Wilson's disease results from mutations in ATP7B, a copper-transporting P-type ATPase. Which biochemical consequence of ATP7B dysfunction explains both the hepatic copper accumulation and low serum caeruloplasmin?

• A ATP7B deficiency leads to increased intestinal copper absorption due to unopposed DMT1 activity
• B ATP7B deficiency causes copper to bind irreversibly to albumin, reducing caeruloplasmin production
• C ATP7B normally exports copper to the blood for caeruloplasmin binding; its deficiency causes all copper to remain in lysosomes
• D ATP7B is required for biliary copper excretion and for loading copper onto apo-caeruloplasmin in the hepatocyte trans-Golgi network; its deficiency prevents both ✓

Explanation

Hepatic ATP7B has two functions: (1) in the trans-Golgi network, it loads copper onto apo-caeruloplasmin (synthesised by liver) to form holo-caeruloplasmin — without this loading step, apo-caeruloplasmin is rapidly degraded, explaining the low serum caeruloplasmin; and (2) it translocates to the canalicular membrane to excrete excess copper into bile — the principal excretory route for copper. ATP7B deficiency therefore causes copper accumulation in hepatocytes (then spillage to other organs: basal ganglia, Descemet's membrane producing Kayser-Fleischer rings, kidneys) and low serum caeruloplasmin simultaneously.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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