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

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Chapter | 22 Trace Minerals
Corresponding defects in the Cu-transporting ATPase,
P-ATPase-7B, in the liver also occur. Recall that this ATPase
directs Cu to plasma ceruloplasmin or to biliary excretion.
Patients with Wilson’s disease frequently present with one
of three major clinical problems, liver disease (liver failure,
hepatitis, or chronic cirrhosis), neurological signs (slurred
speech, difficulty controlling facial muscle, or dystonia),
or psychiatric problems. Unlike Menkes ’ disease, Wilson’s
disease is treatable if diagnosed early with Zn, Cu chelators
(e.g., penicillamine).
A proposed analogue of this disorder in animals is
Cu toxicosis in Bedlington terriers, which affects up to
60% of the breed ( Haywood, 2006 ). Dogs homozygous
for the gene are characterized by extremely high liver Cu
concentrations often exceeding 500 micrograms/g (7.87
micromol/g) compared to controls of less than 75 micrograms/g
(1.180 micromol/g). The associated hepatic injury
is thought to be due to a Cu-initiated, free radical damage
and lysosomal rupture. Several other breeds, including
West Highland white terriers, Skye terriers, Dobermans,
Dalmatians, and Keeshounds, have been identified as having
Cu-associated liver disease as well ( Haywood, 2006 ).
The mechanism by which Cu toxicosis occurs in
Bedlington terriers, however, adds another dimension to
Cu regulation and the P-ATPase relationship. Although
eleven polymorphisms, two in the coding region, have
been identified in the Bedlington terrier ATP7B gene,
another gene, COMMD1 (Cu metabolism gene MURR1),
has been identified that seems to function as a Cu chaperone.
COOMD1 belongs to a family of multifunctional
proteins whose functions have been linked to inhibition of
nuclear factor NF-κB to Cu transport (Forman et al. , 2005 ;
Haywood, 2006 ; Spee et al. , 2006) . COMMD1 was implicated
as a regulator of Cu metabolism by its proposed role
in Cu delivery to P-ATPase-7B (see Fig. 22-4 ). Without
P-ATPase-7B or the chaperone, Cu is sequestered in liver
and promotes ROS-related lesions ( Haywood, 2006 ).
With regard to Cu toxicity, chelation therapy can
be effective for the treatment. The chelating drugs with
worldwide application are dimercaprol, succimer, unithiol,
D-penicillamine, N-acetyl-D-penicillamine, calcium
disodium ethylenediaminetetraacetate, calcium trisodium
or zinc trisodium diethylenetriaminepentaacetate, deferiprone,
triethylenetetraamine (trientine), N-acetylcysteine
(NAC), and Prussian blue. Penicillamine and diethylenetriaminepentaacetate
derivatives are often used first when
there are clear indications that an excess of Cu is the problem.
Monitoring Cu status, however, is important with the
use of any chelating agent or dietary approach (increasing
the Zn intake) to diminish the prospects of a secondary Cu
deficiency (Seguin and Bundy, 2001; Willis et al. , 2005 ).
As a final comment, transmissible spongiform encephalopathies
(TSEs) are a family of neurodegenerative diseases
characterized by their long incubation periods, progressive
neurological changes, and spongiform appearance in
the brain. There is now evidence that TSEs are caused by
an isoform of the normal cellular surface prion protein
PrPC. The normal function of PrPC is still unknown, but
it exhibits properties of a cuproprotein, capable of binding
Cu ions.
There are two differing views on Cu’s role in prion diseases.
Whereas one view looks at the PrPC Cu binding as
the trigger for conversion to PrPSc, the opposing viewpoint
sees a lack of PrPC Cu binding resulting in the conformational
change into the disease-causing isoform. Manganese
and Zn have also been shown to interact with PrPC ( Leach
et al. , 2006 ).
E . Evaluation of Cu Status
Measurement of plasma/serum Cu concentrations can be
useful in suspected cases of Cu deficiency as low levels
are diagnostic. Similarly, measurement of plasma/serum
ceruloplasmin levels in suspected cases of deficiency can
be useful, as 90% of the Cu present in plasma/serum is
associated with this protein. Another possibility is the
analysis of diamine oxidase ( Legleiter and Spears, 2007 ).
However, it should be noted that because synthesis of ceruloplasmin
(an acute phase protein) can increase in acute
or chronic infections; thus, a normal or elevated plasma or
serum ceruloplasmin level does not rule out a deficiency.
Increased synthesis of ceruloplasmin is thought to be in
part mediated by a leukocyte endogenous mediator, and
excessive production of ceruloplasmin is a consequence of
a number of diseases that can result in marked redistribution
of hepatocyte Cu pools into plasma. Elevated plasma or
serum Cu concentrations have been reported to occur as a
result of excessive Cu feeding in rats, sheep, and pigs,
however, given that high plasma/serum Cu levels can also
reflect a number of stress syndromes, a finding of high
whole blood or plasma Cu levels should not be the sole criterion
for diagnosis of Cu toxicosis ( Stern et al. , 2007 ).
In sheep and cattle, Cu concentrations below 0.5 μ g/
ml are considered diagnostic for Cu deficiency. Although
measurement of whole blood Cu has been widely used
in diagnosing Cu deficiency, it is currently thought that
measurement of erythrocyte CuZnSOD is preferable as
it better reflects the functional Cu status of the animal.
Complementary measurements of Cu chaperones, such as
CCS, may also be eventually used for assessment ( Keen
and Uriu-Adams, 2006 ).
Liver Cu concentrations have been used as an indicator
of Cu status in animals. The effect of low Cu diets on liver
Cu levels can be dramatic. Ataxic lambs suffering from Cu
deficiency can have levels below 5 μ g/g (0.079 μ mol/g)
compared to control levels of 25 to 75 μ g/g (0.394 to
1.181 μ mol/g). Similarly, high levels of dietary Cu elevate
hepatic Cu content. Levels in excess of 500 μ g/g
(7.87 μ mol/g) in adult sheep have been reported.