Copper-associated liver disease in North Ronaldsay sheep: a possible animal model for non-Wilsonian hepatic copper toxicosis of infancy and childhood

Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis (ETI C) and idiopathic copper toxicosis (ICT), are clinically and pathologically indistinguishable liver disorders of infants and young children linked wit h exogenous copper and with increasing evidence for a genetic predispositio n. North Ronaldsay sheep are a primitive breed which have adapted to a copp er impoverished environment (< 5ppm) and display an abnormal sensitivity to copper poisoning when transferred to a copper replete (11 ppm) habitat. Th e aetiological parallels prompted a study of copper-associated liver diseas e in North Ronaldsay sheep (RCT) to see if the pathology could contribute t o the understanding of the childhood disorder. A retrospective study was pe rformed in which the livers of 22 mainland-bred North Ronaldsay sheep were compared with three island-bred sheep and categorized for liver copper cont ent and pathomorphology. It was found that all the mainland sheep had accum ulated liver copper (> 300 g/g), in contrast to the island sheep, although 10 sheep with increased liver copper (mean 600 SID 270 mu /g) showed no evi dence of liver damage. A further 10 sheep with liver copper (mean 1276 SD 5 08 mug/g) exhibited periportal to panlobular histochemical copper retention , a periportal and/or panlobular pericellular fibrosis, a mixed inflammator y infiltrate and cholangioplasia. Steatosis was absent and regeneration was in abeyance. Finally, two sheep (liver copper > 2000 mug/g) had a more act ive hepatitis with a florid pencellular, panlobular fibrosis and cirrhosis. Electron microscopy identified large numbers of collagen-producing hepatic stellate (Ito) cells in periportal regions. The pathological findings were sufficiently reminiscent of ICC, ETIC and ICT to warrant further explorati on of RCT as a putative animal model. The North Ronaldsay sheep liver may b e a useful tool for the investigation of copper-induced fibrogenesis. Copyr ight (C) 2001 John Wiley & Sons, Ltd.