A Perspective on Copper and Liver Disease in the Dog

Abstract

Abstract.Copper is a ubiquitous trace metal necessary for normal function of a variety of cellular proteins.

Distinct Wilson’s Disease Mutations in ATP7B Are Associated With Enhanced Binding to COMMD1 and Reduced Stability of ATP7B

“…High copper intake through modern commercial dog food over the years has resulted in hepatic copper concentrations in healthy dogs that are over 10-fold higher than in humans 34 . This might predispose dogs to develop copper toxicosis, as evidenced by the occurrence of copper associated liver disease in a variety of dog breeds other then Bedlington terriers 12, 35. We hypothesize that absence of COMMD1 in affected Bedlington terriers disrupts ATP7B quality control, resulting in a gradual build-up of suboptimally functioning ATP7B, which perturbs the ability of the hepatocyte to cope with such high copper concentrations.…”

“…Equal loading was confirmed by immunoblotting for SCHAD. B: HEK293T cells were transfected with cDNA constructs encoding for ATP7B-Flag or ATP7B-G85V-Flag and biosynthetically labeled with 35 S-labeled methionine and cysteine for 90 minutes. After labeling, cells were chased with cold medium for the indicated time intervals.…”

Canine Liver Iron, Copper, and Zinc Concentrations and Association with Histologic Lesions

“…A wide range of liver copper concentra-tions was found, and the dogs with increased copper had lesions consistent with previously reported findings. 24 Bedlington Terriers aged 1-6 years had the types of lesions described in the copper storage disease that has been documented in this breed. Among other breeds in which increased liver copper has been reported, the 10 West Highland White Terriers and 4 Doberman Pinschers had normal copper concentrations, but 3 of 5 Dalmatians had increased copper concentrations.…”

“…This is in contrast with the finding that there is continued increase in storage of copper over time in Bedlington Terriers. 24 Quantitative analysis of liver copper concentration in young Bedlington Terriers is useful for predicting future liver disease, but usefulness for other breeds needs further evaluation. Because a pattern of liver iron concentration increasing with age was not clearly demonstrated, it does not appear that evaluating liver iron concentration in a young dog would be useful for predicting future liver disease.…”

“…Increased liver copper can occur secondarily to liver disease that prevents normal excretion of copper through the biliary system. 24 The mechanism of liver damage caused by excess liver copper is probably based on free radical-induced damage to lipid membranes, similar to toxicity caused by iron. 4 The trace mineral zinc is a cofactor of many enzymes, including lactate dehydrogenase, alkaline phos-phatase, and carbonic anhydrase.…”