Folate is a generic term that typically refers to a group of water-soluble compounds that play an essential role in deoxyribonucleic acid (DNA) biosynthesis. It is also known as vitamin B9 and is different from folinic acid, or leucovorin, which is more technically known as 5-formyltetrahydrofolate (5-FTHF). Folic acid is the synthetic form of folate. Folate converts into tetrahydrofolic acid (THF), a compound that undergoes several transfer/methylation reactions that are important for the synthesis of nitrogenous bases in DNA and ribonucleic acid (RNA) and are necessary for maturation of red blood cells (RBCs). There are small reserve pools in the liver and kidney. A deficiency of folic acid can result in macrocytic megaloblastic anemia and usually results from chronic alcoholism, malabsorption disorders, hemolytic anemia, or increased requirement during pregnancy. Folate appears naturally in some food sources and must be ingested regularly since humans, and all other animals, cannot synthesize it. Sources of folate in the diet include leafy green vegetables, like spinach, broccoli, and lettuce; meats, such as liver; and milk and eggs. Despite the need for regular amounts of folate, however, daily intake levels are frequently lower than the recommended dosage given by national health authorities.
One of the most important indications for folate use is when considering the development of the central nervous system. Women planning on getting pregnant should take folic acid supplements to reduce the risk of neural tube defects (NTDs), such as spina bifida, arising in the developing fetus. Some have proposed that the mechanism by which NTDs form in the absence of folate involves the increased ubiquitination of neural tube closure–related genes, thereby affecting their expression. One of the beneficial roles of folate appears to be its ability to reduce homocysteine levels in NTDs. The period of greatest vulnerability is during the fourth week of development, when a woman may be unaware that she is pregnant. For this reason, it is advisable for women of childbearing age to be taking folic acid supplements if they are sexually active, especially when they are planning to conceive. If the expectant mother were to take 4mg of folic acid daily, it could take 20 weeks for her body to reach folate levels that are optimal for reducing the risk of a neural tube defect. Because of this, supplementation should be initiated 5 to 6 months before conception. Folic acid is also associated with a decreased risk of preterm birth.
Many other therapeutic uses of folic acid exist, though these uses are less impactful than those already mentioned. Folic acid can help to protect against neoplasia in ulcerative colitis, prevent cervical dysplasia, treat vitiligo, restore hematopoiesis in macrocytic anemia due to a folate deficiency, and increase gingival resistance to local irritants, thereby reducing inflammation. Of these uses, treatment of megaloblastic anemia is the only indication recognized by the FDA, including the prevention of NTDs. Folic acid is also used as an alternative to leucovorin calcium and serves as adjunctive therapy in methanol toxicity. When homocysteine levels increase above baseline, they can reduce global cognition, especially in the elderly.  Because of the role of homocysteine in this pathogenesis and folate’s ability to reduce homocysteine levels, some research has shown that a combination of vitamin B12 and folate can significantly improve cognitive performance, and the two of them together is superior to either folate or B12 administration alone. The toxicity of hyperhomocysteinemia also has detrimental cardiovascular effects and is a complication of chronic kidney disease (CKD). While there is currently a lack of definitive proof that folic acid or vitamin B12 administration in these situations is directly beneficial, it would be reasonable to consider them as appropriate adjunctive therapy.
Folate mainly concentrates in the liver. The synthetic form, folic acid, is given as dihydrofolate (DHF) and is converted to THF by the action of the dihydrofolate reductase enzyme, which is dependent on nicotinamide adenine dinucleotide phosphate hydrogen (NADPH). THF then converts to 5-10-methylenetetrahydrofolate (5-10-MTHF), which can diverge down different paths: toward DNA synthesis via dTMP or toward methionine synthesis.
For DNA synthesis, deoxyuridine monophosphate (dUMP) accepts one methyl group from 5-10-MTHF—via thymidylate synthase, which accepts the other—to become deoxythymidine monophosphate (dTMP) and allows the cell cycle to continue while simultaneously regenerating DHF. Drugs used in cancer chemotherapy disrupt this process by inhibiting vital enzymes necessary for cell cycle progression. Methotrexate, for example, inhibits dihydrofolate reductase. By reducing available THF and its downstream components, methotrexate indirectly deprives thymidylate synthase of its substrates. Humans are unable to create dTMP in the presence of methotrexate, and the DNA pool becomes unbalanced, resulting in cell death.
Methionine is a byproduct synthesized as folate reduces homocysteine levels in the blood; 5-10-MTHF donates a methyl group to an enzyme, methyl-tetrahydrofolate reductase (MTHFR), and then becomes 5-methyl THF. 5-methyl THF donates its remaining methyl group to homocysteine via methionine synthase, converting homocysteine to methionine. This transfer of both methyl groups from the original 5-10-MTHF regenerates THF, which can then re-enter the cycle. Vitamin B12 is a crucial cofactor for methionine synthase, and B12 deficiency can lead to macrocytic megaloblastic anemia, similar to that of folate deficiency but with additional clinical symptoms that are beyond the scope of this article.
Folic acid is often administered as an oral supplement. Dosing is usually dependent on the disorder the physician is attempting to treat. The recommended daily requirement of folate for an adult is 240 mcg. For preventing neural tube defects in pregnancy, the World Health Organization recommends a daily dose of 400 to 800 mcg. Clinicians generally prescribe iron-folic acid supplements as prenatal vitamins during and before pregnancy. Most of these include 1 mg of folate, which is more than enough to meet this criterion. Again, for maximum effect, this supplementation must begin in the earliest stages of pregnancy, if not months before conception.
For macrocytic anemia, folic acid may be given orally, intravenously, or subcutaneously. Oral recommendations are 1 to 5 mg once daily, but doses up to 15 mg once daily have been recommended as well.
For intravenous administration, 5 mg or less of undiluted folic acid may be infused over at least 1 minute, or 5 mg or less of folic acid may be combined with 50 mL of either normal saline (NS) or dextrose 5% in water (D5W) and infused over 30 minutes. Folic acid may also be given as an infusion when added to other IV maintenance solutions. To avoid folic acid deficiency in patients on hemodialysis, the recommended dose is estimated to be in the range of 1 to 5 mg daily.
For the general population, a diet that contains a daily amount of folic acid below the established upper intake level of 1000 mcg has not demonstrated to result conclusively in any adverse health outcomes. The U.S. National Toxicology Program (NTP) examined areas of previous concern, including cognition (relating to vitamin B12 deficiency), cancer, diabetes- and thyroid-related disorders, and hypersensitivity-related outcomes. Researchers identified these areas from previous reports of patients that received more than 400 mcg per day. Overall, the NTP report concluded that, for the areas considered, no definitive evidence exists for adverse effects due to folic acid. However, reports exist of rare instances of GI upset.
This report, as well as other literature reviews performed since, draw their conclusions while still emphasizing the need for further investigation. Overall, the benefits that stand to be gained from folic acid intake justify any potential risk that might be encountered. Furthermore, the mandatory folic acid fortification program guidelines in countries across the world have yielded no established risks for adverse effects.
Hypersensitivity to folic acid or its formulation is a potential contraindication to its administration. One must recall that research has yet to establish hypersensitivity reactions to folic acid, but a history of an anaphylactic reaction from any substance must deter the administration of the offending agent.
Folate deficiency can manifest in numerous ways. The measurement of deficient folate levels in the blood renders a definitive diagnosis, but other signs exist. As mentioned earlier, low levels of folate lead to macrocytic megaloblastic anemia. A simple blood smear of an individual with a folate deficiency will reveal erythrocyte macrocytosis and hyper-segmented polymorphonuclear cells (PMNs). This abnormal morphology is a result of impaired DNA synthesis, which causes precursor cells in the bone marrow to have nuclei that are immature relative to their cytoplasm. Additionally, oral ulcers may appear without neurological symptoms (as opposed to a vitamin B12 deficiency, which causes subacute combined degeneration (SCD)). A folate deficiency in pregnancy contributes heavily to fetal NTDs. The interruption of DNA synthesis due to a folate deficiency will result in elevated homocysteine levels. Hyperhomocysteinemia is also present in vitamin B12 deficiency, but B12 deficiency also has elevated methylmalonic acid levels and the neurological signs associated with SCD that are absent in folate deficiency. Before administering folic acid in apparent folate-deficiency anemia, physicians must rule out a concurrent B12 deficiency. The rationale behind this is that folic acid administration will address the anemia aspect of B12 deficiency, but methylmalonic acid levels will remain elevated and cause toxic neurological effects. A simple measurement of B12 levels before folic acid administration is advisable to avoid potential SCD development.
Deficient folate levels have been detected in up to 16% of patients on antiepileptic drugs, including gabapentin, phenytoin, carbamazepine, valproate, and primidone. Women using antiepileptic drugs may develop a folic acid deficiency during pregnancy (valproic acid impairs folic acid absorption) and would require a higher dose to maintain effective treatment levels. The recommendation is, however, to reduce valproic acid to the minimum effective dose and to increase the dose of folic acid supplementation to achieve maximum protective effect against NTD formation in the fetus. Research found that many women use antiepileptic drugs for non-epileptic disorders, such as migraines. Sexually active women of reproductive age who are not using contraception are encouraged to use AEDs only to treat epilepsy. Together, these consequences of folate deficiency can help guide the examiner to start a workup to look for folate deficiency.
Like other water-soluble vitamins, folic acid does not have significant storage in the body; hence toxicity is not commonly a concern. However, very rare neurologic side effects have been noted in the context of folate supplementation in individuals with pernicious anemia. The direct toxicity of folate only contributes minimally. Rather, the neurologic effects are more directly caused by a masked case of SCD, resulting from a vitamin B12 deficiency that continues to destroy neuronal cells despite folate supplementation appearing to resolve the anemic aspect seen in pernicious anemia. There is one published case report of fatal poisoning, but the authors admit that the findings may be a unique manifestation of folic acid toxicity in humans.
The relative safety of folic acid allows healthcare providers to administer it to patients with little to no concern of adverse effects. However, specific best practice techniques should be kept in mind to ensure positive outcomes. The patient should receive counsel to consume a healthy diet that includes vegetables, eggs, and milk to increase folate levels. Dietary teams can consult on the case to ensure inpatients receive appropriate food selection to enhance the delivery of folate. Pregnant women should be made aware of risks associated with folate deficiency and take appropriate supplements, while pregnant women on antiepileptic drugs must only use them for epilepsy and take the smallest dose possible. Pharmacists can alert physicians that AEDs are on the pregnant patient's list of medications if no changes to dosage start immediately. The source of macrocytic megaloblastic anemia needs to be determined before supplement administration begins, as folate deficiency and vitamin B12 deficiency can both present similarly when considering the anemia alone. When prescribing folic acid, the pharmacy team may consider distributing it on the condition that the patient already has an order for a vitamin B12 level.
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