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J Trace Elem Med Biol. 2018 Dec;50:652-657. doi: 10.1016/j.jtemb.2018.06.013. Epub 2018 Jun 21.

Evaluation of the accuracy of exchangeable copper and relative exchangeable copper (REC) in a mouse model of Wilson's disease.

Author information

1
Hépatologie gastroentérologie et nutrition pédiatrique, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, F-69500 Bron, France; Centre de référence national pour la maladie de Wilson, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, F-69500 Bron, France. Electronic address: sophie.heissat@chu-lyon.fr.
2
Univ Grenoble Alpes, BIG-LCBM, F-38000 Grenoble, France; CNRS, BIG-LCBM, F-38000 Grenoble, France; CEA, BIG-LCBM-BIOMET, F-38000 Grenoble, France.
3
Hépatologie gastroentérologie et nutrition pédiatrique, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, F-69500 Bron, France; Centre de référence national pour la maladie de Wilson, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, F-69500 Bron, France.
4
Service central d'anatomie et cytologie pathologiques, Hospices Civils de Lyon, Hôpital Edouard Herriot, F-69003 Lyon (moved to Centre de Biologie et Pathologie Est, F-69677 Bron since september 2017), France.
5
Centre de référence national pour la maladie de Wilson, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, F-69500 Bron, France.
6
Centre de référence national pour la maladie de Wilson, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, F-69500 Bron, France; Laboratoire d'Analyse de Trace, Biochimie et biologie moléculaire, Hospices Civils de Lyon, Hôpital Edouard Herriot, F-69003 Lyon (moved to Centre de Biologie et d'AnatomoPathologie Sud, F-69495 Pierre-Bénite since september 2016), France.

Abstract

Wilson's disease (WD) is caused by mutations in the ATP7B gene responsible for a toxic copper overload mainly in the liver and the central nervous system. Phenotypic heterogeneity may challenge the diagnostic confirmation. Exchangeable copper (CuEXC) has recently been proposed as a new marker of WD, and its ratio to the total serum copper (Cus), Relative Exchangeable Copper (REC = CuEXC/Cus), as a diagnostic marker. This study aimed to investigate whether this could be confirmed in Atp7b-/- mice, an engineered WD animal model. Atp7b-/- (n = 137) and wild type (WT; n = 101) mice were investigated under the same conditions at 6-8, 20, 39, or 50 weeks of age. Twenty-four Atp7b-/- mice received D-penicillamine treatment from 39 to 50 weeks of age. Serum and liver [histology and intrahepatic copper (IHCu)] data were evaluated. In the WT group, all serum and liver data were normal. Atp7b-/- livers developed a chronic injury from isolated moderate inflammation (6-8 weeks: 16/33 = 48%) to inflammatory fibrosis with cirrhosis (50 weeks: 25/25 = 100% and 16/25 = 64% respectively). Cus and CuEXC increased until week 39, whereas IHCu and REC were stable with increasing age and much higher than in WT mice (mean ± SD: 669 ± 269 vs. 13 ± 3 μg/g dry liver and 39 ± 12 vs. 11 ± 3%, respectively). A threshold value of 20% for REC provided a diagnostic sensitivity and specificity of 100%, regardless of sex, age, or the use of D-penicillamine. Eleven weeks of 100 mg/kg D-penicillamine reduced liver fibrosis (p = 0.001), IHCu (p = 0.026) and CuEXC (p = 0.175). In conclusion, this study confirms REC as a WD diagnostic marker in a mouse model of chronic liver disease caused by copper overload. Further studies are needed to assess the usefulness of CuEXC to monitor the evolution of WD, particularly during treatment.

KEYWORDS:

Atp7b(-/-) mice; Cirrhosis; Diagnostic test; Exchangeable copper; REC

PMID:
30269758
DOI:
10.1016/j.jtemb.2018.06.013
[Indexed for MEDLINE]

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