- Liver, green leafy vegetable (spinach), egg, meat, yeast.
- synthesized by gut flora, but this is largely unavailable for absorption.
- Daily requirement of an adult is < 0.1 mg but dietary allowance of 0.2 mg/day is recommended.
- During pregnancy, lactation or any condition or high metabolic activity, 0.8 mg/day is considered appropriate
- Folic acid is rapidly extracted by tissues and stored in cells as polyglutamates.
- Liver takes up a large part and secretes methyl-THFA in bile which is mostly reabsorbed from intestine: enterohepatic circulation occurs.
- Folic acid is inactive as such and is reduced to the coenzyme form, in two steps: FA à DHFA à THFA by folate reductase (FRase) and dihydrofola1e reductase (DHFRase) enzymes respectively.
- THFA mediates a number of one carbon transfer reactions by carrying a methyl group as an adduct
- Conversion of homocysteine to methionine: This is the most important reaction which releases THFA from the methylated form.
- Generation of thymidylate, an essential constituent of DNA: This reaction consumes THFA, which needs to be regenerated by DHFRase.
- That is why rapidly proliferating tissues are highly susceptible to DHFRase inhibitor methotrexate.
- Conversion of serine to glycine: needs THFA and results in the formation of methylene-THFA which is utilized in thymidylate synthesis.
- Purine synthesis: de novo building of purine ring requires formyl-THFA and methenyl-THFA (generated from methylene-THFA) to introduce carbon atoms at position 2 and 8.
- Generation and utilization of ‘formate pool’
- Histidine metabolism
Deficiency Folate deficiency occurs due to
- Inadequate dietary intake
- Malabsorption: especially involving upper intestine coeliac disease, tropical sprue, regional ileitis, etc.
- In these conditions, deficiency develops more rapidly because both dietary and biliary folate is not absorbed.
- Biliary fistula; bile containing folate for recirculation is drained.
- Chronic alcoholism: intake of folate is generally poor.
- Increased demand: pregnancy, lactation, rapid growth periods, haemolytic anaemia
- Drug induced: prolonged therapy with anticonvulsants (phenytoin, phenobarbitone, primidone) and oral contraceptives.
Manifestations of deficiency are:
- Megaloblastic anaemia, indistinguishable from that due to vit B 12 deficiency.
- However, folate deficiency develops more rapidly if external supply is cut off: body stores last 3-4 months only.
- In malabsorptive conditions megaloblastosis may appear in weeks.
- Epithelial damage: glossitis, enteritis, diarrhoea, steatorrhoea.
- Neural tube defects, including spina bifida in the offspring, due to maternal folate deficiency.
- General debility, weight loss, sterility.
- However, neurological symptoms do not appear in pure folate deficiency.
- Liquid oral preparations and injectables are available only in combination formulation
- Oral therapy is adequate except when malabsorption is present or
- in severely ill patient-given i.m.
- Dose: therapeutic 2 to 5 mg/day, prophylactic 0.5 mg/day.
Who Is at Increased NTD Risk?
- Previous pregnancy with NTD, Close family member with NTD, Obesity, Use of drugs with antifolate effects, Genetic mutations in the folic acid metabolic pathway or folate receptors, Poorly controlled type 1 or type 2 diabetes mellitus, Poor compliance with folic acid supplementation, Smoking, passive or active, Use of oral contraceptives, Celiac and Crohn diseases
- Megaloblastic anaemias due to: Nutritional deficiency: folate deficiency manifests earlier than vit B 12 deficiency.
- Oral folic acid 2- 5 mg/day is adequate, but in acutely ill patients, therapy may be initiated with injection of folic acid 5 mg/day
- Increased demand: which occurs in pregnancy, lactation , infancy, during treatment of severe iron deficiency anaemia or haemolytic anaemias.
- Pernicious anaemia: folate stores may be low and deficiency may be unmasked when vit B12 induces brisk haemopoiesis.
- Folic acid should never be given alone to patients with vit B12 deficiency, because haematological response may occur, but neurological defect may worsen due to diversion of meagre amount of vit B 12 present in the body to haemopoiesis.
- Malabsorption syndromes: tropical sprue, coeliac disease, idiopathic steatorrhoea, etc.
- Antiepileptic therapy: megaloblastic anaemia can occur due to prolonged phenytoin/ phenobarbitone therapy
- Prophylactic use of folic acid is justified only when definite predisposing factors are present.
- Routine folate supplementation ( I mg/day) is recommended during pregnancy to reduce the risk of neural tube defects in the newborn.
- Folinic acid (Leucovorin, citrovorum factor, 5-formyl-THFA) is an active coenzyme form of folate which does not need to be reduced by DHFRase before it can act.
- Methotrexate is a DHFRase inhibitor; its toxicity is not counteracted by folic acid, but antagonized by folinic acid (3.0 mg i.v. repeated as required).
- To enhance anticancer efficacy of 5-fluorouracil (5-FU)
- Folinic acid is now routinely infused i.v. along with 5-FU, because THFA is required for inhibition of thymidylate synthase by 5-FU.
- Adverse effects Oral folic acid is entirely nontoxic. Injections rarely cause sensitivity reactions.