Physiology and Requirements
Total Body Iron
- Full-term newborn total body iron: ~0.5 g.
- Adult total body iron: 5 g.
- Required daily absorption: ~0.8 mg daily during first 15 years; ~1 mg daily to maintain positive balance.
- Required daily dietary intake: 8–10 mg (dietary iron absorption efficiency <10%).
Absorption Mechanisms
- Primary absorption site: Proximal duodenum.
- Gastric acidity essential for converting insoluble environmental iron salts into absorbable forms.
- Agents reducing gastric acidity (e.g., H2 blockers) impair non-heme iron absorption.
- Heme Iron: Derived from animal sources. Most readily absorbed. Independent of gastric pH.
- Non-Heme Iron: Derived from plant sources. Absorption limited by low solubility and natural chelators (e.g., phytates).
- Milk Sources: Breast milk iron bioavailability significantly exceeds cow’s milk. Breastfed infants absorb 20-80% of iron; cow’s milk fed infants absorb ~10%.
Iron Distribution and Storage
- Iron serves essential roles in multiple metabolic processes, oxygen transport, and electron transport.
| Compound | Function in Iron Metabolism |
|---|
| Transferrin | Principal iron transport protein. |
| Ferritin | Primary intracellular iron storage. |
| Hemosiderin | Secondary iron storage. |
| Hemoglobin | Oxygen delivery (circulating RBCs). |
| Myoglobin | Oxygen storage for muscle contraction. |
| Cytochromes | ATP production, electron transport. |
Molecular Regulation of Iron Homeostasis
Hepcidin-Ferroportin Axis
- Hepcidin: Key regulatory protein controlling intestinal iron absorption and systemic tissue distribution.
- Synthesized primarily by hepatocytes; also expressed in monocytes/macrophages.
- Mechanism of Action: Binds to iron exporter ferroportin (expressed in GI tract and reticuloendothelial system).
- Induces internalization and lysosomal degradation of ferroportin.
- Downregulates iron export to circulating transferrin from enterocytes and macrophages.
- TMPRSS6 gene encodes transmembrane protease, serine 6 (matriptase-2).
- Inhibits signaling pathway activating hepcidin.
- Mutations cause uninhibited hepcidin production, limiting iron availability.
Pathophysiology in Disease States
Anemia of Inflammation (Chronic Disease)
- Inflammatory cytokines (e.g., IL-6) and endotoxin stimulate excessive hepatic hepcidin synthesis.
- Hepcidin degrades ferroportin, preventing iron release into plasma.
- Iron accumulates/sequesters in reticuloendothelial macrophages.
- Results in functional iron deficiency, iron-restricted erythropoiesis, and impaired heme synthesis despite normal/high total body iron stores.
- Characteristic laboratory profile: Low serum iron, normal/low transferrin, elevated serum ferritin (acute phase reactant).
- Inherited defects impact absorption, transport, recycling, and utilization.
| Defect Category | Specific Disorder | Genetic/Molecular Mechanism |
|---|
| Absorption | Iron-Refractory Iron-Deficiency Anemia (IRIDA) | TMPRSS6 mutation; elevated hepcidin degrades ferroportin, blocking intestinal absorption. |
| Transport | Atransferrinemia | TF gene mutation; absent serum transferrin leading to severe liver iron overload. |
| Recycling | Aceruloplasminemia | CP gene mutation; absent ceruloplasmin. Iron fails to transport from macrophages to plasma, accumulating in brain/viscera. |
| Utilization | Sideroblastic Anemias | Defective heme synthesis (ALAS2 mutations common). Iron retention within mitochondria of marrow RBC precursors forming ringed sideroblasts. |