The HFE gene mutation most strongly associated with hereditary haemochromatosis in Northern European populations, the resulting biochemical defect, and the approximate threshold for phlebotomy initiation are:
- A H63D homozygosity; reduced transferrin saturation; ferritin > 200 μg/L
- B C282Y/H63D compound heterozygosity; increased ferritin with normal TS; ferritin > 1000 μg/L
- C C282Y homozygosity; reduced hepcidin production causing excessive intestinal iron absorption; ferritin > 300 μg/L in men ✓
- D C282Y homozygosity; increased hepcidin; phlebotomy only if ferritin > 500 μg/L
Correct answer: C. C282Y homozygosity; reduced hepcidin production causing excessive intestinal iron absorption; ferritin > 300 μg/L in men
Explanation
C282Y/C282Y (homozygous) mutation in the HFE gene accounts for ~90% of hereditary haemochromatosis in Northern Europeans. The mutant HFE protein fails to upregulate hepcidin (the master iron-regulatory hormone), resulting in unrestrained intestinal iron absorption. Current EASL guidelines recommend phlebotomy when serum ferritin exceeds 300 μg/L in men (200 μg/L in women) or transferrin saturation > 45%, aiming to achieve ferritin 50–100 μg/L. H63D homozygosity rarely causes clinical haemochromatosis.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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