Copper

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Hepatotoxicity

  • sheep are very susceptible
    • they have poor ability to excrete copper in the bile
  • copper accumulates in hepatocytes until it reaches a critical level
    • the hepatocytes die and release the copper into the blood
    • causes haemolysis of the red blood cells
  • this haemolysis further damages the hepatocytes
    • releases even more copper

Predisposing factors

  • contamination of foodstuffs and pasture with copper
  • any damage to the biliary system as in ragwort poisoning
  • pastures low in molybdenum
    • increases the availability of dietary copper
    • molybdenum combines with copper to form insoluble complexes in the gut

Gross

  • carcass
    • jaundiced
    • reddish
  • liver
    • swollen
    • soft
    • orange in colour
  • kidneys
    • deep red
    • red urine due to haemoglobinuria

Microscopically

  • periacinar hepatic necrosis and profuse bile due to haemolysis and cholestasis
  • copper can be demonstrated with special stain - rhodanine

Genetic inheritance

  • Bedlington and West Highland White Terriers
  • copper toxicosis susceptibility
  • inherited as autosomal defect
  • copper levels can be very high in the livers of these animals
  • there is no haemolytic crisis
Clinical
  • ill thrift
  • progressive neurological signs due to liver failure
Gross
  • liver is small and fibrosed
  • jaundice is not a consistent feature

Copper and liver disease

  • Copper – cofactor for enzymes (lysyl oxidase), electron transport proteins (cytochrome c oxidase) and antioxidant molecules (superoxide dismutase).
  • Primarily absorbed through the small intestine and stomach (upper small intestine in the dog).
  • Enterocyte regulation of absorption – metallothionein and a copper transport protein – ATPase7A.
  • Metallothionein is a low molecular wt cytoplasmic protein, in all tissues; expression in response to heavy metals, various hormones and stress. metallothionein in cytoplasm of enterocytes leads to absorption of copper.
  • ATPase7A – transmembrane copper transporter in a number of cell types.
  • Defective in people with Menke’s disease – the animal model is the mottled mouse – results in faulty transport of copper out of the cell –leads to copper accumulation in enterocytes. Liver and brain that have little of the transporter experience copper deficiency.
  • Chronic diet XS of copper leads to accumulation in the liver .
  • Serum copper – in 2 pools
    • Exchangeable pool – loosely bound to carrier molecules; 80% of it bound to transcuperin, the rest bound to albumin.
    • Other pool – tightly bound to carrier molecules.