title: Copper-induced hepatotoxicosis with hepatic stellate cell activation and severe fibrosis in North Ronaldsay lambs: a model for non-Wilsonian hepatic copper toxicosis of infants.
abstract: Copper-sensitive North Ronaldsay sheep represent a possible model for certain hepatic-overload syndromes of infancy and childhood that are clinically, pathologically and genetically distinct from Wilson's disease. The purpose of this study was to simulate in artificially reared lambs the syndrome produced by copper exposure in susceptible human infants. Twenty four North Ronaldsay lambs were assigned to three groups of eight animals, namely, an unsupplemented control group and two trial groups given milk replacer to which copper (CuSO4) had been added at the rate of 5 mg/litre and 10 mg/litre. Four lambs from each group were killed at 40 or 69 days. Livers were fixed in 10% formalin and analysed for copper by mass spectrometry. Paraffin wax-embedded sections were stained with rhodanine for copper and labelled immunohistochemically for alpha smooth muscle actin (ASMA). At 40 days the maximum amounts of copper in the livers of both copper-supplemented groups was 1466-1605 microg/g dry weight (control group 172-201 microg/g Cu dry weight). Histochemically, copper was demonstrated within hepatocytes, together with marked apoptosis. At 69 days there was a florid pericellular fibrosis complemented by strong ASMA immunolabelling, confirming phenotypic modulation of hepatic stellate cells. Such primary copper-induced fibrogenesis confirms the unique status of this animal model in respect of childhood copper toxicosis.
authors.affiliation: Faculty of Veterinary Science, Department of Veterinary Pathology, University of Liverpool, Liverpool L39 3BX, UK.
authors.forename: S
authors.initials: S
authors.lastname: Haywood
authors.forename: T
authors.initials: T
authors.lastname: Müller
authors.forename: A M
authors.initials: AM
authors.lastname: Mackenzie
authors.forename: W
authors.initials: W
authors.lastname: Müller
authors.forename: M S
authors.initials: MS
authors.lastname: Tanner
authors.forename: P
authors.initials: P
authors.lastname: Heinz-Erian
authors.forename: C L
authors.initials: CL
authors.lastname: Williams
authors.forename: M J
authors.initials: MJ
authors.lastname: Loughran
mesh_terms: D000818:Animals; D003300:Copper / Q000506:poisoning*; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology*; D012756:Sheep; D012757:Sheep Diseases / Q000139:chemically induced* / Q000473:pathology
chemical_list: D003300:Copper