Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 May;45(5):e70089.
doi: 10.1111/liv.70089.

Relative Exchangeable Copper, Exchangeable Copper and Total Copper in the Diagnosis of Wilson Disease

Camilla Lorenzen  1 , Karen Dons  1 , Clàudia García-Solà  2 , Xavier Forns  2   3 , Frederik Teicher Kirk  1 , Emilie Munk Lynderup  1 , Karina Stubkjær Rewitz  1 , Anna Soria  2   3 , Sergio Rodríguez-Tajes  2   3   4 , Lene Damm Christensen  5 , Tua Gyldenholm  5 , Peter Nissen Bjerring  6 , Anna Miralpeix  2 , Mercè Torra  7   8 , Peter Ott  1   4 , Thomas Damgaard Sandahl  1   4 , Zoe Mariño  2   3   4
Affiliations

Relative Exchangeable Copper, Exchangeable Copper and Total Copper in the Diagnosis of Wilson Disease

Camilla Lorenzen et al. Liver Int. 2025 May.

Abstract

Background and aims: Diagnosing Wilson disease (WD) remains challenging. The exchangeable copper (CuEXC) methodology measures the non-ceruloplasmin-bound copper fraction in serum. Relative exchangeable copper (REC), the ratio of CuEXC to total serum copper (Total Cu), has been proposed as a potential diagnostic biomarker. This study aimed to evaluate the diagnostic performance of these three copper biomarkers in WD.

Methods: CuEXC and Total Cu levels were measured in newly diagnosed treatment-naïve patients with WD (n = 13), treated WD (n = 91), non-Wilsonian hepatic disease (n = 206) and non-Wilsonian acute liver failure (n = 22). REC, CuEXC and Total Cu were compared among groups. Receiver-operating characteristic analyses were performed.

Results: Median REC was significantly elevated among patients with WD compared to all other groups combined (23.6% vs. 4.9%, p < 0.001). The opposite was found for Total Cu (3.5 μmol/L vs. 17.2 μmol/L, p < 0.001). In newly diagnosed patients with WD, median REC was significantly higher than in treated patients (29.1% vs. 21.6%, p = 0.008). The optimal diagnostic cut-off value for REC was ≥ 13.8% (sensitivity 100% and specificity 99.6%) for newly diagnosed patients versus those with non-Wilsonian hepatic disease. For Total Cu, the optimal cut-off was ≤ 7.1 μmol/L (sensitivity 61.5% and specificity 99.1%) for newly diagnosed patients with WD versus those with non-Wilsonian hepatic disease.

Conclusion: Our data support the diagnostic value of REC in WD. The more broadly available Total Cu also demonstrates a strong diagnostic performance and may be useful in initial work-up. We suggest including REC and/or Total Cu in a future revision of the Leipzig score.

Keywords: Wilson disease; biomarker; diagnosis; non‐ceruloplasmin‐bound copper; relative exchangeable copper; total copper.

PubMed Disclaimer

Conflict of interest statement

Z.M.: Speaker fees from Orphalan, Gilead; consultancy fees from Orphalan, Alexion, DeepGenomics and Prime Medicine (grants from Gilead). The other authors have no conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1
Biomarkers of copper, distribution between groups. Median value with interquartile range is presented with black solid horizontal lines. (A) Relative exchangeable copper (REC) among groups. Grey lines represent suggested cut‐off values for Wilson disease (WD) diagnosis (Guillaud et al., 18.5% [14]); (Lorenzen et al., 13.8%, from the current paper). (B) Exchangeable serum copper (CuEXC) among groups. The grey area represents the Danish adult reference interval (0.61–1.62 μmol/L), with the upper limit of normal (ULN) and lower limit of normal (LLN). (C) Total serum copper among groups. The grey area represents the Danish adult reference interval with ULN and LLN.
FIGURE 2
FIGURE 2
Receiver‐operating characteristic curves for all patients with Wilson disease versus patients with non‐Wilsonian hepatic disease and acute liver failure. (A) Relative exchangeable copper (REC). (B) Exchangeable serum copper (CuEXC). (C) Total serum copper (Total Cu).
FIGURE 3
FIGURE 3
Receiver‐operating characteristic curves for newly diagnosed treatment‐naïve patients with Wilson disease versus patients with non‐Wilsonian hepatic disease and acute liver failure. (A) Relative exchangeable copper (REC). (B) Exchangeable serum copper (CuEXC). (C) Total serum copper (Total Cu).
FIGURE 4
FIGURE 4
Measurements of copper biomarkers since time of treatment initiation for Danish newly diagnosed patients with Wilson disease. (A) Relative exchangeable copper (REC) over time since time of treatment initiation. Lines represent suggested cut‐off values. (B) Exchangeable serum copper (CuEXC) over time since time of treatment initiation. The grey area represents the Danish adult reference interval (0.61–1.62 μmol/L), with the upper limit of normal (ULN) and lower limit of normal (LLN).
See this image and copyright information in PMC

References

    1. Członkowska A., Litwin T., Dusek P., et al., “Wilson Disease,” Nature Reviews Disease Primers 4, no. 1 (2018): 21, 10.1038/s41572-018-0018-3. - DOI - PMC - PubMed
    1. Hellman N. E. and Gitlin J. D., “Ceruloplasmin Metabolism and Function,” Annual Review of Nutrition 22 (2002): 439–458. - PubMed
    1. Hung I. H., Suzuki M., Yamaguchi Y., Yuan D. S., Klausner R. D., and Gitlin J. D., “Biochemical Characterization of the Wilson Disease Protein and Functional Expression in the Yeast Saccharomyces cerevisiae ,” Journal of Biological Chemistry 272, no. 34 (1997): 21461–21466. - PubMed
    1. Kerkar N. and Roberts E. A., Clinical and Translational Perspectives on Wilson Disease (Academic Press, an imprint of Elsevier, 2019).
    1. Ala A., Walker A. P., Ashkan K., Dooley J. S., and Schilsky M. L., “Wilson's Disease,” Lancet 369, no. 9559 (2007): 397–408. - PubMed