A 42-year-old man has fatigue, arthralgia, skin bronzing, and new-onset diabetes. Transferrin saturation is 78% and serum ferritin is 2100 ng/mL. Genetic testing shows homozygosity for the C282Y mutation in the HFE gene. Which mechanism explains his biochemical picture?
- A Loss of HFE interaction with beta-2 microglobulin causes constitutively high hepcidin and mucosal iron blockade
- B Defective HFE signalling lowers hepatic hepcidin expression, permitting unchecked ferroportin-mediated iron export into plasma ✓
- C Mutant ferroportin becomes resistant to hepcidin binding, trapping iron within macrophages
- D Increased divalent metal transporter 1 activity drives excessive apical iron uptake independent of body stores
Correct answer: B. Defective HFE signalling lowers hepatic hepcidin expression, permitting unchecked ferroportin-mediated iron export into plasma
Explanation
Type 1 hereditary haemochromatosis is caused by homozygous C282Y mutation in HFE. Loss of normal HFE function blunts hepcidin production by the liver. Low hepcidin leaves ferroportin unopposed, so enterocytes and macrophages continuously export iron into plasma, raising transferrin saturation and depositing iron in parenchymal cells. Option A is the reverse of reality since hepcidin is low. Option C describes ferroportin disease, which causes iron retention in macrophages with anaemia.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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Written and medically reviewed by the StethoPrep medical team.