Folate deficiency and toxicity Domina Petric, MD

Folate deficiency I. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Risk factors The most important factor contributing to folate deficiency is insufficient dietary intake. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Risk factors Malabsorption Gastric diseases: atrophic gastritis. Intestinal diseases: tropical sprue, celiac disease. Gastric diseases: atrophic gastritis. Drugs: alcohol, sulfasalazine, p-aminosalicylic acid, gastric acid-suppressants. Genetic: hereditary folate malabsorption. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolic impairments Risk factors Metabolic impairments Acquired: dihydrofolate reductase inhibitors (methotrexate), alcohol, sulfasalazine... Genetic: methylenetetrahydrofolate reductase deficiency, glutamate formiminotransferase deficiency, methylenetetrahydrofolate reductase polymorphisms November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Increased requirements Risk factors Increased requirements Hemodialysis Prematurity Pregnancy Lactation November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Deficiencies of folate result in impaired biosynthesis of DNA and RNA. Signs and symptoms Deficiencies of folate result in impaired biosynthesis of DNA and RNA. The consequence is reduced cell division, which is manifested clinically as anemia, dermatologic lesions and poor growth. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Signs and symptoms The anemia of folate deficiency is characterized by the presence of large, nucleated erythrocyte-precursor cells, called macrocytes, and of hypersegmented polymorphonuclear neutrophils, reflecting decreased DNA synthesis and delayed maturation of bone marrow. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Macrocytic anemia with hypersegmented neutrophils November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Signs and symptoms Megaloblastic changes occur in other cells. These involve increased cellular DNA content, with defects characterized by DNA strand breakage and growth arrest in the G2 phase of the cell cycle just prior to mitosis. These defects are thought to result from the misincorporation of uracil into DNA in place of thymidylate, a potentially mutagenic situation. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Signs and symptoms Severely anemic individuals show weakness, fatigue, difficulty in concentrating, irritability, headache, palpitations and shortness of breath. Folate deficiency also affects the intestinal epithelium, where impaired DNA synthesis causes megaloblastosis of enterocytes. This is manifested clinically as malabsorption and diarrhea and is a contributor to the clinical picture of tropical sprue. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Signs and symptoms Nuclear hypersegmentation of circulating polymorphonuclear leukocytes appears within about two months of deprivation of the vitamin. This is followed by megaloblastic anemia and, then, general weakness, depression and polyneuropathy. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Signs and symptoms In pregnant women, the deficiency can lead to birth defects or spontaneous abortion. Elderly patients tend to have lower circulating levels of folate, indicating that they may be at increased risk of folate deficiency. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Signs and symptoms Twice-weekly treatments of elderly subjects with folate (1.1 mg) in combination with vitamin B12 (1 mg) and vitamin B6 (5 mg) have been shown to reduce plasma concentrations of homocysteine, methylmalonic acid, 2-ethylcitric acid and cystathionine. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Signs and symptoms overview Organ system/function Signs Appetite Decreased Growth Dermatologic Alopecia, achromotrichia, dermatitis Muscular Weakness Gastrointestinal Inflammation Erythrocytes Macrocytic anemia Nervous Depression, neuropathy, paralysis November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Methionine-folate linkage Folate utilization is impaired by insufficient supplies of vitamin B12 and/or the indispensable amino acid methionine. Dietary deficiencies of either of those nutrients can produce signs of folate deficiency. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Methionine-folate linkage Patients with pernicious anemia generally have impaired folate utilization and show signs of folate deficiency. The metabolic basis of this effect involves the methionine synthetase reaction, which is common to the functions of both folate and vitamin B12. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Methionine-folate linkage Methionine supplements cannot correct the low circulating folate levels caused by vitamin B12 deficiency. The amino acid appears to exert its action via S-adenosylmethionine, which inhibits 5,10-methylene-FH4 reductase (thus reducing the de novo synthesis of 5-methyl-FH4) and activates methionine synthetase. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Relationship with zinc Folate utilization can be impaired by depletion of zinc. Dietary zinc deficiency has been found to reduce the absorption of folyl polyglutamates. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Several drugs can impair the absorption and metabolism of folates. Effects of drugs Several drugs can impair the absorption and metabolism of folates. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Methotrexate, also called amethopterin, is an analog of folate. Effects of drugs Methotrexate Methotrexate, also called amethopterin, is an analog of folate. It differs from folate in two ways: the presence of an amino group replacing the 4-hydroxyl group on the pteridine ring and a methyl group at the N-10 position. These differences give methotrexate a greater affinity than the natural substrate for dihydrofolate reductase, resulting in its inhibition. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Effects of drugs Methotrexate The drug produces an effective folate deficiency, with reductions in thymidine synthesis and purines. This antiproliferative effect is the basis for the drug’s role in the treatment of cancer, rheumatoid arthritis, psoriasis, asthma and inflammatory bowel disease. Methotrexate is usually used with accompanying and carefully monitored folate supplementation to reduce the incidence of mucosal and gastrointestinal side effects. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Effects of drugs 5-Fluorouracil The antineoplastic drug 5-fluorouracil is a substrate for thymidylate synthase, being incorporated into the nucleotide as 5-fluorodeoxyuridylate instead of dUMP. The abnormal product binds covalently with the enzyme to inhibit DNA synthesis. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Effects of drugs Other drugs Impairments in folate status/metabolism have been reported for anticonvulsants (diphenylhydantoin, phenobarbital), anti-inflammatory drugs (sulfasalazine), glycemic control drugs (metformin) and alcohol. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Pharmacologic uses of folate II. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Pharmacologic uses of folate High doses of folate (400 µg/day intramuscular; 5 mg/day oral) have been shown to correct the megaloblastic anemia of pernicious anemia patients. Because folate does not affect the neurological lesions of pernicious anemia or vitamin B12 deficiency, it can, by correcting anemia, mask an underlying problem of vitamin B12 nutrition in its early (and more easily treated) stages. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Pharmacologic uses of folate Folate at treatment can also be effective in reducing elevated and normal plasma homocysteine levels. This effect may be realized with doses <1 mg. It appears to be greater when the vitamin is given in combination with vitamin B12. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Pharmacologic uses of folate High doses of 5-methylfolate have been found to benefit patients with acute psychiatric disorders. Both depressed and schizophrenic patients responded to daily doses of 15 mg of 5-methylfolate with improved clinical and social outcomes compared with placebo controls. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Pharmacologic uses of folate FDA has recommended that women who have had a neural tube defect pregnancy should take 4 mg of folate daily. The agency has proposed adding folate to enriched breads, flours, corn meals, pastas, rice and other grain products to achieve a target daily intake, for all women between 15 and 44 years old: 0.4–1.0 mg of folate. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Pharmacologic uses of folate Individuals taking high-level folate supplements typically circulate significant amounts of non-metabolized folic acid, which does not occur at nutritional doses of the vitamin. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Folate toxicity III. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Folate toxicity Inconsistent results have been reported concerning the effects of high-folate levels (1 mg to 10 mg doses) on patients with epilepsy. Some have indicated increases in the frequency or severity of seizures and reduced anticonvulsant effectiveness, whereas others have shown no such effects. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Folate toxicity It has also been suggested that folate may form a non-absorbable complex with zinc, thus antagonizing the utilization of that essential trace element at high intakes of the vitamin. November 7, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Literature Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. November 7, 2018