Inherited copper toxicosis in Bedlington terriers


Robertson, H.M.; Studdert, V.P.; Reuter, R.E.

Australian Veterinary Journal 60(8): 235-238

1983


Chronic hepatitis and increased hepatic copper concentrations, from 1,600 to 6,361 µg/g dry tissue were found in 4 related, Australian-bred Bedlington terriers. Two dogs were asymptomatic and 2 were clinically ill with signs referable to liver dysfunction. Two dogs were treated with d-penicillamine. After one year there was no improvement in the histopathological liver changes in either dog or significant lowering of hepatic copper level in one dog.

11111eI11CU
uuppu
LUAIL.0
I
m
.uutimag tun
IVI
a
H.
M.
ROBERTSONV,
V.
P.
STUDDERT*,
and
R.
E.
REUTERt
School
of
Veterinary
Science,
University
of
Melbourne,
Werribee,
Victoria
3030
SUMMARY:
Chronic
hepatitis
and
increased
hepatic
copper
concentrations,
from
1,600
to
6,361
µg/g
dry
tissue
were
found
in
4
related,
Australian
-bred
Bedlington
terriers.
Two
dogs
were
asymptomatic
and
2
were
clinically
ill
with
signs
referable
to
liver
dysfunction.
Two
dogs
were
treated
with
d-penicillamine.
After
one
year
there
was
no
improvement
in
the
histopathological
liver
changes
in
either
dog
or
significant
lowering
of
hepatic
copper
level
in
one
dog.
Aust.
vet.
✓.
60:
235-238.
Introduction
In
1975
chronic
progressive
hepatitis
associated
with
increased
amounts
of
hepatic
copper
was
described
in
related
Bedlington
terriers
in
the
United
States
(Hardy
et
al
1975)
and
later
was
shown
to
be
due
to
an
inherited
metabolic
defect
in
the
breed
(Johnson
et
al
1980).
There
are
many
similarities
between
the
disease
and
Wilson's
disease
(hepatolenticular
degeneration)
in
man
(Sternlieb
1980).
Both
are
inherited
as
autosomal
recessive
traits,
are
characterised
by
increased
hepatic
copper
concen-
tration
which
precedes
hepatic
injury
and
are
accompanied
by
decreased
biliary
and
increased
urinary
excretion
with
normal
gastrointestinal
absorption
of
copper
(Su
et
al
1982a).
Important
features
of
Wilson's
disease
not
found
in
affected
dogs
are
decreased
►evels
of
serum
or
plasma
copper
and
caeruloplasmin
and
the
various
extrahepatic
signs
related
to
accumulation
of
copper
in
other
sites
which
include
Kayser
-
Fleischer
rings
(copper
deposits
in
the
peripheral
cornea),
neurologic
deficits,
psychiatric
disorders,
kidney
dysfunction
and
arthritis.
Increased
amounts
of
copper
have
been
found
in
the
kidneys
and
brain
of
affected
dogs
(Su
et
al
1982b),
but
clinical
signs
referable
to
these
sites
have
not
been
reported.
Although
there
are
differences
between
these
2
diseases,
important
similarities
make
affected
Bedlington
terriers
useful
animal
models
for
the
study
of
Wilson's
disease
(Owen
and
Ludwig
1982).
Until
now,
there
have
been
no
reports
on
this
disease
occurring
in
Bedlington
terriers
outside
the
United
States
of
America.
Materials
and
Methods
Four
Bedlington
terriers§
that
had
been
bred
and
raised
in
Victoria
were
referred
to
the
University
of
Melbourne
Veterinary
Clinical
Centre.
They
were
fed
mixed
diets
that
included
a
variety
of
commercial
dog
foods,
fresh
meat
and
table
scraps.
Wedge
biopsies
of
liver
were
obtained
from
each
dog
via
laparotomy
and
portions
were
submitted
for
histopathology
and
quantitative
copper
analysis.
Copper
measurements
of
plasma
and
liver
were
made
by
flame
atomic
absorption
spectrometry.
Containers
used
for
tissue
and
blood
were
washed
in
20%
nitric
acid
prior
to
use.
Plasma
caeruloplasmin
levels
were
determined
by
oxidation
of
p-phenylenediamine
(Bingley
and
Dick
1969)
at
pH
6.4.
Haematology,
plasma
biochemistry,
sulfobromphthalein
(BSP)
retention
times
and
urinalyses
were
performed
by
standard
methods.
t
Department
of
Veterinary
Clinical
Sciences
Department
of
Veterinary
Paraclinical
Sciences
Present
address:
School
of
Veterinary
Medicine,
University
of
Pennsylvania,
Philadelphia,
PA
19104,
United
States
of
America
Case
Histories
Case
1:
A
6
-year
-old
bitch
was
presented
with
a
history
of
abdominal
enlargement
for
17
days
and
loose
stools
for
one
week.
There
were
no
other
complaints.
The
dog
previously
had
been
in
good
health
and
was
in
oestrus
2
weeks
before
the
onset
of
signs.
When
examined,
the
dog
was
in
good
body
condition.
Temperature,
pulse
and
respiratory
rates
were
normal.
There
was
marked
distention
of
the
abdomen
with
a
fluid
wave
easily
demonstrated.
Abdominal
palpation
and
radiography
were
restricted
by
the
large
amount
of
fluid
present.
Mam-
mary
enlargement
and
lactation
were
present,
consistent
with
pseudocyesis.
The
only
abnormalities
found
in
the
haemogram,
urinalysis
and
blood
chemistry
were
slight
leucocytosis,
neutrophilia
with
left
shift,
eosinopaenia
and
elevated
plasma
alanine
aminotransferase
(ALT)
and
aspartate
aminotransferase
lev-
els.
The
BSP
retention
time
was
slightly
increased.
Plasma
copper
was
increased
and
caeruloplasmin
was
normal
(Table
1).
Ascitic
fluid
had
properties
of
a
modified
transudate.
It
was
slightly
turbid
and
blood
-tinged
with
a
specific
gravity
of
1.025,
protein
content
of
42
g/L
and
cell
count
of
1,000/mm
3
,
consisting
mainly
of
erythrocytes
with
some
neutrophils,
mesothelial
and
plasma
cells.
Clinical
signs
associated
with
the
original
presentation
did
not
recur
following
the
laparotomy
and
liver
biopsy.
Treat-
ment
was
commenced
with
125
mg
d-penicillamine¶
orally
12
-hourly.
The
dog
remained
asymptomatic
for
the
following
13
months
until
represented
with
a
history
of
lethargy,
anorexia,
polydipsia
and
vomiting
of
3
days
duration.
Oestrus
had
occurred
6
weeks
before.
There
was
a
mucopurulent
vaginal
discharge
and
enlargement
of
the
uterus
seen
in
abdominal
radiographs.
Pyometra
was
diagnosed
and
an
ovariohysterectomy
per-
formed.
With
the
owner's
permission
another
liver
biopsy
was
obtained
in
order
to
assess
treatment
and
progress
of
histopathological
changes.
Case
2:
An
intact
female
littermate
of
Case
1
had
been
clinically
normal,
however
the
owner
requested
investigation
in
view
of
the
inherited
basis
of
the
disease
diagnosed.
The
only
clinical
abnormality
detected
was
a
soft
systolic
murmur
heard
loudest
over
the
mitral
area.
In
a
range
of
examinations
of
blood
and
urine
similar
to
that
described
in
Case
1,
the
only
abnormal
findings
were
elevations
of
plasma
ALT
and
caeruloplasmin
(Table
1).
After
the
liver
biopsy
was
obtained,
this
dog
was
treated
§
Three
of
these
dogs
have
been
recently
described
in
a
talk
(Studdert,
V.
P.
(1982)
Aust.
vet.
J.
59:
128).
Cuprimine
v,
Merck,
Sharpe
and
Dohme
(Australia)
Pty
Ltd,
South
Granville,
New
South
Wales
Australian
Veterinary
Journal,
Vol.
60
No.
8,
August,
1983
235
TABLE
1
Selected
findings
in
4
Bedlington
terrier
dogs
with
inherited
copper
toxicosis
Observation
Case
No.
1
2
3
4
Normal
Plasma
alanine
254
135
127
49
5-80
aminotransferase
(IU/1)
BSP
retention
5.6%
4%
1%
ND
<5%
(30
min)
Hepatic
copper
3,930
4,841
6,361
1,600
49-317*
concentration
/g
dry
tissue)
Plasma
copper
(janol/L)
Plasma
caeruloplasmin
(U/mL)
18
ND
13
ND
6.0-10.1t
18
28
39
ND
15-20t
6.3-19.8t
Range
of
4
normal
dogs
T
Su
et
a/
(1982b)
t
Range
of
6
normal
dogs
ND
Not
done
in
the
same
way
as
Case
1.
It
remained
asymptomatic
for
14
months
until
a
mucopurulent
vaginal
discharge
appeared
6
weeks
after
oestrus.
At
this
time
there
were
no
abnormalities
in
the
haemogram
or
blood
chemistry;
the
plasma
ALT
activity
was
within
the
normal
range.
The
owner
requested
an
ovariohysterectomy
and
gave
permission
for
another
liver
biopsy.
Case
3:
A
5
-year
-old
male
was
presented
with
a
6
-week
history
of
lethargy,
reduced
appetite
and
weight
loss.
Signs
developed
after
the
dog
was
anaesthetised
with
thiopentone
for
minor
surgery
and
experienced
a
very
prolonged
recovery
period.
The
dog
was
thin
and
resented
abdominal
palpation.
No
other
abnormalities
were
noted.
Blood
studies
showed
a
slight
neutrophilia
and
elevated
levels
of
plasma
ALT,
copper
and
caeruloplasmin
(Table
1).
This
dog
was
a
third
and
fourth
generation
descendant
of
the
sire
of
dogs
1,
2
and
4.
Case
4:
A
3
-year
-old
bitch,
by
the
same
sire
as
dogs
1
and
2,
was
clinically
normal.
When
presenting
the
dog
for
an
elective
spay,
the
owner
requested
that
a
liver
biopsy
be
obtained
and
examined
for
evidence
of
copper
toxicosis.
A
related
dog,
not
included
in
this
report,
had
died
with
signs
of
liver
failure.
The
only
blood
examination
obtained
was
a
plasma
ALT
estimation
which
was
found
to
be
normal
(Table
1).
Results
In
3
dogs,
only
minimal
changes
were
detected
in
the
gross
appearance
of
the
liver.
It
was
slightly
pale
with
rounded
edges
and
with
some
areas
resembling
nodular
hyperplasia.
Microscopically,
Cases
1
and
2
showed
disorganisation
of
hepatic
cords
with
foci
of
fatty
infiltration,
most
striking
in
periacinar
areas.
Small
periportal
accumulations
of
neutro-
phils
and
lymphocytes
were
present.
Hepatocytes
were
swollen
and
the
cytoplasm
contained
large
numbers
of
refractile,
light
brown
granules.
These
were
identified
as
accumulations
of
copper
by
positive
reactions
to
rubeanic
acid
and
rhodanine
stains
(Figure
1).
In
Case
2,
there
were
also
large
accumu-
lations
of
dark
brown
pigment
in
Kupffer
cells
and
macro-
phages
which
were
positive
for
iron
with
Prussian
blue
stain.
There
were
no
significant
differences
between
the
first
and
second
biopsies
obtained
from
Cases
1
and
2.
Histopathology
was
not
done
in
Case
3.
In
Case
4
the
liver
was
grossly
normal.
Microscopically
it
showed
similar
but
less
severe
changes
than
the
other
cases,
with
no
evidence
of
lipidosis
or
fibrosis.
Hepatic
copper
concentrations
were
elevated
in
all
4
dogs.
Analysis
of
the
second
liver
biopsy
from
Case
1
was
not
obtained
due
to
technical
difficulties
(see
Discussion).
The
copper
concentration
in
the
second
biopsy
from
Case
2
was
?1,
6
r:$1.
0 M
-
'dr
:is
4
VI
I.
41
,
"Oa
Figure
1.
Section
of
liver
showing
large
vacuoles
of
fat
and
cytoplasmic
granules
of
accumulated
copper
concentrated
most
heavily
in
the
periportal
areas.
Rhodanine
stain
x
160.
t
j
o
,
141
'I
f
1.
)
4
-
410
:
6
.
41
4
I
14
°
4a
t
ft
i
3
r
.
'
!"-
0-4c
.
!....,
#:
or..
r
,
9
/'•••
r
. '
1/1r.
'
0
ea
AP.-
'
‘l
itti
'
11
'
f
ib
(
114(
44
1L
'S
.
1
O
f.
,
.
si°
ifff
,
.
1;.
-11r
-S7
-
•...1.'
'0
7
1
.0
1.-
o
..
.
041'
'
U
r-
.
1.1"
1
*r
-
4
4,437
pg/g
dry
tissue.
Results
of
the
plasma
copper
and
caeruloplasmin
determinations
are
shown
in
Table
1.
Discussion
Most
clinical
features
of
inherited
copper
toxicosis
in
Bedlington
terriers
are
related
to
the
chronic,
slowly
pro-
gressive
hepatitis
that
is
the
major
pathological
feature
of
the
disease.
Affected
dogs
are
asymptomatic
early
in
their
lives
during
the
initial
period
of
copper
accumulation.
There
is
considerable
variation
in
the
time
of
onset
and
manifes-
tations
of
disease,
but
most
dogs,
including
those
described
in
this
report,
conform
to
the
patterns
of
clinical
disease
that
have
been
described
(Hardy
and
Stevens
1977):
older
dogs,
usually
with
a
long
history
of
gradual
deterioration
or
unthriftiness,
develop
overt
signs
of
liver
dysfunction
includ-
ing
ascites
and
jaundice
and
die
from
hepatic
failure;
acute,
sometimes
rapidly
fatal
episodes
of
illness
(described
by
breeders
as
"The
4
-day
Problem")
usually
occur
in
younger
dogs
(2
to
8
years)
signs
may
include
depression,
anorexia,
vomiting,
ascites
and
jaundice
and
many
reports
suggest
stress,
such
as
whelping
and
shipping,
precipitate
these
episodes;
some
dogs
remain
asymptomatic,
detectable
only
by
abnormalities
in
liver
function
tests,
microscopic
and
histochemical
examination
of
liver
tissue
and
copper
assay.
Haematological
findings
are
usually
unremarkable,
but
haemolytic
anaemia,
which
is
associated
with
copper
toxicity
in
other
animal
species
(Hill
1977)
and
in
Wilson's
disease
has
been
reported
in
affected
Bedlington
terriers.
It
may
be
attributed
to
hepatic
necrosis
or
intrahepatic
redistribution
of
copper
with
increased
levels
of
circulating
copper
causing
injury
to
red
cell
membranes
and
resulting
in
intravascular
haemolysis.
This
may
contribute
to
or
account
for
the
very
marked
jaundice
seen
in
some
cases.
It
has
also
been
suggested
that
this
process
occurs
at
subclinical
levels
during
the
progress
of
the
disease
because
increased
amounts
of
hepatic
iron,
as
seen
in
Case
2,
are
commonly
found
(Ludwig
et
al
1980).
Biochemical
findings
are
often
normal
except
those
which
reflect
liver
function.
In
advanced
cases
decreased
total
serum
proteins,
albumin
and
prothrombin
and
increased
alkaline
phospatase
and
bilirubin
values
may
be
found,
but
in
earlier
stages
these
parameters
are
as
variable
and
inconsistent
as
the
clinical
signs.
Elevation
of
plasma
ALT
is
the
most
common
biochemical
abnormality
of
diagnostic
value
at
all
stages
of
the
disease
(Hardy
and
Stevens
1977;
Twedt
et
al
1979;
Su
el
al
1982b),
but
it
too
may
be
normal
or
unconvincingly
elevated,
particularly
in
younger
dogs.
The
236
Australian
Veterinary
Journal,
Vol.
60
No.
8,
August,
1983
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marketed
exclusively
in
the
veterinary
field
by
RANDWICK
VETERINARY
LABORATORIES,
10
Victoria
St.,
Beaconsfield,
N.S.W.
Australia.
Telephone:
(02)
699
6631.
Fungazol's
spectrum
of
activity:
t•li
Dermatophilus
Superficial
Fungi
Fp(
Yeasts
TV
Moulds
[pie
Gram-positive
Bacteria
Trichomonads
)
WIN
WM
I
et
VET
1384
viii
Australian
Veterinary
Journal,
Vol.
60
No.
8,
August,
1983
frequency
of
plasma
ALT
elevation
increases
with
age
(Twedt
et
a!
1979),
corresponding
to
the
progressive
hepatocellular
damage
rather
than
earlier
uncomplicated
copper
accumu-
lation.
This
can
precede
clinical
or
other
biochemical
abnor-
malities,
as
in
Case
2,
but
may
fluctuate,
as
found
in
Cases
2
and
4,
falling
to
within
the
normal
range,
even
when
there
is
histological
evidence
of
continuing
hepatic
injury.
Plasma
copper
and
caeruloplasmin
oxidase
levels
may
be
elevated
in
affected
Bedlington
terriers
(Su
et
a!
1982b).
However
the
distribution
of
values
overlaps
considerably
the
range
found
in
normal
dogs
so
neither
is
a
reliable
diagnostic
indicator
of
this
disease.
Although
other
forms
of
liver
disease
must
also
be
considered,
the
occurrence
of
clinical
signs
and
biochemical
abnormalities
consistent
with
liver
dysfunction
must
suggest
this
copper
-storage
disease
when
found
in
a
Bedlington
terrier.
Clinical
investigation
should
include
a
liver
biopsy
earlier
than
might
otherwise
be
considered.
For
example,
in
Cases
1
and
3,
only
supportive
medical
treatment
was
considered
until
liver
biopsy
findings
were
known.
In
Case
2
a
slight
elevation
of
the
plasma
ALT
in
a
clinically
normal
dog
might
otherwise
have
been
an
inadequate
basis
for
obtaining
a
liver
biopsy.
Accumulation
of
copper
in
the
liver
of
affected
dogs
begins
in
the
first
year
of
life
and
can
be
seen
as
prominent
brown
granules
which
are
copper
-laden
lipolysosomes
(Ludwig
et
al
1980)
scattered
in
the
cytoplasm
of
hepatocytes.
These
granules
give
a
positive
reaction
to
copper
-specific
stains
such
as
rubeanic
acid
or
rhodanine
(Twedt
et
al
1979;
Ludwig
et
al
1980).
Histological
evidence
of
hepatic
injury,
however,
does
not
appear
until
later,
an
important
feature
that
distinguishes
this
as
a
primary
copper
-storage
defect
rather
than
copper
accumulation
secondary
to
hepatic
disease
as
occurs
in
some
human
diseases,
mainly
those
associated
with
chronic
cholestasis
(Sternlieb
1980)
and
recently
reported
in
dogs
with
chronic
active
hepatitis
(Thornburg
et
al
1981;
Johnson
et
al
1982).
Twedt
et
al
(1979)
found
these
granules
in
85%
of
affected
Bedlington
terriers
aged
between
6
and
12
months.
They
found
progressive
liver
disease,
which
began
as
focal
hepatitis,
mainly
in
those
aged
between
one
and
8
years,
with
a
peak
incidence
from
2
to
4
years.
This
was
followed
by
a
chronic
hepatitis,
characterised
by
piecemeal
necrosis,
inflammatory
infiltrates
and
bridging
fibrosis,
seen
most
often
after
4
years
of
age,
and
in
late
stages
cirrhosis.
Hepatic
copper
concentrations
in
4
normal
dogs
ranged
from
49
to
317
µg/g.
This
corresponds
to
other
reports
in
which
control
dogs
(nonaffected
Bedlington
terriers
and
dogs
of
other
breeds)
had
hepatic
copper
concentrations
of
about
200
pg/g
(range
91
to
377
1.4g/g)
dry
tissue
(Twedt
et
al
1979;
Ludwig
et
a/
1980).
Normal
values
for
the
dog
are
much
higher
than
the
normal
concentration
found
in
man
which
is
about
30
pg/g
dry
tissue
(Sternlieb
1980).
In
contrast,
the
4
affected
dogs
in
this
report
had
8
to
35
times
the
normal
concentration,
with
the
lowest
amount
found
in
the
youngest
dog,
Case
4.
Levels
above
850
pig/g
dry
tissue
have
been
reported
(Su
et
a!
1982b).
Although
hepatic
copper
concentrations
of
affected
dogs
are
markedly
elevated, care
is
required
in
collection,
pres-
ervation
and
transportation
of
tissue
or
blood
in
order
to
avoid
or
minimise
contamination
with
copper.
Instruments
and
containers
for
collection
and
storage
of
specimens
should
be
copper
-free.
Treatment
with
ethylenediaminetetraacetic
acid
(EDTA)
or
nitric
acid
has
been
used
for
this
purpose.
Freezing
or
drying
and
preservation
-free
storage
of
tissue
is
recommended.
Formalin,
particularly
technical
grades,
should
be
avoided
as
in
our
experience
it
has
been
heavily
contam-
inated
with
copper,
probably
from
storage
containers,
leading
to
invalid
results
in
the
second
liver
copper
analysis
from
Case
1.
Copper
chelating
agents
are
used
successfully
in
the
treatment
of
Wilson's
disease.
The
drug
of
choice
is
d-
penicillamine
which
binds
and
promotes
urinary
excretion
of
copper
(Walshe
1977;
Sternlieb
1978).
It
is
a
slow
-acting
agent
which
mobilises
and
gradually
reduces
tissue
copper
deposits.
Definite
clinical
improvement
occurs
only
after
3
to
6
months,
which
renders
it
ineffectual
in
the
acute
episodes
of
hepatic
necrosis
and
haemolysis
which
may
sometimes
prove
lethal.
Except
for
these
unfortunate
situations,
peni-
cillamine
has
proved
effective
at
all
stages
of
Wilson's
disease,
preventing
liver
damage
when
given
at
a
presymp-
tomatic
stage
and
causing
remarkable
healing
of
liver
damage
in
quite
advanced
cases.
Most
affected
dogs
would
not
be
presented
for
diagnosis
and
treatment
until
clinical
signs
appear,
usually
correspond-
ing
to
advanced
liver
disease.
In
contrast,
many
cases
of
Wilson's
disease
are
detected
in
the
presymptomatic
stages
as
a
result
of
the
investigation
of
siblings
of
diagnosed
cases
in
much
the
same
way
as
Cases
2
and
4
in
this
report
were
identified.
The
relatively
high
cost
of
penicillamine
and
slow
response
may
be
limiting
factors
in
treatment
of
dogs.
250
mg
penicillamine
orally
per
day
has
been
recommended
as
treatment
for
affected
Bedlington
terriers
(Hardy
and
Stevens
1977)
but
there
are
few
reports
of
its
effectiveness.
Marked
reduction
of
hepatic
copper,
from
5,298
to
228
1.4g/g
dry
tissue
occurred
in
one
dog
following
more
than
2
years
of
treatment
(Ludwig
et
al
1980).
Despite
this,
cirrhotic
changes
had
developed
in
the
dog.
The
slightly
lower
hepatic
copper
concentration
found
in
the
second
biopsy
from
Case
2
suggests
the
14
months
of
treatment
were
not
effective.
It
may
represent
the
decrease
in
copper
concentration
found
in
affected
dogs
past
6
years
of
age
(Twedt
et
a/
1979)
or
merely
a
variation
in
sampling.
It
would
appear
that
the
controlled
therapy
used
in
Wilson's
disease
in
which
cupriuresis
is
monitored
to
accu-
rately
and
individually
establish
an
effective
dose,
has
not
been
used
in
dogs.
We
propose
to
apply
such
methods
in
future
studies
of
these
and
other
affected
dogs.
In
humans,
supplementary
treatment
in
the
form
of
low
-
copper
diets
and
intestinal
copper
-binding
agents,
such
as
sulphurated
potash,
has
been
used
but
is
of
minor
importance
in
the
control
of
the
disease
as
compared
to
the
role
of
a
chelating
agent.
In
order
to
be
effective,
severe
restriction
of
copper,
which
is
not
easily
achieved
with
meat
-based
diets,
is
required.
The
recommended
daily
copper
requirement
for
dogs
is
7.3
mg/kg
of
food
(dry
matter)
(NRC
1974)
and
commercial
dog
foods
often
exceed
this,
depending
on
their
content
of
organ
meats.
It
is
prudent
to
avoid
foods
known
to
have
a
high
copper
content
such
as
liver
and
other
organ
meats,
iamb,
pork,
seafood
and
cereal
products.
Tap
water
may
also
have
a
significant copper
content
especially
if
delivered
by
copper
pipes.
The
dogs
in
this
report
have
been
fed
a
balanced
diet
of
chicken
and
vegetables,
supplemented
with
selected
vitamin
preparations,
since
their
disease
was
diagnosed.
Many
mineral
supplements
and
general
"tonics",
which
might
be
used
in
the
treatment
of
chronically
ill
undiagnosed
cases,
contain
copper
or
liver
extract
which
has
a
high
copper
content.
This
genetic
metabolic
defect
is
transmitted
in
Bedlington
terriers
as
an
autosomal
recessive
trait
(Johnson
et
al
1980).
Affected
dogs,
that
is
those
that
accumulate
copper,
are
homozygous
for
the
defective
gene,
heterozygotes
are
carriers
and
normal
dogs
are
homozygous
for
the
normal
gene.
Carriers
are
asymptomatic
and
at
the
present
time
can
only
be
identified
with
certainty
by
test
matings.
This
is
the
first
published
report
of
this
condition
occurring
in
Bedlington
terriers
outside
the
United
States
where
it
is
known
to
have
been
present
at
least
since
1959
(Padula
1973).
It
is
unlikely
that
it
has
appeared
in
Australia
as
an
identical,
independent
mutation
in
the
same
breed,
but
rather
an
indication
that
in
both
countries,
where
the
breed
is
based
on
dogs
imported
from
the
United
Kingdom,
it
arises
from
common
breeding
stock
in
which
the
defective
gene
is
present.
The
dog
mentioned
as
the
sire
of
Cases
1,
2
and
4
is
common
to
all
dogs
in
this
report,
but
he
is
not
found
in
the
pedigrees
of
both
sire
and
dam
of
every
case.
The
4
affected
dogs
reported
here,
like
most
of
the
200
to
300
Bedlington
terriers
in
Australia,
are
descended
from
6
dogs
imported
from
the
United
Kingdom
between
1963
and
1967.
Although
there
has
been
correspondence
calling
for
reports
of
the
disease
in
that
Australian
Veterinary
Journal,
Vol.
60
No.
8,
August,
1983
237
country
(Smythe
1977;
Cherry
1982),
none
have
appeared
in
the
veterinary
literature.
In
addition
to
the
4
cases
in
this
report,
13
other
confirmed
or
suspected
cases
are
known
to
the
authors,
suggesting
the
trait
is
widespread
in
the
breed
in
Australia.
In
the
United
States,
attempts
are
being
made
to
eliminate
the
trait
by
identification
of
affected
dogs
and
selective
breeding
pro-
grams.
Breeders
in
Australia,
who
until
recently
considered
their
stock
free
of
the
condition,
are
being
encouraged
to
do
the
same.
A
ck
nowledgments
We
are
grateful
to
Professor
D.
M.
Danks,
Department
of
Paediatrics
and
Director,
Birth
Defects
Research
Institute,
and
N.
Francis,
Trace
Element
Laboratory,
Royal
Children's
Hospital,
Parkville,
Victoria,
for
very
helpful
discussions
and
the
copper
analyses.
Drs
W.
Fitzgerald,
R.
Mitten,
V.
Sharp
and
W.
Stott
are
thanked
for
contributing
clinical
material.
References
Bingley,
J.
B.
and
Dick,
A.T.
(1969)
-
Clin.
Chin:.
Acta.
25:
480.
Cherry,
S.
J.
(1982)
-
Vet.
Rec.
110:
482.
Hardy,
R.
M.,
Stevens,
J.
B.
and
Stowe,
C.
M.
(1975)
-
Minn.
Vet.
15:
13.
Hardy,
R.
M.
and
Stevens,
J.
B.
(1977)
-
Current
Veterinarj
Therapy
VI
-
Small
Animal
Practice,
Saunders,
Philadelphia,
p
995.
Hill,
R.
(1977)
-
Br.
vet.
J.
133:
219.
Johnson,
G.
F.,
Sternlieb,
I.,
Twedt,
D.C.,
Grushoff,
P.S.
and
Scheinberg,
I.
H.
(1980)
-
Am.
J.
vet.
Res.
41:
1865.
Johnson,
G.
F.,
Zawie,
D.
A.,
Gilbertson,
S.
R.
and
Sternlieb,
I.
(1982)
-
J.
Am.
vet.
med.
Ass.
180:
1438.
Ludwig,
J.,
Owen,
C.
A.,
Barham,
S.
S.,
McCall,
J.
T.
and
Hardy,
R.
M.
(1980)
-
Lab.
Invest.
43:
82.
N.R.C.
(1974)
-
Nutrient
requirements
of
dogs.
Washington,
National
Academy
of
Sciences,
p
35.
Owen,
C.A.
and
Ludwig,
J.
(1982)
-
Am.
J.
Path.
106:
432.
Padula,
M.
(1973)
-
Am.
Kennel
Gazette
90:
104.
Smythe,
R.
H.
(1977)
-
Vet.
Rec.
101:
65.
Sternlieb,
I.
(1978)
--
Gastroenterology
74:
787.
Sternlieb,
1.
(1980)
--
Gastroenterology
78:
1615.
Su,
L.
-C.,
Owen,
C.
A.,
Zollman,
P.
E.
and
Hardy,
R.
M.
(1982a)
-
Am.
J.
Physiol.
243:
G23I.
Su,
L.
-C.,
Ravanshad,
S.,
Owen,
C.
A.,
McCall,
J.
T.,
Zoilman,
P.
E.
and
Hardy,
R.
M.
(1982b)
-
Am.
J.
Physiol.
243:
G226.
Thornburg,
L.
P.,
Moxley,
R.
A.
and
Jones,
B.
D.
(1981)
-
Vet.
med.
Small
Allifil.
Clin.
76:
363.
Tssedt,
D.
C.,
Sternlieb,
I.
and
Gilbertson,
S.
R.
(1979)
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J.
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Ass.
175:
269.
Walshe,
J.
M.
(1977)
-
Proc.
Roy.
Soc.
Med.
70:
(suppl.
3)
:
1
.
(Accepted
for
publication
23
March
1983)
A
morphometric
analysis
of
the
changes
with
age
in
the
skin
surface
wax
and
the
sebaceous
gland
area
of
Merino
sheep
G.
H.
WARREN*,
P.
J.
JAMESt
and
A.
M.
NEVILLE*
SUMMARY:
Skin
samples
were
collected
from
the
midside
of
Merino
ewes
at
6
weeks,
one
year,
and
3
years
of
age.
The
thickness
of
the
surface
wax
and
the
number
and
area
of
sebaceous
glands
per
unit
length
of
skin
were
measured
with
an
image
analyser.
Three
-year
-old
sheep
had
a
significantly
(P
<
.05)
thicker
skin
surface
wax
layer,
(14.45µ
±
1.45),
than
they
did
as
lambs,
(7.85µ
±
0.88).
Both
the
number
(2.91
±
0.15
per
mm)
and
area
(24.27
;4
2
44
±
1.54)
of
sebaceous
glands
per
unit
length
of
skin
of
3
-year
-old
sheep
were
significantly
less
than
in
lambs,
which
measured
4.10
±
0.15
per
mm
and
39.30
±
4.14
1,1
2
/p1
respectively
and
one
-year
-old
sheep,
which
measured
3.99
±
0.21
per
mm
and
35.43
µ
2
±
3.65
respectively.
Aust
vet.
J.
60:
238-240
Introduction
The
surface
wax
layer
of
the
sheep
is
considered
to
be
an
important
barrier
to
infection.
Roberts
(1963)
found
that
older
sheep
were
more
resistant
to
Dermatophilus
congolensis
infection,
because
the
older
sheep
better
maintained
the
integrity
of
the
wax
layer.
Belschner
(1937)
found
older
sheep
more
resistant
to
fleece
rot
and
fly
strike
than
younger
sheep.
A
number
of
factors
may
operate
to
bring
about
this
increased
resistance
to
infection
and
to
environmental
stress
with
age.
The
fleece
of
an
older
sheep
may
be
a
more
effective
barrier
to
environmental
stress
or
the
wax
layer
and
epidermis
may
have
a
greater
tolerance
to
bacterial
and
climatic
insult.
In
this
study
the
mean
thickness
of
surface
wax
and
the
number
and
area
of
sebaceous
glands
per
unit
length
of
skin
*
Department
of
Human
Morphology,
Flinders
University,
South
Australia
t
South
Australian
Department
of
Agriculture,
Adelaide,
South
Australia
in
sheep
at
3
different
ages
were
measured
to
determine
if
significant
differences
between
age
groups
existed
for
these
characteristics.
The
results
of
this
study
may
increase
the
understanding
of
why
mature
sheep
better
tolerate
environ-
mental
stress
than
immature
sheep.
Materials
and
Methods
The
sheep
used
were
Poll
Merino
ewes
of
the
non
-Peppin
medium
wool
strain
reared
in
the
lower
north
of
South
Australia.
Ten
lambs
were
randomly
selected
from
90
ewe
lambs
of
a
May/June
lambing.
A
skin
sample
was
collected
6
weeks
after
the
period
of
peak
lambing,
and
again
from
the
same
sheep
at
one
year
and
3
years
3
months
of
age
-
the
third
age
being
referred
to
hereafter
as
3
-year
-old.
Midside
skin
samples
taken
by
the
method
of
Carter
and
Clarke
(1957)
were
fixed
in
10
6
7o
formol
saline.
These
samples
were
then
frozen
in
liquid
nitrogen
and
longitudinal
sections
30p
thick
were
cut
serially
on
a
cryostat.
Fixation,
dehydration
and
paraffin
embedding
may
result
in
distortion
or
loss
of
the
outer
layers
of
the
stratum
corneum
(Lloyd
et
al
1979).
238
Australian
Veterinary
Journal,
Vol.
60
No.
8,
August,
1983