Copper-associated chronic hepatitis in the Labrador retriever: Clinical characterization, treatment, and molecular analysis

Abstract

Hypothesis and objectives of this thesis According to international kennel clubs, the Labrador retriever is the most common dog breed in Europe and in the United States, and one of the prime breeds selected as working dogs.1,2 It is commonly recognized that Labrador retrievers are predisposed to the development of chronic hepatitis.3,4 From experience of the past 20 years of clinical, pathobiological and molecular biologic research of a comparable disease in another dog breed (the Bedlington terrier) at the Veterinary Faculty of the University of Utrecht, it appears that the histological characteristics and clinical disease in Labradors is comparable to that observed in Bedlington terriers with copper toxicosis. Therefore, liver biopsies of Labrador patients with chronic hepatitis are routinely stained for copper with rubeanic acid. This allows the detection of copper accumulation in liver tissue in the majority of patients with chronic hepatitis. Based on these results, Labradors with copper-associated chronic hepatitis are treated with the copper-chelating drug, penicillamine, which allows patients that had previously been poorly responsive to the recommended standard treatment for idiopathic chronic hepatitis (prednisone) to recover from the disease. These clinical observations were the basis of the first hypothesis of this thesis: that copper-associated chronic hepatitis is a new metabolic disease in the Labrador retriever, which is caused by a defect in hepatic copper metabolism. Appendant on this assumption, the second hypothesis is that copper accumulation in the liver of Labradors originates from an inherited genetic defect. The objective of this work is to investigate and describe this new breed-related hepatic copper storage disease both clinically and histopathologically, and to demonstrate heritability of copper accumulation in the Labrador retriever. These investigations are described in part 1 of this thesis (chapters 3-5). Furthermore, different treatment strategies have been tested by randomized, double-blind, placebo-controlled treatment studies, which are described in part 2 of the thesis (chapters 6 and 7). In addition, molecular genetic studies have been performed to investigate the genetic defect underlying hepatic copper accumulation in Labradors. These studies are reported in part 3 of this thesis (chapters 8-12).