Inherited copper toxicosis with emphasis on copper toxicosis in Bedlington terriers


Hyun, C.; Filippich, L.J.

Journal of Experimental Animal Science 43(1): 39-64

2004


Canine copper toxicosis is an important inherited disease in Bedlington terriers, because of its high prevalence rate and similarity to human copper storage disease. It can lead to chronic liver disease and occasional haemolytic anaemia due to impaired copper excretion. The responsible gene for copper toxicosis in Bedlington terriers has been recently identified and was found not to be related to human Wilson's disease gene ATP7B. Although our understanding of copper metabolism in mammals has improved through genetic molecular technology, the diversity of gene mutation related to copper metabolism in animals will help identify the responsible genes for non-Wilsonian copper toxicoses in human. This review paper discusses our knowledge of normal copper metabolism and the pathogenesis, molecular genetics and current research into copper toxicosis in Bedlington terriers, other animals and humans.

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43
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39-64
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Inherited
copper
toxicosis
with
emphasis
on
copper
toxicosis
in
Bedlington
terriers
Changbaig
Hyun
l
,
Lucio
J.
Filippich*
Companion
Animal
Sciences,
School
of
Veterinary
Science,
The
University
of
Queensland,
Brisbane
QLD
4072,
Australia
Abstract
Canine
copper
toxicosis
is
an
important
inherited
disease
in
Bedlington
terriers,
because
of
its
high
prevalence
rate
and
similarity
to
human
copper
storage
disease.
It
can
lead
to
chronic
liver
disease
and
occasional
haemolytic
anaemia
due
to
impaired
copper
excretion.
The
responsible
gene
for
copper
toxicosis
in
Bedlington
terriers
has
been
recently
identified
and
was
found
not
to
be
related
to
human
Wilson's
disease
gene
ATP7B.
Although
our
understanding
of
copper
metabolism
in
mammals
has
improved
through
genetic
molecular
technology,
the
diversity
of
gene
mutation
related
to
copper
metabolism
in
animals
will
help
identify
the
responsible
genes
for
non-Wilsonian
copper
toxicoses
in
human.
This
review
paper
discusses
our
knowledge
of
normal
copper
metabolism
and
the
pathogenesis,
molecular
genetics
and
current
research
into
copper
toxicosis
in
Bedlington
terriers,
other
animals
and
humans.
©
2004
Elsevier
GmbH.
All
rights
reserved.
Abbreviations:
ALT,
Alanine
transaminase;
ATOX],
Copper
chaperone
delivering
copper
to
ATP7B;
ATP6H,
Human
vacuolar
proton-ATPase;
ATP7B,
P
-type
ATPase
gene;
BAC,
Bacterial
artificial
chromosome;
CO,
Cytochrome
oxidase;
Cox,
Cytochrome
c
oxidase;
CP,
Ceruloplasmin
gene;
CT
-BT,
Canine
copper
toxicosis
in
Bedlington
terrier
dogs;
DBH,
Dopamine
/3-hydroxylase;
ESD,
Esterase
D;
EST,
Expressed
sequence
tag;
ETIC,
Endemic
Tyrolean
infantile
cirrhosis;
FISH,
Fluorescence
in
situ
hybridisation;
ICC,
Indian
childhood
cirrhosis;
ICT,
Idiopathic
copper
toxicosis;
LEC
rat,
Long
-Evans
Cinnamon
rat;
LO,
Lysyl
oxidase;
LOR2,
Lysyl
oxidase-related
protein
2;
MKD,
Menke's
disease
(syndrome);
MREs,
5'
metal
regulatory
elements;
MT,
Metallothionein;
MURRJ,
Neomorphic
imprinted
gene;
RB,
Retinoblastoma;
RT-PCR,
Reverse
transcription
-polymerise
chain
reaction;
TBARS,
thiobarbituric
acid
-reacting
substances;
TO,
Tyrosinase;
Tx
mice,
Toxic
milk
mice
*Corresponding
author.
Tel.:
+
61-412-818-919;
fax:
+
61-7-3365-1255.
E-mail
address:
l.filippich@uq.edu.au
(L.J.
Filippich).
I
Current
address:
Victor
Chang
Cardiac
Research
Institute,
384
Victoria
St.
Darlinghurst,
Sydney,
Australia.
0939-8600/$
-
see
front
matter
(j)
2004
Elsevier
GmbH.
All
rights
reserved.
doi:10.1016/j.jeas.2004.01.003
40
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
Keywords:
Canine
copper
toxicosis;
Bedlington
terriers;
Copper
metabolism;
Wilson's
disease;
ATP7B;
Autosomal
recessive
inheritance;
CFA10q26;
MURR1
Introduction
The
role
of
copper
in
normal
metabolism
is
essential
as
it
is
involved
in
several
important
body
processes,
such
as
growth,
normal
host
defence
mechanisms,
bone
strength,
red
and
white
blood
cell
maturation,
iron
transport,
cholesterol
and
glucose
metabolism,
myocardial
contractility
and
brain
development
(Olivares
and
Uauy,
1996).
However,
copper
accumulation
can
cause
severe
damage
mainly
to
the
liver
and
erythrocytes
(Rolfe
and
Twedt,
1995)
and
less
severely
to
the
heart
and
brain
(Strausak
et
al.,
2001).
Such
toxicity
has
been
reported
in
dogs
due
to
acute
poisoning,
genetic
derangement
of
copper
metabolism
or
secondary
impairment
associated
with
chronic
hepatobiliary
disease.
Copper
toxicosis
in
certain
dog
breeds,
especially
Bedlington
terriers,
is
of
interest
to
many
researchers
because
of
its
unique
pathogenesis
and
many
similarities
to
human
copper
storage
diseases
such
as
WD
(Su
et
al.,
1982a)
and
non-Wilsonian
copper
toxicoses
including.
ICT,
ICC
and
ETIC
(Aikat
et
al.,
1974;
Maggiore
et
al.,
1987;
Muller
et
al.,
1996;
Scheinberg
and
Gitlin,
1952).
On
the
other
hand,
copper
deficiency
can
be
caused
by
inherited
diseases
such
as
MKD,
aceruloplasminemia
in
human
or
acquired
conditions
such
as
malnutrition.
This
review
discusses
the
current
views
on
normal
copper
metabolism
and
the
pathogenesis
related
to
primary
toxicoses
and
molecular
genetic
of
copper
toxicosis
in
Bedlington
terriers,
other
animals
and
humans.
Normal
copper
metabolism
Copper
is
absorbed
to
some
extent
via
the
stomach,
but
the
major
site
of
absorption
is
the
duodenum
(Van
Campen
et
al.,
1965;
Wapnir,
1998).
An
outline
of
normal
copper
metabolism
in
mammals
is
illustrated
in
Fig.
1.
Some
absorbed
copper
is
retained
in
the
enterocytes
by
binding
to
a
specific
metal
-binding
protein
(e.g.,
MT)
and
later
lost
in
the
faeces
by
desquamation,
while
the
remaining
copper
is
transported
primarily
by
plasma
protein
carriers,
such
as
transcuprein
and
albumin
to
the
liver
(via
enterohepatic
circulation)
and
some
to
the
kidneys
(via
systemic
circulation).
On
entry
into
the
liver
and
kidney,
newly
absorbed
copper
is
incorporated
into
several
endogenous
copper
enzymes
(Table
1)
and,
copper
-
requiring
proteins
(ceruloplasmin
and
MT).
In
the
dog,
although
the
relative
amount
of
the
ceruloplasmin
pool
to
total
copper
is
similar
to
that
in
humans
and
rats,
the
absolute
amount
is
much
smaller
due
to
serum
copper
in
dogs
being
associated
with
the
transcuprein
fraction
(
>
50%),
rather
than
the
albumin
fraction
(<8%;
Table
2).
This
is
due
to
canine
albumin
having
a
much
lower
affinity
for
copper,
as
it
lacks
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
41
Erythrocyte
(SOD)
Export
Storage
*Brain
(DBH)
eruloplasmin
Connective
tissue
(LO)
IR
±
Muscle
(CO,
SOD)
Excretion
Kidney
*
Blood
Transcuprin
+
Copper
Albumin
+
Copper
►Intestine
Dietary
copper
* *
Urine
Faeces
Fig.
1.
Diagrammatic
representation
of
normal
copper
metabolism.
Copper
is
absorbed
to
some
extent
via
the
stomach,
but
the
major
site
of
absorption
is
the
duodenum.
Some
of
this
copper
is
retained
in
the
enterocytes
and
later
lost
in
the
faeces
by
desquamation,
while
the
remaining
copper
is
transported
mainly
by
plasma
protein
carriers
such
as
transcuprein
and
albumin
to
the
liver
(via
enterohepatic
circulation)
and
some
to
the
kidneys
(via
systemic
circulation).
On
entry
into
the
liver
and
kidney,
newly
absorbed
copper
is
incorporated
into
several
endogenous
copper
enzymes
and,
copper
-requiring
proteins
(ceruloplasmin
and
MT).
The
excess
copper
is
eliminated
mainly
by
biliary
excretion
and
partly
by
urinary
excretion.
Copper
(blue;
non
-
incorporated,
green;
incorporated).
SOD,
superoxide
dismutase;
DBH,
dopamine
fl
-hydro-
xylase;
LO,
lysyl
oxidase;
MT,
metallothionein;
GB,
gall
bladder;
CO,
cytochrome
oxidase.
Table
1.
Absolute
copper
concentration
in
mammalian
serum
(Based
on
Montaser
et
al.,
1992)
Fraction
Unit
Dog
Rat
Human
Average
total
copper
ng/ml
322
976
1030
Non-
exchangeable
Ceruloplasmin
ng/ml
135-180
644
600
Exchangeable
Transcuprein
ng/ml
160-200
176
120
Albumin
ng/ml
29
146
170
Low
molecular
wt
ng/ml
6
10
110
histidine
as
the
third
residue
from
the
N
terminus
(Montaser
et
al.,
1992).
Copper
may
be
bound
to
lysosomal
MT
in
the
hepatocytes
and
stored
in
the
liver
or
transported
to
other
tissues
via
the
plasma
carrier
protein,
ceruloplasmin
42
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
Table
2.
The
source
of
copper
binding
proteins
(based
on
Linder,
1991)
Location/tissues
abundant
Albumin
Extracellular/plasma
Transcuprein
Extracellular/plasma
Ceruloplasmin
Extracellular/liver
Metallothionein
Intracellular/intestine,
liver
Superoxide
Extracellular/intracellular;
liver,
kidney,
blood
cells
dismutase
Cytochrome
c
Intracellular/muscle,
liver
oxidase
Lysyl
oxidase
Extracellular/connective
tissues
Tyrosinase
Intracellular/melanin
containing
tissues
Dopamine
fl
-
Intracellular/locus
ceruleus,
brain
stem,
posterior
monooxygenase
Hypothalamus
Peptidyglycine
Extracellular/hypothalamic
granules
monooxygenase
(Gaitskhoki
et
al.,
1990).
Copper,
bound
to
ceruloplasmin,
is
also
transported
in
other
body
fl
uids
found
in
the
brain,
central
nervous
system
and
amniotic
sac
(Linder
and
Hazegh-Azam,
1996)
and can
reappear
in
the
plasma.
In
mammals,
the
elimination
of
excess
copper
is
achieved
mainly
by
biliary
excretion
(80%)
and
partly
by
urinary
excretion
(less
than
3%)
and
is
responsible
for
maintaining
copper
homeostasis
(Cousins,
1985;
Harris,
1991;
Winge
and
Mehra,
1990),
although
our
understanding
of
the
copper
excretory
pathway
remains
unclear.
The
three
detoxification
mechanisms
for
limiting
heavy
metal
toxicity
in
animals
involve
reducing
metal
uptake,
enhancing
metal
exportation,
and
metal
sequestra-
tion
(Dameron
and
Harrison,
1998).
Metal
uptake
can
be
reduced
by
rendering
the
extracellular
metal
unavailable
for
absorption
by
external
chelation
with
adminis-
tered
polysaccharides,
by
bulk
precipitation
of
the
metal,
or
by
regulating
gene
translation
for
specific
proteins
involved
in
metal
transport.
P
-type
ATPases
limit
intracellular
accumulation
of
heavy
metal,
which
in
WD
and
MKD,
is
defective.
Chelating
and
sequestrating
agents
such
as
metallothioneins
or
phytochelatins
can
chelate
and
sequestrate
intracellular
metals
into
relatively
stable
and
innocuous
complexes,
thus
limiting
the
element's
reactivity,
and
aiding
in
its
storage
and
excretion.
A
possible
copper
detoxification
mechanism
is
described
in
Fig.
2.
Pathogenesis
of
copper
toxicosis
in
animals
Hepatic
copper
accumulation
is
a
major
factor
in
the
pathogenesis
of
copper
toxicosis
(Bremner,
1998).
However,
liver
damage
seems
to
be
initiated
not
by
high
copper
accumulation
but
rather
than
by
altered
distribution
of
copper
within
the
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
43
4111111,
Golgi
apparatus
C
1
1
4
,
(m.
i
41
\
.
I
II.
is
—)•••
1
0
—)0.-
('I.
Hepatocyte
(A)
Promoter
Orb
TIT
C
---
Co
1.yiomme
Cs
___
4
511
Ca
A
pu-nietallaihionein
MT
Rene
Bile
anal
Regulelary
domain
(B)
ATP
7
B
P
-type
ATPese
domain
Bile
estoalkolus
Fig.
2.
Suggestive
copper
detoxification
mechanism
in
mammals.
Synthesis
of
metallothio-
nein,
a
major
copper
binding
proteins
white
circle),
to
form
an
active
transcription
factor
complex
TFC)
which
binds
to
metal
response
elements
MREs)
in
the
promoter
of
metallothionein
gene
to
trigger
the
synthesis
of
apo-metallothionein.
Other
divalent
ions,
such
as
zinc
or
iron,
can
bind
to
form
active
TFCs.
After
binding
with
copper,
the
mature
metallothionein
molecule
is
formed
(A).
P
-type
ATPase
acts
to
pump
copper
from
the
hepatocyte
into
the
bile
(B).
Copper
triggers
P
-type
ATPase
to
initiate
translocation
of
copper.
Copper
initiates
a
quaternary
conformational
change
in
the
regulatory
domain,
forming
a
copper
cluster,
which
allows
access
to
the
phosphorylation
site
and
thus
translocation
into
the
bile.
CP,
ceruloplasmin
gene;
ATP7B,
P
-type
ATPase
gene;
ATOXJ,
copper
chaperone
delivering
copper
to
ATP7B.
Based
on
Dameron
and
Harrison
(1998).
liver.
For
example,
in
WD
the
progression
of
liver
disease
is
more
closely
associated
with
changes
in
the
distribution
of
copper
(Bremner,
1998).
Copper
mainly
accumulates
in
the
cytosol
of
liver
cells,
but
as
cell
copper
content
rises,
the
proportion
of
copper
in
the
nucleus
and
lysosomes
increase.
Lysosomal
copper
accumulation
has
been
reported
in
neonates
(Goldfischer
and
Bernstein,
1969),
Bedlington
terriers
(Johnson
et
al.,
1981),
humans
with
WD
(Goldfischer,
1967)
and
rats
(Haywood
et
al.,
1985).
The
lysosomal
accumulation
is
part
of
the
copper
-induced
autophagy
(part
of
the
detoxification
mechanism
for
copper).
However,
increased
fragility
and
decreased
fl
uidity
of
the
lysosomes
can
occur
due
to
lipid
peroxidation
catalysed
by
copper.
Also
the
proton
ATPase
pump
may
be
affected
due
to
changes
in
fatty
acids
composition
and
increased
membrane
pH,
thus
further
impairing
copper
elimination
(Bremner,
1998;
Myers
et
al.,
1993).
44
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
Unsequestrated
copper
generates
oxygen
radicals
that
result
in
increased
lipid
peroxidation
in
cell
membranes
and
DNA
damage.
Recent
in
vivo
studies
have
shown
that
peroxidation
of
mitochondrial
membrane
lipids
can
occur
with
increased
concentrations
of
conjugated
dienes
and
TBARS
produced
by
copper
overload
(Sokol
et
al.,
1990).
Abnormal
peroxidation
of
mitochondrial
membranes
may
interfere
with
mitochondrial
respiration
resulting
in
hepatocellular
energy
changes,
increased
mitochondrial
leakage
of
calcium
into
cytosol,
or
exposing
the
cell
to
increased
amount
of
superoxide
generated
by
the
disruption
of
normal
electron
fl
ow
(Sokol
et
al.,
1993).
Thus,
abnormal
peroxidation
in
the
mitochondria
due
to
copper
overload
results
in
copper
-induced
liver
damage.
When
DNA
is
exposed
to
copper,
it
forms
adducts
and
produces
chromatic
condensation
(Sagripanti
et
al.,
1991).
Nuclear
copper
accumulation
also
destabilises
DNA
(Bryan
and
Frieden,
1967)
and
inhibits
RNA
polymerase
activity
(Novello
and
Stirpe,
1969).
The
endogenous
DNA
-associated
copper
promotes
the
production
of
hydroxyl
radicals,
which
result
in
strand
breakages
and
base
oxidation
of
DNA
(Milne
et
al.,
1993).
The
cytotoxic
effects
of
copper
have
therefore
been
attributed
to
nuclear
disorganisation,
which
leads
to
apoptosis.
Haemolytic
signs
have
been
reported
in
acute
poisoning
in
sheep
and
in
chronic
case
of
CT
-BT
resulting
from
marked
increases
in
blood
copper
levels
due
to
the
release
of
stored
hepatic
copper
(Ishmael
et
al.,
1971;
Robertson
et
al.,
1983).
Considerable
renal
damage
has
been
reported
in
sheep
due
to
increased
renal
copper
concentrations
resulting
from
renal
tubular
reabsorption
of
circulating
copper
(Bostwick,
1982;
Ishmael
et
al.,
1971).
Copper
toxicosis
in
Bedlington
terrier
Inherited
copper
toxicosis
in
Bedlington
terriers
(CT
-BT)
was
fi
rst
reported
in
the
United
States
of
America
(Hardy
et
al.,
1975)
and
later
reported
in
other
countries
(Johnson
et
al.,
1980;
Eriksson
1983;
Rothuizen,
1983;
Robertson
et
al.,
1983;
Kelly
et
al.,
1984).
Similar
canine
copper
toxicosis
has
also
been
reported
in
Doberman
pinschers
(Johnson
et
al.,
1982),
West
Highland
White
terriers
(Thornburg
and
Crawford,
1986;
Thornburg
et
al.,
1986a),
Skye
terriers
(Haywood
et
al.,
1988),
Dalmatians
(Cooper
et
al.,
1997;
Webb
et
al.,
2002)
and
in
some
mixed
breeds
(Thornburg
et
al.,
1990).
The
importance
of
CT
-BT,
compared
to
other
breeds,
is
due
to
its
high
prevalence
rate
(69%
in
USA,
Twedt
et
al.,
1979;
33.9%
in
the
UK,
Herrtage
et
al.,
1987a),
and
similarities
in
aetiology
and
pathogenesis
to
human
WD.
CT
-BT
is
characterised
as
a
chronic
progressive,
often
fatal
liver
disease
associated
occasionally
with
a
haemolytic
crisis.
It
is
due
to
abnormal
accumulation
of
hepatic
copper
as
a
result
of
genetic
derangement
of
copper
metabolism,
and
has
been
reported
in
the
USA
(Hardy
and
Stevens,
1979),
Finland
(Eriksson,
1983),
Netherlands
(Rothuizen,
1983),
Australia
(Robertson
et
al.,
1983),
United
Kingdom
(Kelly
et
al.,
1984)
and
Germany
(Wilsdorf
et
al.,
1985).
C.
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/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
45
Aetiology
In
Bedlington
terriers,
the
inheritance
pattern
is
an
autosomal
recessive
trait
(Johnson
et
al.,
1980)
while
in
other
breeds;
the
inheritance
pattern
is
unclear.
The
exon
2
deletion
of
MURR1
gene
has
been
found
to
be
responsible
for
CT
-BT
(van
de
Sluis
et
al.,
2002).
Pathogenesis
in
canine
copper
toxicosis
The
pathogeneses
of
canine
copper
toxicosis
is
not
completely
understood
(Hardy,
1989),
because
normal
copper
metabolism
in
mammals
has
not
yet
been
fully
described.
Furthermore,
the
pathogenesis
of
copper
toxicosis,
as
seen
in
Bedlington
terriers
(Herrtage
et
al.,
1987b;
Hultgren
et
al.,
1986;
Johnson
et
al.,
1980;
Su
et
al.,
1982b)
is
believed
to
be
different
from
that
seen
with
secondary
choleostasis
as
reported
in
Doberman
Pinscher
with
chronic
hepatobiliary
diseases
(Thornburg
et
al.,
1984a).
Copper
in
the
liver
is
mainly
bound
to
cytosolic
MT
and
sequestered
in
lysosomes.
Copper
absorption
from
the
gastrointestinal
tract
in
affected
Bedlington
terriers
is
normal,
but
biliary
excretion
of
stored
copper
is
reduced
(Su
et
al.,
1982b)
due
to
an
increased
binding
of
copper
to
MT
(Hunt
et
al.,
1986),
arising
from
a
change
either
in
the
structure
of
MT
or
in
the
regulation
of
its
synthesis
(Hultgren
et
al.,
1986).
This
accumulated
copper
is
initially
sequestered
in
lysosomes,
probably
as
a
MT
polymer,
with
minimal
cytoplasmic
and
functional
changes
until
hepatic
copper
concentrations
exceed
2000
ug/g
(Ludwig
et
al.,
1980;
Twedt
et
al.,
1979).
Copper
induced
liver
injury
is
directly
related
to
the
progressive
accumulation
of
copper
within
hepatic
lysosomes
(Haywood
et
al.,
1996).
With
increasing
concentrations
of
hepatic
copper,
copper
storage
in
lysosomes
become
saturated
and
copper
starts
to
be
accumulated
in
the
nucleus
resulting
in
nuclear
injury
brought
about
by
the
production
of
hydroxyl
radicals
through
a
redox
mechanism.
It
is
hypothesised
that
nuclear
damage
stabilises
p53
protein
and
the
accumulated
p53
protein
binds
to
DNA,
triggering
apoptosis.
When
the
liver
copper
content
exceeded
7,000
µg/g,
profound
structural
alterations
including
cytoplasmic
and
nuclear
contraction,
mitochondrial
changes
and
condensation
of
nuclear
chromatin
are
observed
in
the
hepatocyte
(Haywood
et
al.,
1996).
Haemolytic
anaemia
has
been
reported
in
copper
toxicity
in
Bedlington
terriers,
in
other
breeds
and
in
human
WD
(Hill,
1977;
Hardy
and
Stevens,
1978;
Blood
et
al.,
1979;
Twedt
et
al.,
1979).
In
affected
Bedlington
terriers,
a
haemolytic
crisis
is
uncommon
(Hardy
and
Stevens,
1979;
Twedt
et
al.,
1979)
and
is
more
often
a
terminal
event
(Su
et
al.,
1982a;
Hardy,
1984).
Its
occurrence
is
thought
to
be
triggered
by
either
intrahepatic
redistribution
of
copper
or
acute
massive
hepatocellular
necrosis,
releasing
a
large
quantity
of
intracellular
copper
into
the
circulation.
The
released
copper
damages
red
blood
cell
membranes
and
results
in
intravascular
haemolysis
(Hardy
et
al.,
1975;
Hardy
and
Stevens,
1979;
Asano
et
al,
1983;
Robertson
et
al.,
1983).
In
one
affected
Bedlington
terrier
with
haemolytic
anaemia,
plasma
ALT
activity
was
normal
when
measured
2
days
after
the
onset
of
46
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
haemoglobinuria
(Watson
et
al.,
1983).
Haemolysis
may
contribute
or
account
for
the
jaundice
seen
in
some
dogs
(Robertson
et
al.,
1983)
and
the
increase
in
hepatic
haemosiderin
deposition
in
affected
Bedlington
terriers
(Ludwig
et
al.,
1980).
Clinical
signs
The
clinical
signs
are
highly
variable
in
CT
-BT
and
mainly
involve
hepatic
involvement
and
haemolytic
signs
(Twedt
et
al.,
1979).
Ascites
may
be
the
fi
rst
clinical
manifestation
in
some
cases
(Thornburg
et
al.,
1984b,
1985a).
Other
nonspecific
signs
reported
include
polyuria/polydipsia
due
to
acute
renal
tubular
necrosis
(Thornburg
et
al.,
1984b),
coagulopathy
related
signs
such
as
petechial
and
ecchymotic
haemorrhage,
melena,
epistaxis
and
haematemesis
(Kelly
et
al.,
1984).
Since
there
is
no
correlation
between
the
onset
of
clinical
signs
and
hepatic
copper
concentration
(Herrtage
et
al.,
1987a),
affected
dogs
may
be
asymptomatic,
present
with
acute
signs
of
liver
failure
or
with
signs
of
end
stage
chronic
liver
disease
(Hardy,
1989).
Affected
dogs
have
been
divided
into
three
groups,
based
on
the
age
of
onset
and
clinical
signs
(Table
3;
Hardy
and
Stevens,
1978;
Twedt
et
al.,
1979).
Diagnosis
Detailed
history
taking
may
reveal
some
recent
stressful
event
or
the
presence
of
this
inherited
disease
in
family
members.
Clinical
signs
may
be
nonspecific.
Definitive
diagnosis
of
CT
-BT
should
be
made
using
diagnostic
tests
such
as
haematology,
biochemistry,
urinalysis,
blood
and
liver
copper
measurements,
liver
biopsy
in
concordance
with
molecular
detection
of
mutation
in
CT
-BT
gene
(Hardy
et
al.,
Table
3.
Categorization
of
copper
toxicosis
in
Bedlington
terriers
based
on
history
and
clinical
signs
Group
1
Group
2
Group
3
Age
of
Mainly
young
2-6
years
Middle
aged
and
older
onset
Onset
Asymptomatic
Acute
Chronic,
progressive
Clinical
Normal
Nonspecific
clinical
Similar
to
Group
1
but
less
signs
biochemistry
in
1/3
signs
severe.
Cirrhotic,
contracted
of
affected
dogs
liver.
Hepatic
encephalohepatopathy
Subclinical
Jaundice
and
intravascular
hepatomegaly
haemolytic
anaemia
May
die
within
2-3
days
after
acute
haemolytic
attack
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
47
1975;
Herrtage
et
al.,
1987b;
Yuzbasiyan-Gurkan
et
al.,
1997;
Hyun,
1998,
Hyun
et
al.,
2003a).
Haematology,
biochemistry
and
urinalysis
Routine
haematology
is
usually
normal
in
affected
Bedlington
terriers
(Hardy
et
al.,
1975;
Herrtage
et
al.,
1987b;
Hyun,
1998),
although
a
mild
anaemia
may
be
seen.
Dogs
suffering
a
haemolytic
crisis
may
show
anaemia,
bilirubinaemia,
haemoglobinaemia,
haemoglobinuria,
methaemoglobinaemia
and
polychromasia
(Hardy
et
al.,
1975;
Watson
et
al.,
1983).
Plasma
coagulation
factors
are
usually
not
depressed,
unless
chronic
hepatic
failure
is
present
(Owen
et
al.,
1980).
Liver
enzyme
profiles
varies
depending
on
the
stage
of
the
disease
(Hardy
and
Stevens,
1978).
Plasma
ALT
activity
is
most
reliable
(Hardy,
1984),
even
though
only
about
40%
of
asymptomatic
affected
dogs
have
elevated
ALT
activity
(34%:
Hardy
and
Stevens,
1978;
45%:
Twedt
et
al.,
1979),
and
it
can
return
to
normal
despite
evidence
of
hepatic
injury
(Robertson
et
al.,
1983).
Nevertheless,
ALT
activity
is
more
likely
to
increase
with
age
and
increased
severity
(Twedt
et
al.,
1979).
Increased
AP
activity,
low
plasma
albumin
levels
and
increased
bromosulphophalein
clearance
may
be
seen
in
affected
dogs
but
are
inconsistent
(Hardy
et
al.,
1975;
Herrtage
et
al.,
1987b;
Twedt
et
al.,
1979).
Increased
bilirubin
levels
in
blood
and
urine
may
be
seen
in
dogs
undergoing
a
haemolytic
crisis
(Hardy
et
al.,
1975;
Herrtage
et
al.,
1987b).
In
human
WD,
low
blood
ceruloplasmin
oxidase
activity
is
a
significant
diagnostic
fi
nding.
However,
in
affected
dogs
ceruloplasmin
oxidase
activity
is
normal
or
slightly
increased
because
copper
is
mainly
transported
in
dogs
by
transcuprein
(Su
et
al.,
1982a;
Montaser
et
al.,
1992).
Urinalysis
is
normal,
unless
a
haemolytic
crisis
or
severe
liver
disease
is
present.
Hepatic
and
urine
copper
levels
Unlike
human
WD,
blood
copper
levels
in
CT
-BT
have
been
shown
to
vary
(Hardy
et
al.,
1975;
Robertson
et
al.,
1983;
Su
et
al,
1982a;
Twedt
et
al.,
1979)
and
can
increase
steeply
(Hyun,
1998).
However,
their
usefulness
as
an
indicator
of
this
disease
are
limited
(Robertson
et
al.,
1983;
Twedt
et
al.,
1979).
Measurement
of
hepatic
copper
is
highly
informative
and
was
widely
used
for
screening
before
the
microsatellite
marker
test
was
developed
(Hardy
and
Stevens,
1978).
In
normal
Bedlington
terriers,
hepatic
copper
content
(206±
56
ug/g
DW;
range
102-358;
Sternlieb
et
al.,
1977;
Twedt
et
al.,
1979)
was
found
to
be
usually
higher
than
in
other
breeds.
In
CT
-BT,
copper
accumulation
may
exceed
50
times
the
normal
hepatic
copper
content
(average
in
affected
population:
6618
ug/g
DW;
range
850-10683:
Hardy,
1984;
Twedt
et
al.,
1979).
Affected
dogs
with
hepatic
copper
levels
of
less
than
2000
ug/g
DW,
showed
no
signs
of
hepatic
disease,
although
hepatocellular
granules
could
be
visible
under
light
microscopy
in
dogs
with
copper
level
greater
than
850
ug/g
DW
(Hardy
et
al.,
1975;
Johnson
et
al.,
1980;
Su
et
al.,
1982a;
Thornburg
et
al.,
1986b;
Twedt
et
al.,
1979).
Su
et
al.
(1982b)
reported
that
urinary
copper
excretion
in
affected
dogs
was
increased
two
to
three
fold
compared
to
normal
dogs.
48
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/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
64-
0
pper
excretion
After
oral
administration,
a
24-h
plasma
64
Cu
level
is
used
diagnostically
in
human
WD.
This
test
is
not
valid
in
CT
-BT,
however,
a
modified
method,
measuring
faecal
64
Cu
levels,
48
h
after
parenteral
administration,
was
found
to
differentiate
between
affected
and
normal
dogs
(Brewer
et
al.,
1992b).
Gross
pathology
Necropsy
fi
ndings
in
CT
-BT
vary
and
are
not
pathognomonic
for
copper
toxicosis.
They
include
normal
liver,
enlarged
molted
liver
with
rounded
edges,
small/cirrhotic
liver
with
a
mixture
of
fi
ne
and
coarse
nodules
up
to
3
cm
in
diameter,
acquired
portocaval
anomalies,
enlargement
of
enteric
lymph
nodes,
splenomegaly
and
renomegaly
(Eriksson,
1983;
Hardy
and
Stevens,
1978;
Herrtage
et
al.,
1987b;
Hultgren
et
al.,
1986;
Kelly
et
al.,
1984;
Twedt
et
al.,
1979).
Histopathology
Liver
biopsy,
despite
its
potential
risks,
was
traditionally
used
as
a
definitive
method
of
diagnosing
CT
-BT
(Hardy
and
Stevens,
1978;
Nguyen,
1986;
Twedt
et
al.,
1979).
A
conventional
wedge
biopsy
or
a
needle
biopsy
technique
was
shown
to
provide
consistent
results
for
screening
CT
-BT
(Johnson
et
al.,
1984;
Teske
et
al.,
1992).
Histopathological
fi
ndings
in
CT
-BT
are
mainly
confined
to
the
liver,
although
liver
pathology
may
not
correlate
with
the
severity
of
clinical
signs
(Herrtage
et
al.,
1987b;
Ludwig
et
al.,
1980)
but
rather
with
the
degree
of
copper
accumulation
and
the
age
of
the
animal
(Haywood
et
al.,
1996;
Hultgren
et
al.,
1986;
Sternlieb,
1981;
Twedt
et
al.,
1979).
Fig.
3
summarises
liver
pathology
into
four
stages
based
on
the
severity
of
the
liver
lesion
and
accumulation
of
pigment
granules
(Hultgren
et
al.,
1986;
Twedt
et
al.,
1979).
Significant
histopathological
changes
other
than
the
liver
have
not
been
reported,
except
in
one
case
where
mild
histopathological
changes
in
the
central
nervous
system
were
seen
without
accompanying
clinical
signs
(Herrtage
et
al.,
1987b).
Histochemistry
Routine
haematoxylin
and
eosin
staining
is
of
limited
value
for
identifying
copper
laden
hepatocytes
(Hultgren
et
al.,
1986;
Irons
et
al.,
1977;
Johnson
et
al.,
1984;
Shikota
et
al.,
1974;
Thornburg
et
al.,
1985b,
1986b).
Rhodamine
stain
gives
good
reproducible
results
with
95%
sensitivity
and
does
not
bind
with
iron
or
zinc
in
tissue
(Irons
et
al.,
1977;
Johnson
et
al.,
1984).
It
can
detect
copper
at
low
concentrations
in
tissue
(from
60
ug/g
DW,
Johnson
et
al.,
1984)
and
can
semi
-quantitatively
estimate
hepatic
copper
levels
(Irons
et
al.,
1977;
Johnson
et
al.,
1984;
Ludwig
et
al.,
1980;
Twedt
et
al.,
1979).
Nevertheless,
rubeanic
acid
stain
has
been
more
often
used
for
copper
detection,
because,
unlike
rhodamine
stain,
it
did
not
fade
with
time
and
had
a
similar
threshold
for
histochemical
demonstration
of
copper
containing
granules
(Hultgren
et
al.,
1986;
Johnson
et
al.,
1984;
Thornburg
et
al.,
1985b).
However,
according
to
Iron
et
al.,
it
was
a
less
predictable
indicator
of
actual
tissue
copper
levels
than
rhodamine
stain
(Irons
et
al.,
1977).
Timm's
silver
sulphide
stain
is
more
sensitive
for
copper
than
rhodamine
and
rubeanic
acid
stains
(Hultgren
et
al.,
1986),
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
49
STAGE
1
Few
periacinar
accumulations
of
copper
-positive
lipofuscin
granules
in
the
hepatocytes
Minimal
haemosiderin
deposits
in
Kupffer
cells
and
macrophages
>
Random,
mild
focal
hepatitis
Occasional
hydropic
change
in
the
hepatocytes
>
More
numerous
and
larger
copper
-positive
lipofuscin
and
haemosiderin
accumulation
>
Mild
fi
brosis
around
the
portal
triad
and
central
lobular
veins
>
Chronic
active
hepatitis
with
focal
and
piecemeal
necrosis,
predominantly
in
the
periportal
areas
>
Occasional
bridging
necrosis
Hydropic
change
and/or
fatty
infiltration
Extensive
periportal
fi
brosis
>
Bile
stasis
and
bile
duct
hyperplasia
Heavy
accumulation
of
copper
positive
lipofuscin
and
haemosiderin
>
Varying
degrees
of
cirrhosis
with
bile
duct
hyperplasia
and
fi
brosis.
Small
to
large
areas
of
focal
necrosis.
>
Hydropic
change
and/or
fatty
infiltration.
Heavy
accumulations
of
copper
positive
lipofuscin
and
haemosiderin.
EXITamedk.illary
haernatopoiesis
OK"
Fig.
3.
Histopathological
changes
in
the
liver
of
Bedlington
terriers
with
copper
toxicosis
(
x
100,
H&E
stain).
50
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
however,
as
it
binds
to
iron,
it
usefulness
in
affected
Bedlington
terriers
was
limited
as
their
liver
tissue
was
usually
positive
for
iron.
Orcein
stain
is
not
recommended
(Johnson
et
al.,
1984;
Shikota
et
al.,
1974).
In
CT
-BT,
haemosiderin
pigmentation,
using
Perl's
stain
has
been
reported
in
the
liver,
spleen
(Ludwig
et
al.,
1980),
bone
marrow
and
lymph
node
(Hultgren
et
al.,
1986),
possibly
due
to
a
defect
in
iron
metabolism
and/or
an
increase
in
erythrocyte
turnover.
If
histology
and
histochemistry
are
equivocal,
a
liver
copper
estimation
is
recommended
(Hardy
and
Stevens,
1978).
Copper
accumulation,
secondary
to
hepatic
disease
(chronic
cholestasis,
chronic
active
hepatitis)
can
be
differentiated
from
CT
-BT,
because
the
copper
levels
recorded
with
secondary
causes
usually
produce
no
clinical
signs
and
minimal
histopathological
changes
(Hyun
and
Filippich,
2002;
Johnson
et
al.,
1982;
Thornburg
et
al.,
1981).
Ultrastructural
studies
Ultrastructural
changes
related
to
copper
concentrations
have
been
well
documented
for
CT
-BT
(Haywood
et
al.,
1996;
Hyun,
1998).
In
affected
dogs,
nuclear
crenation
and
chromatin
clumping
occur
in
moderately
affected
livers
and
extensive
chromatin
condensation
occurs
in
severely
affected
ones.
Affected
mitochondria
may
show
size
variation,
vacuolation
and
loss
of
cristae,
while
ribosome
becomes
swollen
and
vacuolated.
Absence
of
rough
endoplasmic
reticulum
and
increased
lysosomal
numbers
has
been
reported
in
severe
cases.
Haywood
et
al.
(1996)
claim
that
hepatic
copper
accumulation
induces
apoptotic
changes
such
as
nuclear
chromatin
condensation
with
peripheral
aggregation,
cell
shrinkage
with
preservation
of
organelles
(lysosomes,
mitochondria,
smooth
endoplasmic
reticulum),
and
cellular
fragmentation
into
2-
or
3
-membrane
-bound
bodies
(apoptotic
bodies).
The
increased
apoptotic
changes
in
affected
dogs
were
also
reported
in
the
recent
differential
gene
expression
study
(Hyun,
2001;
Hyun
et
al.,
2003b).
Imaging
studies
Radiography
and
ultrasonography
are
of
limited
diagnostic
use
but
may
confirm
microhepatica
and
cirrhosis
(Johnson
and
Sherding,
1994).
Diagnostic
genetic
analysis
A
microsatellite
DNA
marker
closely
linked
to
CT
-BT
gene
has
been
found
and
used
for
screening
for
this
disease
in
Bedlington
terriers
(Holmes
et
al.,
1998;
Hyun
et
al.,
2003a;
Yuzbasiyan-Gurkan
et
al.,
1997).
However,
the
DNA
marker
test
was
unreliable
in
a
certain
cohort,
especially
unrelated
individuals,
due
to
haplotype
diversity
among
the
Bedlington
terrier
population
(Haywood
et
al.,
2001b).
Direct
detection
of
the
exon
2
deletion
on
CT
-BT
gene
is
also
unreliable
in
a
certain
Bedlington
terrier
population,
because
some
affected
dogs
can
have
intact
exon
2
of
CT
-BT
gene
(Coronado
et
al.,
2003).
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
51
Treatment
Therapy
for
CT
-BT
should
be
aimed
at
reducing
copper
intake
and
absorption
from
the
gastrointestinal
tract,
enhancing
copper
excretion
and
supportive
remedies
for
hastening
recovery
and
preventing
further
damage.
Copper
restricted
diets
have
a
minimal
effect
in
lowering
existing
hepatic
copper
levels
in
affected
dogs.
In
dogs,
the
recommended
daily
copper
requirement
is
0.73
mg/100
g
DM
(Bauer,
1997).
The
copper
content
in
the
diet
should
not
exceed
1.2
mg
copper/100
g
(Bauer,
1997).
Homemade
diets
are
recommended
because
the
copper
content
in
most
commercial
diets
is
more
than
0.7
mg/100
g
DM
(Twedt
and
Whitney,
1990).
High
copper
foods
such
as
organ
meats
(liver,
kidney),
seafood
(shellfish,
crustaceans),
legumes,
dried
legumes,
dried
stone
fruit,
cereals,
broad
beans,
mushroom,
chocolates
and
nuts
should
be
excluded
from
the
diet.
Recommended
low
copper
containing
foods
include
fresh
fruit,
vegetables,
most
meats
(beef,
pork,
chicken)
but
not
organ
meats,
eggs,
fi
sh
(not
shellfish
or
crustaceans),
dairy
products,
processed
cereals
(white
rice,
white
fl
our)
and
processed
meat
(salami,
bologna,
hot
dogs).
Copper
-free
vitamin/mineral
supplements
are
recommended
and
dog
treats
containing
copper,
or
tonics
containing
liver
extracts
should
be
avoided.
Drinking
water
should
not
be
delivered
through
copper
pipes
and
copper
-free
distilled
water
is
preferred
(Rolfe
and
Twedt,
1995;
Twedt
and
Whitney,
1990).
The
copper
content
in
several
diets
and
the
recommended
dietary
formulation
for
affected
Bedlington
terriers
has
been
previously
documented
(Hyun,
1998;
Hyun
and
Filippich,
1999).
Oral
zinc
supplements
(zinc
methionine,
zinc
gluconate)
are
useful
in
preventing
copper
absorption
from
the
intestinal
tract,
because
by
enhancing
the
intestinal
MT
expression,
more
copper
is
bound
to
MT,
thus
inhibiting
copper
absorption
(Brewer
et
al.,
1992a;
Fischer
et
al.,
1983;
Menard
et
al.,
1981).
Plasma
zinc
levels
should
be
monitored
to
ensure
that
a
therapeutic
plasma
zinc
concentration
of
0.2
to
0.3
mg/1
is
achieved
and
maintained.
Potential
side
effects
of
zinc
supplementation
include
haemolytic
anaemia
and
gastrointestinal
signs
when
plasma
concentrations
exceed
2
mg/1
(Fischer
et
al.,
1983).
The
copper
chelator,
D-penicillamine
(dimethylcysteine;
D-penamine
125
mg
tablets,
Dista
Product;
Cuprimine)
has
being
used
to
treat
human
WD
and
CT
-
BT
(Table
4).
Three
different
therapeutic
regimens
have
been
documented
for
use
at
different
stages
of
CT
-BT
(Thornburg
et
al.,
1984b).
The
response
to
treatment
is
slow
and
although
pre-existing
pathology
is
not
reversed,
hepatocellular
damage
does
not
appear
to
be
progressive
(Rolfe
and
Twedt,
1995).
Its
usefulness
is
limited
in
severely
ill
dogs
and
those
undergoing
a
haemolytic
crisis
(Hardy
and
Stevens,
1978;
Robertson
et
al.,
1983;
Sternlieb,
1981).
Vitamin
B6
supplementation
is
recommended
to
avoid
potential
side
effect
on
bone
marrow
depression
and
pyridoxine
deficiency
(Takeda
et
al.,
1980).
Newer
copper
chelators,
such
as
tetramine
cupretic
agents,
trientine
dihydrochloride,
tetramine
tetrahydrochloride
have
been
recommended.
They
appear
to
have
a
greater
affinity
for
plasma
copper
than
D-penicillamine,
less
influence
on
zinc
and
iron
concentrations
and
fewer
adverse
side
effects
(Table
4;
Twedt
et
al.,
1988;
Twedt
and
Whitney,
1990).
52
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
Table
4.
Drug
therapy
for
canine
copper
toxicosis
(Hyun,
1998)
Action
Drug
Dosage
Side
effects
Decrease
absorption
Copper
chelation
Zinc
acetate
D
-penicillamine
Trientine
dihydrochloride
Tetramine
tetrahydrochloride
Supportive
Anti-inflammatory
drugs
medications
Vitamin
E
50-200
mg/day
10-15
mg/kg,
bid
10-15
mg/kg,
bid
15
mg/kg
Depending
on
the
drug
400-500
mg/day
Low
palatability,
haemolytic
anaemia,
gastrointestinal
signs
Anorexia,
vomiting.
In
humans,
dermatological
drug
eruption,
reversible
renal
failure,
bone
marrow
suppression
and
pyridoxine
deficiency.
Fewer
side
effects
than
D-penicillamine
No
significant
side
effects
Depending
on
the
drug
used
Delayed
response
to
iron
therapy
Anti-inflammatory
drugs
can
be
used
to
alleviate
clinical
signs
in
animal
with
chronic
hepatitis
(Hardy,
1984).
Vitamin
E
has
been
suggested,
because
of
its
antioxidant
property,
to
protect
further
free
radical
damage
by
copper
(Rolfe
and
Twedt,
1995).
Prevention
and
prognosis
Lifelong
management
and
routine
health
checks
are
essential
in
CT
-BT,
because
it
is
not
a
disorder
that
can
be
cured
by
intense,
short-term
therapy.
Prevention
is
based
on
selecting
against
affected
and
carrier
dogs
in
a
breeding
program.
Prognosis
varies
depending
on
the
severity
of
the
disease.
Mild
to
moderately
affected
dogs
respond
well
to
supportive
care,
while
in
severely
or
chronically
affected
dogs,
the
prognosis
is
poor.
Copper
toxicosis
in
other
dog
breeds
In
Doberman
pinschers,
copper
toxicosis
is
characterised
by
chronic
active
hepatitis
with
hepatocellular
choleostasis
and
increased
hepatic
copper
content.
Female
Doberman
pinschers
appear
more
predisposed
but
there
is
no
evidence
of
X
-linked
inheritance
(L.
Thornburg,
Personal
communication).
The
pathogenesis
is
unclear
as
to
whether
it
is
a
primary
or
secondary
hepatic
copper
accumulation
because
affected
dogs
may
have
normal
hepatic
copper
levels
(Johnson
et
al.,
1982).
Abnormalities
in
laboratory
tests
and
histopathology
are
mainly
related
to
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
53
intrahepatic
cholestasis.
Abnormal
blood
coagulation,
splenomegaly
and
increased
hepatic
iron
concentration
are
further
fi
ndings.
In
Skye
terriers,
the
inheritance
pattern
has
not
been
described,
but
appears
to
be
inherited.
Intracanalicular
cholestasis
with
358-2257
ppm
of
hepatic
copper
has
been
reported
and
the
severity
and
chronicity
of
hepatic
lesions
are
correlated
to
the
hepatic
copper
content
(Haywood
et
al.,
1988).
In
Western
Highland
White
terriers,
the
inheritance
pattern
has
not
been
fully
described,
although
an
autosomal
dominant
trait
has
been
suggested.
Hepatitis,
hepatic
necrosis
and
cirrhosis
are
characteristic
fi
ndings
in
clinically
ill
dogs
(Thornburg
and
Crawford,
1986).
One
study
showed
that
affected
dogs
had
high
hepatic
copper
concentrations,
which
were
not
related
to
age
(Thornburg
and
Crawford,
1986).
However,
copper
related
signs
are
uncommon
in
dogs
with
hepatic
copper
levels
of
less
than
2000
ppm.
In
Dalmatians,
copper
toxicosis
results
from
primary
defects
in
copper
metabolism
rather
than
secondary
choleostasis
(Webb
et
al.,
2002),
although
the
genetic
and
pathological
mechanism
is
still
unclear.
Due
to
similarities
in
histopatholgy
to
copper
toxicosis
in
LEC
rat,
the
possible
of
its
use
as
an
animal
model
for
Wilson's
disease
has
been
suggested
(Fuentealba
and
Aburto,
2003).
Copper
toxicosis
in
human
WD
is
an
autosomal
recessive
inherited
disease
where
copper
accumulates
in
the
liver
due
to
impaired
biliary
copper
excretion
resulting
from
a
mutation
of
the
ATP7B
involved
in
the
P
-type
ATPase
pump
(Tanzi
et
al.,
1993).
Because
CT
-BT
has
many
similarities
to
WD,
it
has
been
of
interest
to
many
veterinary
and
medical
scientists,
as
a
possible
animal
model
for
human
WD
even
though
evidence
suggests
that
the
genes
involved
in
both
diseases
are
not
homologous
(Dagenais
et
al.,
1999;
Van
de
Sluis
et
al.,
1999).
The
similarities
and
differences
between
CT
-BT
and
WD
have
been
reported
(Table
5;
Herrtage
et
al.,
1987b;
Ludwig
et
al.,
1984;
Su
et
al.,
1982a,
b).
ICT
is
a
fatal
and
rapidly
progressive
liver
disease
that
has
been
reported
in
several
countries,
including
Australia
(Table
6;
Gormally
et
al.,
1994;
Lefkowitch
et
al.,
1982;
Muller-Hocker
et
al.,
1988;
Walker
-Smith
and
Bloomfield,
1973).
Diagnosis
is
based
on
high
hepatic
copper
concentrations,
increased
urinary
copper
excretion,
slightly
increased
or
normal
serum
copper
and
ceruloplasmin
concentrations
and
abnormal
liver
enzyme
activity.
A
definitive
diagnosis
requires
liver
histopathology
which
is
characterised
by
marked
panlobular
and
pericellular
fi
brosis
with
mild
inflammation,
ballooning
degeneration
and
Mallory
bodies
(Adamson
et
al.,
1992).
Histochemical
staining
for
copper
reveals
granular
copper
laden
deposits
in
hepatocytes
and
mesenchymal
cells.
(Muller
et
al.,
1998;
Scheinberg
and
Sternlieb,
1996).
Although
dietary
and
environmental
factors
were
originally
implicated
(Tanner,
1998),
recent
studies
strongly
suggest
that
the
disease
be
transmitted
in
an
autosomal-recessive
mode
of
inheritance
(Scheinberg
and
Sternlieb,
1994)
due
to
54
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Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
Table
5.
Similarities
and
difference
between
copper
toxicosis
in
Bedlington
terriers
and
human
Wilson's
disease
Similarities
Differences
An
autosomal
recessive
inheritance
mode
Increased
hepatic
copper
levels
Presence
of
heavy
hepatic
copper
accumulation
without
clinical
signs
Reduced
ability
to
generate
radioisotoped
ceruloplasmin
Increased
hepatic
uptake
of
radioisotoped
copper
Decreased biliary
excretion
of
copper
Development
of
hepatic
necrosis
and
cirrhosis
Increased
renal
excretion
of
copper
Moderate
increase
in
kidney
copper
content
Psychiatric
symptoms,
such
as
personality
change,
aggression
Responds
to
copper chelation
(penicillamine)
therapy
Different
responsible
gene
mutation
(MURR1
in
CT
-BT
but
ATP7B
in
WD)c
Ceruloplasmin
concentrations
are
normal
or
slightly
increased
in
CT
-BT
but
decreased
in
95%
of
WD
Unlike
WD,
copper
induced
neurological
signs
has
not
been
reported
in
CT
-BT
Copper
deposition
in
the
periphery
of
the
cornea
(Kayser
-Fleischer
ring)
is
frequently
found
in
WD
but not
in
CT
-BT
Mallory
bodies
in
hepatocytes
are
commonly
seen
in
WD
but not
in
CT
-BT
Significant
hepatic
haemosiderosis
occurs
in
CT
-BT
but not
in
WD
Initial
hepatic
lesions
in
CT
-BT
are
periacinar
but
no
predilection
site
is
reported
in
WD
in
vitro
haemolysis
has
been
demonstrated
in
CT
-BT
but not
in
WD.
either
a
mutated
gene
involved
in
the
regulation
of
copper
metabolism
or
allelic
variations
within
the
WD
gene
(Pethrukin
and
Gilliam,
1994;
Thomas
et
al.,
1995a,
b).
ICC
is
a
fatal
hepatic
disease
of
uncertain
aetiology
characterised
by
an
insidious
onset
of
non-specific
signs
that
eventually
progress
to
jaundice
(Table
6).
Copper
concentrations
in
the
liver,
serum
and
urine
are
distinctively
elevated
with
hepatic
copper
levels
usually
greater
that
500
ug/g
DW.
The
disorder
is
predominantly
reported
in
young
male
children
in
the
rural
areas
of
India.
A
high
rate
of
parental
consanguinity
in
the
affected
families
has
been
reported
although
copper
contaminated
milk
feeds
have
been
implicated
as
a
possible
cause
of
ICC
(Bhave
et
al.,
1982;
Pandit
and
Bhave,
1983;
Parekh
and
Patel,
1972).
Genetic
studies
have
indicated
that
the
responsible
gene
is
not
at
or
near
the
WD
locus
and
a
possible
candidate
gene,
metallothionein
was
also
not
involved.
However,
the
gene
involved
in
CT
-BT
may
be
a
plausible
candidate
gene
for
ICC
(Tanner,
1998).
ETIC
was
fi
rst
reported
in
rural
area
of
western
Austria
between
1930
and
1960
and
is
another
type
of
non-Wilsonian
hepatic
copper
toxicosis.
It
is
clinically
and
pathologically
indistinguishable
from
ICC
and
is
inherited
as
an
autosomal
recessive
Table
6.
Comparison
of
characteristics
of
Wilson
disease
(WD),
idiopathic
copper
toxicosis
(ICT),
Indian
child
cirrhosis
(ICC),
endemic
Tyrolean
infantile
cirrhosis
(ETIC)
(Pandit
and
Bhave,
1983;
Scheinberg
and
Sternlieb,
1996)
WD
ICT
ICC
EICC
Age
>
5
years
2
months
-10
years
6
months
-5
years
Infant/young
children
Inheritance
Autosomal
recessive
Suspected
autosomal
Possibly
in
siblings
Autosomal
recessive
recessive
Hepatic
copper
µg/g)
250-1500
1000-2000
>
1000
>
1000
Ceruloplasmin
mg/L)
Low
0-200)
Normal
to
slightly
Normal
to
high
Normal
to
high
high
>
200)
>
200)
>
200)
Histopathology
Nuclear
glycogen,
±)
Marked
panlobular
Pericellular
fi
broses,
Indistinguishable
chronic
active
and
pericellular
Hepatocyte
necrosis,
from
ICT
or
ICC
hepatitis,
±)
cirrhosis
fi
brosis,
Ballooning
Hyaline
deposition
degeneration
and
Mallory
bodies
Orcein
staining'
±
-t
-t -t
-t -t -t
-t -t -t
Aetiology
Deranged
copper
High
copper
ingestion
Acute
copper
Copper
contaminated
metabolism
ingestion
milk
a
Orcein
stain
is
a
special
stain
for
copper
laden
prote.
`1.111/CH
/
Journal
of
Experimental
Animal
S
179
-
(17002)
opu
56
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
pattern.
Copper
contaminated
milk
feeds
may
also
contribute
to
disease
outbreaks
(Muller
et
al.,
1996).
Although
it
appears
to
be
an
allelic
variant
of
the
WND
gene,
mutations
on
ATP7B
are
not
responsible
(Wijmenga
et
al.,
1998).
Recently,
Haywood
et
al.
claimed
that
copper
toxicosis
of
North
Ronaldsay
sheep
resembled
ETIC
and
could
be
an
animal
model
for
this
disease
(Haywood
et
al.,
2001a).
The
responsible
gene
for
CT
-BT
may
be
another
possible
candidate
for
EITC
(V.
Yuzbasiyan-Gurkan,
Personal
communication).
Copper
toxicosis
in
other
species
The
LEC
rat
is
an
inbred
mutant
with
abnormal
copper
metabolism
known
to
develop
spontaneous
hepatitis
and
liver
cancer.
This
mutant
strain
of
rat
has
some
similarities
to
WD,
such
as
excessive
hepatic
copper,
reduced
biliary
excretion
of
copper,
and
autosomal
recessive
inheritance
(Masuda
et
al.,
1988;
Yoshida
et
al.,
1987).
Like
WD,
impaired
biliary
copper
excretion
is
the
major
cause
of
hepatotoxicity
(Sugawara
et
al.,
1991a,
b).
Molecular
studies
have
revealed
that
the
copper
transporting
P
-type
ATPase,
ATP7B,
which
is
the
rat
gene
homologous
to
human
ATP7B,
was
found
to
be
defective
in
the
LEC
rat
thus
making
it
a
rodent
model
for
WD.
In
addition,
recent
studies
have
suggested
that
the
ATP7B
protein
is
involved
in
the
intracellular
transport
of
hepatic
copper.
The
absence
or
diminution
of
ATP7B
function
results
in
abnormal
copper
metabolism
in
the
LEC
rat
and
in
patients
with
WD
(Terada
et
al.,
1998).
Tx
mice
are
a
mutant
strain
derived
from inbred
DL
mice
(Rauch,
1983).
Litters
show
evidence
of
copper
deficiency
at
an
early
age,
because
of
copper
deprivation
in
utero
and
the
low
copper
content
of
the
natural
mother's
milk.
However,
copper
accumulates
excessively
in
the
liver
with
age,
resulting
in
enlarged
and
nodular
livers
(Biempica
et
al.,
1988).
Although
the
pathogenesis
of
copper
toxicosis
in
this
mutant
strain
is
uncertain,
it
is
another
important
animal
model
for
human
WD,
because
Teophilos
et
al.
(1996)
identified
a
mutation
affecting
the
eighth
transmembrane
domain
of
the
WD
homologue
in
the
Tx
mouse.
Ovine
copper
toxicosis
was
fi
rst
reported
in
the
1930s
(Olafson,
1930)
and
called
enzootic
jaundice,
toxaemic
jaundice,
and
icterohaemoglobinuria.
It
is
due
to
sheep
grazing
on
copper
rich
pastures
or
on
pastures
with
normal
copper
content
but
deficient
in
molybdenum
(clover,
Trifoliurn
subterrareurn).
It
may
also
occur
due
to
inadequate
synthesis
of
metallothionein
(Bremner,
1987),
and/or
inadequate
biliary
excretion
of
copper.
Sheep,
compared
to
other
species,
are
more
susceptible
to
copper
toxicosis,
and
susceptibility
varies
among
breeds
(Gooneratne
et
al.,
1980;
Maclachlan
and
Johnston,
1982),
as
well
as
with
the
animal's
size
and
age.
Unlike
other
animals,
biliary
excretion
in
sheep
is
reduced
and
so
is
not
responsive
to
dietary
copper
intake.
Therefore,
hepatic
copper
can
easily
accumulate
with
moderate
level
of
dietary
copper
intake
and
produce
severe
clinical
consequences
(Ishmael
et
al.,
1971).
A
possible
candidate
gene,
ATP7B,
was
found
not
to
be
responsible
for
ovine
copper
toxicosis
(Lockhart
et
al.,
2002).
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
57
Copper
toxicosis
of
North
Ronaldsay
sheep
was
recently
reported
and
shown
to
have
an
aetiology
similar
to
ICC,
ICT
and
ETIC
(Haywood
et
al.,
2001a).
Sudden
transfer
from
a
low
copper
environment
to
a
copper
rich
environment
resulted
in
copper
poisoning.
The
pathological
fi
ndings
are
very
similar
to
non
-Wilson
type
copper
toxicosis
(Haywood
et
al.,
2001a).
Primary
hepatic
copper
toxicosis
due
to
reduced
biliary
excretion
has
been
also
reported
in
white
perch
(Morone
americana)
(Bunton
et
al.,
1987)
and
ferret
(Fox
et
al.,
1994).
Genetic
and
molecular
basis
for
copper
toxicity
The
genes
responsible
for
MKD
and
WD
encode
a
highly
homologous
member
of
the
cation
-transport
P
-type
ATPase
family
(Das
et
al.,
1994;
Tanzi
et
al.,
1993)
which
is
highly
conserved
in
many
species.
It
is
these
proteins
that
are
defected
in
copper
toxicosis
in
LEC
rats
and
WD
and
copper
deficiency
in
mottled
mouse
and
MKD
(Levinson
et
al.,
1994;
Mercer
et
al.,
1994;
Yukitoshi
et
al.,
1994).
Although,
a
recent
study
suggests
that
the
P
-type
ATPase
(ATP7B)
is
not
responsible
for
CT
-BT
(Dagenais
et
al.,
1999)
it
may
still
be
worth
investigating
its
role
in
copper
transport
and
metabolism
and
to
compare
it
to
other
species.
Genetic
diseases
of
copper
metabolism
in
human
Recently,
the
causative
genes
of
some
well
known
human
genetic
diseases
related
to
copper
metabolism
have
been
mapped
(Das
et
al.,
1994;
Tanzi
et
al.,
1993).
Although
the
clinical
manifestations
of
WD
(responsible
gene:
ATP7B;
copper
toxicosis)
and
MKD
(responsible
gene:
ATP7A;
copper
deficiency)
are
quite
different,
both
defective
genes
encode
the
family
of
P
-type
ATPases
(Bull
and
Cox,
1994)
and
have
been
mapped
to
HSA13q14.2-
q21
and
Xq13.3-q13.3,
respectively
(Bull
and
Cox,
1994;
Pethrukin
et
al.,
1993;
Tanzi
et
al.,
1993).
The
amino
acid
sequence
found
in
these
genes
have
59%
sequence
identity
with
each
other
and
share
43%
and
33%
identities
with
bacterial
copper
transporter
CopA.
However,
the
expression
of
ATP7B
is
entirely
in
the
liver
while
ATP7A
is
expressed
in
most
body
tissues,
thus
explaining
the
different
clinical
signs
despite
similar
biochemical
defects
in
copper
transport.
MKD
is
a
X
-linked
recessive
disorder,
characterised
by
severe
copper
deficiency
which
is
unresponsive
to
oral
copper
supplementation
due
to
a
genetic
defect
in
P
-type
ATPase
(ATP7A)
(Das
et
al.,
1994;
Kaler
et
al.,
1994).
Genetic
aspect
of
copper
toxicosis
in
Bedlington
terriers
The
inheritance
pattern
of
CT
-BT
is
autosomal
recessive
(Johnson
et
al.,
1980),
similar
to
human
WD
and
copper
toxicosis
in
LEC
rats.
The
fi
rst
molecular
genetic
investigation
in
CT
-BT
was
performed
by
Yuzbasiyan-Gurkan
et
al.
in
1993(Yuz-
basiyan-Gurkan
et
al.,
1997).
In
that
study,
the
linkage
to
ESD
and
RB
genes
which
58
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
are
closely
linked
to
human
WD
gene
was
not
found
(Yuzbasiyan-Gurkan
et
al.,
1997).
Therefore,
unlike
WD,
the
defective
gene
of
CT
-BT
may
not
be
homologous
to
WD
(Frydman
et
al.,
1985;
Yuzbasiyan-Gurkan
et
al.,
1993).
A
linkage
-based
approach
using
canine
DNA
microsatellite
markers
has
been
developed
for
diagnosing
canine
genetic
diseases,
including
CT
-BT
(Joseph
and
Sampson,
1994;
Yuzbasiyan-Gurkan
et
al.,
1993).
Microsatellite
loci
are
char-
acterised
by
the
presence
of
variable
number
of
repeats
of
a
simple
sequence
(simple
sequence
length
polymorphism;
SSLP)
and
are
very
informative
for
screening
genetic
disease
because
they
are
highly
polymorphic
and
evenly
dispersed
throughout
the
whole
genome.
Yuzbasiyan-Gurkan
et
al.
(1997)
found
a
microsatellite
marker,
C04107,
that
was
linked
to
the
copper
toxicosis
gene
in
some
Bedlington
terrier
pedigrees
(LOD
score
of
5.96
at
recombination
fraction
of
zero),
however,
they
were
unable
to
estimate
its
distance
from
the
copper
toxicosis
locus
because
no
recombination
was
observed
in
the
families
studied.
Further
studies
showed
that
they
are
syntenic
and
tightly
linked
because
few
recombinations
have
been
observed
in
hundreds
of
meioses
(Holmes
et
al.,
1998;
Hyun
et
al.,
2003a,
1998;
Rothuizen
et
al.,
1999).
The
microsatellite
marker
is
now
being
used
diagnostically
in
the
USA,
United
Kingdom
and
other
countries
(Rothuizen
et
al.,
1996;
Yuzbasiyan-Gurkan
et
al.,
1997;
Holmes
et
al.,
1998;
Hyun,
1998).
Two
alleles
of
C04107
marker
were
reported.
Homozygotes
for
allele
one
(163
bp
in
USA
and
Netherlands,
159-160
bp
in
Australia
and
UK)
are
regarded
as
clear
for
CT
-BT,
while
homozygotes
for
allele
two
(167
bp
in
USA
and
Netherlands,
163-164
bp
in
Australia
and
UK)
are
regarded
as
being
affected,
based
on
clinical
examination
and
conventional
laboratory
tests.
However,
the
diagnostic
value
of
this
DNA
marker
is
complicated
by
haplotype
diversity
among
the
Bedlington
terrier
population
due
to
recombination
between
the
C04107
marker
and
CT
-BT
gene
(Holmes
et
al.,
1998,
Hyun
et
al.,
2003a,
van
de
Sluis
et
al.,
2003).
Especially
in
unrelated
individuals
without
pedigree
information,
this
marker
is
unable
to
predict
the
disease
status
(Haywood
et
al.,
2001b).
Using
chromosomal
co
-localisation
of
C04107
marker
by
FISH
techniques,
CT
-
BT
locus
was
mapped
to
the
canine
chromosome
regions
CFA10q26
which
is
mapped
is
homologous
to
the
human
chromosome
2p13
-p16
(van
de
Sluis
et
al.,
1999),
although
this
conclusion
was
based
on
C04107
being
closely
linked
to
CT
-BT
gene.
Then,
CT
-BT
gene
was
confined
to
a
42.3
cR
3000
region
(4.6
cm),
between
two
microsatellite
markers
FH2523
and
C10.602
by
homozygosity
mapping
and
radiation
hybrid
mapping
(van
de
Sluis
et
al.,
2000).
Hyun
et
al.
(2003c)
also
confirmed
this
region
by
association
mapping
study
using
evenly
spaced
polymorphic
markers
on
the
chromosome
10.
About
170
ESTs
were
found
in
this
region.
The
responsible
gene
for
CT
-BT
was
recently
identified
by
the
linkage
disequilibrium
mapping
followed
by
positional
cloning
of
the
canine
BAC
clone
in
the
region
of
CFA10q26
(van
de
Sluis
et
al.,
2002).
By
screening
cDNAs
closely
located
to
C04107,
the
responsible
gene
for
CT
-BT
has
been
identified.
The
deletion
of
the
entire
exon
2
of
MURR1
gene
were
observed
in
the
affected
Bedlington
terriers
by
RT-PCR
and
northern
blot
analysis
and
found
to
be
responsible
for
CT
-BT
(van
de
Sluis
et
al.,
2002).
The
Murrl
gene
is
highly
conserved
in
mouse,
C.
Hyun,
L.J.
Filippich
/
Journal
of
Experimental
Animal
Science
43
(2004)
39-64
59
human
and
dogs,
although
its
biological
role
in
copper
metabolism
remains
elusive.
The
possibility
of
an
animal
model
for
non-Wilsonian
human
copper
toxicoses
(e.g.
ICT,
ETIC
and
ICC)
was
also
ruled
out
by
screening
human
Murrl
in
affected
human
patients
(Muller
et
al.,
2003).
Although
the
responsible
gene
was
found,
the
molecular
diagnosis
of
CT
-BT
is
still
problematic,
due
to
an
unexpected
recombination
between
DNA
marker
and
Murr
I
gene.
The
direct
detection
of
the
exon
2
deletion
of
MURR1
is
also
complicated
by
the
discovery
of
a
new
haplotype
which
is
not
linked
with
exon
2
deletion
and
splicing
site
variance
on
exon
2
(Coronado
et
al.,
2003;
Hyun
et
al.,
2003a).
The
ultimate
genetic
screening
of
CT
-BT
should,
therefore
be
based
on
careful
speculation
on
pedigree
and
supported
by
other
type
of
diagnostic
tests,
such
as
liver
biopsy.
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