## Hepcidin's Role in Iron Homeostasis **Key Point:** Hepcidin is the master regulator of systemic iron homeostasis. It acts as a negative regulator by binding to and internalizing ferroportin, the only known iron exporter. ### Mechanism of Action Hepcidin functions through the following pathway: 1. **Ferroportin Inhibition**: Hepcidin binds to ferroportin on the basolateral membrane of enterocytes and macrophages 2. **Internalization & Degradation**: This binding triggers ferroportin endocytosis and lysosomal degradation 3. **Iron Trapping**: Iron becomes trapped inside cells, reducing systemic iron availability 4. **Feedback Regulation**: High serum iron and ferritin suppress hepcidin; low iron and hypoxia increase hepcidin expression ### Iron Flow Regulation | Site | Effect of High Hepcidin | Effect of Low Hepcidin | |------|------------------------|----------------------| | Enterocytes | ↓ Iron absorption | ↑ Iron absorption | | Macrophages | ↓ Iron recycling | ↑ Iron recycling | | Serum Iron | ↓ Transferrin saturation | ↑ Transferrin saturation | **High-Yield:** Hepcidin mutations cause hereditary hemochromatosis (HFE gene) or iron-refractory iron deficiency anemia (IRIDA). This is a frequently tested mechanism in NEET PG. **Clinical Pearl:** Hepcidin is elevated in inflammation (IL-6 mediated), explaining anemia of chronic disease — iron is sequestered despite adequate stores. 
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