Hepatic copper and metallothionein distribution in Wilson's disease (hepatolenticular degeneration).

Wilson's disease is a rare inherited disorder of copper (Cu) metabolism characterized by the deposition of Cu in the liver, brain, and cornea. The levels of metallothionein (MT), Cu, and zinc (Zn) in the livers of two Wilson's disease patients were analyzed in this study. About 50-fold increase in the Cu levels above normal controls was observed in both patients (160 and 298 micrograms/g of wet tissue). About 73% of subcellular Cu was present in the cytoplasmic fraction and most of it was in association with MT. Analysis of hepatic MT levels showed a 3-fold increase (863 micrograms/g of wet tissue) over control human levels (321 micrograms/g of wet tissue). The two forms of MT (MT-I and MT-II) were isolated from one liver sample. Both forms contained high amounts of Cu (11 to 12 g atoms/mole), indicating saturation of MT which had only 2 to 3 g atoms of zinc. The distribution of MT in the hepatocytes was investigated using an immunohistochemical method. In tissue sections with minimal tissue damage, there was intense cytoplasmic staining for MT in hepatocytes whereas both nuclear and cytoplasmic staining was found in tissue sections with extensive necrosis and fibrosis. These results suggest that MT is the major hepatic Cu-binding protein in Wilson's disease, that it is present in a form saturated with Cu, and that only in degenerating hepatocytes is it found in the nucleus as well as the cytoplasm.