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.

Animal models of Wilson disease

“…However, the status of iron homeostasis in Atp7b −/− mice and WD patients’ needs further investigation because the results in either Atp7b −/− mice of human WD livers are inconsistent (Boaru et al . ; Hachmoller et al . ).…”

Atomic Spectrometry Update: review of advances in elemental speciation

“…229 Wilson's disease is an autosomal recessive disorder in which the liver does not properly release Cu into bile, resulting in signicant Cu accumulation in various tissues. Imaging of Cu and other elements in experimental and clinical samples related to Wilson's disease using LA-ICP-MS has been developed.…”

Lipopolysaccharide-induced acute phase response: New views on trace metal plasticity in hepatic inflammation

“…In previous studies, my group optimized laser ablation inductively coupled mass spectrometry (LA-ICP-MS)-based protocols for trace metal imaging in liver sections from experimental Wilson's disease models and clinical samples of patients suffering from this inherited disorder [14][15][16]. These protocols have multi-element capability and allow the quantification of a large variety of metals and metalloids within the tissue with high spatial resolution.…”

“…By use of this methodology, we showed that copper agedependently accumulated in livers and brains of Atp7b deficient mice and simultaneously induced imbalances in hepatic iron and zinc content suggesting that the LA-ICP-MS technology is powerful and innovative in displaying complex changes in metal composition within a tissue [16].…”

“…C used for normalization is given in %. More information about sample preparation, measurement, and data analysis are given elsewhere [16]. transcriptions factors rapidly resulting in production of acute phase proteins [6,19].…”