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Copper storage hepatopathies in cats

Hurwitz BM, Center SA, et al.  Presumed primary and secondary hepatic copper accumulation in cats.  J Am Vet Med Assoc. 2014;244(1):68-77.

Copper storage hepatopathies are well known in dogs and humans.  While copper is an essential micronutrient, excess copper accumulation in the liver is toxic to hepatocytes, causing oxidative stress and damage to nucleic acids, proteins, and lipids and disrupting cellular metabolism.  Hitherto, very little was known about hepatocellular copper accumulation in cats. This retrospective cross-sectional study documents and discusses primary and secondary copper storage hepatopathies in the feline.

The liver is, in fact, the principal site of copper storage in the cat; in cats the hepatic copper concentration reflects dietary copper intake, rather than copper concentrations in plasma or other tissues.  Distribution of copper in the feline liver is variable; in some animals copper is stored in periportal areas and in others, centrilobular sites.  Hepatic copper concentration in cats is at normal levels when it is <180 µg/g of liver tissue dry weight (DW).

Records of 114 cats evaluated at a veterinary teaching hospital from 1980 to 2013 were reviewed; 100 of the animals had hepatobiliary disease, while 14 did not.  Histologic examination of liver samples and hepatic copper assays had been performed in all subjects.  The 100 cats with hepatobiliary disease were assigned to one of four diagnostic groups:  primary copper-associated hepatopathy (PCH; n = 11), extrahepatic bile duct obstruction (EHBDO; n=14), cholangitis-cholangiohepatitis syndrome (CCHS; n=37), and miscellaneous hepatobiliary disorders (MHBD; n=38).  The miscellaneous hepatobiliary disorders diagnosed in the subjects included hepatic lymphosarcoma (n=9), hepatic lipidosis (n=8), portal hepatitis (n=7), polycystic liver disease or ductal plate malformation (n=5), cholecystitis and cholelithiasis (n=4), suppurative cholangitis (n=2), congenital portosystemic shunt (n=1), biliary hyperplasia without inflammation (n=1), and hepatic metastasis of pulmonary carcinoma (n=1).  All cats that were tested for feline leukemia virus (n=103) were negative; one cat in the MHBD group tested positive for feline immunodeficiency virus.

All cats with PCH had hepatic copper concentrations > 700 µg/g DW; median hepatic copper concentration in PCH cats was 1,830 µg/g DW (range 704-7041 µg/g DW). These cats were significantly younger (median age 2 years; range 0.5-11 years) than the rest of the cats with or without liver disease.  There was no sex or breed prediliection in any disease category, including PCH.  Cats diagnosed with PCH had the following clinical signs: vomiting (n=6), lethargy (6), reduced appetite (6), jaundice (4), bleeding (3), weight loss (2), abdominal effusion (2), and diarrhea (2).  All of the PCH cats had ALT levels a minimum of >1.7 times higher than the upper end of the reference range, and 10/11 had AST activity a minimum of > 1.4 times higher than the upper limit of the reference range.  High liver enzyme activities in all of these patients were what prompted further investigation and subsequent diagnosis of PCH in all of these patients.

Some of the cats with other conditions (EHBDO, n=1; CCHS, n=8; MHBD, n=1) also had hepatic copper concentrations > 700 µg/g DW.  All cats without hepatobiliary disease had hepatic copper concentrations < 190 µg/g DW; but 5/14 cats with EHBDO, 7/37 of those with CCHS, and 23/38 cats with MHBD also had hepatic copper concentrations < 190 µg/g DW.  There were no clincopathologic parameters, such as serum ALT or GGT activity, serum total bilirubin, or coagulation times, found that could definitively distinguish a cat with PCH from one with another hepatobiliary disorder.  Likewise, the gross, ultrasonographic, and histologic appearance of the liver was not specific for PCH.  For the most part, copper accumulation in cats with PCH, as evaluated by special stains, was highest in centrilobular hepatocytes.  In all cats with PCH, there was hepatocyte vacuolation that appeared consistent with glycogen accumulation, confirmed in one patient with special stains.  In contrast to those cats with PCH, those cats with hepatic copper accumulation secondary to cholestatic liver diseases accumulated copper in periportal hepatocytes, similar to that in humans with cholestatic disorders. As with PCH, significant hepatic copper accumulation secondary to other hepatobiliary disorders is in and of itself damaging to the liver.

Those cats in whom PCH was diagnosed post-mortem (n=4) had developed acute hepatic failure at a young age (1-4 years old). The etiology of PCH is presumed to be pathological copper accumulation due either to environmental exposure (food or water) to excess copper, or to genetic factors. Cats who were diagnosed antemortem  were treated in different ways:  chelation with penicillamine or elemental zinc; feeding of liver support diets or a high-protein, low-carbohydrate diet; administration of antioxidants such as Vitamin E, S-adenosylmethionine, and silybin A and B; prednisolone administration to control hepatic and systemic inflammation.  The dietary copper requirements of cats are not well established, so it is hard to determine what might constitute a copper-restricted diet for cats with PCH or those with secondary hepatic copper accumulation.  Based on the limited number of cases that received treatment, successful long-term management of cats with PCH is possible. Chelation therapy along with the administration of antioxidants is most likely to be successful, although one cat receiving chelation therapy developed drug-induced hemolytic anemia.  [PJS]

See also:
Whittemore JC, Newkirk KM, et al.  Hepatic copper and iron accumulation and histologic findings in 104 feline liver biopsies.  J Vet Diagn Invest 2012;24:656-61.