Copper toxicosis in Bedlington Terriers in the United Kingdom


Kelly, D.F.; Haywood, S.; Bennett, A.M.

Journal of Small Animal Practice 25(6): 293-298

1984


This paper summarizes the clinical and laboratory data on two adult Bedlington Terriers with liver disease associated -with copper toxicosis. The younger dog, at 3 years, had elevated serum levels of alanine aminotransferase and alkaline phosphatase with active parenchymal cell degeneration and hepatitis. The second dog developed chronic hepatic failure at 5 years with advanced cirrhosis. Both dogs had stainable copper granules in the liver and chemical analysis of their livers revealed elevated copper contents (1,027 and 10,728,ug/g dry weight; normal less than 300,ug/g). These are the first published cases of this inherited abnormality of copper metabolism in this breed in this country.

J.
small
Anim.
Pract.
(1984)
25,293-298.
Copper
toxicosis
in
Bedlington
Terriers
in
the
United
Kingdom
D.
F.
KELLY,
S.
HAYWOOD
AND
A.
M.
BENNETT*
Department
of
Veterinary
Pathology,
University
of
Liverpool
and
Department
of
Pathology,*
University
of
Bristol
ABSTRACT
This
paper
summarizes
the
clinical
and
laboratory
data
on
two
adult
Bedlington
Terriers
with
liver
disease
associated
-with
copper
toxicosis.
The
younger
dog,
at
3
years,
had
elevated
serum
levels
of
alanine
aminotrans-
ferase
and
alkaline
phosphatase
with
active
parenchymal
cell
degeneration
and
hepatitis.
The
second
dog
developed
chronic
hepatic
failure at
5
years
with
advanced
cirrhosis.
Both
dogs
had
stainable
copper
granules
in
the
liver
and
chemical
analysis
of
their
livers
revealed
elevated
copper
contents
(1,027
and
10,728
,ug/g
dry
weight;
normal
less
than
300
,ug/g).
These
are
the
fi
rst
published
cases
of
this
inherited
abnormality
of
copper
metabolism
in
this
breed
in
this
country.
INTRODUCTION
An
unusual
progressive
and
fatal
liver
disease
affecting
the
Bedlington
Terrier
was
fi
rst
recognized
in
the
USA
(Hardy,
Stevens
&
Stowe,
1975).
The
disease
is
characterized
by
toxic
accumulation
of
copper
in
the
liver,
leading
eventually
to
hepatitis
and,
ultimately,
to
cirrhosis
(Twedt,
Sternlieb
&
Gilbertson,
1979).
This
copper
toxicosis
results
from
a
metabolic
abnormality
that
is
inherited
in
an
autosomal
recessive
manner
(Johnson
et
at.,
1980;
Owen
&
McCall,
1983).
This
paper
records
the
fi
rst
two
published
cases
of
this
copper
toxicosis
occurring
in
the
Bedlington
Terrier
in
the
United
Kingdom.
CASE
REPORTS
Case
1
A
3
-year
-old
female
Bedlington
Terrier
was
presented
with
anorexia,
profound
weight
loss
(from
11.81
to
6.36
kg),
vomiting
and
depression.
Significantly
0022
4510/84/0600
0293$02.00
©
1984
BSA
VA
293
294
D.
F.
KELLY,
S.
HAYWOOD
AND
A.
M.
BENNETT
abnormal
blood
biochemical
values
were:
elevated
alanine
aminotransferase
(ALT)
(313
iu/l)
and
serum
alkaline
phosphatase
(SAP)
(446
iu/l)
normal
values
10-27
and
10-45
iu/l—Rushton,
1981).
Red
and
white
blood
cell
counts,
blood
urea
and
bilirubin
were
within
the
normal
range.
Although
total
serum
protein
level
was
within
the
normal
range
(68
g/l)
the
albumen
(27
g/1)
was
slightly
below
the
lower
limit
of
normality,
and
the
globulin
level
(41
g/l)
was
slightly
higher
than
the
upper
limit
of
normality
(Rushton,
1981).
Exploratory
laparotomy
was
carried
out
revealing
a
liver
that
was
described
as
swollen
and
yellow.
A
wedge
of
liver
was
obtained
at
laparotomy
for
chemical
and
histological
examinations.
The
bitch
was
treated
with
d-penicillamine
and
methionine
but
no
real
clinical
improvement
was
seen
and
euthanasia
was
carried
out
two
months
after
liver
biopsy.
During
the
post
-operative
period,
clinical
chemistry
monitoring
revealed
persistently
elevated
levels
of
ALT
and
SAP.
The
tendency
for
a
slightly
lowered
albumen/globulin
ratio
persisted
during
this
period.
Case
2
A
5
-year
-old
male
Bedlington
Terrier
was
presented
with
the
owner's
complaint
of
anorexia,
vomiting
and
polydipsia.
Physical
examination
revealed
a
dog
with
normal
temperature,
jaundice
and
buccal
hyperaemia.
Urinalysis
revealed
haematuria
and
proteinuria.
Over
the
succeeding
four
weeks
the
jaundice
became
more
profound
and
the
dog's
physical
condition
deteriorated.
Following
an
episode
of
haematemesis
the
dog
was
killed
humanely.
PATHOLOGY
Case
1
The
wedge
biopsy
consisted
of
fi
rm,
granular
tan
-brown
liver.
Histological
examination
revealed
foci
of
parenchymal
cell
necrosis
with
a
scattered
inflam-
matory
response
of
neutrophilic
leucocytes
and
mononuclear
cells.
Early
piecemeal
necrosis
adjacent
to
portal
areas
was
accompanied
by
an
inflammatory
response
of
neutrophilic
leucocytes,
macrophages,
lymphocytes
and
plasma
cells.
Fine
fi
brous
septa
extended
from
the
portal
areas
into
the
lobules.
Hepatocyte
cytoplasm
was
vacuolated
and
contained
conspicuous
yellow
-brown
granules.
A
second
sample
of
liver
obtained
post
mortem
showed
similar
degenerative
and
inflammatory
changes
with
portal
-central
bridging.
In
both
samples
the
parenchymal
cell
granules
were
positive
for
copper
by
the
rubeanic
acid
staining
method.
Copper
content
of
a
post
mortem
liver
sample
(determined
by
atomic
absorption
spectrophotometry)
was
1,027
pg/g
(dry
matter
basis).
Case
2
Post
mortem
examination
revealed
profound
jaundice
without
evidence
of
either
haemolysis
or
extrahepatic
obstruction.
The
liver
was
uniformly
shrunken
and
tan
with
a
fi
nely
nodular
capsular
surface.
A
wedge
of
liver
(Fig.
1)
was
submitted
for
histological
examination
and
copper
analysis.
COPPER
TOXICOSIS
IN
BEDLINGTON
TERRIERS
295
z
t
4.
11
*
rr*
FIG.
I.
Capsular
surface
of
a
liver
wedge
showing
micronodular
cirrhosis
x
2.
Histological
examination
revealed
variable
size
nodules
of
parenchymal
cells
with
focal
degeneration
and
neutrophilic
leucocyte
accumulations.
Nodules
were
separated
by
bands
of
fi
brous
connective
tissue
with
portal
-central
bridging
and
there
was
conspicuous
dilatation
of
capsular
lymphatics.
Intracanalicular
bile
plugs
were
conspicuous.
Parenchymal
cell
cytoplasm
contained
large
numbers
of
faintly
yellow
granules
that
stained
positively
for
copper
by
the
rubeanic
acid
sequence.
These
copper
granules
were
most
conspicuous
in
the
periphery
of
the
nodules.
Ferric
iron
was
plentiful
in
the
cytoplasm
of
Kupffer
cells,
parenchymal
cells
and
in
portal
macrophages
and
connective
tissue.
The
histological
features
are
illustrated
in
Figs
2-4.
Copper
content
of
this
liver
was
10,728
pg/g
(dry
matter
basis).
DISCUSSION
Both
dogs
had
clinical,
biochemical
and
morphological
evidence
of
liver
disease.
The
last
was
characterized
by
degenerative
changes
of
parenchymal
cells,
and
was
associated
with
an
inflammatory
response
and
fi
brosis.
In
the
second
dog
the
296
D. F.
KELLY,
S.
HAYWOOD
AND
A.
M.
BENNETT
1
.4
•—•
'?
It
144-4
jJ
e
e
1
.
..Vg
3
:istit;htl
.
'
U4.•
4
4%=•4.
-
:e
)-
:'
.
cam=
.
-.1
' '
4.
L.....J.
tr
P
?
---..?
...0,41.
•-14
,4..,
"ft
.'''.
4
. ,
51,Kr
-F
..0
-
.::.—'—'-•
ze,A
4
4
4
,--.
-
cc
'
P
•,,,-
-;
r;f•
...›:*F
-.
--e--
--
3
--i•e''--
-
,
-
(14'
7.'
1
,•
4
:.-
-
d
..).,
v,-
-
r.:.
-
1.7
,,,1.-
lit'
LL.-..
..,_:_
--.•:"
4-,
'L
y
.
-
_
..
4
1
t
FIG.
2.
Irregular
nodules
of
parenchymal
cells
separated
by
bands
of
fi
brous
connective
tissue.
Gordon
and
Sweets'
Reticulin
stain
x48.
.
-
v.
`
7,
'
'MIN,.
f C
'',. 14
'
j
.511B
7
11
z '
ir
.,
4
fitt
i
q
i
A
'
-+-
Ik•
-
it
v
4;
I
.
tril
4.
.
.•
14
,,,,,,
,,
"„
,1..
j
"":4
1
.4
.:
1'
..
At*
-
..
t
.
e
.r
7‘..
'1
‘e..%
)
,
4
4Y,
,
-
W,
-
la
k
-Vi
.
.
+-fo
i
:
3
t4k.
,
'
.-
*
r
l''
.
i
1.,
..
a
.
.
:
i t
r'
%,
`.
-
'
r
:%
'..;
•.,
,
..
dri
e
4
'
'
-
2
,
,
.
.,
g
E•
fll
...,.
-
.1
-
,
.
...,
.
4
4..
,
.•
.
,.
''..
1.
;
,
.,
'
;,/,.
1
.
4
-
-
,
•i
-
m
-
It
,
,..-
: '
4-,
.
.
'
1'
IL,
••••
j
et
.
-
;
•,f
.,..
N
.
:•11.
I I :
t•i '1 ..-.14:
,..
,..
,
.
.;
.
.
,.,,
_
-
)-•
;
.;.
'
.i
i:
,
.,
,
v
o
0.
-
i.-'
..
,
-
4.
-
!
7
4
4
.
--'
i-1
t
.
'111
sall,.
I
'
V
tY .;,
.J
.
:'
-
' ' 4
:7
. 4
A
ll
..
.
3t
4.
.-...
t
.
'
- -
t
%
,
....
v,
,
J
. i
.......11
1 *
...f2
L
,
6
!
.
.1
.
1r
---
.i.44.
&
...
,
i.
..
,
._.
•ii
'4
-
...
.
- .
.
,
.
...
1
-
--
o
••
1/
.
/
.
' '
- -
FIG.3.
Heavy
coarse
granularity
of parenchymal
cell
cytoplasm
caused
by
copper
accumulation.
The
less
heavy
granular
appearance
in
the
more
centrally
situated
cells
is
due
to
haemosiderin
accumulation.
Rubeanic
acid-Perls'
Prussian
Blue
x
120.
COPPER
TOXICOSIS
IN
BEDLINGTON
TERRIERS
297
ii
e
r•-•.-4-..41
••••••
ir•-•
r
g -
'0
4
1
6
0.;,-%
0
`--..,
".!
-.---!-7
'
-
.
.
y
.
-
,
:"
II
P
4-
-
v
I
,
:•••
.
mr.
.".;
tiZ
-
-
•e• -
.)h
%-
t.:a
,
;
...-
ir
.,
Ar
:
_
-
..i
..:
.%.
..,
;7;.4".‘
ka
..
4'
••
4,44.1.
:*
S...
=
.
-
.11
...
•‘
'
'.1
.1.
4
1:
..
....
..
.../...
;
1-
7
. 4
Z
,
,
i 1
1,11:iN
7.44
.
.
4:1
,
'';'
',
: .
',
•1
7
.
, t
...
li
k
s
•:;S
:
rk :t
,
:
'
71.
Z
. "
1
.
.
4
-
'
'
%.11
7r
,
••
•4
e
*
'
••
.....•
4
.
4ib
-
"•-
-‘,..
n
-
'
,
/
..
,
;
ST
"
...
..
‘ '
..•
I.
S
.
'
_
A
al;
"
...
i
.
•••
1
.
-
.
-
iL
.
.X
.
.1.
4
'
i
1
,_
,
VI
it.
...
3
N....A.
.,..
a
-
w
k..,
...,
.....,.
''
,,
l
'
.
'
J ,
'.
h
'
.
4
t '
t
:
7
-7
-
7.
'"
-1
-
tZt
•'
r
.
-
=
rt
"
Al
V
ti
r
1,4
4
,r
..
4
0
-
i
1
)
t•-•
P
.
N
i
p
dr
1
6
.
i
.
".,,
....
,
..'
-•
.11.
,*
..,
,
,..:
.-6,
4
,
4
,?
..."
-
.41.,,
1
I
t
1
4.
0.
1
..'...f„t
,
c.
-
•‘_,'ib
re.
'
,
•(-..
,
...
-_-_
_•.
..„6.,;,
4
.
d..2
.
..tv,f-..
i
t
is
•:
4
17
:
4
:
.19
4
44
101.1e1
"
,-,,,
. '
4
4er
,
..
'
0
:
V
,
,
.„..;...,
....:
4
,
no,
4,
j
,
......_
.--.
-
.
ft
.5`ci.1*
'
''
'
'
Ll'
i
ir
.
°
Ir.
-.,'
,"
"
'''
.
4
-!
-
I t , i
6
`•
'.
..
.7
1
V
l'''
,
L'
'
"
!
-
.„
lk.T.
..
v
..
.
'
-
'
D
e
.
-
.
v
tlf
r
$
d
i
FIG.
4.
Nodules
of
heavily
granulated
parenchymal
cells
are
separated
by
bands
of
inflamed
fi
brous
connective
tissue.
There
is
dilatation
of
capsular
lymphatic
vessels.
Haematoxylin
and
eosin
x
120.
hepatic
lesion
had
progressed
to
frank
micronodular
cirrhosis
(Anthony
et
al.,
1977),
possibly
reflecting
the
longer
duration
of
the
abnormality.
In
both
dogs
there
was
a
heavy
accumulation
of
copper
in
the
liver:
the values
of
1,027
and
10,728
pg/g
are
well
outside
the
upper
limit
of
normality
(300
pg/g)
for
the
dog
(S.
Haywood,
unpublished
observations;
Keen,
Lonnerdal
&
Fisher,
1981).
The
morphological
and
analytical
data
are
similar
to
those
in
previously
published
accounts
of
copper
toxicosis
in
the
Bedlington
Terrier,
confirming
the
existence
of
this
genetically
determined
abnormality
in
this
country.
The
nature
of
the
basic
biochemical
abnormality
in
this
disease
is
at
present
unclear
but
it
is
known
that
copper
accumulates
to
excess
within
hepatic
parenchymal
cell
lysosomes;
the
concentration
of
copper
increases
with
time
and
this
is
followed
by
progression
from
focal
and
chronic
hepatitis
to
cirrhosis
(Ludwig
et
al.,
1980;
Sternlieb,
1982).
Early
recognition
of
affected
dogs
is
important:
since
the
disease
is
inherited
as
an
autosomal
recessive
(Johnson
et
al.,
1980)
the
dam
and
sire
of
any
affected
dog
must
be
considered
to
be
carriers
of
the
genetic
trait
(Owen
&
McCall,
1983).
ACKNOWLEDGMENTS
Clinical
details
of
cases
1
and
2
were
provided
by
T.
P.
Brown.
B.
Harrison
and
Gillian
Carlin.
Post
mortem
details
of
Case
2
were
provided
by
B.
Harrison.
298
D.
F.
KELLY,
S.
HAYWOOD
AND
A.
M.
BENNETT
REFERENCES
ANTHONY,
P.P.,
ISHAK,
K.G.,
NAYAK,
N.C.,
POULSEN,
H.E.,
SCHEUER,
P.J.
&
SOBIN,
L.H.
(1977)
The
morphology
of
cirrhosis:
definition,
nomenclature
and
classification.
Bull.
Wld
Hlth.
Org.
55,
521.
HARDY,
R.M.,
STEVENS,
J.B.
&
STOWE,
C.M.
(1975)
Chronic
progressive
hepatitis
in
Bedlington
Terriers
associated
with
elevated
liver
copper
concentrations.
Minn.
Vet.
15,
13.
JOHNSON,
G.F..
STERNLIEB,
I.,
TWEDT,
D.C.,
GRUSHOFF,
P.S.
&
SCHEINBERG,
I.H.
(1980)
Inheritance
of
copper
toxicosis
in
Bedlington
Terriers.
Am.
J.
vet.
Res.
41,
1865.
KEEN,
C.L.,
LONNERDAL,
B.
&
FISHER,
G.L.
(1981)
Age
-related
variations
in
hepatic
iron,
copper,
zinc,
and
selenium
concentrations
in
beagles.
Am.
J.
vet.
Res.
42,
1884.
LUDWIG,
J.,
OWEN,
C.A.,
JR.,
BARHAM,
S.S.,
MCCALL,
J.T.
&
HARDY,
R.M.
(1980)
The
liver
in
the
inherited
copper
disease
of
Bedlington
Terriers.
Lab.
Invest.
43,
82.
OWEN,
C.A.
Jr.
&
MCCALL,
J.T.
(1983)
Identification
of
the
carrier
of
the
Bedlington
Terrier
copper
disease.
Am.
J.
vet.
Res.
44,
694.
RusFiToN,
B.
(1981).
Veterinary
Laboratory
Data.
BVA
Publications.
STERNLIEB,
I.
(1982)
Pathobiology
of
metals.
In:
The
Liver.
Biology
and
Pathobiology
(Eds
I.
Arias,
H.
Popper,
D.
Schachter
and
D.
A.
Shafritz),
p.
385.
Raven
Press,
New
York.
TWEDT,
D.C.,
STERNLIEB,
I.
&
GILBERTSON,
S.R.
(1979)
Clinical,
morphologic
and
chemical
studies
on
copper
toxicosis
of
Bedlington
Terriers.
J.
Am.
vet.
med.
Ass.
175,
269.