Etiology

Folate is present in dietary sources such as green leafy vegetables, legumes, and fruits. In addition, it is present in synthetic form, as folic acid, in fortified cereal-grain products. Folate is also known as vitamin B9.

Folate intake can be inadequate for various reasons:[8][9]

  • Consumption of unfortified cereals (e.g., rice or wheat) as a staple diet by certain populations

  • Excessive cooking, destroying folate, in green vegetables and legumes

  • Poor dietary intake by older people

  • Intake of special diets that are low in folate by patients with certain medical conditions, such as phenylketonuria

  • Goats' milk, which is almost completely deficient in folate, being given exclusively to infants.

Intestinal malabsorption of folate occurs in disorders of the small intestine, such as tropical sprue and celiac disease (nontropical sprue), and after extensive intestinal resection.

Increased demand in pregnancy, lactation, and prematurity can lead to folate deficiency.

Increased loss of folate occurs in patients undergoing chronic peritoneal dialysis, and decreased folate is seen in disorders of increased cell turnover, such as chronic hemolytic disease and exfoliative dermatitis.

Medications including sulfasalazine, trimethoprim, methotrexate, pyrimethamine, and anticonvulsants (e.g., phenytoin, phenobarbital) can cause folate deficiency. Folate deficiency in alcohol-use disorder is caused by multiple mechanisms.

Hereditary folate malabsorption and other inborn errors of folate metabolism are rare causes of folate deficiency.[10] Polymorphisms of the enzyme methylenetetrahydrofolate reductase can cause mildly reduced folate levels and mild hyperhomocysteinemia.

Pathophysiology

Natural dietary folates are present as polyglutamates. The main dietary sources of folate are green leafy vegetables, legumes, some fruits, and fortified cereals.

Folate deficiency affects all rapidly dividing cells. Owing to significant folate catabolism and small losses through excretion from the urine, skin, and bile, body folate must be replenished from the diet. Humans cannot synthesize folate de novo.

Most dietary folate is metabolized to 5-methyl-tetrahydrofolate (5-methyl-THF) when it crosses the intestinal mucosa. When 5-methyl-THF enters the cells in the body, it is catalyzed to tetrahydrofolate by the vitamin B12-dependent enzyme methionine synthase. THF is then polyglutamated (by the enzyme folylpolyglutamate synthetase) and retained in the cell.

Folate, in its reduced form tetrahydrofolate, is a 1-carbon transporter that serves as an essential co-enzyme for three key intracellular processes involved in cell viability and growth: DNA synthesis and repair, methylation reactions, and dihydronicotinamide adenine dinucleotide phosphate (NADPH) generation.[11][12]

Folate is essential for the de novo synthesis of purines and thymidylate.[13] Folate deficiency impairs DNA synthesis and repair, which retards cell division and leads to apoptosis of hematopoietic cells in the marrow.[14] The loss of erythropoietic cells causes anemia. More severe folate deficiency can cause thrombocytopenia and neutropenia subsequent to precursor cell death. Marrow cells that have impaired DNA synthesis, but do not undergo apoptosis, have prolonged cell cycle durations, and relatively increased protein accumulation during the protracted cell cycle, which results in macrocytosis.[14]

Both folate and vitamin B12 (cobalamin) are cofactors in methylation of homocysteine to form methionine; therefore, deficiency of either vitamin increases homocysteine (a biomarker of folate deficiency). Methyl-THF supplies the methyl group for the formation of methyl-cobalamin, which methylates homocysteine, regenerating methionine - an essential amino acid. NADPH reduces glutathione, which mitigates oxidative stress in rapidly dividing cells.

Neural tube defects

Folate is required for normal development of the central nervous system (CNS). The finding of low folate status in women who had children with neural tube defects (NTDs), and the prevention of recurrent NTDs with folic acid supplementation, led to clinical trials demonstrating that folic acid supplements before and during pregnancy prevented some NTDs.[15] NTDs commonly associated with maternal folate deficiency include anencephaly and spina bifida.

NTDs are thought to result from a combination of genetic predisposition and environmental factors that cause failure of neural tube closure during embryogenesis, which occurs at days 21 to 28 post-conception.[16][17] The role of folate in neural tube development has not been fully elucidated, but decreased methylation of DNA, causing variation in gene expression, may play a role.[18]

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