Aetiology

Folate (vitamin B9) 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 intake can be inadequate for various reasons:[3][4][10]​​​​[11][12][13]​​[14][15]

  • Dietary deficiency: insufficient daily consumption of folate-rich foods; consumption of unfortified cereals (e.g., rice, wheat, or corn) as a staple diet; exclusive consumption of goats’ milk (which is almost completely deficient in folate) by infants; excessive cooking of folate-rich foods (which destroys folate); or, poor dietary intake during illness, or by older people or people with an intellectual disability (who are living without assistance)

  • Special diet: patients with phenylketonuria are subject to strict dietary restrictions that may result in folate deficiency

  • Malabsorption: disorders of the small intestine (such as tropical sprue and coeliac disease), and extensive intestinal resection

  • Drugs and toxins: 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

  • Increased physiological demand for folate: pregnancy, lactation, and prematurity

  • States of increased cell turnover: exfoliative dermatitis; haemolysis of any aetiology, but particularly haemoglobinopathies, malaria

  • Reduced hepatic capacity for folate storage: cirrhosis

  • Chronic dialysis: increased loss of folate occurs in patients undergoing chronic peritoneal dialysis or haemodialysis

  • Genetic causes (rare): hereditary folate malabsorption and other inborn errors of folate metabolism are rare causes of folate deficiency; defects include hereditary folate malabsorption, methylenetetrahydrofolate reductase deficiency, glutamate formiminotransferase deficiency, and functional methionine synthase deficiency.

Pathophysiology

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

Most dietary folate is metabolised to 5-methyl-tetrahydrofolate (5-methyl-THF) when it crosses the intestinal mucosa. 5-Methyl-THF enters cells via folate receptors, and is catalysed to tetrahydrofolate by the vitamin B12-dependent enzyme methionine synthase. THF is then polyglutamated (by the enzyme folylpolyglutamate synthetase) and retained in the cell, where it participates as an essential coenzyme.

DNA synthesis

Folate is essential for the de novo synthesis of purines and thymidylate.[16] Folate deficiency impairs DNA synthesis and repair, which retards cell division and leads to apoptosis of haematopoietic cells in the marrow.[17] The loss of erythropoietic cells causes anaemia. 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.[17]

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 (NTDs)

Folate is required for in utero development of the central nervous system.[18] Embryonic neural-tube closure, which is completed by the 28th day of conception, is directly dependent on sufficient provision of maternal folate. There is conclusive evidence that folic acid supplementation pre-conceptually and during pregnancy reduces the incidence of fetal NTDs.[19][20][21]

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