Copper Toxicosis in Bedlington Terriers

Copper toxicosis of Bedlington Terriers (Chronic progressive hepatitis) is a genetically transmitted disease. The typical feature of this disease is accumulation of copper in the liver tissue. The changes vary from mild hepatitis to chronic progressive hepatitis and cirrhosis.The material of this study consists of 2 cases of copper toxicosis examined at the Department of Pathology in Helsinki in the years 1980–82. Moreover a re-examination of tissue samples was made of all Bedlington Terriers examined during the years 1969–1982 at the same department. Six of the 14 examined dogs showed a positive reaction for copper in their liver tissues. The possible relationship of the examined dogs is not yet known.     

Evaluation of haplotypes associated with copper toxicosis in Bedlington Terriers in Australia

OBJECTIVE: To evaluate the haplotype distribution associated with the copper toxicosis gene and the segregation of the mutated allele in a Bedlington Terrier population in Australia. ANIMALS: 131 Bedlington Terriers. PROCEDURE: Samples of DNA and RNA were obtained from each dog. Genetic status of each dog was evaluated by use of the DNA markers C04107; single nucleotide polymorphism (SNP), which was adjacent to exon 2 of Murr1; and a deletion marker for exon 2. A subgroup of the study population was evaluated by use of biochemical and histologic techniques to elucidate the correlation between genotype and phenotype. RESULTS: We identified a recombination between the C04107 marker and Murr1 and a variation in a nucleotide in the splice site of exon 2 in our Bedlington Terrier cohort. Furthermore, we identified a novel haplotype associated with copper toxicosis in this cohort. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings indicate that the deletion of exon 2 was not the sole cause of copper toxicosis, although only exon 2 deletion of Murr1 has been responsible for copper toxicosis in Bedlington Terriers. Although we failed to find a novel mutation in our cohort, we identified an affected dog family with an intact exon 2. Furthermore, we found that an SNP in the 5' splicing site of exon 2 may or may not be associated with a novel mutation of the Murr1 gene or other genes. Loss of linkage between the C04107 marker and the Murr1 gene was also identified in a certain family of dogs.     

Copper toxicosis in the Bedlington terrier: a diagnostic dilemma

Diagnosis of copper toxicosis (CT) in Bedlington terriers by the quantitative and qualitative assessment of copper (Cu) in, and pathology of, biopsies has been largely superseded by a DNA-based assay which uses a microsatellite marker (C04107) linked to the CT disease allele. A retrospective study was conducted comprising 154 liver biopsies from Bedlington terriers with 22 matched DNA markers to compare the two methods in the diagnosis of CT. For the biopsy method, three categories (phenotypes) were identified based on analytical and morphological criteria: 'unaffected' in 83 samples (54 per cent), where Cu was much less than 400 microg/g, and there was an absence of visual Cu or liver damage; 'intermediate' in 18 samples (12 per cent), where Cu was less than 400 microg/g, and there was limited histochemical Cu and no/equivocal damage; and 'affected' in 53 samples (34 per cent), where Cu was greater than 400 microg/g, there was histochemical Cu and liver damage was poorly related to Cu content. In the DNA assay, which was used alone on unrelated individuals, the microsatellite marker failed to identify the CT status of any of the groups. Liver biopsy remains a reliable indicator of Cu accumulation and progressive liver disease in individual dogs. The microsatellite marker C04107 has a predictive value only when supported by a pedigree.     

Clinical, morphologic, and chemical studies on copper toxicosis of Bedlington Terriers.

In a study of 90 Bedlington Terriers, 68 had a defect that resulted in the accumulation of toxic excesses of copper in the liver. Concentrations of copper were 5 to 50 times that of clinically normal mongrel dogs. The bulk of this excess copper was sequestered in lysosomes. When copper concentrations exceeded 2,000 micrograms/g dry liver, progressive signs of functional and morphologic disturbance appeared as focal hepatitis, chronic active hepatitis, and ultimately cirrhosis. The disorder, which appears to be inherited, could only be diagnosed by liver biopsy. It was latent for many years in some dogs but led early in life to acute or chronic hepatic disease and death in others.     

Inherited copper toxicosis in Bedlington terriers

SUMMARY Chronic hepatitis and increased hepatic copper concentrations, from 1,600 to 6,361 fig/g dry tissue were found in 4 related, Australian-bred Bedlington terriers. Two dogs were asymptomatic and 2 were clinically ill with signs referable to liver dysfunction. Two dogs were treated with d-penicillamine. After one year there was no improvement in the histopathological liver changes in either dog or significant lowering of hepatic copper level in one dog.     

Inherited copper toxicosis in the Bedlington terrier: the prevalence in asymptomatic dogs

Copper toxicosis in the Bedlington terrier is an inherited defect. This paper describes the investigation of 62 Bedlington terriers, none of which had shown any clinical signs of liver disease, in order to assess the prevalence of copper toxicosis in the breed in the United Kingdom. Twenty one (33·9 per cent) of the dogs investigated had abnormally high levels of copper in the liver. No reliable circulating haematological or biochemical parameters were found to identify those dogs with increased hepatic copper levels and the diagnosis could only be established by liver biopsy. Affected dogs had liver copper levels of between 257·5 and 2558·0 μpg per g of wet weight (1163·8 ± 164 μg/g, mean ± SEM) compared with normal dogs which had between 9·9 and 118·6 μg/g of wet weight (49·0 & 4·4 μg/g, mean ± SEM). Copper accumulation in the liver of affected dogs could also be detected on histological examination using special stains.     

Copper inhibition of the thiobarbituric acid reaction in Bedlington terriers

The effect of copper on thiobarbituric acid (TBA) reaction values, an index of lipid peroxidation, was examined in Bedlington Terriers, healthy dogs, and rats. High hepatic concentrations of copper appeared to lower TBA values in the inherited, chronic, progressive hepatic degeneration of Bedlington Terriers, a disease associated with copper toxicosis. The suspected TBA inhibition was confirmed when Cu2+ was added to homogenates of healthy dog or rat liver or a malondialdehyde standard. The amount of copper added approximated that in diseased Bedlington Terriers. Because of the interference by copper, the TBA test was judged to be an inappropriate test for the evaluation of lipid peroxidation in samples containing high copper concentrations such as those in diseased Bedlington Terriers.     

Inherited copper toxicosis in the Bedlington terrier: a report of two clinical cases

The clinical signs, laboratory findings and pathological changes are described in two cases of inherited copper toxicosis in the Bedlington terrier. The first case presented with acute signs of depression, vomiting, anorexia, weight loss and jaundice while the second case followed a more chronic course with less severe clinical signs which included weight loss and ascites. Both dogs had elevated circulating levels of alanine aminotransferase (ALT), however other haematological and biochemical parameters, while reflecting liver involvement, varied between the two cases. Chemical analysis of the liver revealed elevated copper levels in both cases (951·7 and 1093·4 μg/g wet weight respectively; normal less than 150 μg/g). These levels, however, are less than some affected but asymptomatic Bedlington terriers. Pathologically the first case had micronodular cirrhosis, while the second had focal hepatitis with fibrosis. Both dogs showed vacuolation of the white matter in the cerebrum, cerebellum, midbrain and medulla. Attention is drawn to the similarities and differences between copper toxicosis in the Bedlington terrier and Wilson's disease in man.     

Copper toxicosis in veal calves

Copper toxicosis was diagnosed in 7 veal calves, 10-16 weeks old, from 5 separate farms. All calves died without specific clinical signs, although 4 of the calves were icteric. The calves' dietary rations had been supplemented with various copper-containing hematinics. Peritoneal hemorrhage was reported at post-mortem in 2 calves. Microscopic evidence of hepatopathy consisted of hepatocellular degeneration and necrosis, hemorrhage, and fibrosis. Concentrations of copper in livers from intoxicated calves ranged from 277 to 684 ppm and in kidneys from 1.1 to 82.0 ppm. The extent and severity of lesions in livers appeared to correlate with concentrations of copper. Nephrosis was minimal, without evidence of hemoglobinuria.     

Polymorphisms in canine ATP7B: candidate modifier of copper toxicosis in the Bedlington terrier

A COMMD1(MURR1) deletion has been reported as the cause of copper toxicosis (CT) in Bedlington terriers. Recent studies identified Bedlington terriers with copper accumulation without homozygous COMMD1 deletions. Wilson disease in humans is a copper storage disorder similar to CT caused by mutations in ATP7B, and COMMD1 has been shown to interact with the ATP7B protein. ATP7B may act as a modifier in CT, allowing for copper accumulation in Bedlington terriers with one deletion or other variations in COMMD1. In this study, ATP7B was cloned and sequence analysis conducted in a subset of Bedlington terriers from a pedigree that does not show complete association between the COMMD1 deletion and CT. Eleven polymorphisms, two in the coding region, were identified in the Bedlington terrier ATP7B gene. However, these are not unique to the Bedlington terrier and pedigree analysis suggests that ATP7B is not a modifier of COMMD1 in this subset of dogs.     

Copper toxicosis in a Boer goat

A 1‐year‐old female Boer goat was presented with a 1‐day history of pigmenturia, anorexia, and shivering. Anemia was not present initially, but progressive hemolytic anemia developed subsequently and was characterized by the finding of Heinz bodies in both intact RBCs and in ghost cells and the presence of atypical fusiform RBCs. Plasma biochemical analysis revealed increased activities of aspartate aminotransferase and gamma‐glutamyltransferase, hyperbilirubinemia, and azotemia. Histopathologic examination of a liver biopsy revealed necrosis of individual hepatocytes and intracytoplasmic rhodamine‐positive granules, consistent with copper. Copper concentration in ante‐mortem hepatic tissue was increased, and a diagnosis of copper toxicosis was made. Despite supportive therapy, the goat continued to decline and was euthanized. Necropsy findings included hepatic necrosis and hemoglobinuric nephrosis. Freshly collected specimens of liver and kidney had markedly increased copper concentrations. The mineral composition of the water, grass hay, and goat chow was evaluated, and toxins and significant mineral imbalances were not found. The underlying cause of the hepatic accumulation and subsequent release of copper remains unclear in this goat. Recently, Boer goats have been recognized as being prone to copper toxicosis and may be more susceptible than other breeds; similar to sheep, Boer goats may experience a hemolytic crisis secondary to copper toxicosis.     

Copper storage disease with intravascular haemolysis in a Bedlington terrier

A 5-year-old male Bedlington terrier was found to have haemoglobinuria from intravascular haemolysis. The owners reported also recent vomiting, occasional diarrhoea, reduced activity and increased drinking and urination. A diagnosis of inherited copper storage disease, as previously described in this breed, was established by demonstrating characteristic light and electron microscopic changes and copper content of 7, 717 micrograms/g in biopsied liver. Treatment by chelation with d-penicillamine and a low copper diet was instituted and the dog remains well 10 months later. Intravascular haemolysis is rare in dogs and an uncommon finding in Bedlington terriers with copper storage disease.     

Population dynamics of inherited copper toxicosis in Dutch Bedlington terriers (1977-1997)

Inherited copper toxicosis in Bedlington terriers was 1st reported in 1975 and the entire Dutch population was examined from 1976 until the present for presence of the disease. To examine the effect on the prevalence of the disease of excluding affected dogs from breeding we have compared 2 time cohorts, the 1st consisting of dogs born from January 1, 1976, to January 1, 1986 (n = 155), and the 2nd of dogs born from January 1, 1990, to January 1, 1997 (n = 195). The diagnosis was made in the 1st cohort by evaluating liver biopsies, and in the 2nd cohort with a DNA marker. The population was also resolved into clusters of related dogs to analyze the familial distribution of the disease in the population and to search for ancient founders of the disease among the ancestors of sick dogs. Forty-six percent of dogs examined between 1976 and 1986 had copper toxicosis. Eleven percent of dogs examined in the 2nd cohort had evidence of disease. This reduction was achieved while maintaining the already limited genetic heterogeneity of the population: the number of clusters and the mean relatedness between the clusters were similar in both time cohorts. The disease was evenly distributed over the clusters of related dogs in both cohorts. All ancestors had contributed to the distribution of copper toxicosis and no specific founders could be identified. This indicates that when the breed was established in The Netherlands, the disease was already highly prevalent in the founding dogs.     

Copper and zinc levels in the blood of thoroughbreds in training in the United Kingdom

The concentration of copper and zinc in the blood and sera of over 300 Thoroughbreds in training was determined by atomic absorption between February 1979 and July 1981. The mean (+/- sd) concentration of copper in the serum of stabled Thoroughbreds (79 +/- 16 micrograms/dl) was significantly (P less than 0.0001) lower than that of those at grass (101 +/- 26 micrograms/dl), whereas the mean serum zinc concentration of stabled Thoroughbreds (170 +/- 54 micrograms/dl) was higher than that of those at grass (111 +/- 45 micrograms/dl). No such differences were observed in whole blood. There were marked differences in the mean serum copper and zinc concentrations in the blood of Thoroughbreds housed in different stables. Significant changes occurred throughout the year in the mean values from individual stables. However, there were no such changes in the mean values of the total population. The observed differences were probably caused by dietary variations. The results emphasise the need to establish reference values related to diet if copper and zinc levels in blood are to be used for interpretative purposes.