Table of Contents<\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5923″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Table 1. Folate contents of foods.<\/b> A relatively small number of foods are concentrated sources of naturally occurring folate (i.e., food folate); including dark green vegetables, orange juice, legumes, nuts and seeds<\/b>. Meat is not a nutrient-dense source of folate<\/b>, except for liver<\/b>. Substantial losses of this vitamin can occur during the cooking process as a result of the combination of thermal degradation and leaching into the cooking water.<\/i><\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”introduction”][vc_column][vc_custom_heading text=”Introduction”][vc_custom_heading text=”Dietary Folate Sources” use_theme_fonts=”yes” el_id=”blog-scroll-point-1″][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The mandatory FA fortification of enriched cereal grain products beginning in the late 1990s in the United States and Canada has increased the folate content of stable foods such as bread, rice, and pasta, as well as thousands of mixed food items [2].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In addition to enriched cereal grain products, fortified RTE cereals are another important dietary source of FA with the majority of products providing 100 \u03bcg\/serving and many contributing an amount comparable to the dosage found in supplements, i.e., 400 \u03bcg\/serving.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n FA is also an ingredient in meal replacement foods<\/b>, infant formulas<\/i><\/b>, and an every-growing number of snack food items such as \u2018nutrient bars<\/i><\/b>.\u2019<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n FA was selected as the form of the vitamin used for food fortification because of its excellent stability characteristics.<\/b> The retention of FA in vitamin-mineral premixes used for food fortification and in RTE cereals has been examined with evidence of little or no loss during storage for up to 6 months, and FA stability during baking of bread products has been reported to be high.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-2″][vc_column][vc_custom_heading text=”Folates in Human Nutrition”][vc_column_text single_style=””]<\/p>\n Sources of food folates in human diet are leafy vegetables, liver, wheat germ, and yeast<\/i><\/b>. The main dietary folate forms are (a) 5-methyl-THF<\/b> and (b)<\/b> formyl-THF<\/b> in poly glutamate forms. Folates enter the circulation after absorption in the small intestine (see Figure 1<\/b>; Table 1<\/b>).<\/p>\n [\/vc_column_text][vc_single_image image=”5929″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 1. Intestinal absorption of dietary folate and transport into circulation.<\/b> [ABCC1, ATP-binding cassette, subfamily C, member 1; FGCP, folyl-\u03b3-polyglutamate carboxypeptidase; FPGS, folylpoly-\u03b3-glutamate synthase; FR, folate receptor; GGH, \u03b3-glutamate hydrolase; PCFT\/HCP1, proton-coupled folate transporter\/heme carrier protein 1; RFC1, reduced folate carrier 1]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In addition to folates supplied by the diet, folates can be synthesized by the microflora of the large intestine<\/span>. These folates can be absorbed in the large intestine and were believed to be insignificant for vitamin supply. However, recent studies revealed that the amount of folate absorbed in the colon can cover 5% of the average folate requirements for healthy adults; and can therefore influence the folate status.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The bioavailability of natural folate depends on,<\/b> for instance:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The bioavailability of polyglutamates is ~<\/sup> 65 to 70% lower than that of folate monoglutamates<\/span> [3].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n For more detailed description of intestinal absorption of dietary folate and transport into circulation: (cf. previous blogs entitled as: (i) <\/b>\u2018Folate Transport Systems \u2013 I: Transmembrane Carriers,\u2019<\/a><\/u><\/i> (ii)<\/b> \u2018Folate Transport Systems \u2013 II: Folate Receptors,\u2019<\/a><\/u><\/i> (iii)<\/b> \u2018Intestinal Absorption of Dietary Folates,\u2019<\/a><\/u><\/i> (iv)<\/b> \u2018Folate Homeostasis and Tissue Accumulation: What You Need to Know.\u2019 <\/a><\/u><\/i>).<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-3″][vc_column][vc_custom_heading text=”Dietary Reference Intake Standards”][vc_column_text single_style=””]<\/p>\n The Recommended Dietary Allowance<\/i><\/b> (RDA<\/b>) which were set by the U.S. Institute of Medicine, represents the average daily intake that is sufficient to meet the nutrient requirements of nearly all (97 \u2013 98%) healthy individuals in each age and gender group (see Table 2<\/b>).<\/p>\n [\/vc_column_text][vc_single_image image=”5926″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Table 2. Recommended reference intake of dietary folate equivalents and upper intake of folate from fortified foods or supplements by the U.S. Institute of Medicine.<\/b> *: Upper intake level = 800 \u03bcg\/day for 14-18 years and 1,000 \u03bcg\/day for adults.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The recommendation for food folate was based on the assumption that the bioavailability of food folates is no more than 50% of that of FA<\/i><\/b>. The RDA for folate is:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n 1 \u03bcg of DFE is defined as 0.6 \u03bcg FA<\/i><\/b>. The upper tolerable limit (UL<\/b>) for synthetic FA for adults is 1000 \u03bcg\/day<\/b>. There is currently little, if any evidence that high intake of natural folates<\/b> can be harmful to human.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-4″][vc_column][vc_custom_heading text=”Bioavailability of Folates in Foods”][vc_column_text single_style=””]<\/p>\n The biological availability of folate in foods has been difficult to assess. Several key factors can affect the utilization of food folates, for instance:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Interaction of these factors complicate the task of predicting the bioavailability of dietary folates. This problem is exacerbated by methodological difficulties in evaluating folate utilization<\/b>, which has been approached with bioassays with animal models<\/i><\/b>, and with studies in humans<\/i><\/b>, such as:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Each has limitations. The result is that estimates of the bioavailability of folates in foods and mixed diets are highly variable (see Table 3<\/strong>) [4].<\/p>\n [\/vc_column_text][vc_single_image image=”5928″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Table 3. Individual variability in reported bioavailability values of folates in foods.<\/b> [FA, folic acid]<\/p>\n [Sources: Tamura T, Stokstad EL. The availability of food folate in man. Br J Haematol. 1973 Oct;25(4):513-32.; Babu S, Srikantia SG. Availability of folates from some foods. Am J Clin Nutr. 1976 Apr;29(4):376-9.; Baker H, Jaslow SP, Frank O. Severe impairment of dietary folate utilization in the elderly. J Am Geriatr Soc. 1978 May;26(5):218-21.]<\/i><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-5″][vc_column][vc_custom_heading text=”Folate Concentrations in Serum, Whole Blood, and Cerebrospinal Fluid (CSF)”][vc_column_text single_style=””]<\/p>\n Serum concentration of folates ranges between ~<\/sup> 10 – 50 nmol\/L, with 5-methyl-THF<\/b> predominating (82 – 93% of total folate serum). Most of the blood folate is unspecifically bound to proteins [e.g., \u03b12-macroglobulin, albumin (Kd ~<\/sup> 1 mmol\/L), and transferrin] with a low affinity.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Folate-binding proteins (FBPs) bind a small amount of blood folate with high affinity (Kd ~<\/sup> 1 nmol\/L). The concentration of FBPs in human serum is approximately 0.6 nmol\/L, whereas there is a 10 – 30 fold higher molar concentration of folate in serum.<\/span> The serum FBPs are fully saturated with folate. The liver is responsible for the maintenance of the serum folate concentration. This is ensured by the reversible formation and depletion of the intracellular non-methylated folate polyglutamates<\/i><\/b>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The reference values of fasting serum folate concentrations for children, adolescents, and adults <\/strong> are presented in Table 4 (see Table 4<\/strong>) [5].<\/p>\n [\/vc_column_text][vc_single_image image=”5925″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Table 4. Folate reference values in fasting serum from countries not applying fortification.<\/b> The data are the 25th<\/sup> \u2013 97.5th<\/sup> percentiles. [C<\/sup><\/i><\/b>, Conversion factor: \u03bcg\/L x 2.27 = nmol\/L<\/i>]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Folates are incorporated into red blood cells (RBCs) during erythropoiesis<\/span>. FBPs are expressed on early stage hematopoietic cells and are involved in the folate uptake. The reduced folate carrier (RFC<\/b>) is necessary for the folate transport in erythroid cells. Folate in erythrocytes are mainly 5-methyl-THF<\/b> and formyl-THF<\/b> in their polyglutamate form, mostly penta- and hexaglutamates. Usually, RBC folate is 30 fold higher than the serum folate concentration ranging from 140 – 450 ng\/mL packed cells<\/span>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Similar to serum, the RBC folates are unspecifically bound to proteins such as hemoglobin. Matured erythrocytes are impermeable for folylpolyglutamates<\/i><\/b>. This leads to an intracellular retention of the folates with a half-life of about 100 days (the lifespan of the erythrocytes, RBCs). Therefore, RBC folate represents a long-term marker for folate status<\/i><\/b>. This maker is not affected by recent changes in the dietary intake.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The 5-methyl-THF and non-methyl-THF concentrations obtained by liquid chromatography-tandem mass spectrometry (LC-MS\/MS<\/b>) methods in serum and EDTA whole blood (WB<\/b>) are summarized in Table 5 (see Table 5<\/b>) [6-8].<\/p>\n [\/vc_column_text][vc_single_image image=”5924″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Table 5. Folate concentrations in serum, plasma, whole blood samples determined by LC-MS\/MS.<\/b> The data are presented as medians (10th<\/sup> \u2013 90th<\/sup> percentiles), b<\/sup>: medians (range); d<\/sup>: means (standard deviations, SDs); or e<\/sup>: means concentrations. a<\/sup>: UPLC-MS\/MS. c<\/sup>: Supplementation with 500 \u03bcg folic acid, 50 mg vitamin B6<\/sub>, and 500 \u03bcg B12<\/sub> for 6 months. f<\/sup>: Supplements included multivitamins, B vitamins, and folic acid. [THF, tetrahydrofolate; FA, folic acid; WB, whole blood; LC-MS\/MS, liquid chromatography-tandem mass spectrometry; UPLC-MS\/MS, ultra-performance liquid chromatography-tandem mass spectrometry]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The folate transport into the cerebrospinal fluid (CSF) occurs in the choroid plexus, where 5-methyl-THF is transported across the blood-CSF barrier<\/span>. The membrane folate receptor \u03b1 (FOLR1\/FR\u03b1<\/b>) is the most abundant folate transporter in the choroid plexus, suggesting its role as major folate transporter across the blood-CSF barrier. The recently described proton-coupled folate transporter\/heme carrier protein 1 (PCFT\/HCP1) functions most likely in concert with the FR\u03b1 <\/b>(adult brain<\/b>) and FR\u03b2<\/b> (fetal brain<\/b>) or might export the folates after FR\u03b1-mediated endocytosis. The folate concentrations in the CSF are up to 3 times higher than in serum<\/span> (see Table 6<\/b>).<\/p>\n [\/vc_column_text][vc_single_image image=”5931″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Table 6. Folate forms distribution in serum\/plasma and CSF determined by immunological methods or LC-MS\/MS.<\/b> The data are medians (10th<\/sup> \u2013 90th<\/sup> percentile) or means (standard deviation, SD). [THF, tetrahydrofolate, LC-MS\/MS, liquid chromatography-tandem mass spectrometry]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The cerebral folate deficiency (CFD)<\/a> is defined as \u201ca neurological syndrome associated with low CSF concentrations of 5-methyl-THF in the presence of normal peripheral folate status<\/span><\/u>.\u201d CFD has an early onset in late infancy<\/i><\/b> and is characterized by, for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n CFD can be associated with peripheral folate deficiency<\/span><\/u>, but this might not be case in some cases. In cases with normal peripheral folate status<\/span><\/u>, CFD may develop due to the impaired folate transport across the blood-CSF barrier at the choroid plexus.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Other disease conditions that are associated with CFD<\/strong> are, for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Oral dose of folinic acid (5-formyl-THF)<\/strong> can normalize the CSF folate and lower the frequency and the severity of the epileptic seizures in affected patients.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_class=”blog-text-35795″ el_id=”blog-scroll-point-6″][vc_column][vc_custom_heading text=”Take Home Messages” el_class=”blog-text-35795″][vc_column_text single_style=””]<\/p>\n Sources of Folate<\/em><\/strong><\/p>\n [\/vc_column_text][vc_column_text single_style=””]Folate Bioavailability<\/em><\/strong><\/p>\n [\/vc_column_text][vc_column_text single_style=””]Serum\/Whole Blood\/CSF Folate <\/em><\/strong><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_class=”blog-text-35795″ el_id=”conclusion”][vc_column][vc_custom_heading text=”Summary and Conclusions” el_class=”blog-text-35795″][vc_column_text single_style=””]<\/p>\n In this blog, we have attempted briefly to characterize the magnitude of folate status\/deficiencies in the United States and elsewhere. Mainly focusing on folate in human nutrition, dietary sources and bioavailability of folates in foods, and most importantly, folate concentrations in serum, whole blood, and CSF in children, adolescents, and adults.<\/p>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”u-orange”]<\/p>\n In general, definite conclusions pertaining to the extent of folate status\/deficiencies could not be drawn because of limitations of the data, including: (a) <\/b>the paucity of population-based studies designed to assess folate status at the national or regional level; (b)<\/b> variation in the life-stage groups (for e.g., children, pregnant women) evaluated in different countries, with very few surveys designed to assess the folate status in the general population; (c)<\/b> use of different analytical methods to measure serum and RBC (erythrocyte) folate, which raises concern regarding assay variability and validity, and (d)<\/b> use of poorly defined and inconsistent cutoff values to define folate deficiency based on serum and\/or RBC folate concentrations.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n It was possible, however, to provide some indication based on the evaluation of available data that in the majority of countries for which there are national survey data, folate deficiency appears to be a public health problem<\/span>. This clearly demonstrates that there is a pressing need for further studies to address the limitations of the folate assessment data, which will facilitate planning for appropriate public health intervention strategies in specific countries around the world, including United States!<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text single_style=”” el_class=”blog-banner-section”]<\/p>\n Folate (vitamin B9) is very important for your child\u2019s brain development!<\/p>\n During pregnancy, it helps prevent neural tube defects and plays a big role in forming a normal and healthy baby\u2019s brain and spinal cord. Folate also helps cells divide and assists in both DNA and RNA synthesis.<\/p>\n Emerging research suggests that the presence of FRAAs negatively impacts folate transport into the brain.<\/p>\n Yes, there is a test – The Folate Receptor Antibody Test (FRAT\u00ae<\/sup>) has emerged as a diagnostic tool for detecting the presence of FRAAs.<\/p>\n It is important to screen at an early age or as soon as possible as there may be corrective measures available. Please consult your physician for further information.<\/p>\n To request a test kit, click on the button below.<\/p>\n Request Now<\/a><\/p>\n<\/div>\n<\/div>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”text-gray-23″]For information on autism monitoring, screening and testing please read our blog<\/a>.[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-references” el_class=”blog-text-35795″][vc_column][vc_custom_heading text=”References” use_theme_fonts=”yes”][vc_column_text single_style=”” el_id=”blog-ref-3564″]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row]<\/p>\n","protected":false},"excerpt":{"rendered":" Discover folate sources, bioavailability, and concentrations in serum, whole blood, and CSF. Learn about folate’s role in health and its impact on various age groups.<\/p>\n","protected":false},"author":3,"featured_media":5927,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[80,64],"tags":[],"yoast_head":"\n\n
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Did You Know? Folate Receptor Autoantibodies (FRAAs) may impede proper folate transport.<\/h4>\n
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Is there a test for identifying Folate Receptor Autoantibodies (FRAAs)?<\/h4>\n
![\"FRAT](\"https:\/\/autism.fratnow.com\/blog\/wp-content\/uploads\/2023\/12\/frat-mascot-image.webp\")
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\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/2697230\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/15831124\/
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\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/19087427\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/8323433\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/17200133\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/18463447\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/19661622\/
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