Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.

BACKGROUND & AIMS: Copper is a trace element essential for enzymatic reactions, but excessive accumulation can cause toxicity. Accurate interpretation of serum copper concentrations is crucial for diagnosing conditions such as Wilson's disease, liver dysfunction, and nutritional deficiencie...

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Authors: Rodriguez-Gonzalez H, Arias A, Poyatos E, de Los Santos MM, Minguez B, Meavilla S, Garcia-Volpe C, Loverdos I, Molera C, Casado M, Ormazabal A, Perera-Lluna A, Artuch R
Format: article
Status:Published version
Publication Date:2026
Country:España
Institution:Fundació Sant Joan de Déu
Repository:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p29905
Online Access:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=29905
Access Level:Open access
Keyword:Acute-phase markers
Inflammation
Pediatric reference intervals
Serum copper
Trace elements
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spelling Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.Rodriguez-Gonzalez HArias APoyatos Ede Los Santos MMMinguez BMeavilla SGarcia-Volpe CLoverdos IMolera CCasado MOrmazabal APerera-Lluna AArtuch RAcute-phase markersInflammationPediatric reference intervalsSerum copperTrace elementsBACKGROUND & AIMS: Copper is a trace element essential for enzymatic reactions, but excessive accumulation can cause toxicity. Accurate interpretation of serum copper concentrations is crucial for diagnosing conditions such as Wilson's disease, liver dysfunction, and nutritional deficiencies. Current reference intervals often ignore the effect of inflammation and are typically established using discrete age groups rather than modelling age as a continuous variable. This study aimed to establish continuous, age-adjusted reference intervals for serum copper and to develop a method for correcting inflammation-related variability. METHODS: We retrospectively analyzed serum copper concentrations in a pediatric cohort of 4,368 unique samples. Inflammatory status was assessed using erythrocyte sedimentation rate (ESR), fibrinogen, and C-reactive protein (CRP). Samples without inflammation were used to generate age-continuous reference intervals through polynomial regression. To quantify and adjust for inflammation effects, we developed a composite inflammation score using partial least squares regression on standardized values of the three acute-phase markers and applied it to correct copper concentrations in samples exhibiting inflammation. RESULTS: Serum copper showed a nonlinear relationship with age. Inflammation elevated copper concentrations by approximately 24 %. The composite inflammation score independently predicted this variability in copper concentrations, and adjustment using the score restored copper concentrations within reference limits, reducing the risk of data misinterpretation. CONCLUSION: Our findings underscore the necessity of considering both age and inflammation variables when interpreting pediatric serum copper concentrations. We provide continuous, age-adjusted reference intervals and a method to correct for inflammation-related variability, enhancing data interpretation. We propose a proof-of-concept potentially applicable to other biomarkers related with metabolic and nutritional disturbances in chronic and acute diseases.CHURCHILL LIVINGSTONE2026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=29905CLINICAL NUTRITIONISSN: 02615614ISSNe: 15321983reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p299052026-05-27T12:37:41Z
dc.title.none.fl_str_mv Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.
title Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.
spellingShingle Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.
Rodriguez-Gonzalez H
Acute-phase markers
Inflammation
Pediatric reference intervals
Serum copper
Trace elements
title_short Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.
title_full Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.
title_fullStr Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.
title_full_unstemmed Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.
title_sort Proof of concept for an age- and inflammation-adjusted model for the establishment of pediatric serum copper reference intervals.
dc.creator.none.fl_str_mv Rodriguez-Gonzalez H
Arias A
Poyatos E
de Los Santos MM
Minguez B
Meavilla S
Garcia-Volpe C
Loverdos I
Molera C
Casado M
Ormazabal A
Perera-Lluna A
Artuch R
author Rodriguez-Gonzalez H
author_facet Rodriguez-Gonzalez H
Arias A
Poyatos E
de Los Santos MM
Minguez B
Meavilla S
Garcia-Volpe C
Loverdos I
Molera C
Casado M
Ormazabal A
Perera-Lluna A
Artuch R
author_role author
author2 Arias A
Poyatos E
de Los Santos MM
Minguez B
Meavilla S
Garcia-Volpe C
Loverdos I
Molera C
Casado M
Ormazabal A
Perera-Lluna A
Artuch R
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Acute-phase markers
Inflammation
Pediatric reference intervals
Serum copper
Trace elements
topic Acute-phase markers
Inflammation
Pediatric reference intervals
Serum copper
Trace elements
description BACKGROUND & AIMS: Copper is a trace element essential for enzymatic reactions, but excessive accumulation can cause toxicity. Accurate interpretation of serum copper concentrations is crucial for diagnosing conditions such as Wilson's disease, liver dysfunction, and nutritional deficiencies. Current reference intervals often ignore the effect of inflammation and are typically established using discrete age groups rather than modelling age as a continuous variable. This study aimed to establish continuous, age-adjusted reference intervals for serum copper and to develop a method for correcting inflammation-related variability. METHODS: We retrospectively analyzed serum copper concentrations in a pediatric cohort of 4,368 unique samples. Inflammatory status was assessed using erythrocyte sedimentation rate (ESR), fibrinogen, and C-reactive protein (CRP). Samples without inflammation were used to generate age-continuous reference intervals through polynomial regression. To quantify and adjust for inflammation effects, we developed a composite inflammation score using partial least squares regression on standardized values of the three acute-phase markers and applied it to correct copper concentrations in samples exhibiting inflammation. RESULTS: Serum copper showed a nonlinear relationship with age. Inflammation elevated copper concentrations by approximately 24 %. The composite inflammation score independently predicted this variability in copper concentrations, and adjustment using the score restored copper concentrations within reference limits, reducing the risk of data misinterpretation. CONCLUSION: Our findings underscore the necessity of considering both age and inflammation variables when interpreting pediatric serum copper concentrations. We provide continuous, age-adjusted reference intervals and a method to correct for inflammation-related variability, enhancing data interpretation. We propose a proof-of-concept potentially applicable to other biomarkers related with metabolic and nutritional disturbances in chronic and acute diseases.
publishDate 2026
dc.date.none.fl_str_mv 2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=29905
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=29905
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv CHURCHILL LIVINGSTONE
publisher.none.fl_str_mv CHURCHILL LIVINGSTONE
dc.source.none.fl_str_mv CLINICAL NUTRITION
ISSN: 02615614
ISSNe: 15321983
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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