Folate deficiency: Difference between revisions
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==[[Folate deficiency historical perspective|Historical Perspective]]== | ==[[Folate deficiency historical perspective|Historical Perspective]]== | ||
Folate deficiency was first discovered by Lucy Wills, an English hematologist, in 1931. While conducting seminal work in India in the late 1920s and early 1930s on macrocytic anemia of pregnancy, she found that this nutrient was needed to prevent the anemia of pregnancy. Dr. Wills demonstrated that this condition could be reversed with brewer's yeast. It was in the later 1930’s that folate, the naturally occuring form of folic acid, was isolated from brewer's yeast and folic acid was identified in the pathogenesis of anemia in pregnant women. | |||
==[[Folate deficiency classification|Classification]]== | ==[[Folate deficiency classification|Classification]]== | ||
Revision as of 16:31, 3 May 2018
| Folate deficiency | |
| Folic acid (B9) | |
| ICD-10 | D52 E53.8 |
| ICD-9 | 266.2 |
| DiseasesDB | 4894 |
| MedlinePlus | 000354 |
| MeSH | D005494 |
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Folate deficiency Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Folate deficiency On the Web |
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American Roentgen Ray Society Images of Folate deficiency |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Folic acid deficiency
Overview
Folate deficiency is the deficiency of folic acid, which is a necessary compound for the normal production of red blood cells. Folic acid is part of the vitamin B complex. The recommended daily amount of folate for adults is 400 micrograms (mcg). Adult women who are planning pregnancy or could become pregnant should be advised to get 400 to 800 mcg of folic acid a day.
The deficiency of folic acid is associated with a type of anemia, characterized by enlarged blood corpuscles, called megaloblastic anemia.The anemia is thought to be due to problems in the synthesis of DNA precursors, specifically in the synthesis of thymine, which is required for normal erythropoesis which is dependent on products of the MTR reaction. Other cell lines such as white blood cells and platelets are also found to be low due to impaired division of the precursor cells. Bone marrow examination may show megaloblastic hemopoiesis. The anemia is easy to cure with folic acid supplementation.
Historical Perspective
Folate deficiency was first discovered by Lucy Wills, an English hematologist, in 1931. While conducting seminal work in India in the late 1920s and early 1930s on macrocytic anemia of pregnancy, she found that this nutrient was needed to prevent the anemia of pregnancy. Dr. Wills demonstrated that this condition could be reversed with brewer's yeast. It was in the later 1930’s that folate, the naturally occuring form of folic acid, was isolated from brewer's yeast and folic acid was identified in the pathogenesis of anemia in pregnant women.
Classification
Pathophysiology
Folate deficiency can occur when the body's need for folate is increased, when dietary intake or absorption of folate is inadequate, or when the body loses more folate than it acquires from the diet. Certain medications (e.g Anticonvuslants, Methotrexate, Sulfasalazine) can also interfere with the folate metabolism in our body. The deficiency is more common among pregnant women, infants, children, and adolescents. Poor diet and chronic alcoholism is also an important cause of folate deficiency.
Moreover, a defect in homocysteine methyltransferase or a deficiency of cobalamine (B-12) may lead to "folate trap". In vitamin B12 deficiency, the utilization of Methyl THF in the B-12 dependent methylation of homocysteine to methionine is impaired. THF is converted to methyl-THF which cannot be further metabolized, and serves as a sink of THF that leads to a subsequent deficiency in folate. Thus, a deficiency in B-12 can generate a large pool of methyl-THF that is unable to undergo reactions and resembles folate deficiency. Folate is absorbed in the small intestine, mainly in the Jejunum, after binding to specific receptor proteins. Inflammatory or degenerative changes in the small intestine, such as Crohn's disease, chronic enteritis, Celiac disease, may reduce the folate uptake, which gives rise to folate deficiency.
Physiology
In human body folic acid serves a lot of functions such as :
- Production and maintenance of new cells
- DNA and RNA synthesis
- Carrying one-carbon groups for various methylation reactions
- Preventing changes to DNA, therefore, for preventing cancer
In adults, normal total body folate is between 10,000–30,000 micrograms (µg) with blood levels of greater than 7 nmol/L (3 ng/mL).
Dietary sources
Folate naturally occurs in a variety of foods, including dark green leaf vegetables, fruits , nuts, soybeans, dairy products, poultry, eggs, seafood, grains, and some beers. Avocado, beetroot, spinach, liver, yeast, asparagus, kale, and Brussels sprouts are among the foods that contain the highest levels of folate. Folate found in food is susceptible to high heat, UV light and may also be susceptible to damage by oxidation. Folic acid is also added to grain products and these fortified products make up a significant source of the population's folate intake. For example enriched flour and fortified rice typically contain folate.
Absorption and Bioavailability
Folates exist as polyglutamates in the diet and need to be enzymatically converted into monoglutamate forms by folate reductase. This takes place in the jejunum where the absorption of folate also occurs. Natural folates are quite unstable and they lose their vitamin activity during food processing. In vegetables the folates can be destroyed by cooking and in grains/cereals folates can be broken down during milling and baking.
Folate itself is not biologically active, but is converted into dihydrofolate, by the enzyme dihydrofolate synthetase, in the liver. This is then converted into tetrahydrofolate (THF) by dihydrofolate reductase.Tetrahydrofolate is converted into 5,10-methylenetetrahydrofolate by serine hydroxymethyltransferase. Tetrahydrofolate and its methylated forms then play a crucial role as methyl donors in different reactions that occurthroughout the body.
Absolute folate deficiency is usually associated with dietary insufficiency but may it also be caused by impairment in the folate absorption. This can occur due to gastrointestinal diseases or certain genetic defects that impair the absorption in the gastrointestinal tract. Other causes may include mutations causing impaired activity of the enzymes involved in folate metabolism. Low levels of blood folate can lead to increased plasma homocysteine, impaired DNA synthesis and DNA repair and may promote the development of some forms of cancers as well.
Causes
- Inadequate intake of folate containing foods e.g. chronic alcoholism, psychiatric causes, elderly patients.
- Impaired absorption in the gastrointestinal tracts e.g. celiac disease, tropical sprue, achlorhydria, anticonvulsant therapy, bacterial overgrowth in blind loops, strictures, adhesions, diverticula
- Impaired metabolism leading to inability to utilize folate in the body e.g. methotrexate and trimethoprim (folate antagonists) inhibit the enzyme dihydrofolate reductase involved in the formation of Tetrahydrofolate (active form of folate in the body)
- Hypothyroidism which leads to decreased hepatic levels of the enzyme dihydrofolate reductase
- Congenital deficiency of enzymes of folate metabolism
- Increased requirement e.g during infancy, pregnancy, lactation, malignancy, chronic hemolytic states (increased hematopoiesis), hemodialysis, peritoneal dialysis, inflammation.
- Increased loss e.g. vitamin B12 deficiency causes "folate trap" and inhibits the utilization of folate in the body, chronic alcoholism leads to increased excretion of folate into bile, excessive urinary excretion as in chronic dialysis
- Increased destruction e.g. superoxides can inactivate folate
Differentiating Folate deficiency from other Diseases
Macrocytosis is defined as a MCV (mean corpuscular volume) greater than 100 fL. It can be divided into megaloblastic and non-megaloblastic types. Following are the causes of Non-megaloblastic anemia i.e. MCV >100 fL without DNA replication problems and megaloblastic changes.
- Alcoholism : This is a result of dietary lack, a weak antifolate action and due to a direct toxic effect of alcohol on the bone marrow.
- Hypothyroidism : Macrocytosis is found in up to 55% patients with hypothyroidism and may result from the insufficiency of the thyroid hormones themselves and also due to 20 times increased risk of pernicious anemia in people with hypothyroidism
- Aplastic anemia : Mild macrocytosis can be observed in association with stress erythropoiesis and elevated fetal hemoglobin levels in aplastic anemia.
- Reticulocytosis : Commonly due to hemolysis or a recent history of blood loss. This is due to increased hematopoeisis and rapid release of immature RBCs from the bone marrow to replace the blood loss.
- Liver disease : Liver enzymes play an important role in the process of normal erythropoiesis
- Myeloproliferative diseas and Myelodysplastic syndromes : due to bone marrow dysfunction
- Chronic exposure to benzene and drugs like 5- Fluorouracil.
Folate and Vitamin B12 deficiencies : These are the two most important causes of Megaloblastic macrocytic anemia associated with impaired DNA synthesis and megaloblastic changes like hypersegmented neutrophils and glossitis. History and physical examination, vitamin B12 level, reticulocyte count, and a peripheral smear are helpful in delineating the underlying cause of megaloblastosis. A measurement of methylmalonic acid in the blood or urine, can provide an indirect method for partially differentiating Vitamin B12 and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency while it is raised in Vitamin B12 (cobalamin) deficiency. Direct measurement of blood cobalamin and folate is the gold standard to differentiate between the two causes.
Epidemiology and Demographics
The prevalence of folate deficiency across the world is quite variable. The deficiency is more common in countries without folic acid fortification of cereal-grain products and rarely in countries with folic acid fortification. National surveys conducted in several countries show that without fortification, folate deficiency can be a public health problem. The primary age groups affected include preschool children (33.8% of the folate-deficient population in Venezuela), pregnant women (48.8% in Costa Rica and 25.5% in Venezuela), and older people (15% in the UK). In the US, folate deficiency was present in school-age children (2.3% of the folate-deficient population), adults (24.5%), and older people (10.8%) before folic acid fortification was introduced. Mandatory folic acid fortification of enriched cereal-grain products was initiated in the US in 1996 and Canada in 1998. Subsequent surveys of regional and nationally representative populations have shown that serum and RBC folate concentrations have increased in the general population in these countries.
Risk Factors
Strong risk factors include :
- Low dietary folate intake
- Age >65 years
- Alcoholism
- Pregnant or lactating mothers
- Prematurity
- Intestinal malabsorptive disorders e.g. celiac disease, tropical sprue, jejunal resection, inflammatory bowel diseases.
- Use of dtugs e.g. trimethoprim, methotrexate, anticonvulsants, sulfasalazine, or pyrimethamine
- Infantile intake of goats' milk which is low in folate content
- Congenital defects in folate absorption and metabolism
Weaker risk factors inlcude :
- States of increased cell turnover e.g. chronic hemolysis
- Intake of special diet
- Chronic dialysis
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms | Physical Examination | Laboratory Findings | Imaging Findings | Other Diagnostic Studies
Treatment
Medical Therapy | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies