Hepcidin is the master regulator of iron homeostasis. In which of the following conditions is hepcidin inappropriately elevated, contributing to the anemia?

• A Hereditary hemochromatosis type 1 (HFE mutation), where hepcidin production is inappropriately high causing excessive iron sequestration
• B Iron deficiency anemia, where low iron stores stimulate hepcidin to retain more iron in enterocytes
• C Beta-thalassemia intermedia, where ineffective erythropoiesis elevates hepcidin to compensate for excess erythroid iron demand
• D Anemia of chronic disease (ACD), where IL-6-driven hepcidin elevation causes ferroportin degradation and sequestration of iron in macrophages ✓

Explanation

In anemia of chronic disease (ACD), proinflammatory cytokines (IL-6, IL-1) stimulate hepatic hepcidin synthesis. Elevated hepcidin binds and induces degradation of ferroportin on enterocytes and macrophages, blocking iron export into plasma. Iron is trapped in macrophages (reticuloendothelial system) and serum iron falls, despite adequate total body iron stores. This is an adaptive mechanism to restrict iron from pathogens, but causes functional iron deficiency and normo-to-microcytic anemia. In iron deficiency, hepcidin is appropriately suppressed. In HFE hemochromatosis, hepcidin is inappropriately LOW (not high), explaining iron overload.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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