The pathophysiology of Wilson’s disease visualized: A human 64Cu PET study

Abstract

Background and Aims Wilson’s disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using PET with copper‐64 (64Cu) as a tracer. Furthermore, we assessed the diagnostic potential of the method. Approach and Results Nine patients with WD, 5 healthy heterozygote subjects, and 8 healthy controls were injected with an i.v. bolus of 64Cu followed by a 90‐min dynamic PET scan of the liver and static whole‐body PET/CT scans after 1.5, 6, and 20 h. Blood 64Cu concentrations were measured in parallel. Hepatic copper retention and redistribution were evaluated by standardized uptake values (SUVs). At 90 min, hepatic SUVs were similar in the three groups. In contrast, at 20 h postinjection, the SUV in WD patients (mean ± SEM, 31 ± 4) was higher than in heterozygotes (24 ± 3) and controls (21 ± 4; p < 0.001). An SUV‐ratio of hepatic 64Cu concentration at 20 and 1.5 h completely discriminated between WD patients and control groups (p < 0.0001; ANOVA). By Patlak analysis of the initial 90 min of the PET scan, the steady‐state hepatic clearance of 64Cu was estimated to be slightly lower in patients with WD than in controls (p = 0.04). Conclusions 64Cu PET imaging enables visualization and quantification of the hepatic copper retention characteristic for WD patients. This method represents a valuable tool for future studies of WD pathophysiology, and may assist the development of therapies, and accurate diagnosis.

Case report: Huppke–Brendel syndrome in an adult, mistaken for and treated as Wilson disease for 25 years

“…Thus, these patients may be found in the populations treated for WD. The newly described 64 Cu PET/CT method may be useful for secure diagnosis but remains experimental and was not performed on this patient ( 20 ).…”

Non-invasive radionuclide imaging of trace metal trafficking in health and disease: “PET metallomics”

“…injection of [ 64 Cu]Cu–chloride. 202 It was possible to derive an uptake ratio value, which discriminated between the two groups without any overlap, thus presenting a tool to diagnose WD based on the measurable impaired hepatic copper clearance.…”

Effect of oral zinc regimens on human hepatic copper content: a randomized intervention study

“…We examined these questions by use of copper-64 ( 64 Cu) PET/CT scans of the liver after oral administration of 64 Cu. We have recently shown that 64 Cu PET/CT can indeed quantify hepatic copper absorption and retention 18 . When administered orally, 64 Cu is absorbed in the intestines and subsequently taken up predominantly in the liver with little copper distributed elsewhere 19 .…”

“…We hypothesized that the regimens had similar ability to inhibit copper uptake and the study was accordingly designed for noninferiority with zinc acetate 50 mg × 3 daily as the standard treatment. The study was carried out in healthy volunteers because the mechanism by which copper is absorbed from the gut is not affected by the WD mutation 17 , 18 .…”