Increased Homocysteine Levels Research Articles

Homocysteine and Cardiovascular Disease

See related article, pages 598–606 An elevated plasma level of homocysteine has long been known as an independent predictor of cardiovascular disease.1,2 However, in the absence of a clear mechanism linking homocysteine to cardiovascular disease, there has been an ongoing debate about whether this relationship is one of cause and effect or whether an elevated level of plasma homocysteine is an epiphenomenon, reflecting the presence of some other proatherogenic factor that is actually responsible for the cardiovascular disease. In the current issue of this journal, Liao et al3 suggest that the mechanistic link may be a homocysteine-induced reduction in the concentration of high density lipoproteins (HDLs). Liao et al3 report that homocysteine reduces the concentration of HDL cholesterol in plasma by inhibiting the hepatic synthesis of apoA-I, the main HDL apolipoprotein. This conclusion supports the findings from another recent study by Mikael et al4 who also reported that homocysteine inhibits apoA-I synthesis. The results of these 2 studies not only explain the documented inverse correlation between the plasma concentrations of HDL cholesterol and homocysteine5,6 but also raise the real possibility that a homocysteine-induced inhibition of apoA-I synthesis is the mechanism linking homocysteine to the development of atherosclerosis. A low concentration of HDL cholesterol has been shown in numerous human population studies to be highly predictive of premature cardiovascular disease.7,8 Furthermore, treatments that increase the level of HDL cholesterol in plasma in both animals9,10 and humans11,12 reduce the progression or even promote …

Anesthesia for cesarean section in a patient with placenta previa and methylenetetrahydrofolate reductase deficiency

We describe the anesthetic management of a patient with placenta previa presenting for a cesarean section, who had methylenetetrahydrofolate reductase (MTHFR) deficiency. Methylenetetrahydrofolate reductase deficiency increases homocysteine levels in the body and, therefore, predisposes to thrombosis. After a cerebrovascular accident at 8 weeks of gestational age, the patient received anticoagulants throughout the course of her pregnancy. Bleeding from the placenta previa occurred at 30 weeks of gestational age. Although general anesthesia was indicated for this patient because of her hemodynamic instability and an anticoagulated state, nitrous oxide is contraindicated in such patients. Thus, we chose a subarachnoid block because the patient remained hemodynamically stable, and anticoagulation had been stopped 8 hours before surgery. To our knowledge, there is no reported case of a parturient with MTHFR deficiency complicated with a cerebrovascular accident and associated with placenta previa presenting for a cesarean section. Anesthetic considerations are discussed in patients presenting with placenta previa associated with MTHFR deficiency.

Dietary folate, vitamin B 12 , and vitamin B 6 and the risk of Parkinson disease

Increased homocysteine levels might accelerate dopaminergic cell death in Parkinson disease (PD), through neurotoxic effects. Higher dietary intakes of folate, vitamin B12, and vitamin B6 (cofactors in homocysteine metabolism) might decrease the risk of PD through decreasing plasma homocysteine. Moreover, vitamin B6 might influence the risk of PD through antioxidant effects unrelated to homocysteine metabolism and through its role in dopamine synthesis. In the Rotterdam Study, a prospective, population-based cohort study of people aged 55 years and older, the authors evaluated the association between dietary intake of folate, vitamin B12, and vitamin B6 and the risk of incident PD among 5,289 participants who were free of dementia and parkinsonism and underwent complete dietary assessment at baseline. PD was assessed through repeated in-person examination and continuous monitoring by computer linkage to medical records. Data were analyzed using Cox proportional hazards regression analysis. After a mean follow-up of 9.7 years, the authors identified 72 participants with incident PD. Higher dietary intake of vitamin B6 was associated with a significantly decreased risk of PD (hazard ratio per SD, 0.69 [95% CI 0.50 to 0.96]; for highest vs lowest tertile, 0.46 [0.22 to 0.96]). Stratified analyses showed that this association was restricted to smokers. No association was observed for dietary folate and vitamin B(12). Dietary vitamin B6 may decrease the risk of Parkinson disease, probably through mechanisms unrelated to homocysteine metabolism.

Homocysteine Levels in Plasma and Sensorineural Hearing Loss in Patients with Pseudoexfoliation Syndrome

To determine the incidence and severity of hearing loss in different frequencies in patients with pseudoexfoliation. Furthermore, possible links between homocysteine and pseudoexfoliation were evaluated. Seventy-five consecutive patients with pseudoexfoliation and 75 sex- and age-matched subjects without pseudoexfoliation as control group were included in this prospective case-control study. Pure-tone audiometry was obtained in all subjects in both groups. Blood samples were obtained from 70 patients with pseudoexfoliation after overnight fasting for levels of homocysteine and analyzed by routine laboratory measurements. Fifty-two (69%) patients with pseudoexfoliation and 39 (52%) controls had sensorineural hearing loss in speech frequencies. The difference between pseudoexfoliation and control group with regard to the frequency of sensorineural hearing loss in speech frequencies was statistically significant (p=0.03). No relationship was found between the degree of glaucomatous damage and hearing threshold variables in the patients with pseudoexfoliation glaucoma. Plasma homocysteine levels showed no significant difference when patients with pseudoexfoliation and hearing loss were compared with patients with pseudoexfoliation and normal hearing threshold (p=0.5). Hyperhomocysteinemia was found in 58% (29/50) of pseudoexfoliation patients with hearing loss, and 55 % (11/20) of pseudoexfoliation patients with normal hearing threshold (p=0.8). No statistically significant correlation was found between plasma homocysteine and hearing loss in patients with pseudoexfoliation. These findings suggest an association between sensorineural hearing loss and pseudoexfoliation in patients with pseudoexfoliation and glaucoma. The severity of hearing loss was not correlated with the degree of glaucomatous damage. There is no association between increased homocysteine levels and hearing loss in patients with pseudoexfoliation.

The I Allele of the Angiotensin-Converting Enzyme Gene Polymorphism may Determine an Increase in Homocysteine Levels in Fibrate-Treated Subjects

The aim of the study was to investigate the influence of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on nonlipid effects of statins and fibrates in hypercholesterolemic subjects. C-reactive protein, homocysteine, adhesion molecules, CD40 ligand, interleukin-6 and monocyte chemoattractant protein-1 were measured prior to and following 30 days of simvastatin or fenofibrate therapy. Decreases in all the variables except for adhesion molecules and homocysteine were observed in both treatment groups, without genotype-related differences. Interestingly, fenofibrate treatment led to a significant increase in homocysteine levels (p = 0.03) only in carriers of the I allele. In conclusion, ACE genotype might help identify patients prone to this effect of fibrates.

Junge Patientin mit Pfortader- und Mesenterialvenenthrombose sowie Proteus-Syndrom

In the 26th year of life a young woman suffered a portal and mesenteric thrombosis followed by portal hypertension with splenomegaly, esophageal varices and pancytopenia. After splenorenal shunt surgery and splenectomy hematologic parameters resolved rapidly. Also, she was suffering of Proteus syndrome, which is an extremely rare and sporadic hamartomatous disorder characterized by a variety of cutaneous and subcutaneous tumors including vascular malformations, several types of nevi, partial gigantism of the hands and/or feet and cystic visceral affections. It has been demonstrated that concurrence of several prothrombotic risk factors occur relatively often in patients with portal vein thrombosis. An extensive investigation of thrombophilic factors revealed reproduced high anti-beta2-glycoprotein I antibody titers together with mildly increased homocysteine levels. Other coagulation parameters were normal or negative. The presence of myeloproliferative moglobinuria was ruled out. Together with the history of recurrent superficial thrombophlebitis and portal vein thrombosis in the absence of other underlying diseases allowed for diagnosis of primary antiphospholipid syndrome being aggravated by hyperhomocysteinemia and vascular malformations caused by Proteus syndrome. Because of combined risk factors for further thrombembolisms permanent oral anticoagulant therapy was initiated.

MTHFR 677 TT genotype in a mother and her child with Down syndrome, atrioventricular canal and exstrophy of the bladder: implications of a mutual genetic risk factor?

Apart from Husmann and Vandersteen [in: Gearhart JP, Matthews R (eds) The Epispadias-Exstrophy Complex. Kluwer, New York, pp 199-206, 1999], we report only the second case of Down syndrome (DS) associated with exstrophy of the bladder (EB). Besides the appearance of DS, the newborn exhibited a complete atrioventricular canal (CAVC) and classical EB, including diastases of the symphysis, an epispadic penis and an open bladder plate. Despite current recommendations, the mother had not supplemented her intake of folic acid during the periconceptional period. In a comparable case, Al-Gazali et al. (Am J Med Genet 103:128-132, 2001) found the homozygous 677T allele of the methylenetetrahydrofolate (MTHFR) gene 677C-->T polymorphism in a mother and her child with DS and cervical meningomyelocele. They found that the mother, who also had not supplemented her folic acid intake, had a secondarily altered folate status with an increased homocysteine level, suggesting that the homozygous TT mutation in the MTHFR gene in both mother and her child had contributed to the presentation of DS and a neural tube defect. The combined clinical findings of the present case and the observations of Al-Gazali et al. led us to investigate the 677C-->T polymorphism in our mother-child pair. Likewise we found that mother and child were homozygous for the mutant 677T allele. Our findings support the suggestion of Al-Gazali et al. that the MTHFR 677TT could be a mutual genetic risk factor for the co-occurrence of trisomy 21 and midline defects, the risk of which may be reduced by periconceptional folic acid supplementation.

Influence of Age and Coronary Artery Disease on Homocysteine Levels in the Young Old Compared With the Old Old and the Oldest Old

A total of 172 elderly individuals, divided into case and control groups based on the diagnosis of coronary artery disease, underwent coronary angiography to investigate the influence of age and coronary artery disease on homocysteine levels. The subjects were divided into three age ranges: 65-74 years, 75-79 years, and 80 years and older. Continuous homocysteinemia was associated with a risk ratio for coronary artery disease of 1.07 for each micromol/L increase in homocysteine level. Hyperhomocysteinemia (values above 14 micromol/L) constituted an independent risk factor for coronary artery disease, with a risk ratio of 2.03. There was a progression of homocysteine levels between the young old and the oldest old only among the case group elderly. There was no difference among the control group elderly. There were no significant differences in vitamin levels. The rise in homocysteine levels from the young old to the oldest old may be considered not a normal pattern, but rather a pattern associated with coronary artery disease.

Raised serum homocysteine levels in patients of coronary artery disease and the effect of vitamin B12 and folate on its concentration

Homocysteine(Hcy) has been implicated as a novel risk factor of Coronary Artery Disease (CAD) among Asian Indians, but many studies done in India failed to reveal any direct correlation. It has also been reported that Folic acid and Vitamin B12 levels inversely affect serum levels of homocysteine. In this study, we looked at the levels of homocysteine among patients with CAD. The effect of Vitamin B12, Folate and other risk factors on homocysteine levels were also evaluated. Mean homocysteine levels in cases (22.81±13.9, n=70) were significantly higher (p=<0.001) than the controls (7.77±7.3, n=70). However no statistically significant correlation could be deduced between homocysteine Vitamin B12, and Folate. Cumulative analysis have indicated an increase in homocysteine levels among patients with CAD with every additional risk factor.

Influence of methionine synthase (A2756G) and methionine synthase reductase (A66G) polymorphisms on plasma homocysteine levels and relation to risk of coronary artery disease

Background — Elevated plasma total homocysteine (tHcy) is increasingly being recognized as a risk factor for coronary artery disease (CAD) and other defects. Recent genetic studies have characterized molecular determinants contributing to altered homocysteine metabolism. Our objectives were therefore to confirm the relationship of tHcy with CAD and to examine the importance of genetic influence on tHcy in the coronary angiograms and conventional cardiovascular risk factors recorded in 230 subjects.We also determined the genotype frequencies distribution of the A2756G transition of the B12-dependent methionine synthase (MTR) gene and the A66G mutation of the methionine synthase reductase (MTRR) gene.Results — Patients with CAD (n = 151) had significantly higher tHcy concentrations than control subjects (15.49 ± 2.75 μmol/l vs. 11.21 ± 3.54 μmol/l, P < 0.001). Hyperhomocysteinaemia (tHcy ≥15 μmol/l) was a risk factor for CAD [RR = 4.07, 95% CI: 2.21 – 7.47, P < 0.001]. The homocysteine concentrations were significantly different between smokers and non-smokers, at 15.63 ± 3.10 vs. 12.45 ± 3.84 μmol/l, P < 0.05. In addition, smokers with hyperhomocysteinaemia demonstrated a markedly increased risk of CAD (OR = 2.50, 95% CI: 1.67 – 3.32, P < 0.05) compared with non-smokers with normal homocysteine.The 2756G and the 66G allele contribute to a moderate increase in homocysteine levels (P = 0.008 and P = 0.007, respectively), but not to CAD (P > 0.05). Combined MTR and MTRR polymorphisms, the 2756AG + 66AG and the 2756AG + 66GG were the combined genotypes that were a significant risk factor for having hyperhomocysteinaemia (14.4 ± 2.8 μmol/l, OR = 2.75, IC 95% = 1.21 – 6.24, P = 0.016 and 17.9 ± 4.1 μmol/l, OR = 6.28, IC 95% = 1.46 – 12.1, P = 0.021, respectively). Statistic analysis using the UniANOVA test shows that these two polymorphisms have an interactive effect circulating homocysteine levels (P < 0.05).Conclusion — Our data suggest that moderately elevated tHcy levels are prevalent in our population and are associated with an increased risk for CAD. This study provides evidence that the MTR A2756G and MTRR A66G polymorphisms significantly influence the circulating homocysteine concentration. In addition, the MTR and MTRR genes may interact to increase the risk for having hyperhomocysteinaemia.

Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, Vitamin B12, folic acid and Vitamin B6

There is emerging evidence to support the unfavorable effects of some anti-epileptic drugs on the plasma homocysteine concentrations. Elevated homocysteine levels induced by anti-epileptic drug administration can theoretically increase not only the risk of vascular occlusive diseases, but also the risk of resistance to anti-epileptics and development of refractory epilepsy. To investigate the effect of common anti-epileptic drugs on the homocysteine metabolism, a total of 75 epileptic patients receiving phenytoin (n=16), carbamazepine (n=19), or valproic acid (n=22) and no anti-epileptic drug (n=18) were enrolled. Eleven age- and sex-matched healthy subjects served as the control group. Blood concentrations of homocysteine, folic acid, Vitamin B12 and pyridoxal 5'-phosphate (active circulating form of Vitamin B6) were measured. Compared to the control group, epileptic patients on anti-epileptic drug had higher blood levels of homocysteine. No difference in homocysteine concentrations was observed among epileptic patients in terms of the anti-epileptic drug used. Patients receiving phenytoin had significantly lower folic acid levels and those receiving carbamazepine had marginally lower pyridoxal 5'-phosphate levels in comparison with those using other anti-epileptic drugs. A negative correlation between homocysteine and folic acid concentrations was detected in epileptic patients on anti-epileptic drug. The duration of anti-epileptic drug use was correlated to the decrease of folic acid levels, but not with changes observed in homocysteine, Vitamin B12 and pyridoxal 5'-phosphate levels. No relationship between seizure frequency and homocysteine levels was observed in epileptic patients. Our results confirm that common anti-epileptic drugs has disadvantageous effects on homocysteine status. Because there was no significant change in homocysteine concentrations in epileptic patients who were not receiving an anti-epileptic drug, and no positive correlation between seizure frequency and homocysteine levels, we suggest that increase of homocysteine levels may be due to anti-epileptic drug use, rather than being epileptic in origin. Additionally, the underlying mechanism for homocysteine increase seems to be a decrease of cofactor molecules in patients using carbamazepine and phenytoin (pyridoxal 5'-phosphate and folic acid, respectively). However, changes observed are not related to the alteration in the levels of cofactors and remain unclear in the patients using valproic acid.

Aminothiols in human brain tumors

Aminothiols are sulfur-containing amino acids involved in methionine metabolism. Changes in their levels play negative roles in the genesis of many diseases. These mechanisms involve direct toxicity, either on glutamate neurotransmitter receptors or cerebrovascular endothelium, and have an indirect inhibitory effect on transmethylation reactions. Oxidative stress and excitotoxicity are factors that may rise as a consequence of increased homocysteine levels in brain tissues. We discovered new information concerning concentrations of the main aminothiols in human neoplastic brain tissues. The cytosolic fractions of 73 tissue samples from human brain tumors were used for the determination of total homocysteine, total cysteine and methionine levels. Gas chromatography with flame ionization detection after reduction of disulfide bonds was the method used. Average concentrations of the aminothiols examined were as follows: total homocysteine, 0.58-1.51 nmol/mg; methionine, 1.16-2.07 nmol/mg; and total cysteine 5.08-7.82 nmol/mg of total protein. Significantly higher levels of total homocysteine were found in pituitary adenoma and glioblastoma multiforme compared with other types of tumors. Methionine and cysteine concentrations did not differ significantly according to diagnosis. This is the first work concerning the concentrations of aminothiols in brain tissues. The results obtained indicate the metabolic pathways that are involved in tumor formation and/or its progress, including the toxic effects of homocysteine.

The Antiphospholipid Syndrome: The Mount Sinai Hematology Perspective.

Objective: To evaluate the clinical manifestations, type and persistence of antiphospholipid (aPL) antibodies, and outcomes of patients evaluated in a hematology practice clinic for the diagnosis of antiphospholipid syndrome (APLS).Methods: We systematically reviewed the medical records of all patients referred to our Hemostasis and Thrombosis Practice Clinic for evaluation of APLS from January 1995 to July 2005. APLS was defined by the Sapporo criteria.180 patients were identified who either had APLS as defined by the Sapporo criteria or had documented aPL antibodies on 2 separate occasions at least 6 weeks apart without any clinical manifestation for APLS. Data collected included demographics, clinical manifestations, type of aPL antibodies, presence or absence of lupus anticoagulant (LAC), persistence or fluctuation of the aPL antibodies, presence of other thrombophilias, antithrombotic therapy, and outcomes.Results: Of the 180 patients, 141 were females and 39 were males. The age range was 21 to 89 yr. 119 patients (66%) fulfilled the clinical criteria for APLS and 61(34%) did not. Among the 119 patients with APLS, the clinical manifestations included arterial thromboembolism (ATE) in 53 (46 idiopathic, 7 secondary), venous thromboembolism (VTE) in 44 (31 idiopathic, 13 secondary), both ATE and VTE in 7 and pregnancy losses (PL) in 30. Among the 30 patients with PL, 19 had recurrent PL before the 10th week of gestation and 11 had PL after the 10th week of gestation. 5 patients with PL also had ATE and/or VTE.94 patients had anticardiolipin (aCL) antibody (medium titer IgG isotype), 57 had aCL antibody (high titer IgG), 29 had antiphosphatidylserine (aPS) antibody (medium titer IgG), 27 had aPS antibody (high titer IgG), 11 had anti-β2 glycoprotein I (anti-β2GPI) antibody (medium titer), 13 had anti-β2GPI antibody (high titer), 47 had aCL antibody (medium titer IgM), 15 had aCL antibody (high titer IgM), 74 had aPS antibody (medium titer IgM), 43 had aPS antibody (high titer IgM), 20 had anti-β2GPI medium titer IgM, 12 had anti-β2GPI high titer IgM, 10 had anti-β2GPI medium titer IgA isotype, 6 had anti-β2GPI high titer IgA isotype and 36 had LAC. 115 patients had persistent aPLA and 65 had fluctuating aPLA.33 patients had other thrombophilias: factor V Leiden (n=5), prothrombin gene mutation (G20210A) (n=6), protein S deficiency (n=4), increased homocysteine level (>12 mcmol/L) (n=9), hyperfibrinogenemia (n=3), elevated factor VIII (n=4) and factor XI (n=1) and plasminogen deficiency (n=1).Antithrombotic therapy included warfarin in 71 patients, aspirin in 85, clopidogrel in 3, and LMWH in 36 (2 on chronic therapy and 34 during pregnancy). 21 patients were on no antithrombotic medications.Of the 180 patients, 110 patients had succesful outcomes defined as either absence of recurrent thrombosis or pregnancy losses. 7 patients had recurrent PL while 10 had recurrent thrombosis. 1 patient died. 52 patients were lost to follow-up.Conclusions: The majority of our patients with APLS were women. The most common clinical manifestations were ATE, followed by VTE and PL. The most prevalent aPL antibody was aCL medium titer IgG isotype and the least common was anti-β2GPI high titer IgA. Antithrombotic therapy resulted in successful outcomes in approximately 2/3 of patients.

Inherited and Acquired Thrombophilia in Children and Young Adults with Bcr-Abl Negative Chronic Myeloproliferative Disorders.

Several associated thrombophilic abnormalities have been reported in adults with Bcr-Abl negative chronic myeloproliferative disorders (MPD), mostly essential thrombocythemia (ET) and polycythemia vera (PV), but sporadic data are available in younger patients (pts). In order to define coagulation abnormalities in very young pts, we evaluated thrombophilic parameters in MPD pts aged <20 years (yrs) at diagnosis. Prothrombin time (PT), activated partial thromboplastin time (aPTT), lupus anticoagulant (KCT and dRVVT), functional protein C (PC), free protein S (PS) antigen, functional antithrombin (AT), homocysteine (HCY), factor V Leiden (FVL) mutation, factor II (FII) G20210A mutation and methylentethrahydrofolate reductase (MTHFR) C677T polymorphism were investigated. Thirty-two MPD pts (16 males and 16 females) with a median age of 166/12 yrs (range: 3mo-1911/12 yrs) diagnosed at the study Institution between March 1980 and February 2005 were tested after informed consent of pts or parents. Twenty-five had a diagnosis of ET (7 familial forms) and 5 had PV, according to the criteria of the PV Study Group; in 2, a diagnosis of MPD with thrombocytosis and erythrocytosis was made. Cytogenetic and molecular studies were normal in all cases. At diagnosis, median platelet count for ET and MPD pts was 1,184 x 109/L (range 611–2,640); median hematocrit level for PV and MPD pts was 54% (range 52–72%). Among the ET cohort, 6 asymptomatic pts received no treatment, 4 were treated with aspirin alone and 15 received cytoreductive therapy. PV and MPD pts were phlebotomized to maintain a hematocrit level <50%. Median interval between diagnosis and the time of the study was 8.8 yrs (range: 1 mo – 24 yrs ). No thrombotic events occurred. Four female ET became pregnant and had 4 children, 1 of them being affected by familial thrombocythemia. At the time of the coagulation study, median platelet count for ET and MPD pts was 695 x 109/L (range 325–1,120); the median hematocrit level for those with PV and MPD was 53% (range 52–60.5%). Increased PT and aPTT ratios (n.v. <1.14 and <1.16) were observed in 8/32 (20%) and 16/32 (50%) pts, combined in 7. KCT ratio (n.v. <1.31) was increased in 4/31 (13%) pts, while the dRVVT ratio was normal in 31/31 tested pts. Functional PC and free PS levels were decreased in 3/30 (10%) and 3/31 (10%) tested pts, respectively. AT levels were normal in all pts (32/32). An increased HCY level was found in 1 PV pt. Of the 27 pts investigated for FVL, FII G20210A mutations and MTHFR C677T polymorphism, 1 ET pt was heterozygous for both the FVL and FII G20210A mutations, 1 ET pt was heterozygous for both MTHFR C677T polymorphism and FII G20210A mutation. One ET pt showed an isolated FII G20210A mutation. Screening for the C677T polymorphism in the MTHFR gene revealed that 18 pts (66.5%) were heterozygous, 15 of them affected by ET (7 with the familial form). In our MPD population of children and young adults, the frequencies of heterozygosis of FII G20210A mutation (3/27 pts = 11%) and MTHFR C677T polymorphism (66.5%) were higher than those reported in the normal population (about 2.5% and 45%, respectively). Larger multicenter studies are required to further extend these observations.

Cardiovascular Disease in Children with Chronic Kidney Disease

In children with end-stage renal disease (ESRD), cardiovascular disease (CVD) mortality has not changed for the past 3 decades. Cardiac disease remains the second most common cause of death. Recent data demonstrate a high incidence and prevalence of traditional and chronic kidney disease (CKD)-related CVD risk factors in children. Early markers of cardiomyopathy, such as left ventricular hypertrophy (LVH) and left ventricular dysfunction (LV dysfunction), and early markers of atherosclerosis, such as increased carotid artery intima-media thickness (IMT) and carotid arterial wall stiffness, are frequently found in this patient population. Early identification of modifiable risk factors and treatment of asymptomatic CVD might lead to decrease of cardiovascular morbidity and mortality in young adults who developed CKD during childhood.

Hiper-homocisteinemia como fator de risco para doença aterosclerótica coronariana em idosos

To investigate whether hyperhomocysteinemia is an independent risk factor for atherosclerotic disease in elderly individuals. A case-control study with 172 elderly individuals, 88 belonging to control group and 84 to case group, who showed coronary angiography requested for clinical indications. Quantitative coronary angiography was performed in 91% of the patients. Homocysteinemia was assessed in a continuous and categorized way, through univariate and multivariate analysis. When analyzed continuously, in univariate analysis, it was verified that case group elderly individuals showed an average homocysteinemia levels significantly higher than the control group individuals' (14.33 +/- 4.59 micromol/l against 11.99 +/- 4.59 micromol/l, p = 0.015). In multivariate analysis, continuous homocysteinemia was associated to the risk rate for coronary artery disease of 1.07 for each 1 micromol/l increase of homocysteine level. Na increase of 5 micromol/l corresponded to the risk rate of 1.40. When analyzed in categorized way, the values found over percentile 75 of control group (14 micromol/l) were defined as hyperhomocysteinemia. Hyperhomocysteinemia was found in 34% of elderly individuals, being 37.3% in control group and 62.7% in case group (p = 0.009). In multivariate analysis, hyperhomocysteinemia constituted an independent risk factor for coronary atherosclerotic disease for elderly individuals, with a risk rate for coronary artery disease of 2.03, confidence interval 95%, 1.02-4.03. Hyperhomocysteinemia was an independent risk factor for coronary artery disease in elderly individuals.

Hyperhomocysteinemia in patients with mild chronic renal failure

Background The aim of this study was to evaluate the prevalence of high plasma levels of homocysteine in patients with mild renal failure. Methods Forty-six chronic renal failure patients (25 males and 21 females, mean age 55.6 ± 14.4 years) were recruited for the study. Mean plasma creatinine was 2.1 ± 1.0 mg/dl and mean creatinine clearance was 50.6 ± 26.3 ml/min. Patients with severe renal failure were excluded. Patients were compared with a control group with normal renal function ( n = 35, 22 men and 13 women, mean age 50.0 ± 11.5 years). Plasma homocysteine values were measured in both groups at baseline and after an oral overload of methionine. Results Baseline homocysteine levels of patients were higher than those of controls (16.5 ± 7.3 vs. 10.4 ± 4.2 μmol/l, p < 0.0001). Some 34 patients and 4 controls had increased plasma homocysteine levels at baseline. After the oral overload, 4 more patients had abnormally increased homocysteine levels, meaning that 83% of the patients with chronic renal failure had hyperhomocysteinemia. Conclusions Hyperhomocysteinemia is a very common finding among patients with mild renal failure. The need for vitamin supplementation should be evaluated in the first stage of chronic renal failure.

Therapy Insight: systemic lupus erythematosus as a risk factor for cardiovascular disease

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a strong female predilection. Cardiovascular morbidity and mortality is a frequent complication, particularly in females aged 35-44 years, in whom the risk of myocardial infarction is raised 50-fold. The mechanisms underlying this increased risk are not fully understood. Certain traditional risk factors, such as hypertension and diabetes mellitus, are more common in SLE patients than in the general population. These factors do not, however, completely account for the increased cardiovascular risk; factors such as renal impairment, increased homocysteine levels and early menopause probably have a role. In addition, several factors more specifically related to lupus are proposed to be of importance, including chronic inflammation, antiphospholipid antibodies and therapy, especially corticosteroid use. Thus, we need to be proactive in our approach to risk-factor management in SLE patients. Here, we propose that, like diabetes mellitus, SLE should be considered a coronary heart disease equivalent condition for baseline risk and that assessment of cardiovascular risk should be done routinely. In addition to lifestyle modifications, blood pressure and cholesterol levels should be stringently controlled, and administration of aspirin should be considered in selected patients. The increased use of certain interventions, such as statins, also needs to be more widely investigated in this population.

Rapid thrombophilia genetic test facilitates improved prenatal care for mother and child

AbstractPhysiological changes in coagulation factors during pregnancy are important to minimise blood loss during gestation and delivery, but may also lead to a 4–6 fold increased risk of venous thromboembolism during pregnancy and after delivery. Approximately 25% of maternal mortality can be ascribed to thromboembolism if untreated, while this figure is reduced to less than 1% when diagnosed on time. Clinical diagnosis is complicated by the fact that the symptoms associated with venous thrombosis are relatively common complaints of pregnant women. A rapid genetic test has been developed for simultaneous detection of the most common genetic risk factors associated with thrombophilia, the factor V 1691GA (Leiden) and prothrombin 20210GA mutations. Mutation 677CT in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, which increases homocysteine levels by 15–25% when two copies of the T-allele is present, is also included as part of this “prenatal care genetic test”. Hyperhomocysteinaemia has been a...

Do Maternal Folate and Homocysteine Levels Play a Role in Neurodevelopmental Processes That Increase Risk for Schizophrenia?

Evidence from many different lines of research supports the hypothesis that schizophrenia is a disorder of development with etiological factors implicated as early as the second trimester in utero. We suggest that low maternal folate, acting to increase homocysteine levels, may provide a functional link between many of the identified prenatal risk factors and the hypothesized mechanisms whereby neurodevelopmental patterning deviates toward a schizophrenic potential. PubMed was searched from the present back to 1963, when elevated homocysteine was identified as a pathogen in homocystinuria as first described by Carson and colleagues (Arch Dis Child 1963;38:425-36). All articles for homocystinuria, homocysteine, folate, and development with schizophrenia were evaluated. The findings from this review support the hypothesis that maternal low folate and high homocysteine levels may provide a potential teratogenic mechanism that increases the risk for developing schizophrenia. The potential role of maternal folate deficiency and hyperhomocystinemia in the genesis of schizophrenia would extend the range of their known teratogenic effects. Given the potential for preventive treatment offered by this hypothesis, we believe further investigation into this mechanism is warranted.