Folate deficiency

What is 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 four months. Almost half of the body folate is found in the liver.

• Good food sources of folate include broccoli, Brussels 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).

• Insufficient folate can result in megaloblastic anaemia. Megaloblastic anaemia is a heterogeneous group of disorders sharing 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.

• 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 (NTDs).¹

• Folate is a vital regulator in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased cardiovascular and stroke risk.^{2 3}

• Folate deficiency may be associated with causing some types of cancer.⁴

Causes of folate deficiency

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

• Malabsorption (eg, 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 preferences.

• NB: goat's milk has a much lower folate concentration than cow's milk; infants fed exclusively on this may become deficient, unless commercial folic acid-fortified goat's milk is used.

Excessive requirements

• Physiological (eg, pregnancy, lactation, prematurity and infancy).

• Malignancy (eg, leukaemia, carcinoma, lymphoma).

• Blood disorders (eg, haemolytic anaemias, sickle cell anaemia, thalassaemia major, chronic myelosclerosis).

• Inflammation (eg, tuberculosis, Crohn's disease, malaria).

• Metabolic (eg, homocystinuria).

• Haemodialysis or peritoneal dialysis.

Excessive urinary excretion

This includes, for example, congestive heart failure, acute liver damage and chronic dialysis.

Antifolate drugs

• With uncertain mechanism of action (eg, anticonvulsants and possibly alcohol and nitrofurantoin).

• Causing malabsorption of folate (eg, colestyramine, sulfasalazine, methotrexate).

• Trimethoprim may exacerbate pre-existing folate deficiency but does not cause megaloblastic anaemia.

Genetic disorders

Mutations in the SLC46A1 gene, leading to proton-coupled folate transporter deficiency.⁵ Hereditary folate malabsorption has been described in 60 individuals worldwide.⁶

Folate deficiency symptoms

• On a folate-deficient diet, folate deficiency develops over the course of about four 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 folate deficiency anaemia or of the underlying cause.

• Glossitis can occur.

• Neurological symptoms (eg, paraesthesia, numbness, cognitive changes, visual disturbance) are more typical of vitamin B12 deficiency but patients with folate deficiency may report mild symptoms of peripheral neuropathy or psychiatric disturbance (eg, depression).

Differential diagnosis

• Other causes of megaloblastic anaemia - eg, vitamin B12 deficiency.

• Causes of macrocytosis without megaloblastic changes - eg:

  • Pregnancy.

  • Alcohol excess.

  • Liver disease.

  • Reticulocytosis.

  • Hypothyroidism.

  • Aplastic anaemia, sideroblastic anaemia, pure red cell aplasia.

  • Drugs - eg, cytotoxics.

  • Cold agglutinins due to autoagglutination of red cells.

Diagnosing folate deficiency (investigations)⁷

• FBC and blood film: features of megaloblastic anaemia: the mean corpuscular volume (MCV) is characteristically greater than 96 fL unless there is a co-existing 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 leukopenia and thrombocytopenia.

• There is no clear consensus on the level of serum folate that indicates folate deficiency. Conventionally, clinicians have used serum folate lower than 7 nmol/L (3 lg/L) as a guideline because the risk of megaloblastic anaemia greatly increases below this level.

• There is no clear consensus on the level of serum folate that indicates folate excess. Concern about excess folate level only occurs in the context of folic acid supplementation in pregnancy or the safety of dietary supplementation. Further research is needed.⁸The normal range in most UK labs is 4-10 microg per litre. Levels above 20 microg per litre are not of concern unless the patient is taking supplements in which case they should stop or reduce. There is an increase in the risk of malignancy in people taking too much folic acid supplementation.³

• Vitamin B12 levels should be assessed at the same time due to the close relationship in metabolism. If there is combined B12 and folate deficiency, B12 should be treated first and the folate deficiency afterwards.

• Severe folate deficiency can cause pancytopenia as well as megaloblastic anaemia.

• Both biochemical and clinical evidence of folate deficiency can be observed in the absence of clinical symptoms.

• The 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.

• Red cell folate is assayed by radioisotope dilution or immunological methods. This is to be preferred to serum folate which fluctuates with dietary intake. In about 5% of patients the measurement of red cell folate may be useful in patients with macrocytosis who have a normal serum folate.

• An erythrocyte folate level less than 340 nmol/L (150 ng/mL) indicates reduced body stores. However, routine red cell folate testing is not necessary because serum folate alone is sufficient in most cases.

• 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 if there is a high index of clinical suspicion.

• LFTs, gamma-glutamyl transpeptidase and/or TFTs may be necessary if other causes of macrocytosis such as excessive alcohol intake or hypothyroidism are suspected.

Folate deficiency management⁷

• Folate deficiency can be corrected by giving 5 mg of folic acid daily for four 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 - eg, coeliac disease - should be treated.

Folate deficiency prevention

• Prophylactic folic acid (400 micrograms daily) is recommended for all women planning a pregnancy.

• Women who have had a child with an NTD should take 5 mg folic acid daily before and during a subsequent pregnancy.

• The higher dose of 5 mg during pregnancy is also recommended for the following:

  • Where either partner has an NTD or has already had a pregnancy affected by NTD.

  • Family history of NTD.

  • Anti-epileptic medication.

  • Coeliac disease.

  • Diabetes (type 1 or 2).

  • Thalassaemia trait (5 mg daily until birth of the baby).

  • Haemolytic anaemia, particularly thalassaemia or sickle cell anaemia (5-10 mg until birth of the baby).

  • Women with a BMI >30 kg/m².

• For those patients receiving renal dialysis, the prophylactic dose suggested is 5 mg daily to weekly, depending on the diet and rate of haemolysis.

• Prevention of methotrexate-induced side-effects in rheumatic disease for an adult aged 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.

Fortification of food

• Folic acid fortification in flour is mandatory in the UK to prevent NTDs in babies.

• Fortification with folic acid has been shown to reduce the prevalence of NTDs in the countries where it has been implemented.⁴

• Uncertainty surrounding possible unintended consequences of fortification of food with folic acid has led to concerns about higher folic acid intake and food fortification programmes. This uncertainty emphasises the need to monitor fortification programmes continually, for accurate measures of their effect and the ability to address concerns as they arise.⁹