Copper

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.