Copper toxicosis in Bedlington Terriers in the United Kingdom

This paper summarizes the clinical and laboratory data on two adult Bedlington Terriers with liver disease associated with copper toxicosis. The younger dog, at 3 years, had elevated serum levels of alanine aminotransferase and alkaline phosphatase with active parenchymal cell degeneration and hepatitis. The second dog developed chronic hepatic failure at 5 years with advanced cirrhosis. Both dogs had stainable copper granules in the liver and chemical analysis of their livers revealed elevated copper contents (1,027 and 10,728 μg/g dry weight; normal less than 300 μg/g). These are the first published cases of this inherited abnormality of copper metabolism in this breed in this country.     

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.     

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.     

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.     

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.     

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.     

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.     

Iatrogenic copper deficiency associated with long-term copper chelation for treatment of copper storage disease in a Bedlington Terrier

A 9-year-old Bedlington Terrier was evaluated because of weight loss, inappetence, and hematemesis. Copper storage disease had been diagnosed previously on the basis of high hepatic copper concentration. Treatment had included dietary copper restriction and administration of trientine for chelation of copper. A CBC revealed microcytic hypochromic anemia. High serum activities of liver enzymes, high bile acid concentrations, and low BUN and albumin concentrations were detected. Vomiting resolved temporarily with treatment, but the clinicopathologic abnormalities persisted. Results of transcolonic portal scintigraphy suggested an abnormal shunt fraction. Results of liver biopsy and copper quantification revealed glycogen accumulation and extremely low hepatic copper concentration. Serum and hair copper concentrations were also low. Chelation and dietary copper restriction were tapered and discontinued. Clinical signs and all clinicopathologic abnormalities improved during a period of several months.     

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.     

Microsatellite marker C04107 as a diagnostic marker for copper toxicosis in the Danish population of Bedlington terriers

The linkage phase of marker C04107 was evaluated before implementation of the marker in a diagnostic test. Blood samples from 68 dogs were collected and genotyped by PCR. Two alleles were detected with sizes of 160 bp and 164 bp and allele frequencies of 0.45 and 0.55 respectively. Genotyping revealed that 35 dogs were heterozygous (51.5%), 22 dogs were homozygous for the normal allele (32.3%) and 11 dogs were homozygous for the disease allele (16.2%). Liver biopsies were taken from 14 selected dogs and the copper content was evaluated histologically. Biopsies from 8 dogs homozygous for the disease allele showed many copper granules along with single cell necrosis, haemosiderosis and cellular infiltration. In liver biopsies from 6 dogs genotyped to be heterozygous or homozygous for the normal allele, copper granules were absent or moderate in number and no lesions were present. The survey demonstrates that the linkage phase of marker C04107 in the Danish population of Bedlington terriers is similar to the linkage phase detected in other countries. Thus, the marker can be used in a diagnostic test for copper toxicosis in Denmark.     

von Willebrand's disease in Scottish Terriers in Australia

SUMMARY Over a 5-year period (1988–92), von Willebrand factor antigen (vWf:Ag) assays were performed on plasma samples from 207 Scottish Terriers. Based on these tests, 47 dogs (23%) had vWf:Ag concentrations < 50 canine units (CU)/dL and were classified as heterozygous carriers of the von Willebrand's disease (vWD) gene, while 9 (4%) had concentrations below the sensitivity of the assays and were classified as homozygous. There was thus an overall prevalence of 27% for the vWD gene in the Scottish Terriers tested. The homozygous dogs (median age 0.6 years at diagnosis) consisted of 7 males and 2 females. Eight of these had haemorrhage attributable to the disease, mostly spontaneous and from the oral mucosa. Other signs included haemorrhage induced by trauma or surgery, easy bruising and epistaxis. Many haemorrhagic episodes were severe enough to warrant therapeutic intervention and there was a single fatality. Pedigree analysis, possible in 7 of the dogs, revealed that each was the progeny of a mating between dogs with vWf:Ag concentrations < 50 CU/dL, which supported an autosomal recessive mode of inheritance. A single heterozygous carrier suffered haemorrhage after surgery that, in contrast to the homozygotes, was mild and did not require therapy. The data indicate that vWD is a significant problem in Scottish Terriers in Australia. Accordingly, we recommend that steps be taken to reduce the prevalence of the disease and thereby the number of clinically affected dogs, such as the establishment of a national testing scheme to determine the vWD status of all breeding dogs.     

Ultrastructural and kinetic studies of copper metabolism in Bedlington Terrier dogs

The objectives of this study were to determine the time course of copper (Cu) absorption in the Bedlington Terrier (BT) dog after duodenal infusion of Cu and to determine the onset of Cu accumulation in BT puppies. At 80 minutes after infusion, Cu was present in the bile and liver at 26.1 and 2675 microg/g dry weight (dw), as compared with 598 and 224 microg/g dw, respectively, in the control. In the puppies, the mean liver Cu concentrations were 443 +/- 216 microng/g dw as compared with 54 +/- 34 microg/g dw in their controls. The BT puppies had large numbers of Cu granules in their hepatic lysosomes, with very few in the bile canaliculi. In contrast, the controls had few granules in their lysosomes and large numbers in their canaliculi. These results suggest that hepatic Cu accumulation occurs rapidly and in utero in the BT.     

Retinopathy associated with ivermectin toxicosis in two dogs

CASE DESCRIPTION: 2 dogs (dogs 1 and 2) were examined for sudden onset of blindness. Both dogs had mild obtundation and mydriasis in both eyes. It was thought that dog 1 may have ingested ivermectin; dog 2 had been treated with ivermectin for demodectic mange. CLINICAL FINDINGS: On initial examination, both dogs had mydriasis and decreased pupillary light reflexes in both eyes. Dog 1 had an absent menace response bilaterally. Fundic examination of both eyes in both dogs revealed regions of multifocal retinal edema and folds with low-lying retinal separation. The electroretinogram was extinguished in dog 1 and attenuated in dog 2. Ivermectin was detected in serum samples from both dogs. TREATMENT AND OUTCOME: Both dogs made a complete clinical recovery following cessation of exposure to ivermectin; electroretinographic findings improved, and retinal edema resolved with some residual chorioretinal scarring. CLINICAL RELEVANCE: To our knowledge, this is the first report of resolution of retinal edema and electroretinographic changes associated with ivermectin toxicosis in dogs. In dogs that develop blindness suddenly, fundic examination, electroretinography, and assessment of serum ivermectin concentration are diagnostically useful, even if exposure to ivermectin is unknown.