Inherited, chronic, progressive hepatic degeneration in Bedlington terriers with increased liver copper concentrations: clinical and pathologic observations and comparison with other copper-associated liver diseases
Hultgren, B.D.; Stevens, J.B.; Hardy, R.M.
American Journal of Veterinary Research 47(2): 365-377
1986
ISSN/ISBN: 0002-9645 PMID: 3954222 Document Number: 278885
One hundred nineteen hepatic tissue samples from 117 Bedlington Terriers were divided into 6 groups depending on the severity of histopathologic hepatic changes. Group 0 comprised dogs with microscopically normal livers. Group 1 dogs had copper-positive, lipofuscin-containing lysosomes present in centrilobular hepatocytes. Microfoci of hepatic necrosis, in addition to the increased numbers of the copper-positive, lipofuscin-containing lysosomes in centrilobular and periportal hepatocytes, were present in group II dogs. Group III dogs had more copper-positive, lipofuscin-containing lysosomes present translobularly and morphologic changes consistent with chronic active hepatitis. Mixed micro- or macronodular cirrhosis and translobular presence of copper-positive, lipofuscin-containing lysosomes characterized group IV dogs. Dogs in groug V had massive hepatic necrosis and morphologic changes that were consistent with the changes in group III and IV dogs. Histochemical staining for copper was useful in making the microscopic diagnosis of this disease and was shown to be necessary in early diagnosis (group I) when other clinical and pathologic values associated with this syndrome were not consistently abnormal. Copper histochemical stains varied in sensitivity. Timm's silver sulfide was more sensitive for copper than was rubeanic acid, which was more sensitive than rhodanine staining. The brown pigment associated with the copper in the lysosomes was shown to be lipofuscin pigment with the aid of histochemical staining with orcein, Prussian blue, periodic acid-Schiff, and acid-fast stains together with fluorescent microscopy (excitation maxima : 365 nm; emissions: 450 + nm). Since these were positive only in later stages of the hepatic disease, they were not especially useful in its early diagnosis. The severity of the histopathologic hepatic changes was shown to increase with age and was associated with increasing hepatic copper concentration. These observations illustrate that this inherited, chronic hepatic degeneration in the Bedlington Terrier is progressive. Clinical chemical tests were diagnostically useful only in later stages of the diseases. Alanine transaminase activity was of most value, but was not always abnormal, even when severe hepatic damage was present. Clinical signs of hepatic disease were seen in dogs in groups III, IV, and V. Death due to hepatic failure occurred only in dogs in groups III, IV, and V. Hemosiderin was present in increased amounts in the liver, bone marrow, spleen, and lymph nodes of affected Bedlington Terriers, indicating that a possible defect in iron metabolism and/or an increase in RBC turnover existed. Hemolytic anemia had been suspected as a result of finding erythroid hyperplasia, normoblastosis, and polychromasia in the diseased dogs; however, packed-cell volumes were not depressed. This could indicate that RBC oxygen-carrying capacity or tissue respiration may be impaired (cytotoxic anemia). This copper-associated disease in the Bedlington Terrier was shown to be similar to other copper-associated liver diseases in other species. As species' sensitivity to copper differs, some differences in clinical signs and lesions of toxicosis were expected. Other than a reported difference in the lobular distribution of the copper-positive, lipofusin-containing lysosomes (primarily periportal) in Wilson's disease, the lack of CNS disease seemed to be the only major difference between Wilson's disease and this disease in the Bedlington Terrier. Indian childhood cirrhosis has not been completely studied; it seems to be a similar syndrome, only more rapidly progressive than this canine disease. Differences, such as the primary lobular distribution of the copper-positive, lipofuscin-containing lysosomes or subcellular distribution of copper, were shown between the disease in Bedlington Terriers and copper toxicosis in many animal species and the copper accumulation associated with chronic cholestasis in persons and animals. However, many more similarities than differences were repor.