Megaloblastic anemias

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Pathophysiology - Big Cells, Big Problems

  • Core Defect: Impaired DNA synthesis due to Vitamin B12 or Folate deficiency.
  • Mechanism: Affects all rapidly dividing cells, primarily hematopoietic precursors in bone marrow.
    • Nuclear maturation arrests.
    • Cytoplasmic maturation continues, creating a "nuclear-cytoplasmic asynchrony."
  • Result:
    • Megaloblasts: Large, abnormal hematopoietic precursors in the marrow.
    • Macrocytic Anemia: Release of large RBCs (macrocytes, MCV > 100 fL) into circulation.
    • Ineffective erythropoiesis leads to pancytopenia.

Hallmark Finding: Hypersegmented neutrophils (>5 lobes) appear due to abnormal nuclear maturation. They are often one of the first signs.

Vitamin B12 Deficiency - The Neuro Anemia

  • Etiology:

    • Pernicious Anemia: Most common cause; autoimmune destruction of gastric parietal cells → no Intrinsic Factor (IF).
    • Malabsorption: Gastrectomy, ileal resection (Crohn's), metformin, D. latum tapeworm.
    • Dietary: Strict veganism (takes 4-5 years to manifest due to large hepatic stores).
  • Pathophysiology: B12 (cobalamin) deficiency impairs two key reactions:

    • DNA Synthesis → Megaloblastic anemia (ineffective erythropoiesis).
    • Myelin Synthesis → ↑ Methylmalonic Acid (MMA) → demyelination.
  • Clinical Features:

    • Heme: Macrocytosis (MCV > 100 fL), hypersegmented neutrophils, pancytopenia, glossitis.
    • Neuro: Subacute Combined Degeneration (SCD) of the spinal cord (dorsal columns, lateral corticospinal tracts) → symmetric paresthesias, ataxia.
  • Diagnosis: ↓ Serum B12, ↑ MMA, ↑ Homocysteine.

⭐ Neurological symptoms can be permanent if treatment is delayed. Correcting the anemia with folate alone can worsen the neurotoxicity.

Folate Deficiency - Just the Hematology

  • Pathophysiology: Impaired DNA synthesis (purine & thymidylate) affecting rapidly dividing hematopoietic cells.
  • Complete Blood Count (CBC): Macrocytic anemia (MCV > 100 fL). Pancytopenia may occur in severe cases.
  • Peripheral Smear:
    • Hypersegmented neutrophils (≥ 5 lobes).
    • Macro-ovalocytes.
    • Basophilic stippling.
  • Key Biochemical Markers:
    • ↓ Serum folate.
    • ↑ Serum homocysteine.
    • Normal methylmalonic acid (MMA).

Exam Cornerstone: The single most important lab finding to distinguish folate from B12 deficiency is a normal methylmalonic acid (MMA) level. MMA is elevated in B12 deficiency only.

Diagnosis & Management - The Workup & Fix

  • Initial Labs: CBC shows macrocytic anemia (MCV > 100 fL), often with pancytopenia. Peripheral smear reveals hypersegmented neutrophils and macro-ovalocytes. Expect signs of intramedullary hemolysis (↑ LDH, ↑ indirect bilirubin).
  • Treatment:
    • B12 Deficiency: Start with IM cyanocobalamin weekly, then monthly. High-dose oral B12 is an alternative if absorption is intact.
    • Folate Deficiency: Daily oral folic acid. Crucially, always rule out concurrent B12 deficiency first.

High-Yield: Folate supplementation can mask the hematologic signs of B12 deficiency, allowing severe, irreversible neurological damage (subacute combined degeneration) to progress silently.

High‑Yield Points - ⚡ Biggest Takeaways

  • Megaloblastic anemia results from impaired DNA synthesis, causing macrocytosis (MCV > 100) and hypersegmented neutrophils.
  • Vitamin B12 deficiency causes irreversible neurological symptoms (subacute combined degeneration); folate deficiency does not.
  • Both show ↑ homocysteine; only B12 deficiency shows ↑ methylmalonic acid (MMA).
  • Pernicious anemia is the most common cause of B12 deficiency, while alcoholism is a key cause for folate deficiency.
  • Folate supplementation can mask B12 deficiency anemia, but neurological damage will progress.

Practice Questions: Megaloblastic anemias

Test your understanding with these related questions

A 26-year-old man from India visits the clinic with complaints of feeling tired all the time and experiencing lack of energy for the past couple of weeks. He also complains of weakness and numbness of his lower limbs. He has been strictly vegan since the age of 18, including not consuming eggs and milk. He does not take any vitamin or dietary supplements. Physical examination reveals a smooth, red beefy tongue along with lower extremity sensory and motor deficits. What other finding is most likely to accompany this patient’s condition?

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Flashcards: Megaloblastic anemias

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Megaloblastic anemia is a cause of _____ (MCV) anemia

TAP TO REVEAL ANSWER

Megaloblastic anemia is a cause of _____ (MCV) anemia

macrocytic

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