Diagnosing and treating canine copper-associated hepatopathies


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.

In 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 inflammatory hepatic disease may facilitate copper accumulation because of chronic cholestasis. Although substantial variability exists in patient presentation and the amount of copper accumulated, specific therapies aimed at reducing hepatic copper concentrations appear to be beneficial. In this article, we review the pathophysiology, clinical presentation, definitive diagnosis, and treatment of copper-associated hepatopathies in dogs.


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 circulation 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.


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 inflammation and, eventually, to cirrhosis.

In veterinary medicine, copper-associated hepatopathy was first described in Bedlington terriers in 1979.2 Since then, this breed-specific, 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 final process of vesicular copper movement and excretion at the canalicular membrane of hepatocytes.3 Affected Bedlington terriers can now be identified 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 non-Bedlington 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 flow is the underlying cause of copper retention in many of these other breeds.4 Cholestasis is a common finding in many hepatic disorders and could theoretically compromise biliary copper excretion enough to permit toxic accumulation.

Much uncertainty exists about the relevance of copper concentrations in liver samples with or without evidence of disease, and it may be necessary to develop breed-specific reference ranges. This controversy highlights the need for careful interpretation of laboratory data, biopsy results, and quantitative liver copper concentrations in light of a patient's breed and clinical condition.


Genetically predisposed Bedlington terriers accumulate hepatotoxic copper concentrations and manifest clinical signs by 2 to 4 years of age. Other breeds may develop clinical disease at any age depending on the severity and nature of their hepatic dysfunction.

Some dogs may present without clinical signs but with persistent blood work abnormalities, such as elevations in liver enzyme activities and other indicators of liver dysfunction. Dogs with chronic liver disease may present with weight loss, decreased appetite, polyuria and polydipsia, diarrhea, or intermittent vomiting. Jaundice, ascites, or hepatic encephalopathy may also occur in severely affected patients. Dogs may also present in acute crisis, which may reflect a sudden decompensation of occult chronic liver disease. Clinical signs may include anorexia, melena, vomiting, jaundice, or lethargy.