assessment of isolated folate deficiency ( folic acid deficiency ) and macrocytosis with a normal haemoglobin

Last edited 06/2018 and last reviewed 09/2022

• serum folate levels are a reflection of recent dietary intake and are therefore may be of limited diagnostic value
  • a low red cell folate is unequivocal evidence of folate deficiency (a consequence of a reduced supply of folate occurring over several months) (1,2)
    • however national guidance suggests that " routine red cell folate testing is not necessary because serum folate alone is sufficient in most cases" (3)
      
      
      
• if folate is reduced then:
  • often the cause is dietary - may be associated with other factors such as chronic disease, alcoholism, pregnancy
    
    
  • other causes include malabsorption, drugs, excessive utilisation of folate in malignancy, chronic well-compensated haemolysis (this may even occur with a normal haemoglobin level)
    
    
  • take a detailed history - consider causes noted above - diet, drugs, alcohol, symptoms of malabsorption
    
    
  • further investigations include:
    • blood film and reticulocyte count
    • Hb electrophoresis
    • liver function tests
    • other haematinics - if not already undertaken - a useful assessment of nutritional status
    • coeliac disease serology
    • consider assessing red cell folate
      • refer if red cell folate levels are particularly low to exclude malabsorption or chronic inflammatory states (2)
      • if borderline levels then a response to physiological doses of folic acid may be diagnostic of dietary deficiency (2)
    • consider referral for specialist investigation if assessment of possible cause of deficiency is unrewarding (1)
      
      
  • treatment:
    • oral folic acid 5 mg per day for four months (up to 15 mg per day may required in malabsorption states)
    • the raised MCV may take time to correct because of the normal 120-day red cell turnover
    • also patients should be encouraged to increase their dietary intake - it is important that serum B12 levels are normal because treatment with folic acid can precipitate subacute combined deficiency of the cord (neuropathy) if a patient is also deficient in vitamin B12
    • the need for maintenance folic acid will be dependent on cause

Notes (3):

• there is no clear consensus on the level of serum folate that indicates deficiency
  • conventionally, clinicians have used serum folate lower than 7 nmol/l (3µg/l) as a guideline because the risk of megaloblastic anaemia greatly increases below this level
    • however, there is a sizeable 'indeterminate zone' [between approximately 7 and 10 nmol/l (3 and 4.5 µg/l)]
      • therefore, a low serum folate level should be taken as suggestive of deficiency rather than as a highly sensitive diagnostic test
  • red cell folate level gives an assessment of the tissue folate status over the lifetime of the red cells and is therefore regarded as an indicator of longer term folate status than the serum folate assay
    • however routine red cell folate testing is not necessary because serum folate alone is sufficient in most cases
• anaemia due to folate deficiency is now most often seen in cases of poor diet, severe alcoholism and in certain gastrointestinal diseases - may be a presenting feature of coeliac disease
• alcohol and folate deficiency
  • risk is increased when >80 g of ethanol is consumed daily
• there are increased folate requirements if there is the presence of exfoliative skin disease
• low blood folate status is seen following chronic use of some medications such as anticonvulsants
• there is no clearly defined progression from the onset of inadequate tissue folate status to development of megaloblastic anaemia
  • both biochemical and clinical evidence of folate deficiency can be observed in the absence of clinical symptoms

Reference:

1. Pulse (2003); 63 (6): 84.
2. Pulse (2004); 64(35):88.
3. Guidelines for the diagnosis and treatment of cobalamin and folate disorders; British Committee for Standards in Haematology (2014)