The effect of methylenetetrahydrofolate reductase C677T common variant on hypertensive risk is not solely explained by increased plasma homocysteine values

The C677T transition of methylenetetrahydrofolate reductase (MTHFR) gene causes a moderate increase in total plasma homocysteine (tHcy). We studied the effect of MTHFR TT homozygosity and mild hyperhomocysteinemia on arterial hypertension. Normotensive controls (n = 223) and hypertensive subjects (n = 235) were matched for age, gender, and history of cardiovascular disease. Homocysteine levels were measured by a polarization immunoassay method. Methylenetetrahydrofolate reductase we determined by polymerase chain reaction and restriction fragment analysis. Hypertensives showed elevated tHcy compared to normotensive group in men (P = 0.039). Homocysteine values higher than 15 micromol/L were associated with increased hypertensive risk in the male population [odds ratios (OR) = 1.63; 95% confidence interval (CI) = 1.06-2.52; P = 0.027]. In multivariate analysis, TT genotype was associated with an increased risk of hypertension in males (OR = 2.27; 95% CI = 1.12-4.60; P = 0.022) An increased hypertensive risk was observed in those TT males with tHcy levels higher than 15 micromol/L (OR = 2.78; 95% CI = 1.05-7.3; P = 0.032) but not in those non-TT males with tHcy levels higher than 15 micromol/L (P = 0.33). Our findings do not support the possibility that mild hyperhomocysteinemia my solely account for the hypertensive risk associated to the TT genotype.     

Program

The C677T transition of methylenetetrahydrofolate reductase (MTHFR) gene causes a moderate increase in total plasma homocysteine (tHcy). We studied the effect of MTHFR TT homozygosity and mild hyperhomocysteinemia on arterial hypertension. Normotensive controls (n = 223) and hypertensive subjects (n = 235) were matched for age, gender, and history of cardiovascular disease. Homocysteine levels were measured by a fluorescense polarization immunoassay method. Methylenetetrahydrofolate reductase genotypes were determined by polymerase chain reaction and restriction fragment analysis. Hypertensives showed elevated tHcy compared to normotensive group in men (P = 0.039). Homocysteine values higher than 15 µmol/L were associated with increased hypertensive risk in the male population [odds ratios (OR) = 1.63; 95% confidence interval (CI) = 1.06–2.52; P = 0.027]. In multivariate analysis, TT genotype was associated with an increased risk of hypertension in males (OR = 2.27; 95% CI = 1.12–4.60; P = 0.022). An increased hypertensive risk was observed in those TT males with tHcy levels higher than 15 µmol/L (OR = 2.78; 95% CI = 1.05–7.3; P = 0.032) but not in those non‐TT males with tHcy levels higher than 15 µmol/L (P = 0.33). Our findings do not support the possibility that mild hyperhomocysteinemia may solely account for the hypertensive risk associated to the TT genotype.     

Hyperhomocysteinemia increases the risk of venous thrombosis independent of the C677T mutation of the methylenetetrahydrofolate reductase gene in selected Brazilian patients.

Fasting total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation were evaluated in 91 patients with venous thromboembolism and without acquired thrombophilia, and in 91 age-matched and sex-matched controls. Hyperhomocysteinemia was detected in 11 patients (12.1%) and in two controls (2.2%), yielding an odds ratio (OR) for venous thrombosis of 6.1 [95% confidence interval (CI), 1.3-28.4]. After excluding 21 patients and four controls with other known genetic risk factors for venous thrombosis, the OR was not substantially changed (7.0; 95% CI, 1.5-33.1). The prevalence of the MTHFR 677TT genotype was not significantly different in patients (9.9%) and in controls (5.5%), with an OR for venous thrombosis of 1.8 (95% CI, 0.6-5.8). Subjects with the MTHFR 677TT genotype showed higher levels of tHcy compared with the 677CC genotype in patients (P = 0.010) and in controls (P = 0.030). In conclusion, we found that fasting hyperhomocysteinemia is a risk factor for venous thrombosis in patients without known acquired thrombophilia and other genetic risk factors for venous thrombosis. Although tHcy levels are significantly higher in those homozygous for the MTHFR C677T mutation, this genotype does not increase the thrombotic risk in our study population.     

Age, sex and vitamin status affect plasma level of homocysteine, but hyperhomocysteinaemia is possibly not an important risk factor for venous thrombophilia in Taiwanese Chinese

The biological effects of age, sex and vitamin status on plasma total homocysteine (tHcy), and association of hyperhomocysteinaemia with venous thromboembolism in Taiwanese Chinese individuals, were investigated. Eighty patients (16-85 years) with venous thrombophilia and 123 healthy subjects (15-85 years) without history of vascular thrombosis were studied for plasma levels of tHcy, folate and vitamin B12. A multivariate analysis in healthy subjects revealed that plasma tHcy levels tended to increase with age (P < 0.001) and with decreasing plasma levels of folate (P=0.001) or vitamin B12 (P < 0.029); men tended to have higher plasma tHcy levels than women (P=0.006). Thrombotic risk assessment in a case-control study demonstrated that neither plasma level of tHcy [odds ratio (OR), 1.07; 95% confidence interval (CI), 0.96-1.18; P=0.210] nor hyperhomocysteinaemia (OR, 1.65; 95% CI, 0.50-5.49; P=0.415) was significantly associated with venous thrombophilia. The relationship between hyperhomocysteinaemia and recurrence of episode remained insignificant (P=0.560). We conclude that age, sex and vitamin status affect plasma tHcy but hyperhomocysteinaemia is possibly not an important risk factor for venous thrombophilia in Taiwanese Chinese.     

Risk factors for thrombophilia in extrahepatic portal vein obstruction

Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for thrombophilia screening, including the search for gain-of-function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, for odds ratios of 4.0 (95% CI, 2.3-7.0) and 4.4 (95% CI, 3.3-5.9), respectively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8-17.5) and the deficiencies of antithrombin, protein C, or protein S taken together (odds ratio, 4.5; 95% CI, 1.1-18.0). The odds ratio for the prothrombin G20210A was approximately twice that for lower limb DVT. Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1-6.4) and for lower limb DVT of 7.5 (95% CI, 4.4-13.0). The odds ratio for EHPVO in patients with hyperhomocysteinemia was 2.0 (95% CI, 0.9-4.9). At variance with lower limb DVT, oral contraceptive use was not associated with an increased risk of EHPVO. Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. In conclusion, the risk for EHPVO is increased in the presence of thrombophilia resulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden.     

Mechanisms of Venous and Arterial Thrombosis in Heparin-Induced Thrombocytopenia

This pictorial introduction to homocysteine illustrates at a glance the nature of homocysteine and its role in cardiovascular disease by means of eight simple figures and an essential bibliography. Homocysteine is a sulfur-containing metabolite of methionine. Conversion back to methionine or transsulfuration to cysteine are the two major metabolic pathways that reduce total homocysteine (tHcy) concentrations in cells and blood. B vitamins are essential cofactors in homocysteine metabolism. Median fasting total homocysteine levels in adult males are 10 µmol/L. Increased plasma tHcy concentrations are found with methionine-rich diets, low vitamin B intake, male gender, age, impaired renal function, and genetically determined defects of the enzymes involved in homocysteine metabolism. An inverse relation exists between plasma tHcy and circulating folate or vitamin B₆ concentrations, and folic acid supplements of 0.5 mg/d can reduce tHcy levels by 25%. Homocystinuric patients, who have severe hyperhomocysteinemia, die prematurely of atherothrombotic disease. Many (but not all) cross-sectional and prospective studies indicate, on average, that plasma tHcy levels <.10 µmol/L are associated with, or predict the development of, coronary, cerebral, and peripheral vascular disease. The risk conferred by hyperhomocysteinemia is graded and is independent of traditional risk factors, with an estimated odds ratio for ischemic heart disease of 1.4 for every 5 µmol/L increase in plasma tHcy. In vitro and in vivo, tHcy has been found to impair endothelial function. It is now well established that tHcy represents a marker of current or subsequent ischemic vascular disease. However, irrefutable proof that hyperhomocysteinemia actually causes atherothrombosis will come only if interventions to lower plasma tHcy will produce concomitant reductions in cardiovascular events.     

The relation between plasma cysteine, plasma homocysteine and coronary atherosclerosis

Several studies have reported that elevated plasma levels of total homocysteine (tHcy) are related to an increased risk of cardiovascular disease. Only a few studies have looked at the effect of cysteine, another amino thiol, on cardiovascular disease risk. Therefore, in the present case-control study we compared plasma total cysteine (tCys) levels and plasma tHcy levels among subjects with severe coronary atherosclerosis (cases, n=131), subjects without severe coronary atherosclerosis (coronary controls, n=88) and healthy subjects (population-based controls, n=101). Cases were defined as those having > or =90% occlusion in one and > or =40% occlusion in a second coronary artery, while coronary controls had a maximum of 50% occlusion in only one coronary artery. Both males and females, aged 26--64 years were studied. We have previously reported that plasma tHcy is an independent risk factor for coronary atherosclerosis in this study population. In the present analysis, we found that cases had statistically significant higher mean plasma tCys levels than coronary controls and population-based controls (295.8+/-40.2, 279.0+/-35.5 and 282.6+/-32.4 micromol/l, respectively). The odds ratio (OR) of coronary atherosclerosis for the upper tertile of tCys compared with the bottom tertile was 2.5 (95% confidence interval (CI), 1.4--4.3). However, the association between tCys and coronary atherosclerosis was confounded to a great extent by risk factors (OR, 1.0; 95% CI, 0.5--2.0). The multivariate adjusted OR of coronary atherosclerosis per 1 S.D. increase in plasma tCys was 1.0 (95% CI, 0.8--1.3). The corresponding OR per 1 S.D. increase in plasma tHcy was 1.4 (95% CI, 1.1--1.8). We conclude that plasma tCys, unlike plasma tHcy, is not an independent risk factor for atherosclerosis.     

Elevated levels of plasma homocysteine are associated with neurotoxicity

OBJECTIVE: The aim of the present study is to investigate whether increased plasma homocysteine (tHcy) has an effect on the cerebral metabolic concentrations, reflecting neurotoxicity, measured with Magnetic Resonance Spectroscopy (MRS). METHODS: One hundred and thirteen patients had a MRS investigation of the brain and the concentration of N-acetyl-aspartate (NAA), choline and creatine was measured and fasting plasma tHcy was assessed. We used linear regression models to investigate the association between tHcy and cerebral metabolic concentrations. RESULTS: We found that tHcy is associated with cerebral NAA (B = -0.09 mmol/l (95% CI, -0.17 to -0.00)) and with creatine (B = -0.09 mmol/l (95% CI, -0.16 to -0.02)) per 1 micromol/l increase tHcy. Patients with a tHcy >/=14 micromol/l had a lower concentration cerebral of NAA (P < 0.05) and creatine (P < 0.01) compared with patients with a tHcy <14 micromol/l. No significant association was found for the cerebral choline. CONCLUSION: Elevated levels of tHcy were associated with low concentrations of cerebral NAA and creatine, independent of renal function or the presence of atherosclerotic disease. These preliminary results suggest that tHcy has a neurotoxic effect in vivo.     

Hyperhomocysteinemia in women with advanced breast cancer

Patients with malignancy have an increased risk of venous thromboembolic disease but the pathophysiology of this association has not been precisely defined. Hyperhomocysteinemia has become established as one of the commonest conditions associated with venous and arterial thrombosis. We examined the prevalence of hyperhomocysteinemia in women with early (group A, n = 31), metastatic breast cancer (group B, n = 41) and in a group of healthy females (group C, n = 29). Blood samples were collected at diagnosis or prior to treatment. We measured both total plasma homocysteine (tHcy) and red cell folate (RCF). The Mean (SD) tHcy were group A - 9.43 micromol/l (5.6), group B - 11.34 micromol/l (5.1) and group C - 7.9 micromol/l (1.5). A total of 39% of patients with metastatic and 22.6% with early breast cancer had tHcy concentrations above the upper limit of normal. Women with metastatic disease had significantly higher tHcy compared with controls (P < 0.01) but not when compared with women with early breast cancer. Also, no difference was observed when women with early disease were compared with controls. We found no correlation between age and tHcy. Lower RCF levels were identified in group B compared with group A, but this does not fully explain the increased tHcy levels seen within the same group. We conclude that hyperhomocysteinemia is common in women with advanced breast cancer. This observation could explain the high rate of venous thrombosis in women with metastatic breast malignancy.     

Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases

Elevated plasma homocysteine is increasingly being recognized as a risk factor for coronary artery disease (CAD). Although there is general agreement on the importance of micronutrients and genetic predisposition to elevated plasma homocysteine, the exact influence of the known prevalent mutations in genes which regulate homocysteine metabolism is not clear. We studied 376 cases of individuals with premature CAD with respect to their fasting and post-methionine load (PML) total homocysteine (tHcy) concentrations. We also determined the presence or absence of the T833C and G919A mutations of the cystathionine-beta-synthase (CBS) gene, the C677T mutation of the methylene tetrahydrofolate reductase (MTHFR) gene, and the A2756G transition of the B12 dependent methionine synthase (MS) gene. Our objectives were therefore both to confirm the relationship of plasma homocysteine with premature CAD and to examine the importance of genetic influence on both fasting and PML homocysteine. Approximately 32% of the CAD patients had fasting hyperhomocysteinemia and 16% had PML hyperhomocysteinemia. Of these, 8.5% had both forms of hyperhomocysteinemia (combined hyperhomocysteinemia). The T133C mutation in the CBS gene and the thermolabile C677T mutation in the MTHFR gene seem to play an important role in the subset of individuals with combined hyperhomocysteinemia. The A2756G transition in the MS gene is not associated with elevated plasma tHcy. Many cases (47%) of hyperhomocysteinemia are not associated with micronutrient deficiencies, impaired renal function, and/or currently known genetic mutations. Further work is needed to study whether unknown mutations, particularly those residing in the intronic sequences of the genes involved in homocysteine metabolism, other environmental factors, or interaction of gene, nutrient, and environmental factors may be the cause of currently unexplained cases of mild hyperhomocysteinemia.     

Hyperhomocysteinaemia and adverse events complicating coronary catheter interventions

BACKGROUND: Since hyperhomocysteinaemia is an independent risk factor for development of atherosclerosis as well as for arterial and venous thrombosis we investigated whether elevated homocysteine levels are associated with procedural excess risk which complicates coronary interventions including coronary angioplasty (PTCA), stenting, or directional coronary atherectomy (DCA). Design: Consecutive cases receiving coronary catheter interventions. SETTING: Tertiary referral centre in Germany. METHODS: Fasting total plasma homocysteine levels (tHcy) were determined in 648 consecutive coronary artery disease patients who underwent catheter interventions (272 PTCA, 102 DCA, and 274 stenting). Hyperhomocysteinaemia was defined as tHcy >/=15 micromol/l. The patients were investigated for a 30-day composite endpoint, including need for target-vessel revascularization, myocardial infarction, and death. RESULTS: Among the 648 patients, 78 (12%) demonstrated elevated tHcy levels. The composite endpoint occurred in 41 patients (6.3%). For the entire intervention group there was no evidence that hyperhomocysteinaemia was associated with excess procedural risk (odds ratio [OR]: 1.27; 95% confidence interval [CI]=0.52 to -3.13; P=0.62). In further analyses according to device, hyperhomocysteinaemia also failed to predict complications in the device related subgroups. CONCLUSION: The results indicate that hyperhomocysteinaemia is not a major risk factor for 30-day adverse events complicating PTCA, DCA, or stenting.     

Hyperhomocysteinemia is a significant risk factor for silent cerebral infarction in patients with chronic renal failure undergoing hemodialysis

In patients with chronic renal failure undergoing hemodialysis (HD), the presence of silent cerebral infarction (SCI) is associated with high mortality. Plasma total homocysteine (tHcy), which increases with renal dysfunction, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of SCI correlates with tHcy in HD patients. Based on brain magnetic resonance imaging findings, 44 patients undergoing HD were divided into a with-SCI group (61+/-9 years [mean+/-SD]; n=24) and a without-SCI group (60+/-8 years, n=20), in whom 24-hour ambulatory blood pressure monitoring was performed. The number of patients with diabetes or hypertension was not different between the 2 groups. We made the following observations: (1) the percentage of smokers was higher in the with-SCI group than in the without-SCI group (P<.05); (2) plasma levels of high-density lipoprotein cholesterol were lower and tHcy was higher in the with-SCI group than in the without-SCI group (P<.05 and P<.0001, respectively); (3) and systolic ambulatory blood pressure and mean heart rate during nighttime were higher in the with-SCI group than in the without-SCI group (P<.05). Multivariate logistic analysis identified hyperhomocysteinemia as an independent and significant risk factor for SCI (odds ratio, 1.22; 95% CI, 1.10-1.36; P<.01). Our findings indicate that plasma tHcy may be a novel useful predictor for SCI in patients with chronic renal failure undergoing HD.     

Hyperhomocysteinemia and inflammatory bowel disease: prevalence and predictors in a cross-sectional study

OBJECTIVE: Homocysteine is a sulfur-containing amino acid formed during the demethylation of methionine. Vitamin B12 and folate deficiency and therapy with antifolate drugs may predispose patients with inflammatory bowel disease (IBD) to hyperhomocysteinemia. The known associations between hyperhomocysteinemia and smoking, osteoporosis, and thrombosis make it an interesting candidate as a pathogenetic link in IBD. The aim of this study was to identify the prevalence and risk factors of hyperhomocysteinemia in patients with IBD. METHODS: Sixty-five consecutive IBD patients were recruited from a tertiary outpatient gastroenterology practice. Fasting plasma homocysteine levels were measured, along with vitamin B12 and folate. Data regarding medication use, multivitamin use, disease location and severity, and extraintestinal manifestations of IBD were gathered. Homocysteine levels in 138 healthy control subjects were compared with the IBD cohort, and adjustments for age and sex were made using logistic regression. Multivariate analysis was performed to seek predictors of homocysteine levels. RESULTS: The mean age in the IBD cohort was 42+/-13.4 yr (+/-SD), and 43% were male. The mean disease duration was 13.8+/-9.4 yr, and 32% had used steroids within the last 3 months. Immunomodulator therapy had been used in 32%, and 75% had had an intestinal resection. Osteoporosis was present in 33% of patients. Five patients had experienced venous thrombosis or stroke, but only one of these had hyperhomocysteinemia. Of the 10 IBD patients (15.4%) with hyperhomocysteinemia, only two had vitamin B12 deficiency. The homocysteine levels in the IBD cohort cases and controls were 8.7 and 6.6 micromol/L, respectively (p < 0.05). IBD significantly increased the risk of hyperhomocysteinemia (adjusted odds ratio = 5.9 [95% CI: 1.5-24]). Advanced age, male sex, vitamin B12 deficiency or lower vitamin B12 serum levels, and multivitamin therapy were independently associated with higher homocysteine levels in the multivariate analysis (R2 = 0.55; p = 0.001). CONCLUSIONS: Hyperhomocysteinemia is significantly more common in patients with IBD compared with healthy controls, and is associated with lower (but not necessarily deficient) vitamin B12 levels.     

Association between serum total homocysteine and arterial stiffness in adults: a community‐based study

Both increased arterial stiffness and higher total homocysteine (tHcy) are associated with an elevated risk for cardiovascular disease. However, the relationship between tHcy and arterial stiffness is still inconclusive. The authors aimed to test the relationship of tHcy with carotid‐femoral pulse wave velocity (cfPWV) and examine the possible effect modifiers in adults. A study was conducted from July to September 2016 in Jiangsu Province, China. A total of 16 644 participants were enrolled in the final analysis. Increased arterial stiffness is defined as a cfPWV ≥10 m/s. Overall, there was a positive association between tHcy and cfPWV levels (per 5‐μmol/L tHcy increase: β = 0.10; 95% confidence interval [CI], 0.08–0.13) and increased arterial stiffness (per 5‐μmol/L tHcy increase: odds ratio, 1.11; 95% CI, 1.07–1.14). Compared with participants with tHcy <10 μmol/L, the significantly higher cfPWV levels were observed in those with tHcy ≥15 μmol/L (β = 0.37; 95% CI, 0.28–0.47). Accordingly, a higher prevalence of increased arterial stiffness was found in patients with tHcy10 to <15 μmol/L (odds ratio, 1.18; 95% CI, 1.05–1.33) and tHcy ≥15 μmol/L (odds ratio, 1.50; 95% CI, 1.32–1.71) as compared with participants with tHcy <10 μmol/L. Furthermore, the stronger positive association was found in participants who were older (≥60 years, P for interaction = .008), had low body mass index (<25 kg/m², P for interaction = .026), high systolic blood pressure levels (≥145 mm Hg [median], P for interaction = .048), or diabetes mellitus (P for interaction = .045). The present study demonstrated that serum tHcy concentrations were positively associated with cfPWV and the prevalence of increased arterial stiffness. These results suggest that the cardiovascular effects of tHcy may partly be mediated through arterial stiffness.     

Association between hyperhomocysteinemia and primary pulmonary hypertension

STUDY OBJECTIVE: This case-control study was conducted to test the hypothesis that fasting homocysteine levels are higher in PPH patients than in healthy controls. DESIGN: Levels of plasma total homocysteine, serum folate, vitamin B-12, and serum creatinine in 18 consecutive patients with PPH were compared with data from 36 age- and sex-matched controls. RESULTS: Eight of the 18 patients (44.4%) and three of the 36 controls (8.3%) had elevated plasma total homocysteine (tHcy) levels (> or = 15 mol/l, odds ratio 8.8; 95% CI: 2.0-39.6; P = 0.005). There was an inverse correlation between tHcy levels and creatinine clearance in patients with PPH (P = 0.036). CONCLUSION: PPH patients are significantly more likely to have hyperhomocysteinemia, and higher mean plasma total homocysteine levels than in controls. Plasma total homocysteine may be an important factor in the pathogenesis of PPH.     

Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women.

BACKGROUND: Elevated fasting total homocysteine (tHcy) levels were recently shown to confer an independent risk for all-cause and cardiovascular disease (CVD) mortality among selected Norwegian patients with confirmed coronary heart disease. We examined whether elevated fasting plasma tHcy levels were predictive of all-cause and CVD mortality in a large, population-based sample of elderly US women and men. METHODS: Nonfasting plasma tHcy levels were determined in 1933 elderly participants (mean age, 70 +/- 7 years; 58.9% women) from the original Framingham Study cohort, examined between 1979 and 1982, with follow-up through 1992. Unadjusted and adjusted (ie, for age, sex, diabetes, smoking, systolic blood pressure, total and high-density lipoprotein cholesterol, and creatinine) relative risk estimates (with 95% confidence intervals [CIs]) for total and CVD mortality were generated by proportional hazards modeling, with tHcy levels (quartiles) as the independent variable. RESULTS: There were 653 total deaths and 244 CVD deaths during a median follow-up of 10.0 years. Proportional hazards modeling revealed that tHcy levels of 14.26 micromol/L or greater (the upper quartile), vs less than 14.26 micromol/L (the lower three quartiles), were associated with relative risk estimates of 2.18 (95% CI, 1.86-2.56) and 2.17 (95% CI, 1.68-2.82) for all-cause and CVD mortality, respectively. The relative risk estimates after adjustment for age, sex, systolic blood pressure, diabetes, smoking, and total and high-density lipoprotein cholesterol levels attenuated these associations, but they remained significant: 1.54 (95% CI, 1.31-1.82) for all-cause mortality; 1.52 (95% CI, 1.16-1.98) for CVD mortality. CONCLUSION: Elevated nonfasting plasma tHcy levels are independently associated with increased rates of all-cause and CVD mortality in the elderly.     

Hyperhomocysteinemia: could the post-methionine oral loading test sometimes be avoided?

BACKGROUND AND OBJECTIVES: Measurement of homocysteinemia, a risk factor for venous and arterial thrombosis, is carried out in patients fasting for 12 hours and after an oral methionine load (PML). The procedure is time-consuming and several of the patients suffer from nausea and malaise. We wondered whether methionine loading could sometimes be avoided by considering fasting homocysteinemia (tHcy) levels. DESIGN AND METHODS: We evaluated whether fasting tHcy levels were useful to predict PML and deltaPML tHcy with acceptable sensitivity and specificity in 381 patients with venous and arterial thrombosis through the generation of receiver operating characteristic curves. RESULTS: Both PML and deltaPML tHcy correlated with fasting tHcy values. The cut-off of fasting tHcy value yielding a 100% sensitivity in predicting normal PML and deltaPML tHcy was 6.5 and 5.0 micromol/L in females, and 7.1 and 7.2 micromol/L in males. Fasting tHcy values yielding a 95% specificity in predicting a positive PML and tHcy result ranged from 12.5 to 13.1 micromol/L in males and from 10.4 to 10.5 micromol/L in females. A 95% specificity in predicting a positive deltaPML tHcy result ranged from 10.8 to 11.6 micromol/L in females and from 15.9 to 17.0 micromol/L in men. Considering PML tHcy, 186 out of 381 patients could have avoided methionine loading while using deltaPML tHcy 123 out of 381 could have done so. INTERPRETATION AND CONCLUSIONS: Nearly 50% of our patients considering PML tHcy, and about 30% considering deltaPML tHcy could have been spared the methionine loading test. We propose this model for those who wish to carry out this analysis on their own.     

Homocysteine, vitamins and gene mutations in peripheral arterial disease.

A case-control study was undertaken involving 51 consecutive patients with peripheral artery obstructive disease (PAOD) scheduled for angioplasty. Blood samples of these patients were analysed for plasma homocysteine (tHcy) and levels of vitamin B12 and folate, and the MTHFR gene was assessed for mutation. Patients were compared with age- and sex-matched controls who did not present with cardiovascular risk factors. Mean tHcy did not differ between cases and controls (13.3 +/- 5.7 and 12.6 +/- 4.9 micromol/l, P = 0.49). More patients were above the 95th percentile as determined from the data in the control group with an odds ratio (OR) that almost reached statistical significance [OR, 2.8; 95% confidence interval (CI), 0.9-8.7], but on separate analyses only female patients showed higher tHcy than female controls (15.6 versus 12.0 micromol/l, P = 0.05), with an odds ratio for tHcy above the 95th percentile of 10.5 (95% CI, 1.1-96.6). The TT genotype of the MTHFR gene was found in 24% of the patients and in 12% of the controls (OR, 2.3; 95% CI, 0.8-6.7). Our findings point to a modest association between tHcy and PAOD, with a difference between cases and controls restricted to the highest percentile in female patients. A weak but not significant association was also found for the TT genotype of the MTHFR gene.     

Both vitamin B6 and total homocysteine plasma levels predict long-term atherothrombotic events in healthy subjects.

AIMS: The contribution of homocysteine and group B vitamins in determining cardiovascular risk is debated. We assessed the predictive value of total homocysteine (tHcy), vitamin B12, folate, and vitamin B6 on the long-term occurrence of coronary and cerebral atherothrombotic events in a nested case-control study. METHODS AND RESULTS: Within a cohort of 1021 healthy subjects (490 men and 531 women) recruited in 1987, 66 first-ever coronary and 43 first-ever cerebrovascular events were recorded at a 12-year follow-up (cases, n=109). A total of 109 control subjects (remaining free from events) were matched with cases according to age, sex, smoking, hypertension, dyslipidaemia, and body mass index. Serum samples obtained in 1987 at baseline were used to measure tHcy, folate, and vitamins B12 and B6, as well as C-reactive protein plasma concentrations. We found a significant graded association between tHcy levels and the risk of coronary and cerebrovascular events [odds ratio (OR) for uppermost vs. lowermost quartile=1.34, 95% CI 1.01-1.76)]. Folate and vitamin B12 did not significantly differ between cases and controls, but were negatively (P<0.01) correlated with tHcy. Vitamin B6 did not correlate with tHcy levels, but differed significantly between cases and controls: for subjects in the uppermost quartile vs. the lowermost quartile of vitamin B6, OR=0.69 (95% CI 0.49-0.98). For subjects in the lowermost quartile of vitamin B6 and the uppermost quartile of tHcy, OR=17.50 (95% CI 1.97, 155.59). Cases and controls were not different as to C-reactive protein. CONCLUSION: tHcy and plasma vitamin B6 are long-term independent risk factors for coronary and cerebrovascular events.     

Folate, but not homocysteine, predicts the risk of fracture in elderly persons

BACKGROUND: Recent prospective studies reported that increased plasma homocysteine levels are an independent predictor of osteoporotic fracture in elderly persons. These studies, however, did not take into account folate and vitamin B12, which are the major nutritional determinants of homocysteinemia. METHODS: Incident osteoporotic fractures were assessed in 702 Italian participants aged 65-94 years with a mean follow-up of 4 years (1999/2000-2003/2004). A multivariable logistic regression model was used to study the relation of baseline plasma homocysteine, serum folate, and serum vitamin B12 with risk of fracture. RESULTS: After adjustment for sociodemographic and clinical confounders, the odds ratio (OR) for each increase of 1 standard deviation in log-transformed plasma homocysteine was 1.39 (95% confidence interval [CI], 1.01-1.91), but decreased to 1.22 (95% CI, 0.85-1.74) after further adjustment for serum folate and vitamin B12. The corresponding multivariable-adjusted OR for hyperhomocysteinemia (plasma total homocysteine [tHcy] > 15 micromoL) was 1.58 (95% CI, 0.71-3.53). Participants in the lowest serum folate quartile (< or =9.3 nmol/L) had an increased risk of fracture than did those in higher quartiles (multivariable-adjusted OR = 2.06; 95% CI. 1.02-4.18), but no dose-related protective effect for increasing serum folate levels was found (multivariable-adjusted OR = 0.84 for each increase of 1 standard deviation in log-transformed serum folate, 95% CI, 0.59-1.19). No independent association was found for serum vitamin B12. CONCLUSIONS: Low serum folate is responsible for the association between homocysteine and risk of osteoporotic fracture in elderly persons.