In Indian childhood cirrhosis (ICC) and related disorders of infancy,
hepatic copper overload is associated with cirrhosis, Since copper adm
inistration alone has not been shown to induce cirrhosis in animals, s
ynergy between copper and a second hepatotoxin has been suggested. Thi
s study investigates the ability of long-term exposure to copper and a
pyrrolizidine alkaloid, retrorsine, to produce a model of copper-asso
ciated 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 die
t copper and retrorsine in varying dosage for 13 weeks. Histological s
imilarities between the human disease and rats given copper with retro
rsine 5 mg/kg diet included parenchymal destruction, fibrosis, nodular
regeneration, and copper accumulation, There were significant histolo
gical differences from the human disorder, possibly attributable to in
ter-species variability or the critical timing or duration of exposure
to hepatotoxins in the neonatal period, The hypothesis that ICC resul
ts from copper and a second hepatotoxin has not been disproved, (C) 19
98 John Wiley & Sons, Ltd.