Folate deficiency

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Folate deficiency
Folic acid structure.svg
Folic acid, a precursor of active B9
Specialty Endocrinology
Symptoms Feeling tired, shortness of breath, changes in the color of the skin or hair, irritability [1]
Complications Megaloblastic anemia [1]
Diagnostic method Blood tests [1]
Treatment Folic acid supplementation [1]
FrequencyVery rare (countries with fortification programs) [2]

Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. [1] This may result in megaloblastic anemia in which red blood cells become abnormally large, and folate deficiency anemia is the term given for this medical condition. [3] Signs of folate deficiency are often subtle. [4] Symptoms may include fatigue, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. [1] [5] Temporary reversible infertility may occur. [6] Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects. [6]

Contents

Not consuming enough folate can lead to folate deficiency within a few months. [1] Otherwise, causes may include increased needs as with pregnancy, and in those with shortened red blood cell lifespan. [1] Folate deficiency can be secondary to vitamin B12 deficiency or a defect in homocysteine methyl transferase that leads to a "folate trap" in which is an inactive metabolite that cannot be recovered. [1] Diagnosis is typically confirmed by blood tests, including a complete blood count, and serum folate levels. [1] Increased homocysteine levels may suggest deficiency state, but it is also affected by other factors. [1] Vitamin B12 deficiency must be ruled out, if left untreated, may cause irreversible neurological damage. [1]

Treatment may include dietary changes and folic acid supplements. [1] Dietary changes including eating high foods in folate such as, fruits and green leafy vegetables can help. [1] Prevention is recommended for pregnant women or those who are planning a pregnancy. [1]

Folate deficiency is very rare in countries with folic acid fortification programs. [2] Worldwide prevalence of anemia due to folic acid deficiency generally is very low. [2]

Signs and symptoms

Signs of folate deficiency anemia most of the time are subtle. [4] Anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency in adults. [1] Folate deficiency anemia may result in feeling tired, weakness, changes to the color of the skin or hair, open sores on the mouth, shortness of breath, palpitations, lightheadedness, cold hands and feet, headaches, easy bleeding or bruising, low-grade fevers, loss of appetite, weight loss, diarrhea, decreased taste, irritability, and behavioral disorders. [1] [5]

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, neurological deterioration. An abnormally small head, irritability, developmental delay, seizures, blindness and cerebellar ataxia can also be observed. [7]

Causes

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. [8] [9] [10] [11] [12] [13] Some research indicates that exposure to ultraviolet light, including the use of tanning beds, can lead to a folate deficiency. [14] [15] 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. [16]

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. [17] Thus, a deficiency in B12 can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency.[ citation needed ]

Folate (pteroylmonoglutamate) is absorbed throughout the small intestine, though mainly in the jejunum. Important steps in the absorption are 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 disease, celiac disease, chronic enteritis or the presence of an entero-enteric fistula may reduce absorption. [18] [19]

Situational

Some situations that increase the need for folate include:[ citation needed ]

Medication

Medications can interfere with folate metabolism, including:

When methotrexate is prescribed, folic acid supplements are sometimes given with the methotrexate. The therapeutic effects of methotrexate are due to its inhibition of dihydrofolate reductase and thereby reduce the rate de novo purine and pyrimidine synthesis and cell division. Methotrexate inhibits cell division and is particularly toxic to fast dividing cells, such as rapidly dividing cancer cells and the progenitor cells of the immune system. Folate supplementation is beneficial in patients being treated with long-term, low-dose methotrexate for inflammatory conditions, such as rheumatoid arthritis (RA) or psoriasis, to avoid macrocytic anemia caused by folate deficiency. Folate is often also supplemented before some high dose chemotherapy treatments in an effort to protect healthy tissue. However, it may be counterproductive to take a folic acid supplement with methotrexate in cancer treatment. [21]

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. [22] Symptoms typically appear at about five months of age. Without treatment there may be poor muscle tone, trouble with coordination, trouble talking, and seizures. [22] The causes of cerebral folate deficiency include mutations of genes responsible for folate metabolism and transport. [23] 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. [22] [24]

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. [25] Sickle cell anemia and living in areas of malaria result in even higher folate needs for women who are pregnant. [25] When supplemented with 450 micrograms of folic acid per day, the risk of developing birth defects, specifically neural tube defects, is decreased. [25] Supplementation to prevent birth defects is most effective one month prior to and during the first twelve weeks of pregnancy. [26] [27] Utilization of folic acid supplementation before conception has shown to result in a decrease in neural tube defects by 70%. [28]

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 methylhydrofolate is the quasi unique form of "folate" in the blood [29] ).

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).[ citation needed ]

More specifically, according to a 2014 UK guideline, [30]

Management

Diet

Folate is acquired in the diet by the consumption of leafy green vegetables, legumes and organ meats. [31] When cooking, use of steaming, a food steamer, or a microwave oven can help keep more folate content in the cooked foods. [32] [33] [34]

Supplementation

Folic acid is a synthetic derivative of folate and is acquired by dietary supplementation. [25] 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.[ citation needed ]

Fortification

After the discovery of the link between insufficient folic acid and neural tube defects, [35] 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. [36] A meta-analysis of global birth prevalence of spina bifida showed that when 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, [37] with some countries reported a greater than 50% reduction. [26]

Over 80 countries require folic acid fortification in some foods. [31] Fortification of rice is common. [27] The USDA has required the fortification of flour since 1998. [26] Since then, Hispanics in the United States have seen the greatest reduction of neural tube defects. [26] Canada has mandated folic acid fortification of flour since 1998 which has resulted in a 42% decrease in neural tube defects. [28] 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%. [26]

Epidemiology

Folate deficiency is very rare in countries with folic acid fortification programs. [2] Overall, the worldwide prevalence of anemia due to folic acid deficiency is very low. [2] However, data on the prevalence of deficiency amongst specific high risk groups is lacking.[ citation needed ]

Research

Folate deficiency during gestation or infancy due to development by the fetus or infant of autoantibodies to the folate receptor might result in various developmental disorders. [38]

Studies suggest that insufficient folate and vitamin B12 status may contribute to major depressive disorder and that supplementation might be useful in this condition. [39] 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 (e.g. serotonin, epinephrine, nicotinamides, purines, phospholipids). [39] [40] The proposed mechanism, is that low levels of folate or vitamin B12 can disrupt transmethylation reaction, leading to an accumulation of homocysteine (hyperhomocysteinemia) and to impaired metabolism of neurotransmitters (especially the hydroxylation of dopamine and serotonin from tyrosine and tryptophan), 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. [39] [40]

Related Research Articles

<span class="mw-page-title-main">Folate</span> Vitamin B9; nutrient essential for DNA synthesis

Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.

<span class="mw-page-title-main">Homocysteine</span> Chemical compound

Homocysteine or Hcy: is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the body, homocysteine can be recycled into methionine or converted into cysteine with the aid of vitamin B6, B9, and B12.

B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. They are a chemically diverse class of compounds.

<span class="mw-page-title-main">Pernicious anemia</span> Lack of red blood cells due to vitamin B12 deficiency

Pernicious anemia is a disease where not enough red blood cells are produced due to a deficiency of vitamin B12. Those affected often have a gradual onset. The most common initial symptoms are feeling tired and weak. Other symptoms may include shortness of breath, feeling faint, a smooth red tongue, pale skin, chest pain, nausea and vomiting, loss of appetite, heartburn, numbness in the hands and feet, difficulty walking, memory loss, muscle weakness, poor reflexes, blurred vision, clumsiness, depression, and confusion. Without treatment, some of these problems may become permanent.

<span class="mw-page-title-main">Megaloblastic anemia</span> Medical condition

Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis. Megaloblastic anemia has a rather slow onset, especially when compared to that of other anemias. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency. Loss of micronutrients may also be a cause.

<span class="mw-page-title-main">Nutrition and pregnancy</span> Nutrient intake and dietary planning undertaken before, during and after pregnancy

Nutrition and pregnancy refers to the nutrient intake, and dietary planning that is undertaken before, during and after pregnancy. Nutrition of the fetus begins at conception. For this reason, the nutrition of the mother is important from before conception as well as throughout pregnancy and breastfeeding. An ever-increasing number of studies have shown that the nutrition of the mother will have an effect on the child, up to and including the risk for cancer, cardiovascular disease, hypertension and diabetes throughout life.

<span class="mw-page-title-main">Neural tube defect</span> Group of birth defects of the brain or spinal cord

Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo begin to change shape and form the neural tube. When the neural tube does not close completely, an NTD develops.

<span class="mw-page-title-main">Hyperhomocysteinemia</span> Medical condition

Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of total homocysteine in the blood, conventionally described as above 15 μmol/L.

<span class="mw-page-title-main">Hydroxocobalamin</span> Form of vitamin B12

Hydroxocobalamin, also known as vitamin B12a and hydroxycobalamin, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia. Other uses include treatment for cyanide poisoning, Leber's optic atrophy, and toxic amblyopia. It is given by injection into a muscle or vein, by pill or sublingually.

<span class="mw-page-title-main">Levomefolic acid</span> Chemical compound

Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6S)-5-methyltetrahydrofolate, and (6S)-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine. It is also the form found in circulation and transported across membranes into tissues and across the blood–brain barrier. In the cell, L-methylfolate is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is the immediate acceptor of one carbon unit for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine. The un-methylated form, folic acid (vitamin B9), is a synthetic form of folate, and must undergo enzymatic reduction by dihydrofolate reductase (DHFR) to become biologically active.

Vitamin B<sub>12</sub> deficiency Disorder resulting from low blood levels of vitamin B12

Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition in which the blood and tissue have a lower than normal level of vitamin B12. Symptoms can vary from none to severe. Mild deficiency may have few or absent symptoms. In moderate deficiency, feeling tired, headaches, soreness of the tongue, mouth ulcers, breathlessness, feeling faint, rapid heartbeat, low blood pressure, pallor, hair loss, decreased ability to think and severe joint pain and the beginning of neurological symptoms, including abnormal sensations such as pins and needles, numbness and tinnitus may occur. Severe deficiency may include symptoms of reduced heart function as well as more severe neurological symptoms, including changes in reflexes, poor muscle function, memory problems, blurred vision, irritability, ataxia, decreased smell and taste, decreased level of consciousness, depression, anxiety, guilt and psychosis. If left untreated, some of these changes can become permanent. Temporary infertility, reversible with treatment, may occur. A late finding type of anemia known as megaloblastic anemia is often but not always present. In exclusively breastfed infants of vegan mothers, undetected and untreated deficiency can lead to poor growth, poor development, and difficulties with movement.

<span class="mw-page-title-main">Antifolate</span> Class of antimetabolite medications

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).

Vitamin B<sub><small>12</small></sub> Vitamin used in animal cells metabolism

Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, and in both fatty acid and amino acid metabolism. It is important in the normal functioning of the nervous system via its role in the synthesis of myelin, and in the circulatory system in the maturation of red blood cells in the bone marrow. Plants do not need cobalamin and carry out the reactions with enzymes that are not dependent on it.

The term macrocytic is from Greek words meaning "large cell". A macrocytic class of anemia is an anemia in which the red blood cells (erythrocytes) are larger than their normal volume. The normal erythrocyte volume in humans is about 80 to 100 femtoliters. In metric terms the size is given in equivalent cubic micrometers. The condition of having erythrocytes which are too large, is called macrocytosis. In contrast, in microcytic anemia, the erythrocytes are smaller than normal.

<span class="mw-page-title-main">MTRR (gene)</span> Protein-coding gene in the species Homo sapiens

Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene.

Anemia is a deficiency in the size or number of red blood cells or in the amount of hemoglobin they contain. This deficiency limits the exchange of O2 and CO2 between the blood and the tissue cells. Globally, young children, women, and older adults are at the highest risk of developing anemia. Anemia can be classified based on different parameters, and one classification depends on whether it is related to nutrition or not so there are two types: nutritional anemia and non-nutritional anemia. Nutritional anemia refers to anemia that can be directly attributed to nutritional disorders or deficiencies. Examples include Iron deficiency anemia and pernicious anemia. It is often discussed in a pediatric context.

<span class="mw-page-title-main">Nutritional neuroscience</span> Scientific discipline

Nutritional neuroscience is the scientific discipline that studies the effects various components of the diet such as minerals, vitamins, protein, carbohydrates, fats, dietary supplements, synthetic hormones, and food additives have on neurochemistry, neurobiology, behavior, and cognition.

<span class="mw-page-title-main">Imerslund–Gräsbeck syndrome</span> Medical condition

Imerslund–Gräsbeck syndrome is a rare autosomal recessive, familial form of vitamin B12 deficiency caused by malfunction of the "Cubam" receptor located in the terminal ileum. This receptor is composed of two proteins, amnionless (AMN), and cubilin. A defect in either of these protein components can cause this syndrome. This is a rare disease, with a prevalence about 1 in 200,000, and is usually seen in patients of European ancestry.

Relatively speaking, the brain consumes an immense amount of energy in comparison to the rest of the body. The mechanisms involved in the transfer of energy from foods to neurons are likely to be fundamental to the control of brain function. Human bodily processes, including the brain, all require both macronutrients, as well as micronutrients.

Anemia is a condition in which blood has a lower-than-normal amount of red blood cells or hemoglobin. Anemia in pregnancy is a decrease in the total red blood cells (RBCs) or hemoglobin in the blood during pregnancy. Anemia is an extremely common condition in pregnancy world-wide, conferring a number of health risks to mother and child. While anemia in pregnancy may be pathologic, in normal pregnancies, the increase in RBC mass is smaller than the increase in plasma volume, leading to a mild decrease in hemoglobin concentration referred to as physiologic anemia. Maternal signs and symptoms are usually non-specific, but can include: fatigue, pallor, dyspnea, palpitations, and dizziness. There are numerous well-known maternal consequences of anemia including: maternal cardiovascular strain, reduced physical and mental performance, reduced peripartum blood reserves, increased risk for peripartum blood product transfusion, and increased risk for maternal mortality.

References

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