An animal model for copper-associated cirrhosis in infancy

In Indian childhood cirrhosis (ICC) and related disorders of infancy, hepatic copper overload is associated with cirrhosis. Since copper administration alone has not been shown to induce cirrhosis in animals, synergy between copper and a second hepatotoxin has been suggested. This study investigates the ability of long-term exposure to copper and a pyrrolizidine alkaloid, retrorsine, to produce a model of copper-associated cirrhosis in rats. Groups of rat pups suckled on mothers fed 25 mg/kg diet retrorsine were weaned onto a diet containing 0.5 g/kg diet copper and retrorsine in varying dosage for 13 weeks. Histological similarities between the human disease and rats given copper with retrorsine 5 mg/kg diet included parenchymal destruction, fibrosis, nodular regeneration, and copper accumulation. There were significant histological differences from the human disorder, possibly attributable to inter-species variability or the critical timing or duration of exposure to hepatotoxins in the neonatal period. The hypothesis that ICC results from copper and a second hepatotoxin has not been disproved.