Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine

OBJECTIVE: To evaluate plasma homocysteine (Hcy) concentrations in children receiving sodium valproate (VPA) and carbamazepine (CBZ), monotherapy, in comparison with healthy control subjects and to determine the possible relationship between Hcy levels and dosage and plasma concentrations of the antiepileptic drugs. METHODS: We measured levels of fasting and post-methionine Hcy, plasma pyridoxal 5'-phosphate (PLP, active vitamin B6), serum folate, erythrocyte folate and serum vitamin B12 in 60 epileptic patients (29 females, 31 males), aged from 14.2 to 17.9 years, subdivided into two groups according to their therapy. Sixty-three healthy sex- and age-matched children served as controls. These measurements have been performed before the beginning of therapy and after 1 year of therapy with VPA or CBZ. RESULTS: Before the beginning of therapy, there were no significant differences in fasting and post-methionine Hcy, plasma PLP, serum folate, erythrocyte folate and serum vitamin B12 values between the control group and the two groups of epileptic children. After 1 year of therapy, patients treated with VPA and CBZ showed a significant increase of the plasma concentrations of Hcy when compared to baseline data and controls values. Moreover, was observed a significant decrease of serum folate and plasma PLP. On the contrary, serum vitamin B12 and erythrocyte folate levels remained in the normal range. CONCLUSIONS: Our study demonstrates that prolonged treatment with VPA and CBZ increases plasma concentrations of Hcy.     

Plasma homocysteine levels in multiple sclerosis

BACKGROUND: There is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been observed in patients with multiple sclerosis (MS). OBJECTIVE: To investigate if and why plasma homocysteine levels are increased in MS, and whether they play a role in the disease course. METHODS: We compared plasma levels of homocysteine in 88 patients with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary progressive. To explore the underlying mechanisms, we measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12, tumour necrosis factor (TNF)-alpha, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative stress). RESULTS: Mean (SD) plasma homocysteine concentration was higher in patients (13.8 (4.9) micromol/l) than in controls (10.1 (2.5) micromol/l; p<0.0001). However, there were no significant differences in homocysteine levels between the three clinical subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls. In the MS group, there were no correlations between plasma homocysteine levels and the serum concentrations of IL-12 or TNF-alpha, leukocyte nitric oxide production, or plasma diene conjugate levels. CONCLUSIONS: Elevated plasma homocysteine occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a deficiency in vitamin B6, vitamin B12, or folate.     

轻度认知障碍患者血浆同型半胱氨酸和血清维生素B12及叶酸水平变化研究

目的 探讨轻度认知障碍(MCI)患者血浆同型半胱氨酸(Hcy)、血清维生素B12及叶酸水平的变化及相互关系.方法 MCI组80例,正常对照组80例,检测所有观察对象的血浆同型半胱氨酸、血清VitB12及叶酸水平并分析相互关系.结果 MCI组血浆Hey水平较正常组显著增高为(18.9±8.8)μmol/L vs(14.35±5.7)μmol/L,而血清叶酸和VitB12水平在正常组和MCI组之间并没有显著差异;相对于血浆Hey正常组,MCI比值比(0R)在轻、中度高同型半胱氨酸血症组中增高(OR=1.85,95%CI=1.56～2.95;OR=3.32,95%CI=1.61～6.48;P=0.001);无论在MCI组还是在正常组中,血浆Hey与血清叶酸及Vit B12的水平均呈负相关.结论 血浆Hey水平升高与MCI相关,叶酸和VitB122缺乏可能导致血浆Hcy水平升高.     

Plasma homocysteine, vitamin B12 and folate in Alzheimer's patients and healthy Arabs in Israel

High plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and stroke and Alzheimer's disease (AD). An inverse relationship has been reported between tHcy and plasma B12 and folate levels. Seventy-nine AD patients and 156 controls from three Arab villages in northern Israel participated. Plasma tHcy, B12 and folate levels were determined. Data were analyzed using univariate statistical tests and logistical regression with confounders. tHcy was significantly higher in AD patients (20.6+/-8.7 micromol/l) than in controls (16.4+/-6.5 micromol/l) (p=0.03) after correction for year of birth, gender and smoking status. Plasma B12 (322.9+/-136.0/350.5+/-175.3 pmol/l) and plasma folate (4.5+/-3.8/4.9+/-2.6 nmol/l) levels did not differ significantly between AD patients and controls. Subjects in the highest tHcy tertile or in the lowest B12 and folate tertiles did not have greater risk to develop AD. In this population residing in Arab villages in northern Israel, tHcy levels were significantly higher among AD patients than in controls. Plasma B12 and folate levels were lower among cases but were not significant. There was not a significant association between plasma tHcy, B12 and folate levels in controls or AD patients. High levels of tHcy may suggest the need for folate and vitamin B12 supplementation in this population.     

Plasma homocysteine, folate and B12 in chronic schizophrenia

Elevated plasma levels of the amino acid homocysteine have been associated with schizophrenia, particularly in young male patients. Among other factors, low folate and vitamin B12 levels have been implicated in the increase in homocysteine. In order to investigate this association, we determined plasma homocysteine, folate and B12 levels in 97 (67 males and 30 females) inpatients with chronic schizophrenia and 103 (46 males and 57 females) controls. Patients and controls did not differ in folate or B12 levels, after adjusting for age. Patients with schizophrenia had higher plasma homocysteine than controls (mean=15.42 micromol/l in cases versus 11.54 micromol/l in controls: F(1,195)=17.978; p<0.001). This difference persisted after controlling for folate and B12 concentrations. Both male and female patients had increased plasma homocysteine compared to controls [(males: mean=16.61 micromol/l in cases versus mean=13.72 in controls: F(1,110)=5.54; p=0.020) (females: mean=12.78 micromol/l in cases versus mean=9.79 micromol/l in controls: F(1,84)=13.54; p<0.001)]. When dividing our sample into two age groups (age < and > or =50 years), both young and older females and younger males with schizophrenia had increased plasma homocysteine compared to controls. We therefore suggest that homocysteinemia is a general risk factor for schizophrenia. We further suggest that it is not limited to young male patients and is not necessarily associated with low folate or B12 levels.     

The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events

Total fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 +/- 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 +/- 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 microM in men and >15 microM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous thrombosis: 3.25, 1.78-5.91). The 677TT MTHFR genotype was not significantly more prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42: 0.84-2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for case/control status: 8.29, 4.61-14.9). The 2756GG MS genotype, observed in 4 patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was negatively correlated to folate and vitamin B12 levels, with better correlation found in subjects with the 677TT mutation (r = -0.42 and -0.25) than with the 677CC or CT MTHFR genotype (r = 0).37 and -0.11). However, folate was similar in patients and controls and vitamin B12 was higher in patients (460 +/- 206 vs. 408 +/-185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p < or =0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p < or =0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B,2 levels (p = 0.023). Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12 requirements irrespective of the A2756G polymorphism of the MS gene. Yet unidentified abnormalities of MS or of any of the enzymes participating in the synthesis of methylated vitamin B12 may play an important role in the phenotypic expression of moderate hyperhomocysteinemia.     

Effects of vitamin B12, folate,and entacapone on homocysteine levels in levodopa-treated Parkinson’s disease patients: A randomized controlled study

IntroductionPrevious studies have suggested a significant increase in plasma homocysteine (Hcy) levels in levodopa-treated Parkinson’s disease (PD) patients, and vitamin B12 and folate supplementation may decrease Hcy levels. However, the effects of catechol-O-methyltransferase inhibitors on levodopa-induced increase in Hcy levels were conflicting. The aim of this study was to evaluate whether Hcy levels are increased in levodopa-treated PD patients and to evaluate the effects of vitamin B12 and folate or entacapone on Hcy levels in levodopa-treated PD patients.MethodsWe analyzed and compared plasma Hcy levels in 20 levodopa-naïve PD patients and 42 levodopa-treated PD patients, followed by randomized assignment of 42 levodopa-treated patients to treatment groups with either vitamin B12 and folate, entacapone, or no medication.ResultsPlasma Hcy levels in levodopa-treated PD patients were higher than those in the control group, but the difference was not statistical significant (15.25 ± 6.70 and 13.13 ± 4.68, P = 0.216). Patients treated with vitamin B12 and folate had a significant decrease in plasma Hcy levels (P < 0.001). In the entacapone group, Hcy levels were mildly decreased, but the change did not reach statistical significance.ConclusionLevodopa-treated PD patients had higher plasma Hcy than levodopa-naive PD patients. Unlike entacapone, combination supplementation with vitamin B12 and folate was associated with significantly decreased plasma Hcy. We suggest that plasma Hcy levels should be monitored during levodopa treatment, and supplementation with inexpensive vitamin B12 and folate is beneficial for levodopa-treated patients.     

Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy

We hypothesized that elevated plasma homocysteine concentrations (hyperhomocysteinemia) exist in patients receiving antiepileptic drugs (AED), and a long-term administration of AED may result in an increased risk of occlusive vascular disease in these patients. A total of 62 patients who received AED monotherapy (phenytoin, lamotrigine, carbamazepine or valproate) participated in this study. Blood concentrations of homocysteine, folate, vitamin B-12 and pyridoxal-5'-phosphate (PLP, a coenzyme form of vitamin B-6) were measured, and thermolabile genotypes of 5, 10-methylenetetrahydrofolate reductase (MTHFR) were also determined. Of 62 patients, only seven (11.4%) had hyperhomocysteinemia. Of 20 patients who received phenytoin, three (15.0%) had hyperhomocysteinemia, whereas 85% of these had plasma folate concentrations below the normal range. However, erythrocyte folate concentrations were abnormally low in only 25% of the patients who received phenytoin. Valproate administration increased serum vitamin B-12 concentrations. Over 55% of the entire patients had PLP concentrations below the normal range, although the reason is unknown. Only three patients had the homozygous thermolabile genotype of MTHFR; therefore, meaningful statistical analysis was not possible in this study. However, one patient with homozygous genotype who received phenytoin therapy had hyperhomocysteinemia with poor folate nutritional status, and the other two had normal homocysteine concentrations with normal folate status. Our data suggest that hyperhomocysteinemia is not a serious clinical concern in epileptic patients when folate nutriture is adequate.     

同型半胱氨酸与兔脑动脉损伤的关系及维生素B6、B12、叶酸对其预防作用的探讨

目的探讨高蛋氨酸(Met)喂饲兔引发高同型半胱氨酸(Hcy)血症与脑动脉损伤的关系,同时观察补充VitB6、VitB12、叶酸对血Hcy水平和动脉损伤的影响.方法采用纯种雄性新西兰兔26只,分为三组对照组、高蛋氨酸组、干预组,分别喂以普通兔饲料每只200g/d、普通饲料添加0.5%Met、普通饲料每天每只兔添加0.5%Met、叶酸2.5mg、VitB6 10mg、VitB12 200mg,喂养6个月,测定血浆总Hcy(tHcy),光镜检测脑动脉组织学改变.结果实验前血浆tHcy浓度三组间无明显差异,实验后断食2 h和7 h血tHcy浓度高Met组明显高于对照组(P＜0.01),而干预组血tHcy浓度明显低于高Met组(P＜0.01),但仍高于对照组.光镜组织学检测发现高Met组和干预组脑动脉可见内皮细胞坏死、脱落、溃疡形成,附壁血栓,中膜平滑肌散乱疏松.结论高Met引发高Hcy血症对脑动脉有损伤,且VitB6、VitB12、叶酸的补充可以降低高Met引发的高Hcy浓度的水平.