Pathology in Practice

Keiichi Kuroki Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Brad M. DeBey Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Christal G. Pollock Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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John M. Ragsdale Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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History

A 1.5-year-old sexually intact male sugar glider (Petaurus breviceps) underwent an emergency evaluation at the Kansas State University Veterinary Teaching Hospital because of decreased activity, tenesmus, and possible seizure-like activity. The sugar glider became increasingly lethargic and developed emesis, voided red-brown urine, and died within hours after arrival at the hospital. The body was submitted to the Kansas State Veterinary Diagnostic Laboratory for necropsy.

Clinical and Gross Findings

No clinicopathologic tests were performed prior to the death. At necropsy, the sugar glider weighed 85 g (0.19 lb) and was in fair body condition with mild postmortem autolysis. The footpads, mucous membranes, subcutis, and adipose tissues were icteric (Figure 1). The liver was fragile and had an irregular surface with rounded edges. The gallbladder was distended with bile, but the cystic duct was patent. Both kidneys were mottled dark red. The urinary bladder was empty.

Figure 1—
Figure 1—

Photographs of the abdominal cavity (A) and kidneys (B) of a sugar glider (Petaurus breviceps) that was evaluated because of decreased activity, tenesmus, and possible seizure-like activity. The sugar glider died shortly after it developed lethargy and emesis and voided red-brown urine. Notice that the liver has an irregular surface with rounded edges. The footpads, subcutis, and omental fat were icteric. Both kidneys were mottled dark red.

Citation: Journal of the American Veterinary Medical Association 239, 12; 10.2460/javma.239.12.1549

Formulate differential diagnoses from the history, clinical and gross findings, and Figure 1—then turn the page

Histologic and Laboratory Findings

Samples of the liver and portions of the gastrointestinal tract, pancreas, spleen, adrenal glands, urinary bladder, heart, lungs, brain, and skeletal muscles were examined histologically. In the liver tissue, there was evidence of centrilobular hepatocellular degeneration and necrosis with disruption of hepatic cords and individualized hepatocytes. Numerous hepatocytes in these areas were swollen with vacuolated cytoplasm or had pale eosinophilic to hypereosinophilic cytoplasm with pyknotic or absent nuclei (Figure 2). Many centrilobular hepatocytes contained intracytoplasmic copper deposits as determined via rubeanic acid staining. In the kidneys, many lumina of the cortical tubules were dilated and contained hemoglobin casts (Figure 3). The affected renal tubules had signs of degeneration and necrosis characterized by swollen tubular epithelial cells or hypereosinophilic cytoplasm with loss of cellular detail and pyknotic or absent nuclei. Occasionally, affected tubular lumina contained small numbers of neutrophils. No remarkable microscopic lesions were observed in sections of gastrointestinal tract, pancreas, spleen, adrenal glands, urinary bladder, heart, lungs, brain, and skeletal muscles. Analysis of copper content of a liver specimen revealed that the hepatic copper concentration was 709 μg/mL (709 ppm [wet-weight basis]).

Figure 2—
Figure 2—

Photomicrographs of sections of the liver obtained from the sugar glider in Figure 1 following routine staining with H&E stain (A) or rubeanic acid stain (for detection of copper; B). Histologically, widespread centrilobular hepatocellular degeneration and necrosis is evident. In panel B, brown stained intracytoplasmic copper granules are visible in many centrilobular hepatocytes. In each panel, bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 239, 12; 10.2460/javma.239.12.1549

Figure 3—
Figure 3—

Photomicrograph of a section of a kidney obtained from the sugar glider in Figure 1. Notice that many renal tubules are dilated with hemoglobin casts and have evidence of degeneration and necrosis. Occasional affected tubular lumina contain small numbers of neutrophils. H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 239, 12; 10.2460/javma.239.12.1549

Morphologic Diagnosis

Marked, acute, centrilobular hepatocellular degeneration and necrosis with hepatocellular copper accumulation and marked, acute, multifocal renal tubular degeneration and necrosis with hemoglobin casts.

Comments

The gross and histologic findings in the liver and kidneys in the sugar glider of this report were indicative of copper toxicosis on the basis of their similarity to the gross and microscopic lesions associated with copper toxicosis in other domestic animals. Affected animals may be clinically normal during the copper accumulation phase, but excessive hepatic accumulation of copper eventually causes hepatocellular degeneration and necrosis due to copper-induced oxidative damage1; acute intravascular hemolysis with concomitant jaundice and hemoglobinuria develop when a large amount of copper is released from hepatocytes during their death.2 The hypoxia associated with hemolytic anemia further compromises the liver with additional centrilobular necrosis and copper release, and affected animals often die after a short duration of clinical disease. This concert of pathological changes, as in this sugar glider, is characteristic of lesions observed in species for which copper toxicosis more commonly develops, such as sheep. Sheep are highly prone to copper toxicosis because of their poor biliary excretion of copper,3 and copper toxicosis usually develops in 1 of 3 ways: via excessive copper intake as a result of contamination of water, pasture, or prepared feed; as a result of increased availability of dietary copper, particularly when dietary intake of molybdenum is low; or as a result of liver damage caused by other hepatotoxins (eg, pyrrolizidine alkaloids).4 In contrast to sheep, cattle, horses, swine, poultry, and dogs are considered to be more resistant to excessive tissue accumulations of copper.2 Clinical and pathological findings are more variable in cattle than in sheep,5 and acute intravascular hemolysis may or may not develop.4 In dogs, copper toxicosis is an inherited condition in Bedlington Terriers and West Highland White Terriers. Contrary to the pathological changes in sheep, acute terminal chain reaction is not a manifestation of copper toxicosis in dogs, and affected dogs commonly have chronic hepatitis, weight loss, and anorexia.2 Goats are generally considered to be resistant to copper; however, a recent report6 has suggested that Boer goats are susceptible to copper toxicosis with pathological changes similar to those in sheep.

In the sugar glider of this report, abundant hepatic copper accumulation was revealed via rubeanic acid staining. Reference data regarding hepatic copper concentrations in sugar gliders have not been established, to our knowledge; however, copper concentration in the liver was examined for further delineation of the disease condition. The hepatic copper concentration in this sugar glider was 709 ppm (wet-weight basis), which was presumed high given the concentrations known to be toxic for other species.7 Moreover, that copper concentration was approximately 9 times as high as the value in a 9-month-old male sugar glider (78 ppm [wet-weight basis]) that died of reasons unrelated to hepatic disease and underwent necropsy at the University of Missouri Veterinary Medical Diagnostic Laboratory (unpublished data). Although renal or serum copper concentration was not evaluated in the sugar glider of this report, assessment of liver, kidney, and serum copper concentrations should be performed at necropsy in suspected cases of copper toxicosis because copper release from dying hepatocytes could lower liver copper concentrations and increase copper concentrations in the serum and kidneys. In clinical cases, serum copper concentration can be difficult to interpret because it often remains within reference limits until hepatocellular necrosis develops2; hence, analysis of copper concentrations in hepatic biopsy specimens can be considered the best antemortem diagnostic method.8 Nevertheless, reference data for copper concentrations in serum and tissues need to be established for individual animal species.

Sugar gliders are small, arboreal marsupials originally native to Australia and New Guinea9 that have gained popularity as a pet outside these areas. Although all exotic small mammals are susceptible to a wide variety of disease processes, malnutrition and improper husbandry are common underlying factors in diseases affecting exotic pets, including sugar gliders.10 The sugar glider of this report had been fed a diet consisting chiefly of fruit, yogurt, and baby food with mineral and vitamin supplements. Copper analysis of the mineral supplement and the vitamin supplement revealed copper concentrations of 2.26 and 250 μg/mL (2.26 and 250 ppm), respectively. Although the vitamin supplement contained a substantial amount of copper, we do not know whether this finding was clinically important because it is unclear how much of that supplement was being consumed by the sugar glider on a daily basis. Nevertheless, the copper toxicosis in this sugar glider may have been attributable to the vitamin supplement. Despite the increased popularity of sugar gliders as a companion animal, information regarding their nutritional requirements and medical needs is still limited. It is advisable to use caution when administering nutritional supplements containing copper to animals and to consider copper toxicosis as a cause of hepatopathy or icterus.

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