title: Laser ablation inductively coupled plasma mass spectrometry imaging of metals in experimental and clinical Wilson's disease.
abstract: Wilson's disease is an autosomal recessive disorder in which the liver does not properly release copper into bile, resulting in prominent copper accumulation in various tissues. Affected patients suffer from hepatic disorders and severe neurological defects. Experimental studies in mutant mice in which the copper-transporting ATPase gene (Atp7b) is disrupted revealed a drastic, time-dependent accumulation of hepatic copper that is accompanied by formation of regenerative nodes resembling cirrhosis. Therefore, these mice represent an excellent exploratory model for Wilson's disease. However, the precise time course in hepatic copper accumulation and its impact on other trace metals within the liver is yet poorly understood. We have recently established novel laser ablation inductively coupled plasma mass spectrometry protocols allowing quantitative metal imaging in human and murine liver tissue with high sensitivity, spatial resolution, specificity and quantification ability. By use of these techniques, we here aimed to comparatively analyse hepatic metal content in wild-type and Atp7b deficient mice during ageing. We demonstrate that the age-dependent accumulation of hepatic copper is strictly associated with a simultaneous increase in iron and zinc, while the intrahepatic concentration and distribution of other metals or metalloids is not affected. The same findings were obtained in well-defined human liver samples that were obtained from patients suffering from Wilson's disease. We conclude that in Wilson's disease the imbalances of hepatic copper during ageing are closely correlated with alterations in intrahepatic iron and zinc content.
authors.affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapie and Clinical Chemistry, RWTH Aachen University Hospital Aachen, Aachen, Germany.
authors.forename: Sorina Georgiana
authors.initials: SG
authors.lastname: Boaru
authors.forename: Uta
authors.initials: U
authors.lastname: Merle
authors.forename: Ricarda
authors.initials: R
authors.lastname: Uerlings
authors.forename: Astrid
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Christa
authors.initials: C
authors.lastname: Flechtenmacher
authors.forename: Claudia
authors.initials: C
authors.lastname: Willheim
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Eder
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D003952:Diagnostic Imaging / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D006527:Hepatolenticular Degeneration / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D053685:Laser Therapy; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008670:Metals / Q000378:metabolism*; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D053583:Interleukin-1beta; D008670:Metals; D019715:Tissue Inhibitor of Metalloproteinase-1; D003300:Copper; D007501:Iron; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D015032:Zinc
keywords: Wilson's disease; laser ablation inductively coupled plasma mass spectrometry; liver; metal bio-imaging; trace metals