Plasma tHcy Levels Research Articles

Total homocysteine levels relation with chronic complications of diabetes, body composition, and other cardiovascular risk factors in a population of patients with diabetes mellitus type 2

Objective The significance of hyperhomocysteinemia in type 2 diabetes is further complicated by the multiple ways of considering impaired renal function and vitamin status. The aim of our study was to analyze the relationship between total homocysteine (tHcy) in a population of type 2 diabetic patients and chronic complications. We also analyzed the relationship between tHcy and the body composition of these patients and other cardiovascular risk factors. Design In a cross-sectional study, a total of 155 patients with diabetes mellitus attending in our diabetes service (90 females/65 males) were enrolled in a consecutive way. Material and methods All enrolled patients underwent the following examinations: (i) biochemical cardiovascular risk factors including total cholesterol, triglyceride, lipoprotein (a), low-density lipoprotein (LDL-cholesterol), high-density lipoprotein (HDL-cholesterol), glucose, HbA 1c, fibrinogen, homocysteine, vitamin B12, folate, and microalbuminuria; and (ii) fat mass assessed by body mass index, weight, percentage of fat mass, and tricipital skinfold. Results Patients were divided in two groups (Group I: tHcy≥15 μmol/l; Group II: tHcy<15 μmol/l). Smoking habit was similar in both groups. A prevalence of cerebrovascular accident was present in 3.3% in the total group. This prevalence was not different in both groups (7.4% vs. 2.3%; ns) (OR 3.3; 95% CI 0.49–19.68). The prevalence of coronary heart disease in the total group was 5.8% without statistical differences between groups (3.5% vs. 6.3%; ns) (OR 0.57; 95% CI 0.065–4.53). Concerning macrovascular complications, only peripheral vascular disease prevalence was higher in Group I (16% vs. 3.1%; P<0.05; OR 5.33; 95% CI 1.18–21.5). A prevalence of nephropathy was higher in Group I (93.3% vs. 12.8%; P<0.05; OR 7.15; 95% CI 2.9–17.9). No statistical differences were detected in prevalence of retinopathy (global group 41.9%) (42.5% vs. 40.9%; ns) (OR 1.75; 95% CI 0.78–3.9). Also, peripheral neuropathy was similar in both groups (7.1% vs. 6.5%; ns) (OR 1.1; 95% CI 0.15–8.2). No correlation was detected among homocysteine and anthropometric parameters (body mass index, weight, percentage of fat mass, fat mass, and tricipital skinfold). Elevated levels of fibrinogen, lipoprotein (a), microalbuminuria, and blood pressure were detected in Group I. Conclusion The present study shows that elevation of plasma tHcy levels in type 2 diabetic patients is associated with a higher prevalence of peripheral arteriopathy and nephropathy. Our data suggest that hyperhomocysteinemia is not associated with fat mass but it is associated with high levels of fibrinogen, lipoprotein (a), microalbuminuria, and blood pressure levels.

Total homocysteine levels' relation with chronic complications of diabetes, body composition, and other cardiovascular risk factors in a population of patients with diabetes mellitus type 2

The significance of hyperhomocysteinemia in type 2 diabetes is further complicated by the multiple ways of considering impaired renal function and vitamin status. The aim of our study was to analyze the relationship between total homocysteine (tHcy) in a population of type 2 diabetic patients and chronic complications. We also analyzed the relationship between tHcy and the body composition of these patients and other cardiovascular risk factors. In a cross-sectional study, a total of 155 patients with diabetes mellitus attending in our diabetes service (90 females/65 males) were enrolled in a consecutive way. All enrolled patients underwent the following examinations: (i) biochemical cardiovascular risk factors including total cholesterol, triglyceride, lipoprotein (a), low-density lipoprotein (LDL-cholesterol), high-density lipoprotein (HDL-cholesterol), glucose, HbA 1c , fibrinogen, homocysteine, vitamin B12, folate, and microalbuminuria; and (ii) fat mass assessed by body mass index, weight, percentage of fat mass, and tricipital skinfold. Patients were divided in two groups (Group I: tHcy≥15 μmol/l; Group II: tHcy<15 μmol/l). Smoking habit was similar in both groups. A prevalence of cerebrovascular accident was present in 3.3% in the total group. This prevalence was not different in both groups (7.4% vs. 2.3%; ns) (OR 3.3; 95% CI 0.49–19.68). The prevalence of coronary heart disease in the total group was 5.8% without statistical differences between groups (3.5% vs. 6.3%; ns) (OR 0.57; 95% CI 0.065–4.53). Concerning macrovascular complications, only peripheral vascular disease prevalence was higher in Group I (16% vs. 3.1%; P <0.05; OR 5.33; 95% CI 1.18–21.5). A prevalence of nephropathy was higher in Group I (93.3% vs. 12.8%; P <0.05; OR 7.15; 95% CI 2.9–17.9). No statistical differences were detected in prevalence of retinopathy (global group 41.9%) (42.5% vs. 40.9%; ns) (OR 1.75; 95% CI 0.78–3.9). Also, peripheral neuropathy was similar in both groups (7.1% vs. 6.5%; ns) (OR 1.1; 95% CI 0.15–8.2). No correlation was detected among homocysteine and anthropometric parameters (body mass index, weight, percentage of fat mass, fat mass, and tricipital skinfold). Elevated levels of fibrinogen, lipoprotein (a), microalbuminuria, and blood pressure were detected in Group I. The present study shows that elevation of plasma tHcy levels in type 2 diabetic patients is associated with a higher prevalence of peripheral arteriopathy and nephropathy. Our data suggest that hyperhomocysteinemia is not associated with fat mass but it is associated with high levels of fibrinogen, lipoprotein (a), microalbuminuria, and blood pressure levels.

Association between plasma homocysteine levels and coronary artery disease: a population-based study in northern Greece

SUMMARYObjective: Elevated plasma total homocysteine (tHcy) levels constitute a risk factor for coronary artery disease (CAD). We prospectively examined the association of fasting tHcy levels in patients in Northern Greece who had established CAD.Patients and methods: Plasma fasting tHcy levels were measured in 42 patients with angiographically documented CAD and compared to 42 age-, sex-, BMI- and smoking habit-matched control subjects. We also determined the plasma vitamin B12, folic acid and lipoprotein levels in all patients and controls. Conventional risk factors for CAD were also estimated.Results: In a univariate analysis, tHcy (jumol/l) levels were higher in patients compared to controls almost reaching statistical significance (13 (7–41) vs 11.3 (4–39); p = 0.07). Multivariate analysis of conventional risk factors showed that tHcy levels were not an independent risk factor for CAD. However, tHcy levels were significantly higher in patients with a previous history of myocardial infarction compared to patients without such a history and to controls (15 (8.8-29) vs 11.7 (7-41); p = 0.007 and 15 (8.8-29) vs 11.3 (4-39); p = 0.002, respectively). Hyperhomocysteinaemia (> 15|imol/l) was detected in 35.7% of patients and 11.9% of controls (p < 0.05).Conclusions: In Northern Greece, plasma tHcy levels may not be an independent risk factor for CAD in patients with angiographically documented CAD. However, patients with CAD have a trend towards higher tHcy levels. Additionally, plasma tHcy levels may be associated with the development of myocardial infarction.

Relationship between postrenal transplant osteonecrosis of the femoral head and gene polymorphisms related to the coagulation and fibrinolytic systems in Japanese subjects.

Nontraumatic osteonecrosis of the femoral head (ONFH) is one of the complications that may occur after renal transplantation. We investigated the relationship between the incidence of ONFH and polymorphisms in the genes for plasminogen activator inhibitor (PAI)-1, which is one of the major regulatory proteins of the fibrinolytic system, and 5,10-methylenetetrahydrofolate reductase (MTHFR), which is associated with the plasma levels of homocysteine in Japanese subjects. Thirty-one patients with postrenal transplant ONFH and 106 patients without ONFH were selected. Genotypes of PAI-1 4G/5G and MTHFR C677T were determined by direct sequencing of genomic DNA. In addition, plasma PAI-1 antigen (Ag) levels and plasma total homocysteine (tHcy) levels at the steady state were measured. The relationships between the incidence of ONFH and these genotypes, as well as plasma levels of the gene products, were investigated. Plasma PAI-1 Ag levels were the highest in patients with the 4G/4G genotype, and plasma tHcy levels were the highest in patients with TT genotypes of MTHFR C677T. However, the relationship between the incidence of ONFHH and PAI-1 4G/5G or MTHFR C677T was not observed. The relationship between the incidence of ONFH and plasma levels of PAI-1 Ag or tHcy was not observed. Genotypes of PAI-1 4G/5G and MTHFR C677T or plasma concentrations of PAI-1 Ag and tHcy had no effect on the incidence of ONFH in Japanese subjects, unlike the results of studies performed in white subjects. The effect of genetic background on the pathologic conditions that developed in patients with postrenal transplant ONFH may differ according to race.

COMMON POLYMORPHISMS IN METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR): RELATIONSHIPS WITH PLASMA HOMOCYSTEINE CONCENTRATIONS AND COGNITIVE STATUS IN ELDERLY NORTHERN ITALIAN SUBJECTS

Hyperhomocysteinemia may be a risk factor for cognitive impairment. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in homocysteine (Hcy) metabolism. Both the MTHFR 677C-->T and the 1298A-->C polymorphisms are associated with mild hyperhomocysteinemia, particularly in conditions of low folate status. The prevalence of these MTHFR polymorphisms and their relationships with plasma total Hcy (tHcy), serum folate and cognitive function was evaluated in 194 elderly Italian individuals: 122 healthy controls (73.8 +/- 7.1 years of age), 24 cognitively- impaired- not-demented individuals (78.6 +/- 9.3 years), and 48 subjects with Alzheimer dementia (AD = 26), vascular dementia (VD =22; 85.5 +/- 7.0 years). Twenty-one percent of all subjects were homozygous for 677C-->T and 7 % for 1298A-->C polymorphism. No significant relationship was found betweenMTHFR polymorphisms and age, cognitive status and type of dementia. Plasma tHcy did not differ significantly by MTHFR genotypes, but, subjects of all genotypes with low serum folate (<12 nmole/l) had higher plasma tHcy (p < 0.001), than subjects with high serum folate (>= 12 nmole/l). The study suggests that 677C-->T and 1298A-->C polymorphisms are common in the Northern Italian population, but do not significantly affect plasma tHcy levels of elderly individuals, even under conditions of low folate status. The lack of association of age and cognitive function with MTHFR genotypes argues against a negative selection for these polymorphisms.

Elevated plasma homocysteine is positively associated with age independent of C677T mutation of the methylenetetrahydrofolate reductase gene in selected Egyptian subjects

This study aimed to evaluate the plasma homocysteine (tHcy) and folate levels as well as the methylenetetrahydrofolate reductase (MTHFR) C677T mutation in Egyptian subjects. Fasting total homocysteine (tHcy) and the (MTHFR) C677T mutation were evaluated in 50 healthy young control males (age 35-50 years, Gp1), 50 elderly males age ranged between 50-75 years without any cardiovascular diseases (Gp2) and 50 age matched elderly male patients (Gp3) with myocardial infarction. There was a significant elevation of plasma tHcy in the patients group and Gp2 compared to the young control group (Gp1). The total plasma homocysteine (tHcy) in the control group, Gp2 and the patients group were 17.99 +/- 9.76, 39.9 +/- 20.06 and 43.8 +/- 13.13 mumol/L respectively. The frequency of the TT genotype was 12% in the patient group compared with 8 % in the young healthy controls and elderly subjects (Gp2). The CT genotype constituted 36%, 48% and 44% in the control group, Gp2 and the patients group respectively. There was no significant difference in the occurrence of the TT genotype between the studied groups. Plasma tHcy correlated positively with age, total cholesterol, urea, creatinine, glucose levels and carotid intimal thickness (CIT). Conclusion: The MTHFR mutation does not seem to be associated with either high tHcy or the occurrence of cardiovascular diseases in the studied patients. However, elevated plasma tHcy level positively correlates with age in the studied subjects.

Meta-analysis of plasma homocysteine, serum folate, serum vitamin B 12, and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease

Purpose To assess the role of plasma total homocysteine (tHcy) levels, serum folate and vitamin B 12levels, and homozygosity for the thermolabile methylenetetrahydrofolate reductase genotype (TT) as risk factors for retinal vascular occlusive disease. Design Meta-analysis of literature. Methods A MEDLINE search was performed to identify all published case–control studies of plasma tHcy levels, serum folate and vitamin B 12 levels, and TT genotype in persons with retinal vascular occlusive disease. Main outcome measures included calculation of plasma tHcy, serum folate, and serum vitamin B 12 standard differences and odds ratios (OR) of TT genotype between cases and controls. Results In total, 614 patients with all types of retinal vein occlusion had higher plasma tHcy levels than 762 control subjects (standard difference, 0.867; 95% confidence interval [CI] = 0.735, 0.999; P < .001). Plasma tHcy levels were also higher in 154 patients with retinal artery occlusion compared with 358 control subjects (standard difference 1.174; 95% CI = 0.947, 1.402; P < .001). Serum folates, but not vitamin B 12 levels, were lower in 287 patients with retinal vascular occlusion than in the same number of control subjects (standard difference, 0.508; 95% CI = 0.340, 0.675; P < .001; and −0.060; 95% CI = −0.024, 0.104; P = .474, respectively). Similar proportions of 690 patients with retinal vein occlusion and 2754 control subjects demonstrated the TT genotype (OR = 1.332; 95% CI = 0.995, 1.783; P = .054) as did 152 patients with retinal artery occlusions and 435 control subjects (OR = 1.716; 95% CI = 0.977, 3.014; P = .060). Conclusions Retinal vascular occlusion is associated with elevated plasma tHcy levels and low serum folate levels, but not serum vitamin B 12 levels and TT genotype. Until a prospective multicenter trial is undertaken, plasma tHcy levels and serum folate levels should be determined in patients with retinal vascular occlusions, and dietary supplementation with low doses of folate and vitamin B 12 should be considered for affected persons.

Hyperhomocysteinemia: an important risk factor for cardiovascular disease? Potentially, yes

Hyperhomocysteinemia: an important risk factor for cardiovascular disease? Potentially, yes

Asymmetric dimethylarginine and total homocysteine in plasma after oral methionine loading

Background: Elevation of homocysteine (Hcy) and asymmetric dimethylarginine (ADMA) in plasma are believed to be involved in the pathogenesis of cardiovascular disease (CVD). In humans, oral methionine loading results in acute elevation of plasma Hcy. This is associated with impaired NO‐dependent vasodilatation, a mechanism that may explain the relationship between elevated Hcy and risk of CVD. ADMA, an endogenous competitive inhibitor of NO‐synthase, may be elevated in plasma of patients with CVD. It was proposed that ADMA is synthesized in a methionine‐dependent reaction which also forms Hcy. In this study plasma total homocysteine (tHcy) and ADMA concentrations were measured before and after oral methionine loading of human subjects. Methods: Plasma tHcy and ADMA levels were measured in 12 healthy males (age 32–58 years) before and after oral loading with L‐methionine (100 mg/kg body weight in orange juice). Results: At noon, 4 h after methionine loading, tHcy and ADMA levels (35.4±10.9 and 0.80±0.13 μmol/L, mean ±SD) were significantly higher than the corresponding values obtained at noon the day before (15.6±7.4 and 0.63±0.10 μmol/L, both p<0.001). Noon values 4 h after methionine loading were also significantly higher than values obtained immediately before the methionine load (13.7±5.9 and 0.66±0.10 μmol/L, both p<0.001). Reinvestigation of 8 of 12 subjects showed that at 4 and 8 h after compared with levels immediately before methionine loading there was a significant increase in tHcy (28.4±10.2 and 33.45±11.1 vs. 10.8±3.3 μmol/L, both p<0.001). However, the corresponding ADMA levels did not increase (0.73±0.17 and 0.76±0.22 vs. 0.70±0.10 μmol/L, both not significant). Conclusions: No clear evidence was found to support the supposition that methionine‐induced hyperhomocysteinaemia may be accompanied by elevated levels of ADMA, an endogenous competitive NO‐synthase inhibitor that may represent an alternative pathogenic mechanism for homocysteine‐associated impairment of endothelial NO‐dependent functions.

Hyperhomocysteinemia in cerebral vein thrombosis

AbstractHigh plasma levels of total homocysteine (tHcy) are a risk factor for deep vein thrombosis. Because no information on the relationship between cerebral vein thrombosis and hyperhomocysteinemia is available, a case–control study of 121 patients with a first episode of cerebral vein thrombosis and 242 healthy control subjects was carried out. Fasting plasma levels of tHcy and their postmethionine load (PML) increments, together with other laboratory markers of thrombophilia, were measured in plasma or DNA. Hyperhomocysteinemia (high fasting tHcy and/or PML increments) was diagnosed in 33 patients (27%) and 20 control subjects (8%) (odds ratio, 4.2; 95% confidence interval [CI], 2.3-7.6). Low levels of serum folate and the 677TT methylene tetrahydrofolate reductase were associated with hyperhomocysteinemia, but in a multivariate model hyperhomocysteinemia only was associated with an increased risk of cerebral vein thrombosis. Oral contraceptive intake was associated with the disease with an odds ratio of 6.1 (95% CI, 3.3-11.0). The combined presence of the latter and hyperhomocysteinemia increased the risk of the disease with an odds ratio of 19.5 (95% CI, 5.7-67.3). In conclusion, hyperhomocysteinemia is associated with a 4-fold increased risk of cerebral vein thrombosis; whether or not its correction with vitamins reduces the risk of the disease remains to be demonstrated.

Plasma homocysteine levels in obese and non-obese subjects with or without hypertension; its relationship with oxidative stress and copper

Objectives: The relationship between plasma total Homocysteine (tHcy) and oxidative stress and plasma levels of lipids, insulin and copper levels were investigated in obese and nonobese hypertensives. Design and Methods: Plasma tHcy levels were determined by an enzyme immunoassay method. Plasma lipid peroxidation levels were measured as thiobarbituric acid reactive substances (TBARS) by spectrofotometric methods. Plasma levels of copper and insulin were measured by atomic absorption spectrophotometer and electrochemiluminescence method, respectively. Results: Plasma tHcy, copper and insulin levels did not differ in nonobese hypertensives compared to nonobese normotensives. Plasma TBARS levels were significantly increased in nonobese hypertensives when compared to nonobese normotensives ( p < 0.001). Plasma tHcy, TBARS, copper and fasting insulin levels were significantly higher in obese normotensives and hypertensives than in nonobese normotensives and hypertensives, respectively (for each comparison; p < 0.001). There was a significant difference in plasma tHcy, TBARS and copper levels between obese subjects with or without hypertension (for each comparison p < 0.01). The univariate analyses demonstrated a significant positive correlation between tHcy and TBARS (coefficient ± SE, 0.411 ± 0.115, p < 0.01) and copper (coefficient ± SE, 0.425 ± 0.135, p < 0.01) in obese subjects. In a multivariate regression analysis in obese subjects tHcy was positively correlated with TBARS (coefficient ± SE, 0.480 ± 0.155, p < 0.01) and copper (coefficient ± SE, 0.486 ± 0.140, p < 0.01). Conclusions: We hypothesize that in the presence of other traditional risk factors, Hcy may have a permissive role in the endothelium damage even within the normal range and this role may be related to free radical generating systems. Therefore, modest elevation of plasma Hcy may causally be involved in the pathogenesis of atherosclerosis and/or cardiovascular disease.

Effects of the glutamate carboxypeptidase II (GCP2 1561C>T) and reduced folate carrier (RFC1 80G>A) allelic variants on folate and total homocysteine levels in kidney transplant patients

The effect of the glutamate carboxypeptidase II GCP2 1561C>T and the reduced folate carrier 1 RFC1 80G>A polymorphisms on folate and total homocysteine (tHcy) plasma levels of kidney transplant patients are unknown. In a cross-sectional study of 730 kidney allograft recipients, GCP2 1561C>T, RFC1 80G>A, folate, and tHcy plasma levels were analyzed using linear regression models that allowed dependent covariates to follow a gamma distribution for univariate and multivariate analyses. The allele frequency for GCP2 1561C>T was 0.05, and 0.43 for RFC1 80G>A. Heterozygosity or homozygosity for GCP2 1561C>T was associated with higher folate plasma levels compared to patients without mutation (P < 0.0001), while RFC1 80G>A showed no influence. Multiple testing, also including MTHFR 677C>T and MTHFR 1298A>C, revealed no interaction between the different genotypes and the folate plasma concentration. Neither GCP2 1561C>T nor RFC1 80G>A showed an association with tHcy plasma levels. We conclude that GCP2 1561C>T is associated with elevated folate levels. GCP2 1561C>T and RFC1 80G>A are no major determinants of tHcy plasma levels in kidney transplant patients.

Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid.

The aim of this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency. We measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid (CSF) MMA and tHcy in 72 patients with MS and 23 controls. The mean plasma tHcy level was significantly increased in MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (P = 0.002). Seven patients showed low serum vitamin B12 levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MCV), haemoglobin concentration, CSF tHcy or CSF MMA between patients and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum MMA, plasma tHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age. The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism relevant for the development of neuroinflammation/degeneration. Our findings indicate that, regardless of a significant increase in plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF tHcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.

5,10-Methylenetetrahydrofolate reductase 677C-->T and 1298A-->C mutations are genetic determinants of elevated homocysteine.

Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Elevated plasma total homocysteine (tHcy) is a major risk for cardiovascular disease. A common 677C-->T mutation in the MTHFR gene results in decreased enzymic activity, and contributes to increased plasma tHcy, in association with low plasma folate. A recently described 1298A-->C mutation in the MTHFR gene clearly reduces MTHFR activity (although to a lesser extent than the 677C-->T) but its effect on plasma tHcy levels is not yet clear. To investigate the frequency of these two MTHFR polymorphisms in a Portuguese population, and to correlate the MTHFR genotype with the biochemical phenotype at the level of homocysteine and folate concentrations. Prospective population survey. We studied 117 healthy volunteers (71 females, 46 males). The 677C-->T and 1298A-->C mutations were screened by PCR-RFLP. Levels of plasma tHcy and folate, and red blood cell folate, were determined. The allele frequencies of the 677C-->T and 1298A-->C mutations were 0.33 and 0.28, respectively. Homozygotes for the 677C-->T mutation had significantly elevated plasma tHcy and RBC folate levels and significantly lowered plasma folate concentrations than subjects without the mutation. The 1298A-->C mutation showed a significant effect on plasma tHcy, but not on plasma folate or RBC folate levels. The observed 677T allele frequency is not consistent with the idea of a north-south gradient as previously suggested. The 1298A-->C mutation is common in Portugal. Both MTHFR mutations showed effects on plasma tHcy levels.

Hyperhomocysteinemia and its relationship to cardiovascular disease in ESRD: Influence of hypoalbuminemia, malnutrition, inflammation, and diabetes mellitus

Background: In the general population, a mildly elevated plasma total homocysteine (tHcy) level is an independent and graded risk factor for cardiovascular disease (CVD). In patients with end-stage renal disease (ESRD), CVD is highly prevalent and a major cause of premature mortality, and plasma tHcy levels are as much as three to four times greater than in the general population. Several other risk factors, such as diabetes mellitus (DM), inflammation, and malnutrition, also are prevalent and contribute to CVD in patients with ESRD, and there are strong associations between inflammation, malnutrition, and hypoalbuminemia in these patients. Several investigations in patients with ESRD have shown the important role of vitamin status for plasma tHcy, but little attention has been given to the influence of nutritional status. However, it is obvious that hypoalbuminemia is of interest because a substantial fraction of tHcy (>70%) is protein bound, mainly to albumin. Results: In studies of patients with ESRD in whom the prevalence of hyperhomocysteinemia was very high (>90%), tHcy level was strongly related to serum albumin level, and patients with malnutrition had lower levels of both tHcy and serum albumin than those with normal nutritional status. Furthermore, inflammation, DM, and CVD are associated with hypoalbuminemia and therefore a lower degree of hyperhomocysteinemia. In our studies, in different groups of patients with ESRD, we showed that greater tHcy levels were associated with lower CVD mortality. However, this apparently paradoxical association between lower CVD mortality and lower plasma tHcy levels (although still abnormally high) does not refute the concept that hyperhomocysteinemia is a risk factor for CVD because almost all patients may have had long-standing elevated plasma tHcy levels within a range that makes them prone to develop atherosclerosis. Instead, a potentially detrimental effect of hyperhomocysteinemia on CVD in patients with ESRD may be obscured by the influence of hypoalbuminemia, whatever the cause, because hypoalbuminemia and its causes are strong predictors of mortality. Conclusion: Our findings imply that nutritional status and serum albumin level, as well as the presence of inflammation and DM, should be taken into consideration when evaluating tHcy as a risk factor for CVD in patients with ESRD. Am J Kidney Dis 41(S1):S89-S95. © 2003 by the National Kidney Foundation, Inc.

Folate and cobalamin levels as determinants of plasma homocysteine in different age groups of healthy controls and psychogeriatric patients.

Homocysteine (Hcy) is the demethylated derivate of methionine and can be metabolized by two pathways. It is either catabolized by the transulfuration pathway to cysteine or remethylated to methionine mainly by the folate- and cobalamin-dependent enzyme methionine synthase. Previous findings suggest that folate is the most important vitamin determinant of plasma total homocysteine (tHcy) concentration but also that the relation between plasma tHcy levels and levels of cobalamin and folate in the circulation might differ in different populations. In the present study, we have analyzed these parameters in different age groups of healthy subjects and psychogeriatric patients, who are known to have increased plasma tHcy. The present study shows that serum cobalamin concentration is a more important determinant of plasma tHcy concentration than blood folate concentration in the age groups <65 years in both psychogeriatric patients and control subjects, whereas with increasing age blood folate concentration becomes the most important vitamin determinant. The findings of increased plasma tHcy with folate being the main vitamin determinant in the oldest age groups of patients and controls, suggest that tissue levels of folate in elderly subjects are too low and that vitamin supplementation should be given.

The effects of hyperhomocysteinemia on the presence, extent, and severity of coronary artery disease.

Most cross-sectional and case-control studies indicate that an increased plasma total homocysteine (tHcy) level is an independent risk factor for coronary artery disease (CAD). However, this is still a controversial issue. Recently, it was reported that the level of tHcy is related to the extent and severity of CAD. This study was designed to investigate the relationship between plasma tHcy levels and the presence, extent, and severity of CAD. Three hundred and forty-one patients who underwent coronary angiography were included in the study. Of these patients, 195 had CAD and 146 had normal coronary arteries (control group). The mean tHcy level was found to be higher in patients with significant CAD (16.4 +/- 7.4 micromol/L vs 13.2 +/- 3.6 micromol/L, P < 0.001). This group also had a higher rate of hyperhomocysteinemia (HHcy) (22.6% vs 5.5%, P < 0.001). There were positive relationships between tHcy levels and male gender (P = 0.03, r = 0.16), smoking (P < 0.001, r = 0.19), hyperlipidemia (P = 0.006, r = 0.15), and hypertension (P < 0.001, r = 0.20). Using regression analysis HHcy was determined to be an independent risk factor for CAD (OR = 3.69, CI 95% 1.51-9.06, P = 0.004). However, HHcy was not an independent risk factor in patients with low cardiovascular risk profiles. There was no relationship between the level of tHcy and the severity, extent, and vessel scores of CAD. On the other hand, age and diabetes mellitus were related with all scores of CAD. In conclusion, although hyperhomocysteinemia is an independent risk factor for CAD in our region, it appears to be unrelated to the extent and severity of the disease.

The H475Y Polymorphism in the Glutamate Carboxypeptidase II Gene Increases Plasma Folate without Affecting the Risk for Neural Tube Defects in Humans

In the diet, folate exists predominantly in the form of polyglutamates. Before absorption, these polyglutamates must be deconjugated to monoglutamates by the enzyme folylpoly-gamma-glutamate carboxypeptidase (FGCP), which is located in the jejunum. Recently, a H475Y polymorphism in the glutamate carboxypeptidase II (GCPII) gene, encoding the FGCP enzyme, was reported to be associated with decreased plasma folate and increased plasma homocysteine (tHcy) levels. Low folate and elevated tHcy levels are risk factors for neural tube defects (NTD). Therefore, we examined whether this polymorphism is associated with NTD risk and plasma folate, erythrocyte folate and plasma tHcy levels in 96 NTD patients, 113 mothers, 97 fathers and 101 controls. This variation was associated with increased plasma folate (P < 0.04) and tended to be associated with decreased plasma tHcy (P < 0.09). It was not associated with erythrocyte folate or the risk for NTD. The H475Y polymorphism in the GCPII gene may increase the deconjugation activity of the FGCP enzyme, resulting in an increased absorption of folate in the body, as reflected by the increased plasma folate and decreased plasma homocysteine concentrations.

Homocisteína plasmática en pacientes con lupus eritematoso sistémico

Cardiovascular disease is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). An association between hyperhomocysteinemia and increased cardiovascular risk has been reported. On the other hand, renal failure and deficiency of vitamin B12 and/or folic acid are common causes of hyperhomocysteinemia. The aims of this study were to determine plasma total homocystein (tHcy) concentrations in SLE patients and to analyze the association of plasma tHcy with age, sex, plasma creatinine, vitamin B12, folates and total cholesterol, as well as with other clinical conditions linked to atherothrombosis in SLE patients. Fasting plasma levels of tHcy, vitamin B12, folates, total cholesterol and creatinine were measured in 94 SLE patients (11 males, 83 females) and in a control group of 308 healthy volunteers (122 males, 186 females). A review of the medical records of SLE patients was performed. Plasma tHcy concentrations were higher in patients with SLE (median 10.54 (mol/L) than in controls (median 8.49 (mol/L, p < 0.001). Hyperhomocysteinemia (tHcy >=15 (mol/L) was found in 17.02% SLE patients. In a multivariate analysis, plasma creatinine (p < 0.001), total cholesterol (p = 0.038), male sex (p = 0.003) and smoking (p = 0.001) were associated with higher plasma tHcy concentrations. No associations were found between plasma tHcy and hypertension, SLE duration, prednisone therapy and antiphospholipid antibodies. Plasma tHcy concentrations are higher in SLE patients than in healthy controls. High concentrations of plasma creatinine and total plasma cholesterol, male sex and smoking are associated with a higher concentration of plasma tHcy in SLE. Since the clinical consequences of hyperhomocysteinemia are not well established, routine determination of plasmatic tHcy and supplemental therapy in patients with high levels of tHcy are not recommended.

TGF-?1 impairs homocysteine metabolism in human renal cells: possible implications for transplantation

We hypothesized that TGF-beta1 influences the metabolism of homocysteine (Hcy) and increases its cellular export, which may lead to hyperhomocysteinemia in patients with renal transplants. We exposed human renal proximal tubule epithelial cells (huRPTECs) to different concentrations of TGF-beta1, IL-1alpha, IL-10, or methionine and measured total Hcy (tHcy) in culture supernatants. We then examined the relationship between plasma levels of tHcy and TGF-beta1 in renal graft recipients. In multivariate analysis, the factors mediator (TGF-beta1, IL-1alpha, IL-10), mediator concentration, methionine concentration, and "mediator x concentration" interaction independently influenced tHcy concentrations in culture supernatants. A 31% increase in tHcy was observed after exposure of huRPTECs to TGF-beta1 compared to medium alone. However, TGF-beta1 plasma levels in kidney graft recipients showed no independent association with tHcy plasma concentrations. We demonstrated that the release of Hcy from huRPTECs is enhanced by TGF-beta1, but that TGF-beta1 plasma levels in renal graft recipients show no independent relationship with hyperhomocysteinemia.