Conditions · Vitamins and minerals
Megaloblastic anaemia (B12 or folate deficiency) !
Anaemia with large red cells caused by lack of vitamin B12 or folate, which stops the bone marrow copying DNA properly.
Updated 2026-11-01
Structures involved
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In biochemistry
- Methionine cycle and transsulfuration: Step 4 · Methionine synthase (MTR), B12-dependent
- Lactate dehydrogenase (LDH) as a lab marker
- Histidine
- Folate (vitamin B9)
- Cobalamin (vitamin B12)
Microorganisms that cause it
In immunology
In histology
In embryology
In the clinical exam
- Sensory examination: modalities and dermatomes
- Romberg test
- Spinal cord syndromes: complete, Brown-Séquard, central, anterior
- Anemia syndrome
In physiology
- Anemia physiology and compensation
- Erythropoiesis and erythropoietin
- Absorption of iron, calcium and vitamin B12
- Somatosensory pathways: dorsal column and anterolateral
Why it happens
- Vitamin deficiencies: what each one does to tissue
- Alcohol: how it injures the liver, brain, heart and fetus
What it is
A macrocytic anaemia caused by defective DNA synthesis, almost always from vitamin B12 or folate deficiency. It affects every rapidly dividing cell: bone marrow, mucosa and fetus.
Who gets it
Folate deficiency is seen with malnutrition, alcoholism and pregnancy; it fell where flour is fortified, as in Colombia. B12 deficiency is commoner in older adults, vegans, after gastric surgery and with long-term metformin.
Causes
- B12 deficiency: pernicious anaemia, gastrectomy or bariatric surgery, ileal disease or resection, vegan diet, metformin, proton pump inhibitors, fish tapeworm
- Folate deficiency: poor diet, alcoholism, pregnancy, chronic haemolysis, coeliac disease
- Drugs that block DNA or folate: methotrexate, trimethoprim, phenytoin, hydroxyurea, zidovudine
Risk factors
- Older age
- Alcoholism
- Pregnancy and breastfeeding
- Gastric or bowel surgery
- Diet without animal foods
Pathophysiology
Without methylene-tetrahydrofolate, thymidylate synthase cannot make dTMP; uracil enters DNA and replication lags while the cytoplasm keeps maturing (nuclear-cytoplasmic asynchrony). Precursors grow without dividing (megaloblasts) and many die in the marrow (ineffective erythropoiesis): LDH and indirect bilirubin rise. In B12 deficiency, folate is trapped as 5-methyl-THF, and methylmalonic acid also builds up and damages myelin.
Classification
- From vitamin B12 deficiency
- From folate deficiency
- From drugs or inborn defects of DNA synthesis
Symptoms and signs
- Tiredness, pallor, breathlessness on exertion
- Red, smooth, sore tongue (glossitis), mouth ulcers
- Mild jaundice (lemon-yellow tint)
- In B12 deficiency: tingling hands and feet, poor balance, forgetfulness, mood change
- Diarrhoea, weight loss
Diagnosis
- Clinical
- Anaemia with high MCV and glossitis; ask about diet, drugs, surgery, alcohol and look for neurological signs.
- Tests
- Blood count with high MCV, hypersegmented neutrophils, macro-ovalocytes, low reticulocytes; high LDH and indirect bilirubin. Serum B12 and folate; methylmalonic acid (high only in B12 deficiency) and homocysteine (high in both). Intrinsic factor antibodies if B12 is low.
- Imaging
- Not needed for diagnosis; upper GI endoscopy if atrophic gastritis or a gastric lesion is suspected.
Treatment
- Medical
- Replace the missing vitamin: B12 (intramuscular or high-dose oral) or folic acid, after measuring both
- Medical
- Treat the cause: malabsorption, drugs, alcoholism, parasites
- Follow-up
- Monitor potassium in the first days and the reticulocyte response
- Lifestyle
- Diet with leafy greens and legumes (folate) or animal or fortified foods (B12)
Drugs for this condition
Complications
- Subacute combined degeneration of the spinal cord (B12)
- Neural tube defects in pregnancy (folate)
- Heart failure from anaemia
- Hypokalaemia when treatment starts
Prognosis
The anaemia responds within weeks (reticulocytes rise within days); long-standing nerve damage may remain.
Prevention
- Folic acid before and during pregnancy
- B12 for vegans, after bariatric surgery and for at-risk older adults
- Flour fortification
Test yourself
Think of the answer, then tap the question to see it.
Why are the cells large in megaloblastic anaemia?
DNA synthesis lags while the cytoplasm matures; precursors grow without dividing.
Which test tells B12 from folate deficiency?
Methylmalonic acid: raised in B12 deficiency, normal in folate deficiency; homocysteine rises in both.
Why is LDH raised in megaloblastic anaemia?
Ineffective erythropoiesis: many precursors die inside the bone marrow.
Which blood film finding is typical?
Hypersegmented neutrophils (five or more lobes) and macro-ovalocytes.
Why is B12 measured before giving folic acid?
Folic acid corrects the anaemia of B12 deficiency but does not stop its nerve damage.
Related conditions
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Vitamin B12 deficiency anemia: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); Folate-deficiency anemia: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); Methylmalonic Acid (MMA) Test: MedlinePlus Medical Test (MedlinePlus, US National Library of Medicine, 2026); Homocysteine Test: MedlinePlus Medical Test (MedlinePlus, US National Library of Medicine, 2026); RBC indices: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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