What is megaloblastic anaemia?
Megaloblastic anaemia is a group of macrocytic anaemias in which the bone marrow contains megaloblasts — abnormally large red-cell precursors. The defect is impaired DNA synthesis: nuclear division is slowed, while cytoplasmic maturation (which depends on RNA and protein synthesis) carries on. This nuclear–cytoplasmic asynchrony produces big cells with immature, open 'sieve-like' nuclei.
Every rapidly dividing tissue is affected, not just the marrow — that is why patients also get glossitis, other mucosal changes and sometimes malabsorption. The commonest causes are vitamin B12 (cobalamin) and folate deficiency; less common causes are drugs that interfere with DNA synthesis, copper deficiency and rare inherited disorders such as thiamine-responsive megaloblastic anaemia.
Why do B12 and folate deficiency cause the same anaemia?
Vitamin B12 is a cofactor for just two enzymes in humans. The way they fail explains almost every exam question on this topic.
| Enzyme | Cofactor form | Reaction | In B12 deficiency |
|---|---|---|---|
| Methionine synthase | Methylcobalamin | Homocysteine + methyl-THF → methionine + THF | Homocysteine rises; folate trapped as methyl-THF → DNA synthesis fails |
| Methylmalonyl-CoA mutase | Adenosylcobalamin | Methylmalonyl-CoA → succinyl-CoA | Methylmalonic acid (MMA) rises; linked to defective myelin |
Folate (as tetrahydrofolate) is needed to make thymidine for DNA. Without B12, methionine synthase stalls and folate is locked away as 5-methyl-THF — the methyl-folate trap. The cell is functionally folate-deficient even though serum folate is normal or high. Hence both deficiencies give identical blood and marrow pictures, but only B12 deficiency raises MMA.
What are the causes of vitamin B12 deficiency?
B12 comes only from animal foods (meat, fish, eggs, dairy). Dietary B12 is released from protein by gastric acid and pepsin, binds haptocorrin, then in the duodenum binds intrinsic factor (IF) from gastric parietal cells; the IF–B12 complex is absorbed in the terminal ileum through the cubam receptor (cubilin and amnionless) and carried in blood by transcobalamin. Body stores last years, so deficiency develops slowly.
| Step | Cause |
|---|---|
| Intake | Vegetarian or vegan diet; infants of B12-deficient mothers; low animal-food intake common in low- and middle-income countries |
| Stomach — acid and IF | Pernicious anaemia (autoimmune gastritis), atrophic gastritis, gastrectomy, bariatric surgery; PPIs and H2-receptor antagonists |
| Terminal ileum | Terminal ileal resection, coeliac disease; inherited Imerslund-Gräsbeck syndrome (CUBN/AMN — cubam defect with proteinuria) |
| Drugs (NICE NG239) | Metformin, colchicine, phenobarbital, primidone, pregabalin, topiramate, PPIs, H2-receptor antagonists |
| Inactivation / transport | Recreational nitrous oxide (inactivates B12); transcobalamin II deficiency |
What is pernicious anaemia?
Pernicious anaemia is B12 deficiency due to autoimmune metaplastic atrophic gastritis of the gastric body and fundus. Autoantibodies target the parietal-cell proton pump (H+/K+-ATPase) and intrinsic factor; parietal cells are destroyed, acid (achlorhydria) and IF disappear, and B12 cannot be absorbed. It accounts for roughly 20–50% of B12 deficiency in adults. NICE now prefers the term autoimmune gastritis.
| Test | Sensitivity | Specificity | Use |
|---|---|---|---|
| Anti-intrinsic factor antibody | 50–70% | > 95% | Highly specific — a positive result supports the diagnosis |
| Anti-parietal cell antibody | > 90% | About 50% | Sensitive but non-specific — positive in some healthy people |
- Loss of acid → raised gastrin (G cells unchecked) → enterochromaffin-like cell hyperplasia.
- Associated autoimmune diseases: type 1 diabetes, autoimmune thyroiditis, Addison's disease.
- Increased risk of gastric adenocarcinoma and gastric carcinoid tumours — periodic gastric surveillance is recommended.
- Needs lifelong B12 replacement.
What causes folate deficiency, and how does it differ from B12?
Folate comes from green leafy vegetables, legumes, fruit and liver, and is absorbed in the upper jejunum (not the ileum). Recommended intake is about 400 µg/day of dietary folate equivalents for adults, 600 µg in pregnancy and 500 µg in lactation.
| Mechanism | Examples |
|---|---|
| Poor intake | Poor diet, alcoholism |
| Malabsorption | Coeliac disease, inflammatory bowel disease |
| Increased requirement | Pregnancy, lactation, chronic haemolysis |
| Drugs | Methotrexate, trimethoprim, phenytoin |
| Feature | Vitamin B12 deficiency | Folate deficiency |
|---|---|---|
| Site of absorption | Terminal ileum (needs IF) | Upper jejunum |
| Blood and marrow | Megaloblastic | Megaloblastic (identical) |
| Homocysteine | Raised | Raised |
| Methylmalonic acid | Raised | Normal |
| Serum folate | Normal or high (methyl-folate trap) | Low |
| Neurological disease (SACD) | Yes | Not generally seen |
| Classic setting | Pernicious anaemia, vegans, ileal resection, metformin | Alcoholism, pregnancy, haemolysis, methotrexate, phenytoin |
What does the peripheral smear and bone marrow show?
| Where | Finding |
|---|---|
| Red cells | Macro-ovalocytes (oval macrocytes), marked anisopoikilocytosis, raised RDW (often the earliest change), Howell-Jolly bodies, Cabot rings, basophilic stippling; nucleated red cells or megaloblasts in severe cases |
| Neutrophils | Hypersegmentation — more than 5% of neutrophils with 5 or more lobes, or any neutrophil with 6 or more lobes |
| Counts | Low reticulocyte count; pancytopenia in severe or long-standing cases (can mimic aplastic anaemia) |
| Bone marrow | Hypercellular with erythroid hyperplasia and reversed M:E ratio; megaloblasts with open, lacy chromatin; giant metamyelocytes and band forms; large hyperlobulated megakaryocytes |
Hypersegmented neutrophils are an early sign and often appear before the anaemia. They are a hallmark of megaloblastic change but are not entirely specific — similar features can occur in myelodysplastic syndrome and drug-induced disorders of DNA synthesis. Up to about a quarter of patients have masked macrocytosis because of coexisting iron deficiency or thalassaemia trait.
Which laboratory tests confirm the diagnosis?
Much of the abnormal erythroid output dies inside the marrow — ineffective erythropoiesis (intramedullary haemolysis). This produces a haemolysis-like picture: very high LDH, raised unconjugated bilirubin and low haptoglobin, with an inappropriately low reticulocyte count. Pallor plus mild jaundice gives the classic lemon-yellow tint.
| Total B12 (serum cobalamin) | Active B12 (holotranscobalamin) | Interpretation |
|---|---|---|
| < 180 ng/L (133 pmol/L) | < 25 pmol/L | Deficiency confirmed |
| 180–350 ng/L | 25–70 pmol/L | Indeterminate — consider MMA |
| > 350 ng/L (258 pmol/L) | > 70 pmol/L | Deficiency unlikely |
- Serum B12 or active B12 is the first test; active B12 is preferred in pregnancy.
- Methylmalonic acid — functional marker raised only in B12 deficiency; used when B12 results are indeterminate.
- Homocysteine — raised in both B12 and folate deficiency.
- Serum folate below about 3 ng/mL indicates folate deficiency; red-cell folate reflects stores.
- Anti-IF antibody if pernicious anaemia is suspected.
- Bone marrow is not needed routinely — only for atypical features or to exclude MDS, leukaemia or aplastic anaemia.
- Take all samples before starting replacement.
What are the neurological features of B12 deficiency?
B12 deficiency, unlike folate deficiency, damages myelin. The best-known lesion is subacute combined degeneration (SACD) of the spinal cord — demyelination of the dorsal (posterior) columns and lateral corticospinal tracts.
| Site | Features |
|---|---|
| Dorsal columns | Loss of vibration and joint-position sense, sensory ataxia, balance problems and falls |
| Lateral corticospinal tracts | Weakness, hyperreflexia, spasticity; paraplegia in severe untreated cases |
| Peripheral nerves | Peripheral neuropathy with paraesthesia and numbness |
| Brain and optic nerve | Memory loss, depression, 'brain fog'; optic atrophy and visual-field loss |
| Infants | Developmental delay or regression, hypotonia, tremors, seizures |
Other clinical clues: Hunter (Moeller) glossitis — a smooth, beefy red tongue — angular stomatitis, hyperpigmentation of the knuckles, premature greying, and in severe cases pancytopenia with infections and bleeding.
How is megaloblastic anaemia treated — and why is folate alone dangerous?
- B12 deficiency: replace with vitamin B12 — intramuscular injections are standard; high-dose oral B12 normalised levels as well as IM in a Cochrane review of adults and is acceptable for diet-related deficiency.
- Lifelong IM B12 (NICE NG239) for autoimmune gastritis (pernicious anaemia), total gastrectomy or complete terminal ileal resection.
- Do not delay B12 while awaiting results if megaloblastic anaemia is suspected with neurological symptoms, especially SACD.
- Folate deficiency: oral folic acid 1–5 mg daily, after B12 deficiency has been excluded or treated.
- Transfusion only for cardiorespiratory compromise from severe anaemia.
| Marker | Timing |
|---|---|
| Patient feels better | Within 24 hours |
| Reticulocyte rise | Starts at 48–72 hours, peaks at the end of week 1 — best early sign of response |
| MMA and homocysteine | Normalise within about 5 days |
| White cells and platelets | Normal within about 1 week |
| Hypersegmented neutrophils | Disappear by 10–14 days |
| MCV | Begins to fall by day 14; normal by 6–8 weeks |
During the burst of new red-cell production, iron deficiency may be unmasked and need treatment. A poor response should prompt a search for coexisting iron or folate deficiency or a wrong diagnosis such as MDS.
How is megaloblastic anaemia asked in NEET PG and INI-CET?
- Smear image with an oval macrocyte and a 6-lobed neutrophil → megaloblastic anaemia.
- Marker that separates B12 from folate deficiency → methylmalonic acid (raised only in B12).
- Neurological signs (SACD: dorsal and lateral columns) → B12 only, not folate.
- Most specific test for pernicious anaemia → anti-intrinsic factor antibody.
- Earliest sign of response to B12 → reticulocytosis, peaking at the end of the first week.
- Drug causes: metformin and PPIs (B12); methotrexate, trimethoprim and phenytoin (folate).
- Why not folate alone? → corrects anaemia, lets neurological damage progress.
Megaloblastic anaemia is one of the nutritional deficiency topics that link Pathology, Biochemistry and Medicine — revise it alongside kwashiorkor and marasmus and rickets. For past papers, see the NEET PG pathology PYQs.