In hereditary haemochromatosis (HFE-related), homozygous C282Y mutation disrupts the interaction of HFE protein with TfR1/TfR2, leading to decreased hepcidin synthesis. The resulting low hepcidin causes iron overload by which mechanism?

• A Failure to degrade ferroportin, allowing unlimited iron export from enterocytes and macrophages ✓
• B Increased transferrin synthesis in liver
• C Excess erythropoiesis consuming ferritin reserves
• D Downregulation of DMT-1 in duodenal enterocytes

Explanation

Hepcidin normally binds to ferroportin (the only known mammalian iron exporter) on enterocytes, hepatocytes, and macrophages, causing ferroportin internalisation and degradation — thus limiting iron export into plasma. In HFE haemochromatosis, reduced hepcidin fails to degrade ferroportin, causing unrestricted iron export from duodenal enterocytes (increasing absorption) and macrophages, leading to hyperferraemia and progressive parenchymal iron deposition. This is the central mechanism of all forms of hereditary haemochromatosis.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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