A 48-year-old man found on family screening to carry the HFE genotype C282Y/H63D (compound heterozygote) has ferritin 480 ng/mL and transferrin saturation 45 percent. Liver enzymes are normal. Which statement regarding his prognosis is most accurate?

• A He requires annual liver biopsy to monitor fibrosis
• B He will inevitably develop cirrhosis by age 60
• C Progression to clinically significant iron overload requiring phlebotomy is uncommon ✓
• D His phenotype will match C282Y homozygotes if he drinks alcohol regularly

Explanation

Compound heterozygosity for A282Y and H63D produces a much milder phenotype than A282Y homozygosity; most such individuals never accumulate enough iron to need venesection, and biochemical penetrance is low. A282Y homozygotes show full biochemical penetrance in only a minority, yet still far exceed compound heterozygotes. Serial biopsy is unwarranted when enzymes and saturation are near normal, and alcohol modestly modifies but does not equalise genotypic severity.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.