Higher Plasma Homocysteine Levels Research Articles

Failure of the combination of sequential oral and transdermal estradiol plus norethisterone acetate to affect plasma homocysteine levels

Objective: A high level of plasma homocysteine may be deleterious to vascular health. We therefore compared the effect of combinations of sequential oral and transdermal estradiol plus norethisterone acetate on plasma homocysteine. Design: Prospective, randomized study. Setting: Outpatient department of obstetrics and gynecology in a university hospital. Patient(s): Forty-two healthy, nonsmoking postmenopausal women starting hormone replacement therapy (HRT) to control climacteric symptoms. Intervention(s): In a randomized order, the women started using either oral HRT (2 mg of estradiol on days 1–12, 2 mg of estradiol plus 1 mg of norethisterone acetate (NETA) on days 13–22, and 1mg of estradiol on days 23–28; n = 21) or transdermal HRT (50 μg/d of estradiol on days 1–28 and 250 μg/d of norethisterone acetate on days 15–28, n = 21) for 1 year. Main Outcome Measure(s): Fasting plasma levels of homocysteine were measured before the treatment and during the combined estradiol-plus-NETA phases of the sixth and 12th treatment cycles. Result(s): Basal homocysteine levels in the oral group (8.2 ± 3.1 μmol/L, mean plusmn;SD) and transdermal group (8.7 plusmn; 1.8 μmol/L, mean plusmn;SD) were not affected by the estradiol-plus-NETA combination. Conclusion(s): Neither an oral nor a transdermal combination of sequential estradiol and NETA causes significant changes in plasma homocysteine in Finnish postmenopausal women with normal baseline homocysteine levels.

CME Paper: Homocysteine: The New Risk Factor for Cardiovascular Disease in the Elderly.

Higher levels of plasma homocysteine are associated with a variety of atherosclerotic conditions that are particularly pertinent to elderly persons. Cross sectional data have suggested that the lower deciles of plasma and dietary folate are highly associated with the presence of carotid stenosis in the elderly. Recent prospective studies have demonstrated strong associations between elevated concentrations of homocysteine and the incidence of cardiovascular mortality, total mortality, and stroke in elderly men and women. The impact of folate fortification on homocysteine levels has been assessed in middle-aged adults, but the clinical impact of fortification or supplementation of the diet with folate on clinical end points of cardiovascular disease is presently unknown, although clinical trials with folate supplementation are underway. (c) 2000 by CVRR, Inc.

Folic acid and folates: the feasibility for nutritional enhancement in plant foods

In mammalian and plant cells the folates play a key role in the methylation cycle and in the DNA biosynthesis cycle (in the de novo biosynthesis of purines and pyrimidines). Deficiency of folate in the diet is likely to result in a reduction in the capacity to synthesise DNA and maintain the usual rate of cell division. This most evidently results in the production of anaemia from folate deficiency due to a reduction in the biosynthesis of cells in the bone marrow. In addition it has been shown that high levels of plasma homocysteine occur which is an important risk factor in cardiovascular disease. Furthermore it has been shown that reduced maternal folate status is associated with the progressive increase in neural tube defects in infants. There is good evidence for folate deficiency in a considerable number of the population in developed countries, even where folate supplementation of foods is practised, and for a level of intake in excess of the recommended dietary allowance. This paper reviews the principal routes of folate biosynthesis in plants and the potential for increasing the levels of natural folates through conventional plant breeding and biotechnological means. The effect of the major food preservation processes on the levels of folates in plants is also reviewed. The current information about the bioavailability of folates from plant food sources, and how this might be improved, is also summarised. The important health benefits that would arise from increasing folate intake in the diet provide a strong incentive for considering how this might be achieved. © 2000 Society of Chemical Industry

Clinical relevance of hyperhomocysteinaemia in atherothrombotic disease.

High fasting plasma homocysteine levels (> 12 to 15 mumol/L) are commonly encountered in clinical practice and are associated with increased risk of atherothrombotic disease. Treatment with folic acid (1 to 5 mg/day) is inexpensive and effective in normalising plasma homocysteine levels. High plasma homocysteine levels after methionine loading (> 40 to 50 mumol/L) are also common and can be treated with pyridoxine-based regimens (50 to 250 mg/day). As compared with fasting plasma homocysteine levels, the association between high postmethionine loading plasma homocysteine levels and atherothrombotic disease has been less extensively studied. There is reasonable, but not clearly definitive, evidence that high plasma homocysteine levels are causally related to atherothrombotic disease. Results of randomised trials of homocysteine-lowering treatment with clinical end-points will be available in 4 to 6 years. At present, a reasonable policy for the practising clinician would be to consider homocysteine-lowering treatment in individuals at very high risk of atherothrombotic disease, such as patients with clinically manifest atherothrombotic disease with onset before 55 years of age, patients with end stage renal disease, and healthy subjects with a strong family history of early-onset atherothrombotic disease. Such a policy should be reassessed as the results of randomised trials become available.

Increased plasma homocysteine after menopause

Besides genetic defects in the enzymes involved in homocysteine metabolism and nutritional deficiencies in vitamin cofactors, sex steroid hormones may modulate plasma homocysteine levels. The post-menopausal state has been found to be associated with higher plasma homocysteine levels, but data are inconsistent and studies published so far did not adjust for age, which is an important confounding factor in studying the effect of menopause. In the present study total plasma homocysteine levels were measured in a meticulously selected population in which the contrast in estrogen status between pre- and postmenopausal women of the same age was maximized. The study comprised 93 premenopausal and 93 postmenopausal women of similar age (range 43–55 years). Women were selected from respondents to a mailed questionnaire on menopause, which was sent to all women aged 40–60 years in the Dutch town of Zoetermeer ( n=12 675). Postmenopausal women who were at least three years after menopause or whose menses had stopped naturally before age 48 were age-matched with premenopausal women with regular menses and without menopausal complaints. Plasma homocysteine levels in the fasting state were related to menopausal status; the age-adjusted geometric mean was 10.7 μmol/l in premenopausal and 11.5 μmol/l in postmenopausal women (difference of 7%, 95% confidence interval 0.3–14%, P=0.04). Additional adjustment for plasma creatinine, body mass index, smoking habit (yes, no) and alcohol intake did not influence this difference. The results of this population-based study indicate that plasma homocysteine is affected by menopause.

Plasma Homocysteine and Premature Atherosclerosis

In patients with hereditary hyperhomocysteinemia, high plasma homocysteine levels are associated with increased risk for atherothrombotic events -- a risk that can be lowered with vitamin B6 and folic acid treatment. Recent data suggest that mildly elevated homocysteine levels also might be independent predictors of cardiovascular risk, but the …

Severe retinopathy in type 1 diabetic patients is not related to the level of plasma homocysteine

The vascular-injuring amino acid homocysteine was previously shown to be increased in plasma in type 1 diabetic patients with clinical signs of nephropathy. Previous studies have also shown an inconsistent relationship between the development of diabetic nephropathy and retinopathy, indicating different pathogenetic mechanisms. In this study, plasma homocysteine was measured in 25 type 1 diabetic patients with a well-characterized form of severe retinopathy. Furthermore, a group of 24 type 1 diabetic patients with similar age at onset of diabetes and diabetes duration with no or minimal background retinopathy were investigated, in order to determine whether plasma homocysteine levels are different from those in patients with severe retinopathy. Patients with severe retinopathy did not have higher plasma levels of homocysteine (13.9 micromol/L; 5.9-30.7, median and range) than those without retinopathy (10.4 micromol/L; 5.7-18.9). Within the group of patients with severe retinopathy, increased homocysteine levels were confined to the patients (19.9 micromol/L; 10.0-30.7, n=9) with serum creatinine levels > 100 micromol/L, compared to those patients (9.6; 5.9-14.3 micromol/L, n=15) with a serum creatinine below 100 micromol/L. None of the patients without or with minimal background retinopathy had serum creatinine levels > 100 micromol/L. We conclude that diabetic retinopathy is not associated with increased plasma homocysteine levels, but plasma homocysteine accumulates, probably owing to reduced glomerular filtration, in diabetic patients with signs of nephropathy. In these patients, the promoting effect of nephropathy on the development of retinopathy does not seem to be mediated through homocysteine.

The Clinical Significance of Serum Homocysteine in Coronary Artery Diseases

Background:Hyperhomocyt (e) inemia is known to be one of independent risk factors for atherosclerosis. The relationship between hyperhomocysteinemia and coronary artery diseases was evaluated in Korean adults. Materials and Methods:Basal fasting plasma homocysteine level was measured in 307 patients (174 males, 58±11 years;133 females, 60±11 years). Coronary artery disease (CAD) was diagnosed in 194 patients. According to the clinical presentation of CAD and the number of significantly stenotic coronary artery, the plasma homocysteine level was analyzed. Results:The plasma homocysteine level was 9.4±3.0 μmol/L in male and 8.5±3.5 μmol/L in female (p=0.016). Homocysteine was 10.0±3.3 μmol/L in 130 smokers, 8.3±3.0 μmol/ L in 162 non-smokers (p<0.001). The plasma homocysteine level was 9.4±3.2 μmol/L in 194 patients with CAD and 8.4±3.2 μmol/L in 113 patients without CAD (p=0.008). The homocysteine was 10.2±3.2 μmol/ L in 63 patients with acute myocardial infarction (MI), 9.8±3.1 μmol/L in 37 old MI, 8.7±3.0 μmol/L in 67 unstable angina, and 8.8±3.7 μmol/L in 27 stable angina. The plasma homocysteine was related with the clinical presentation of CAD (p=0.035), but was not an independent risk factor for coronary artery diseases. Conclusions:The elevated value of plasma homocysteine level is a risk factor for pateint with coronary artery diseases, and male and smokers had higher plasma homocysteine level than those in female and nonsmokers. (Korean Circulation J 2000;30(11):1357-1365)

Can lowering homocysteine levels reduce the incidence of stroke?

Hyperhomocysteinaemia has been identified as an independent risk factor for atherosclerotic and thromboembolic diseases such as cerebro-vascular diseases, coronary artery disease and venous thrombosis. This review will discuss the role of high levels of plasma homocysteine in stroke disease.

Normohomocysteinaemia and vitamin-treated hyperhomocysteinaemia are associated with similar risks of cardiovascular events in patients with premature peripheral arterial occlusive disease. A prospective cohort study.

Mild hyperhomocysteinaemia (HHC), fasting or after methionine loading, is associated with an increased risk and severity of atherosclerotic vascular disease. Post-methionine and fasting HHC are responsive to treatment with vitamin B, and folic acid. We performed a prospective cohort study amongst normohomocysteinaemic and vitamin-treated (vitamin B6, 250 mg plus folic acid, 5 mg daily) hyperhomocysteinaemic patients with premature peripheral arterial occlusive disease and assessed the incidence of cardiovascular events. We studied 273 consecutive patients with clinically manifest peripheral arterial occlusive disease with onset before the age of 56, 79 (28.9%) of whom had postmethionine HHC. Follow-up was obtained in 232 (85'%o) patients. At baseline, 70 (30')/) were hyperhomocysteinaemic after methionine loading and started treatment with vitamin B, and folic acid; 162 (70%) were normohomocysteinaemic (reference group). During the follow-up period (median 20, range 1-63 months), 48 (29.6%) and 23 (32.9%) of the normo- and the hyperhomocysteinaemic patients, respectively, had a new cardiovascular event. Most (75%) involved the peripheral arterial system. The crude incidence rate for any cardiovascular event was 0.16 (95% CI, 0.12-0.21) per person per year in the normohomocysteinaemic and 0.16 (95% CI, 0.09-0.22) per person per year in the hyperhomocysteinaemic group. Multivariate Cox regression analyses showed that higher plasma homocysteine levels were associated with an increased risk of new cardiovascular events in the normohomocysteinaemic patients (relative risk [RR] per 1 micromol L(-1), 1.17 [CI, 1.05-1.30] for fasting and 1.06 [CI, 1.01-1.12] for postmethionine levels), but not in the hyperhomocysteinaemic (vitamin-treated) patients. The adjusted RR for new cardiovascular events in the hyper- as compared to the normohomocysteinaemic patients was 0.76 (CI, 0.33-1.74). These data are consistent with a protective effect of treatment with vitamin B6 and folic acid in patients with premature peripheral arterial occlusive disease and postmethionine HHC. Double-blind randomized trials are necessary to confirm this.

Plasma Homocysteine Levels Elevated and Inversely Related to Insulin Sensitivity in Preeclampsia

In Brief Objective To study the plasma levels of homocysteine in preeclampsia and relate them to insulin sensitivity. Methods In association with a 3-hour intravenous glucose-tolerance test (glucose 0.3 g/kg at 0 and 0.03 IU insulin 20 minutes later), we measured plasma levels of homocysteine, vitamin B12, and folic acid in 22 women with preeclampsia and 16 controls between 29 and 39 weeks' gestation. In 14 women with preeclampsia and 11 controls, plasma samples also were collected 3 months after delivery. Results Levels of homocysteine in women with preeclampsia (6.7 ± 0.4 μmol/L, mean ± standard error) were higher (P < .001) than those in controls (3.8 ± 0.2 μmol/L) and related significantly to the level of proteinuria (r = .49, P = .02). Vitamin B12 concentrations were lower in women with preeclampsia (166.0 ± 10.4 compared with 212.4 ± 16.4 pmol/L, P = .02), whereas levels of folic acid showed no difference between the groups. After delivery, levels of homocysteine increased to 9.1 ± 0.6 and 8.2 ± 0.6 μmol/L in women with preeclampsia and controls, vitamin B12 increased to 298.8 ± 28.6 compared with 334.9 ± 24.0 pmol/l, and folic acid decreased to 10.6 ± 2.0 compared with 7.9 ± 0.8 nmol/L, with no difference emerging between the groups. In women with preeclampsia but not in controls, plasma homocysteine was negatively related to insulin sensitivity (r = −.51, P = .02). The mean 2.9-fold increase in glucose or 52.5-fold increase in insulin during the insulin-sensitivity test failed to affect homocysteine levels. Conclusion Women with preeclampsia have high plasma homocysteine levels that are inversely related to insulin sensitivity. Plasma homocysteine levels in preeclamptic women are elevated and in an inverse relationship to insulin sensitivity.

Plasma homocysteine levels elevated and inversely related to insulin sensitivity in preeclampsia

Objective: To study the plasma levels of homocysteine in preeclampsia and relate them to insulin sensitivity. Methods: In association with a 3-hour intravenous glucose-tolerance test (glucose 0.3 g/kg at 0 and 0.03 IU insulin 20 minutes later), we measured plasma levels of homocysteine, vitamin B 12, and folic acid in 22 women with preeclampsia and 16 controls between 29 and 39 weeks’ gestation. In 14 women with preeclampsia and 11 controls, plasma samples also were collected 3 months after delivery. Results: Levels of homocysteine in women with preeclampsia (6.7 ± 0.4 μmol/L, mean ± standard error) were higher ( P < .001) than those in controls (3.8 ± 0.2 μmol/L) and related significantly to the level of proteinuria ( r = .49, P = .02). Vitamin B 12 concentrations were lower in women with preeclampsia (166.0 ± 10.4 compared with 212.4 ± 16.4 pmol/L, P = .02), whereas levels of folic acid showed no difference between the groups. After delivery, levels of homocysteine increased to 9.1 ± 0.6 and 8.2 ± 0.6 μmol/L in women with preeclampsia and controls, vitamin B 12 increased to 298.8 ± 28.6 compared with 334.9 ± 24.0 pmol/l, and folic acid decreased to 10.6 ± 2.0 compared with 7.9 ± 0.8 nmol/L, with no difference emerging between the groups. In women with preeclampsia but not in controls, plasma homocysteine was negatively related to insulin sensitivity ( r = −.51, P = .02). The mean 2.9-fold increase in glucose or 52.5-fold increase in insulin during the insulin-sensitivity test failed to affect homocysteine levels. Conclusion: Women with preeclampsia have high plasma homocysteine levels that are inversely related to insulin sensitivity.

ホモシステイン

McCully first proposed the idea that, in patients with homocysteinemia, high plasma levels of homocysteine (Hcy) resulted in severe and premature atherosclerosis. Epidemiologic studies indicate that hyperhomocysteinemia is an independent risk factor for atherosclerosis. Meta analysis revealed that for every 5μmol/l increase in homocysteine, men had a 1.6-fold increase in the coronary heart disease risk. A 5μmol/l increase in plasma homocysteine is equivalent to an increase in blood cholesterol of 0.5μmol/l. Increasing in the dietary intake of folic acid by 200μg should reduce homocysteine levels by 4μmol/l. Studies investigating the mechanism of action of homocysteine suggest that an increased level of plasma homocysteine may be a physiological risk factor for thrombosis and arterial injury as well as for increased risk of fibrous plaque formation.A key enzymes for homocysteine metabolism is cystathionine β-synthase and methylenetetrahydrofolate reductase (MTHFR). Recently, polymorphism of these enzymes has been reported to play an important role in the genesis of hyperhomocysteinemia. There is a polymorphysm of the MTHFR (C677T), Ala/Val and Val/Val genotype associated with coronary artery disease.

Plasma homocysteine levels in indigenous Australians.

To determine plasma homocysteine levels in indigenous Australians living in urban areas, and the relationship of these levels with other risk factors in this population. Cross-sectional study. 365 urban indigenous Australian subjects, 153 men and 212 women, mean (SE) age 42 (1) years, ascertained without regard to history of atherosclerotic disease, in collaboration with community-based health centres in five indigenous communities in south-east Queensland, 1997-1998. Plasma homocysteine levels, age, sex, smoking history, metformin therapy, history of atherosclerotic vascular disease, serum creatinine level, red cell folate and serum vitamin B12 levels. 89 subjects (24%) had plasma homocysteine levels 15 mumol/L or above. Homocysteine levels were higher in men than in women (men: 14.4 mumol/L; 95% confidence interval [CI], 13.6-15.2; women: 11.9 mumol/L; 95% CI, 11.4-12.5) (P < 0.001); correlated with age (P < 0.001); higher in current smokers (P = 0.02); higher in subjects taking metformin therapy (P = 0.007); and higher in subjects with a history of atherosclerotic vascular disease (P < 0.001). Homocysteine levels were also correlated with serum levels of creatinine (P < 0.001), red cell folate (P < 0.001), and vitamin B12 (P < 0.001). These data indicate that the high plasma levels of homocysteine of Australian indigenous subjects are associated with a history of vascular disease, and correlated with, among other things, smoking, and folate and vitamin B12 nutritional deficiency. These are potentially reversible risk factors, and our data suggest that focusing public health initiatives on these issues may reduce the high prevalence of cardiovascular disease in the Australian indigenous population.

Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: Low folate status alone may be the critical factor

Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the first folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 microg/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88-7.18; P < 0.001), and those with RCF less than 150 microg/L had eight times higher risk of NTD than subjects with levels over 400 microg/L. Plasma homocysteine levels of non-TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food-fortification program as a population strategy for reducing the occurrence of NTDs.

Effect of homocysteine and cholesterol in raising plasma homocysteine, cholesterol and triglyceride levels

A high plasma homocysteine level is a newly regarded risk factor for coronary artery disease. We report a synergistic effect of homocysteine plus cholesterol feeding on further raising total plasma homocysteine, cholesterol and triglycerides levels than each agent alone, which further enhances the risk of coronary artery disease.

Central splanchnic vein thrombosis is most often related to anti-cardiolipin antibody syndrome or high plasma homocysteine levels

Central splanchnic vein thrombosis is most often related to anti-cardiolipin antibody syndrome or high plasma homocysteine levels

Association Between Plasma Homocysteine and Coronary Artery Disease in Older Persons

The data demonstrate that high plasma homocysteine levels and low plasma folate and vitamin B12 levels are associated with a higher prevalence of coronary artery disease (CAD) in older men and women. Elevated plasma homocysteine levels were observed in 43% of the older men with CAD versus 18% of the older men without CAD, and in 37% of the older women with CAD versus 12% of the older women without CAD.

Homocysteine: update on a new risk factor.

A high fasting plasma homocysteine level is an independent risk factor for atherosclerosis and venous thrombosis. Vitamin therapy can lower homocysteine levels, but no benefit has yet been demonstrated; studies using clinical outcomes as endpoints are now in progress.

Homocysteine: More Lethal Than Cholesterol?

Does homocysteine play a role in the blockage of arteries? If it does, what can be done to rid our bodies of homocysteine? Is homocysteine more lethal than cholesterol ? A meta-analysis of 5-study outcomes is presented for the purpose of describing intervention effectiveness for folate, vitamin B12, and vitamin B6 on plasma homocysteine concentrations. The differences in measurement techniques and study designs preclude direct, quantitative comparisons between studies. However, the 5-study outcomes reviewed for the correlation of vitamin status and homocysteine plasma level, show that there are inverse associations between homocysteine plasma levels and folate, vitamin B12, and vitamin B6 plasma levels and that elevated plasma homocysteine levels can be reduced by increasing the dietary and/or supplemental intake of these three B vitamins. A greater heart disease risk has been linked to people with higher plasma levels of homocysteine, and this may be more lethal than cholesterol.