THE latest series of Dechra
Academy CPD events proved to be a
great attraction at five venues across
the UK. Meeting rooms were filled
to capacity as vets and vet nurses
gathered to hear Grant Petrie tackle
the subject of Canine
hyperadrenocorticism (HAC) – a
diagnostic challenge.
Right from the start, Grant’s
message was clear. “We are dealing with
dogs that show some clinical signs but
that are generally well,” he said. “There
is no substitute for thorough history
taking, observation
and a proper physical
examination, because
there is no single
diagnostic test for
Cushing’s syndrome
(HAC). We use
different tests to
confirm a diagnosis.”
In an innovative
two-hour presentation,
the speaker assumed the role of a dog
owner and interacted with the audience
as he visited their “practice” with Otto,
his 12-year-old miniature Dachshund,
each time developing the diagnosis a
stage further.
He explained that the clinical signs
exhibited by dogs with HAC are caused by the production of excessive amounts
of cortisol; and that in 80-85% of cases
this is the consequence of over-
stimulation of the adrenal glands by a
benign ACTH-secreting tumour situated
in the pituitary gland. Less commonly –
and mainly in larger breeds of dogs –
there may be a tumour in the adrenal
glands themselves.
Regardless of its cause, over time, a
dog suffering from HAC will develop a
combination of clinical signs which
clients may initially simply associate with
the ageing process. These signs are variable in extent and
result from the effects of
excessive cortisol on
target organs leading to
gluconeogenesis, lipolysis,
protein catabolism, anti-
inflammatory responses
and immunosuppressive
activity. There may also
be signs resulting from the physical presence of
the tumours themselves.
Certainly age is a factor and dogs
over nine years old are prime candidates
for HAC. Some breeds are predisposed
to the condition too, including Bichon
Frise, Dachshunds, Miniature Poodles
and Terriers. Of the larger breeds,
Boxers and German Shepherd dogs feature strongly.
Throughout his talk, Grant emphasised that definitive diagnosis of
the syndrome is a real challenge and that
to all intents and purposes, certainly in
its early stages, one is dealing with a
“clinically-well dog”. Indeed, it is often
discovered when dogs are presented for
other reasons or for routine vaccination.
Presenting signs
There is often a low level of owner
concern because progressive external
signs – such as changes to coat texture –
are slow, and polyuria/polydipsia and
polyphagia are sometimes perceived as
being positive things (owners will worry
if their dog stops eating but are
generally quite happy if it has what they
consider to be a “healthy” appetite).
HAC dogs rarely have a poor appetite
or vomiting and diarrhoea; panting and
muscle weakness are put down as being
part of the ageing process.
Polyuria/polydipsia is common in
HAC cases and often it is the marked
increase in the frequency of urination
that owners first mention. In nine out of
10 cases, polyphagia is observed,
together with scavenging without any
other gastro-intestinal disease. The
reason for this is unclear, but it may
represent a direct effect of the increased
glucocorticoid levels.
Owners may also report that their
dogs are showing signs of poor exercise
tolerance, panting, weakness and
lethargy. These are linked to the
underlying protein catabolism which, in
turn, leads to muscle wasting.
Thus, panting is a consequence of
weakened respiratory muscles; the
increased frequency of ruptured
cruciate ligaments, seen in smaller
breeds, is the result of reduced joint
stability and ligament weakness; and a
combination of heavier abdominal
contents and weakened abdominal
muscles manifests itself as the classical
“pot belly”. There may also be some
redistribution of fat.
The skin and coat in HAC cases will
invariably show classic changes too –
non-pruritic alopecia, poor hair re-
growth, hyperpigmentation, skin
thinning, more prominent blood vessels,
and the appearance of keratin plugs, or
comedomes. There may be some areas of calcium deposition in the skin too
and this so-called “calcinosis cutis” is
almost pathognomic for the syndrome.
Indeed, calcium deposition can occur in
other soft tissues including the kidneys,
tracheobronchial tree and the “great”
blood vessels.
Initial screening tests
Turning to the question of the routine
work-up in suspected cases of HAC, the
speaker reminded his audience that they
would be looking for elevated levels of
“stress hormones” in clinically normal
dogs. Therefore, any concomitant
disease should be ruled out first as sick
dogs will already have increased “stress
hormone” levels anyway.
So in uncomplicated HAC cases, the
classic haematologic changes are a
“stress leukogram” with a mature
neutrophilia, eosinopaenia,
lymphopaenia and monocytosis. The
red blood cell count is usually normal
and there may be an increase in the
number of platelets.
Serum biochemistry may show mild
hyperglycaemia, decreased blood urea,
mild increases in ALT, moderate to
marked increases in ALKP, elevated
cholesterol/triglycerides and a mild
hypophosphataemia. Electrolyte levels
are usually normal.
Urine is usually dilute (SG <1.020)
with proteinuria (UPC ratio <5) and in
about 5% of cases glucosuria may
feature. Up to half of HAC cases will
have urinary tract infection; so although
the sediment may appear to be inactive,
this is often the anti-inflammatory effect
of the increased steroid levels and it is
advisable to culture the urine anyway.
Putting imaging procedures into
diagnostic context, Grant Petrie
suggested that radiology had modest but limited value, in that
the adrenals are usually
invisible unless calcified,
although generalised
osteopaenia and signs of
dystrophic calcification
could be useful
indicators.
Abdominal
ultrasound can be useful
to help differentiate between pituitary
and adrenal forms of HAC. The normal
left adrenal gland is peanut-shaped and
typically <7.5mm in width, whereas the
right adrenal is oval-shaped.
Confirming the diagnosis
In summary so far then, dogs suspected
of having HAC should have an
appropriate history, with some
compatible physical findings and
suspicious clinico-pathologic results.
Confirming the diagnosis requires the
application of screening adrenocortical
function tests and these tests would
ideally be both sensitive and specific.
The speaker explained that
sensitivity is defined as the proportion
of cushingoid dogs with a positive test
result (i.e. a highly sensitive test that
correctly identifies a high proportion of
dogs with the disease) and specificity
relates to the number of normal dogs
with a negative result (i.e. a highly
specific test correctly identifies a high proportion of
dogs that do not
have the
disease).
However, such
an ideal test
(with high
sensitivity and
specificity) does
not exist.
“There is no single gold standard
test for the diagnosis of
hyperadrenocorticism,” he said. “But
combining tests of differing sensitivities
and specificities will improve accuracy.
Establish normal ranges for your usual
laboratory and never base the diagnosis
of HAC solely on endocrine tests.”
The first test – which has good
sensitivity but poor specificity – is to
determine the urine cortisol:creatinine
ratio (UCCR). In order to reduce the
effects of stress, this should be
performed on home-collected, morning,
“free-catch” urine. Levels of <10 x 10-6
likely rule out HAC.
The ACTH response test assesses
adrenal gland reserve in response to a
pharmacological dose of ACTH. It is a
simple and quick test and, in general,
normal dogs stimulate to
<450nmol/litre whereas HAC cases
stimulate to >600nmol/litre.
It is a useful screening test although
a significant number have false negative results. It is the only test to distinguish
iatrogenic from spontaneous HAC and
it is useful as a baseline test for
monitoring responses to medical
therapy. However, it does not
differentiate pituitary-dependent
hyperadrenocorticism (PDH) from a
functional adrenal tumour (FAT).
The low dose dexamethasone
(DXM) suppression test is based upon
the principle that, in normal dogs,
administration of a low dose of DXM
inhibits pituitary ACTH and suppresses
cortisol production.
Pituitary tumours, however, are
resistant to the feedback effects of
cortisol – otherwise PDH would not
develop – and exogenous DXM does
not suppress pituitary ACTH. FATs
secrete cortisone autonomously,
independent of pituitary ACTH, and
DXM will, therefore, not suppress
cortisol production.
Normal dogs suppress to
<40nmol/litre at three and eight hours.
Cortisol levels >40nmol/litre at eight
hours is consistent with HAC.
The speaker said that the low dose
DXM supression test was his preferred
initial screening test in that it gives him
great confidence in a negative test result
and is extremely sensitive if used in
appropriate candidates. It is, however,
poorly specific and one should not test
“sick” patients until the associated
illness has been resolved.
Having made a positive diagnosis of
HAC, it is sometimes useful when
considering the alternatives of medical
management or surgery, to differentiate
between HAC resulting from PDH and
that arising from a FAT.
Adrenal gland ultrasonography is
one option. Measurement of
endogenous ACTH (eACTH) can be
useful but eACTH is labile and the
protocol needs to be strictly followed.
The high dose DXM suppression test is another alternative.
Management of HAC
At many points during his presentation,
Grant stressed the importance of
communicating clearly and openly with
the owners of potential HAC dogs. This
is particularly important once a positive
diagnosis has been made and treatment
options are under consideration. All
options should be discussed with the
owner and dialogue established.
The decision may be affected by the
bias of the clinician, financial
considerations, factors in the owner’s
lifestyle and a consideration of the
benefits versus the risks. If there are no
clinical signs, should we treat? Or are
there benefits from treating sooner?
What are the consequences of not
treating the patient?
Certainly, HAC has been associated
with conditions such as diabetes
mellitus, pulmonary thrombo-embolism,
calcium oxalate urolithiasis and systemic
hypertension.
Although surgical management is
possible (adrenalectomy for FAT or
trans-sphenoidal hypophysectomy for
PDH), the majority of cases are
managed medically. The veterinary
licensed product in the UK is trilostane
(Vetoryl, Dechra).
Trilostane competitively inhibits
steroid synthesis by blocking 3β-
hydroxysteroid dehydrogenase. “The
aim is to control serum cortisol levels,
not stop cortisol production,” said
Grant Petrie.
Starting with a low dose initially,
administered with food, the trilostane
dose is increased if necessary until a
good clinical and biochemical response
is achieved.
Normally, metabolic signs of HAC
resolve within a month and
dermatologic signs improve after about
four months, but each case must be
assessed on an individual basis.
It is recommended that the ACTH
response test is performed 10-14, 30
and 90 days after starting initial
therapy and after each dose
adjustment, and then, once the patient
is stable, every three to six months
thereafter.
