Folate (Folic Acid): Reference Range, Interpretation, Collection and Panels (2023)

Reference Range

Folate measurements are used in the diagnosis and management of megaloblastic anemia.The reference range of the plasma folate level varies by age, as follows [1] :

  • Adults -2-20 ng/mL, 2-20 μg/L, or 4.5-45.3 nmol/L

  • Children -5-21 ng/mL, 5-21 μg/L, or 11.3-47.6 nmol/L

  • Infants -14-51 ng/mL, 14-51 μg/L, or 31.7-115.5 nmol/L

The reference range of thered blood cell (RBC) folate level also varies by age, as follows [1] :

  • Adults: 140-628 ng/mL or 317-1422 nmol/L

  • Children: Over 160 ng/mL or over 362 nmol/L

However, since the United States institutedmandatory fortification of cereal grain products with folic acid, new adult reference values of 5.8-32.8 ng/mL (13.1-74.3 nmol/L) for serum folate and 153-515 ng/mL (347-1167 nmol/L) for erythrocyte folate have been proposed, demonstrating the importance of establishing regional and national reference values. [2]

Biochemical deficiency has been defined as a concentration of less than 3 ng/mL (< 6.7 nmol/L) for serum folate and less than 140 ng/ml (< 322 nmol/L) for erythrocyte folate. [3]

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Interpretation

Circulating folate levels are strongly influenced by recent intake and are an unreliable index of tissue stores. The plasma folate level can be restored to normal with one folate-rich meal. Principal food sources of folate are liver, spinach, legumes, and orange juice, although in countriesthat fortifycereal with folic acid, this is often the major source. [3]

RBC folate provides information about folate status over the lifetime of RBCs, similar to hemoglobin A1Cas used inblood glucose monitoring. Approximately 5% of people with normal serum folate levels may have evidence of folate deficiencyif analyzed usingRBC folate testing. [4]

In patents with normal or low-normal folate levels in whom folate deficiency is clinically suspected (based on risk factors such as malabsorption or other findings,including megaloblastic anemia), it is more common to use ancillary testing of methylmalonic acid (MMA) and homocysteine, rather than RBC folate analysis,to confirm folate deficiency. In folate deficiency, the plasma homocysteine level is elevated but MMA is normal, whereas both plasma homocysteine and MMA are elevated in vitamin-B12 deficiency. [5]

Causes of folate deficiency include the following [6] :

Researchers found higher rates of anemia and other blood abnormalities in people with low vitamin-B12 levels who also had high folate levels. [7] To address the concerns associated withthis finding, the National Institutes of Health (NIH) conducted a study on vitamin-B12 and folic acid levels in the population, particularly as high folic acid levels may result from the fortification of grains in the United States and other Western nations, and concluded that high folic acid levels do not worsen the manifestations of vitamin-B12 deficiency. [8]

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Collection and Panels

Most commercial laboratories offer the quantitative determination of folate in human serum, plasma, and RBCs using the ARCHITECT chemiluminescent microparticle immunoassay (CMIA, Abbott) [9] orelectrochemiluminescence (ECL)technology with flexible assay protocols (Roche). Otheranalytic tools are alsoavailable, such as the Immulite immunoassay (Siemens), [10] the Quantaphase II Folate/Vitamin B12 radioassay kit (Bio-Rad), [11] and themicrobiologic method. [12] Another analytic technique, using acompetitive binding receptor assay (the access folate assay) isavailable at Mayo Clinic Laboratories. [13]

Specifics oftheARCHITECTand the Immulite systems are listed below.

ARCHITECT folate assay - serum folate level

Specifics for this assay include the following [9] :

  • Specimen type -Venous blood

  • Container -Serum (glass or plastic tube), serum separator tube (SST), lithium heparin plasma separator tube (PST); do not use plasma in ethylenediaminetetraacetic acid (EDTA) tubes for folate; protect specimen from light; hemolyzed specimens will give falsely elevated levels

  • Collection method - Venipuncture

  • Specimen volume -3 mL

  • Collection instructions -Test should be performed after an8-hour fast; avoid vitamin-B12 injection before test

  • Other instructions -Do not use specimens that have been heat inactivated, pooled, or hemolyzed orthat haveobvious bacterial contamination

The following lead to inaccurate results:

  • The use of human anti-mouse antibodies (HAMA)

    (Video) Folate Deficiency, Causes (ex. medications), Pathogenesis, Symptoms, Diagnosis and Treatment

  • Routine exposure to animals/animal serum productsthat have heterophilic antibodies in their serumand can react with reagent immunoglobulins

  • The use of methotrexate, aminopterin, or folinic acid (leucovorin)

If testingis not being performed immediately, specimens may be stored at 2-8 ºC for 7 days or at -10 ºC for 30 days.

Immulite 2000 folic acid test - RBC folate level

Specifics for this assay include the following [10] :

  • Specimen type -Venous blood; calculation of RBC folate requires simultaneous testing of the patient’s hematocrit and serum folate level

  • Container - Fresh heparinized or EDTA whole blood (EDTA plasma should not be used)

  • Collection method -Venipuncture

  • Specimen volume -100 μLfresh heparinized or EDTA whole blood for RBC folate, 50 μL serum/heparinized plasma for serum folate

  • Collection instructions -Test should be performedafter an8-hour fast; avoid vitamin-B12 injection before test

  • Other instructions - To clear a lipemic sample,ultracentrifuge use is recommended; ensure complete clot formation prior to centrifugation

If testing will not be performed immediately, specimens may be stored at 2-8 ºC for 8 hours or at -20 ºC for 6-8 weeks.

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Background

The naturalvariety ofvitamin B9 is known as folate. Although the terms folate and folic acid are used interchangeably, folic acid is synthetically made.

Folate itself is not biologically active. It is converted to its active form, tetrahydrofolic acid (THF), by the enzyme dihydrofolate reductase.Compounds such as serine, glycine, and histidine contribute one-carbon fragments to THF,which transfers them into intermediates used in amino acid, purine, and thymidine synthesis, with thymidine being the characteristic pyrimidine in DNA. [14]

THF is involved in the conversion of homocysteine to methionine; hence, elevated homocysteine levels are noted in folate deficiency.

Folate is found in the following foods [15] :

  • Meats -Liver, chicken, kidney, egg yolk

  • Legumes -Dried beans, lentils, soya products, almonds, nuts

  • Starches -Whole-grain breads, wheat flour, potatoes

  • Fruit and vegetables -Spinach, beetroot, Brussels sprouts, broccoli, cabbage, asparagus, bananas, oranges, peaches

    (Video) Folic Acid Test | Vitamin B9 Test | Folic Acid Deficiency | Serum & RBC Folate Test |

Normal folate requirements are about 200-400 µg/day. The requirements in pregnant and lactating individuals increase to 500-800 µg/day. Healthy individuals have about 500-20,000 µg of folate stored, mainly in the liver.

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Indications

Folate testing is mainly indicatedas part ofthe workupformegaloblastic anemiaand hypersegmented neutrophils.

Screening forfolate deficiency is performed by checking the serum folic acid level. Serum levels are sensitive to false elevation after a meal, sofasting levels are more reliable. RBC levels are not recommended as a screening test but rather as a diagnostic test when serum levels are low or low-normal. However, although RBC folate is more accurate, it is acostly and less available test. Alternatively, elevated serum homocysteine levels with normal MMA levelscan beused to confirm folate deficiency. [4]

Pregnancy is not an indication for routine folate screening, although it is an indication for prophylactic folate supplementation.

Folate deficiency is treated with folic acid supplementation and management of the underlying cause.

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Considerations

The main presentation of folate deficiency is megaloblastic anemia without neurologic changes, in contrast to vitamin-B12 deficiency, in which neurologic changes may be observed.

Folic acid can partially reverse some of the hematologic abnormalities of vitamin-B12 deficiency but not the neurologic manifestations. Thus, megaloblastic anemia is not treated with folic acid until vitamin-B12 deficiencyhas beenexcluded.

Folate deficiency can also cause congenital neural tube defects, the incidence of which is reduced by the administration of folic acid supplements in pregnant women.

The fact thatfolate is required for the synthesis and repair of DNA makes it a target for many cancer medications. Methotrexate, for example, is a dihydrofolate reductase inhibitorthat prevents the conversion of inactive folate to its active form, THF.

In a case-control study that evaluated 750 patients with documented vascular disease and 800 control subjects, low levels of folate and vitamin B6 were associated with an increased risk for atherosclerosis, independent of conventional risk factors. The folate-linkedrisk waspartially explained by increased serum homocysteine. [16]

Folate (Folic Acid): Reference Range, Interpretation, Collection and Panels (6)

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(Video) Folic Acid Test - Checking Folic Acid Deficiency

Contributor Information and Disclosures

Author

Rugheed Ghadban, MD Assistant Professor, Division of Cardiovascular Medicine, University of Missouri-Columbia School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Rajaa Almourani, MD Resident Physician, Department of Internal Medicine, St Louis University Hospital

Rajaa Almourani, MD is a member of the following medical societies: National Arab American Medical Association, Syrian American Medical Society

Disclosure: Nothing to disclose.

Catherine Anastasopoulou, MD, PhD, FACE Associate Professor of Medicine, The Steven, Daniel and Douglas Altman Chair of Endocrinology, Sidney Kimmel Medical College of Thomas Jefferson University; Einstein Endocrine Associates, Einstein Medical Center

Catherine Anastasopoulou, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American Society for Bone and Mineral Research, Endocrine Society, Philadelphia Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Sridevi Devaraj, PhD, DABCC, FAACC, FRSC, CCRP Medical Director of Clinical Chemistry and Point of Care Technology (POCT), Texas Children’s Hospital and Clearlake Health Center; Director of Laboratories, TCH Centers for Women and Children; Professor of Pathology and Immunology, Director, Clinical Chemistry Fellowship and Clinical Chemistry Resident Rotation, Baylor College of Medicine; Associate Director, Texas Children’s Microbiome Center

Disclosure: Nothing to disclose.

Additional Contributors

Ejaz Mahmood, MBBS, MRCGP Resident Physician, Department of Internal Medicine, Einstein Medical Center

Ejaz Mahmood, MBBS, MRCGP is a member of the following medical societies: Philadelphia Endocrine Society

Disclosure: Nothing to disclose.

(Video) Why You Should Take Folic Acid BEFORE Pregnancy

FAQs

What is a good folate score? ›

Normal Results

The normal range is 2.7 to 17.0 nanograms per milliliter (ng/mL) or 6.12 to 38.52 nanomoles per liter (nmol/L). Normal value ranges may vary slightly among different labs. Talk to your provider about the meaning of your test results.

How do you read folate test results? ›

For red blood cells, a normal result ranges from 140 to 628 ng/mL or 317 to 1,422 nmol/L. A test result that's lower than normal means you have a folate deficiency, and your healthcare provider may recommend folic acid supplements.

What does my folate level mean? ›

High values. High levels of folate in the blood may mean that you eat a diet rich in folate or folic acid, take vitamins, or take folic acid pills. Consuming more folate than the body needs does not cause problems. High folate levels can also mean a vitamin B12 deficiency. Body cells need vitamin B12 to use folate.

What happens if your folate is low? ›

Vitamin B12 or B9 (commonly called folate) deficiency anaemia occurs when a lack of vitamin B12 or folate causes the body to produce abnormally large red blood cells that can't function properly. Red blood cells carry oxygen around the body using a substance called haemoglobin.

What cancers cause folic acid deficiency? ›

Folic acid deficiency in humans has been linked with megaloblastic anaemia, neural tube defects in the neonate, and heart disease. Folate has also been implicated in the development of cancer, especially cancer of the colorectum.

What should a woman's folate be? ›

Most vitamins sold in the United States have the recommended daily amount of folic acid (400 mcg) that women need to prevent neural tube defects. Vitamins can be found at most local pharmacy, grocery, or discount stores.

What level of folate is considered low? ›

Biochemical deficiency has been defined as a concentration of less than 3 ng/mL (< 6.7 nmol/L) for serum folate and less than 140 ng/ml (< 322 nmol/L) for erythrocyte folate.

Can folate cause nerve pain? ›

Causing too much folate (vitamin B9) is associated with increased risk for a nerve-damage disorder in older adults who have a common genetic variant.

What is a toxic level of folate? ›

It is extremely rare to reach a toxic level when eating folate from food sources. However, an upper limit for folic acid is set at 1,000 mcg daily because studies have shown that taking higher amounts can mask a vitamin B12 deficiency.

Which is one of the first symptoms of folate deficiency? ›

diarrhoea. numbness and tingling in the feet and hands. muscle weakness. depression.

What is the most common cause of folate deficiency? ›

Folate deficiency caused by a lack of dietary folate is more common in people who have a generally unbalanced and unhealthy diet, people who regularly misuse alcohol, and people following a fad diet that does not involve eating good sources of folate.

What does low folate feel like? ›

Common symptoms of folate deficiency can include: Tiredness, fatigue and lethargy. Muscle weakness. Neurological signs, such as a feeling of pins and needles, tingling, or burning, or peripheral neuropathy, i.e. a numbness in the extremities.

What diseases cause low folate? ›

Causes
  • Diseases in which folic acid is not well absorbed in the digestive system (such as celiac disease or Crohn disease)
  • Drinking too much alcohol.
  • Eating overcooked fruits and vegetables. ...
  • Hemolytic anemia.
  • Certain medicines (such as phenytoin, sulfasalazine, or trimethoprim-sulfamethoxazole)
19 Jul 2021

What should I take if my folate is low? ›

Your healthcare provider will treat your folate deficiency with a folic acid supplement. Most adults need 400 micrograms (mcg) of folic acid each day. Your healthcare provider will let you know how much you should take. Your healthcare provider will also advise you to eat a healthy, balanced diet.

Can low folate cause anxiety? ›

“Problems with folate metabolism have been associated with depression and/or anxiety.

Does low folate cause weight gain? ›

Furthermore, folate deficiency may lead to body weight gain and adiposity [12]. Several studies has indicated a link between low folate intake or low serum folate concentration and greater body mass, BMI, overall fat accumulation, and higher waist circumference [13,14,15,16].

How big of a problem is folic acid deficiency? ›

Untreated folic acid deficiency can lead to megaloblastic anemia and pancytopenia. In addition, it can cause glossitis, angular stomatitis, and oral ulcers [2].

Can low folate cause weightloss? ›

The link between folate metabolism and obesity has recently been underlined, suggesting that folate deficiency may lead to body weight gain and adiposity.

Is folic acid and vitamin B12 the same thing? ›

Your body needs vitamin B-12, also called cobalamin, and folate, also called folic acid, to function normally. Both nutrients play important roles in creating red blood cells and making DNA and RNA to help build cells.

What part of the body does folate affect? ›

Folate (vitamin B-9) is important in red blood cell formation and for healthy cell growth and function. The nutrient is crucial during early pregnancy to reduce the risk of birth defects of the brain and spine.

How does folate affect the brain? ›

Some of the important functions folate aides in are the creation of DNA and RNA, formation of neurotransmitters, and the formation of the nervous system during pregnancy. Folate is also known to help with depression, mental fatigue, and irritability because it can be quickly broken down and supply the body with energy.

Does folate affect blood pressure? ›

It has been demonstrated that low serum folate levels are related to increased cardiovascular risk. Epidemiologic evidence suggests that a deficiency of folic acid may lead to hypertension, and a negative association between plasma folic acid and blood pressure (BP) has been reported.

Can too much folate cause symptoms? ›

However, getting too much folic acid may cause several side effects, including slower brain development in children and accelerated mental decline in older adults. While further research is needed, you can work with your healthcare professional to determine your folate levels and whether you need to take a supplement.

Can folic acid cause problems? ›

Is folic acid safe? At this time, folic acid taken at or up to the recommended amount of 400 micrograms per day (mcg/day) has not been shown to be harmful. Additional information continues to be assessed as it becomes available. The benefits of taking folic acid are well established.

How much folate is too much for a woman? ›

Yet, for most women, consuming more than 1,000 mcg of folic acid daily is of no benefit. Unless their doctor advises them to take more, most women should limit the amount they take to 1,000 mcg a day.

Can low folate cause heart problems? ›

Research has shown a lack of folate in your body may increase your risk of cardiovascular disease (CVD). CVD is a general term that describes a disease of the heart or blood vessels, such as coronary heart disease.

Can low folic acid cause nerve damage? ›

In conclusion, our results suggest that folate deficiency is a risk factor for neuropathy in patients younger than 40 years. Importantly, the risk of peripheral neuropathy increased as serum folate decreased, and even insufficient serum folate of 6.8 to 13.5 nmol/L appeared to be important.

Can low folate cause dizziness? ›

The signs can come gradually and mimic other common symptoms such as feeling tired, irritable or dizzy. These symptoms indicate folate-deficiency anemia, a condition that happens when the body's lack of folate or folic acid limits the production of red blood cells.

What disease is associated with folate? ›

Low levels of folic acid can cause megaloblastic anemia. With this condition, red blood cells are larger than normal. There are fewer of these cells. They are also oval-shaped, not round.

Can folic acid cause headaches? ›

Though excess folic acid consumption isn't likely to cause serious harm, it can cause side effects. Too much folic acid can cause headaches, stomach upset, diarrhea, and other discomfort.

What deficiency causes weight gain? ›

Vitamin D deficiency is linked to many disease processes. It also plays a role in weight gain. If you're struggling with weight loss, there's a very good chance you're also struggling to store adequate amounts of vitamin D in your body.

Can low folate cause mental health problems? ›

Folate deficiency has been associated with the presence of depression,1 may hinder response to antidepressants,1,2 and may contribute to relapse of depression. 3 Low levels of folate, a B vitamin, have also been associated with poor cognitive function,4 which is common among patients with depression.

Why has my doctor prescribed folic acid? ›

Folic acid is used to: treat or prevent folate deficiency anaemia. help your baby's brain, skull and spinal cord develop properly in pregnancy, to avoid development problems (called neural tube defects) such as spina bifida.

What causes low b12 and folate? ›

Vitamin deficiency anemia is a lack of healthy red blood cells caused by lower than usual amounts of vitamin B-12 and folate. This can happen if you don't eat enough foods containing vitamin B-12 and folate, or if your body has trouble absorbing or processing these vitamins.

How does low folate affect the brain? ›

Over the past 35 years numerous studies have shown a high incidence of folate deficiency correlated with mental symptoms, especially depression and cognitive decline in epileptic, neurological, psychiatric, geriatric, and psychogeriatric populations.

How long does it take to recover from low folate? ›

Folate-deficiency anemia most often responds well to treatment within 3 to 6 months. It will likely get better when the underlying cause of the deficiency is treated.

Is 10 a good folate level? ›

For adults, normal serum folate levels range from 3–10 ng/mL. Normal red blood cell folate levels are typically between 140–630 ng/mL.

What is considered low folate level? ›

Biochemical deficiency has been defined as a concentration of less than 3 ng/mL (< 6.7 nmol/L) for serum folate and less than 140 ng/ml (< 322 nmol/L) for erythrocyte folate.

Is a folate level of 20 good? ›

Optimal Result: 3 - 20 ng/mL, or 6.80 - 45.32 nmol/L.

Is 12 a good folate level? ›

If the test is done on your blood plasma, a normal range for folate is 2 to 10 ng/mL. If the test is done on red blood cells, a normal range is 140 to 960 ng/mL. If your folate results are low, it may mean you have: A diet that doesn't provide enough folate.

What is a normal b12 folate level? ›

Normal values are 160 to 950 picograms per milliliter (pg/mL), or 118 to 701 picomoles per liter (pmol/L). Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or may test different samples. Talk to your provider about what your specific test results mean.

Why is folate level important? ›

Folate (vitamin B-9) is important in red blood cell formation and for healthy cell growth and function. The nutrient is crucial during early pregnancy to reduce the risk of birth defects of the brain and spine.

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