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

Camilla Lorenzen; Karen Dons; Clàudia García-Solà; Xavier Forns; Frederik Teicher Kirk; Emilie Munk Lynderup; Karina Stubkjær Rewitz; Anna Soria; Sergio Rodríguez-Tajes; Lene Damm Christensen; Tua Gyldenholm; Peter Nissen Bjerring; Anna Miralpeix; Mercè Torra; Peter Ott; Thomas Damgaard Sandahl; Zoe Mariño

doi:10.1111/liv.70089

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

Camilla Lorenzen^*, Karen Dons, Clàudia García-Solà, Xavier Forns, Frederik Teicher Kirk, Emilie Munk Lynderup, Karina Stubkjær Rewitz, Anna Soria, Sergio Rodríguez-Tajes, Lene Damm Christensen, Tua Gyldenholm, Peter Nissen Bjerring, Anna Miralpeix, Mercè Torra, Peter Ott, Thomas Damgaard Sandahl, Zoe Mariño^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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.

Originalsprog	Engelsk
Artikelnummer	e70089
Tidsskrift	Liver International
Vol/bind	45
Nummer	5
ISSN	1478-3223
DOI	https://doi.org/10.1111/liv.70089
Status	Udgivet - maj 2025

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10.1111/liv.70089Licens: CC BY-NC

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Lorenzen, C., Dons, K., García-Solà, C., Forns, X., Kirk, F. T., Lynderup, E. M., Rewitz, K. S., Soria, A., Rodríguez-Tajes, S., Christensen, L. D., Gyldenholm, T., Bjerring, P. N., Miralpeix, A., Torra, M., Ott, P., Sandahl, T. D., & Mariño, Z. (2025). Relative Exchangeable Copper, Exchangeable Copper and Total Copper in the Diagnosis of Wilson Disease. Liver International, 45(5), Artikel e70089. https://doi.org/10.1111/liv.70089

@article{506d8fec50874e21bf4e2e194fbd2548,

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

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-na{\"i}ve 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 = "biomarker, diagnosis, non-ceruloplasmin-bound copper, relative exchangeable copper, total copper, Wilson disease",

author = "Camilla Lorenzen and Karen Dons and Cl{\`a}udia Garc{\'i}a-Sol{\`a} and Xavier Forns and Kirk, {Frederik Teicher} and Lynderup, {Emilie Munk} and Rewitz, {Karina Stubkj{\ae}r} and Anna Soria and Sergio Rodr{\'i}guez-Tajes and Christensen, {Lene Damm} and Tua Gyldenholm and Bjerring, {Peter Nissen} and Anna Miralpeix and Merc{\`e} Torra and Peter Ott and Sandahl, {Thomas Damgaard} and Zoe Mari{\~n}o",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Liver International published by John Wiley & Sons Ltd.",

year = "2025",

month = may,

doi = "10.1111/liv.70089",

language = "English",

volume = "45",

journal = "Liver International",

issn = "1478-3223",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "5",

}

Lorenzen, C, Dons, K, García-Solà, C, Forns, X, Kirk, FT , Lynderup, EM , Rewitz, KS, Soria, A, Rodríguez-Tajes, S, Christensen, LD, Gyldenholm, T, Bjerring, PN, Miralpeix, A, Torra, M, Ott, P, Sandahl, TD & Mariño, Z 2025, 'Relative Exchangeable Copper, Exchangeable Copper and Total Copper in the Diagnosis of Wilson Disease', Liver International, bind 45, nr. 5, e70089. https://doi.org/10.1111/liv.70089

TY - JOUR

T1 - Relative Exchangeable Copper, Exchangeable Copper and Total Copper in the Diagnosis of Wilson Disease

AU - Lorenzen, Camilla

AU - Dons, Karen

AU - García-Solà, Clàudia

AU - Forns, Xavier

AU - Kirk, Frederik Teicher

AU - Lynderup, Emilie Munk

AU - Rewitz, Karina Stubkjær

AU - Soria, Anna

AU - Rodríguez-Tajes, Sergio

AU - Christensen, Lene Damm

AU - Gyldenholm, Tua

AU - Bjerring, Peter Nissen

AU - Miralpeix, Anna

AU - Torra, Mercè

AU - Ott, Peter

AU - Sandahl, Thomas Damgaard

AU - Mariño, Zoe

PY - 2025/5

Y1 - 2025/5

N2 - 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.

AB - 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.

KW - biomarker

KW - diagnosis

KW - non-ceruloplasmin-bound copper

KW - relative exchangeable copper

KW - total copper

KW - Wilson disease

UR - http://www.scopus.com/inward/record.url?scp=105002252261&partnerID=8YFLogxK

U2 - 10.1111/liv.70089

DO - 10.1111/liv.70089

M3 - Journal article

C2 - 40198317

AN - SCOPUS:105002252261

SN - 1478-3223

VL - 45

JO - Liver International

JF - Liver International

IS - 5

M1 - e70089

ER -

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

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