Bovine ephemeral fever in beef cattle herds in the Jordan Valley, Israel

excretion of copper via bile (Su and others 1982). It is caused by a deletion in the MURRI gene (van de Sluis and others 2002), of which the precise function remains to be determined. In affected dogs the hepatic copper concentrations increase progressively. Accumulated copper becomes sequestered in lysosomes, first, in pericentral hepatocytes, and then, when copper concentrations increase with time, storage becomes more diffusely spread over the liver acinus (Twedt and others 1979, Ludwig and others 1980, Johnson and others 1984, Thornburg and others 1985, 1990). Severe copper accumulation may eventually result in chronic hepatitis and cirrhosis or, in some dogs, in acute hepatic necrosis leading to disseminated intravascular coagulation and haemolysis. Intrahepatic copper concentrations correlate positively with the severity of the liver damage (Twedt and others 1979). Clinical signs such as anorexia, intermittent vomiting and diarrhoea, can sometimes be recognised weeks to months before development of overt liver failure (Twedt and others 1979). In the liver biopsies of the Anatolian shepherd in this case, a close association was found between the localisation of severely increased copper concentrations in hepatocytes and macrophages, and the necroinflammatory liver changes. This may indicate that copper was the primary cause of the hepatitis. A primary role for a defect in copper metabolism is also supported by the finding that the activity of the hepatic inflammation and the reduced level of liver cell apoptosis was associated with a reduction in hepatic copper obtained over the course of medication with the D-penicillamine. However, the combined use of prednisolone and D-penicillamine means the improvement may not be attributed to the penicillamine alone. Copper accumulation is also seen as a secondary phenomenon of cholestasis. This is most prominent in chronic cases of complete extrahepatic bile duct obstruction in which hepatic copper levels of 1mg000to 5w000 g/g can be reached. The biliary excretion of copper may also be impaired in diffuse intrahepatic cholestasis. In these cases, copper accumulates less than with extrahepatic obstruction. In this Anatolian shepherd dog, extrahepatic obstruction could be excluded, but intrahepatic cholestasis was present as a logical consequence of the hepatitis. However, there was no histological evidence of pronounced cholestasis or clinical jaundice. In addition, the plasma was not icteric and the cholestasisrelated parameter ALP in plasma was only mildly increased. As there was no evidence supporting an important role of cholestasis to explain the very high copper concentration in the liver of ths daog, arimanry defet in th copper homeostasis, comparable with that in Bedlington terriers with copper toxicosis, appears to be the most logical explanation of the condition. A late onset of signs is also seen in Bedlington terriers as an expression of a gradual, life-long accumulation of copper in the liver. Such a primary defect is most likely to be caused by a genetic defect, and so this may be the first report of a new inherited disease of copper metabolism. Special attention is therefore recommended when hepatitis is diagnosed in this breed, in case a genetic mutation has spread through the Anatolian shepherd population. Investigation of the hepatic copper status of family members of affected Anatolian shepherd dogs, and then of DNA focusing on potential candidate genes, may help to increase knowledge of copper storage syndromes.