What Is a Good Folate Serum Level

Folic Acid Blood Level

The reduction in serum folate levels is more marked in men with genetically inactive aldehyde dehydrogenase 2 (ALDH-2) that encoded mutant allele ALDH2*2, than those with active ALDH2 encoded by ALDH2*1/ALDH2*1 genotype.

From: Molecular Aspects of Alcohol and Nutrition , 2016

Investigation of Megaloblastic Anaemia

Dominic J. Harrington , in Dacie and Lewis Practical Haematology (Twelfth Edition), 2017

Clinical and diagnostic pitfalls of folate assays

Serum folate is altered by acute dietary change and interruption of enterohepatic recycling; it can therefore be low without significant tissue deficiency. Red cell folate was originally advocated as correlating better with megaloblastic change ^{42 , 43} reflecting the mean folate status over the lifespan of the red cells (2–3 months), but a subsequent study suggested that little was to be gained by the addition of red cell folate analysis. ⁴⁴ Minor haemolysis in vitro may cause spurious elevation of serum folate levels because the red cell folate may be 10–20 times the serum value. More than half of patients with severe cobalamin deficiency have a low red cell folate because impaired methionine synthesis results in accumulation of 5-methyl THF monoglutamate, which diffuses out of cells resulting in a high serum folate. ^{45 , 46} Treatment with cobalamin alone will correct the low red cell folate and high serum folate levels. The interplay between serum vitamin B₁₂, serum folate, red cell folate, plasma homocysteine and methylmalonic acid is shown in Table 10-7. In the USA, some authors have advocated cessation of folate testing because folate deficiency has become very unusual since the introduction of dietary supplementation of flour. The causes of clinical deficiency and supportive information or diagnostic tests are shown in Table 10-2.

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Neurologic Manifestations of Nutritional Disorders

Priya S. Dhawan , Brent P. Goodman , in Aminoff's Neurology and General Medicine (Fifth Edition), 2014

Diagnosis

Serum folate, erythrocyte folate, and homocysteine levels may be used to evaluate an individual with suspected folate deficiency. Results of these studies are highly dependent upon the methods and laboratories used. Serum folate levels fluctuate considerably and do not always accurately reflect tissue stores. ⁵¹ Erythrocyte folate levels may more accurately predict tissue stores, but there is considerable laboratory assay variability. ^52,53 Homocysteine levels have been demonstrated to be elevated in 86 percent of patients with clinically significant folate deficiency. ⁵⁴ Typically, a serum folate level of 2.5   μg/l has been utilized as the cut-off for folate deficiency ¹² ; however, it has been suggested that levels in the range of 2.5 to 5   ng/ml may reflect mildly compromised folate status.

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Methods for assessment of folate (Vitamin B9)

Agata Sobczyńska-Malefora , in Laboratory Assessment of Vitamin Status, 2019

Clinical Application of Measurement

Serum folate, red cell folate (RCF), and tHcy are the most commonly used laboratory markers for the assessment of folate status. Serum folate reflects recent dietary intake and is the earliest marker suggestive of suboptimal folate status. RCF is an indicator of long-term folate status (the preceding 120 days) and represents folate accumulated during red cell synthesis. Plasma homocysteine is a functional marker of folate status. Folate deficiency is the most common reason for elevated tHcy. Others reasons for elevated tHcy concentrations include deficiencies of vitamins B₁₂, B₆, B₂, and renal impairment. Elevated homocysteine has been also implicated in many other disease states.

Other laboratory markers of folate status with potential clinical use include unmetabolized folic acid (UFA), urinary folate and folic acid, serum and urinary para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (apABG), DNA methylation, uracil misincorporation into DNA and micronuclei, plasma and urinary formiminoglutamate, and aminoimidazole carboxamide riboside. ^{3, 18} The availability of these markers is currently limited and clinical utility has not been fully explored. However, a test that requires a 24   h urine collection will not likely be used widely in a diagnostic setting because of the inherent inter- and intraindividual variability, relative lack of sensitivity, and cumbersome sample collection, even though unique insights may be gained when used in combination with serum and RCF measurements. ¹⁸ The presence of unmetabolized serum folic acid has been linked with various adverse health effects including carcinogenesis, the masking of vitamin B₁₂ deficiency, childhood obesity, and both type 2 and gestational diabetes. ⁵⁴ The measurement of this marker may be clinically useful, especially in certain population groups such as pregnant women or in the elderly. Global DNA methylation correlates well with serum folate and is potentially a sensitive tool for the identification of folate depletion. ^{55, 56} Studies have shown that, for example, a diet containing 50–120   μg of folate per day for 7–9 weeks was sufficient to induce genomic DNA hypomethylation of blood mononuclear cells, and that folate repletion over several weeks caused hypomethylation to return to normal. ^{57, 58} Based on their study, Jacobs et al. suggested that "normal" folate concentrations (>   3   μg/L) are borderline at best and are probably too low to maintain DNA methylation, since tHcy begins to rise recognizably before the concentration of plasma folate falls into a true deficient state. ⁵⁷ Moreover, rises in plasma tHcy appear earlier than in DNA hypomethylation. ⁵⁵

The clinical utility of the most commonly used markers of folate status is briefly described as follows.

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Folate

Allyson A. West PhD, RD , ... Lynn B. Bailey PhD , in Present Knowledge in Nutrition (Eleventh Edition), 2020

B Assessment of Status

Folate status is most often assessed using blood folate concentrations (Table 14.3). Functional indicators, including plasma homocysteine and genomic biomarkers, can also offer insight into the function and capacity of folate-dependent metabolic pathways. ⁴

Table 14.3. Serum and RBC folate concentrations for folate status assessment. ^{a , 36,39}

	nmol/L	ng/mL	Interpretation
IOM criteria for dietary inadequacy
Serum	< 7	< 3	Deficiency based on increased risk of megaloblastic anemia
RBC	< 305	< 140
WHO criteria for insufficiency
RBC b	< 906	< 400	Insufficiency based on increased risk of NTDs with population-level status below cutoff
RBC c	< 748	< 330

a

Homocysteine concentrations were also considered in determining the adequacy of folate intake.

b

Assay specific cutoff for folate analysis by microbiologic assay with chloramphenicol-resistant strain and folic acid calibrator. ⁴⁴

c

Assay specific cutoff for folate analysis by microbiologic assay with chloramphenicol-resistant strain and 5-methyl-THF calibrator. ⁴⁴

Serum folate

Serum or plasma folate is a sensitive indicator of recent dietary folate intake and may also be used to assess long-term status when recurrent measures in the same individual are conducted overtime.

RBC folate

In contrast to serum folate, RBC folate is responsive to changes in status over the long term. Folate is taken up by developing reticulocytes in the bone marrow and not by mature RBCs in circulation, thus RBC folate represents the amount accumulated early in the ∼120   day RBC life span. In addition, RBC folate concentration is associated with liver folate content and is considered representative of tissue folate stores. ³⁶

Functional indicators of folate status

Plasma homocysteine concentration

Total plasma homocysteine can be a sensitive functional indicator of folate status. 5-MethylTHF is used in the remethylation of homocysteine to methionine (Fig. 14.2), and it is well established that plasma homocysteine rises under conditions of folate inadequacy. ³⁶ However, elevated total plasma homocysteine concentration is not specific to folate deficiency as homocysteine levels may also be influenced by several other nutrient deficiencies (e.g., vitamin B12), genetic abnormalities, or renal insufficiency. ³⁶ In folic acid–fortified populations, elevated plasma homocysteine is more likely to be associated with inadequate vitamin B12 than folate deficiency. ³⁸

Genomic biomarkers

Because of the essential role folate plays in nucleotide biosynthesis and methylation reactions, folate inadequacy has the potential to impact indices reflecting DNA synthesis, repair, modification, and stability (e.g., the misincorporation of uracil into DNA, DNA methylation, and micronuclei formation). ⁴ However, like plasma homocysteine, these genomic biomarkers can be affected by other nutritional and environmental factors and cannot be used in isolation to assess folate status. Nevertheless, used in the proper context, these indicators can provide valuable information about the functional effects of folate status at the genomic level, as well as folate-mediated 1-C metabolism at the cellular level. ⁴

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VITAMINS

TOM BRODY , in Nutritional Biochemistry (Second Edition), 1999

Measure of Serum and Red Blood Cell Folate

Serum folates can be determined by the competitive binding assay (as detailed under Vitamin B₁₂) or by microbiological assays. Microbiological assays can be used to measure most vitamins, including folate, vitamins B₆ and B_12, thiamin, and biotin. The concept behind the microbiological assay is the same in all cases. A test organism, such as a lactic acid bacterium, is used. Lactic acid bacteria are similar to animals in that they require a wide variety of nutrients, including a number of vitamins. Most other species of bacteria, in contrast, are able to synthesize all of the vitamins from glucose and other simple nutrients. A special type of growth medium is required. In the case of the assay for folate, the synthetic growth medium contains all of the required nutrients except folate. The lactic acid bacterium cannot grow on this medium; however, addition of known quantities of the vitamin, or of a biological sample containing an undetermined amount of folate, does support growth. The growth of the bacterium can reflect in a very sensitive and precise manner the exact amount of folate included in the growth medium.

Lactobacillus casei is the bacterium used in microbiological assays for folate. A series of tubes containing increasing amounts of folic acid are used to construct a standard curve. The tubes in the standard curve contain folic acid in concentrations ranging from 0 to 1.0 nM (Figure 9.15). The tubes are inoculated with a very small number of bacterial cells and incubated 20 hours. In the tubes containing little or no vitamin, there is little or no growth. Where the tubes contain larger amounts of vitamin, there are corresponding increased densities of cell growth. The results from the standard curve are shown in Figure 9.15. Cell growth densities in tubes containing unknown quantities of folate were also measured and compared with the standard curve to calculate the amount of folate in the unknown sample.

FIGURE 9.15. Growth of Lactobacillus casei. Growth of L. casei in a sample containing an unknown quantity of folate and in a series of tubes containing known quantities of folic acid is shown. The growth of the cells can be easily assessed by measuring the absorbance of the cell suspension in a spectrophotometer. The growth data from the tubes containing folic acid in the concentration range 0–1.0 nM is used to form the standard curve. The concentration of folate in the unknown is determined by measuring the absorbance of the bacterial suspension in the tube and then reading the folate level from the standard curve.

Serum contains folate monoglutamates. The normal level of serum folate is 6.0 ng/ml or greater. A value of 3.0 ng/ml or less indicates a folate deficiency. Serum folate levels are sensitive to recent dietary practices and hence may not accurately reflect the amount of folate in tissues. True folate status is closely related to the tissue or cellular level of folate, rather than the serum level.

Red blood cell folate levels closely reflect the true folate status of the subject, as these folates are an intracellular form. The folates of red blood cells, as well as of all other cells, occur mainly as folylpentaglutamates. Folylpentaglutamates, as well as other folylpolyglutamates, are poorly absorbed by bacterial cells. Hence, microbiological assays might not be expected to be useful in determining tissue folate levels. The problem can be avoided by treating tissue folates with γ-glutamyl hydrolase. This enzyme catalyzes the hydrolysis of folylpolyglutamates, producing folylmonoglutamate. The various folylmonoglutamates, such as 5-methyl-H₄PteGlu, H₄PteGlu, 10-formyl-H₄PteGlu, and PteGlu, are readily used by L. casei for growth. A red blood cell folate level greater than 160 ng/ml of packed cells indicates normal folate status. Values of 140 ng/ml or less indicate a deficiency.

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Megaloblastic Anemias

Aśok C. Antony , in Hematology (Seventh Edition), 2018

Plasma Transport and Enterohepatic Circulation

The normal serum folate level is maintained by dietary folate and a substantial enterohepatic circulation that amounts to about 90 µg/day of folate. ¹⁵ Biliary drainage results in a dramatic fall in serum folate (to about 30% of basal levels in 6 hours), whereas abrupt interruption of dietary folate leads to a fall in serum folate levels in about 3 weeks. In the plasma, one-third of the folate is free, two-thirds are nonspecifically bound to serum proteins, and a small fraction binds soluble folate receptors. However, in contrast to cobalamin uptake, there is no specific serum transport protein that enhances cellular folate uptake.

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FOLIC ACID | Physiology

C.J. Bates , in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003

Biochemical Status Measurements

Folate biochemical status is monitored most commonly by the assay of folate concentrations in plasma or in the red cells of the peripheral blood.

Plasma folate essentially reflects recent intakes and the magnitude of intertissue transfer, whereas red cell levels represent longer-term tissue stores, since intracellular (red cell) folate does not readily exchange with extracellular folate. Infants have much higher serum and red cell folate levels than those of adults, and this may be connected with the greater rate of cell division in infancy. Assays for folate which are based on competitive protein binding (radioassay or fluorescence assay), or on antibody binding, are now widely used, and several commercial kits for competitive-binding assays are now available. It is commonly accepted that serum (or plasma) levels below 3   μg l⁻¹ or erythrocyte levels below 100   μg l⁻¹ are indicative of biochemical deficiency, and should be further investigated or treated.

'Functional' tests, based on the efficiency of catabolism of a histidine load, or on deoxyuridine suppression of preformed thymidine utilization for DNA synthesis in tissue biopsies such as bone marrow cells, may provide useful functional evidence of tissue folate adequacy, although they are not used for routine measurement of status. Folate deficiency, like vitamin B₁₂ or B₆ deficiencies, results in raised plasma homocysteine (see below), and this functional index can provide useful information about folate status and dietary adequacy. (See IMMUNOASSAYS | Radioimmunoassay and Enzyme Immunoassay.)

A useful cytological indicator of marginal folate deficiency, which is more sensitive than overt anemia or megaloblastosis, is an increase in the lobe average count of the polymorphonuclear neutrophils in the circulation. Fewer than 3.3 lobes per cell is considered normal; more than 3.65 per cell indicates a significant functional deficiency.

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Nutritional Disorders of the Nervous System

Elliott L. Mancall , in Neurology and General Medicine (Fourth Edition), 2008

FOLIC ACID

Reduced serum folate levels have long been recognized in patients with subacute combined degeneration of the spinal cord and vitamin B₁₂ deficiency, and the association of maternal dietary folate deficiency in pregnancy with fetal neural tube defects is well established. Reversible depression and cognitive decline have frequently been reported in individuals with folate deficiency, especially the elderly, and perhaps related to homocysteine levels. ^77,78 A link to Alzheimer's disease has been suggested, though never adequately demonstrated. A single case of Kearns–Sayre syndrome associated with reduced plasma and cerebrospinal fluid folate has been reported. ⁷⁹

An infantile sporadic cerebral folate deficiency syndrome has been defined, recently suggested as being due to the presence of autoantibodies to folate receptors. ⁸⁰ The disorder develops ordinarily within 4 to 6 months postpartum and is characterized clinically by psychomotor retardation, ataxia, signs of upper motor neuron dysfunction, and a variety of abnormal movements. Some patients have seizures, and a small number with mental retardation appear autistic. Visual failure with optic atrophy may be manifested late in the course. At least some clinical abnormalities appear to respond to the administration of folinic acid.

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Biochemical Indices

C.M. Pfeiffer , ... K.L. Caldwell , in Encyclopedia of Human Nutrition (Third Edition), 2013

Folate

Folate status can be assessed by serum or plasma folate, which provides information on recent intake, and erythrocyte folate, indicative of body folate stores and long-term nutritional status. Traditionally, folate has been measured by microbiologic assay, however, in clinical settings where high throughput is needed, commercial protein-binding assays on automated clinical analyzers are used. If folate vitamers are of interest, for e.g., the measurement of free folic acid in serum or the measurement of various methyl- and nonmethyl-folate forms in erythrocytes depending on MTHFR C677T genotype, chromatography-based separation techniques need to be employed. Nowadays, they are often coupled to mass spectrometry (HPLC-MS/MS), because this detection method offers superior sensitivity, specificity, and selectivity compared to other detection methods such as fluorometric or electrochemical detection. Although the comparability of serum folate methods has been somewhat improved recently because serum-based standard reference materials have become available, diagnostic kits are not yet sufficiently standardized and no progress has yet been made in improving the comparability of assays for erythrocyte folate. Folate is the least stable of the B vitamins; careful sample handling and use of antioxidants are required to maintain sample integrity. Dried blood spots can also be used to measure folate by microbiologic assay. This presents a field-friendly alternative when prompt specimen processing cannot be performed or blood collection is limited to a finger stick.

In the absence of vitamin B₁₂ and B₆ deficiencies, measurement of plasma tHcy is a sensitive functional test for folate status. Because an elevated plasma tHcy concentration is associated with an increased risk of cardiovascular diseases, the determination of this amino acid in plasma has become very common. Various methods are available for tHcy determination, but the most commonly used research methods are HPLC with fluorescence detection or coupled to mass spectrometry. They allow simultaneous measurement of other thiols in the same sample. Many fully-automated commercial kits are available on the basis of immunoassay and enzymatic methods. Prompt separation of the plasma from the red cells needs to be ensured to avoid artificial elevation of tHcy. Urinary formiminoglutamic acid (FIGLU) and lymphocyte deoxyuridine (dU) suppression assays are older functional tests for folate status that are no longer used routinely. Hypersegmentation of neutrophilic granulocytes are sometimes seen as a functional indicator during the examination of blood smears following routine cellular blood counts.

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Flour Fortification and the Prevention of Neural Tube Defects (NTDs)

Emma Beckett , Mark Lucock , in Flour and Breads and their Fortification in Health and Disease Prevention (Second Edition), 2019

Fortification of Flour and the Prevention of NTDs

Overall increases in dietary folic acid intake and blood folate concentrations have been reported in response to folic acid fortification programs. ^44,45 Longitudinal data from the United States [specifically, from the National Health and Nutrition Examination Survey (NHANES)], has demonstrated that serum and erythrocyte folate levels have increased dramatically postfortification. ⁴⁶ Similar increases in serum and erythrocyte folate levels have also been reported in other jurisdictions, including Canada, ^45,47 Chile, ^48,49 and Australia. ^50,51

These enhanced biological levels of folate have reportedly translated into a reduction in NTD rates in a number of places. ^44,47,52,53 Countries with mandatory policies on folic acid fortification of staple foods have lower NTD prevalence than countries that have no fortification or only voluntary fortification, ⁵⁴ although the results may vary depending on ethnicity. Between 1995 and 2005 mandatory folic acid fortification was less effective in reducing NTDs in non-Hispanic blacks than in other ethnic groups. ⁵⁵ Most countries with mandatory food-fortification policies have achieved NTD prevalence estimates as low as 0.6 per 1000 total births. ^8,47,56,57 Conversely, in countries without mandatory food-fortification policies, the average prevalence is approximately 2.5 per 1000 live births, with rates in some countries as high as 20 per 1000 live births. ^8,58,59

However, even in countries where fortification has been implemented, NTD prevalence can still be variable within areas. This is a function of the effectiveness of folic acid fortification implementation methods, the penetration of programs, and genetic and dietary characteristics of the population in question. ^60,61 It is also important to note that although more than 80 countries have mandated folic acid fortification, to date, evidence of impact exists in only a minority of these. As such, there is a need for additional research to assess the impact of delivery methods of mandatory fortification regimens. ⁶¹

A 2013 systematic review on the impact of folic acid fortification of flour on the prevalence of NTDs across multiple countries (Chile, Argentina, Brazil, Canada, Costa Rica, Iran, Jordan, South Africa, and the United States) found a drop in the prevalence of NTDs in response to fortification in 15 of the 27 studies. ⁵⁷ It is important to note that in some of these countries, mandatory fortification is not limited to wheat flour; Costa Rica, for example, also requires fortification of maize flour, cow's milk, and rice. ⁵⁷

For all NTDs, the most significant drops were observed in Costa Rica (58%), ⁶² Argentina (49%), ⁶³ and Canada (49%). ⁶⁴ The smallest decrease occurred in the United States (15%). ⁶⁵ Of the 21 studies included in the meta-analysis, ⁵⁷ the greatest reductions in spina bifida rates reported were in Costa Rica (61%), ⁶² Canada (55%), ⁴⁷ and Chile (55%). ⁶³ The smallest reduction in the prevalence of spina bifida was in the United States, at just 3%. ⁶⁶ Variance in the reduction of incidence may be due to differences in previous voluntary fortification programs, socioeconomic factors, levels of fortification, and the number of flours or other staple foods fortified. When the prevalence of NTDs was related to levels of flour fortification, the lowest prevalence was observed at a folic acid level of 1.5   mg/kg.

Implementation of such programs is performed less in countries that do not industrially mill or import the majority of their grain products, making flour products difficult to fortify. ⁶¹ This is particularly the case in the low- to middle-income countries that do not currently employ mandated fortification programs. It is also essential that the delivery of currently mandated regimens be monitored to determine the quality of fortification programs. ⁴⁵ For example, based on single-sample testing of fortified foods in a range of national mandatory programs, a large proportion of samples do not meet nationally mandated standards. ⁶⁷ While these results are obtained from suboptimal single-sampling methods, in the absence of other data, it provides an inference about ongoing quality issues that can adversely affect the potential impact.

An example of a potentially suboptimal nationally mandated fortification implementation is Guatemala. In Guatemala, wheat and maize are fortified with folic acid. Despite this fact, there is considerable variance in the erythrocyte folate concentrations among women of reproductive age. Many indigenous Guatemalan populations living in rural, low-income regions do not purchase industrially milled flour, but instead process corn privately. As such, these populations are not exposed to fortification, leading to a higher risk for NTDs in offspring ⁶⁸ compared to urban-dwelling Guatemalans.

Similarly, a survey including six African countries fortifying maize or wheat flour with folic acid found that only two programs—South Africa (maize flour fortification) and Senegal (wheat flour fortification)—reached coverage of 40% or more for two or more "vulnerable groups," with vulnerability defined as using a composite indicator of poverty, poor women's dietary diversity score, and rural residence. ⁶⁹ Additionally, across all these countries, only 35% of wheat flour consumed was found to be fortifiable, and only 18.5% of that flour was found to be fortified at all. For maize flour, 48% consumed fortifiable maize flour, and only 29% of the maize flour that could be fortified was. Coverage was generally higher among urban populations and lower among at-risk population groups. ⁶⁹

Therefore, implementation of mandated fortification programs alone is not sufficient. Issues remain that are related to government and industry incentives, follow-up actions, regulations, monitoring, and enforcement of mandatory fortification programs. ^45,67 It is vital that mandatory legislation is underpinned with strong regulatory measures to ensure the quality of fortified foods. ⁴⁵

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What Is a Good Folate Serum Level

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