Q3 LONG ANSWER 10M ★ High-yield

Describe megaloblastic anaemia with its causes, laboratory findings and clinical features. Differentiate B12 from folate deficiency.

Pathology · 2nd Professional — Para-Clinical

Definition

Megaloblastic anaemia results from impaired DNA synthesis, most often from deficiency of vitamin B12 or folate, producing nuclear–cytoplasmic asynchrony: the nucleus matures more slowly than the cytoplasm.

The defect affects all dividing cells, not only the marrow — hence the changes in gut epithelium and in the cervix
A megaloblast is an abnormally large erythroid precursor with a characteristically open, sieve-like ("lacy") nuclear chromatin and relatively mature cytoplasm

Causes

Vitamin B12 deficiency	Folate deficiency
Pernicious anaemia — autoimmune destruction of parietal cells, with anti-intrinsic factor and anti-parietal cell antibodies	Poor dietary intake — the commonest; folate is destroyed by overcooking
Gastrectomy or atrophic gastritis	Increased demand — pregnancy, lactation, chronic haemolysis, malignancy, exfoliative skin disease
Ileal disease or resection (Crohn, tuberculosis)	Malabsorption — coeliac disease, tropical sprue
Blind loop with bacterial overgrowth; fish tapeworm (Diphyllobothrium latum)	Drugs — methotrexate, trimethoprim, phenytoin, sulfasalazine, oral contraceptives
Strict vegan diet (B12 is only of animal origin)	Alcohol
Nitrous oxide abuse — oxidises cobalamin	Haemodialysis

Body stores differ enormously — B12 stores last 3 to 5 years, folate stores only 3 to 4 months. This is why folate deficiency develops quickly and B12 deficiency takes years even after total gastrectomy
In India, nutritional B12 deficiency is common because of widespread vegetarianism — unlike the West, where pernicious anaemia predominates

Laboratory Findings

Test	Finding
MCV	Raised, often above 110 fL — the higher it is, the more likely the cause is megaloblastic
Peripheral smear	Macro-ovalocytes; hypersegmented neutrophils (more than 5 lobes, or 5% with 5 lobes) — an early and characteristic change; anisocytosis and poikilocytosis; Howell–Jolly bodies
Reticulocytes	Low or normal
White cells and platelets	Often reduced — pancytopenia in severe cases
Bone marrow	Hypercellular with megaloblasts; open lacy chromatin; giant metamyelocytes and band forms; nuclear–cytoplasmic asynchrony
Serum LDH and unconjugated bilirubin	Raised — from ineffective erythropoiesis, that is intramedullary destruction of precursors
Serum B12 and red cell folate	Low in the respective deficiency; red cell folate reflects stores better than serum folate
Methylmalonic acid and homocysteine	Both raised in B12 deficiency; only homocysteine is raised in folate deficiency — the most reliable way to distinguish them
Anti-intrinsic factor antibody	Specific for pernicious anaemia, though only about 60% sensitive

CLINICAL PEARL

Methylmalonic acid is the discriminator. B12 is a cofactor for two reactions — methylmalonyl-CoA mutase and methionine synthase — whereas folate is needed for only the second. So B12 deficiency raises both methylmalonic acid and homocysteine, while folate deficiency raises homocysteine alone. The biochemistry answers the clinical question directly.

Clinical Features

Feature	B12 deficiency	Folate deficiency
Anaemia	Yes	Yes
Glossitis, angular stomatitis	Yes	Yes
Neurological disease	Yes — the crucial difference	NO
Mild jaundice ("lemon-yellow" tint)	Yes	Yes
Onset	Years	Months
Neural tube defects in offspring	—	Yes — prevented by periconceptional folic acid

Neurological features of B12 deficiency

Subacute combined degeneration of the cord — demyelination of the dorsal columns and corticospinal tracts
Symmetrical paraesthesiae, loss of vibration and position sense, sensory ataxia with a positive Romberg sign
Brisk reflexes with extensor plantars — the combination of upper and lower motor neurone signs that names the condition
Dementia, depression and optic atrophy
Neurological damage may occur without anaemia, and may be irreversible if treatment is delayed beyond a few months

Applied Aspects

Never give folate alone to a patient who may be B12 deficient — it corrects the anaemia while the neurological damage progresses unchecked, and may precipitate it. Always check B12 first, or give both
Treatment — intramuscular hydroxocobalamin for B12; oral folic acid for folate. A brisk reticulocytosis at 5–7 days confirms the diagnosis
Watch for hypokalaemia during the response, as potassium is taken up by the rapidly proliferating marrow
Pernicious anaemia carries a raised risk of gastric carcinoma and is associated with other autoimmune disease — thyroid disease, vitiligo, Addison disease
Periconceptional folic acid prevents about 70% of neural tube defects, and must be started before conception
Metformin causes B12 malabsorption with long-term use, and levels should be checked periodically in diabetic patients
The Schilling test is of historical interest only, having been replaced by antibody testing and by empirical treatment
Macrocytosis without anaemia is common and is most often due to alcohol, liver disease or hypothyroidism rather than to a deficiency
Mixed deficiency is common in India — iron and B12 together may give a normal MCV with a raised RDW and a "dimorphic" smear showing two populations of cells
Nitrous oxide used repeatedly, whether medically or recreationally, inactivates B12 and can cause subacute combined degeneration with normal serum levels
Megaloblastic changes affect the cervix and gut too, so a cervical smear may show megaloblastic dyskaryosis that is mistaken for dysplasia
The marrow is HYPERcellular despite the anaemia — a paradox explained by ineffective erythropoiesis, and the reason bilirubin and LDH are raised
Tropical sprue causes combined B12 and folate deficiency and remains an important cause of megaloblastic anaemia in India
Treat before the neurology is established — the anaemia always recovers, but nerve damage present for more than six months often does not
Oral B12 in high dose works even in pernicious anaemia, because about 1% is absorbed by passive diffusion independently of intrinsic factor

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