Folic acid/folate deficiency

Folic Acid (folate). Chemically, folic acid is a pteryl-glutamic acid. The several forms that occur in nature depend on the numbers of glutamic acid units and methyl groups in the molecules. Because of its usual low concentration, folic acid is generally determined in food materials by the microbiological assay with lactobacillus casei and measured turbidimetrically or titrimetrically. Deficiency of this vitamin could result in... 

Frenkel EP, Yardley DA. Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin Bj (cobalamin) in pregnancy and gynecology. Hematol Oncol Clin North Am 2000 14(5) 1079-100. 

The folate antagonists, pyrimethamine and sulfadiazine, inhibit the parasite s DHFR/TS synthase enzyme complex and the DHPS, respectively (Fig. 4) (see antimalarial drugs). To avoid deficiency of folic acid in patients treated with antifolate antagonists, folinic acid supplementation is recommended to reduce bone-marrow suppression. 

Pernicious anemia arises when vitamin B,2 deficiency blocks the metabohsm of folic acid, leading to functional folate deficiency. This impairs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia). The commonest cause of pernicious anemia is failure of the absorption of vitamin B,2 rather than dietary deficiency. This can be due to failure of intrinsic factor secretion caused by autoimmune disease of parietal cells or to generation of anti-intrinsic factor antibodies. 

Deficiency of folic acid Decreased intake, defective absorption, or increased demand (eg, in pregnancy) for folate... 

Administer prophylactic folic acid supplementation to SCD patients receiving hydroxyurea because folate deficiency may be masked by the use of hydroxyurea. 

Folate, the anion of folic acid, is made up of three different components—a pteridine derivative, 4-aminobenzoate, and one or more glutamate residues. After reduction to tetrahydrofolate (THF), folate serves as a coenzyme in the Q metabolism (see p. 418). Folate deficiency is relatively common, and leads to disturbances in nucleotide biosynthesis and thus cell proliferation. As the precursors for blood cells divide particularly rapidly, disturbances of the blood picture can occur, with increased amounts of abnormal precursors for megalocytes megaloblastic anemia). Later, general damage ensues as phospholipid... 

Folic acid appears in the plasma approximately 15 to 30 minutes after an oral dose peak levels are generally reached within 1 hour. After IV administration, the drug is rapidly cleared from the plasma. Folic acid is metabolized in the liver. Normal serum levels of total folate have been reported to be 5 to 15 ng/mL normal CSF levels are approximately 16 to 21 ng/mL. In general, folate serum levels less than 5 ng/mL indicate folate deficiency, and levels less than 2 ng/mL usually result in megaloblastic anemia. A majority of the metabolic products appeared in the urine after 6 hours excretion was generally complete within 24 hours. 

About 10-25%, i.e. 50-200 pg, of the daily dietary intake of folic acid in yeasts, liver, and green vegetables is absorbed via active and passive transport in the proximal jejunum. As humans do not have dihydropteroate synthetase, which synthesizes folic acid in bacteria, we require folic acid in the diet. Only small amounts of folate can be stored in the body and dietary deficiency for only a few days can result in symptomatic folate deficiency. 

Folate deficiency can be dietary, especially in the eiderly, due to increased demand like in pregnancy, or due to maiabsorption syndromes. Agents which can cause folic acid deficiency with long-term use include phenytoin, oral contraceptives, isoniazid and glucocorticosteroids. In rare instances the use of dihydrofolate reductase inhibitors like trimethoprim, methotrexate or pyrimethamine can contribute to the occurrence of folate deficiency. Folinic acid can circumvent the need for the inhibited dihydrofolate reductase. 

Folic acid is used for the treatment of folate deficiency. Oral folic acid is usually the therapy of choice. For megaloblastic anemia doses of 5 mg daily for 4 months should be effective. Folinic acid is available in a parenteral formulation which may be indicated when oral therapy is not feasible and for rescue treatments following certain anti-cancer regimens. 

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... 

Since sulfasalazine inhibits the absorption of folic acid, patients may become folate deficient during longterm therapy. Sulfasalazine decreases the bioavailabiUty of digoxin. Cholestyramine reduces the metabolism of sulfasalazine. Sulfasalazine causes a reversible decrease in sperm counts. Sulfasalazine is safe in pregnancy. 

Because both drugs may interfere with folic acid metabolism, their use during pregnancy is usually contraindicated by the potential for effects on the fetus, such as the development of neural tube defects associated with folate deficiency. The use of trimethoprim is contraindicated in patients with blood dyscrasias, hepatic damage, and renal impairment. 

CBC serum folate concentrations <0.005 mcg/ml indicate folic acid deficiency and concentrations <0.002 mcg/ml usually result in megaloblastic anemia... 

Folic acid antagonist overdose PO 2-15 mg/day for 3 days or 5 mg every 3 days. Megaloblastic anemia secondary to folate deficiency IM 1 mg/day Colon cancer IV 200 mg/m followed by 370 mg/m fluorouracil daily for 5 days. Repeat course at 4-wk intervals for 2 courses then 4-5 wk intervals or 20 mg/m followed by 425 mg/m fluorouracil daily for 5 days. Repeat course at 4-wk intervals for 2 courses then 4-5 wk intervals. 

Reduced forms of folic acid are required for essential biochemical reactions that provide precursors for the synthesis of amino acids, purines, and DNA. Folate deficiency is not uncommon, even though the deficiency is easily corrected by administration of folic acid. The consequences of folate deficiency go beyond the problem of anemia because folate deficiency is implicated as a cause of congenital malformations in newborns and may play a role in vascular disease (see Folic Acid Supplementation A Public Health Dilemma). 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Patients with alcohol dependence and patients with liver disease can develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Patients who require renal dialysis develop folic acid deficiency because folates are removed from the plasma during the dialysis procedure. 

Folic acid deficiency can be caused by drugs. Methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. Long-term therapy with phenytoin can also cause folate deficiency, but only rarely causes megaloblastic anemia. 

Parenteral administration of folic acid is rarely necessary, since oral folic acid is well absorbed even in patients with malabsorption syndromes. A dose of 1 mg folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients. Therapy should be continued until the underlying cause of the deficiency is removed or corrected. Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy. Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients, including pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis. 

Folic acid (or folate) deficiency, one of the most common vitamin deficiencies in the population consuming few dietary fruits and vegetables, causes chromosome breaks in humans,34 analogous to those caused by radiation. Folate supplementation above... 

Other vitamins—vitamin R6 and niacin—complement folic acid. Vitamin R6 deficiency apparently causes chromosome breaks by the same mechanism as folate deficiency.43 Niacin is... 

Folic acid (or folate), which plays a key role in one-carbon metabolism, is essential for the biosynthesis of several compounds. Folic acid deficiency is probably the most common vitamin deficiency in the United States, particularly among pregnant women and alcoholics. 

Some of the unusual features of folic acid noled by investigators include (I) folic acid antagonists used in cancer therapy with temporary remissions (2) lolic acid occurs in chromosomes (3) folic acid is distributed throughout cells (4) needed for mitotic step metaphase to anaphase (5) antibody formation decreased in lolic acid deficiency (6) choline-sparing effects (7) analgesic in humans—pain threshold is increased (8) antisulfonatnide effects (9) enterohepatic circulation of folate (10) synthesized by psittacosis virus (11) concentrated in spinal fluid. 

There exists an inverse association between folate and cardiovascular disease. Folic acid deficiency may result from ... 

Anyone taking diuretics for longer than six months may experience a folate, or folic acid, deficiency. Folic acid plays a part in the health and reproduction of virtually every cell in the body. It is responsible for protein metabolism, the prevention of neural tube defects in pregnancy, blood cell production, and the synthesis of neurotransmitters. Individuals with folate deficiencies may suffer from anemia, depression and other mood disorders, and may give birth to babies with neural tube defects. Supplementation with folic acid may be useful in reversing these effects. 

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