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Case for folic acid and vitamin B12 fortification in Europe.

The number of pregnancies affected by neural tube defects has been estimated to be 4000/year in Europe, with a higher prevalence in Celtic populations and in women of low socioeconomic status. Since the 1980s, it has been shown that supplementation with folic acid during the periconceptual period reduces the risk of neural tube defects in the fetus. However, in view of the period during which supplementation should be taken (< 4 weeks before conception until 8-10 weeks after) and the fact that in some countries 30-50% of pregnancies are unplanned, a public health initiative based solely on increasing dietary folate intake or recommendations on use of folic acid supplements is likely to be insufficient. Mandatory fortification has been started in 38 countries throughout the world. Several European countries have advocated mandatory flour folic acid fortification over the last 6 years, but none has introduced it. A recent public health decision in Hungary stimulated flour fortification on a voluntary basis, but it remains the only European country to take this action. Many European countries have deferred a decision to introduce fortification because of concerns about possible masking of vitamin B (12) deficiency. This review advocates a proposal for combined fortification of folic acid and vitamin B (12) to address possible hazards of fortification with folic acid alone.

Europe↗

Folic acid rivals methylenetetrahydrofolate reductase (MTHFR) gene-silencing effect on MEPM cell proliferation and apoptosis.

It's clear that environmental factors play a role in the aetiology of orofacial clefting (OFC) and an important area of future research will be to unravel interactions that occur between candidate genes and environmental factors during early development of the embryo. Periconceptional folic acid supplementation may reduce the risk of OFC. Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability of 5-methylenetetrahydrofolate, the predominant circulating form of folic acid. To determine the effect of MTHFR gene mutation on murine embryonic palatal mesenchymal (MEPM) cells and the interaction with folic acid supplement, we used RNAi study in the primary cultures of MEPM cells. The cells of MTHFR gene silencing grew slower and the apoptosis cell number was more than the cells of control. Supplement with 20 microg/ml folic acid was the best to preventing teratogenic effect of MTHFR gene silencing. By flow cytometry analysis of cell cycle, results were shown that the MEPM cells were retarded in G(0)/G(1) after MTHFR gene silencing. While using 20 microg/ml folic acid supplements could make cell transit the G(1)/S restriction point and the cells growth was close to normal level.

Animals↗

Long-term variations of folic acid concentrations in the Northern Adriatic.

Folic acid (FA), which belongs to B-group vitamins has recently been recognized as possible nutrient for some phytoplankton species (a diatom Phaeodactylum tricornutum). The beneficial role of FA in human health is widely documented. In some countries food fortification with FA has already become mandatory. FA is also used under commercial name of Dosfolat for the treatment of industrial and domestic wastewaters. This is an exploratory study on seasonal and depth variability of FA concentrations in the Northern Adriatic Sea (station 101-max depth 30 m, under the Po River influence). Seawater samples were analysed in the period from February 1998 to February 2003 based on monthly determinations. Those preliminary findings showed that in the upper layer (10 m) FA concentrations were in the range from 0.1 to 28 nM. In the lower layer (20-30 m) FA concentrations were in the range from 0.1 to 12 nM. It was found that phytoplankton and microorganisms which are responsible for the production of FA in the Northern Adriatic (Station 101) were situated at the depth from 5 to 10 m. The observed water column and seasonal distributions depended on a sensitive balance between the production and the consumption of FA.

Environmental Monitoring↗

A long-term study of the absorption of large oral doses of folic acid.

Large daily doses of oral folic acid ranging from 25 to 1,000 mg and totalling between 1,875 and 16,000 mg per course of treatment were well tolerated without any evidence of toxic effects by four hyperuricemic men of the ages of 26, 38, 46 and 50 years. The minimum folate absorption in the gut as measured by urinary excretion ranged from 10.1 to 45.7 percent. The percentage of absorption within a give patient remained similar in successive courses and there was no evidence of saturation of the absorption process related to dose or time. The pattern of urinary excretion of folates did not indicate that appreciable fractions relative to the large folate doses were retained by the patients. Serum, erythrocyte, and urine folates returned to pretreatment levels within 120 days after treatment. These findings suggest that the folate stores of the body do not expand by orders of magnitude even when megadoses of folates are absorbed in the gut. The rise of the folate levels in erythrocytes was gradual and continuous during treatment and is best explained by postulating that incorporation of folate into red cell takes place mostly at the precursor and reticulocyte stages. The decrease of erythrocyte folate values seen 40 to 66 days after folate treatment indicates that the folate content of erythrocytes diminishes during their life span.

Adult↗

Serum lipids, vitamin B12 and folic acid levels in children receiving long-term valproate therapy.

In this study, serum triglyceride, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), vitamin B12 and folic acid levels were studied in children with epilepsy who had been receiving long-term valproate (VPA) therapy. Our purpose was to determine that whether or not there was any affect of VPA therapy on serum lipids, vitamin B12 and folic acid levels. The study includes 26 patients (13 males, 13 females) with epilepsy who had been receiving long-term VPA therapy and in 28 healthy children (14 males, 14 females). The age ranged from 14 months-12 years (8.22 +/- 3.64 years) and 9 months-18 years (8.97 +/- 4.85 years) in the study and control group, respectively. Because serum lipid ranges may be changed according to the age groups in childhood, the children were divided into three groups as follows; younger than < 5 years, between 5-10 years, and older than > 10 years. The duration of VPA use was between 10 months and 7 years (1.83 +/- 1.80 years). Serum VPA level changed between 42-108 micrograms/ml (75.09 +/- 21.42 micrograms/ml). When comparing the results we did not find any significant difference in all parameters including lipid profiles, vitamin B12 and folic acid levels between the groups (P > 0.05). Additionally, we did not find any correlation between lipid profile and age at start of therapy, duration of therapy, serum VPA level (P > 0.05). In conclusion, our findings showed that VPA therapy did not change serum lipids, vitamin B12 and folic acid concentrations; therefore, we suggest that VPA may be safely used with regard to lipid composition, vitamin B12 and folic acid levels in childhood epilepsy.

Anticonvulsants↗

The effect of folic acid, vitamin B6 and vitamin B12 on the homocysteine levels in rabbits fed by methionine-enriched diets.

Atherosclerosis is an important cause of cardiovascular morbidity and mortality in recent years. Hyperhomocysteinemia is recognized as an independent risk factor for premature atherosclerosis and venous thrombosis. It is suggested that administration of folic acid, vitamin B6 and vitamin B12 may decrease homocysteine levels. In our study, we induced hyperhomocysteinemia in rabbits by giving methionine and studied the effects of folic acid, vitamin B6 and vitamin B12 on homocysteine levels. A total of 40 (20 female, 20 male New Zealand rabbits) were divided into four groups, each consisting of 10 rabbits. Methionine (100 mg/kg/day), methionine (100 mg/kg/day) plus vitamin B6 (30 mg/kg/day), methionine (100 mg/kg/day) plus vitamin B12 (80 mg/kg/day) and methionine (100 mg/kg/day) plus folic acid (20 mg/kg/day) were given to the first, second, third and forth groups respectively. These rabbits were followed up for two months. We studied homocysteine levels on the 0, 20th, 40th and 60th days in all groups. In rabbits we induced hyperhomocysteinemia by giving methionine for 2 months. The decreases of homocysteine levels in the forth group were significant with respect to the second and third groups. Folic acid supplementation clearly resulted in a reduction of plasma homocysteine levels, whereas vitamin B12 was little effective and vitamin B6 failed to show an effect. We conclude that even folic acid treatment alone may be sufficient for decreasing negative effects of homocysteine.

Animals↗

Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification.

BACKGROUND: A relation between low folate status and depression has been recognized since the 1960s. Since 1998, flour in the United States has been fortified with folic acid, and the prevalence of folate deficiency has decreased dramatically. OBJECTIVE: We investigated whether, in this era of folic acid fortification, low folate status is a determinant of depressive symptoms in a cohort of elderly Latinos (aged >/=60 y) participating in the Sacramento Area Latino Study on Aging (SALSA). DESIGN: In a cross-sectional logistic regression analysis of data from SALSA (n = 627 M, 883 F), odds ratios (ORs) were ascertained for elevated depressive symptoms [Center for Epidemiologic Studies Depression Scale (CES-D) score >/=16] among tertiles of plasma folate. Depressive symptoms were assessed by using the CES-D. Plasma folate concentrations were determined by radioassay. RESULTS: The prevalence of folate deficiency (plasma folate </= 6.8 nmol/L) in the SALSA population was <1%. For men, no significant association between folate tertile and high CES-D score was observed. The adjusted OR for high CES-D score in women in the lowest tertile of folate was 2.04 (95% CI: 1.38, 3.02), which was significantly different from that in women in the highest tertile of folate (P < 0.001). CONCLUSION: These data indicate that, despite folic acid fortification, low folate status is associated with depressive symptoms in elderly Latina women (but not elderly Latino men).

Acculturation↗

[Increased kidney cell proliferation caused by folic acid treatment after dichromate induced renal failure (author's transl)].

Folic acid is given intravenously to rats 5 to 10 days after a dichromate induced damage of the kidneys. These injection cause an additional damage in the function and structure of the kidneys, but on the other hand, they induce a cell proliferation detected by the increased uptake of thymidine. This cell proliferation in the kidney-tissue seems to be a part of specific reactions to the folic acid.

Animals↗

[Acute neurological disclosure of B12 avitaminosis induced by folic acid administration].

A paradigmatic case of acute combined spinal cord degeneration and delirium due to inappropriate administration of folic acid in the context of chronic cobalamin deficiency is described. Rapid improvement was obtained with immediate cessation of folate administration and parenteral cobalamin supplementation. Folic acid and cobalamin prescription rules are recalled. Pathophysiological hypotheses tentatively explaining the neurotoxicity of folic acid in case of vitamin B12 deficiency are summarized.

Acute Disease↗

Anaemia in rheumatoid arthritis: the role of iron, vitamin B12, and folic acid deficiency, and erythropoietin responsiveness.

Thirty six patients with rheumatoid arthritis (RA) (25 with anaemia) were studied to establish the role of iron, vitamin B12, and folic acid deficiency, erythropoietin responsiveness, and iron absorption in the diagnosis and pathogenesis of anaemia in RA. Iron deficiency, assessed by stainable bone marrow iron content, occurred in 13/25 (52%), vitamin B12 deficiency in 7/24 (29%), and folic acid deficiency in 5/24 (21%) of the anaemic patients. Only 8/25 (32%) had just one type of anaemia. The iron deficiency of anaemia of chronic disease (ACD) was distinguished by ferritin concentration, which was higher in that group. Mean cell volume (MCV) and mean cell haemoglobin (MCH) were lower in both anaemic groups, but most pronounced in iron deficient patients. Folic acid, and especially vitamin B12 deficiency, masked iron deficiency by increasing the MCV and MCH. Iron absorption tended to be highest in iron deficiency and lowest in ACD, suggesting that decreased iron absorption is not a cause of ACD in RA. No specific causes were found for vitamin B12 or folic acid deficiency. Haemoglobin concentration was negatively correlated with erythrocyte sedimentation rate in the group with ACD. Erythropoietin response was lower in ACD than in iron deficient patients. It was concluded that generally more than one type of anaemia is present simultaneously in anaemic patients with RA. The diagnosis of each type may be masked by another. Studies on pathogenesis of the anaemia are difficult as deficiencies generally coexist with ACD. Disease activity and, possibly, erythropoietin responsiveness are major factors in ACD pathogenesis.

Aged↗

Vitamin B6, B12, and folic acid supplementation and cognitive function: a systematic review of randomized trials.

BACKGROUND: Despite their important role in cognitive function, the value of B vitamin supplementation is unknown. A systematic review of the effect of pyridoxine hydrochloride (hereinafter "vitamin B(6)"), cyanocobalamin or hydroxycobalamin (hereinafter "vitamin B(12)"), and folic acid supplementation on cognitive function was performed. METHODS: Literature search conducted in MEDLINE with supplemental articles from reviews and domain experts. We included English language randomized controlled trials of vitamins B(6) and/or B(12) and/or folic acid supplementation with cognitive function outcomes. RESULTS: Fourteen trials met our criteria; most were of low quality and limited applicability. Approximately 50 different cognitive function tests were assessed. Three trials of vitamin B(6) and 6 of vitamin B(12) found no effect overall in a variety of doses, routes of administration, and populations. One of 3 trials of folic acid found a benefit in cognitive function in people with cognitive impairment and low baseline serum folate levels. Six trials of combinations of the B vitamins all concluded that the interventions had no effect on cognitive function. Among 3 trials, those in the placebo arm had greater improvements in a small number of cognitive tests than participants receiving either folic acid or combination B-vitamin supplements. The evidence was limited by a sparsity of studies, small sample size, heterogeneity in outcomes, and a lack of studies that evaluated symptoms or clinical outcomes. CONCLUSION: The evidence does not yet provide adequate evidence of an effect of vitamin B(6) or B(12) or folic acid supplementation, alone or in combination, on cognitive function testing in people with either normal or impaired cognitive function.

Cognition↗

Folic acid absorption in regional enteritis.

The authors have investigated intestinal absorption of folic acid by jejunal perfusion with a triple lumen tube in five subjects with regional enteritis. The subjects' intestinal disabilities ranged from terminal ileitis to short bowel syndrome. Two had steatorrhea and two had low serum folate levels. Absorption of pteroylglutamic acid was normal in all five. This suggests that folic acid deficiency, common in this disorder, is largely caused by malnutrition, not malabsorption.

Adult↗

Folic acid: are current fortification levels adequate?

OBJECTIVE: Beginning on January 1, 1998, all cereal and grain products in the United States were fortified with folic acid to reduce the occurrence of the very common congenital malformations known as neural-tube defects. Three years have passed since the fortification program began, and it is time to evaluate whether the current fortification levels have met their intended objective. METHODS: We offer an overview of folate and its potential role in the etiology of neural-tube defects, review some of the highlights of the deliberations that led to the decision by the Food and Drug Administration to fortify the food supply, and offer a perspective on how to measure whether current fortification levels are adequate. RESULTS: There is no national system in the United States that monitors neural-tube and other birth defects over time, and no postmarketing surveillance was mandated to monitor the safety of the fortification program. Therefore, we must evaluate the program in other ways. Blood biomarkers of folate status such as the levels of folate in red blood cells and homocysteine in plasma provided the best evidence of the effectiveness of the folic-acid-fortification program because of their relatively high sensitivities in relation to their specificities as markers of folate status. In addition, these biomarkers might provide information about the risks of other diseases related to folate status such as vascular disease. CONCLUSION: Federal agencies should coordinate efforts to gather and evaluate markers of folate status at the population level. These measures can be used to evaluate the safety and efficacy of folic-acid fortification and whether changes are warranted in fortification levels.

Biomarkers↗

Plasma homocysteine levels in renal transplanted patients on cyclosporine or tacrolimus therapy: effect of treatment with folic acid.

Hyperhomocysteinemia, an independent risk cardiovascular factor, has been reported in renal transplanted patients (RTP). The aim of the present study was to evaluate homocysteine levels in RTP treated with cyclosporine or tacrolimus, and the changes observed in the two groups of patients after treatment with folic acid. Forty-two RTP with stable function (21 treated with cyclosporine and 21 with tacrolimus, matched by gender and age) were studied. Forty healthy control subjects were matched by age and gender with the patients. In RTP, homocysteine was increased compared with the controls (16.4 +/-5.2 vs 8.0 +/- 1.8 micromol/L; p < 0.001), but there was no difference in vitamin B12 and folic acid levels. Thirty-three patients and one control showed hyperhomocysteinemia (78.5 vs 2.5%; p < 0.001). Homocysteine correlated negatively with creatinine clearance in the patients (p = 0.04), but no correlation was found with vitamin B12, folic acid and lipoproteins. By univariate analysis, patients treated with cyclosporine had higher homocysteine than those treated with tacrolimus (p = 0.03), but multivariate analysis did not confirm these results. In 21 patients with hyperhomocysteinemia and folate levels similar to those of the controls, folic acid (5 mg/d for 3 months) was administered. Homocysteine decreased significantly (19.1 +/- 4.8 vs 13.2 +/- 3.4 micromol/L; p < 0.001), with a median reduction of 31% and with no differences observed in patients treated with either cyclosporine or tacrolimus. We concluded that hyperhomocysteinemia is very frequent in RTP, but homocysteine levels are not different in patients treated with cyclosporine or tacrolimus. Folic acid therapy produces a significant decrease in homocysteine concentrations, in the absence of clear folate deficiency, without differences in relation to immunosuppressant therapy.

Analysis of Variance↗

[In vitro activity of folic acid on the proliferation dynamics of human bone marrow CFU-GM in propyphenazone-induced granulocytopenia].

The in vitro action of folic acid was tested on the proliferation of bone marrow granulocyte-macrophage progenitor cells from a patient with drug-induced (propyphenazone) neutropenia in remission 20 days after the drug had been suspended. Various bone marrow cultures were prepared with standard stimulant, adding, respectively: folic acid, propyphenazone and both folic acid and propyphenazone together. Growth was tested on day 7, 12 and 19 of incubation. Under baseline culture with standard stimulant, CFU-GM growth was characterized by successive proliferation waves of various entity: the first on day 7 was very high, the second, on day 12 was rather low, and the third, on day 19 was intermediate. This behaviour is different from what is usually observed in normal subjects in steady-state, whose first (AC-A+AC-B) and second (AC-C) proliferation period are of similar entity. The prevalence of the first proliferation period in our case is interpreted as the result of a renewed granulocytopoietic activity after drug-induced bone marrow suppression. This indicates a maintained integrity of the negative-feedback mechanism of homeostatic regulation on granulocytopoietic activity. The sole addition of propyphenazone on the in vitro bone marrow cell cultures of our patient produced a reduction of those CFU-GM that had grown during the first period whereas the growth during the second and third period remained unvaried. Thus the growth peak in cultures treated with propyphenazone occurred on day 19, which seems to correspond with the necessary time for a spontaneous remission from neutropenia, clinically observed to be 20 days after suspension of the propyphenazone-containing drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Agranulocytosis↗

Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation.

It has been suggested that oral supplements of folic acid interfere with the intestinal absorption of zinc and may have toxic side effects. The concentrations of Zn and folate in blood were monitored in a group of women with cervical dysplasia randomly assigned to receive 10 mg/d of either folic acid (pteroylglutamic acid) or ascorbate. Fifty subjects were evaluated after 2 mo; 21 of the same subjects were evaluated again after 4 mo. No untoward clinical effects were observed. Significant elevation of erythrocyte folate above the baseline value was observed in the supplemented group but not in the placebo group (p less than 0.001). The concentration of Zn in plasma and erythrocytes did not change significantly in either the folate-treated or placebo groups after 2 and 4 mo. It is concluded that carefully controlled clinical intervention trials of this type do not impose a risk of depleting the concentration of Zn in erythrocytes and plasma.

Clinical Trials as Topic↗

Folic acid deficiency in the United States: folate assays in a prenatal clinic.

Tissue deficiency of folic acid, as measured by a red cell folate level below 150 ng. per milliliter, was present in 16 per cent of 110 sequential pregnant women at the time of their first prenatal visit to a municipal clinic. A further 14 per cent of subjects had red cell folate levels in the range "suggestive but not conclusive for tissue folate depletion" (150 to 199 ng. per milliliter). All of the subjects were from low-income families in New York City and most were black or of Puerto Rican origin. Serum folate levels showed good general correlation with red cell folate but were of less value as a diagnostic test, since they were below the lower limit of normal in 64 per cent of subjects, including many subjects who did not yet have low tissue folate. In contrast to their value in other folate deficiency states, neutrophil lobe counts showed no correlation with serum or red cell folate levels in pregnancy and thus appeared of little diagnostic value in pregnancy. It is suggested that surveys of folate deficiency in other pregnant population groups in the United States be carried out. These results support the recommendations of the Committee on Maternal Nutrition and the Committee on Dietary Allowances of the Food and Nutrition Board, National Research Council (U.S.A.) that folic acid supplements (200 to 400 mug per day) should be taken throughout pregnancy.

Black or African American↗