What diseases are associated with Copper?

In Australasia, copper deficiency could almost be regarded as producing the ÒclassicÓ trace-element deficiency diseases, involving a range of differing species, organs involved and ages of animals affected. The nutritional biochemstry is complex, and deficiency states may be primary and absolute or secondary and conditioned. Harmful effects may eventuate in the foetus/neonate , the young actively growing animal and in the adult . In Australasia the ruminant species are most at risk. 

What happens in the foetus/neonate and young growing animal?

Copper deficiency during pregnancy can result in the birth of offspring with congenital disease of the nervous system. This situation is most common in lambs. In addition neonatal lambs, apparently normal at birth, often express neurologic disease at any time between 1 week and several months of age. This delayed effect is still an expression of the copper-deficient state of the dam. In goat kids and piglets, such delayed disease is well documented, but congenital disease is rare. The terms swayback and enzootic ataxia are frequently used in reference to these diseases. Young animals may also suffer osteoporosis (bone fragility) and anaemia.

Basic cellular disturbance

 

 
 
 

1) There are a number of severe effects on nerve cells and myelin, in which destructive changes range from degeneration of neurons and axons within intact supporting tissues, to wholesale loss of all nervous tissue components, with resulting cavitation (in lambs) of some areas of cerebral white matter. Neural degeneration may extend widely throughout the brain, spinal cord and peripheral nerves. The fundamental biochemical defects remain undefined, but it is suspected that the role of Cu2+ as a component of the enzymes superoxide dismutase and cytochrome oxidase may be significant.

 

 

2) Defective crosslinking of collagen and elastin is the result of the role of Cu2+ in the activity of the enzyme lysyl oxidase. This may be the basis of is reduced production of osteoid in growing bones. 

3) Defective production of red blood cells by the bone marrow. The basic cause remains undefined.

Pathologic consequences

1) In congenital disease, affected lambs often have gelatinous softening and/or cavitation in the white matter of the cerebral hemispheres (JKP Fig. 3.72).

In addition they have the changes described below for the delayed disease 

2) In the delayed disease there are no macroscopically visible changes, but the microscope reveals swollen and dying nerve cells in many parts of the brain and spinal cord (JKP Fig. 3.16), together with disintegrating myelinated axons in parts of the brain and cord (JKP Fig. 3.22A) and in spinal motor nerves (JKP Fig. 3.21). The changes in goat kids and piglets are essentially similar, but with some differences which need not concern us here. 

In the bones, there is production of thin trabeculae, with abnormally fragile and thin metaphyseal and diaphyseal bone. This state is called osteoporosis and can result in bowing of long bones, metaphyseal enlargement, and spontaneous fractures 

In the bone marrow there is ineffective production and output of red blood cells in spite of an increased number (hyperplasia) of precursor cells. Consequentially there will be reduced numbers of circulating erythrocytes, and a reduced concentration of haemoglobin in the blood, producing a state of anaemia.

Functional/clinical effects

1) In regard to nervous disease, congenitally affected animals may be blind and unable to stand In general, affected animals are ataxic (unable to control balance), and have a staggering gait.

 

 

2) In regard to skeletal disease, there may be lameness and deformity. 

3) In regard to bone marrow disease, there will be fatigue, listlessness and pale mucous membranes.

The outcomes of copper deficiency in older and mature animals may reflect the effects on bone and bone marrow, as described above, and can also be manifested by changes in the hair coat. This last-mentioned effect is a consequence of Cu2+ being: 1) an essential component of the enzyme tyrosinase, which is active the the production of melanin and 2) of having a role in the process of keratinization during hair growth.

There is hypopigmentation (deficient melanization) of hair or wool, and a change in the quality of the fiber. 

Thus in affected cattle, normally dark-brown or black hair will become pale, especially around the eyes, producing a spectacled appearance. In black sheep, the wool is characteristially banded , reflecting periods of differing copper status during wool growth. (JKP Fig. 5.24).

Although the oral intake of ionic copper may produce acute severe gastroenteritis, due to directly irritant effects on the mucosa of the alimentary tract, such events are rare, and usually the result of Òmanagement accidentsÓ. By far the commonest problem is the steady accumulation of copper stores in the liver, due either to high dietary levels, or to two associated factors which cause hepatic copper storage. These are, low levels of dietary molybdenum, which results in enhanced absorption of Cu2+ from the gut, and a genetically-based tendency to store copper in the lysosomes of liver cells.

What happens when there is HEPATIC copper storage in sheep?

Basic cellular disturbances

1. A key factor is the ability of the liver to produce new cells by mitosis. Copper is stored, complexed to protein, within the lsyosomes of hepatocytes. When the concentration exceeds about 300 ppm, some damage is done to the storing hepatocytes, and many undergo apoptosis, and release their stored copper.

 

 

If the released copper can be taken up by new cells produced by increased mitosis, the situation can be kept in hand, even when the liver concentration exceeds 1000 ppm. If the mitotic activity cannot supply new cells at a sufficent rate, copper begins to leak into the plasma, and the stage is set for the real disease.

2. Critical elevation of plasma copper places severe oxidative stress on red blood cells, exhausts their antioxidant systems and results in denaturation of globin.

Key Point: If the sheep is concurrently affected by an agent which inhibits mitosis in the liver, the threshold for release of copper into the plasma is greatly reduced. Two common plant-derived toxins which have this effect are the pyrrolizidine alkaloids and the phomopsins.

Pathologic consequences

Denaturation of globin in red blood cells causes massive intravascular haemolysis and acute anaemia. The anaemia causes further anoxic damage to the liver, and its capacity to take up, conjugate and excrete bilirubin is overwhelmed.. A massive load of free haemoglobin and red cell fragments is filtered through the kidneys, which suffer acute tubular injury. There is intense icterus, and dark brown-red discolouration of the kidneys and the urine.

Functional/clinical consequences

Severe anemia, hepatic necrosis and renal damage result in shock, prostration and frequently death, although animals may surive acute haemolytic crises.

What happens when there is HEPATIC copper storage in cattle or pigs?

Key Point: Key Point: In these species, genetic predisposition to store copper on normal intakes is not a problem, so disease is the result of high copper intake.

The hepatic and haematologic outcomes are similar to those in sheep, but there is far less tendency for massive acute haemolysis. Generally the major effect is chronic liver damage, with fibrosis in the portal tracts reflecting continual loss of hepatocytes.

What happens in dogs genetically predisposed to storing copper?

In the Bedlington and West Highland White terrier breeds, susceptibility to copper storage is inherited as an autosomal recessive trait in some breeding lines.

 

 

The disease differs from that in sheep,cattle and pigs, in that haemolysis is never a prominent clinical feature. The dominant change is chronic progressive hepatic atrophy and fibrosis, which at the end-stage results in a small, nodular and tough liver. The affected animals have a chronic wasting disease which reflects the progressive destruction of the liver.
 
 

Betty Walsh (e_walsh@cleo.murdoch.edu.au) 6 October 1995

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