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This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
Key points
- Macrocytic megaloblastic anaemia identical to B12 deficiency on blood film (hypersegmented neutrophils, oval macrocytes)
- Red cell folate is the best measure of tissue folate stores; serum folate reflects recent intake only
- Commonest causes: poor dietary intake (elderly, alcoholism), increased demand (pregnancy, haemolytic anaemias), malabsorption (coeliac disease), drugs (methotrexate, trimethoprim, phenytoin)
- Treatment: folic acid 5 mg daily for 4 months — BUT must exclude B12 deficiency FIRST
- Prevention: 400 µg folic acid daily pre-conception and until 12 weeks gestation to prevent neural tube defects
Overview
Folate (vitamin B9) is essential for DNA synthesis and red cell maturation. Body stores of folate are limited (approximately 4 months' supply), so deficiency develops more rapidly than B12 deficiency. The blood film and bone marrow appearances are identical to B12 deficiency (megaloblastic). Unlike B12 deficiency, folate deficiency does NOT cause neurological damage (subacute combined degeneration). However, the critical clinical rule is to exclude B12 deficiency before treating with folic acid, because folic acid can correct the anaemia of B12 deficiency while allowing neurological damage to progress silently.
Epidemiology
Folate deficiency is common, particularly in the elderly, pregnant women, and those with poor nutritional intake including patients with alcohol use disorder. In the UK, dietary deficiency is the most common cause. Malabsorption (coeliac disease, Crohn's affecting jejunum) and drug-induced deficiency (methotrexate, phenytoin, trimethoprim) are also important causes. Since the UK does not mandate flour fortification with folic acid (unlike the USA), dietary deficiency remains prevalent.
Clinical Features
Symptoms
Fatigue and lethargy — often insidious
Breathlessness on exertion
Glossitis — sore, smooth tongue
Mouth ulcers
Weight loss (if malabsorptive cause)
Diarrhoea or steatorrhoea (suggests coeliac or small bowel pathology)
Signs
Pallor
Glossitis
Angular stomatitis
No neurological signs (unlike B12 deficiency — key differentiator)
Signs of underlying cause: malnutrition, alcohol stigmata, signs of coeliac disease
Investigations
First-line
FBC and blood filmMacrocytic anaemia (MCV >100 fL), oval macrocytes, hypersegmented neutrophils — identical to B12 deficiency film
Serum folate and red cell folateLow serum folate reflects recent dietary intake. Red cell folate is better measure of tissue stores
Serum B12MUST check to exclude B12 deficiency before starting folic acid — critical patient safety point
Second-line
Coeliac screen (tTG-IgA)Exclude coeliac disease in all patients with unexplained folate deficiency
LFTsAssess for liver disease; check for alcohol excess
LDH and bilirubinRaised in megaloblastic anaemia (as with B12 deficiency)
Specialist
HomocysteineRaised in folate deficiency (and B12 deficiency)
Methylmalonic acid (MMA)NORMAL in folate deficiency (raised only in B12 deficiency) — helps distinguish the two
1
Exclude B12 deficiency
- CRITICAL FIRST STEP — check serum B12 before starting folic acid
- If B12 is low or borderline, replace B12 FIRST (or concurrently) before giving folic acid
- Giving folic acid alone in B12 deficiency corrects anaemia but masks and worsens neurological damage
2
Folic acid replacement
- Folic acid 5 mg daily for 4 months
- Continue long-term if underlying cause is not correctable (e.g. chronic haemolysis, myelofibrosis)
- Address underlying cause: dietary advice, treat coeliac disease, review causative medications
3
Prevention in pregnancy
- Folic acid 400 µg daily — from pre-conception to 12 weeks gestation for ALL women
- High-dose folic acid 5 mg daily if previous NTD-affected pregnancy, on anti-epileptic drugs, BMI >30, diabetes, or sickle cell disease
Complications
- Neural tube defects: Folate deficiency in early pregnancy causes NTDs (spina bifida, anencephaly) — hence universal supplementation advice
- Pancytopenia: Severe deficiency can affect all cell lines
- Cardiovascular disease: Raised homocysteine from folate deficiency is a risk factor for cardiovascular disease (though supplementation has not been shown to reduce events)
UKMLA Exam Tips
- 1MMA is the key discriminator: raised in B12 deficiency, NORMAL in folate deficiency
- 2Folate deficiency does NOT cause neurological damage — if neuro signs present, think B12
- 3The single most important exam rule: NEVER give folic acid without checking B12 first
- 4Folate stores last ~4 months (short) vs B12 stores lasting 3–4 years (long) — so folate deficiency develops FASTER
- 5Drugs causing folate deficiency: methotrexate, trimethoprim, phenytoin, sodium valproate — classic SBA list
- 6Folic acid 400 µg pre-conception for ALL women; 5 mg if high-risk (previous NTD, anti-epileptics, sickle cell)
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