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J Pathol Clin Res. 2016 Jun 6;2(3):175-86. doi: 10.1002/cjp2.48. eCollection 2016 Jul.

Rapid and reliable diagnosis of Wilson disease using X-ray fluorescence.

Author information

1
INSERMUnité 1193, Villejuif, F-94800France; Univ Paris-SudUMR-S 1193, Villejuif, F-94800France; DHU HepatinovVillejuif, F-94800France.
2
Ligne de lumière NANOSCOPIUM, Synchrotron SOLEIL Gif sur Yvette, F-91192 France.
3
Laboratoire de Physique des Solides UMR CNRS 8502, Univ Paris-Sud, Bâtiment 510 Orsay Cedex 91405 France.
4
INSERM, Unité 1064, Centre de Recherche en Transplantation & Immunologie, ITUN, CHU Hôtel DieuNantesFrance; Univ d'AngersHIFIH, UPRES 3859AngersFrance.
5
INSERMUnité 1193, Villejuif, F-94800France; Univ Paris-SudUMR-S 1193, Villejuif, F-94800France; DHU HepatinovVillejuif, F-94800France; AP-HP Hôpital Paul Brousse, Centre Hépato-BiliaireVillejuifF-94800France; Centre de Référence National de la Maladie de Wilson, AP-HPFrance.
6
Centre de Référence National de la Maladie de Wilson, AP-HPFrance; AP-HP Hôpital Lariboisière, Laboratoire de toxicologie biologiqueParis Cedex 1075475France.
7
Ligne de lumière SMIS, Synchrotron SOLEIL Gif sur Yvette, F-91192 France.
8
Service de Génétique Moléculaire Pharmacogénétique et Hormonologie Hôpital Bicêtre, Le Kremlin-Bicêtre Cedex F-94276 France.
9
DHU HepatinovVillejuif, F-94800France; Centre de Référence National de la Maladie de Wilson, AP-HPFrance; Service d'Hépatologie et de Transplantation Hépatique Pédiatriques, Hôpital Bicêtre, AP-HP, Université Paris SudLe Kremlin Bicêtre Cedex, F-94275France; Univ Paris-SudUMR-S 1174OrsayF-91400France.
10
INSERM, Unité 1064, Centre de Recherche en Transplantation & Immunologie, ITUN, CHU Hôtel Dieu Nantes France.
11
Univ Paris 6, Sorbonne Universités, UPMC, Collège de France, Laboratoire de Chimie de la Matière Condensée de Paris (LCMCP) Paris F-75005 France.
12
INSERMUnité 1193, Villejuif, F-94800France; Univ Paris-SudUMR-S 1193, Villejuif, F-94800France; DHU HepatinovVillejuif, F-94800France; AP-HP Hôpital Paul Brousse, Service d'Anatomo-PathologieVillejuifF-94807France.

Abstract

Wilson's disease (WD) is a rare autosomal recessive disease due to mutations of the gene encoding the copper-transporter ATP7B. The diagnosis is hampered by the variability of symptoms induced by copper accumulation, the inconstancy of the pathognomonic signs and the absence of a reliable diagnostic test. We investigated the diagnostic potential of X-ray fluorescence (XRF) that allows quantitative analysis of multiple elements. Studies were performed on animal models using Wistar rats (n = 10) and Long Evans Cinnamon (LEC) rats (n = 11), and on human samples including normal livers (n = 10), alcohol cirrhosis (n = 8), haemochromatosis (n = 10), cholestasis (n = 6) and WD (n = 22). XRF experiments were first performed using synchrotron radiation to address the elemental composition at the cellular level. High-resolution mapping of tissue sections allowed measurement of the intensity and the distribution of copper, iron and zinc while preserving the morphology. Investigations were further conducted using a laboratory X-ray source for irradiating whole pieces of tissue. The sensitivity of XRF was highlighted by the discrimination of LEC rats from wild type even under a regimen using copper deficient food. XRF on whole formalin-fixed paraffin embedded needle biopsies allowed profiling of the elements in a few minutes. The intensity of copper related to iron and zinc significantly discriminated WD from other genetic or chronic liver diseases with 97.6% specificity and 100% sensitivity. This study established a definite diagnosis of Wilson's disease based on XRF. This rapid and versatile method can be easily implemented in a clinical setting.

KEYWORDS:

Wilson disease; X‐ray fluorescence spectroscopy; copper; diagnosis

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