Copper-Associated Hepatitis in Dogs

Copper-associated hepatitis resulting from copper overload has been well documented in Bedlington Terriers for many years now - and the faulty gene has now been almost eliminated - but other breeds can still be at risk, as Hille Fieten discusses in her paper.

Introduction

Copper is an essential trace element which plays a vital role in a wide variety of biological processes. However, in excessive amounts copper is extremely toxic, because free copper ions can generate reactive oxygen species that damage proteins, lipids and DNA. In order to prevent toxic effects, copper homeostasis in the body is tightly regulated by many different copper-binding proteins (1). Copper contained in food or drinking water is absorbed via the gastrointestinal (GI) tract. At the basolateral side of the enterocytes, the copper transporter ATP7A is responsible for the movement of copper across the basolateral membrane into the portal circulation (Figure 1). Through the portal system copper reaches the liver, which has a central role in the metabolism, storage and excretion of the element. Within the hepatocytes, copper is chaperoned to distinct cellular organelles and incorporated into proteins to exert its different functions. Hepatocytes also have a storage function for copper and regulate redistribution of copper to other organs in the body. Excess copper is transported over the canalicular apical membrane of the hepatocytes and excreted in the bile. The copper transporter ATP7B, which is structurally related to ATP7A, plays an important role in this excretion process (Figure 1). The protein COMMD1 is believed to be important for proper functioning of ATP7B in the process of biliary excretion of excess copper. The importance of the transporters ATP7A and ATP7B in copper homeostasis is illustrated by the disruptive effects of hereditary defects in each of these proteins in human patients. Babies and children with mutations in ATP7A develop Menkes disease, a lethal disease that is characterized by a severe copper-deficiency phenotype, with neurological defects (2). Mutations in ATP7B cause Wilson disease in humans, whereby copper overload in the liver and neuronal tissues results in liver failure and/or neurological or mental disease (3). [...]