Serum vitamins and homocysteine levels in autoimmune liver disease: A systematic review and meta-analysis.

OBJECTIVE: Vitamins and homocysteine (Hcy) are involved in liver metabolism and related to the pathogenesis of autoimmune liver disease (AILD), but consensus is lacking. This study aims to systematically summarize relevant evidence to clarify the association of serum vitamins and Hcy levels with AILD. METHODS: The English and Chinese literature was searched until August 29, 2023. Studies were included if they were observational studies of investigating serum vitamins and Hcy levels in patients with AILD and their healthy comparisons. Quality assessment was performed by using the Newcastle-Ottawa Scale, and a meta-analysis was conducted using ReviewManager 5.3. The protocol was registered in the international prospective register of systematic reviews (PROSPERO), with registration number CRD42023455367. RESULTS: A total of 25 case-control studies comprising 3487 patients (1673 patients and 1814 healthy controls) were included for analysis. There were 548 autoimmune hepatitis (AIH) cases, 1106 primary biliary cholangitis (PBC) cases, and 19 primary sclerosing cholangitis (PSC) cases. We found that serum A and E were decreased in both AIH and PBC/PSC; but vitamin C was reduced only in patients with PBC, not AIH. In addition, decreased content of 25(OH)D3 was found in both AIH and PBC. However, levels of 25(OH)D did not differ between the patients and controls, and were independent of disease types and the country. Only one study that met the inclusion criteria reported vitamin B6, B9, B12, and Hcy changes, and found that vitamin B6 and B9 were significantly decreased in patients with PBC, while serum vitamin B12 and Hcy levels were significantly elevated in them. One eligible study each confirmed a reduction in plasma vitamin K1 and 1,25(OH)2D3 in patients with PBC. CONCLUSION: Most vitamins are deficient in AILD, so appropriate vitamin supplementation should be necessary. Further studies with larger sample sizes are needed to validate these findings.

Folic acid supplementation on inflammation and homocysteine in type 2 diabetes mellitus: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The beneficial effects of folate have been observed under different conditions, but the available evidence on inflammation and reduction of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) is limited. The study aimed to explore the effects of folate on inflammation and homocysteine amongst individuals with T2DM. METHODS: PubMed, Scopus, and Cochrane Library were used to search for evidence. A random-effect model meta-analysis through Review Manager (version 5.4) and metaHun was performed. Results were reported as standardized mean differences (SMD) and 95% confidence intervals graphically using forest and funnel plots. RESULTS: Data from 9 trials with 426 patients living with T2DM were analyzed. Folic acid supplementation significantly revealed a large effect size on homocysteine levels compared to placebo, SMD = -1.53, 95%CI (-2.14,-0.93), p < 0.05. Additionally, we observed a medium marginal effect size on C-reactive protein (SMD = -0.68, 95%CI (-1.34, -0.01), p = 0.05). However, no significant effect on tumor necrosis factor-α (SMD = -0.86, 95%CI (-2.65, 0.93), p = 0.34), and interleukin-6 (SMD = -0.04, 95%CI (-1.08, 1.01), p = 0.95) was observed. CONCLUSION: Evidence analyzed in this study suggests that folic acid supplementation in T2DM reduces homocysteine and may mitigate CVDs. However, its effect on inflammation is inconclusive.

Homocysteine serum levels correlate with the number of failed IVF cycles even when within normal range.

INTRODUCTION: Repeated implantation failure is a common challenge in daily practice. Homocysteine and vitamin B12 have been associated with reproductive processes among patients undergoing in vitro fertilization; however, their involvement in repeated implantation failure has not been assessed. We explored possible associations of serum homocysteine and vitamin B12 with repeated implantation failure. MATERIAL AND METHODS: A retrospective analysis of 127 women who underwent ≥ 3 unsuccessful embryo transfers during 2005-2016, at the Fertility and In Vitro Fertilization Unit at Carmel Medical Center. After at least 3 IVF failures serum levels of homocysteine and vitamin B12 were measured. RESULTS: The mean patient age was 33.5 ± 5.2 years. The mean number of embryo transfers was 4.6 ± 1.5. The mean total cumulative number of embryos transferred was 10.4 ± 5.2. Mean serum levels of homocysteine were 8.6 ± 3.7 µM/L, and of vitamin B12 were 302.5 ± 155.3 pg/ml. Homocysteine levels were within the normal range (< 14 µM/L) in 95.8% of the patients. Yet, the levels of homocysteine correlated with both the number of failed embryo transfers (r = 0.34, p = 0.004) and the total cumulative number of transferred embryos (r = 0.36, p = 0.002). CONCLUSIONS: Our findings suggest an association between serum homocysteine levels and the occurrence of repeated implantation failure, even when homocystein levels were within the normal range. It should be studied whether nutritional supplementation to modulate serum homocysteine levels may improve treatment outcome.

The Effect of Three-Month Vitamin D Supplementation on the Levels of Homocysteine Metabolism Markers and Inflammatory Cytokines in Sera of Psoriatic Patients.

Psoriasis is an autoimmune and inflammatory skin disease. Psoriatic patients express higher levels of plasma homocysteine (Hcy) concentration and pro-inflammatory mediators than healthy people; this is frequently associated with vitamin D deficiency. The aim of this clinical study was to investigate the effects of high doses of vitamin D supplementation on the parameters of Hcy metabolism and cytokines in sera of psoriatic patients. This prospective study was conducted on 40 psoriatic patients who had the vitamin D deficiency. All patients received vitamin D 5000 IU/day for three months. Clinical and biochemical measurements were taken at baseline and at follow up (3 months). The results showed that the severity of clinical features, measured by the psoriasis area severity index (PASI) score, were considerably improved in patients after vitamin D supplementation. After vitamin D supplementation, most of the patients (n = 25 or 62.5%) had mild clinical form (p < 0.001). After twelve weeks of intervention period, there were significant increases in vitamin D and B12 serum levels in comparison to the levels that had been measured at the beginning of the study (56.77 ± 14.66 nmol/L and 301.08 ± 95.02 pg/mL vs. 103.85 ± 32.20 nmol/L and 362.81 ± 118.56 pg/mL, respectively; p < 0.001). Moreover, serum levels of Hcy and folate were significantly lower at the end of the study in comparison with the initial levels (12.45 ± 1.92 µmol/L and 8.01 ± 3.88 mg/mL vs. 10.38 ± 1.66 µmol/L and 6.27 ± 2.60 mg/mL, respectively). High doses of vitamin D supplementation led to a significant decrease in pro-inflammatory cytokines (IFN-ɤ, TNF-α, IL-1ß, IL-6, IL-8, and IL-17) and high-sensitivity C-reactive protein (hsCRP), whereas the production of anti-inflammatory cytokines (IL-10, IL-5) was up-regulated. In conclusion, supplementation with high doses of vitamin D could be one of the possible preventive and therapeutic measures to reduce systemic inflammation in psoriatic patients.

Association of air pollution and homocysteine with global DNA methylation: A population-based study from North India.

BACKGROUND: Anthropogenic air pollution has been implicated in aberrant changes of DNA methylation and homocysteine increase (>15µM/L). Folate (<3 ng/mL) and vitamin B12 (<220 pg/mL) deficiencies also reduce global DNA methylation via homocysteine increase. Although B-vitamin supplements can attenuate epigenetic effects of air pollution but such understanding in population-specific studies are lacking. Hence, the present study aims to understand the role of air pollution, homocysteine, and nutritional deficiencies on methylation. METHODS: We examined cross-sectionally, homocysteine, folate, vitamin B12 (chemiluminescence) and global DNA methylation (colorimetric ELISA Assay) among 274 and 270 individuals from low- and high- polluted areas, respectively, from a single Mendelian population. Global DNA methylation results were obtained on 254 and 258 samples from low- and high- polluted areas, respectively. RESULTS: Significant decline in median global DNA methylation was seen as a result of air pollution [high-0.84 (0.37-1.97) vs. low-0.96 (0.45-2.75), p = 0.01]. High homocysteine in combination with air pollution significantly reduced global DNA methylation [high-0.71 (0.34-1.90) vs. low-0.93 (0.45-3.00), p = 0.003]. Folate deficient individuals in high polluted areas [high-0.70 (0.37-1.29) vs. low-1.21 (0.45-3.65)] showed significantly reduced global methylation levels (p = 0.007). In low polluted areas, despite folate deficiency, if normal vitamin B12 levels were maintained, global DNA methylation levels improved significantly [2.03 (0.60-5.24), p = 0.007]. Conversely, in high polluted areas despite vitamin B12 deficiency, if normal folate status was maintained, global DNA methylation status improved significantly [0.91 (0.36-1.63)] compared to vitamin B12 normal individuals [0.54 (0.26-1.13), p = 0.04]. CONCLUSIONS: High homocysteine may aggravate the effects of air pollution on DNA methylation. Vitamin B12 in low-polluted and folate in high-polluted areas may be strong determinants for changes in DNA methylation levels. The effect of air pollution on methylation levels may be reduced through inclusion of dietary or supplemented B-vitamins. This may serve as public level approach in natural settings to prevent metabolic adversities at community level.

Dietary Intake of Folate and Assessment of the Folate Deficiency Prevalence in Slovenia Using Serum Biomarkers.

Folate deficiency is associated with various health issues, including anemia, cardiovascular disease, and birth defects. Low folate intake and suboptimal folate status were found in several countries; however, this topic has not yet been investigated in Slovenia. Dietary folate intake and serum folate status were investigated through the nationally representative food consumption study SI.Menu/Nutrihealth. Folate intake was estimated using a sample of N = 1248 subjects aged 10-74 years, stratified in three age groups (adolescents, adults, elderly population), through two 24 h-dietary recalls and food propensity questionnaire. Data on serum folate and homocysteine was available for 280 participants. Very low folate intake (<300 µg/day) was observed in 59% of adolescents, 58% of adults and 68% of elderlies, and only about 12% achieved the WHO recommended level of 400 µg/day. Major dietary contributors were vegetables and fruit, and cereal products. Living environment, education, employment status and BMI were linked with low folate intake in adults; BMI, and sex in adolescents; and sex in elderlies. Considering low serum folate (<7 nmol/L) and high serum homocysteine (>15 nmol/L), folate deficiency was found in 7.6 and 10.5% in adults and elderlies, respectively. Additional public health strategies should be employed to promote the consumption of folate-rich foods. With current folate intakes, supplementation with folic acid is relevant especially in specific vulnerable populations, particularly in women planning and during pregnancy.

The Relationship between Folic Acid and Vitamin B12 Serum Levels with High Sensitivity C-reactive Protein and Homocysteine in Chronic Hemodialysis Patients: A Cross-sectional Study.

BACKGROUND: Folic acid (FA) and vitamin B12 treatment have been routinely prescribed to lower serum homocysteine levels and to reduce inflammation. However, no study has been conducted to determine serum folic acid (SFA) and vitamin B12 (B12) levels in patients who have twice-weekly hemodialysis. The aim of our study was to assess serum folate and B12  levels in chronic hemodialysis patients and their relationship with hsCRP and homocysteine levels. METHODS: Our study was a cross-sectional study involcing patients who had twice-weekly hemodialysis in Dr Cipto Mangunkusumo National Hospital Jakarta, Indonesia. Predialysis blood samples were taken to measure SFA, B12, homocysteine and hsCRP levels. Patients with medical conditions affecting the assays were excluded. Spearman correlation was used to compare variables. RESULTS: Eighty subjects enrolled in this study. Among those of non-given folic acid and vitamin B-12 supplementation, only 3.85% of subjects had low folic acid levels, and none had low vitamin B12 levels. A moderate negative correlation between serum folic acid and homocysteine level (p≤0.001; r=-0.42) and a weak correlation between serum vitamin B12 and homocysteine level (p=0.009; r=-0.29) was found. Among the high-risk cardiovascular group (CRP>3, n=49), there is a moderate negative correlation between serum folic acid and homocysteine level (p≤0.001; r=-0.561) and a weak negative correlation between vitamin B12 and homocysteine level (p=0.018; r=-0.338). CONCLUSION: There is a significant negative correlation between serum vitamin B12 and folic acid with homocysteine levels, especially in high-risk cardiovascular group.

Hypohomocysteinemia may increases the risk of dementia and Alzheimer's disease: A nationwide population-based prospective cohort study.

BACKGROUND: Hyperhomocysteinemia has been repeatedly found to increase the risk of dementia. However, the effects of hypohomocysteinemia on the risk of dementia have been barely investigated. If hypohomocysteinemia, like hyperhomocysteinemia, increases the risk of dementia, misuse or overuse of homocysteine-lowing agents such as vitamin supplements may increase the risk of dementia. AIMS: To investigate whether hypohomocysteinemia, like hyperhomocysteinemia, could increase the risk of dementia and Alzheimer's disease (AD) in a large population-based cohort of older adults. METHODS: This prospective cohort study followed 2655 randomly sampled, community-dwelling, non-demented individuals aged 60 years or older from 2010 to 2018. We measured baseline serum total homocysteine (tHcy) levels and examined the effect of serum tHcy on the risks of dementia and AD using Cox proportional hazards models. RESULTS: During the follow-up period (mean = 5.4 years, SD = 0.9), dementia and AD developed in 85 and 64 participants, respectively. Not only the participants with high serum tHcy (≥10.6 µmol/L) but also those with low serum tHcy (≤8.9 µmol/L) were 4-5 times more likely to develop dementia and AD compared to those with serum tHcy levels between 9.0 and 10.5 µmol/L. With the increase in serum tHcy concentration, the use of vitamin supplements decreased, and 41.2% of the participants with low serum tHcy (≤8.9 µmol/L) were taking vitamin supplements. CONCLUSIONS: Not only hyperhomocysteinemia but also hypohomocysteinemia considerably increased the risk of dementia and AD in older adults. The risk of dementia that results from overuse or misuse of vitamin supplements should be acknowledged and homocysteine-lowering health policies should be tailored to consider dementia risks that are associated with hypohomocysteinemia.

The Effects of Medicinal Plants and Bioactive Natural Compounds on Homocysteine.

BACKGROUND: Among non-communicable diseases, cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity in global communities. By 2030, CVD-related deaths are projected to reach a global rise of 25 million. Obesity, smoking, alcohol, hyperlipidemia, hypertension, and hyperhomocysteinemia are several known risk factors for CVDs. Elevated homocysteine is tightly related to CVDs through multiple mechanisms, including inflammation of the vascular endothelium. The strategies for appropriate management of CVDs are constantly evolving; medicinal plants have received remarkable attention in recent researches, since these natural products have promising effects on the prevention and treatment of various chronic diseases. The effects of nutraceuticals and herbal products on CVD/dyslipidemia have been previously studied. However, to our knowledge, the association between herbal bioactive compounds and homocysteine has not been reviewed in details. Thus, the main objective of this study is to review the efficacy of bioactive natural compounds on homocysteine levels according to clinical trials and animal studies. RESULTS: Based on animal studies, black and green tea, cinnamon, resveratrol, curcumin, garlic extract, ginger, and soy significantly reduced the homocysteine levels. According to the clinical trials, curcumin and resveratrol showed favorable effects on serum homocysteine. In conclusion, this review highlighted the beneficial effects of medicinal plants as natural, inexpensive, and accessible agents on homocysteine levels based on animal studies. Nevertheless, the results of the clinical trials were not uniform, suggesting that more well-designed trials are warranted.

Different dietary combinations of folic acid and vitamin B12 in parental diet results in epigenetic reprogramming of IGF2R and KCNQ1OT1 in placenta and fetal tissues in mice.

Genomic imprinting is important for mammalian development and its dysregulation can cause various developmental defects and diseases. The study evaluated the effects of different dietary combinations of folic acid and B12 on epigenetic regulation of IGF2R and KCNQ1OT1 ncRNA in C57BL/6 mice model. Female mice were fed diets with nine combinations of folic acid and B12 for 4 weeks. They were mated and off-springs born (F1) were continued on the same diet for 6 weeks postweaning and were allowed to mate. The placenta and fetal (F2) tissues were collected at day 20 of gestation. Dietary deficiency of folate (BNFD and BOFD) and B12 (BDFN) with either state of other vitamin or combined deficiency of both vitamins (BDFD) in comparison to BNFN, were overall responsible for reduced expression of IGF2R in the placenta (F1) and the fetal liver (F2) whereas a combination of folate deficiency with different levels of B12 revealed sex-specific differences in kidney and brain. The alterations in the expression of IGF2R caused by folate-deficient conditions (BNFD and BOFD) and both deficient condition (BDFD) was found to be associated with an increase in suppressive histone modifications. Over-supplementation of either folate or B12 or both vitamins in comparison to BNFN, led to increase in expression of IGF2R and KCNQ1OT1 in the placenta and fetal tissues. The increase in the expression of IGF2R caused by folate over-supplementation (BNFO) was associated with decreased DNA methylation in fetal tissues. KCNQ1OT1 noncoding RNA (ncRNA), however, showed upregulation under deficient conditions of folate and B12 only in female fetal tissues which correlated well with hypomethylation observed under these conditions. An epigenetic reprograming of IGF2R and KCNQ1OT1 ncRNA in the offspring was evident upon different dietary combinations of folic acid and B12 in the mice.

Changes in Biothiol Levels Are Closely Associated with Alzheimer's Disease.

BACKGROUND: Serum homocysteine (Hcy) level is considered to be an important biomarker for Alzheimer's disease (AD); however, the status of Hcy in brain tissue, and the association between brain and serum levels of Hcy in AD patients remain unclear. OBJECTIVE: We aimed to examine whether the changes of three thiols are consistent in serum of AD patients and the brain of APP/PS1 mice, and to verify the effectiveness of Hcy as a biomarker for early AD detection. METHODS: The levels of Hcy, cysteine (Cys), and glutathione (GSH) in Aß1-42-treated PC12 cells, the brain and hippocampus of APP/PS1 mouse, and the serum of AD patients were evaluated using ethyl (E)-3-(9-chloro-11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f] pyrido [3,2,1 -ij] quinolin-10-yl)-2-cyanoacrylate (Probe 1) and ELISA assay or LC-MS. RESULTS: Measurement by Probe 1 revealed a significant increase in Hcy level, and a decrease in Cys and GSH levels in Aß1-42-treated PC12 cells and the serum of AD patients. The hippocampus and whole brain of APP/PS1 mice also showed a significant increase in Hcy level alongside the accumulation of age-related AD symptoms. The upregulation of Hcy and the downregulation of Cys and GSH were reversed in the Aß1-42-treated PC12 cells and the brain of APP/PS1 mice when supplemented with VB6. CONCLUSION: Changes in Hcy, Cys, and GSH levels in the brain of APP/PS1 mice and Aß1-42-treated PC12 cells were observed in situ with a new fluorescent probe, which were consistent with the abnormal changes in Hcy, Cys, and GSH levels in the serum of AD patients. VB6 supplementation was successful in ameliorating abnormal increases in Hcy levels.

Association Between Homocysteine and Vitamin Levels in Demented Patients.

BACKGROUND: Although it is known that the nutritional status among elderly persons and, in particular, patients with dementia, is compromised, malnutrition that results in insufficient uptake of several vitamins is often not diagnosed. OBJECTIVE: An elevated homocysteine level is a known strong risk factor for vascular dementia (VaD) and Alzheimer's disease (AD). Several B vitamins are involved in the metabolism of homocysteine. Therefore, we investigated the serum levels of vitamin B1, vitamin B6, folate, and vitamin B12 in 97 patients with mild cognitive impairment (MCI) or different forms of dementia and 54 elderly control persons without dementia. RESULTS: Compared to aged non-demented people, vitamins B1, B6, B12, and folate were decreased in serum of patients with AD, and patients with Lewy body dementia had reduced vitamin B12 level. Vitamin B6 was diminished in VaD. Patients with frontotemporal dementia showed no alterations in vitamin levels. Age was identified as an important factor contributing to the concentrations of vitamin B1 and B6 in serum, but not vitamin B12 and folate. Increased levels of total homocysteine were detected especially in MCI and AD. Homocysteine correlated negatively with levels of vitamins B6, B12, and folate and positively with Q Albumin. CONCLUSION: Our data suggest that despite increased homocysteine already present in MCI, vitamin levels are decreased only in dementia. We propose to determine the vitamin levels in patients with cognitive decline, but also elderly people in general, and recommend supplementing these nutrients if needed.

A Novel Review of Homocysteine and Pregnancy Complications.

Homocysteine (Hct) is a substance produced in the metabolism of methionine. It is an essential type of amino acid gained from the daily diet. Methylenetetrahydrofolate reductase (MTHFR) gene mutation is related to elevated total homocysteine (tHct) expressions, in particular, among women with low folate intake. Hyperhomocysteinemia (HHct) is caused by numerous factors, such as genetic defects, lack of folic acid, vitamin B6 and B12 deficiency, hypothyroidism, drugs, aging, and renal dysfunction. Increased Hct in peripheral blood may lead to vascular illnesses, coronary artery dysfunction, atherosclerotic changes, and embolic diseases. Compared to nonpregnant women, the Hct level is lower in normal pregnancies. Recent studies have reported that HHct was associated with numerous pregnancy complications, including recurrent pregnancy loss (RPL), preeclampsia (PE), preterm delivery, placental abruption, fetal growth restriction (FGR), and gestational diabetes mellitus (GDM). Besides, it was discovered that neonatal birth weight and maternal Hct levels were negatively correlated. However, a number of these findings lack consistency. In this review, we summarized the metabolic process of Hct in the human body, the levels of Hct in different stages of normal pregnancy reported in previous studies, and the relationship between Hct and pregnancy complications. The work done is helpful for obstetricians to improve the likelihood of a positive outcome during pregnancy complications. Reducing the Hct level with a high dosage of folic acid supplements during the next pregnancy could be helpful for females who have suffered pregnancy complications due to HHct.

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

INTRODUCTION: Previous 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. METHODS: We 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. RESULTS: Plasma 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. CONCLUSION: Levodopa-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.

Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women.

Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL, p < 0.0001) and decreased the homocysteine level (8.2 ± 3.1 to 5.8 ± 0.8 nmol/mL, p < 0.0001) to minimize the risk of NTDs in all women, regardless of MTHFR genotype. Regardless of MTHFR genotype, multivitamin supplements could control folate and homocysteine levels. Tests for folate and homocysteine levels and optimal multivitamin supplementation in women with risk of NTDs one month or more before pregnancy should be recommended to women who are planning a pregnancy.

The Effect of Omega-3 Fatty Acids on Thromboxane, Brain-Derived Neurotrophic Factor, Homocysteine, and Vitamin D in Depressive Children and Adolescents: Randomized Controlled Trial.

In the DEPOXIN project, we have found that a high ratio of omega-6/omega-3 fatty acids (FA) is associated with worsening of depressive symptoms in children and adolescents with depressive disorder (DD) and that the 12-week omega-3 FA supplementation modulates DD symptoms. Here we present our results of the secondary outcomes: the levels of thromboxane (TXB), brain-derived neurotrophic factor (BDNF), homocysteine (HCy) and vitamin D. Fifty-eight patients were randomized into two arms. One group received a fish oil emulsion enriched with omega-3 FA, and the other received a sunflower oil emulsion containing omega-6 FA, for 12 weeks. Depressive symptoms were evaluated, using the Child's Depressive Inventory (CDI). The patients with DD had elevated TXB levels and decreased vitamin D levels, as compared to healthy controls. Both CDI and omega-6/omega-3 ratio correlated positively with TXB and negatively with BDNF at baseline. Compared to the omega-6 FA group, the supplementation with omega-3 FA for 12 weeks significantly reduced plasma TXB (p = 0.024) and increased BDNF (p = 0.011) levels. No changes in HCy and vitamin D were observed. Our results demonstrate the possible role of TXB and BDNF in the pathophysiology of DD and the benefits of omega-3 FA supplementation. The study was registered with the ISRCTN registry (ISRCTN81655012).

Cardiovascular manifestations of intermediate and major hyperhomocysteinemia due to vitamin B12 and folate deficiency and/or inherited disorders of one-carbon metabolism: a 3.5-year retrospective cross-sectional study of consecutive patients.

BACKGROUND: The association of moderate hyperhomocysteinemia (HHcy) (15-30 µmol/L) with cardiovascular diseases (CVD) has been challenged by the lack of benefit of vitamin supplementation to lowering homocysteine. Consequently, the results of interventional studies have confused the debate regarding the management of patients with intermediate/severe HHcy. OBJECTIVE: We sought to evaluate the association of intermediate (30-100 µmol/L) and severe (>100 µmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes. METHODS: We performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay in a French University Regional Hospital Center. Patients with CVD outcomes were assessed for vitamin B12, folate, Hcy, methylmalonic acid, and next-generation clinical exome sequencing. RESULTS: We evaluated 165 patients hospitalized for thromboembolic and other cardiovascular (CV) manifestations among 1006 patients consecutively recruited. Among them, 84% (138/165) had Hcy >30 µmol/L, 27% Hcy >50 µmol/L (44/165) and 3% Hcy >100 µmol/L (5/165). HHcy was related to vitamin B12 and/or folate deficiency in 55% (87/165), mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11% (19/165), and severe renal failure in 15% (21/141) of the studied patients. HHcy was the single vascular risk retrieved in almost 9% (15/165) of patients. Sixty % (101/165) of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L (IQR: 33.6-60.4 compared with 12.1-28). No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after ∼4 y of follow-up. CONCLUSION: The high frequency of intermediate/severe HHcy differs from the frequent moderate HHcy reported in previous observational studies of patients with pre-existing CVD. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes.

Effect of zinc supplementation on hemogram parameters and circulating concentrations of homocysteine, vitamin B12, and folate in zinc-deficient children and adolescents.

BACKGROUND: Zinc deficiency may exacerbate some pathologies and may also explain alterations in circulating concentrations of various molecules. Zinc has previously been reported to affect plasma concentrations of vitamin B12, homocysteine, and folate; however, the current evidence is inconclusive. We aimed to evaluate plasma zinc, hemoglobin, red blood cell count, mean corpuscular volume, ferritin, vitamin B12, folate, and homocysteine concentrations during and after zinc supplementation for treatment of zinc deficiency. METHODS: This prospective, open-label, single-arm study included children who presented to outpatient clinics with symptoms of growth retardation, anorexia or frequent infections, and who were considered deficient based on plasma zinc concentrations (<70 mcg/dl). Zinc supplementation of 15 mg per day was administered to all participants, and fasting blood samples collected 3 months later were analyzed for plasma zinc, vitamin B12, homocysteine, and folate concentrations. RESULTS: Eighty-three children (27 males and 26 females) admitted to the outpatient clinics with anorexia, growth retardation, and complaints of frequent infections. The mean age of the children was 9.64 ± 5.05 (min-max, 1-15) years, and the mean plasma zinc concentration before zinc supplementation was 61.7 ± 6.3 mcg/dl. Zinc concentrations were significantly elevated after zinc sulfate supplementation for 3 months, at 107.1 ± 18.8 mcg/dl (p < 0.01). Hemoglobin (p < 0.01), mean corpuscular volume (p < 0.01), and ferritin (p = 0.049) levels were significantly increased after zinc supplementation, but no significant difference was found in red blood cell count (p = 0.83). Vitamin B12 and homocysteine concentrations were significantly decreased after zinc treatment (743.5 ± 498.8 vs 373.3 ± 128 mcg/dl p < 0.01; and 11.2 ± 5.3 vs 6.7 ± 3.4 mcg/dl p < 0.01, respectively). However, the change in folate concentrations was not significant (p = 0.05). CONCLUSIONS: Anemia was not detected in patients with zinc deficiency, but ferritin level significantly increased after zinc treatment. Therefore, it can be said that zinc therapy has a positive effect on iron absorption. Elevations in vitamin B12 and homocysteine may be associated with zinc deficiency, and these elevations may in turn influence the prognoses of liver, kidney, cardiorespiratory, and neoplastic conditions. This can be corrected through appropriate zinc supplementation.

Liver transplant as a curative treatment in a pediatric patient with classic homocystinuria: A case report.

We report a patient with homocystinuria and hyperoxaluria who was cured of homocystinuria-related disease following liver transplant. The patient was diagnosed with homocystinuria as a newborn and was treated with dietary modifications and supplements. At 22 months, he passed a calcium oxalate stone and was found to have numerous bilateral kidney stones. Genetic testing confirmed primary hyperoxaluria, type 1. He underwent preemptive liver transplant at age four to treat primary hyperoxaluria. Following transplant, his serum methionine and homocysteine levels normalized, thus, demonstrating resolution of homocystinuria. Methionine and homocysteine levels remained normal 6 years later. Homocystinuria is associated with ophthalmologic, skeletal, neurologic, and thromboembolic complications. As cystathionine beta-synthase resides in the liver, transplant was hypothesized to be an effective treatment. Primary hyperoxaluria generally progresses to chronic kidney disease and is treated with combined kidney-liver transplant at the time of end stage kidney disease. Given this patient's dual diagnoses, we proceeded with preemptive liver transplantation. Three prior cases of patients with homocystinuria treated with liver transplantation have been reported. In all cases, transplant resolved metabolic effects. However, our case represents a pediatric patient without disease-related complications prior to transplant. This case supports liver-targeted gene therapies as an effective treatment for homocystinuria.

Vitamin B-6 intake is related to physical performance in European older adults: results of the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) study.

BACKGROUND: Maintenance of high physical performance during aging might be supported by an adequate dietary intake of niacin, vitamins B-6 and B-12, and folate because these B vitamins are involved in multiple processes related to muscle functioning. However, not much is known about the association between dietary intake of these B vitamins and physical performance. OBJECTIVES: The objectives of this study were to investigate the association between dietary intake of niacin, vitamins B-6 and B-12, and folate and physical performance in older adults and to explore mediation by niacin status and homocysteine concentrations. METHODS: We used baseline data from the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) trial, which included n = 1249 healthy older adults (aged 65-79 y) with complete data on dietary intake measured with 7-d food records and questionnaires on vitamin supplement use and physical performance measured with the short physical performance battery and handgrip dynamometry. Associations were assessed by adjusted linear mixed models. RESULTS: Intake of vitamin B-6 was related to lower chair rise test time [ß: -0.033 ± 0.016 s (log); P = 0.043]. Vitamin B-6 intake was also significantly associated with handgrip strength, but for this association, a significant interaction effect between vitamin B-6 intake and physical activity level was found. In participants with the lowest level of physical activity, higher intake of vitamin B-6 tended to be associated with greater handgrip strength (ß: 1.5 ± 0.8 kg; P = 0.051), whereas in participants in the highest quartile of physical activity, higher intake was associated with lower handgrip strength (ß: -1.4 ± 0.7 kg; P = 0.041). No evidence was found for an association between intake of niacin, vitamin B-12, or folate and physical performance or for mediation by niacin status or homocysteine concentrations. CONCLUSIONS: Vitamin B-6 intake was associated with better chair rise test time in a population of European healthy older adults and also with greater handgrip strength in participants with low physical activity only. Homocysteine concentrations did not mediate these associations. The NU-AGE trial was registered at clinicaltrials.gov as NCT01754012.