5.2 Approach to Anaemia: Microcytic, Megaloblastic & Haemolytic

Approach to Anaemia: Microcytic, Megaloblastic & Haemolytic

Anaemia is defined by WHO as Haemoglobin <13 g/dL in adult males and <12 g/dL in non-pregnant adult females. In UPSC CMS, questions frequently test differential diagnosis based on Red Cell Indices (MCV, MCH, RDW), reticulocyte response, bone marrow findings, and targeted biochemical assays.

1. Morphological Classification & Initial Workup

Evaluation begins with Mean Corpuscular Volume (MCV) and the Reticulocyte Production Index (RPI):

• Microcytic Anaemia (MCV <80 fL): Differential includes TAILS (Thalassemia, Anaemia of Chronic Disease, Iron Deficiency, Lead poisoning, Sideroblastic Anaemia).
• Normocytic Anaemia (MCV 80-100 fL): Divide by reticulocyte response:
  • RPI >2% (Hyperproliferative): Acute blood loss, Haemolysis.
  • RPI <2% (Hypoproliferative): Early iron deficiency, Aplastic anaemia, Renal failure (EPO deficiency), Bone marrow infiltration.
• Macrocytic Anaemia (MCV >100 fL):
  • Megaloblastic (Hypersegmented neutrophils): Vitamin B12 deficiency, Folate deficiency, Drug-induced (Hydroxyurea, Methotrexate, AZT).
  • Non-Megaloblastic (No hypersegmentation): Alcoholism, Liver disease, Hypothyroidism, Reticulocytosis.

2. Microcytic Anaemias

Differential Diagnosis & Laboratory Panel

Clinical & High-Yield Disease Pearls

1. Iron Deficiency Anaemia (IDA):
   • Etiology: Most common cause worldwide. In adult males and postmenopausal females, IDA is gastrointestinal blood loss until proven otherwise (hookworm infestation Ancylostoma duodenale in tropical regions; peptic ulcer disease or colonic malignancy in older adults).
   • Clinical Signs: Pica (dirt/ice eating), koilonychia (spoon-shaped nails), angular stomatitis, glossitis, Plummer-Vinson Syndrome (triad of IDA, dysphagia due to esophageal webs, and glossitis; increased risk of hypopharyngeal squamous cell carcinoma).
   • Treatment Response: Oral Ferrous Sulfate (200 mg elemental iron 3 times daily). The earliest objective laboratory marker of therapeutic response is reticulocytosis peaking at 7 to 10 days.
2. Beta-Thalassemia Major (Cooley's Anaemia):
   • Genetics: Point mutations in the HBB gene on chromosome 11 leading to absent (β0) or reduced (β+) beta-globin synthesis.
   • Pathophysiology: Excess unpaired alpha-globin chains precipitate within erythroid precursors, causing severe intramedullary hemolysis (ineffective erythropoiesis) and severe peripheral extravascular hemolysis.
   • Clinical Manifestations: Severe transfusion-dependent anaemia presenting at 6-9 months of age (as HbF declines), massive hepatosplenomegaly, skeletal deformities due to marked erythroid hyperplasia (chipmunk facies, frontal bossing, "hair-on-end" appearance on skull X-rays).
   • Lab Findings: Microcytic hypochromic red cells, severe target cells, nucleated RBCs (normoblasts), Hb Electrophoresis demonstrates absent HbA, markedly elevated HbF (85-95%), and variable HbA2.
3. Anaemia of Chronic Disease (ACD):
   • Mediated by inflammatory cytokines (especially Interleukin-6 / IL-6), which stimulate hepatic synthesis of Hepcidin.
   • Hepcidin binds to and degrades Ferroportin (the iron export channel on enterocytes and macrophages), trapping iron inside reticuloendothelial macrophages and preventing systemic iron utilization.

3. Megaloblastic Anaemias (Vitamin B12 vs. Folate Deficiency)

Both Vitamin B12 (Cobalamin) and Folate (Vitamin B9) deficiencies impair DNA synthesis (thymidylate synthesis), leading to nuclear-cytoplasmic asynchrony in bone marrow erythroid precursors (large immature nuclei with mature cytoplasm).

Comparison & Diagnostic Differentiation

CRITICAL CLINICAL PEARL: Treating Vitamin B12 deficiency with Folate alone will correct the haematological abnormalities but will allow irreversible progression of neurological damage (Subacute Combined Degeneration of the dorsal and lateral columns)!

4. Haemolytic Anaemias

Haemolytic anaemias are categorized into Intravascular vs Extravascular haemolysis.

• Intravascular Haemolysis: RBC destruction inside blood vessels. Classic triad: Decreased serum Haptoglobin, Hemoglobinuria, and Hemosiderinuria. Elevated serum LDH and indirect bilirubin.
• Extravascular Haemolysis: RBC destruction by splenic macrophages. Characterized by splenomegaly, jaundice, pigment gallstones, elevated LDH and indirect bilirubin, but no hemoglobinuria.

Key Specific Haemolytic Disorders

1. G6PD Deficiency:
   • Inheritance: X-linked recessive. Glucose-6-Phosphate Dehydrogenase is the rate-limiting enzyme in the HMP shunt, generating NADPH to maintain reduced glutathione.
   • Triggers: Oxidative stress induced by drugs (Primaquine, Dapsone, Cotrimoxazole, Nitrofurantoin), infection, or ingestion of fava beans (Favism).
   • Smear: Oxidized hemoglobin precipitates as Heinz bodies (visible on Crystal Violet stain). Splenic macrophages bite out Heinz bodies, forming Bite cells (degmacytes).
2. Hereditary Spherocytosis:
   • Defect: Autosomal dominant mutation in RBC membrane skeleton proteins (Ankyrin, Spectrin, Band 3), leading to membrane loss, reduced surface-area-to-volume ratio, and spherical rigid RBCs.
   • Lab Findings: Microcytic/normocytic with elevated MCHC (>36 g/dL). Osmotic Fragility Test positive (spherocytes lyse in hypotonic saline solution). Treatment: Splenectomy (requires pneumococcal, meningococcal, and Hib vaccination prior to surgery).
3. Autoimmune Haemolytic Anaemia (AIHA):
   • Warm AIHA: Mediated by IgG antibodies acting at 37°C. Extravascular hemolysis in spleen. Associated with CLL, SLE, drugs (Methyldopa, Penicillin). Direct Coombs Test (DAT) positive for IgG/C3.
   • Cold AIHA: Mediated by IgM antibodies (agglutinins) acting at <37°C. Binds complement; intravascular/extravascular. Associated with Mycoplasma pneumoniae and EBV (Infectious Mononucleosis).
4. Paroxysmal Nocturnal Hemoglobinuria (PNH):
   • Pathogenesis: Acquired somatic mutation in the PIGA gene in hematopoietic stem cells, causing deficiency of GPI-anchor proteins. Consequently, complement regulatory proteins CD55 (DAF) and CD59 (MIRL) are absent on cell membranes.
   • Clinical Triad: Episodic nocturnal intravascular hemolysis/hemoglobinuria, venous thrombosis (at atypical sites like hepatic vein - Budd-Chiari Syndrome), and bone marrow failure (pancytopenia).
   • Diagnosis: Flow cytometry demonstrating absence of CD55 and CD59 on granulocytes/RBCs.