Folate deficiency

Definition

Folate deficiency causes a megaloblastic, macrocytic anemia that cannot be distinguished from the anemia of vitamin B12 deficiency on the blood count. Folates are needed for purine and pyrimidine synthesis, red cell maturation and development of the fetal nervous system. Unlike B12 deficiency, the typical neurological deficits of subacute combined degeneration are absent.

Occurrence & epidemiology

Folate deficiency is common. In countries where cereal products are routinely fortified with folic acid (e.g. the USA and Canada), however, it has become rare. Those mainly affected are people with undernutrition or alcohol use disorder, pregnant and breastfeeding women, and people with malabsorption or chronic hemolysis.

Aetiopathogenesis

Folate is plentiful in raw green leafy vegetables, fruit and offal; prolonged cooking destroys it. It is absorbed in the duodenum and upper jejunum, and there is an enterohepatic circulation. Liver stores last only a few months – the deficiency therefore develops much faster than B12 deficiency.

• Inadequate intake: undernutrition, diet lacking raw vegetables, restrictive diets, anorexia, alcohol use disorder
• Impaired absorption: celiac disease, tropical sprue, short bowel syndrome and other malabsorption syndromes, congenital folate malabsorption
• Impaired utilisation: folate antagonists and certain antiseizure drugs, congenital or acquired enzyme defects
• Increased demand: pregnancy, lactation, infancy, chronic hemolysis (e.g. hemoglobinopathies), increased metabolism

Alcohol impairs absorption, metabolism, renal excretion and enterohepatic reabsorption of folate and also reduces food intake.

Clinical features

• insidiously developing anemia, often more severe than symptoms suggest because of compensation: fatigue, weakness, pallor, exertional dyspnea
• glossitis, diarrhea, loss of appetite
• depressed mood and confusion
• in pregnancy an increased risk of neural tube defects in the child and possibly other brain malformations

Histology

Blood smear and bone marrow

The picture is the same as in B12 deficiency: macro-ovalocytes, anisocytosis and poikilocytosis, Howell-Jolly bodies and early hypersegmented neutrophils. The bone marrow is megaloblastic with nuclear-cytoplasmic maturation asynchrony in all cell lines; leukopenia and thrombocytopenia follow in later stages.

Diagnosis

• Blood count: macrocytic anemia with high RDW and reticulocytopenia; neutrophil hypersegmentation is a sensitive and readily available sign.
• Serum folate: values below 3 ng/ml (below 7 nmol/l) make deficiency likely. Serum folate, however, reflects intake over recent days; if this has changed recently, red cell folate reflects tissue stores more reliably.
• Homocysteine: raised, but also influenced by B12 and B6 deficiency, renal insufficiency and genetic factors.
• Methylmalonic acid: normal in folate deficiency, raised in B12 deficiency – which helps to distinguish the two.
• Vitamin B12 is always measured as well.
• Search for the cause depending on suspicion, e.g. celiac serology, dietary and alcohol history.

Keep learning in the app

Further reading (open access)

1. MSD Manual Professional: Folate Deficiency
2. MSD Manual Professional: Megaloblastic Macrocytic Anemias

Cross-references