Copper is an essential element for a number of metabolic processes in the body. It is provided via diet and drinking water and after absorption in the upper intestine, the liver is responsible for storage, redistribution en excreting excess copper into the bile. Hepatic copper accumulation due to increased intake or metabolic disturbances eventually leads to hepatitis and liver cirrhosis. Copper homeostasis is tightly regulated by a large number of copper-binding proteins. Mutations in genes coding for these proteins result in a disturbance in copper metabolism. In humans, the best described examples are the copper deficiency disorder Menkes disease and copper overload disease Wilson disease which are respectively caused by mutations in the copper transport pumps ATP7A and ATP7B.

In Bedlington terriers, autosomal recessive copper toxicosis is caused by a large deletion in the COMMD1 gene which functions in stabilizing both the ATP7A and ATP7B copper transporters. Mutations in both ATP7A and ATP7B influence hepatic copper levels in Labrador retrievers and Dobermanns (only ATP7B). The allele frequency of the ATP7B mutation in Labrador retrievers is estimated to be ~30% in the Netherlands.

Dietary intake of copper and zinc have a large impact on hepatic copper levels in Labrador retrievers and possibly other breeds. Therefore, canine copper storage disease is caused by a combination of Nature and Nurture.The balance between Nature and Nurture is breed dependent. In Bedlington terriers with the COMMD1- mutation the effect on hepatic copper is highly genetically determined. In genetically more complex forms of copper toxicosis like in Labrador retrievers, Dobermanns and possibly other predisposed breeds, the effect of copper and zinc in diet has a major impact on hepatic copper levels.

Learning Objectives

1. Attendants will have an overview of genes involved in copper metabolism and an understanding of the role of these genes in copper metabolism on cellular level and organism level. 
2. The role of mutations in ATP7A, ATP7B and COMMD1 in different dog breeds will be discussed.
3. The role of diet as an environmental factor in the pathogenesis of copper-associated hepatitis will be discussed.