Folate Deficiency Prevention and Treatment

Folate deficiency, also known as vitamin B₉ deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. It is characterized by the appearance of large-sized, abnormal red blood cells (megaloblasts), which form when there are inadequate stores of folic acid within the body. 

What is folate deficiency?

Folate, or folic acid, is a type of B vitamin. It helps to: make DNA, repair DNA, and produce red blood cells (RBCs). If you don’t have enough folate in your diet, you may end up with a folate deficiency. Certain drinks and foods, such as citrus juices and dark green vegetables, are particularly good sources of folate. Not eating enough folate can lead to a deficiency in just a few weeks. Deficiency may also occur if you have a condition or genetic mutation that prevents your body from absorbing or converting folate to its usable form.

Folate deficiency Symptoms

Loss of appetite and weight loss can occur. Additional signs are weakness, sore tongue, headaches, heart palpitations, irritability, and behavioral disorders. In adults, anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency.

Women with folate deficiency who become pregnant are more likely to give birth to low birth weight premature infants, and infants with neural tube defects and even spina bifida. In infants and children, folate deficiency can lead to:

• Failure to thrive or slow growth rate,
• Diarrhea,
• Oral ulcers,
• Megaloblastic anemia, and
• Neurological deterioration.

An abnormally small head, irritability, developmental delay, seizures, blindness, and cerebellar ataxia can also be observed.

Risk factors for folate deficiency

Factors that may increase the likelihood of having a folate deficiency include:

• Heavy alcohol abuse,
• Pregnancy,
• Being of childbearing age,
• Eating overcooked foods,
• Consuming a vitamin-poor diet,
• Medical conditions, such as sickle cell disease,
• Low socioeconomic status,
• Elderly people living in institutions,
• A genetic polymorphism in the MTHFR gene,
• Malabsorption syndromes, such as celiac disease and inflammatory bowel disease, and
• Certain medications.

Folate deficiency Causes

When the body’s need increases

A deficiency of folate can occur when the body’s need for folate is increased when dietary intake or absorption of folate is inadequate, or when the body excretes (or loses) more folate than usual. Medications that interfere with the body’s ability to use folate may also increase the need for this vitamin.

Some research indicates that exposure to ultraviolet light, including the use of tanning beds, can lead to folate deficiency. The deficiency is more common in pregnant women, infants, children, and adolescents. It may also be due to poor diet or a consequence of alcoholism.

Defects in homocysteine methyltransferase

Additionally, a defect in homocysteine methyltransferase or a deficiency of vitamin B₁₂ may lead to a so-called “methyl-trap” of tetrahydrofolate (THF), in which THF is converted to a reservoir of methyl-THF which thereafter has no way of being metabolized, and serves as a sink of THF that causes a subsequent deficiency in folate. Thus, a deficiency in B₁₂ can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency.

Folate is absorbed throughout the small intestine

Folate (pteroylmonoglutamate) is absorbed throughout the small intestine, though mainly in the jejunum. Important steps in the absorption are the reduction of the polyglutamate chain by pteroylpolyglutamate hydrolase (gamma-glutamyl hydrolase) and then transport across the brush border membrane by the proton-coupled folate transporter (SLC46A1).

Diffuse inflammatory or degenerative diseases of the small intestine, such as Crohn’s disease, celiac disease, chronic enteritis, or the presence of an entero-enteric fistula may reduce absorption.

Situational Folate deficiency

Some situations that increase the need for folate include:

• Bleeding,
• Kidney dialysis,
• Liver disease,
• Malabsorption, including celiac disease and fructose malabsorption,
• Pregnancy and lactation (breastfeeding),
• Tobacco smoking, and
• Alcohol consumption.

Medication

Medications can interfere with folate metabolism, including:

• Anticonvulsant medications (such as phenytoin, primidone, carbamazepine or valproate),
• Metformin (sometimes prescribed to control blood sugar in type 2 diabetes),
• Methotrexate is an anti-cancer drug also used to control inflammation associated with Crohn’s disease, ulcerative colitis, and rheumatoid arthritis,
• 5-fluorouracil,
• Hydroxyurea,
• Trimethoprim,
• Sulfasalazine (used to control inflammation associated with Crohn’s disease, ulcerative colitis, and rheumatoid arthritis),
• Triamterene, and
• Birth control pills may reduce serum folate levels but without inducing clinically significant folate deficiency.

When methotrexate is prescribed, folic acid supplements are sometimes given with methotrexate. 

Cerebral folate deficiency

Cerebral folate deficiency is when levels of 5-methyltetrahydrofolate are low in the brain as measured in the cerebral spinal fluid despite being normal in the blood. Symptoms typically appear at about five months of age. Without treatment, there may be poor muscle tone, trouble with coordination, trouble talking, and seizures.

The causes of cerebral folate deficiency include mutations of genes responsible for folate metabolism and transport. Mutations of the SLC46A1 gene that encodes the proton-coupled folate transporter (PCFT) result in CFD syndromes with both systemic folate deficiency and cerebral folate deficiency. Even when the systemic deficiency is corrected by folate, the cerebral deficiency remains and must be treated with folinic acid.

Folate deficiency during Pregnancy

Folate deficiency can occur during pregnancy as a result of the increasing number of cells of the growing fetus, decreased absorption and intake of folate, maternal hormones that mediate its metabolism, vascular circulation of maternal and fetal blood, and an increasing amount of blood resulting in dilution. Sickle cell anemia and living in areas of malaria result in even higher folate needs for women who are pregnant.

When supplemented with 450 micrograms of folic acid per day, the risk of developing birth defects, specifically neural tube defects, is decreased. Supplementation to prevent birth defects is most effective one month prior to and during the first twelve weeks of pregnancy. Utilization of folic acid supplementation before conception has shown to result in a decrease in neural tube defects by 70%.

Folate deficiency Diagnosis

Folate deficiency is diagnosed with a blood test to measure the serum level of folate, measured as methyltetrahydrofolate (in practice, “folate” refers to all derivatives of folic acid, but methyl-hydro folate is the quasi-unique form of “folate” in the blood).

Homocysteine is elevated (5-MTHF is used to convert homocysteine to methionine) as in vitamin B₁₂ deficiency, whereas methylmalonic acid is normal (elevated in vitamin B₁₂ deficiency and vitamin B6 deficiency).

More specifically, according to a 2014 UK guideline,

• A serum folate level of less than 7 nmol/l is indicative of folate deficiency;
• Red blood cell folate testing is not routinely performed, since serum folate is sufficient in most cases, however, if there is a strong suspicion of folate deficiency despite a normal serum folate level, a red cell folate test may be performed.
• Plasma total homocysteine is only measured in special circumstances. A local reference range should be taken into account.

Folate deficiency Prevention and treatment

Diet

Folate is acquired in the diet by the consumption of leafy green vegetables, legumes, and organic meats. When cooking, the use of steam, a food steamer, or a microwave oven can help keep more folate content in the cooked foods.

Supplementation

Folic acid is a synthetic derivative of folate and is acquired by dietary supplementation. Multi-vitamin dietary supplements contain folic acid as well as other B vitamins. Non-prescription folic acid is available as a dietary supplement in some countries, and some countries require the fortification of wheat flour, corn meal, or rice with folic acid with the intention of promoting public health through increasing blood folate levels in the population.

Fortification

Discovery of the link

After the discovery of the link between insufficient folic acid and neural tube defects, governments and health organizations worldwide made recommendations concerning folic acid supplementation for women intending to become pregnant. Because the neural tube closes in the first four weeks of gestation, often before many women even know they are pregnant, many countries in time decided to implement mandatory food fortification programs.

A meta-analysis of global birth prevalence of spina bifida showed that when the mandatory fortification was compared to countries with healthcare professionals advising women but no mandatory fortification program, there was a 30% reduction in live births with spina bifida, with some countries reporting a greater than 50% reduction.

Folic acid fortification

Over 80 countries require folic acid fortification in some foods. The fortification of rice is standard. The USDA has required the fortification of flour since 1998. Since then, Hispanics in the United States have seen the greatest reduction in neural tube defects.

Canada has mandated folic acid fortification of flour since 1998 which has resulted in a 42% decrease in neural tube defects. Fortification of wheat and corn flour, milk, and rice is required in Costa Rica which has led to a reduction of neural tube defects of as much as 60%.

The recommended intake of folate

The Recommended Daily Allowance (RDA) of folate differs depending on age. The RDA for various ages are:

• 0–6 months: 65 mcg,
• 7–12 months: 80 mcg,
• 1–3 years: 150 mcg,
• 4–8 years: 200 mcg,
• 9–13 years: 300 mcg,
• 14 years and older: 400 mcg,
• During pregnancy: 600 mcg, and
• During lactation: 500 mcg.

Of course, if you have a folate deficiency, your healthcare provider may recommend a different amount of the vitamin. If you suspect, you may have a folate deficiency, reach out to a medical professional before supplementing with folic acid.

Does folate have risks?

In moderate amounts, folate is not dangerous to most people. However, in large amounts, folate may pose certain health risks. Depending on the situation, this could include:

• Masking vitamin B12 deficiency: People with vitamin B12 deficiency may develop megaloblastic anemia, which can cause neurological damage if left untreated. As folate can help treat certain symptoms of anemia, but not the neurological damage it can cause, folate could mask symptoms until the consequences of the true deficiency become irreversible.
• Preneoplastic lesions: These lesions consist of altered cells that are more likely to become cancerous than regular cells. High folic acid intake has been linked to faster progression of these cells, which may increase the risk of certain cancers, such as colorectal cancer.
• Unmetabolized acid: If a person has more folic acid than the body can metabolize and transform, it could affect the immune system. Some scientists have also suggested there may be a link between unmetabolized folic acid and cognitive impairment in older adults. However, there is not much research on this, so the risk is unknown.
• Medication interaction: Folate supplements may interact badly with various medications, including epilepsy medications, methotrexate, and sulfasalazine.

Before taking any dietary supplement, it is important to speak with a doctor to check that it is safe and there are no other deficiencies or conditions that need to be addressed.

Benefits of folate

Folate is necessary for many bodily functions. Its health benefits include:

Lower risk of neural tube defects

An adequate amount of folic acid is essential during pregnancy to help prevent neural tube defects. This issue occurs when the neural tube, which forms the early brain and spinal cord, does not close properly. This happens in early pregnancy and can result in conditions such as spina bifida or anencephaly.

Lower risk of stroke

According to the National Institutes of Health (NIH), researchers have found that folic acid supplements lower levels of the amino acid homocysteine. High levels of this amino acid are linked to a higher risk of cardiovascular disease and stroke.

While studies have not proven that folic acid reduces the risk of cardiovascular disease, several have found that higher intake is associated with a lower risk of stroke.

Possible reduced risk of cognitive decline

Homocysteine is also associated with a higher risk of dementia. While studies have not shown that taking folic acid reduces the risk of dementia in otherwise healthy people, those who are at risk of cognitive decline in older age may benefit from taking it.

Folate and cancer

Research on the link between folate and cancer has produced varied results. Some studies suggest that folate may offer protection against certain cancers. Low folate levels are associated with an increased risk of certain cancers, such as lung, breast, cervical, and stomach cancers.

Folate deficiency Research

Folate deficiency during gestation or infancy due to the development by the fetus or infant of autoantibodies to the folate receptor might result in various developmental disorders.

Studies suggest that insufficient folate and vitamin B₁₂ status may contribute to major depressive disorder and that supplementation might be useful in this condition. The role of vitamin B₁₂ and folate in depression is due to their role in transmethylation reactions, which are crucial for the formation of neurotransmitters.

The proposed mechanism is that low levels of folate or vitamin B₁₂ can disrupt the transmethylation reaction, leading to an accumulation of homocysteine (hyperhomocysteinemia) and to impaired metabolism of neurotransmitters, phospholipids, myelin, and receptors. High homocysteine levels in the blood can lead to vascular injuries by oxidative mechanisms which can contribute to cerebral dysfunction. All of these can lead to the development of various disorders, including depression.