Increased Plasma Homocysteine Concentrations Research Articles

Methylenetetrahydrofolate reductase C677T polymorphism and Factor V Leiden variant in Mexican women with preeclampsia/eclampsia

The etiology of preeclampsia is still a matter of controversy. An association between hyperhomocysteinemia and preeclamptic patients has been described. A common missense mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased plasma homocysteine concentrations. In addition, the polymorphism of gene encoding for Factor V Leiden G1691A is associated with a prothrombotic state in heterozygous subjects. Both mutations in these thrombophilic proteins appear to have different prevalence in the general population and in patients with preeclampsia/eclampsia (PE/E). We studied single nucleotide polymorphisms for MTHFR C677T and coagulation Factor V Leiden in 33 Mexican patients with PE/E as a genetic risk factor for these diseases, comparing with a normotensive pregnant control group. The genotype and allele frequencies of MTHFR C677T and Factor V Leiden mutations between Mexican women with PE/E and healthy controls were not different. We conclude that these polymorphisms do not contribute in the etiology of PE/E as it has been reported in other populations.

Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load2–3

Elevated concentrations of homocysteine in blood may be an independent risk factor for the development of atherosclerosis. Elevated homocysteine concentrations can be caused by decreased methylation of homocysteine to form methionine, as occurs in folate deficiency. A parallel pathway exists for methylation of homocysteine, in which choline, by way of betaine, is the methyl donor. Our goal was to determine whether choline deficiency results in a decreased capacity to methylate homocysteine. C57BL/6J mice were fed diets containing 0, 10, or 35 mmol choline/kg diet for 3 wk. We then administered an oral methionine load to the animals and measured plasma homocysteine concentrations. Also, in a pilot study, we examined 8 men who were fed a diet providing 550 mg choline/d per 70 kg body weight for 10 d, followed by a diet providing almost no choline, until the subjects were clinically judged to be choline deficient or for <or=42 d. A methionine load was administered at the end of each dietary phase. Two hours after the methionine load, choline-deficient mice had plasma homocysteine concentrations twice those of choline-fed mice. Four hours after the methionine load, clinically choline-depleted men had plasma homocysteine concentrations that were 35% greater than those in men not choline depleted. These results suggest that choline, like folate, plays an important role in the metabolism of homocysteine in humans and that response to a methionine load may be useful when assessing choline nutriture.

Effect of antihypertensive treatment with candesartan or amlodipine on glutathione and its redox status, homocysteine and vitamin concentrations in patients with essential hypertension

To compare the effect of candesartan or amlodipine on concentrations of cellular markers of oxidative stress, plasma homocysteine and vitamins in hypertensive patients. Forty-nine middle-aged patients with untreated stage I-II essential hypertension were recruited in a randomized double-blind double-dummy study to receive a daily dose either of 8 mg candesartan (n = 25) or 5 mg amlodipine (n = 24) for 16 weeks. Blood pressure, reduced glutathione (GSH) and oxidized glutathione (GSSG), glutathione redox ratio (GSSG : GSH) in red blood cells, plasma homocysteine, vitamin B12 and folic acid status were measured at baseline, at week 2 and at week 16. The same parameters were measured in 32 healthy age- and sex-matched controls. An increase in homocysteine of at least 2 micromol/l was considered significant. Hypertensive patients had significantly greater oxidative stress and homocysteine concentrations than controls. In addition to a significant decrease in blood pressure, in both treatment groups GSSG decreased (P < 0.03), GSSG : GSH had a tendency to decrease (P = 0.054), but homocysteine did not change. An increase in homocysteine concentration of at least 2 micromol/l was found in 12 patients (five in the candesartan group, seven in the amlodipine group), with a significant decrease in folic acid concentration and no changes in cellular oxidative stress. In patients with no increase in homocysteine concentration, both GSSG (P < 0.02) and GSSG : GSH (P = 0.051) decreased. GSH and vitamin B12 did not change in any of the groups studied. Untreated hypertension is associated with disturbed glutathione redox status and increased plasma homocysteine concentrations. Both candesartan and amlodipine had favourable effects on cellular oxidative stress, but the oxidative stress status did not decrease in patients with adverse changes in homocysteine.

Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load

Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load

Elevated plasma homocysteine: cause or consequence of myocardial infarction?

To determine whether a first myocardial infarction leads to increased plasma homocysteine concentrations and whether the association between homocysteine and myocardial infarction was greater at follow-up compared with baseline. A population-based, prospective, nested case-referent study. Screening took place at the nearest health survey centre in northern Sweden. Of more than 36,000 persons screened, 78 developed a first myocardial infarction (average 18 months after sampling). Fifty of these had participated in a follow-up health survey (average 8(1/2) years between surveys) and were sex- and age-matched with 56 referents. Comparison of plasma homocysteine levels in case and referent subjects before and after development of a first myocardial infarction. No statistically significant difference was found between cases and referents regarding homocysteine at baseline or follow-up. Plasma homocysteine and plasma creatinine increased significantly, and plasma albumin decreased significantly over time. Conditional univariate logistic regression indicated that high homocysteine at follow-up but not baseline was associated with first myocardial infarction (OR 2.49; 95% CI: 1.03-6.02), but the relation disappeared in multivariate analyses including plasma creatinine and plasma albumin. High plasma creatinine remained associated with first myocardial infarction at both baseline (OR 2.94; 95% CI: 1.05-8.21) and follow-up (OR 3.38; 95% CI: 1.21-9.48). In this study, first myocardial infarction did not cause increased plasma homocysteine concentration.

Plasma homocysteine: an independent or an interactive risk factor for coronary artery disease

Background Coronary artery disease (CAD) is emerging as a major public health concern in most developing countries. Further conventional risk factors for CAD do not solely account for the increased mortality, particularly in Asians. Recently, increased plasma homocysteine is being considered as a risk factor, but the strength of relationship and interaction of plasma homocysteine with other risk factors is yet obscure. In this study, the association of plasma homocysteine with CAD and other risk factors was estimated. Methods In the present study, 100 patients of CAD and 50 controls of both sexes were included. Plasma total homocysteine (tHcy) concentrations were measured using reverse phase high-performance liquid chromatography. Results Plasma homocysteine concentrations were significantly raised in cases as compared to age-matched controls (16.57±6.86 and 11.47±5.19 μmol/l, p<0.001). On calculating relative risk (RR) of each factor by univariate analysis smoking, hypertension, plasma cholesterol and homocysteine appeared to be significant risk factors. However, on applying multiple logistic regression only the latter three emerged as independent risk factors ( p<0.005). Further, strong interactive effects were observed between homocysteine levels and increasing age, hypertension and smoking. Conclusion An increase in plasma homocysteine concentration confers an independent risk for CAD. It further increases the risk associated with increasing age, smoking and hypertension. Thus, increased homocysteine concentrations are a significant medical problem and effective strategies are urgently required to counter this challenge.

Methionine Synthase Reductase 66A→G Polymorphism Is Associated with Increased Plasma Homocysteine Concentration When Combined with the Homozygous Methylenetetrahydrofolate Reductase 677C→T Variant

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are important for homocysteine remethylation. This study was designed to determine the influence of genetic variants (MTHFR 677C-->T, MTHFR 1298A-->C, and MTRR 66A-->G), folate, and vitamin B-12 status on plasma homocysteine in women (20-30 y; n = 362). Plasma homocysteine was inversely (P < 0.0001) associated with serum folate and plasma vitamin B-12 regardless of genotype. Plasma homocysteine was higher (P < 0.05) for women with the MTHFR 677 TT/1298 AA genotype combination compared with the CC/AA, CC/AC, and CT/AA genotypes. Women with the MTHFR 677 TT/MTRR 66 AG genotype had higher (P < 0.05) plasma homocysteine than all other genotype combinations except the TT/AA and TT/GG genotypes. There were 5.4-, 4.3-, and 3.8-fold increases (P < 0.001) in risk for plasma homocysteine in the top 5, 10, and 20%, respectively, of the homocysteine distribution for subjects with the MTHFR 677 TT compared with the CC and CT genotypes. Predicted plasma homocysteine was inversely associated with serum folate (P = 0.003) and plasma vitamin B-12 (P = 0.002), with the degree of correlation dependent on MTHFR 677C-->T genotype. These data suggest that coexistence of the MTHFR 677 TT genotype with the MTRR 66A-->G polymorphism may exacerbate the effect of the MTHFR variant alone. The potential negative effect of combined polymorphisms of the MTHFR and MTRR genes on plasma homocysteine in at-risk population groups with low folate and/or vitamin B-12 status, such as women of reproductive potential, deserves further investigation.

Diet and dementia

The ageing brain adapts to the accumulation of damage caused by oxidative stress and inflammation. Adaptive processes include neuroprotective and neurorestorative mechanisms. Individual differences in susceptibility to dementia arise when these mechanisms are impaired or are overwhelmed by the molecular pathology of Alzheimer's disease. Neuroprotection relies upon extrinsic and intrinsic defences. An adequate intake of antioxidant micronutrients (eg, vitamin C and vitamin E) and anti-inflammatory macronutrients (eg, omega-3 polyunsaturated fatty acids) forms an essential component of extrinsic defences against brain ageing. There are many epidemiological data to support an association between an inadequate intake of antioxidants and/or fish oils (an important source of omega-3 polyunsaturated fatty acids) and a greater than expected incidence of late onset dementia. These associations are confounded by established links between poverty, poor diet and failing health, especially in old age. Such links may be sufficient to explain some of the effects of an inadequate diet on the retention of cognitive function and increased risk of dementia in old age. More compelling is the association between increased plasma homocysteine concentration and later increased risk of dementia. This association is possibly caused by an inadequate intake of vitamin B(12)/folate.

Taurine protected myocardial mitochondria injury induced by hyperhomocysteinemia in rats.

Taurine can protect against cardiovascular diseases, whereas elevated levels of plasma homocysteine are associated with atherosclerotic and thromboembolic cardiovascular diseases. To illustrate the effects of taurine on hyperhomocysteinemia, we observed the myocardial mitochondria dysfunction in the rats with hyperhomocysteinemia induced by diet methionine loading, and the therapeutic effect of taurine. A methionine diet increased plasma homocysteine concentration (133.51 +/- 27.91 micromol/L vs 12.31 +/- 2.58 micromol/L in control, P < 0.01), stimulated the production of reactive oxygen species (ROS) in the myocardial mitochondria, and inhibited the activities of mitochondrial Mn-superoxide dismutase and catalase. The 45Ca uptake and Ca2+-ATPase activity in the myocardial mitochondria were significantly lowered in rats with hyperhomocysteinemia. Taurine supplements effectively attenuated the hyperhomocysteinemia-induced ROS production and inhibition of Mn-superoxide dismutase and catalase activities in the myocardial mitochondria, and increased its 45Ca uptake and Ca2+-ATPase activity. Thus, taurine antagonizes the oxidative stress injury in the myocardial mitochondria induced by the hyperhomocysteinemia.

Plasma homocysteine is elevated in patients with exfoliation syndrome

PurposeTo compare plasma homocysteine concentrations among patients with exfoliation syndrome, exfoliative glaucoma, normal-tension glaucoma, and normal control subjects without vascular or inflammatory ocular disease or glaucoma. DesignCross-sectional study. MethodsWe tested 25 patients with exfoliation syndrome, 50 with exfoliative glaucoma, 25 with normal-tension glaucoma, and 24 control subjects. Fasting plasma homocysteine concentrations were measured by fluorescence polarization immunoassay. Patients using vitamin supplements or medications known to alter serum homocysteine were excluded. ResultsHomocysteine levels were higher in both exfoliation groups compared with controls (exfoliation syndrome: P = .003; exfoliative glaucoma: P = .009); levels in normal-tension glaucoma were higher than but not significantly different from those in controls (P = .2). Hyperhomocysteinemia was present in 16 of 25 (64%) exfoliation syndrome patients, 28 of 50 (56%) exfoliative glaucoma patients, 13 of 25 (52%) normal-tension glaucoma patients, and 7 of 24 (29.2%) controls (P = .005). Multiple logistic regression analyses comparing exfoliation syndrome and exfoliative glaucoma patients with controls indicated that elevated plasma homocysteine concentration was a significant risk factor for exfoliation syndrome, in both those patients (odds ratios per 1.0 μmol/l increase in plasma homocysteine concentrations = 1.47; 95% confidence interval [CI] = 1.08–2.0) and in exfoliative glaucoma patients (odds ratio = 1.3; 95% CI = 1.07–1.6). Although exfoliative glaucoma and normal-tension glaucoma patients were not signficantly different with respect to hyperhomocysteinemia, logistic regression modeling of exfoliative glaucoma vs normal-tension glaucoma patients showed that an increased homocysteine concentration was a significant risk factor for exfoliation syndrome in the presence of glaucoma (odds ratio per 1.0 μmol/l increase in homocysteine = 1.2, 95% CI = 1.0–1.4). These relationships were not affected by adjustment for potential confounding due to sex, history of hypertension, or other factors. ConclusionsElevated plasma homocysteine, a risk factor for cardiovascular disease, is more common in exfoliation syndrome and exfoliative glaucoma patients than healthy controls. Patients with exfoliation syndrome may benefit from measurement of homocysteine levels.

The status of plasma homocysteine and related B-vitamins in healthy young vegetarians and nonvegetarians.

Exclusion of animal products and having only plant protein in vegetarian diets may affect the status of certain B-vitamins, and further cause the elevation of plasma homocysteine concentration. The purpose of this study was to assess the status of homocysteine and related B-vitamins in vegetarians and nonvegetarians. The effects of biochemical parameters of B-vitamins and dietary protein on plasma homocysteine were also examined. The study was performed at the Chung Shan Medical University, Taichung, in the central part of Taiwan. Thirty-seven vegetarians (28.9 +/- 5.5 y) and 32 nonvegetarians (22.9 +/- 1.6 y) were recruited. Nutrient intake was recorded using 3-day dietary records. Fasting venous blood samples were obtained. Plasma homocysteine, folate and vitamin B-12 were measured. Vitamin B-6 status was assessed by direct measures [plasma pyridoxal 5'-phosphate (PLP) and urinary 4-pyridoxic acid (4-PA)] and indirect measures [erythrocyte alanine (EALT-AC) and aspartate (EAST-AC) aminotransaminase activity coefficient]. There was no significant difference in vitamin B-6 intake between the two groups, although the vegetarian group had a significantly lower vitamin B-12 intake than the nonvegetarian group. Vegetarian subjects had significantly lower mean plasma PLP and vitamin B-12 concentrations than did nonvegetarian subjects (p < 0.05); however, a significantly higher mean plasma folate concentration was found in the vegetarian group. Vegetarian subjects had a significantly higher mean plasma homocysteine concentration than nonvegetarian subjects (13.2 +/- 7.9 vs. 9.8 +/- 2.2 micromol/L). Negative correlations were seen between plasma homocysteine and vitamin B-12 concentrations in the vegetarian (p = 0.004), nonvegetarian (p = 0.026), and pooled (p < 0.001) groups. From best subsets regression analyses, the plasma homocysteine concentration could be significantly predicted by total protein intake (p = 0.027) and plasma vitamin B-12 concentration (p = 0.005) in the pooled group. When the intake of protein is not considered, vitamin B-12 concentration is still a strong predictor of plasma homocysteine concentration (p = 0.012). Vitamin B-12 intake and mean plasma vitamin B-12 concentration were lower for vegetarian subjects than for nonvegetarian subjects, leading to an increase in plasma homocysteine concentration. Vitamin B-6 and folate had little effect on plasma homocysteine concentration when individuals had adequate vitamin B-6 and folate status.

Association between plasma homocysteine concentrations and asymptomatic cerebral infarction or leukoaraiosis in elderly diabetic patients

Background: The purpose of the present study was to investigate the possible contribution of plasma homocysteine to asymptomatic cerebral infarction (CI) or leukoaraiosis.Methods: The relationship between plasma homocysteine concentrations and cerebral lesions was investigated in 233 elderly diabetic patients (mean age: 74 years) who were divided into three groups based on the neurological and brain MR findings: asymptomatic cerebral infarction (CI), symptomatic CI, and a control group with no evidence of cerebrovascular disease. Plasma total homocysteine concentrations were measured by high‐performance liquid chromatography. The C677T polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene was assessed by PCR‐RFLP. The total score of T2 high‐intensity lesions on the brain MR images was summed from the focal T2 high‐intensity scores in 24 areas of the brain.Results: Diabetic patients with asymptomatic or symptomatic CI had significantly higher homocysteine concentrations in plasma than the control group. The plasma homocysteine concentration was more strongly associated with the presence and number of small infarctions or infarction of the putamen, which may explain the association between increased plasma homocysteine concentrations and asymptomatic CI in elderly diabetic patients. In the diabetic patients, high plasma homocysteine concentrations were also significantly associated with high scores of total T2 high‐intensity lesions or focal T2 high‐intensity scores in some periventricular regions. Although there was no significant relationship between the MTHFR TT genotype and CI, a significant association was found between the MTHFR TT genotype and total T2 high‐intensity scores.Conclusion: An elevated plasma homocysteine concentration is independently associated with asymptomatic CI and T2 high‐intensity lesions on brain MR images in elderly patients with diabetes mellitus. The association between the MTHFR TT genotype and periventricular T2 high‐intensity lesions, but not with CI, suggests an important effect of C677T MTHFR gene mutation on leukoaraiosis, independent of hyperhomocysteinemia in elderly diabetic patients.

Moderate coffee consumption increases plasma glutathione but not homocysteine in healthy subjects.

The consumption of unfiltered coffee, containing bioactive diterpenes, causes an increase in plasma homocysteine concentration. A slight increase in plasma homocysteine is also caused by large quantities of filtered coffee. Coffee terpenes also raise plasma glutathione in mice. To verify the effect of Italian-style coffee consumption on the plasma concentration of glutathione and homocysteine in healthy subjects. Twenty-two volunteers consumed five cups of coffee per day for 1 week and maintained their usual diet. Five subjects were enrolled as controls. The intervention trial was preceded and followed by seven coffee-free days. Plasma glutathione increased by 16% (P < 0.05) on coffee consumption, and returned to the original concentration after the washout period. The increase in plasma homocysteine concentration (13% after 1 week of coffee intake) was not significant. No differences in glutathione or homocysteine concentration were observed in the control group. No variation of plasma hydroperoxide concentration was detectable. A coffee intake regimen, representing the average consumption of coffee drinkers in Italy, increased the plasma concentration of glutathione, but no significant increase in the plasma homocysteine concentration was detected.

Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial

Cigarette smoking is associated with increased plasma homocysteine concentrations, endothelial dysfunction and arterial stiffening. Homocysteine per se induces endothelial dysfunction and arterial stiffening and might account, at least partly, for the vascular abnormalities observed in smokers. We sought to determine whether folic acid supplementation, by reducing plasma homocysteine concentrations, enhanced endothelial function and reduced arterial stiffness in smokers. Double-blind, randomized controlled, parallel-group, trial. Academic medical centre. A consecutive sample of 24 healthy cigarette smokers (age 37.8 +/- 2.5 years, mean +/- SEM). Subjects were randomly assigned to 4-week folic acid 5 mg day-1 or placebo. The following were measured before and after treatment: (i) peripheral vasoreactivity (forearm arterial blood flow, FABF) during intra-arterial administration of endothelium-dependent (acetylcholine 1.5, 4.5 and 15 microg min-1) and endothelium-independent (sodium nitroprusside 1, 2 and 4 microg min-1) vasodilators; (ii) carotid-femoral pulse-wave velocity (PWV); (iii) blood pressure (BP). Folic acid reduced homocysteine concentrations (10.8 +/- 0.6 vs. 8.2 +/- 0.5 micromol L-1, P < 0.001) and enhanced endothelium-dependent vasodilatation during each acetylcholine infusion rate (ratio between the FABF in the infused and control arm during increasing infusion rates at baseline 1.09 +/- 0.03 vs. 1.41 +/- 0.09 after treatment, P < 0.01; 1.39 +/- 0.07 vs. 1.83 +/- 0.12, P < 0.01; 1.65 +/- 0.16 vs. 2.72 +/- 0.36, P < 0.05) whilst endothelium-independent vasodilatation was unaffected. A significant fall in BP was also observed (mean BP 88 +/- 2 vs. 83 +/- 1 mmHg, P < 0.01). By contrast, PWV did not significantly change (8.4 +/- 0.3 vs. 7.8 +/- 0.4 m s-1). No significant changes in plasma homocysteine concentrations, FABF, BP, and PWV were observed in the placebo group. A multiple regression analysis showed that changes in folic acid plasma concentrations independently predicted both FABF changes during maximal acetylcholine-mediated vasodilatation (P < 0.01) and BP changes (P = 0.01). Short-term folic acid supplementation significantly enhanced endothelial function and reduced BP in young chronic smokers. These effects were largely independent from the homocysteine lowering effects. Thus, a simple, nontoxic, and relatively inexpensive vitamin intervention might be useful in primary cardiovascular prevention in this high-risk group.

A 31 bp VNTR in the cystathionine beta-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels.

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinaemia, an independent and graded risk factor for cardiovascular disease (CVD). Although heterozygosity for cystathionine beta-synthase (CBS) deficiency has been excluded as a major genetic cause of mild hyperhomocysteinaemia in vascular disease, mutations in (non-)coding DNA sequences may lead to a mildly decreased CBS expression and, consequently, to elevated plasma homocysteine levels. We assessed the association between a 31 bp VNTR, that spans the exon 13-intron 13 boundary of the CBS gene, and fasting, post-methionine load and increase upon methionine load plasma homocysteine levels in 190 patients with arterial occlusive disease, and in 381 controls. The 31 bp VNTR consists of 16, 17, 18, 19 or 21 repeat units and shows a significant increase in plasma homocysteine concentrations with an increasing number of repeat elements, in particular after methionine loading. In 26 vascular disease patients the relationship between this 31 bp VNTR and CBS enzyme activity in cultured fibroblasts was studied. The CBS enzyme activity decreased with increasing number of repeat units of the 31 bp VNTR. RT-PCR experiments showed evidence of alternative splicing at the exon 13-intron 13 splice junction site. The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.

Levels of Plasma Homocysteine in Persons with Spinal Cord Injury

Background: Premature coronary vascular disease is a leading cause of morbidity and mortality in persons with chronic spinal cordinjury (SCI). Evidence indicates that an elevated plasma homocysteine level is an independent risk factor for vascular disease.Methods: Plasma homocysteine levels were collected in 845 subjects with SCI and compared to those in a reference population. Differences in plasma homocysteine were determined for sex, race/ ethnicity, neurological deficit, and age, as well as for serum creatinine concentration.Results: Plasma homocysteine was significantly higher in men than in women. Men were more likely to have moderately or severely elevated plasma homocysteine levels. Stratifying by male sex, greater percentages of whites and African Americans had severely elevated plasma homocysteine levels (>20 11moi/L) compared with Latinos (12% and 14% versus 8%; P > .01 J. For the total group with SCI, plasma homocysteine levels were not significantly different by race/ ethnicity or neurological deficit subgroup. For the total group (P < .05) and within each sex (men, P < .05; women, P < .01 ), the older age group with SCI (>50 years) had significantly higher mean plasma homocysteine levels than the younger age group. Age was positively related to plasma homocysteine levels in men (P < .05) and women (P <.01 J. Plasma homocysteine levels were higher among men for any given age than among women (P <.0001) by an average of 3.19 ± 0.51 µmoi/L. Regardless of age or sex, persons with SCI tended to have higher levels of plasma homocysteine than able-bodied persons matched for age and sex.Conclusion: Because the risk of a vascular event increases with age, elevated levels of plasma homocysteine place older persons with SCI at further increased risk for a vasa-occlusive event. Of note, there was a stepwise increase in plasma homocysteine concentration for each quartile of higher serum creatinine concentration. Patients who have elevated levels of plasma homocysteine should receive a trial course of daily supplementation with oral folic acid and vitamin B12 . If that is ineffective, they should receive vitamin B6 supplementation to lower their plasma homocysteine levels.

Homocysteine levels during fasting and after methionine loading in adolescents with diabetic retinopathy and nephropathy

Objective: To assess plasma homocysteine levels in adolescents and young adults with type 1 (insulin-dependent) diabetes with and without microvascular complications. Study design: Homocysteine levels were measured during fasting and after methionine loading in plasma of 61 patients with onset of diabetes before the age of 12 years and duration of disease longer than 7 years. They had an albumin excretion rate (AER) between 20 and 200 μg/min in 2 of 3 overnight urine collections in a period of 6 months and/or retinopathy. Patients with persistent microalbuminuria were divided into 2 groups: subjects with AER of 20 to 70 μg/min and patients with AER of 70 to 200 μg/min. Adolescents (n = 54) without signs of diabetic retinopathy or nephropathy and matched control subjects (n = 63) were also studied. Results: Homocysteine concentrations before and after methionine load were higher in adolescents with diabetic complications than in healthy subjects (fasting values: 12.4 ± 7.9 μmol/L vs 7.8 ± 4.2 μmol/L; P <.01; after methionine load: 28.1 ± 13.2 μmol/L vs 16.6 ± 7.3 μmol/L; P <.005). Values of 11.9 μmol/L or higher were considered to constitute fasting hyperhomocysteinemia. The increase of homocysteine concentrations was particularly evident in young diabetic patients with AER >70 μg/min (fasting values: 14.7 ± 5.6 μmol/L; after methionine load: 34.2 ± 12.6 μmol/L) and in patients with proliferative retinopathy (fasting values: 15.1 ± 5.0 μmol/L; after methionine load: 36.8 ± 12.5 μmol/L). Conclusions: Increased plasma homocysteine concentrations may contribute to increased morbidity and death from cardiovascular disease in adolescents and young adults with diabetic retinopathy and nephropathy. (J Pediatr 2000;137:386-92)

Redox status of plasma homocysteine and other plasma thiols in stroke patients

Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Studies are difficult as a result of the fact that little is known about the formation of different homocysteine species in vivo. Since extracellular glutathione and cysteine may influence the formation of different homocysteine species, we have in the present study investigated the different fractions of homocysteine and their relation to the different fractions of glutathione and cysteine in stroke patients and control subjects. We found a ratio of about 32–33% between reduced and total plasma glutathione concentrations and 2.6–3.0% between reduced and total plasma cysteine concentrations both in patients and in healthy control subjects. We noted an elevated concentration of total plasma homocysteine in stroke patients, but no difference in the ratio between reduced and total plasma homocysteine concentrations in patients and control subjects (mean value 1.20 and 1.10%, respectively). However, in a subgroup of patients with higher concentrations of total plasma homocysteine, we observed a significantly lower ratio of reduced to total plasma homocysteine compared to a subgroup of patients with lower concentration of total plasma homocysteine. A low reduced/total ratio of plasma homocysteine in combination with elevated plasma homocysteine concentrations might reflect an increased pro-oxidant activity in plasma from these patients. Thus, increased pro-oxidant activity in plasma might be one factor, besides genetic and nutritional factors, that could explain hyperhomocysteinemia. Since substantial evidence indicates that progression of atherosclerosis is related to enhanced pro-oxidant activity, the premature vascular disease associated with increased plasma homocysteine concentration might be as a result of increased pro-oxidant activity and the elevated plasma homocysteine concentration may only reflect the increased oxidative stress.

Case-control study of plasma folate, homocysteine, vitamin B(12), and cysteine as markers of cervical dysplasia.

An association between B-complex vitamins and related compounds with the development of cervical neoplasia is biologically plausible, yet to the authors' knowledge epidemiologic investigations of these potential biomarkers are limited. A case-control study was designed to examine the relation between plasma folate, homocysteine, vitamin B(12), and cysteine and early, premalignant changes in cervical epithelial cells among women identified from several clinics on Oahu, Hawaii, between 1992 and 1996. Fasting blood samples for plasma nutrient analysis, cervical smears for cytologic diagnosis, exfoliated cervical cells for human papillomavirus DNA testing by polymerase chain reaction, and a personal interview were obtained from 185 women with atypical squamous cells of undetermined significance (ASCUS) of the cervix, 147 women with squamous intraepithelial lesions (SIL), and 191 women with cytologically normal (Papanicolaou) smears. Age-adjusted and ethnicity-adjusted mean plasma concentrations of cysteine, but not other nutrients, were significantly lower among ASCUS cases (P = 0.006) and SIL cases (P = 0.01) than controls. A positive trend in the odds ratio for SIL but not ASCUS was found for increased plasma homocysteine concentrations, but this finding was not statistically significant. High plasma levels of cysteine were associated with a reduced risk of ASCUS (P value for trend = 0.006), with an odds ratio of 0.3 (95% confidence interval, 0.2-0.7) for the highest compared with the lowest quartile of cysteine concentration. A weak, negative relation between cysteine and the development of low grade SIL (LSIL) but not high grade SIL (HSIL) also was found. The results of the current study do not support the hypothesis that folate, homocysteine, or B(12) are markers of cervical dysplasia risk. A possible inverse association between plasma cysteine concentrations and the risk of cervical dysplasia needs further study.

Plasma Homocysteine Is a Sensitive Marker for Tissue Deficiency of Both Cobalamines and Folates in a Psychogeriatric Population

The concentration of blood folates was decreased and the concentration of plasma homocysteine was increased in a psychogeriatric population, whereas the concentrations of methylmalonic acid or serum cobalamins were not changed compared with healthy subjects. The highest frequency of abnormal values was shown by plasma homocysteine concentration, which was increased in 88 of 168 patients. In 29 of these 88 patients increased concentration of plasma homocysteine could possibly be attributed to tissue cobalamin deficiency. One patient had only a lowered concentration of blood folate. Thirteen patients had elevated concentrations of serum creatinine which could explain increased plasma homocysteine concentration. Even if the remaining patients (n = 45) had normal vitamin levels in circulation, the increased plasma homocysteine concentration in most cases must be attributed to tissue deficiency of cobalamins and/or folates. Thus, many patients with increased plasma homocysteine concentrations need further vitamin supplementation despite their normal vitamin levels in serum and blood.