Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease

Członkowska, Anna; Rodo, M; Wierzchowska-Ciok, Agata; Smoliński, Łukasz; Litwin, Tomasz

doi:10.1111/liv.13715

Cited by 38 publications

(33 citation statements)

References 34 publications

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“…The use of radioactive Cu isotopes to assess copper metabolism in humans was introduced decades ago, and many studies on this topic have been published since then (Sternlieb and Scheinberg 1972;Gunther et al 1975;Harvey et al 2005;Czlonkowska et al 2018). Most recently, Czlonkowska et al showed that measurements of 64 Cu in blood and in urine following intravenous injection accurately distinguished between patients with Wilson's disease and heterozygote controls (Czlonkowska et al 2018). The obvious advantage of 64 Cu-copper PET/CT is however, the potential for assessing also the hepatic uptake, accumulation, and turnover; this includes oral administration where the biodistribution is dominated by first pass extraction by the liver, as demonstrated in the present study.…”

Section: Copper Metabolismmentioning

confidence: 99%

Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT

Kjærgaard

Sandahl

Frisch

et al. 2020

EJNMMI radiopharm. chem.

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Purpose: Copper is essential for enzymatic processes throughout the body. [ 64 Cu]copper (64 Cu) positron emission tomography (PET) has been investigated as a diagnostic tool for certain malignancies, but has not yet been used to study copper homeostasis in humans. In this study, we determined the hepatic removal kinetics, biodistribution and radiation dosimetry of 64 Cu in healthy humans by both intravenous and oral administration. Methods: Six healthy participants underwent PET/CT studies with intravenous or oral administration of 64 Cu. A 90 min dynamic PET/CT scan of the liver was followed by three whole-body PET/CT scans at 1.5, 6, and 20 h after tracer administration. PET data were used for estimation of hepatic kinetics, biodistribution, effective doses, and absorbed doses for critical organs. Results: After intravenous administration, 64 Cu uptake was highest in the liver, intestinal walls and pancreas; the gender-averaged effective dose was 62 ± 5 μSv/ MBq (mean ± SD). After oral administration, 64 Cu was almost exclusively taken up by the liver while leaving a significant amount of radiotracer in the gastrointestinal lumen, resulting in an effective dose of 113 ± 1 μSv/MBq. Excretion of 64 Cu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of 64 Cu from blood was 0.10 ± 0.02 mL blood/min/mL liver tissue, and the rate constant for excretion into bile or blood was 0.003 ± 0.002 min − 1. Conclusion: 64 Cu biodistribution and radiation dosimetry are influenced by the manner of tracer administration with high uptake by the liver, intestinal walls, and pancreas after intravenous administration, while after oral administration, 64 Cu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq 64 Cu yielded images of high quality for both administration forms with radiation doses of approximately 3.1 and 5.7 mSv, respectively, allowing for sequential studies in humans.

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Section: Copper Metabolismmentioning

confidence: 99%

Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT

Kjærgaard

Sandahl

Frisch

et al. 2020

EJNMMI radiopharm. chem.

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“…Ceruloplasmin (enzymatic) ferroxidase activity could aid in the direct quantification and speciation of copper in plasma, but it is not normally provided in clinical practice. Other parameters, including radioactive copper incorporation and exchangeable copper, appear promising and could potentially enable a better assessment of copper status, but remain unvalidated [32,33]. To study the effects of dietary components such as sugar consumption on transition metal levels and the resulting metabolic changes, improved clinical parameters for assessing these metal levels are necessary.…”

Section: Introductionmentioning

confidence: 99%

Effects of Dietary Glucose and Fructose on Copper, Iron, and Zinc Metabolism Parameters in Humans

et al. 2020

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Alterations of transition metal levels have been associated with obesity, hepatic steatosis, and metabolic syndrome in humans. Studies in animals indicate an association between dietary sugars and copper metabolism. Our group has conducted a study in which young adults consumed beverages sweetened with glucose, fructose, high fructose corn syrup (HFCS), or aspartame for two weeks and has reported that consumption of both fructose- and HFCS-sweetened beverages increased cardiovascular disease risk factors. Baseline and intervention serum samples from 107 participants of this study were measured for copper metabolism (copper, ceruloplasmin ferroxidase activity, ceruloplasmin protein), zinc levels, and iron metabolism (iron, ferritin, and transferrin) parameters. Fructose and/or glucose consumption were associated with decreased ceruloplasmin ferroxidase activity and serum copper and zinc concentrations. Ceruloplasmin protein levels did not change in response to intervention. The changes in copper concentrations were correlated with zinc, but not with iron. The decreases in copper, ceruloplasmin ferroxidase activity, ferritin, and transferrin were inversely associated with the increases in metabolic risk factors associated with sugar consumption, specifically, apolipoprotein CIII, triglycerides, or post-meal glucose, insulin, and lactate responses. These findings are the first evidence that consumption of sugar-sweetened beverages can alter clinical parameters of transition metal metabolism in healthy subjects.

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“…DNA analyses with Sanger's sequencing method showed two variants classified as disease-causing variants in the Wilson Disease Mutation Database (http://www.wilsondisease.med. This test measures the incorporation of radioactive intravenous copper into ceruloplasmin and involves the assessment of blood radioactivity after 2 (the starting value), 24, and 48 hours [6]. In healthy people, radioactive copper accumulates in the liver after a few hours, forms ceruloplasmin and is released into the blood, with almost all radioactive copper found in the blood after 24-48 hours.…”

Section: To the Editorsmentioning

confidence: 99%

“…In WD patients, 24 hour/2 hour and 48 hour/2 hour 64 Cu ratios are generally ≤ 0.36 and ≤ 0.4, respectively [6]. This test reflects the functional activity of the copper transporter ATP7B and is characterised by very high sensitivity (48 hour/2hour 64 Cu ratio -98.6%) and specificity (48 hour/2hour 64 Cu ratio -100%).…”

Section: To the Editorsmentioning

confidence: 99%

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

Antos

Litwin

Skowrońska

et al. 2020

Neurol Neurochir Pol.

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Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease

Abstract: The radioactive copper test had excellent diagnostic accuracy and may be useful in the evaluation of new therapies aimed at restoring ATP7B function.

Cited by 38 publications

References 34 publications

Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT

Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT

Effects of Dietary Glucose and Fructose on Copper, Iron, and Zinc Metabolism Parameters in Humans

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

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