Distribution of non-ceruloplasmin-bound copper after i.v. 64Cu injection studied with PET/CT in patients with Wilson disease

Abstract

Background and aimsIn 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 (64Cu). Methods: Eight WD patients, five heterozygotes, and nine healthy controls were examined by dynamic PET/CT for 90 minutes and static PET/CT up to 20 hours after injection. We measured 64Cu activity in blood and tissue and quantified the kinetics by compartmental analysis. Results: Initially, a large fraction of injected 64Cu distributed to extrahepatic tissues, especially skeletal muscle. Thus, across groups, extrahepatic tissues accounted for 45-58% of injected dose (%ID) after ten minutes, and 45-55% after one hour. Kinetic analysis showed rapid exchange of 64Cu between blood and muscle as well as adipose tissue, with 64Cu retention in a secondary compartment, possibly mitochondria. In this way muscles and adipose tissue may protect the brain from spikes in non-ceruloplasmin bound copper. Tiny amounts of cerebral 64Cu were detected (0.2%ID after 90 min and 0.3%ID after six hours), suggesting tight control of the cerebral copper in accordance with a cerebral clearance 2-3 orders of magnitude lower than in muscles. Compared to controls, WD patients accumulated more hepatic copper 6-20 hours after injection, and also renal copper at six hours. Conclusion: Non-ceruloplasmin-bound copper initially distributes into a number of tissues and redistributes 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 implicationsMaintaining non-ceruloplasmin bound copper within normal range is an important treatment goal in Wilson Disease (WD) as this “free” copper is considered toxic for 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 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 number2016–001975-59

Topics & Concepts