Wilson's disease results from mutations in ATP7B, a copper-transporting P-type ATPase located in hepatocyte trans-Golgi. Which two functions of ATP7B are impaired in Wilson's disease, and what accounts for the elevated free serum copper despite low ceruloplasmin?
- A ATP7B normally absorbs copper from the intestine; its loss prevents dietary copper uptake, causing paradoxical free copper elevation by unknown mechanism
- B ATP7B normally incorporates copper into apoceruloplasmin and excretes excess copper into bile; its loss causes copper to accumulate in hepatocytes (spilling into serum as free copper) while ceruloplasmin is secreted as an apo-protein without copper (which is rapidly degraded, lowering total ceruloplasmin) ✓
- C ATP7B incorporates copper into superoxide dismutase; its absence reduces SOD activity and increases oxidative stress that releases copper from metalloproteins
- D ATP7B exports copper from blood into urine; its loss causes renal copper retention with secondary hepatocyte copper overflow
Explanation
ATP7B in the hepatocyte trans-Golgi performs two essential functions: (1) loads copper into apoceruloplasmin (the copper-free form) to form holoceruloplasmin, which is secreted into plasma, and (2) translocates excess copper into bile canaliculi for faecal excretion. In Wilson's disease, both fail — copper accumulates in hepatocytes and eventually spills into plasma as free (non-ceruloplasmin-bound) copper. Ceruloplasmin is secreted without its copper (as apoceruloplasmin), which has a much shorter half-life in plasma (~5 h vs. 5 days for holoceruloplasmin), explaining the characteristically low serum ceruloplasmin. The total serum copper may be paradoxically normal or low (due to low ceruloplasmin), but free (unbound) copper is elevated — hence the emphasis on measuring 24-hour urine copper and serum free copper in diagnosis.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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