The significance of variations in the distribution of copper in liver disease

Biopsy and autopsy specimens of liver from patients with Wilson's disease in various stages, chronic cholestatic conditions (including primary biliary cirrhosis, extrahepatic biliary obstruction, sclerosing cholangitis, and biliary atresia), chronic active hepatitis, and Indian childhood cirrhosis, as well as normal neonates, were examined by means of histochemical techniques for copper and copper-associated protein. The intracellular localization of copper and the lobular distribution of the metal and its associated protein differed in these conditions. Periportal hepatocytes containing granules (lysosomes) that were reactive for copper and for copper-associated protein were characteristic of cholestasis and neonatal liver. However, in cholestasis extralysosomal copper was often present in the hepatocellular cytoplasm. In contrast, in Wilson's disease, despite very high concentrations of copper in the early stages, the metal was diffuse in the cytoplasm, and the histochemical reactions for granular copper and its associated protein were usually negative. Therefore, a failure to stain for copper does not exclude the diagnosis of Wilson's disease. In the late stages of Wilson's disease staining varied in different nodules. In Indian childhood cirrhosis copper was present throughout the parenchyma, with periportal predominance. Differences in the distribution of copper and the cellular changes associated with its deposition suggest that different pathogenetic mechanisms and possibly different intracellular targets are susceptible to the toxic effects of the metal. For diagnosis, staining for copper and for copper-associated protein may assist in the differentiation of primary biliary cirrhosis from chronic active hepatitis.