therapies may prevent stroke, but without significant benefit in the prevention of cardiovascular disease and myocardial infarction.

The mainstay of therapy for hyperhomocysteinemia is supplementation with folic acid, vitamin B6, and vitamin B12, often in the form of a B-complex vitamin.

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 hyperhomocysteinemia consists of oral administration of large doses of pyridoxine (250 to 1200 mg daily). Approximately 50% of people with cystathionine beta-synthase deficiency do not respond to pyridoxine; folic acid and cyanocobalamin are often added empirically to improve response.

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.

The following two randomized controlled trials with a primary outcome of stroke prevention showed no clear benefit of vitamin supplementation.

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 (51).

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 (52).

However, other studies have suggested a benefit. The SU.FOL.OM3 trial, which included patients with a history of myocardial infarction, unstable angina, or ischemic stroke. did not show benefit for the primary outcome of nonfatal myocardial infarction, stroke, or death from cardiovascular disease. However, B vitamins were associated with a 46% reduced risk of ischemic stroke as a secondary endpoint (15).

The HOPE 2 trial in patients with vascular disease or diabetes showed no benefit in preventing the primary outcome of death from cardiovascular causes, myocardial infarction, and stroke (18). However, B vitamins did show a significant reduction in the secondary endpoint of stroke.

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 (19). Further analysis of this study 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 homocysteine-lowering treatment, but patients with the CT or CC genotype treated with folate had a lower risk of stroke (09). A Cochrane review involving 15 studies totaling over 70,000 patients showed a very mild benefit in stroke risk reduction, with statistical analysis showing a need to treat 143 people for 5.4 years to prevent one stroke (32).

Based on the above studies, the 2021 American Heart Association guidelines for the secondary prevention of ischemic stroke concluded that there was no benefit in supplementation of folate, vitamin B6, and vitamin B12 for hyperhomocysteinemia for secondary prevention of stroke (23). However, other experts pointed out that the guideline methodology did not allow consideration of primary prevention studies or results of secondary analyses in determining the final class of recommendation and level of evidence (49). Given this and other factors, they proposed that B vitamins should be recommended for stroke prevention. In particular, they recommended serum B12 and homocysteine be measured in all ischemic stroke patients and treated. The authors defined abnormally elevated homocysteine levels as greater than 14 to 15 umol/L, with a target of less than 10 umol/L.

Several randomized controlled trials of vitamin B complex therapy for cognitive decline have been studied, yet most of them have been inconclusive (35; 01; 12; 25). 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 on cognitive function was not tested (48). A meta-analysis of four 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 (56).

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.

Pirfenidone, an anti-fibrotic agent primarily used in the treatment of pulmonary fibrosis, has shown some potential benefit in rabbit models of hyperhomocysteinemia. The proposed mechanism is the inhibition of inflammation and oxidative stress induced by homocysteine, which prevents the development of atherosclerosis (24). Due to this differing mechanism, it could feasibly be used in conjunction with homocysteine-lowering therapies. No human studies are yet available.

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Contributors

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

Authors

Bradley S Jacobs MD

Dr. Jacobs of Wright State University Boonshoft School of Medicine has no relevant financial relationships to disclose.
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Stephen Fuqua DO

Dr. Fugua of Clinical Neuroscience Institute at Miami Valley Hospital has no relevant financial relationships to disclose.
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Editor

Steven R Levine MD

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

Bradley S Jacobs MD
Yongwoo Kim MD
Nikolaos Papamitsakis MD
Steven R Lentz MD PhD (original author)

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-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
ICD-11: Hyperhomocysteinaemia: 3B61.00

Disorders of methionine cycle or sulphur amino acid metabolism: 5C50.B

Disorders of folate metabolism or transport: 5C63.1

Classical organic aciduria: 5C50.E0

Megaloblastic anaemia due to vitamin B12 deficiency, unspecified: 3A01.Z
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

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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

	• Acute systemic illness
	• Arteriopathies
		- Sickle cell disease
		- Arterial dissection
		- Parainfectious vasculitis
	• Cardiac disease
		- Congenital cardiac malformations
		- Arrhythmias
		- Endocarditis
	• Congenital metabolic disease
		- Mitochondriopathy
		- Fabry disease
		- Methylmalonic acidemia
		- Propionic acidemia
	• Connective tissue disorders, especially in patients with marfanoid features
	• Hypercoaguable conditions
		- Factor V Leiden
		- Protein C/S deficiency
		- Lupus anticoagulant
	• Malignancy

	• Homocysteine can be lowered with folic acid, vitamin B6, and vitamin B12.
	• Screening for hyperhomocysteinemia is not recommended due to the expense of the test and relative ineffectiveness of treatment.

	• Hyperhomocysteinemia is diagnosed with a fasting total plasma homocysteine test.
	• Blood samples must be promptly centrifuged and stored appropriately to avoid false elevations of homocysteine.

Hyperhomocysteinemia

Cite this article

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

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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