Veterinary Medicine - August 2008 - (Page 434)

PEER-REVIEWED Diagnosing and treating canine copper-associated hepatopathies Whether from inﬂammatory hepatic disease or an inherited metabolic defect, copper accumulation can lead to hepatocellular damage and even cirrhosis. Treatment can successfully mitigate or even reverse copper-associated changes. Brier Bostrom, DVM, and Audrey K. Cook, BVM&S, MRCVS, DACVIM, DECVIM-CA I n the past 30 years, the impact of copper accumulation on hepatic function in dogs has received considerable attention. In some terrier breeds, an inherited metabolic defect compromises copper excretion; in other breeds, primary inammatory hepatic disease may facilitate copper accumulation because of chronic cholestasis. Although substantial variability exists in patient presentation and the amount of copper accumulated, speci c therapies aimed at reducing hepatic copper concentrations appear to be bene cial. In this article, we review the pathophysiology, clinical presentation, de nitive diagnosis, and treatment of copper-associated hepatopathies in dogs. lation by the liver, the principal organ involved in copper homeostasis. Within the hepatocytes, copper proceeds through one of several metabolic pathways. It may be incorporated into enzymes for use within hepatocytes or into ceruloplasmin that is returned to the circulation for transport to extrahepatic tissues. Alternatively, copper may be stored within hepatocyte lysosomes as copper metallothionein or excreted by the hepatocyte into bile.1 Biliary excretion is the principal route by which unused or excess copper leaves the body. Copper-associated hepatopathy was ﬁrst described in Bedlington terriers in 1979. COPPER ACCUMULATION AND HEPATOPATHY Excessive ingestion, derangements in storage, or compromised excretion of copper leads to copper accumulation. Excessive hepatocellular copper accumulation overwhelms the lysosomal storage capacity, resulting in oxidative stress. Such stress leads to free radical formation, lipid peroxidation, and DNA damage. Hepatocellular damage leads to acute then chronic in ammation and, eventually, to cirrhosis. In veterinary medicine, copperassociated hepatopathy was rst described in Bedlington terriers in 1979.2 Since then, this breed-speci c, autosomal recessive inherited disease has been well-characterized, and affected individuals are known to have inadequate biliary excretion of copper because of a gene deletion. This gene encodes a small cytosolic protein termed Murr1 that is required for the nal process of vesicular copper movement and excretion at the canalicular membrane of hepatocytes.3 COPPER METABOLISM Copper is a trace element and an essential micronutrient. Adequate amounts are required as cofactors for numerous enzymes, electron transport proteins, and antioxidant molecules, all of which are crucial for everyday cellular function. After the stomach and small intestines absorb it, copper is transported into the portal venous circulation by the enterocyte via ATPase7A.1 Copper is rapidly taken up from the portal venous circuBrier Bostrom, DVM Audrey K. Cook, BVM&S, MRCVS, DACVIM, DECVIM-CA Department of Small Animal Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Texas A&M University College Station, TX 77843 Affected Bedlington terriers can now be identi ed by genetic tests (CT-Marker, CT-Deletion—VetGen). Copper has been implicated in several other breed-related hepatopathies, including disorders described in West Highland white terriers, Skye terriers, Dalmatians, Doberman pinchers, and Labrador retrievers. Findings in these breeds share some similarities with the Bedlington terrier disorder, but notable differences are evident. For example, progressive, lifelong copper accumulation has not been demonstrated in the nonBedlington breeds. Also, the severity of liver damage does not necessarily correlate with hepatic copper concentrations; biopsy samples may show marked hepatitis with minimal copper accumulation. Since the primary mechanism for excreting unused copper is through bile, some researchers speculate that compromised bile ow is the underlying cause of copper retention in many of these other breeds.4 Cholestasis is a common nding in many hepatic disorders and could theoretically compromise biliary copper excretion enough to permit toxic accumulation. Getty Images 434 August 2008 VETERINARY MEDICINE

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Veterinary Medicine - August 2008 Contents Editors' Note Leading Off ClinQuiz Idea Exchange Practical Matters Diagnosing and Treating Canine Copper-Associated Hepatopathies Canine and Feline Demodicosis CE Form Advertiser Index Product Preview Marketplace/Classifieds Mind Over Miller

Veterinary Medicine - August 2008

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