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

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

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).

Prevention

Moderate hyperhomocysteinemia can often be prevented by dietary supplementation with folic acid (400 to 1000 µg daily), with or without other B vitamins. Dietary supplementation with folic acid appears to decrease total plasma homocysteine concentration even in the absence of a clinically-apparent deficiency of folic acid (22).

In 1996, the US Food and Drug Administration (FDA) mandated that all enriched grain products be fortified with 140 µg of folic acid per 100 g of cereal grain due to the potential beneficial effects of folic acid for prevention of neural tube defects and vascular disease (34). Based on data from the Framingham Offspring Study, this policy appears to have been successful in decreasing population mean plasma homocysteine concentrations (23).

Population-wide screening for moderate hyperhomocysteinemia is not recommended currently because of the lack of randomized trials proving efficacy of lowering homocysteine and the high cost of the test (33).

Prenatal diagnosis is feasible for cystathionine β-synthase deficiency, which is the most common cause of hereditary severe hyperhomocysteinemia.

Differential diagnosis

Differential diagnoses of hereditary severe hyperhomocysteinemia are:

Moderate hyperhomocysteinemia must be included when ischemic stroke occurs in young adults. Other differential diagnoses of stroke in young age are:

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.

Special considerations

Pregnancy

Women with severe hyperhomocysteinemia have increased risk of fetal loss, and may be predisposed to thrombosis during pregnancy and the puerperium (40). Hyperhomocysteinemia during pregnancy also is associated with increased risk of neural tube defects (39). Elevated homocysteine level and deficiency of folate and vitamin B12 during pregnancy may be a risk factor for preeclampsia and future cardiovascular disease (27). Successful pregnancies have been reported in patients with homozygous deficiency of cystathionine β-synthase who are responsive to pyridoxine.

Anesthesia

Hyperhomocysteinemia does not usually necessitate special considerations for anesthesia other than recognition of increased risk of postsurgical thromboembolic complications. The use of intraoperative nitrous oxide may cause transient hyperhomocysteinemia (03).