Insulin is an independent correlate of plasma homocysteine levels in obese children and adolescents

OBJECTIVE: The aim of the study was to investigate whether anthropometric and metabolic risk factors for coronary heart disease (CHD) contribute to the variation in homocysteine levels in obese children and adolescents. RESEARCH DESIGN AND METHODS: A total of 84 children and adolescents were assessed for fasting total homocysteine, methylenetetrahydrofolate reductase polymorphism (C677T mutation), folate and vitamin B12 status, and anthropometric and metabolic risk factors for CHD. RESULTS: No significant sex differences were found for all available anthropometric and metabolic characteristics except for homocysteine, which was significantly higher in boys than in girls (7.1 vs. 6.3 micromol/l; P<0.05). After adjustment for age and sex, homocysteine correlated significantly with BMI, fat mass, percentage of fat mass, and insulin and showed an inverse correlation with folate levels. Homocysteine did not correlate with vitamin B12; total cholesterol; LDL, HDL, and VLDL; triglycerides; and glucose. BMI and fat mass correlated significantly with insulin and showed a significant inverse correlation with folate. We found no association between homocysteine and the C677T mutation. In multiple regression analyses, insulin was found to be the main correlate of homocysteine. CONCLUSIONS: Our study demonstrates for the first time that insulin is a main correlate of homocysteine in obese children and adolescents and suggests that fat mass-associated hyper-insulinism may contribute to impairment of homocysteine metabolism in childhood obesity     

Alzheimer's disease: relationship between muscarinic cholinergic receptors, β-amyloid and tau proteins

Summary— Senile dementia is one of the most important health problems in developed countries. The main disease causing dementia is Alzheimer's disease that is characterized by the progressive deterioration of the cholinergic system, β-amyloid production and deposition, and neurofibrillary tangle formation. Most of the reviewed data, along with data from experiments performed in our laboratory, suggest that there are no changes in the number of muscarinic receptors between Alzheimer and control brains, although the receptors expressed in Alzheimer's disease brains can be anomalous in their function. The muscarinic receptor-G-protein interaction also seems to be impaired in Alzheimer's disease compared with control brains, as well as the G-protein system, with an important decrease in the function of the Gq/11, the most important G-protein stimulating phosphoinositide hydrolysis in human brain; in addition, the second messenger system is also impaired, with a decrease in the synthesis of phosphoinositides and in the number of IP₃ receptors. Muscarinic cholinergic receptors are also linked to β-amyloid production, stimulation of the M₁ subtype with agonists results in the processing of the β-amyloid precursor protein to non-amyloidogenic products and administration of a fraction of the β-amyloid (β-amyloid 25–35) to rats, results in a decrease in the number of muscarinic receptors in brain. M₁ agonists also decrease the phosphorylation of tau proteins, playing again a modulatory role in the pathogenesis of Alzheimer's disease. The existence of a link between β-amyloid and tau proteins also has been reported; treatment of hippocampal neurones with β-amyloid, or the 25–35 residue fragment, resulted in an increase in tau protein phosphorylation. The particular contribution of muscarinic receptors, β-amyloid and tau proteins in the pathogenesis of Alzheimer's disease remains still unclear. Probably Alzheimer's disease could be due to a progressive degeneration in the relationship between the three components covered in this review.     

Homocysteine, type 2 diabetes mellitus, and cognitive performance: The Maine-Syracuse Study.

Type 2 diabetes mellitus and higher total plasma homocysteine concentrations are each associated with an increased incidence of cardiovascular disease and with diminished cognitive performance. Relations between homocysteine concentrations and cardiovascular disease incidence are stronger in the presence of type 2 diabetes mellitus. Therefore, we hypothesized that relations between homocysteine concentrations and cognitive performance would be stronger in the presence of type 2 diabetes. We related homocysteine concentrations and cognitive performance on the Mini-Mental State Examination in 817 dementia- and stroke-free participants of the Maine-Syracuse Study, 90 of whom were classified with type 2 diabetes mellitus. Regardless of statistical adjustment for age, sex, gender, vitamin co-factors (folate, vitamin B6, vitamin B12), cardiovascular disease risk factors, and duration and type of treatment for type 2 diabetes mellitus, statistically significant inverse associations between homocysteine concentrations and cognitive performance were observed for diabetic individuals. The weaker inverse associations between homocysteine concentrations and cognitive performance obtained for non-diabetic individuals were not robust to statistical adjustment for some covariates. Interactions between homocysteine concentrations and type 2 diabetes mellitus are observed such that associations between homocysteine and cognitive performance are stronger in the presence of diabetes.     

Correlation of folate, vitamin B12 and homocysteine plasma levels with depression in an elderly Greek population

BACKGROUND: Alterations in folate, vitamin B12 and homocysteine plasma levels have been associated with aging, neuronal development and depressive symptomatology. Nevertheless, the associations are not strong enough to suggest the use of these parameters in every day practice for diagnostic or therapeutic purposes. OBJECTIVES: The aim of the study was to investigate the relationship between plasma folate, vitamin B12 and homocysteine in depressive states in the elderly. METHODS: Community-dwelling, elderly individuals over 60 years of age were screened with the Geriatric Depression Scale. The study population was divided into two groups: (a) 33 subjects with depression and (b) 33 healthy controls. All participants were clinically evaluated and completed a questionnaire for socio-demographic and clinical data. Measurements of folate, vitamin B12 and homocysteine were estimated in all blood samples and results were statistically evaluated at p<0.05 level of significance. RESULTS: No statistical significance emerged for the socio-demographic data between the two groups. Chronic diseases such as stroke, hypercholesterolemia, hypertension and diabetes also did not differ between the depression and control group. Group (a) had significantly lower levels of folate and vitamin B12 than group (b). Homocysteine was significantly higher in depressed individuals than in controls. CONCLUSION: Lower levels of plasma folate and/or vitamin B12, and higher levels of plasma homocysteine are associated with depression in elderly individuals.     

Association of vitamin B12, folate and homocysteine with functional and pathological characteristics of the elderly in a mountainous village in Sicily.

BACKGROUND: Homocysteine is associated with age, folate and vitamin B(12). Our study investigated the functional and clinical characteristics of the elderly (aged 60-85 years) of San Teodoro, a village in Central Sicily, and evaluated associations with vitamin B(12), folate and homocysteine. METHODS: Subjects (n=280) were examined after door-to-door recruitment using interview, physician examination and laboratory tests. RESULTS: A total of 19.3% of the population had a low blood level of folate (<7 nmol/L) and 3.2% had low vitamin B(12) concentration (<100 pmol/L). The level of dependency, determined by the Barthel index, influenced homocysteine blood levels (p<0.0001), independent of age (p<0.0001), folate (p=0.0028) and vitamin B(12) (p=0.0165). Homocysteine was significantly associated with stroke (p=0.0027) and peripheral arterial vascular disease (p=0.0001), but not with myocardial infarction, angina pectoris, venous thrombosis or cancer. Vitamin B(12) was lower in myocardial infarction and higher in diabetes and venous thrombosis compared to the other diseases. CONCLUSIONS: The prevalence of deficits in folate and vitamin B(12) was paradoxically high in the mountainous northeastern area of Sicily. Our study also underlines the association of homocysteine with dependency of the elderly and with stroke and peripheral arteriopathy.     

S-adenosylhomocysteine and the ratio of S-adenosylmethionine to S-adenosylhomocysteine are not related to folate,cobalamin and vitamin B6 concentrations

BACKGROUND: It is unclear whether homocysteine itself is causal in the pathogenesis of cardiovascular disease. Alternatively or additionally, the association between homocysteine and cardiovascular disease may be because of its metabolic precursor, S-adenosylhomocysteine, or of the ratio of S-adenosylmethionine to S-adenosylhomocysteine. Therefore, it is relevant to know how these moieties are interrelated, and whether, as is the case for homocysteine, they are influenced by blood levels of folate, cobalamin or vitamin B6. DESIGN: We cross-sectionally studied a population-based cohort of 97 Caucasian subjects aged 60-85 years. Concentrations of homocysteine, S-adenosylhomocysteine, S-adenosylmethionine, folate, cobalamin and vitamin B6 were measured in fasting blood samples. RESULTS: In multiple regression analysis, homocysteine was associated with vitamin B12 (per 50 pmol L-1 increase of cobalamin, change in homocysteine, -0.70 mmol L-1; 95% CI, -1.30 to -0.10 mmol L-1) and folate (per 100 nmol L-1 increase in erythrocyte folate, change in homocysteine, -0.68 mmol L-1; 95% CI -1.28 to -0.08 mmol L-1). S-adenosylhomocysteine, S-adenosylmethionine and the ratio of S-adenosylmethionine to S-adenosylhomocysteine were not associated with serum folate, cobalamin or vitamin B6, nor with erythrocyte folate. Furthermore, plasma homocysteine showed a negative correlation with the ratio of S-adenosylmethionine to S-adenosylhomocysteine in plasma (r = -0.27; P < 0.01) but not in erythrocytes. CONCLUSIONS: In contrast to homocysteine, the plasma concentrations of S-adenosylhomocysteine and the ratio of S-adenosylmethionine to S-adenosylhomocysteine were not associated with the folate, cobalamin and vitamin B6 concentrations in the present study. If these precursors in part explain why homocysteine is associated with cardiovascular disease, homocysteine-lowering treatment with B vitamins may be less effective than currently expected, at least in an elderly population.     

Homocysteine,folate, methylene tetrahydrofolate reductase genotype and vascular morbidity in diabetic subjects

In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n=354; Type II, n=392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P<0.01), remaining significant when additionally adjusted for serum folate (P=0.043 and P=0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes (P<0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.     

Homocysteine,vitamin B12, folate and cognitive functions: a systematic and critical review of the literature

Elevated serum homocysteine, decreased folate and low vitamin B₁₂ serum levels are associated with poor cognitive function, cognitive decline and dementia. Despite evidence of an epidemiological association, randomised controlled trials did not provide any clear evidence so far that supplementation with vitamin B₁₂ and/or folate improves dementia or slows cognitive decline, even though it might normalise homocysteine levels. In this report, we review the current knowledge on the relationship between homocysteine, folate and vitamin B₁₂ levels and the way their disruption influences cognitive function in adults.     

血浆同型半胱氨酸、叶酸、维生素B12水平测定与脑卒中的关系

目的探讨血浆同型半胱氨酸(Hcy)、叶酸、维生素B12水平与脑卒中的关系及临床意义。方法用循环酶法和化学发光法检测168例脑卒中患者(脑梗死96例,脑出血42例,短暂性缺血发作30例)血浆中同型半胱氨酸、叶酸、维生素B12水平,并与同期40例健康体检者进行了对照。结果脑卒中患者血浆中Hcy含量均明显高于对照组(P<0.01);叶酸和维生素B12水平明显低于对照组(P<0.05)。结论高同型半胱氨酸血症为脑卒中发病的独立危险因素之一,与叶酸和维生素B12水平下降有关。     

Altered folate and vitamin B12 metabolism in families with spina bifida offspring

Folic acid intake reduces the risk of neural tube defects (NTDs). Although the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for NTDs, it only partly explains the elevated homocysteine levels in mothers of children with NTDs. We measured vitamin B12, folate and homocysteine in patients with spina bifida (SB), their parents, and in controls, to investigate which other enzymes of homocysteine metabolism might be defective. Because homozygosity for the 677C-->T mutation causes decreased plasma folate and increased red-cell folate (RCF) and plasma homocysteine levels, we excluded individuals homozygous for that mutation. The remaining SB patients and their parents still had lowered plasma folate and elevated total homocysteine levels, and a small subset had decreased vitamin B12 levels. Red-cell folate was the same in all groups, suggesting that dietary folate intake and its uptake was normal. Risk of SB was increased at the 25th percentile of plasma folate and at the 75th percentile of homocysteine values in SB patients and their parents, and at the 5th and 25th percentiles of vitamin B12 in mothers with SB- affected offspring. This underlines the functional importance of homocysteine remethylation to methionine. There was no correlation between vitamin B12 and homocysteine or RCF. In combination with the lowered plasma folate (80-90% 5-methyltetrahydrofolate), our data do not support a major involvement of methionine synthase in the aetiology of SB. Our data rather favour the involvement of genetic variation at loci coding for the formation of 5-methyltetrahydrofolate, such as MTHFR, methylenetetrahydrofolate dehydrogenase or serine hydroxymethyltransferase.      

Fasting and post-methionine homocysteine levels in NIDDM. Determinants and correlations with retinopathy, albuminuria, and cardiovascular disease.

OBJECTIVE: The increased cardiovascular risk in subjects with NIDDM is partly explained by an association with established risk factors like hypertension, dyslipidemia, and obesity. Mild hyperhomocysteinemia has emerged as a new risk factor for cardiovascular disease. The purpose of this study was to assess its role in NIDDM. RESEARCH DESIGN AND METHODS: We studied predictors of homocysteine levels and correlations between homocysteine and (micro-)albuminuria, retinopathy, and history of cardiovascular disease in normotensive NIDDM subjects under stable metabolic control. This was done in 85 NIDDM subjects by measuring fasting and post-methionine-loading homocysteine levels together with blood pressure, BMI, serum cholesterol, triglyceride, HDL cholesterol, folate, vitamin B12, pyridoxal-5-phosphate, HbA1c, and (micro-)albuminuria and creatinine clearance in triplicate 24-h urine samples. The relationship between micro- and macrovascular complications and fasting homocysteine only was studied in an additional 65 subjects, giving a total of 150 subjects. RESULTS: In multiple regression analysis, significant (P < 0.05) predictors of fasting homocysteine were low-normal values of creatinine clearance (threshold effect at < 80 ml.min-1 .1.73 m-2), folate (< 20 nmol/l), and vitamin B12 (< 350 pmol/l), and postmenopausal status in women. Determinants of post-methionine homocysteine were pyridoxal-5-phosphate levels < 80 nmol/l, creatinine clearance, and sex (higher levels in women). Hyperhomocysteinemia did not cluster with other cardiovascular risk factors, like hypertension, obesity, or dyslipidemia. Regarding cardiovascular complications, fasting homocysteine, but not post-methionine homocysteine, was higher in subjects with a history of cardiovascular disease. There was a stepwise increase in the prevalence of subjects with cardiovascular disease with increasing fasting homocysteine. The prevalence of cardiovascular disease was 19.4% in the bottom quartile of fasting homocysteine, versus 55.0% in the top quartile (P for trend < 0.01). Neither fasting homocysteine nor post-methionine homocysteine correlated with (micro-)albuminuria or with retinopathy. CONCLUSIONS: The findings suggest that homocysteine levels in NIDDM rise even with modest deterioration of renal function and when vitamin status is in the low to low-normal range. Fasting homocysteine correlates with macrovascular disease, but we found no evidence of a correlation with retinopathy or (micro-)albuminuria. Post-methionine homocysteine levels do not show a correlation with micro- or macrovascular complications.     

Genetic mouse models of brain ageing and Alzheimer's disease

Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed.     

同型半胱氨酸、叶酸及VitB12与血管性痴呆的相关性研究

目的:探讨血浆同型半胱氨酸(Hcy)、叶酸(FA)、VitB12与血管性痴呆(VaD)的相关性。方法:检测VaD患者86例(VaD组),非VaD患者87例(非VaD组),健康体检正常者90例(正常组)血浆Hcy、FA、VitB12浓度。并对3组受检者进行简易智能状态量表(MMSE)评定。结果:VaD组患者Hcy浓度显著高于非VaD组及正常组(P<0.01)。FA、VitB12浓度与Hcy浓度负相关。血浆Hcy、FA、VitB12水平与VaD、MMSE得分显著相关(P<0.01)。结论:VaD高危人群应定期检测Hcy浓度,推荐服用VitB12和FA可预防VaD的发生。     

Ultrastructural Study of Senile Plaques and Microvessels in the Brain with Alzheimer's Disease and Down's Syndrome

This study examined the relation between amyloid fibrils and senile plaques in brains of patients with Alzheimer's disease. All the senile plaques contained some amyloid fibrils, which seemed to be produced in the basement membranes of capillary endothelial cells and projecting into surrounding parenchyma. Even when amyloid fibrils could not be seen in senile plaques using light microscopy, at least one degenerate capillary containing amyloid fibrils was found when serial sections were examined by electron microscopy. Amyloid fibrils consisted of hollow rods and were composed of filaments arranged as a tightly coiled helix, each turn comprising five globular subunits. Many capillaries and microvessels showed degenerative changes. Many terminal arterioles had smooth muscle cells with an irregular shape and arrangement, often showing a series of focal constrictions.

The findings suggest that the capillary degeneration with the formation of amyloid fibrils may be a primary change in the genesis of senile plaques. Furthermore, degenerative changes in the microvessels may also be an important factor in the loss of neurons in the brain of subjects with Alzheimer's disease.     

Homocysteine levels in patients treated with lipid apheresis: effect of a vitamin therapy

BACKGROUND: Patients treated with lipid apheresis already suffer from familial hypercholesterolemia and severe coronary heart disease: any additional risk factor is dangerous for these patients. Hyperhomocysteinemia has been recognized as an independent risk factor for atherosclerotic disease. We checked the frequency of hyperhomocysteinemia in lipid apheresis patients and measured the effect of a vitamin therapy. MATERIALS AND METHODS: Sixteen heterozygous patients (10 males, 6 females) were studied, who were being treated by three different apheresis procedures. Homocysteine was measured using an enzyme conversion immunoassay. Cystathionine and methylmalonic acid were assessed by gas chromatography/mass spectrometry. Serum levels of folic acid, vitamin B12, and vitamin B6 were also determined. The patients received a vitamin therapy (3 mg folate, 60 microg cyanocobalamine, 10 mg pyridoxine hydrochloride daily) for 12 weeks. RESULTS: In 9 out of 16 patients, plasma homocysteine levels were found to be elevated (> 12 micromol L(-1)). Cystathionine concentrations were also increased, especially in those patients with elevated homocysteine. Methylmalonic acid levels were not elevated. Serum folic acid, vitamin B6, and vitamin B12 concentrations were initially in the normal range and not correlated to plasma homocysteine. The vitamin therapy reduced the plasma homocysteine concentrations in all patients significantly by 33%. Among those patients with elevated homocysteine levels, the optimal range < 12 micromol L(-1) for homocysteine was rarely reached. CONCLUSIONS: In patients treated with lipid apheresis, a hyperhomocysteinemia can be frequently seen. The constellation of both elevated homocysteine and cystathionine levels points to the existence of tissue vitamin deficiencies, folate and vitamin B-6, which were improved by vitamin supplements. Because methylmalonic acid was mostly normal, a vitamin B-12 deficiency was not proven.     

Concentrations of B vitamins and homocysteine in children with sickle cell anemia

BACKGROUND: Elevated concentration of serum homocysteine contributes to thrombosis, a frequent event in patients with sickle cell anemia. We aimed to test whether children with sickle cell anemia have elevated concentrations of serum homocysteine with diminished levels of folate or B vitamins from accelerated blood cell turnover. METHODS: We conducted a case-control study of children with homozygous sickle cell anemia (n = 17) and unaffected children (n = 11). We measured serum and red blood cell folate, vitamin B6, vitamin B12, and homocysteine concentrations, and assessed micronutrient intake. RESULTS: Children with sickle cell anemia had concentrations of homocysteine slightly higher than those of unaffected children. They had lower vitamin B6 concentrations and comparable concentrations of folate and vitamin B12. Homocysteine concentration was inversely related to vitamin B12 concentration and was not independently associated with levels of vitamin B6 or folate. CONCLUSION: Despite comparable intake, children with sickle cell anemia had lower concentrations of vitamin B6 than unaffected children. Larger studies are needed to determine if chronically low serum vitamin B6 concentration contributes to hyperhomocysteinemia in this population.     

Urinary methylmalonic acid levels in patients with acute ischemic stroke

ObjectivesVitamin B-12 and folate deficiency are common, especially in people aged 55 or over, and accompanied by elevated methylmalonic acid (MMA) and homocysteine concentrations. The aims of the study were to investigate the relationship between serum vitamin B-12, homocysteine, folate, erythrocyte folate and urinary MMA in patients with ischemic stroke, and to develop a simple screening HPLC method for the measurement of urinary MMA.Design and methodsTwenty-eight patients aged 55 years and over with ischemic stroke and 23 age- and sex- matched healthy controls were included in the study. Serum vitamin B-12 and folate were measured by immunoassay; serum total homocysteine and urinary MMA concentrations by HPLC.ResultsThere was no significant difference in vitamin B-12, folate and homocysteine concentrations between the patient and control groups. Urinary MMA concentrations and erythrocyte folate levels were significantly higher in patients than controls. There was a significantly negative correlation between vitamin B-12 and MMA.ConclusionsIncreased urinary MMA excretion is associated with ischemic stroke and it may more robustly reflect vitamin B-12 deficiency in patients with ischemic stroke. The method used in this study is eligible for routine urinary MMA measurements.     

Vitamin supplementation during weight reduction — favourable effect on homocysteine metabolism

Moderately elevated homocysteine concentrations, reflecting deficiency of some nutritional factors required for homocysteine metabolism (folate, vitamin B-6, vitamin B-12) and/or less severe genetic defects, are common in the general population. Several studies have indicated the role of homocysteine as an independent risk factor for vascular disease. A pilot study published recently suggested that plasma homocysteine levels increase during weight reduction in slightly overweight, otherwise healthy subjects (group A). We examined a comparable group of 13 overweight subjects (group B) using a standardised caloric intake and defined vitamin supplementation (Medyn: folate 0.2 mg/ vitamin B-6 8.0 mg/ vitamin B-12 0.010 mg three times the day orally) to determine the effect of weight reduction on serum homocysteine levels and to compare the results with those of the pilot study. Mean body weight declined from 87.0±20.2 to 84.2±20.1 kg (P<0.05) in group A and 85.7±11.3 to 82.5±9.9 kg (P=0.049) in group B. Serum homocysteine levels rosed from 7.9±2.0 to 8.7±2.3 ìmol/l (P<0.0001) in group A and decreased from 8.19±1.73 to 7.35±0.88 ìmol/l (P=0.0022) in group B. No correlation was found between the changes in body weight and in homocysteine levels (r=0.02 in group A, r=0.18 in group B). Additionally, no correlation was found between serum folate levels and changes in homocysteine levels (r=0.03 in group A, r=0.09 in group B). The results suggest that an adequate oral vitamin-supplementation protects against increased homocysteine production during weight reduction.     

Hyperhomocysteinaemia and immune activation in patients with cancer.

BACKGROUND: Recently, homocysteine production was observed in tumour cell lines and homocysteine was proposed as a tumour marker. Furthermore, homocysteine production by activated immunocompetent cells was demonstrated. METHODS: In this study, homocysteine metabolism and immune activation status were investigated in 128 patients suffering from various types of cancer (haematological disorders, lung cancer, gastrointestinal tumours, gynaecological cancer and tumours of other localisation) and healthy age-matched controls. RESULTS: A high percentage of patients (39.1%) showed moderate hyperhomocysteinaemia, while cysteine, folate and vitamin B(12) concentrations were within reference ranges. Most patients were found to have elevated concentrations of the immune activation and inflammation markers neopterin and C-reactive protein (CRP), as well as a higher erythrocyte sedimentation rate (ESR). Patients of different cancer groups differed significantly regarding vitamin B(12) and neopterin concentrations; higher B(12) levels were also associated with tumour progression. Univariate regression analysis showed that CRP, ESR and neopterin were suited best to predict death. In multivariate analysis, neopterin was best suited to predicting death, while homocysteine and B vitamins were not associated with patient outcome. Homocysteine concentrations were correlated with folate and cysteine levels. Higher neopterin concentrations coincided with lower folate concentrations, but higher vitamin B(12) concentrations. CONCLUSIONS: Associations between neopterin and folate concentrations may indicate that cellular immune activation might partly contribute to the development of folate deficiency in cancer patients, thus possibly also impairing homocysteine remethylation.     

The risk of venous thromboembolism associated with the factor V Leiden mutation and low B-vitamin status.

Venous thromboembolism (VTE) is a multi-factorial disease involving numerous genetic and environmental risk factors. In this study we investigated the occurrence and the risk associated with factor V Leiden, hyperhomocysteinemia and low folate and vitamin B12 levels in young patients with thrombosis. We studied 78 patients (33 females/45 males, mean age 33 years) with a history of thrombosis in a lower limb. Additionally, 98 healthy subjects (45 females/54 males, mean age 44 years) were included. Serum levels of homocysteine (Hcy), folate and vitamin B12 were assayed. Factor V Leiden and methylenetetrahydrofolate reductase (MTHFR) C677T mutations were investigated in all subjects. Factor V Leiden was highly prevalent in the patients (39% heterozygous, 10% homozygous vs. 6.3% heterozygous in controls). An increase in the risk of idiopathic VTE was associated with Hcy levels > 15.2 micromol/l (odds ratio, OR = 2.83), folate < 15.1 nmol/l (OR = 7.49) and vitamin B12 < 182 pmol/l (OR = 11.97). Low levels of folate or vitamin B12 were independently and strongly associated with the risk of VTE in a multivariate model (OR for idiopathic thrombosis = 16.44 and 10.76, respectively). Twenty patients (53%), carriers of factor V Leiden, had low levels of vitamin B12, compared to 28% of patients who were non-carriers of the mutation (p = 0.03). In contrast, none of the control carriers of the mutation had a low level of vitamin B12. The risk of VTE associated with lower levels of vitamin B12 and folate was stronger than that introduced by elevated Hcy levels. The increased risk of VTE, accompanied by factor V Leiden, may be related to confounding environmental factors.