Abstract
BACKGROUND & AIMS: In Wilson disease (WD), copper accumulation and increased non-ceruloplasmin-bound copper in plasma lead to liver and brain pathology. To better understand the fate of non-ceruloplasmin-bound copper, we used PET/CT to examine the whole-body distribution of intravenously injected 64-copper ((64)Cu). METHODS: Eight patients with WD, five heterozygotes, and nine healthy controls were examined by dynamic PET/CT for 90 min and static PET/CT up to 20 h after injection. We measured (64)Cu activity in blood and tissue and quantified the kinetics by compartmental analysis. RESULTS: Initially, a large fraction of injected (64)Cu was distributed to extrahepatic tissues, especially skeletal muscle. Thus, across groups, extrahepatic tissues accounted for 45-58% of the injected dose (%ID) after 10 min, and 45-55% after 1 h. Kinetic analysis showed rapid exchange of (64)Cu between blood and muscle as well as adipose tissue, with (64)Cu retention in a secondary compartment, possibly mitochondria. This way, muscle and adipose tissue may protect the brain from spikes in non-ceruloplasmin-bound copper. Tiny amounts of cerebral (64)Cu were detected (0.2%ID after 90 min and 0.3%ID after 6 h), suggesting tight control of cerebral copper in accordance with a cerebral clearance that is 2-3-fold lower than in muscle. Compared to controls, patients with WD accumulated more hepatic copper 6-20 h after injection, and also renal copper at 6 h. CONCLUSION: Non-ceruloplasmin-bound copper is initially distributed into a number of tissues before being redistributed slowly to the eliminating organ, the liver. Cerebral uptake of copper is extremely slow and likely highly regulated. Our findings provide new insights into the mechanisms of copper control. IMPACT AND IMPLICATIONS: Maintaining non-ceruloplasmin-bound copper within the normal range is an important treatment goal in WD as this "free" copper is considered toxic to the liver and brain. We found that intravenously injected non-ceruloplasmin-bound copper quickly distributed to a number of tissues, especially skeletal muscle, subcutaneous fat, and the liver, while uptake into the brain was slow. This study offers new insights into the mechanisms of copper control, which may encourage further research into potential new treatment targets. CLINICAL TRIAL NUMBER: 2016-001975-59.