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Indian Childhood Cirrhosis (ICC) is associated with excessive copper ingestion and hepatic deposition, is preventable by preventing copper ingestion and is partially treatable by copper chelation. However, copper administration causes only minimal hepatic damage in the rat and an acute rather than chronic liver injury in sheep. The hypothesis is explored that a second hepatic insult is synergistic with copper in causing cirrhosis. D-galactosamine was administered, to control rats and to rats orally dosed with copper acetate, to induce an acute hepatic injury documented by serum transaminases and liver histology. Surprisingly, copper-dosed rats (liver copper 607+129 ug/g, controls 48+7) were resistant to galactosamine-induced injury. Oral copper reduced the quantitative faecal anaerobical1y cultured bacterial count, suggesting that reduction in gut-derived portal vein endotoxin may explain the protective effect. Using the carbon tetrachloride model, copper again ameliorated, rather than aggravated, the hepatic injury. Impaired prostaglandin or leukotriene synthesis are discussed as possible mechanisms. To evaluate a possible disorder of copper transport in ICC, copper distribution amongst human serum proteins was investigated. In normal adults, copper was associated with caeruloplasmin (71+4%), "transcuprein" (7+2%), albumin (19+4%) and with amino acids (2+3%). Caeruloplasmin and caeruloplasmin-copper concentrations were low in neonates and symptomatic Wilson's disease. In contrast to the neonate, Wilson's disease exhibited raised total serum copper and non-caeruloplasmin-copper. In ICC, serum levels of caeruloplasmin and caeruloplasmin-copper were normal, but transcuprein- and albumin-bound copper were elevated. Raised concentrations of non-caeruloplasmin-copper in ICC and Wilson's disease perhaps represent overspill into the serum from a copper-laden liver. In serum from children with malignancy, copper and caeruloplasmin concentrations were high as previously reported. Unexpectedly transcuprein- and albumin-bound copper were also markedly elevated. It is to be determined whether this results from tissue catabolism of caeruloplasmin or from increased hepatic caeruloplasmin synthesis and copper turnover. Caeruloplasmin gene expression was investigated in adult and neonatal rat liver, to determine whether the copper profile seen in neonates results from a pre-translational defect in caeruloplasmin synthesis. Detection of mRNA in samples of Northern blotted polyadenylated RNA, using a 32P-labelled caeruloplasmin cDNA probe, demonstrated that the mRNA species isolated from the neonates was not different from that in the adults, with an apparent size of 4400 nucleotides. A reduced mRNA detection in neonatal rats was also shown. Whether this was sufficient to account for the diminished total serum copper and caeruloplasmin oxidase activity is not understood.

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published_or_final_version / Mechanical Engineering / Doctoral / Doctor of Philosophy

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