Anatomic Pathology: Liver Pathology

• Chronic cholestasis of any cause (e.g., primary sclerosing cholangitis (PSC), primary biliary cirrhosis [PBC]) results in impaired secretion of copper in the bile, with increased copper-binding protein accumulation in periportal hepatocytes that is stainable with either Victoria blue or orcein stains.

• Normal excretion of copper in bile and within the hepatocyte follows an obligatory translysosome-to-bile canaliculus route in periportal hepatocytes. Any type of chronic biliary tract disease that impairs bile flow results in overload of copper in periportal hepatocytes with a resultant upregulation of synthesis of copper-binding protein.

• Copper-binding protein is a metallothionein and is a nonglycogen glycoprotein that is stainable with Victoria blue, orcein, and diastase PAS methods. Increased copper-binding protein in periportal hepatocytes in late PSC or PBC or even Wilson disease may also be visible on hematoxylin-eosin stain as very small bright red granules (to be differentiated from the refractile and glassy brown-yellow granules of hemosiderin).

• When a chronic biliary tract disorder such as PSC or PBC is suspected, the pathologist should make a point of examining the periportal hepatocytes to exclude the pallor and swelling of pseudoxanthomatous change and to look for the presence of bright red granules (on hematoxylin-eosin stain) of copper-binding protein, which would serve as further evidence of chronic cholestatic disease.