Hyperhomocysteinemia: An emerging risk factor for cardiovascular disease

Conclusion  There is considerable epidemiological evidence, which confirms the importance of plasma homocysteine as a powerful predictor of future risk of coronary heart disease and other complications of atherosclerosis. Treatment of hyperhomocysteinemia varies with the underlying cause. However, an inexpensive vitamin supplementation with folic acid, vitamin B12 and vitamin B 6 is generally effective in reducing homocysteine concentrations. Several randomised, controlled trials evaluating the effects of folic acid based supplements on homocysteine concentrations have been conducted over the last decade. In most patients, folic acid alone, and in combination of vitamin B12 and B6, has been shown to reduce homocysteine concentrations within four to six weeks after the initiation of therapy (34). However, no study has yet demonstrated that lowering of homocysteine by vitamin supplementation decreases the cardiovascular morbidity or mortality. Avoidance of excessive meat intake and increased consumption of fresh vegetables and fruits is a dietary measure, which has many health benefits, including a potential to reduce elevated homocysteine levels. The other reasonable approach is to determine levels of fasting homocysteine in high risk patients and it may be advisable to increase their intake of vitamin fortified foods and/or to suggest the daily use of supplemental vitamins. Several large scale randomised trials like Heart Outcomes Prevention Evaluation (HOPE-2) Study, Mcmaster University, Canada, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SERCH), Clinical Trial Service Unit, Oxford, U.K, Cambridge Heart Antioxidant Study (CHAOS-2) University of Cambridge, U.K, Bergen Vitamin Study, University of Bergen Norway, Women's Antioxidant and Cardiovascular Disease Study (WACS) Harvard Medical School, U.S.A, Prevention with a combined inhibitor and folate in Coronary Heart Disease (PACIFIC) study, University of Sydney, Australia, and many others are ongoing to assess the effect of homocysteine—lowering by vitamin supplementation on risk of vascular disease.     

A case of vitamin B12 deficiency neurological syndrome in a young adult due to late-onset cobalamin C (CblC) deficiency: a diagnostic challenge

Vitamin B12 deficiency can present with neurologic and psychiatric symptoms without macrocytic anaemia. We describe a case of late-onset cobalamin C deficiency which typically presents with normal serum vitamin B12 concentrations, posing an additional diagnostic challenge. A 23-year-old woman with decreased muscle strength and hallucinations was diagnosed with ‘catatonic depression’ and admitted to a residential mental health facility. She was referred to our hospital for further investigation 3 months later. Heteroanamnesis revealed that the symptoms had been evolving progressively over several months. Magnetic resonance imaging (MRI) of the brain showed diffuse symmetrical white matter lesions in both hemispheres. Routine laboratory tests including vitamin B12 and folic acid were normal except for a slight normocytic, normochromic anaemia. Over the next 6 weeks her symptoms deteriorated, and she became unresponsive to stimuli. A new MRI scan showed progression of the white matter lesions. The neurologist requested plasma homocysteine (Hcys) which was more than 8 times the upper limit of normal. Further testing revealed increased methylmalonic acid and the patient was diagnosed with adult-onset cobalamin C deficiency. This case illustrates that Hcys and/or methylmalonic acid should be determined in patients presenting with neuropsychiatric symptoms suggestive of vitamin B12 deficiency with a normal serum vitamin B12 to rule out a late-onset cobalamin C deficiency.     

Effect of Vitamin B<Subscript>12</Subscript> and Folate on Homocysteine levels in colorectal cancer

Folate and cobalamin (Vitamin B₁₂) are two essential micronutrients involved in one-carbon metabolism, which affects heart disease, neural tube defects and cancer. Methylenetetrahydrofolate reductase, the key enzyme involved in one carbon metabolism produces methyl tetrahydrofolate from methylene tetrahydrofolate, which in turn donates methyl group to homocysteine to generate methionine. There exist two common low function polymorphic variants of the methylenetetrahydrofolate reductase gene involving nucleotides 677 C→T and 1298 A→C, which are associated with hyperhomocysteinemia. These polymorphisms are also linked with increased risk for certain cancers such as breast cancer and at the same time providing a protective effect on colorectal cancer. In this case control study, we have evaluated levels of folic acid, vitamin B₁₂ and homocysteine in patients with colorectal cancer. Folate and homocysteine levels did not differ significantly between the two groups; however an increasing trend was noticed with increase in homocysteine levels. Vitamin B₁₂ levels were increased in cases compared to control group.     

Effect of folic acid and vitamin B<Subscript>12</Subscript> administration on phenytoin induced toxicity in rats

Folic acid and vitamin B₁₂ are very important vitamins needed for normal cellular metabolic activities. The effects of folic acid and vitamin B₁₂ on liver integrity of growing Wistar albino rats following therapeutic dose of phenytoin administration were investigated. The activities of serum AST, ALT, ALP were investigated. Serum total protein level and lipid profile were also measured as indices of biochemical changes. The ingestion of phenytoin alone in rats significantly reduced serum protein while AST, ALT activities incresed as compared to the control (P<0.05). Supplementation of phenytoin with oral administration of 70microgram/kg body wt of folic acid resulted in a significant reversal in serum total protein and suppression in serum AST and ALT activities. Vitamin B₁₂ supplementation did not afford any significant protection against the effect of phenytoin ingestion but rather phenytoin toxicity was exacerbated in this study. However, the combined effects of vitamin B₁₂ and folic acid ameliorated the effects of phenytoin on serum enzymes of experimental rats. The effect of combination of phenytoin with folic acid or folic acid and vitamin B₁₂ is an interesting finding. Supplementation of phenytoin with folic acid or combination of these vitamins may be recommended for the purpose of ameliorating the adverse biochemical changes which are associated with phenytoin therapy. Further work is ongoing to help elucidate the effects of phenytoin and these vitamins on oxidative stress inducing mechanism.     

Relationship of plasma homocysteine with lipid profile parameters in ischemic heart disease

The present study was undertaken to explore the relationship of plasma homocysteine with other biochemical parameters in ischemic heart disease. Plasma levels of total homocysteine was measured by HPLC—fluorescence detection with internal standard in 60 ischemic heart disease patients and were compared with 30 age matched normal healthy controls. The significant increase of plasma homocysteine was observed in both myocardial infarction and chronic stable ischemic heart disease patients when compared with the controls. The hyperhomocysteinemia appears be to due to increased body demand of vitamins such as folic acid, vitamin B₁₂, B₆, B₂ either alone or in combination to regulate normal homocysteine metabolism.     

Polymorphism (C677T) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene: A preliminary study on north Indian men

An elevated level of plasma homocysteine, sulfur containing amino acid generated through demethylation of methionine has been widely accepted as a risk factor for cardiovascular disease (CVD). The increase can result from genetic and/or nutrient related disturbances in the remethylation or transsulfuration pathways for homocysteine metabolism. A common mutation (C677T) in the gene encoding for the enzyme 5, 10-methylenetetrahydrofolate reductase (MTHFR) or deficiency of the B vitamins namely folic acid, B₁₂, B₆ can lead to hyperhomocysteinemia. In the present study, we have investigated the incidence of the (C677T) MTHFR polymorphism in the North Indian males. 141 angiographically proven coronary artery disease (CAD) patients and 55 age and sex matched healthy volunteers were examined for the association between MTHFR gene polymorphism and CAD. The MTHFR genotyping was performed using polymerase chain reaction (PCR) followed by restriction-isotyping with Hinf 1 endonuclease. A trend for higher ‘T’ allele frequency (0.19) was observed in patients than in controls (0.16). However no significant association was found between C677T mutation and CAD severity. The lack of statistical significance could be due to the small sample size studied. Hence a larger study including various ethnic groups is warranted.     

Evaluation of oxidative stress in pregnancy induced hypertension

This work was undertaken to investigate correlation between oxidative stress and initiation of pathogenesis of pregnancy induced hypertension (PIH). Fifty primigravidae in age group of 20–35 years and gestational age 28–42 weeks with PIH were taken as cases. Twenty healthy primigravidae with no medical and surgical complications of pregnancy and with blood pressure ≤140/90 mm Hg served as controls. The cases were again subgrouped as severe preeclampsia (12 in number) and mild pre-eclampsia (38 in number). All of them were evaluated for serum malondialdehyde (MDA), Serum vitamin E and plasma vitamin C levels. The serum MDA levels were raised significantly in women with mild preeclampsia (P<0.01) and in women with severe preeclampsia (P<0.01) in comparison to normal primi gravida. The serum vitamin E levels were decreased in primi gravida with mild preeclampsia (p<0.1) and in primi with severe pre eclampsia (P<0.1) in comparison to normal primi gravida but the fall was not statistically significant. There was a significant fall (P<0.05) in the vitamin C levels in primi with mild preeclampsia than in the normal primi. The vitamin C levels in severe preeclamptic patients were lower than the normal primi but the fall was not statistically significant (P=0.10). The serum MDA and vitamin E showed a negative correlation in all the cases. The serum MDA and plasma vitamin C also showed a negative correlation in the control and study group. This observation suggests that in hypertensive disorders of pregnancy there is an imbalance between lipid peroxidation and antioxidant vitamin status because of oxidative stress. The decreased serum concentrations of the antioxidant vitamins supports the hypothesis that lipid peroxidation is an important causative factor in the pathogenesis of preeclampsia. The rise in antioxidants is probably to compensate the increased peroxide load in severe preeclampsia.     

Raised serum homocysteine levels in patients of coronary artery disease and the effect of vitamin B12 and folate on its concentration

Homocysteine(Hcy) has been implicated as a novel risk factor of Coronary Artery Disease (CAD) among Asian Indians, but many studies done in India failed to reveal any direct correlation. It has also been reported that Folic acid and Vitamin B12 levels inversely affect serum levels of homocysteine. In this study, we looked at the levels of homocysteine among patients with CAD. The effect of Vitamin B12, Folate and other risk factors on homocysteine levels were also evaluated. Mean homocysteine levels in cases (22.81±13.9, n=70) were significantly higher (p=<0.001) than the controls (7.77±7.3, n=70). However no statistically significant correlation could be deduced between homocysteine Vitamin B12, and Folate. Cumulative analysis have indicated an increase in homocysteine levels among patients with CAD with every additional risk factor.     

Association between plasma homocysteine and riboflavin status in Acute Lymphoblastic Leukemia in children

Remethylation of homocysteine to methionine is dependent on an adequate supply of one or more of the B vitamins like folate, vitamin B₁₂ and vitamin B₆. Plasma total homocysteine (tHcy) is also influenced by genetic factors such as polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene. MTHFR is a flavo enzyme and a key player in folate metabolism and changes in its activity could modify the susceptibility to Acute Lymphoblastic Leukemia (ALL). In this case — control study we have examined the effect of riboflavin status as measured by erythrocyte glutathione reductase activation coefficient (EGRAC) on homocysteine levels along with vitamin B₁₂ and folate in pediatric ALL. Folate and B₁₂ levels were significantly lower among cases as compared to controls while EGRAC and tHcy did not differ significantly among the groups. The multivariate regression analysis revealed that in the ALL group EGRAC significantly influences tHcy levels suggesting that riboflavin availability may be a predictor of tHcy levels in patients with ALL. This finding may have implications for tHcy lowering therapy.     

Evaluation of Serum Vitamin B12 Levels and Its Correlation with Anti-Thyroperoxidase Antibody in Patients with Autoimmune Thyroid Disorders

Vitamin B12 deficiency has been reported in patients with Autoimmune thyroid disorders. However there is limited data on exact prevalence of low B12 and its correlation with anti-thyroperoxidase antibody (anti-TPO) levels in these patients. The aim of our study was to estimate serum vitamin B12 levels in autoimmune thyroid disorders and to correlate B12 levels with anti-TPO. 350 patients were selected by convenient sampling. Vitamin B12 levels and thyroid parameters were estimated using fully automated chemiluminescence method on Access 2. Results of our study shows that using the manufacturer’s cut-off of 145 pg/mL, the prevalence of low serum vitamin B12 was found to be 45.50 %. Higher prevalence (55 %) was seen based on the published cut-off of 200 pg/mL The study however did not demonstrate any significant correlation between vitamin B12 levels and anti-TPO (r = −0.11 and p value of 0.30).

Electronic supplementary material

The online version of this article (doi:10.1007/s12291-014-0418-4) contains supplementary material, which is available to authorized users.     

Association of Inflammatory Cytokines,Lipid Peroxidation End Products and Nitric Oxide with the Clinical Severity and Fetal Outcome in Preeclampsia in Indian Women

Preeclampsia is a multisystem disorder associated with maternal hypertension, placental abnormalities and adverse fetal outcomes. The various pathways involved in its etiology include endothelial dysfunction, inflammatory milieu, lipid peroxidation and immunological imbalance. The present study was conducted to evaluate the causative and predictive role of nitric oxide, lipid peroxidation end products (MDA) and inflammatory cytokines (IL-6, TNF-α) in clinical presentation, severity and fetal outcome in preeclampsia. The study population was divided into 3 groups- Non- pregnant females comprising the control population; G1 and G2 groups included normal pregnant and pregnant females with preeclampsia with 50 patients in each group. Nitric Oxide and MDA levels were found to be highest in the preeclamptic patients as compared to other two groups. ROC curve analysis shows the superiority of the inflammatory markers as determinants of severity of preeclampsia which suggests the emerging role of pro inflammatory markers in the various pathological changes in preeclampsia. TNF-α emerged as the best marker in multivariate analysis and thus, has the potential for being used as a marker for PIH. Our study illustrates the multifactorial etiology of preeclampsia involving oxidative stress, proinflammatory milieu and endothelial dysfunction.     

Relationship Between Xanthine Oxidase,Ischemia Modified Albumin,Nitric Oxide with Antioxidants in Non Pregnants,Pre and Post-delivery of Normal Pregnants and Preeclampsia

Preeclampsia is a multisystem disorder involves altered homeostasis of oxidants–antioxidants, inflammatory process and endothelial dysfunction. The present study aim was to determine the levels of oxidative stress parameters (malondialdehyde, protein carbonyl, ischemia modified albumin and xanthine oxidase), nutrient antioxidants (vitamin C and vitamin E), enzyme antioxidants (catalase, superoxide dismutase, glutathione peroxidase glutathione reductase), total antioxidant status (TAS) and its association with nitric oxide. The study population consists of three groups, non pregnants (Group 1, n = 57), normotensive pregnants (Group 2, n = 57) and Preeclampsia (Group 3, n = 57). Group 2 and 3 were followed after delivery within 48 h. In preeclampsia xanthine oxidase, malondialdehyde and uric acid levels were significantly increased (p < 0.001), while TAS decreased (p < 0.05) when compared to normotensive pregnant and non pregnant. Catalase, glutathione reductase levels were increased (p < 0.005) and vitamin E, super oxide dismutase levels were decreased (p < 0.001) in preeclampsia when compared to normal pregnants. Receiver operating characteristics curve analysis showed area under curve for xanthine oxidase (0.8), malondialdehyde (0.804), Uric acid (0.84), ischemia modified albumin (0.92) and catalase (0.88) which indicated as good markers in preeclampsia. Amongst, ischemia modified albumin is a better marker of intrauterine hypoxic reperfusion risk with sensitivity 87.7 % and specificity 91.2 %. The increased hydrogen peroxide from xanthine oxidase adds to oxidative stress and increased catalase activity in preeclampsia represents combating action. Increased oxidative stress, decreased TAS and its apparent reversible changes evinced within 48 h after delivery in preeclampsia illustrated that placental abnormality is the contributing factor in the pathogenesis.     

Homocysteine status and acute myocardial infarction among Tamilians

Myocardial infarction is a major consequence of coronary artery disease. Apart from the traditional risk factors of myocardial infarction, recently many reports have suggested that hyperhomocysteinemia plays important role in myocardial infarction. Plasma homocysteine level was determined in 60 myocardial infarction patients and in 35 age matched healthy individuals. Statistically significant differences (p<0.01) were observed in the mean of plasma homocysteine concentrations between the acute myocardial infarction patients (24.59±6.14 mM/L) and in normal healthy individuals (13.73 ±3.54 mM/L). The level of homocysteine in myocardial infarction patients is significantly high (p <0.01) among myocardial infarction patients when compared to that of the controls. The the present study indicates a strong association between plasma homocysteine and acute myocardial infarction among Tamilians, thus implying plasma homocysteine as a possible risk factor for myocardial infarction.     

Vitamin B<Subscript>12</Subscript> Immunoassay on Roche Elecsys 2010: Effects of High Excess Concentration of Serum Vitamin B<Subscript>12</Subscript> in CKD Patients on Parenteral Administration

Vitamin B₁₂ being water soluble is excreted in the urine when administered in excess. The probability of finding an abnormally excess serum concentration would be almost surreal. We report a peculiar clinical situation that may impact the vitamin B₁₂ immunoassay on the Roche Elecsys 2010 due to excess analyte concentration. In separate episodes (Feb and June 2010), the Biochemistry laboratory of a tertiary-care hospital, Kolkata, India, encountered two critically ill patients with background chronic kidney disease (CKD), low urine output, and on cyanocoabalamin supplementation, who had serum vitamin B₁₂ concentrations far exceeding expected values; even post dialysis. The B₁₂ assays (pmol/l) were performed using electrochemiluminiscence immunoassay on Roche Elecsys 2010, the assay validity confirmed by concomitant quality control runs. The immunoassays failed to deliver results, flagged with “signal level below limit”. Biotin therapy was ruled out as a possible interferent. In the first episode, re-assay of a repeat draw yielded same outcome; outsourcing on Immulite provided concentration of >738 pmol/l. Serial dilution gave result of >29520 pmol/l on Elecsys 2010. In the second, we gained from past experience. Vitamin B₁₂ concentration >59040 pmol/l was conveyed to the treating nephrologist the very day. The B₁₂ immunoassay on the Elecsys 2010 employs sequential incubation steps for competitive binding that is compromised in the event of abnormally excess B₁₂ concentration in patient sera akin to the prozone effect. This knowledge may be beneficial while assaying sera of CKD patients to avoid financial loss due unnecessary repeats and delay in turnaround time.     

Serum Vitamin D Levels in Indian Patients with Multiple Sclerosis

Low serum vitamin D level has an increased association with risk of multiple sclerosis (MS).There has been no published data on the levels of this vitamin in Indian population with MS. Hence we decided to undertake this study to document if there is evidence of vitamin D deficiency in patients with MS in our population. 26 patients with diagnosis of MS by modified Mc Donald’s criteria were enrolled in this study. Serum vitamin D (1,25 hydroxy) levels were measured by electro-chemiluminescence in our biochemistry lab. An age-matched control group of 202 patients who did not have a diagnosis of MS were included. In our study group 76.9 % had vitamin D level less than 20 ng/ml compared to 65.5 % of control group (p value of 0.019). Our study revealed a trend towards low vitamin D values in Indian MS patients.     

Association of hyperhomocysteinemia to alcohol withdrawal in chronic alcoholics

This study is conducted in chronic alcoholics to assess the association of an Individual’s level of serum homocysteine with the success of achieving alcohol deaddiction in the patient. The patients’ nutrition status is also assessed. 50 chronic alcoholics admitted to a deaddiction center were inducted into the study. Patients underwent an 8 weeks holistic program to promote rehabilitation from alcoholism. All the patients were addicted to alcohol for 8 – 10 years. Of the 50 patients enrolled, 39 of them completed the 8 weeks program including complete abstinence from alcohol during this period. Fasting blood samples were collected on admission and again after 8 weeks of alcohol abstinence for analyses of serum homocysteine and serum prealbumin, transferrin, total proteins and albumin, gammaglutamyl transferase (GGT) and alanine transaminase (ALT). Of the 50 patients enrolled in the study, 39 completed the 8 weeks rehabilitation program. 11 patients discontinued within 2 weeks of admission. During the 8 weeks of complete alcohol abstinence, patients were given a balanced diet and multivitamin supplements. A significant improvement in their nutritional status was noted by the elevation of serum levels of prealbumin, transferrin, total proteins and albumin. Serum homocysteine levels decreased significantly (p<0.002) to normal levels from previous hyperhomocytenemia. This was accompanied by decrease in serum GGT and ALT levels indicating improved liver functions. Serum estimation of homocysteine in chronic alcoholics is important to assess whether the patient will have a successful rehabilitation. Normal homocysteine levels are achieved after dietary changes and abstinence from alcohol. Timely correction of hyperhomocysteinemia also provides successful rehabilitation.     

C677T MTHFR Gene Polymorphism is Contributing Factor in Development of Renal Impairment in Young Hypertensive Patients

Homocysteine concentration affected by the activities of the enzymes methylene tetra-hyrdofolate reductase (MTHFR). Polymorphisms in MTHFR gene associated with an impairment of MTHFR activity. Hyperhomocysteinemia is a result of single nucleotide polymorphisms (SNPs) in MTHFR 677 C>T that can cause homocysteine levels in the blood to increase. The purpose of this study is to investigate the relationships between MTHFR C677T (rs1801133) gene polymorphism, changes in homocysteine concentrations and progress of renal impairment in young adult hypertensive patients. Two hundred young hypertensive patients (age 21–24 years) were involved in this study; they were classified into patients with and without renal impairment in addition to 200 age and sex matched healthy controls. All participants were submitted to laboratory investigations as assay of MTHFR gene polymorphism C677T (rs1801133) by PCR/RFLP, determination of lipid profile, homocysteine and folic acid concentrations in addition to urinary albumin creatinine ratio (UACR). The levels of both homocysteine and UACR in the TT genotype patients were higher than those in the CC genotype group. Individuals who carry the T allele were more risky to hypertension and progress to early renal impairment in young age compared with those carrying the C allele [OR 2.02 (1.33–3.08), P < 0.001]. Genetic variants of C677T MTHFR gene and hyperhomocysteinemia may be responsible for rapid progress of renal impairment in Egyptian young age hypertensive patients. TT genotype or T allele may be considered as a predisposing factor for both elevated Hcy levels and the development of renal impairment. This study believed that lowering of homocysteine level can reduce renal impairment of hypertensive patients.     

Role of Homocysteine in Cognitive Impairement and Alzheimer’s Disease

A high circulating concentration of the non proteinogenic amino acid homocysteine has been implicated as a risk factor for Alzheimer’s Disease and its prodromal stage, mild cognitive impairement. Furthermore, hyperhomocysteinaemia has been directly attributed to a deficiency in vitamins B12, folate, and B6. Several studies have demonstrated decrease in progression of mild cognitive impairement to Alzheimer’s Disease, and some have even shown an improvement in cognition after vitamin supplements with B12 and folate. Plausible mechanisms linking hyperhomocysteinaemia to Alzheimer’s and cognitive impairement have been hypothesized and demonstrated in hyperhomocysteinemic mice models. However, some studies have not elucidated any benefit of vitamin supplements in subjects with cognitive impairment. Hence, multicentric clinical studies need to be conducted to substantiate the mechanisms of neuronal degeneration due to hyperhomocysteinaemia and to demonstrate the beneficial effect of folate, B6 and B12 supplements on cognition.     

Interplay Between Inflammation and Hemostasis in Patients with Coronary Artery Disease

Coronary artery disease (CAD) is a global epidemic currently. This study was planned to evaluate markers of inflammation and hemostasis and their possible association, if any, in patients with CAD. The study was carried out in 60 patients with acute myocardial infarction (AMI) and 60 age and gender matched controls. The following parameters were assayed in all study subjects-inflammatory-interleukin (IL)-10, high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-α, fibrinogen; hemostatic-fibrinogen, fibrin D-dimer and a novel risk factor—homocysteine. Inflammatory markers (hs-CRP, TNF-α and IL-10), fibrinogen, fibrin D-dimer and homocysteine levels were significantly higher in the patients with AMI, as compared with controls. A positive correlation was observed between D-dimer and the inflammatory markers—hs-CRP and TNF-α. Upon multivariate analysis, TNF-α emerged as the best determinant of CAD in our study. Our results indicate that there is a possible interplay of inflammation and hemostasis in CAD, underlining their synergistic role in the pathogenesis of CAD.     

Serum homocysteine levels in cerebrovascular accidents

Hyperhomocysteinemia has been considered an independent risk factor in the development of stroke. The present study was undertaken to evaluate serum homocysteine levels in patients with cerebrovascular accidents among the Manipuri population and to compare with the normal cases. Ninety-three cerebrovascular accident cases admitted in the hospital were enrolled for the study and twenty-seven age and sex matched individuals free from cerebrovascular diseases were taken as control group. Serum homocysteine levels were estimated by ELISA method using Axis homocysteine EIA kit manufactured by Ranbaxy Diagnostic Ltd. India. The finding suggests that hyperhomocysteinemia is associated with cerebrovascular accident with male preponderance, which increases with advancing age. However, whether hyperhomocysteinemia is the cause or the result of cerebrovascular accidents needs further investigations.