Exchangeable serum copper: Adult and pediatric reference intervals and in vitro stability in a nordic cohort

Silje Hoveden Christensen; Frederik Kirk; Tua Gyldenholm; Emilie Munk Lynderup; Britta Eilersen Hjerrild; Helene Kvistgaard; Lene Damm Christensen; Thomas Damgaard Sandahl; Anders Abildgaard

doi:10.1016/j.cca.2024.119978

Exchangeable serum copper: Adult and pediatric reference intervals and in vitro stability in a nordic cohort

Silje Hoveden Christensen, Frederik Kirk, Tua Gyldenholm, Emilie Munk Lynderup, Britta Eilersen Hjerrild, Helene Kvistgaard, Lene Damm Christensen, Thomas Damgaard Sandahl, Anders Abildgaard^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Wilson disease (WD) is a rare genetic disorder characterized by copper overload, primarily affecting the liver and brain, and the organ damage is believed to be caused by non-ceruloplasmin-bound copper (NCC). Accurate and early diagnosis is important for prognosis. Recently, a method for the measurement of NCC, exchangeable serum copper (CuEXC), was developed and shown to be a promising marker of WD, especially as the fraction of total copper, relative exchangeable copper (REC). This study aimed to validate the CuEXC extraction method and establish reference intervals for CuEXC and REC, as well as to examine short- and long-term stability of CuEXC in serum samples. The adult reference interval for CuEXC was 0.61–1.62 µmol/L and for REC 3.0–9.7 % based on 120 blood donors. Based on 88 children, the reference intervals for CuEXC was 0.45–1.16 µmol/L. The intervals for REC were 1.8–5.8 % for children <10 years and 2.3–8.5 % for children ≥10 years. Regarding stability, CuEXC increased following a logarithmic scale in uncentrifuged serum and exceeded the permissible difference of 10 % after 4 h. With long-term freezing at −20 °C, CuEXC was stable for 1.7 months. In conclusion, reference intervals for CuEXC and REC were established and confirmed to be substantially lower in children. Accurate reference intervals are important to ensure timely diagnosis of WD. Finally, our findings on stability have important implications and highlight the need for standardization of the pre-analytical handling of CuEXC samples in order to obtain comparable results within and between laboratories both for clinical and research use.

Original language	English
Article number	119978
Journal	Clinica Chimica Acta
Volume	565
Pages (from-to)	1-7
ISSN	0009-8981
DOIs	https://doi.org/10.1016/j.cca.2024.119978
Publication status	Published - 15 Jan 2025

Keywords

Copper
Exchangeable copper
Non-ceruloplasmin bound copper
Reference values
Relative exchangeable copper (REC)
Stability study
Wilson's disease

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10.1016/j.cca.2024.119978

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@article{de6e05419c9d4f5b8d15968e87f7606e,

title = "Exchangeable serum copper: Adult and pediatric reference intervals and in vitro stability in a nordic cohort",

abstract = "Wilson disease (WD) is a rare genetic disorder characterized by copper overload, primarily affecting the liver and brain, and the organ damage is believed to be caused by non-ceruloplasmin-bound copper (NCC). Accurate and early diagnosis is important for prognosis. Recently, a method for the measurement of NCC, exchangeable serum copper (CuEXC), was developed and shown to be a promising marker of WD, especially as the fraction of total copper, relative exchangeable copper (REC). This study aimed to validate the CuEXC extraction method and establish reference intervals for CuEXC and REC, as well as to examine short- and long-term stability of CuEXC in serum samples. The adult reference interval for CuEXC was 0.61–1.62 µmol/L and for REC 3.0–9.7 % based on 120 blood donors. Based on 88 children, the reference intervals for CuEXC was 0.45–1.16 µmol/L. The intervals for REC were 1.8–5.8 % for children <10 years and 2.3–8.5 % for children ≥10 years. Regarding stability, CuEXC increased following a logarithmic scale in uncentrifuged serum and exceeded the permissible difference of 10 % after 4 h. With long-term freezing at −20 °C, CuEXC was stable for 1.7 months. In conclusion, reference intervals for CuEXC and REC were established and confirmed to be substantially lower in children. Accurate reference intervals are important to ensure timely diagnosis of WD. Finally, our findings on stability have important implications and highlight the need for standardization of the pre-analytical handling of CuEXC samples in order to obtain comparable results within and between laboratories both for clinical and research use.",

keywords = "Copper, Exchangeable copper, Non-ceruloplasmin bound copper, Reference values, Relative exchangeable copper (REC), Stability study, Wilson's disease",

author = "{Hoveden Christensen}, Silje and Frederik Kirk and Tua Gyldenholm and Lynderup, {Emilie Munk} and Hjerrild, {Britta Eilersen} and Helene Kvistgaard and Christensen, {Lene Damm} and Sandahl, {Thomas Damgaard} and Anders Abildgaard",

year = "2025",

month = jan,

day = "15",

doi = "10.1016/j.cca.2024.119978",

language = "English",

volume = "565",

pages = "1--7",

journal = "Clinica Chimica Acta",

issn = "0009-8981",

publisher = "Elsevier B.V.",

}

Exchangeable serum copper: Adult and pediatric reference intervals and in vitro stability in a nordic cohort. / Hoveden Christensen, Silje; Kirk, Frederik ; Gyldenholm, Tua et al.
In: Clinica Chimica Acta, Vol. 565, 119978, 15.01.2025, p. 1-7.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Exchangeable serum copper: Adult and pediatric reference intervals and in vitro stability in a nordic cohort

AU - Hoveden Christensen, Silje

AU - Kirk, Frederik

AU - Gyldenholm, Tua

AU - Lynderup, Emilie Munk

AU - Hjerrild, Britta Eilersen

AU - Kvistgaard, Helene

AU - Christensen, Lene Damm

AU - Sandahl, Thomas Damgaard

AU - Abildgaard, Anders

PY - 2025/1/15

Y1 - 2025/1/15

N2 - Wilson disease (WD) is a rare genetic disorder characterized by copper overload, primarily affecting the liver and brain, and the organ damage is believed to be caused by non-ceruloplasmin-bound copper (NCC). Accurate and early diagnosis is important for prognosis. Recently, a method for the measurement of NCC, exchangeable serum copper (CuEXC), was developed and shown to be a promising marker of WD, especially as the fraction of total copper, relative exchangeable copper (REC). This study aimed to validate the CuEXC extraction method and establish reference intervals for CuEXC and REC, as well as to examine short- and long-term stability of CuEXC in serum samples. The adult reference interval for CuEXC was 0.61–1.62 µmol/L and for REC 3.0–9.7 % based on 120 blood donors. Based on 88 children, the reference intervals for CuEXC was 0.45–1.16 µmol/L. The intervals for REC were 1.8–5.8 % for children <10 years and 2.3–8.5 % for children ≥10 years. Regarding stability, CuEXC increased following a logarithmic scale in uncentrifuged serum and exceeded the permissible difference of 10 % after 4 h. With long-term freezing at −20 °C, CuEXC was stable for 1.7 months. In conclusion, reference intervals for CuEXC and REC were established and confirmed to be substantially lower in children. Accurate reference intervals are important to ensure timely diagnosis of WD. Finally, our findings on stability have important implications and highlight the need for standardization of the pre-analytical handling of CuEXC samples in order to obtain comparable results within and between laboratories both for clinical and research use.

AB - Wilson disease (WD) is a rare genetic disorder characterized by copper overload, primarily affecting the liver and brain, and the organ damage is believed to be caused by non-ceruloplasmin-bound copper (NCC). Accurate and early diagnosis is important for prognosis. Recently, a method for the measurement of NCC, exchangeable serum copper (CuEXC), was developed and shown to be a promising marker of WD, especially as the fraction of total copper, relative exchangeable copper (REC). This study aimed to validate the CuEXC extraction method and establish reference intervals for CuEXC and REC, as well as to examine short- and long-term stability of CuEXC in serum samples. The adult reference interval for CuEXC was 0.61–1.62 µmol/L and for REC 3.0–9.7 % based on 120 blood donors. Based on 88 children, the reference intervals for CuEXC was 0.45–1.16 µmol/L. The intervals for REC were 1.8–5.8 % for children <10 years and 2.3–8.5 % for children ≥10 years. Regarding stability, CuEXC increased following a logarithmic scale in uncentrifuged serum and exceeded the permissible difference of 10 % after 4 h. With long-term freezing at −20 °C, CuEXC was stable for 1.7 months. In conclusion, reference intervals for CuEXC and REC were established and confirmed to be substantially lower in children. Accurate reference intervals are important to ensure timely diagnosis of WD. Finally, our findings on stability have important implications and highlight the need for standardization of the pre-analytical handling of CuEXC samples in order to obtain comparable results within and between laboratories both for clinical and research use.

KW - Copper

KW - Exchangeable copper

KW - Non-ceruloplasmin bound copper

KW - Reference values

KW - Relative exchangeable copper (REC)

KW - Stability study

KW - Wilson's disease

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U2 - 10.1016/j.cca.2024.119978

DO - 10.1016/j.cca.2024.119978

M3 - Journal article

C2 - 39332658

SN - 0009-8981

VL - 565

SP - 1

EP - 7

JO - Clinica Chimica Acta

JF - Clinica Chimica Acta

M1 - 119978

ER -

Exchangeable serum copper: Adult and pediatric reference intervals and in vitro stability in a nordic cohort

Abstract

Keywords

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