Chronic copper poisoning in sheep: liver injury

Abstract

Pathogenesis of liver injury in chronic copper poisoning of sheep was investigated using two experiments. Test sheep were dosed orally with a 0.2 % solution of CuSO4.5H2O at the rate of 10 ml/Kg body weight on five days of the week, until first day of the haemolytic crisis (HC). Liver samples were taken during the pre-haemolytic period and on the first or second day of the HC, liver changes were evaluated using trace element, histochemical, subcellular fractionation, ultrastructural and morphometric methods. Copper concentrations in liver samples increased at a steady linear rate of 10.35 μg/g liver wet weight per day; uptake of copper among hepatocytes, among Kupffer cells and between zones of liver lobules was unequal. Individual hepatocytes became packed with copper loaded lysosomes and underwent degeneration and necrosis. Excess copper in liver cells was sequestered by the lysosomes leading to linear increases in volume density, numerical density and mean volume during the pre-haemolytic period. On the first day of HC, numerical density reduced, volume density remained unchanged and the mean volume increased. Linear increase in liver copper concentration indicates that copper absorption from the gut; excretion into bile and release into sinusoids by hepatocytes occur at linear steady rates. Thus, copper homeostasis in sheep is different to that of the humans and rats. In hepatocytes packed with copper loaded lysosomes, synthesis of new lysosomes reduced, causing decreased uptake of excess copper leading to accumulation of ionic copper in the cytoplasm, resulting in the degeneration and necrosis of the hepatocytes.