Folate Deficiency

Folate (folic acid) is one of the B-group of vitamins found in small amounts in many foods. Folate is usually absorbed through the upper part of the small intestine. The body's reserves of folate, unlike vitamin B12, are low and only sufficient for around 4 months.¹

• Good food sources of folate include broccoli, brussel sprouts, asparagus, peas, chickpeas and brown rice. Other useful sources include fortified breakfast cereals, beans, some bread and some fruit (such as oranges and bananas).²
• Insufficient folate results in megaloblastic anaemia. Megaloblastic anaemias are a heterogeneous group of disorders that share common morphological characteristics. Erythrocytes are larger and have higher nuclear-to-cytoplasmic ratios compared to normoblastic cells. Neutrophils can be hypersegmented, and megakaryocytes are abnormal. The maturation of nuclei in megaloblastic cells is delayed while cytoplasmic development is normal.³
• Folate is also required for the development of a healthy fetus and plays an important role in the development of the fetus' spinal cord and brain. There is no simple relationship between maternal folate status and fetal abnormalities but folic acid supplements at the time of conception and in the first 12 weeks of pregnancy reduce the incidence of neural tube defects.
• Folate deficiency may be associated with cardiovascular disease and some cancers.¹ Folate and related B-vitamins may have a role in the primary prevention of cerebrovascular disease.⁴

The main cause of folate deficiency is poor intake, which may occur alone or in combination with excessive utilisation or malabsorption. Folate deficiency can occur for a number of reasons, including:

• Dietary deficiency (e.g. alcoholism, dietary fads)
  • Malabsorption (e.g. coeliac disease, tropical sprue, congenital specific malabsorption, jejunal resection, inflammatory bowel disease)
  • Poor intake
  • Old age
  • Poor social conditions
  • Malnutrition
  • Alcohol excess (also causes impaired utilisation)
  • Poor intake due to anorexia
  • Food fads
• Excessive requirements:
  • Physiological, e.g. pregnancy, lactation, prematurity and infancy
  • Malignancy (e.g. leukaemia, carcinoma, lymphoma)
  • Blood disorders (e.g. haemolytic anaemias, sickle cell anaemia, thalassaemia major, chronic myelosclerosis)
  • Inflammation (e.g. tuberculosis, Crohn's disease, malaria)
  • Metabolic (e.g. homocystinuria)
  • Haemodialysis or peritoneal dialysis
• Excessive urinary excretion (e.g. congestive heart failure, acute liver damage, chronic dialysis)
• Antifolate drugs:
  • With uncertain mechanism of action (e.g. anticonvulsants, and possibly alcohol and nitrofurantoin)
  • Causing malabsorption of folate (e.g. colestyramine, sulfasalazine, methotrexate)
  • Trimethoprim may exacerbate pre-existing folate deficiency, but does not cause megaloblastic anaemia

• On a deficient diet, folate deficiency develops over the course of about 4 months but folate deficiency may develop rapidly in patients who have both a poor intake and excess utilisation of folate.
• Patients with folate deficiency may be asymptomatic or present with symptoms of anaemia or of the underlying cause.
• Glossitis can occur.
• Neurological symptoms (e.g. paraesthesia, numbness, cognitive changes, visual disturbance) are more typical of B₁₂ deficiency but patients with folate deficiency may report mild symptoms of peripheral neuropathy or psychiatric disturbance (e.g. depression).⁵

• Other causes of megaloblastic anaemia, e.g. vitamin B₁₂ deficiency
• Causes of macrocytosis without megaloblastic changes, e.g.:
  • Pregnancy
  • Alcohol excess
  • Liver disease
  • Reticulocytosis
  • Hypothyroidism
  • Aplastic anaemia, sideroblastic anaemia, pure red cell aplasia
  • Drugs, e.g. cytotoxics
  • Cold agglutinins due to autoagglutination of red cells

• Full blood count and blood film: features of megaloblastic anaemia: the mean corpuscular volume (MCV) is characteristically greater than 96 fL unless there is a coexisting microcytosis when there may be a dimorphic picture with a normal/low average MCV. The peripheral blood film shows macrocytes with hypersegmented polymorphs with six or more lobes in the nucleus. If severe, there may be leucopenia and thrombocytopenia.
• Serum and red cell folate are assayed by radioisotope dilution or immunological methods.
• Serum folate is a short-term indicator of folate status; levels are normally within the range of 5-16 ng/mL (11-36 nmol/L folic acid activity).
• Red cell levels are more stable and reflect long term intake, levels less than 140 ng/mL (317 nmol/L) indicate reduced body stores.
• Negative folate balance is therefore indicated by a serum folate concentration less than 3 ng/mL, but folate deficiency is indicated by erythrocyte and liver folate levels below 120 ng/mL or 1.6 mg/kg respectively.
• In many cases of folate deficiency the cause is not obvious from the clinical picture or dietary history. Occult gastrointestinal disease should then be suspected and appropriate investigations, such as small bowel biopsy, should be performed.

• Folate deficiency can be corrected by giving 5 mg of folic acid daily for 4 months for adults (until term in pregnant women); up to 15 mg daily may be required in malabsorption states. Maintenance is 5 mg every 1-7 days.
• Any underlying cause, e.g. coeliac disease, should be treated.

• Prophylactic folic acid (400 micrograms daily) is recommended for all women planning a pregnancy.
• Women who have had a child with a neural tube defect should take 5 mg folic acid daily before and during a subsequent pregnancy.
• Prevention of methotrexate-induced side-effects in rheumatic disease for an adult over 18 years: 5 mg once weekly.
• Prophylactic folic acid is also given in chronic haematological disorders where there is rapid cell turnover (haemolysis): 5 mg every 1-7 days for an adult depending on underlying disease.
• Prophylaxis of folate deficiency in dialysis, by mouth, 5 mg every 1-7 days for adults.

Fortification of food

• The Food Standards Agency Board have agreed that 'mandatory fortification' with folic acid should be introduced, alongside controls on voluntary fortification and advice on the use of supplements.⁷
• Mandatory fortification means that it would be compulsory to add folic acid to either bread or flour. The purpose of mandatory fortification with folic acid is to reduce the number of neural tube defects.⁷
• Fortification with folic acid has been shown to reduce the prevalence of neural tube defects in the countries where it has been implemented.⁸
• However the fortification of food with folic acid remains controversial. Studies have confirmed that unmetabolised folic acid accelerates cognitive decline in the elderly with low vitamin B₁₂ status (about 20% of over 65s in the UK have low B₁₂ status) and, although dietary folates have a protective effect against cancer, folic acid supplementation may increase the incidence of bowel cancer and may also increase the incidence of breast cancer in postmenopausal women.⁹