Anemia: Biochemical Aspects

Iron Metabolism Overview - Rusty Road to Red

• Absorption (Duodenum):
  • Fe²⁺ via Divalent Metal Transporter 1 (DMT1). Exit via Ferroportin (FPN1).
  • ↑ by Vitamin C, acidic pH; ↓ by phytates, tannins, Ca²⁺.
• Transport (Blood):
  • Transferrin: Binds 2 Fe³⁺ ions. Delivers to cells via Transferrin Receptor (TfR).
• Storage:
  • Ferritin: Main intracellular storage (Fe³⁺). Serum ferritin reflects body iron stores.
  • Hemosiderin: Insoluble iron storage, accumulates in iron overload.
• Regulation:
  • Hepcidin (liver peptide hormone): Master regulator.
    • Blocks Ferroportin (FPN1) on enterocytes and macrophages, ↓ iron absorption & ↓ iron release from stores.

    ⭐ Hepcidin is the primary negative regulator of iron absorption and macrophage iron release.

  • ↑ Hepcidin: Iron overload, inflammation.
  • ↓ Hepcidin: Iron deficiency, hypoxia, ↑ erythropoiesis.
• Loss: Minimal; primarily via desquamation of skin/GI cells, minor blood loss.

Hemoglobin Synthesis & Catabolism - Red Cell Recipe

• Synthesis (Mitochondria & Cytosol):
  • Glycine + Succinyl CoA $\xrightarrow{ALA \text{ Synthase (B6)}}$ δ-ALA (Rate-limiting).
  • δ-ALA → Porphobilinogen → Protoporphyrin IX.
  • Protoporphyrin IX + Fe²⁺ $\xrightarrow{\text{Ferrochelatase}}$ Heme.
  • Heme + Globin chains → Hemoglobin (Hb).
  • Adult Hb: HbA ($α_2β_2$, >95%), HbA2 ($α_2δ_2$, 1.5-3.5%), HbF ($α_2γ_2$, <1%).
• Catabolism (Reticuloendothelial System, ~120 day RBC lifespan):
  • Hb → Heme + Globin (recycled to amino acids).
  • Heme $\xrightarrow{\text{Heme Oxygenase}}$ Biliverdin + Fe²⁺ (recycled) + CO.
  • Biliverdin $\xrightarrow{\text{Biliverdin Reductase}}$ Unconjugated Bilirubin.
  • Transported to liver, conjugated, excreted in bile.

⭐ ALA synthase is the rate-limiting enzyme in heme synthesis and requires pyridoxal phosphate (Vitamin B6) as a cofactor; its deficiency or inhibition (e.g., by lead) can cause sideroblastic anemia.

IDA - Biochemical Focus - The Empty Tank

• Depleted iron stores (ferritin) → impaired heme & Hb synthesis.
• Key Markers:
  • ↓ Serum Ferritin (< 15-30 ng/mL): Earliest change.
  • ↓ Serum Iron.
  • ↑ TIBC (Total Iron Binding Capacity).
  • ↓ Transferrin Saturation (< 16%). Formula: $\frac{\text{Serum Iron}}{\text{TIBC}} \times 100%$.
  • ↑ sTfR (Soluble Transferrin Receptor).
  • ↑ RBC Protoporphyrin / Zinc Protoporphyrin (ZPP).
  • ↓ Hepcidin (key iron regulator).
• Stages:
  • Iron store depletion (↓ Ferritin).
  • Iron-deficient erythropoiesis (↓ Serum Fe, ↑ TIBC, ↓ Transferrin Sat).
  • IDA (↓ Hb, ↓ MCV, microcytic hypochromic).

⭐ In Iron Deficiency Anemia, serum ferritin is the first marker to decrease, while Total Iron Binding Capacity (TIBC) increases.

Other Anemias - Biochemical Insights - Faulty Factories

• Megaloblastic Anemia (Impaired DNA Synthesis):

  • Vitamin B12 (Cobalamin) Deficiency:
    • Enzymes: Methionine synthase, Methylmalonyl-CoA mutase.
    • Labs: ↑ Methylmalonic Acid (MMA), ↑ Homocysteine, ↑ MCV.
    • Neurological symptoms.
  • Folate (Vitamin B9) Deficiency:
    • Enzyme: Thymidylate synthase (dTMP synthesis).
    • Labs: Normal MMA, ↑ Homocysteine, ↑ MCV.
    • No neurological symptoms.

  ⭐ Megaloblastic anemia due to Vitamin B12 deficiency is characterized by elevated methylmalonic acid (MMA) and homocysteine levels, while folate deficiency only elevates homocysteine.

• Sideroblastic Anemia (Impaired Heme Synthesis):

  • Defect: Defective protoporphyrin synthesis; iron trapped in mitochondria.
  • Enzyme: Often ALA synthase (cofactor: Vitamin B6).
  • Labs: Ring sideroblasts (bone marrow), ↑ Serum Iron, ↑ Ferritin, ↓ TIBC.
  • Causes: Lead (inhibits ALA dehydratase, ferrochelatase), alcohol, isoniazid, congenital.

• Anemia of Chronic Disease (ACD) / Inflammation:

  • Mechanism: ↑ Hepcidin (inflammation) → ↓ iron release from stores & absorption.
  • Labs: ↓ Serum Iron, ↓ TIBC, Normal/↑ Ferritin (acute phase reactant).

High‑Yield Points - ⚡ Biggest Takeaways

• Iron Deficiency Anemia (IDA): ↓ Ferritin (best indicator), ↓ Serum Iron, ↑ TIBC, ↓ Transferrin Saturation.
• Megaloblastic Anemia: Vit B12/Folate deficiency impairs DNA synthesis. ↑ MCV, ↑ Homocysteine; ↑ MMA in B12 def.
• Anemia of Chronic Disease (ACD): ↑ Hepcidin blocks iron release. ↓ Serum Iron, ↓ TIBC, Normal/↑ Ferritin.
• Hemolytic Anemias: Key biochemical markers include ↑ LDH, ↑ Indirect Bilirubin, and ↓ Haptoglobin.
• Thalassemias: Result from defective globin chain synthesis; diagnosed by Hb electrophoresis.
• Sideroblastic Anemia: Impaired heme synthesis leads to ring sideroblasts; ↑ Serum Iron, ↑ Ferritin.