Page 23 - Copper-associated hepatitis in the Labrador retriever diagnosis, treatment and genetics

Copper storage diseases in dogs
In addition to copper toxicosis in the Bedlington terrier, hereditary copper- associated liver disease has also been described in other dog breeds such as the Dobermann38, the West Highland white terrier36 and the Dalmatian37. More incidental reports of copper storage related hepatitis are available for Anatolian shepherd112 and Skye terriers35. Recently, the by far largest purebred dog population worldwide, the Labrador retriever, has been documented to have an inherited form of copper-associated hepatitis39. In addition, results from a large survey of hepatic copper concentrations in dogs113 as well as results from a retrospective review on dogs diagnosed with primary hepatitis114 suggest that there may be more dog breeds in which high hepatic copper concentration and copper-associated hepatitis are present. Histologically, copper toxicosis in different dog breeds shows many similarities. Accumulation of copper precedes inflammatory changes in the liver and always starts in the centrolobular regions of the liver lobules (zone 3). Around the central vein branches, multifocal regions with increased copper develop, first in the hepatocytes which then become apoptotic and are phagocytised, after which part of the copper is concentrated in the Kupffer cells. The disease is characterized by progressive inflammation, necrosis, and bridging fibrosis between centrolobular areas eventually leading to irreversible liver cirrhosis. Cholestasis can be present in very advanced stages of the disease, but is never the main histological finding. This is also underscored by blood examinations in which is seen that in copper toxicosis the liver enzyme alanine-aminotransferase is often much more increased than alkaline phosphatase, indicating hepatocellular rather than cholestatic liver disease. Clinical signs can result from acute, severe liver failure or end- stage cirrhosis and include lethargy, anorexia, vomiting, icterus, ascites and hepato-encephalopathy. In some breeds acute hemolytic crisis due to massive release of copper in the circulation are recognized. As in humans, treatment with the copper chelators D-penicillamine and 2,3,2-tetramine is effective in decreasing liver copper levels in dogs115-118. Administration of zinc-acetate or -gluconate is described to have beneficial effects in de-coppering as well as in maintenance therapy119-121. Although there are many similarities in copper toxicosis phenotypes between breeds, differences exist in clinical presentation and hepatic copper concentrations as will be outlined in the following section and is summarized in Table 1.
General introduction
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Chapter 1