Signalment:  
Gross Description:  
Histopathologic Description:
Liver: Hepatic cords are poorly defined, containing dissociated cells, particularly in centrilobular and midzonal locations. Individualized cells at these and other sites have eosinophilic cytoplasm and pyknotic or absent nuclei. Some contain brown-gray cytoplasmic granules that are positive for copper by rhodanine staining. Occasional canaliculi are outlined by bile pigment. Small numbers of well-defined unstained cytoplasmic vacuoles, interpreted as lipid, also occur in hepatocytes. In most instances, areas of degeneration and necrosis are devoid of inflammation, although clusters of eosinophils and other leukocytes occasionally occur.
Kidney: Some cortical renal tubules contain flocculent to eosinophilic granular casts, often with granules possessing a more pronounced red color, while others contain degenerating cells. Renal tubular epithelial cells are attenuated, coagulated and pyknotic, or absent. Similar casts occur in the medulla, with less tubular damage. Thrombi occur in small, thin-walled interstitial blood vessels.
Special stains revealed bile retention in hepatic canaliculi and granules positive for copper by rhodanine were found in the liver but not the kidney. Iron stains were positive for sloughed cells in renal tubules, but the liver contained little iron pigment.
Morphologic Diagnosis:  
1. Liver: Hepatocellular degeneration and necrosis, acute, predominantly centrilobular, with cytoplasmic granularity, mild lipidosis and mild bile stasis.
2. Kidney: Acute renal tubular degeneration and necrosis, severe, with hemoglobinuric casts and interstitial thrombosis.
Lab Results:  
Condition:  
Contributor Comment:  
Hemolytic crisis has been reported to follow acute exposure of pre-ruminant kid goats exposed to milk replacer intended for calves,(6) but an outbreak of copper intoxication in lactating dairy goats was characterized by hepatopathy without hemolytic crisis.(2) However, copper intoxication with hemolysis is becoming more recognized in adult and juvenile Boer goats. In this particular animal, the lesions are consistent with a post-hemolytic phase of disease, in which renal damage associated with hemoglobinuria is evident.
Liver damage in copper intoxication is thought to result from a combination of hepatocyte lysis due to the effects of the toxin and anoxia secondary to anemia. Renal damage may likewise have hemoglobinuria and anemia as cofactors affecting the lesion development. Ultrastructurally, the preclinical phase is morphometrically associated with hepatocyte and Kupffer cell swelling at the expense of the sinusoids and space of Disse, with pronounced lysosomal proliferation. At the time of crisis, lysosomes become even more enlarged and contain many residual bodies.(3)
Copper concentrations should not be above 230 mg/kg in liver, 12 mg/kg in kidney or 1.2 mg/kg in blood as measured by flame atomic absorption spectrometry.
A variety of copper storage diseases occur in humans, rodents and companion animals.(4) In Wilsons disease of humans, the rate of ceruloplasmin binding of copper is reduced, as is excretion, due to mutation of the ATP7B gene. The specific genetic defect resulting in variable breed susceptibility in other species is not known.
JPC Diagnosis:  
1. Liver: Hepatocellular degeneration and necrosis, centrilobular to mid-zonal, diffuse, moderate, with bile stasis, edema, and intracytoplasmic amphophilic granular material (copper).
2. Kidney: Tubular degeneration and necrosis, diffuse, severe, with multifocal tubular regeneration, tubular protein, granular and hemoglobin casts, and occasional fibrin thrombi.
Conference Comment:  
Participants discussed the histomorphologic features of tubular regeneration. Approximately one week after the initial injury, evidence of regeneration is evident. Tubules are lined by attenuated epithelium with hyperchromatic nuclei, and occasional mitotic figures may be seen. As regeneration continues, cells appear smaller with increased cytoplasmic basophilia, and may be closely packed with the appearance of piling up. The moderator offered additional guidelines to aid in the interpretation of tubular regeneration, such as uneven nuclear size (anisokaryosis) and variable distance between nuclei due to cells in different stages of growth and re-epithelialization.(7)
Cases of hemoglobinuric nephrosis often have characteristic port wine- colored urine. There are three possible causes of such urine color: hematuria, hemoglobinuria and myoglobinuria. Identifying the cause of discoloration often provides insight as to the underlying disease process; therefore, one must be able to differentiate the three causes in the laboratory. Hematuria is easily diagnosed by centrifugation of the urine specimen; erythrocytes will be present in the urine sediment. Hemoglobinuria and myoglobinuria both lack erythrocytes in the sediment and the urine remains discolored after centrifugation. Addition of saturated ammonium sulfate will cause hemoglobin to precipitate out of the urine sample, resulting in a clear sample; myoglobin does not precipitate, and the urine remains discolored. If a blood sample is also available, centrifugation of a hemoglobinemic sample will result in pink serum, while in a myoglobinemic sample the plasma will remain clear.(4)
References:
1. Bozynski CC, Evans TJ, Kim DY, et al. Copper toxicosis with hemolysis and hemoglobinuric nephrosis in three adult Boer goats. Vet Diagn Invest. 2009;21:395-400.
2. Cornich J, Angelos J, Puschner B, Miller G, George L. Copper toxicosis in a dairy goat herd. J Am Vet Med Assoc. 2007;231:586-589.
3. Gooneratne SR, Howell JM, Cook RD. An ultrastructural and morphometric study of the liver in normal and copper-poisoned sheep. Am J Pathol. 1980;99:429-480.
4. Gregory CR. Urinary system. In: Latimer KS, Mahaffey EA, Prasse KW, eds. Duncan and Prasses Veterinary Laboratory Medicine: Clinical Pathology. 4th ed. Ames, IA: Blackwell Publishing; 2003:240-241.
5. Hoffman G. Copper-associated liver diseases. Vet Clin North Am Small Anim Pract. 2009;39: 489-511.
6. Humphries WR, Morrice PC, Mitchell AN. Copper poisoning in Angora goats. Vet Rec. 1987;121: 231.
7. Maxie MG, Newman SJ. Urinary system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals Vol. 2, 5th ed. Philadelphia, PA: Elsevier Ltd; 2007:467.
8. Simpson DM, Beynon RJ, Robertson DHL, Loughran MJ, Haywood S. Copper-associated liver disease: a proteomics study of copper challenge in a sheep model. Proteomics. 2004;4:524-536.