Estado periconcepcional de ácido fólico: revisión sobre su relevancia para la salud de la madre y de la descendencia. Relevancia del estado periconcepcional de ácido fólico sobre el neurodesarrollo / Perioconceptional folic acid status: review about his relevance on the health of the mother and the offspring. Relevance of perioconceptional folic acid status on neurodevelopment

Fundamento: El déficit de ácido fólico durante el embarazo puede derivar en defectos del tubo neural en el feto, bajo peso al nacer y desórdenes del neurodesarrollo como trastornos de la conducta y de la cognición en el niño pero también puede conllevar anemia megaloblástica en la madre así como desprendimiento de la placenta, abortos, partos prematuros, preeclampsia e incluso eclampsia en algunas ocasiones. Objetivo: El objetivo de este trabajo es revisar los principales hallazgos científicos con relación a la importancia fisiológica del ácido fólico durante el embarazo así como los efectos negativos resultantes de un inadecuado nivel de folato periconcepcional, tanto por déficit como por exceso, y la evidencia existente sobre la relación entre suplementación con folato y los diferentes parámetros de salud, tanto de la madre como del recién nacido. Métodos: Se ha realizado una búsqueda amplia en la que se incluyen artículos originales, revisiones y guías de recomendaciones. Resultados/Conclusión: Tanto el déficit como el exceso de ácido fólico durante el embarazo pueden desencadenar efectos adversos para la madre y para el hijo. Por ello, la suplementación de ácido fólico debería ser individualizada para cada mujer teniendo en cuenta sus características fenotípicas, genotípicas y metabólicas (AU)

Background: The folic acid deficit during pregnancy may lead to a neural tube defects in the fetus, low birth weight and neurodevelopmental disorders as behavior disturbance or cognitive disabilities. Also may carry to the megaloblastic anemia in the mother as well as placental abruption, abortion, premature labor, pre-eclampsia and sometimes eclampsia. Objective: The objective of this work is to review the main scientific finds in relation with the physiological importance of folic acid during pregnancy and negative effects resulting of the inadequate level of folate periconceptional, both deficit and excess. Also review the evidence about the relationship between the folate supplementation and the different health parameters in the mother and the newborn. Methods: The search has been wide and this review includes original articles, review articles and recommendation guides. Results/Conclusion: Both deficit and excess folic acid during pregnancy can trigger adverse effects to the mother and the child. Therefore, supplementation with folic acid should be individualized for each woman considering its phenotypic, genotypic and metabolic characteristics (AU)

Genetic Variation in Glutamate Carboxypeptidase II and Interaction with Dietary Natural Vitamin C May Predict Risk for Adenomatous Polyp Occurrence.

BACKGROUND: The C1561T variant of the glutamate carboxypeptidase II (GCPII) gene is critical for natural methylfolylpolyglutamte (methylfolate) absorption, and has been associated with perturbations in folate metabolism and disease susceptibility. However, little is known on C1561T-GCPII as a risk factor for colorectal cancer. Therefore, this study examined whether C1561T-GCPII influences folate metabolism and adenomatous polyp occurrence. MATERIALS AND METHODS: 164 controls and 38 adenomatous polyp cases were analysed to determine blood folate and plasma homocysteine (Hcy) level, dietary intake of natural methylfolate, synthetic pteroylglutamic acid (PteGlu), vitamin C and C1561T-GCPII genotype. RESULTS: In controls and cases, 7.3 and 18.4 percent of subjects respectively, were found to have the CT genotype, increasing the risk for adenomatous polyp occurrence 2.86 times (95% CI:1.37-8.0, p=0.035). Total dietary folate, methylfolate and PteGlu intake and the level of erythrocyte folate and plasma Hcy did not predict the occurrence of an adenomatous polyp. However, dietary natural vitamin C intake was associated with adenomatous polyp risk within C1561T-GCPII CT genotype subjects (p=0.037). CONCLUSIONS: The findings suggest that C1561T-GCPII variation may be associated with risk for adenomatous polyp, and vitamin C may modify risk by interacting with the variant gene, its expression product and/or folate substrates.

Micronutrient supplementation may reduce symptoms of depression in Guatemalan women / Potencial reducción de síntomas de depresión en mujeres en Guatemala mediante la suplementación con micronutrientes

Evidence for the impact of micronutrient supplementation trials on depression in women from developing countries is limited. This study examines this association and compares the impact of weekly versus daily combinations of micronutrient supplements on symptoms of depression. A randomized, positive-controlled trial was conducted in Guatemala. A total of 459 women were assigned randomly to 4 groups to receive weekly (5,000 or 2,800µg) or daily (400 or 200 µg) folic acid (FA) plus iron, zinc and vitamin B-12 for 12 weeks. Depression was measured using the Center for Epidemiologic Studies-Depression 20-item Scale (CES-D). A score=16 was used as an indication of depression. The association between micronutrient status and depression was assessed using baseline data. Generalized linear regression models were used to assess treatment effects. The baseline mean CES-D score was 17.1±8.5 and the prevalence of depression was 49.3 percent. Women in the lowest tertile of red blood cell folate (RBC) were 1.7 times more likely to be depressed than those in the highest tertile (OR=1.71; 95 percent CI: 0.91, 3.18). There were no associations between depression and serum folate, homocysteine, vitamin B-12, hemoglobin, ferritin or zinc (p > 0.05). Mean depression scores decreased by 2.3 points post-intervention and depression decreased to 37.7 percent, with no differences in degree of improvement by group (p = 0.64). Low RBC folate was associated with elevated symptoms of depression at baseline. Supplementation with FA-containing micronutrients may be equally efficacious in improving symptoms of depression when provided daily or weekly. Our findings that poor folate status may increase depression needs to be further investigated.

La evidencia del impacto de ensayos de suplementación con micronutrientes en mujeres con depresión en países en desarrollo es limitada. El presente estudio examina esta asociación y compara el impacto de varias combinaciones de micronutrientes proporcionadas de manera semanal o diaria en los síntomas de depresión, utilizando datos de un ensayo controlado (control positivo) y aleatorizado realizado en Guatemala. Un total de 459 mujeres fueron asignadas al azar entre cuatro grupos para recibir semanalmente (5.000 o 2.800 µg) o diariamente (400 o 200 µg) de ácido fólico (AF) combinado con hierro, cinc y vitamina B-12 durante 12 semanas. La depresión fue medida utilizando la escala de 20 ítems del Centro de Estudios Epidemiológicos de la Depresión (CES-D). Un puntaje =16 fue considerado indicativo de depresión. Se evaluó la asociación entre el nivel de micronutrientes en sangre y depresión utilizando datos provistos por la línea de base. Se utilizaron modelos de Regresión Linear Generalizada para evaluar los efectos del tratamiento. La media del puntaje de la línea de base CES-D fue de 17,1±8,5 y la prevalencia de depresión fue del 49,3 por ciento. Las mujeres en el tercil más bajo del folato eritrocitario presentaron 1,7 veces más probabilidades de estar deprimidas que aquellas en el tercil más alto (OR=1,71; 95 por ciento CI: 0,91, 3,18). No se encontró asociación entre depresión y folato sérico, homocisteína, vitamina B-12, hemoglobina, ferritina sérica o cinc (p>0,05). Los puntajes de depresión medios post-intervención disminuyeron en 2.3 puntos y la depresión se redujo a 37,7 por ciento, sin presentar diferencias en el grado de mejoría por grupo (p=0,64). En síntesis, el bajo nivel de folato eritrocitario se asoció a síntomas elevados depresivos en la línea de base. La suplementación con AF sumado a otros micronutrientes puede ser igualmente eficaz en la mejora de síntomas depresivos cuando provista diaria o semanalmente...

A dual-isotope-labeling method of studying the bioavailability of hexaglutamyl folic acid relative to that of monoglutamyl folic acid in humans by using multiple orally administered low doses.

BACKGROUND: The bioavailability of dietary folate may be hampered by the need of the glutamate moieties to be deconjugated before absorption. Previous studies comparing the bioavailabilities of polyglutamyl and monoglutamyl folic acid had inconsistent results. OBJECTIVE: The objective was to estimate the bioavailability of polyglutamyl relative to that of monoglutamyl folic acid by using a sensitive stable-isotope approach that allowed for the administration of multiple low doses in humans. DESIGN: Twenty subjects aged 20-50 y ingested 2 capsules daily for 28 d; each capsule contained approximately 50 nmol [(13)C(6)]hexaglutamyl and approximately 50 nmol [(13)C(11)]monoglutamyl folic acid. Amounts of the isotopically labeled compounds in the capsules were verified by various methods. The degrees of isotopic enrichment of plasma 5-methyltetrahydrofolate with (13)C(6) and (13)C(11) were measured by using liquid chromatography tandem mass spectrometry, and the ratio of (13)C(6) to (13)C(11) ((13)C(6):(13)C(11)) in plasma on day 28 was used as a measure of their relative bioavailability. RESULTS: The (13)C(11):(13)C(6) in plasma 5-methyltetrahydrofolate reached equilibrium on day 4 and was 0.66 (95% CI: 0.58, 0.74) on day 28. The (13)C(11):(13)C(6) content in the capsules varied between 1.18 and 1.96. After correction for this ratio, the estimated bioavailability of hexaglutamyl relative to that of monoglutamyl folic acid was >/=78%. CONCLUSION: Multiple dosing of low amounts of labeled folic acid is a sensitive, accurate, and efficient method of measuring the relative bioavailability of folic acid compounds, provided that the administered doses can be reliably assessed.

Estimación de la ingesta y necesidades de enriquecimiento de folatos y ácido fólico en alimentos / Folate and folic acid ontake estimation and food enrichment requirements

El término folato se utiliza de forma genérica para denominar las distintas formas químicas derivadas del ácido fólico, una de las vitaminas del grupo B (concretamente la vitamina B). Son esenciales en el metabolismo al actuar como cofactores en las reacciones de transferencia de un carbono. No obstante, solamente las plantas y los microorganismos son capaces de sintetizarlos de novo, de tal forma que tanto los animales como el hombre necesitan ingerirlos a tráves de los alimentos de la dieta. se encuentra ampliamente extendido en la naturaleza, presentándose en mayor cantidad en las verduras de hoja ancha, en hígado y en cereales Aún así, en la actualidad es una de las deficiencias nutricionales más comunes en todo el mundo, y tiene graves consecuencias sobre la salud humana. Existe evidencia de que incluso en países desarrollados la ingesta de folatos es generalmente baja, e incluso en algunos casos por debajo de los niveles óptimos. Las autoridades competentes de numerosos países están tomando medidas a este respecto, de tal forma que se está realizando la fortificación, de numerosos alimentos considerados de consumo diario, tales como leche o cereales, ya sea de forma obligatoria (Estados Unidos, Canadá o Chile) o voluntaria (la mayoría de los países de Europa)

Bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid in subjects with different genotypes of the glutamate carboxypeptidase II gene.

BACKGROUND: Before dietary folate is absorbed, polyglutamate folates are deconjugated to monoglutamates by folylpoly-gamma-glutamyl carboxypeptidase in the small intestine. The 1561T allele of the glutamate carboxypeptidase II gene (GCPII), which codes for folylpoly-gamma-glutamyl carboxypeptidase, may impair intestinal absorption of dietary folates. OBJECTIVE: Our aim was to study the bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid across GCPII 1561 genotypes. DESIGN: In a randomized study, 180 healthy adults aged 50-75 y received 323 nmol monoglutamyl folic acid/d (n = 59), 262 nmol heptaglutamyl folic acid/d (n = 61), or placebo (n = 60) for 12 wk. Genotypes were assessed after the intervention. The bioavailability of heptaglutamyl folic acid relative to that of monoglutamyl folic acid was calculated by using the changes in serum folate concentration in the treatment groups, after correction for changes in the placebo group and for the administered dose. RESULTS: No subjects with the TT genotype were encountered. At baseline, serum and erythrocyte folate concentrations were higher (P < 0.05) in subjects with the CT genotype [16.3 nmol/L (geometric x; 95% CI: 13.7, 19.3 nmol/L) and 863 nmol/L (735, 1012 nmol/L), respectively; n = 19] than in subjects with the CC genotype [13.7 (13.1, 14.3) and 685 (652, 721) nmol/L, respectively; n = 161]. Baseline homocysteine concentrations were not significantly different between genotypes. The bioavailability of heptaglutamyl folic acid relative to that of monoglutamyl folic acid was not significantly different between subjects with the CC (64%; 52%, 76%) and CT genotypes (70%; 49%, 91%). CONCLUSIONS: The 1561T allele of the GCPII gene does not impair the bioavailability of polyglutamyl folic acid. However, the allele is associated with higher folate status. This association may be explained by yet unidentified factors controlling the expression of the GCPII gene.

Single oral doses of 13C forms of pteroylmonoglutamic acid and 5-formyltetrahydrofolic acid elicit differences in short-term kinetics of labelled and unlabelled folates in plasma: potential problems in interpretation of folate bioavailability studies.

Single (13)C6-labelled doses of pteroylmonoglutamic acid (PteGlu; 634 nmol) or 5-formyltetrahydrofolic acid (431-569 nmol) were given to fasted adult volunteers, and the rise in total and (13)C-labelled plasma 5-methyltetrahydrofolic acid metabolite monitored over 8 h by HPLC and liquid chromatography-MS. The dose-adjusted area under the curve (AUC) for total (labelled plus unlabelled) plasma 5-methyltetrahydrofolic acid following a 5-formyltetrahydrofolic acid test dose was 155 % that obtained following a PteGlu test dose. Surprisingly, an average 60 and 40 % of the total plasma 5-methyltetrahydrofolic acid response to [(13)C6]PteGlu and [(13)C6]5-formyltetrahydrofolic acid, respectively, was unlabelled; an observation never before reported. Short-term kinetics of plasma [(13)C6]5-methyltetrahydrofolic acid showed a slower initial rate of increase in plasma concentration and longer time to peak following an oral dose of [(13)C6]PteGlu compared with that for an oral dose of [(13)C6]5-formyltetrahydrofolic acid, while the [(13)C6]5-methyltetrahydrofolic acid AUC for [(13)C6]5-formyltetrahydrofolic acid was 221 % that for [(13)C6]PteGlu. These data indicate that PteGlu and 5-formyltetrahydrofolic acid, which are thought to be well absorbed (about 90 %) at physiological doses, exhibit dramatically different rates and patterns of plasma response. A limitation in the rate of reduction of PteGlu before methylation could result in slower mucosal transfer of [(13)C6]5-methyltetrahydrofolic acid derived from [(13)C6]PteGlu into the plasma. This, when coupled with an observed similar plasma clearance rate for [(13)C6]5-methyltetrahydrofolic acid metabolite derived from either folate test dose, would yield a comparatively smaller AUC. These findings suggest potential problems in interpretation of absorption studies using unlabelled or labelled folates where the rate of increase, the maximum increase, or the AUC, of plasma folate is employed for test foods (mainly reduced folates) v. a 'reference dose' of PteGlu.

Dietary monoglutamate and polyglutamate folate are associated with plasma folate concentrations in Dutch men and women aged 20-65 years.

Dietary folate consists of monoglutamate and polyglutamate folate species. In the small intestine, folate polyglutamate is deconjugated to the monoglutamate form before absorption takes place. This enzymatic deconjugation might limit the bioavailability of polyglutamate folate. Until now, no data have been available on dietary intake of both folate forms and their associations with folate status. Therefore, we estimated the intake of monoglutamate and polyglutamate folate in the Dutch population and studied whether the association with plasma folate is different for these two folate forms. Dietary intake of monoglutamate and polyglutamate folate from nonfortified foods was estimated for 2435 subjects (1275 men; 1160 women) aged 20-65 y. The intake of monoglutamate folate was about one third of total folate intake, derived mainly from bread (approximately 20%) and meat (approximately 18%), whereas two thirds consisted of polyglutamates, derived mainly from vegetables (approximately 25%). The predictive power of the regression model with total folate intake as the independent variable adjusted for age, smoking and alcohol intake, did not increase when including the ratio of monoglutamate to polyglutamate folate intake. In addition, linear regression models showed that both monoglutamate and polyglutamate folate intake were associated positively with plasma folate levels. However, in men, the monoglutamate folate form appeared to be a threefold stronger determinant of plasma folate levels than polyglutamate folate, whereas in women, both folate forms were equally strong determinants. This might be explained by different food intake patterns of men and women, including alcohol intake. At present, it does not seem necessary to distinguish between food folate forms in advising an increase in folate intake from nonfortified foods.

Alzheimer y la alimentación / Alzheimer´s disease and nutrition

La enfermedad de Alzheimer es la demencia senil de mayor prevalencia en la población occidental. Aunque de origen multifactorial, a medida que se profundiza en su fisiopatología, gana fuerza la hipótesis de la implicación de factores de riesgo nutricionales, como son bajos niveles de antioxidantes y de las vitaminas folato, B6 y B12, implicadas en el ciclo metabólico de la homocisteína. El diagnóstico precoz es esencial para mantener al paciente en un estado funcional el mayor tiempo posible. Hay que garantizar el aporte de energía y nutrientes, bien mediante alimentos, suplementos o alimentación enteral. Aunque es prematuro hablar de una prevención nutricional de la demencia, puede estar indicada la suplementación de vitaminas a dosis fisiológicas en los mayores de 60 años con una buena relación coste-beneficio (AU)

Effects of folate supplementation on two provisional molecular markers of colon cancer: a prospective, randomized trial.

OBJECTIVES: Dietary folate intake is inversely associated with the risk of colorectal cancer. This study investigated the effect of folate supplementation on genomic DNA methylation and DNA strand breaks in exons 5-8 of the p53 gene of the colonic mucosa, two provisional biomarkers of colon cancer. METHODS: Twenty subjects with adenomas were randomized to receive either folate (5 mg/day) or placebo for 1 yr after polypectomy. At baseline, 6 months and 1 yr, systemic and colonic measures of folate status were determined, as were the biomarkers mentioned earlier. RESULTS: Folate supplementation increased serum, red blood cell and colonic mucosal folate concentrations (p < 0.02). Folate supplementation also increased the extent of genomic DNA methylation at 6 months and 1 yr (p = 0.001), whereas placebo administration was associated with an increase in the extent of genomic DNA methylation only at 1 yr. Similarly, folate supplementation decreased the extent of p53 strand breaks in exons 5-8 at 6 months and 1 yr (p < 0.02), whereas placebo administration was associated with a decrease in the extent of p53 strand breaks only at 1 yr. CONCLUSIONS: Both of these provisional biomarkers of colon cancer underwent accelerated improvement at 6 months with folate supplementation. However, these markers also improved with placebo at 1 yr. Therefore, potential confounding factors that seem to modulate these biomarkers need to be identified and corrected in order for these markers to serve as suitable surrogate endpoints in folate chemoprevention trials.

Absorption of dietary and supplemental folate in women with prior pregnancies with neural tube defects and controls.

BACKGROUND: The Public Health Service of the United States recommends that all women capable of childbearing consume .4 mg (400 microg) folic acid per day to decrease the risk of having a pregnancy affected by a neural tube defect such as spina bifida or anencephaly. Three strategies are available to women to achieve this goal: use of dietary supplements; use of fortified foods; and/or increased intake of naturally occurring folate from foods. Identification of the most effective vehicle for delivery of folate to all women is critical in order to prevent these devastating congenital defects. OBJECTIVE: To investigate the difference in response to an oral load of folate both from naturally occurring food sources and synthetic supplements among women with prior pregnancies affected by neural tube defects and controls. METHODS: We compared the absorption of test doses of 400 microg pteroylglutamic acid (unconjugated or synthetic folic acid found in supplements) and 400 microg pteroylpolyglutamic acid (conjugated or food folate) in 10 women with a history of neural tube defect affected pregnancies and eight controls with normal birth outcomes. The folate test dose was given as either 32 fluid ounces of orange juice or a folic acid single supplement pill. All participants received each test dose at separate clinic visits. The response to each test dose was measured by constructing an area under the curve (AUC) from the serum folate levels at 1, 2 and 3 hours post dose and applying a t-test to compare within and between cases and controls. We also compared red cell folate, vitamin B12, zinc and homocysteine between cases and controls. RESULTS: Within group comparisons showed that the area under the curve was significantly greater for the pteroylglutamic acid dose compared to the pteroylpolyglutamic acid dose for both cases and controls (p=0.02 and p=0.03, respectively). In a between group comparison, control women had a greater serum folate response to both forms of the vitamin compared to the case women, but the difference reached statistical significance only for the pteroylglutamic acid dose (p=0.02). Other measured nutrients differed between cases and controls, but did not reach statistical significance. CONCLUSION: We conclude that for all women synthetic folic acid as supplements or fortified foods may be the best way to increase acute folate levels in the blood, and thus delivery to the developing embryo. Further, since case women had a diminished response to both forms of the vitamin, and some case women had almost no response, we speculate that women with prior affected pregnancies may need a larger dose of folate to elicit a plasma response equivalent to the general population.

Bioavailability for humans of deuterium-labeled monoglutamyl and polyglutamyl folates is affected by selected foods.

Dietary folate exists mainly as polyglutamyl forms that require deconjugation by Zn-dependent pteroylpolyglutamate hydrolase prior to intestinal absorption. Because deconjugation by pteroylpolyglutamate hydrolase is an essential step in the absorption of dietary polyglutamyl folates, factors influencing the deconjugation process may affect folate bioavailability. This study was conducted to evaluate in vivo the bioavailability of [2H4]folic acid (d4-PteGlu1) and [2H2]-pteroylhexaglutamate (d2-PteGlu6) administered in solution in water or citrate buffer or added to selected foods using a single-dose, dual-label protocol. In each of six trials, healthy men (n = 7) were given a single oral dose of d2-PteGlu6 and d4-PteGlu1 (677 nmol of each form) blended into orange juice, tomatoes, lima beans, 52 mmol/L citrate (pH 4.1), or water as the control. Urine was collected for 48 h and the isotopic labeling of urinary folates used as criteria of the relative bioavailability of administered PteGlu1 and PteGlu6. Urinary excretion of d4-folates and d2-folates derived from the respective oral doses did not differ from the control in any treatment within the statistical power of this protocol. High relative bioavailability of the polyglutamyl folate was reflected by ratios of urinary d2/d4 folates of approximately 1.0 for control, tomato, lima bean and citrate buffer trials, whereas the ratio of urinary d2/d4 folates when subjects consumed orange juice was approximately 33% less than the control ratio (P < 0.05). These findings suggest that the bioavailability of polyglutamyl folates in orange juice would be partially incomplete. However, this would be compensated by the high total folate concentration of orange juice. The relation of these findings to endogenous dietary folates requires further investigation.

Relative bioavailability of deuterium-labeled monoglutamyl and hexaglutamyl folates in human subjects.

The bioavailability of orally administered mono- and polyglutamyl folates was examined in humans by using stable-isotope methods. [3',5'-2H2]Folic acid (d2-FA) and [3',5'-2H2]pteroylhexaglutamate (d2-PteGlu6) were prepared for oral administration and (glu-2H4)folic acid (d4-FA) was prepared for intravenous (iv) injection. In two trials, adult males (n = 7) on a folate saturation regimen (2 mg/d) were given a single 677-nmol oral dose of either d2-FA or d2-PteGlu6 in apple juice along with an iv injection of 502 nmol d4-FA as a control. Urine was collected for 48 h and the isotope labeling of urinary folates determined by mass spectrometry. The excretion ratio of urinary folates (% of d2-folate dose/% of d4-folate dose) resulting from oral d2-FA and iv d4-FA was 1.45 +/- 0.10 (mean +/- SEM) whereas the ratio for oral d2-PteGlu6 and iv d4-FA was 0.67 +/- 0.04. These results indicate that the d2-PteGlu6 is available to humans as a source of folate although its bioavailability is substantially less than that of d2-FA under these conditions.