DIAGNOSTIC HISTOPATHOLOGY AND CYTOLOGY

CASE OF INTEREST

Copper Toxicosis in a Mouse Deer.

By Richard Fox, Veterinary Pathologist
Case Donated by Malcolm Silkstone, Veterinary Pathologist

One of two rare Mouse Deer presented with bloody nasal discharge. Clinical signs also included abdominal pain on palpation and lethargy. Bloating was not noted. The animal then suffered cardiac failure and was recuscitated but then died shortly afterwards.

Post mortem examination did not reveal any obvious gross abnormalities. Histological investigation was performed on submitted tissues including liver, spleen, lung, myocardium and kidney.

On histologic examination of the kidney congestion was noted. Several sections of kidney displayed tubular degeneration and necrosis with haemoglobin-stained granular casts and the presence of haemoglobin pigment within tubular epithelial cells. Note: Mouse Deer erythrocyes are approximately 1/10th of the size of mamalian erythrocytes.

Figure 1. Histological section of the renal cortex displaying tubular necrosis with intra-tubular haemoglobin resorption droplets. HE Stain.

In the liver there was centrolobular to mid-zonal hepatocellular swelling with cytoplasmic vacuolation, the affected hepatocytes also contained abundant copper-like pigment. There were lesser amounts of lipofuscin-like pigment. Portal triads contain a few lymphocytes and plasma cells and pigmented macrophages.

Figure 2. Histological section showing centrolobular to mid-zonal hepatocellular swelling with cytoplasmic vacuolation and affected hepatocytes containing abundant copper-like pigment. HE Stain.

Examination or urine revealed plentiful proteinaceous deposits and granular reddish casts consistent with haemoglobin casts.

Figure 3. Photograph of urine sediment showing haemoglobin casts. HE Stain.

As a trace element, copper has a crucial role in mammalian metabolism, but it can be toxic in excess. The importance of a balanced copper homeostasis is illustrated by several copper-associated disorders in man and in a wide variety of animal models (eg, mice, dogs, and sheep). Proteins (copper transporters) involved in controlling copper metabolism have been well studied.

Copper storage disorders have also been observed in several dog breeds, such as Bedlington Terriers, Labrador Retrievers, West Highland White Terriers, and Doberman Pinschers. However, for some breeds it is still unclear whether the affected hepatic copper metabolism is the primary cause of hepatitis. The autosomal recessive disorder of copper toxicosis in Bedlington Terriers is at present the best-characterised copper storage disease. Copper toxicosis is caused by defective biliary copper excretion resulting in hepatic copper accumulation after chronic progressive hepatitis and cirrhosis. The onset is between 2 and 6 y of age and the clinical phenotype resembles Wilson disease, although neurologic defects are absent and affected animals have normal serum ceruloplasmin concentrations. The mutation in dogs affected with copper toxicosis is found in the COMMD1 gene, has been identified, although some Bedlington Terriers with copper toxicosis in the United Kingdom and Australia were identified without this homozygous deletion. No other COMMD1 mutations have been seen in these dogs, which suggests that other, as yet unknown, genetic defects are involved in copper toxicity in Bedlington Terriers without a COMMD1 deletion.

Generally speaking, during the accumulation or pre-hemolytic phase, animals may be clinically normal, even with liver copper concentrations of 1,000 ppm, so long as increasing mitotic rate produces enough new hepatocytes to take up the copper released by dying cells. However, liver damage does occur during this period as indicated by increased levels of lactic dehydrogenase and AST. The second phase, or hemolytic crisis, lasts from hours to days and is characterised by the sudden onset of severe intravascular hemolysis and hemoglobinemia associated with increased blood copper levels, with resulting liver, kidney, and brain damage. The sudden increase in blood copper concentrations causes formation of methemoglobin and Heinz bodies as well as lipid peroxidation of erythrocyte membranes and intravascular hemolysis of damaged erythrocytes.

In this case it was not clear as to whether these Mouse Deer were susceptible to copper toxicosis due to an underlying abnormality in copper metabolism and uptake or if their diet contained excess copper or they ingested copper containing compounds.

References:

1. Fuentealba IC, Aburto EM. Animal models of copper-associated liver disease.Comp Hepatol. 2003 Apr 3;2(1):5. Link

2. Vonk WI, Wijmenga C, van de Sluis B. Relevance of animal models for understanding mammalian copper homeostasis.Am J Clin Nutr. 2008 Sep;88(3):840S-5S. Link