Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

III. Copper
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pigs, deer, camels, and rats. Originally described in lambs,
the disorder, which is often referred to as enzootic ataxia
or swayback, is characterized by spastic paralysis, especially
of the hind limbs, severe in coordination of movement,
blindness in some cases, and anemia. The brains of
affected animals are smaller than normal with collapsed
cerebral hemispheres and shallow convolutions and are
characterized by a paucity of myelin. It has been suggested
that the neural lesions associated with enzootic ataxia are
in part the result of a Cu deficiency-induced reduction
in brain cytochrome oxidase activity and impairment in
phospholipid synthesis with a subsequent block in myelin
synthesis. Motor incoordination and tremors have been
ascribed to the effects of perinatal Cu deficiency on brain
catecholamine metabolism. Norepinephrine levels are
decreased in the whole brain and brainstem. The reduction
in norepinephrine levels is most likely due to a decreased
activity of dopamine beta-hydroxylase (monooxygenase),
which catalyzes the hydroxylation of dopamine to norepinephrine
(Engel et al. , 2000; Gambling and McArdle,
2004 ; Gooneratne et al. , 1989 ; Keen et al. , 1998 ).
Additional consequences of Cu deficiency, particularly
during early development, are alterations in the immune
system and systemic metabolism. Regarding immune function,
effects of Cu deficiency include impaired neutrophil
function, increased susceptibility to bacterial infections,
decreased resistance to tumor challenge, reduced cellmediated
and humoral immunity, and alterations in lymphocyte
subpopulations. Arthur and Boyne ( Arthur and
Boyne 1985 ; Boyne and Arthur, 1986 , 1990) reported that
the loss of neutrophil microbicidal activity associated with
Cu deficiency in cattle is secondary to a failure to produce
superoxide within the neutrophil phagosome. A primary
biochemical defect can also be a reduction in lymphopoiesis
secondary to a decrease in erythropoiesis. Cu deficiency
also reduces splenocyte production of interleukin-1 and
T cell replacing factor. Thus, it is possible that some of the
immune defects observed in Cu-deficient animals are the
result of reductions in hormonal signals ( Arthur and Boyne,
1985 ; Boyne and Arthur, 1986 , 1998; Gooneratne et al. ,
1989 ; Keen et al. , 1998 ; Milanino and Buchner, 2006 ).
Regarding metabolism, abnormal pancreatic function is
associated with marginal Cu deficiency.
Histological lesions suggest that the basic biochemical
defect is one of excessive membrane lipid peroxidation
or serum protease infiltration ( Tosh et al. , 2007 ). Altered
insulin secretion and glucose regulation can also be
disturbed.
4 . Cu Excesses
Acute Cu toxicity is rarely a serious problem in domestic
animals, probably because of the strong emetic effect of
the element. In contrast, chronic Cu toxicosis is a frequent
occurrence in some species, particularly sheep . In sheep,
there are two phases associated with Cu toxicosis. In the
first phase, there is a gradual accumulation of Cu in tissues
and a rise in serum aspartate aminotransferase, lactate
dehydrogenase, sorbitol dehydrogenase, arginase, and
glutamic dehydrogenase. As liver Cu accumulates, there is
swelling and necrosis of the hepatic parenchymal cells and
Kupffer cells resulting in a focal necrosis of liver tissue.
The primary biochemical lesion arising from Cu toxicosis
is thought to be Cu-initiated free radical damage. The
hemolysis can also occur with Cu toxicity and is thought
to be a result of changes within the erythrocyte rather than
a direct effect of Cu on the erythrocyte membrane. During
the hemolytic crisis, sheep have swollen, partially cirrhotic
livers and dark, hemoglobin stained kidneys. Renal and
hepatic tissues from Cu intoxicated sheep with hemolytic
crises have cytoplasmic lipofuscin granules in the renal
tubular epithelium and hepatic parenchyma, suggesting
lysosomal rupture. Additional pathology can occur in the
white matter of the cerebrum, pons, and cerebellum.
Liver Cu has also been shown to be markedly elevated
in animal models for diabetes, but it is not clear if similar
increases occur in spontaneous diabetes or whether the
increased liver Cu represents increased risk of liver disease.
Kidney Cu concentrations can also be markedly increased
with diabetes. However, similar to other metabolic and
inflammatory-induced elevations in hepatic Cu levels, it is
not known if the diabetes-associated changes in renal Cu
represent a threat (Keen and Uriu-Adams, 2005) .
5 . Cu-Related Genetic Models and Other Conditions
(e.g., Prions)
Genetic defects mimicking Cu deficiency have been
reported for humans (Menkes ’ disease) and mice (mottled
mutants). Menkes ’ disease is X-linked and is characterized
by progressive degeneration of the brain and spinal
cord, hypothermia, connective tissue defects, and failure
to thrive ( Keen et al. , 1998 ; Pena et al. , 1999 ; Puig and
Thiele, 2002 ; Stern et al. , 2007 ; Thiele, 2003 ). Death often
occurs before 3 years of age. The mottled mutants have
been developed as animal models for Menkes ’ disease. It is
now appreciated that the major defect is gene deletions and
transpositions associated with Cu-ATPase-7 A. There is a
lack of normal cupper egress from cells. Cu is not directed
to lysyl oxidase and some cases other proteins (dopamine
beta-monooxygenase, peptidylglycine a-amidating monooxygenase,
or tyrosinase depending on the cell type). Thus,
lesions arise associated with defects in collagen and elastin
metabolism and Cu catalyzed oxidative damage.
Similarly, genetic defects mimicking Cu toxicity
have been reported in humans (Wilson’s disease) as well
(Theile, 2003). Wilson’s disease is an autosomal recessive
inherited disorder of Cu metabolism in which there is
a failure to excrete Cu through the biliary system because
of a mutation in the gene coding for an ATPase Cu pump.