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

TY - JOUR

T1 - The pathophysiology of Wilson’s disease visualized

T2 - A human 64Cu PET study

AU - Sandahl, Thomas Damgaard

AU - Gormsen, Lars Christian

AU - Kjærgaard, Kristoffer

AU - Vendelbo, Mikkel

AU - Munk, Ditte Emilie

AU - Munk, Ole Lajord

AU - Bender, Dirk

AU - Keiding, Susanne

AU - Vase, Karina Højrup

AU - Frisch, Kim

AU - Vilstrup, Hendrik V Arenstorff

AU - Ott, Peter

PY - 2022/6

Y1 - 2022/6

N2 - 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 (Cu-64) 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 Cu-64 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 Cu-64 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 Cu-64 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 Cu-64 was estimated to be slightly lower in patients with WD than in controls (p = 0.04). Conclusions Cu-64 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.

AB - 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 (Cu-64) 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 Cu-64 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 Cu-64 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 Cu-64 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 Cu-64 was estimated to be slightly lower in patients with WD than in controls (p = 0.04). Conclusions Cu-64 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.

KW - (CUCL2)-CU-64 PET/CT

KW - COPPER-METABOLISM

KW - DIAGNOSIS

KW - EXPERIENCE

KW - LIVER

KW - MOUSE MODEL

KW - RADIOCOPPER

KW - Hepatolenticular Degeneration/diagnostic imaging

KW - Positron Emission Tomography Computed Tomography

KW - Humans

KW - Heterozygote

KW - Positron-Emission Tomography

U2 - 10.1002/hep.32238

DO - 10.1002/hep.32238

M3 - Journal article

C2 - 34773664

SN - 0270-9139

VL - 75

SP - 1461

EP - 1470

JO - Hepatology

JF - Hepatology

IS - 6

ER -