Iron Deficiency & Megaloblastic Anaemia
Pathology · Haematology · lean revision notes
Iron Deficiency & Megaloblastic Anaemia
Two of the highest-yield anaemias for NEET PG, sitting at opposite ends of the RBC size spectrum: iron deficiency produces a microcytic hypochromic picture, while B12/folate deficiency produces a macrocytic megaloblastic picture. Mastering the iron-study panel (serum iron, TIBC, ferritin, transferrin saturation) and the peripheral smear clues lets you crack almost any lab-interpretation MCQ.
Morphological classification of anaemia
Anaemia is first triaged by MCV (normal 80–100 fL). This single value funnels you toward the correct differential before you order another test.
| MCV | Class | Key causes |
|---|---|---|
| < 80 fL | Microcytic | Iron deficiency, thalassaemia trait, anaemia of chronic disease (late), sideroblastic anaemia, lead poisoning |
| 80–100 fL | Normocytic | Acute blood loss, haemolysis, anaemia of chronic disease (early), CKD, marrow failure |
| > 100 fL | Macrocytic | Megaloblastic (B12/folate), non-megaloblastic (alcohol, liver disease, hypothyroidism, myelodysplasia, reticulocytosis) |
High-yield: The classic mnemonic for microcytic anaemia is TAILS — Thalassaemia, Anaemia of chronic disease, Iron deficiency, Lead poisoning, Sideroblastic anaemia.
Part A — Iron deficiency anaemia (IDA)
Iron metabolism essentials
Total body iron ≈ 3–4 g. Most is in haemoglobin (~2.5 g); the rest is stored as ferritin and haemosiderin (liver, spleen, marrow macrophages). Dietary iron is absorbed in the duodenum and proximal jejunum. Ferrous (Fe²⁺) iron is absorbed far better than ferric (Fe³⁺); vitamin C aids absorption by reducing Fe³⁺ → Fe²⁺. Iron is transported in plasma bound to transferrin and stored intracellularly as ferritin.
Hepcidin is the master negative regulator: it is the hormone that degrades ferroportin (the basolateral exporter on enterocytes and macrophages), thereby trapping iron inside cells and lowering serum iron. Hepcidin rises in inflammation (→ anaemia of chronic disease) and falls in iron deficiency and hypoxia.
High-yield: Anaemia of chronic disease = high hepcidin → iron trapped in macrophages → low serum iron but normal/high ferritin. Iron deficiency = low hepcidin but exhausted stores → low ferritin.
Etiology
The cause depends on age and sex — and finding the cause matters as much as treating the anaemia.
- Chronic blood loss — the commonest cause in adults. Menorrhagia in premenopausal women; GI loss (colon cancer, peptic ulcer, hookworm/Ancylostoma, NSAIDs) in men and postmenopausal women.
- Increased demand — pregnancy, infancy, adolescent growth spurts.
- Decreased intake — poor diet, exclusive prolonged breastfeeding/cow-milk diet in infants.
- Malabsorption — coeliac disease, post-gastrectomy, atrophic gastritis, H. pylori.
High-yield: In an Indian setting, hookworm infestation is a classic cause of IDA; in a Western adult male or postmenopausal woman, occult GI malignancy must be excluded.
Clinical features
- General anaemia: fatigue, pallor, dyspnoea, palpitations.
- Epithelial/tissue iron-dependent signs: koilonychia (spoon-shaped nails), angular stomatitis, atrophic glossitis, brittle hair.
- Pica — craving for ice (pagophagia), clay (geophagia).
- Plummer–Vinson / Paterson–Brown–Kelly syndrome = IDA + post-cricoid oesophageal web + dysphagia; premalignant for post-cricoid squamous carcinoma.
Peripheral smear & indices
- Microcytic, hypochromic RBCs with increased central pallor.
- Anisocytosis and poikilocytosis; pencil cells (elliptocytes), target cells.
- High RDW (red cell distribution width) — a key discriminator from thalassaemia trait.
- Platelets often raised (reactive thrombocytosis from blood loss).
Iron studies — the money table
This panel is the single most tested concept in haematology MCQs. Learn it cold.
| Parameter | Iron deficiency | Anaemia of chronic disease | Thalassaemia trait | Sideroblastic anaemia |
|---|---|---|---|---|
| Serum iron | ↓ | ↓ | Normal | ↑ |
| TIBC (transferrin) | ↑ | ↓ | Normal | Normal/↓ |
| Transferrin saturation | ↓ (<15%) | ↓ | Normal | ↑ |
| Serum ferritin | ↓ (<15 µg/L) | Normal/↑ | Normal | ↑ |
| Marrow iron stores | Absent | Present (in macrophages) | Present | Ring sideroblasts |
| RDW | ↑ | Normal | Normal | Variable |
| Mentzer index (MCV/RBC) | > 13 | — | < 13 | — |
High-yield: Serum ferritin is the single most useful test for diagnosing iron deficiency and the earliest lab abnormality. A ferritin < 15 µg/L is virtually diagnostic. BUT ferritin is an acute-phase reactant — it can be falsely normal in coexisting inflammation/infection.
High-yield: TIBC is HIGH in iron deficiency and LOW in anaemia of chronic disease — this is the cleanest single discriminator between the two. Soluble transferrin receptor (sTfR) is raised in IDA and normal in ACD, useful when ferritin is uninterpretable.
Mentzer index = MCV ÷ RBC count. > 13 favours iron deficiency (low RBC count); < 13 favours thalassaemia trait (RBC count preserved/high). Thalassaemia trait also shows normal/low RDW and disproportionately low MCV for the degree of anaemia.
Sequence of iron depletion (flow)
Depleted stores → falling transport iron → impaired erythropoiesis. In order:
Serum ferritin ↓ → marrow iron stores absent → serum iron ↓ & TIBC ↑ → transferrin saturation ↓ → free erythrocyte protoporphyrin ↑ → MCV ↓ (microcytosis) → haemoglobin ↓
So ferritin falls first; haemoglobin falls last.
Management — drug of choice
- Oral ferrous sulphate is the drug of choice (200 mg tablet ≈ 65 mg elemental iron; give ~150–200 mg elemental iron/day). Take on an empty stomach with vitamin C; avoid tea/antacids/calcium with the dose.
- Reticulocytosis appears within 5–10 days; haemoglobin rises ~2 g/dL over ~3 weeks. This is the earliest sign of a response.
- Continue iron for 3–6 months after Hb normalises to replenish stores.
- Parenteral iron (iron sucrose, ferric carboxymaltose) for intolerance, malabsorption, CKD on erythropoietin, or non-compliance. Calculate dose by deficit.
- Always treat the underlying cause (deworming, treat menorrhagia, scope the gut).
High-yield: The earliest response to oral iron is the reticulocyte rise (day 5–10). Failure to respond = wrong diagnosis, ongoing loss, non-compliance, malabsorption, or combined deficiency.
Complications
Heart failure (high-output) in severe chronic anaemia, growth & cognitive impairment in children, adverse pregnancy outcomes, and the premalignant Plummer–Vinson web.
Part B — Megaloblastic anaemia
Definition & mechanism
A macrocytic anaemia caused by defective DNA synthesis (impaired thymidine production) from vitamin B12 (cobalamin) or folate deficiency. Cytoplasmic maturation (RNA/Hb synthesis) proceeds normally while nuclear maturation lags → nuclear–cytoplasmic asynchrony. The marrow shows large megaloblasts; ineffective erythropoiesis causes intramedullary haemolysis (raised LDH, raised indirect bilirubin).
B12 vs folate metabolism
| Feature | Vitamin B12 (cobalamin) | Folate |
|---|---|---|
| Dietary source | Animal products (meat, egg, dairy) — not plants | Green leafy vegetables, liver |
| Body stores | Large — 3–5 years | Small — 3–4 months |
| Absorption site | Terminal ileum (needs intrinsic factor) | Proximal jejunum |
| Carrier protein | Transcobalamin II | — |
| Deficiency speed | Slow (years) | Fast (months) |
B12 biochemistry: B12 is a cofactor for two reactions —
- Methylmalonyl-CoA → succinyl-CoA (methylmalonyl-CoA mutase). Block → methylmalonic acid (MMA) accumulates → abnormal myelin → neurological disease.
- Homocysteine → methionine (methionine synthase), regenerating tetrahydrofolate (the "methyl-folate trap"). Block → homocysteine ↑ and folate trapped as methyl-THF, unavailable for DNA synthesis → the megaloblastic anaemia.
High-yield: Both B12 and folate deficiency raise homocysteine, but only B12 deficiency raises methylmalonic acid (MMA). Elevated MMA + homocysteine distinguishes B12 deficiency from folate deficiency.
Etiology
B12 deficiency
- Pernicious anaemia — autoimmune atrophic gastritis with anti-intrinsic factor and anti-parietal cell antibodies; associated with achlorhydria, gastric carcinoid risk, vitiligo, thyroid disease.
- Terminal ileal disease/resection (Crohn's), tropical sprue, coeliac disease.
- Fish tapeworm Diphyllobothrium latum; blind-loop bacterial overgrowth.
- Strict vegans; metformin and PPIs reduce absorption; nitrous oxide oxidises and inactivates B12.
Folate deficiency
- Poor diet/alcoholism (commonest), overcooking food.
- Increased demand: pregnancy, haemolysis, malignancy.
- Malabsorption (coeliac, jejunal disease).
- Drugs: methotrexate (DHFR inhibitor), trimethoprim, phenytoin, sulfasalazine.
High-yield: Pernicious anaemia is the classic cause of B12 deficiency. Antibodies: anti-intrinsic factor is highly specific; anti-parietal cell is sensitive but less specific.
Clinical features
- Anaemia + mild jaundice (lemon-yellow tinge from ineffective erythropoiesis) → "lemon-yellow" pallor.
- Glossitis (beefy-red smooth tongue), angular stomatitis, weight loss.
- Neurological — B12 only: subacute combined degeneration (SACD) of the cord — symmetrical degeneration of dorsal columns (loss of vibration & proprioception, positive Romberg) and lateral corticospinal tracts (spasticity, upgoing plantars). Also peripheral neuropathy and dementia.
High-yield: Folate deficiency does NOT cause neurological disease. Giving folate alone to a B12-deficient patient corrects the anaemia but precipitates/worsens SACD — always check/replace B12 before folate. This is a favourite trap MCQ.
Peripheral smear & marrow
- Macro-ovalocytes (large oval RBCs), high MCV (often > 110–120 fL).
- Hypersegmented neutrophils — ≥ 5% with 5 lobes or any with 6 lobes (or "right shift"). One of the earliest peripheral signs.
- Pancytopenia in severe cases (ineffective trilineage haematopoiesis).
- Marrow: megaloblasts, giant metamyelocytes/band forms, hypercellular.
- Low reticulocyte count, raised LDH and indirect bilirubin (intramedullary haemolysis).
High-yield: Hypersegmented neutrophils on smear are the classic clue to megaloblastic anaemia and may appear before frank macrocytosis.
Diagnosis & investigations
- Macrocytic anaemia → check reticulocyte count (low → not haemolysis/reticulocytosis).
- Serum B12 and serum/red-cell folate. Red-cell folate reflects body stores better than serum folate.
- If borderline B12 → measure MMA and homocysteine (both raised in B12 deficiency; only homocysteine in folate deficiency).
- Pernicious anaemia work-up: anti-IF and anti-parietal cell antibodies; gastrin (raised), endoscopy.
Schilling test (classic, now largely historical/obsolete) — was used to localise the cause of B12 malabsorption.
- Stage 1: oral radiolabelled B12 + IM unlabelled B12 flushing dose → measure urinary radioactivity. Low excretion = malabsorption.
- Stage 2: repeat with intrinsic factor. Correction → pernicious anaemia. No correction → ileal disease or bacterial overgrowth.
- Stage 3: repeat after antibiotics → correction suggests bacterial overgrowth.
- Stage 4: repeat after pancreatic enzymes → pancreatic insufficiency.
High-yield: In the Schilling test, correction with added intrinsic factor (Stage 2) localises the defect to lack of IF = pernicious anaemia. Modern practice uses antibody testing instead, but the test's logic is still examined.
Diagnostic approach to macrocytic anaemia (flow)
MCV > 100 → reticulocyte count: high → haemolysis/blood loss (non-megaloblastic). Low/normal → smear: hypersegmented neutrophils + macro-ovalocytes → megaloblastic → measure B12 & folate → if B12 low/borderline, MMA + homocysteine → treat the deficient vitamin (B12 first).
Management — drug of choice
- B12 deficiency: intramuscular hydroxocobalamin (or cyanocobalamin). Typical pernicious anaemia: loading IM doses then lifelong maintenance (oral high-dose B12 works in some dietary cases). A brisk reticulocytosis at day 5–7 confirms the diagnosis.
- Folate deficiency: oral folic acid 5 mg/day. Pregnancy prophylaxis 400 µg/day (5 mg if prior NTD/high risk).
- Watch for hypokalaemia during the early response (rapid cellular uptake of potassium as haematopoiesis resumes).
High-yield: Always correct B12 before (or together with) folate to avoid precipitating subacute combined degeneration. The reticulocyte response peaks around day 5–7 of replacement.
Complications
Subacute combined degeneration (may be irreversible if untreated), heart failure from severe anaemia, infertility, and (in folate deficiency in pregnancy) neural tube defects in the fetus. Pernicious anaemia carries increased risk of gastric carcinoma and carcinoid.
Key differentials at a glance
| Scenario | Pointer to diagnosis |
|---|---|
| Microcytic, high RDW, low ferritin, high TIBC | Iron deficiency |
| Microcytic, normal/low RDW, normal ferritin, Mentzer < 13, raised HbA2 | β-Thalassaemia trait |
| Microcytic/normocytic, low serum iron, low TIBC, high ferritin | Anaemia of chronic disease |
| Microcytic, high serum iron & ferritin, ring sideroblasts, basophilic stippling | Sideroblastic anaemia / lead poisoning |
| Macrocytic + hypersegmented neutrophils + neuro signs | B12 deficiency |
| Macrocytic + hypersegmented neutrophils, no neuro signs, pregnancy/alcohol | Folate deficiency |
| Macrocytic, high reticulocytes, no hypersegmentation | Non-megaloblastic (haemolysis/blood loss) |
High-yield: Basophilic stippling + microcytic anaemia + abdominal pain + raised serum iron → think lead poisoning / sideroblastic anaemia. Lead inhibits ALA dehydratase and ferrochelatase.
Recently asked / exam angle
- Iron-study pattern recognition ("Low serum iron, high TIBC, low ferritin — diagnosis?") is the single most repeated format — answer: iron deficiency.
- TIBC direction to separate IDA (high) from ACD (low).
- Ferritin as the earliest/most useful IDA marker, and its pitfall as an acute-phase reactant.
- Mentzer index and RDW to separate IDA from thalassaemia trait.
- MMA vs homocysteine to separate B12 from folate deficiency (only MMA up in B12).
- Folate-alone correction precipitating SACD — classic single-best-answer trap.
- Hypersegmented neutrophil definition (≥ 5% with 5 lobes / any 6-lobed).
- Schilling test Stage 2 with intrinsic factor → pernicious anaemia.
- Hepcidin/ferroportin physiology linking ACD to high hepcidin.
- Plummer–Vinson syndrome triad and its premalignant web.
- Site of absorption: iron (duodenum) vs B12 (terminal ileum) vs folate (jejunum).
Rapid revision
- Ferritin is the earliest and most useful test for iron deficiency; < 15 µg/L is diagnostic but it is an acute-phase reactant.
- TIBC high in IDA, low in anaemia of chronic disease — the cleanest discriminator.
- Mentzer index > 13 → iron deficiency; < 13 → thalassaemia trait; RDW high in IDA, normal in trait.
- Iron absorbed in the duodenum; hepcidin degrades ferroportin and is high in inflammation (ACD).
- Earliest sign of response to oral iron = reticulocytosis at day 5–10; continue iron 3–6 months after Hb normalises.
- Plummer–Vinson = IDA + post-cricoid oesophageal web + dysphagia (premalignant).
- B12 stores last 3–5 years; folate stores only 3–4 months.
- Only B12 deficiency raises MMA; both raise homocysteine; only B12 causes SACD (dorsal columns + lateral corticospinal tracts).
- Never give folate alone in B12 deficiency — corrects anaemia but worsens neuro disease.
- Hypersegmented neutrophils (≥5 lobes) + macro-ovalocytes = megaloblastic anaemia; low retics, high LDH & indirect bilirubin.
- Pernicious anaemia = autoimmune; anti-IF (specific) + anti-parietal cell (sensitive); Schilling Stage 2 corrects with IF.
- Drug of choice: oral ferrous sulphate (IDA), IM hydroxocobalamin (B12), oral folic acid 5 mg (folate); watch hypokalaemia on treatment.