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The Basics:
Hypoadrenocorticism – the correct term for Addison’s – is
caused by the adrenal glands, situated near the kidneys, failing to
secrete enough glucocorticoid (primarily cortisol) and
mineralocorticoid (primarily aldosterone) hormones. In the
majority of cases both types of hormone are affected. Less
commonly the problem is not with the adrenal glands but with the
pituitary gland. The pituitary secretes a hormone called
adrenocorticotrophic hormone (ACTH), which regulates the adrenal
secretion of cortisol and has little effect on aldosterone. In
these cases of secondary Addison’s only glucocorticoid secretion
is generally affected. The secretion of aldosterone is
regulated by a number of factors, but the most important is the
level of potassium ions in the serum. By far the most common
cause of primary adrenal failure is autoimmune disease, but it can
be the result of granulomatous disease, hemorrhage, inflammation,
infarction (due to interrupted blood supply), cancer or the
deposition of amyloid tissue in the adrenal glands. Immune
mediated destruction of the adrenal glands often occurs in
conjunction with other autoimmune endocrine diseases such as
thyroiditis (hypothyroidism), diabetes mellitus or
hypoparathyroidism. Lesions of the hypothalamus or pituitary
can result from a tumor or other space occupying lesion. Drugs
given to treat hyperadrenocorticism (Cushing’s disease) –
mitotane, trilostane or ketoconazole – can result in Addison’s
due to adrenal destruction/suppression, in the case of mitotane this
is not reversible, but adrenal function will usually rebound once
the patient stops taking the other two drugs. Ketoconazole is
also given to treat fungal infections. Corticosteroids, such
as prednisone, suppress an animal’s normal adrenal production and
release of glucocorticoids, as well as causing adrenal atrophy.
This can happen within a few days, and abrupt termination of these
drugs can result in symptoms of Addison’s, and is by far the most
common cause of secondary Addison’s disease. The biggest
risk is from the long acting glucocorticoid drugs, which can
suppress adrenal function for five to six weeks.
Diagnosing Addison’s is
complicated by the wide range of presenting symptoms. In some
dogs there will be acute collapse, while in others symptoms come on
gradually and may wax and wane, so that the owner is not really
aware how sick the dog was until treatment shows a significant
improvement. 85 or 90% of adrenal hormone reserves have to
have been depleted before a dog will show clinical signs, and
usually some stress then triggers the onset of illness. Lack
of glucocorticoids can produce loss of appetite, vomiting,
lethargy/depression, weakness, weight loss, diarrhea, blood in the
stool (melena), shivering, increased urination and drinking, as well
as abdominal pain. Not all dogs will show all these symptoms.
When the mineralocorticoids are also affected signs tend to be more
severe with dehydration, shock and collapse accompanying the other
signs. Gastrointestinal hemorrhage and seizures (due to low
blood sugar and electrolyte imbalances) are less common signs.
Heart rate slows, and pulses become weak, in some cases the heart
may stop beating and death may be the first symptom.
Blood work can be equally
confusing. The hematocrit can be increased by dehydration or
show anemia. In about 20-30% of cases white cell counts will be
elevated, especially eosinophil and lymphocyte numbers, a so called
stress leukogram, due to decreased glucocorticoids. If
aldosterone is deficient there will be significant electrolyte
abnormalities with reduced sodium and chlorine and increased
potassium, calcium and phosphate. The role of aldosterone is
to increase retention of sodium and water by the kidneys.
Without it, urine is dilute and the animal easily dehydrated.
Lack of aldosterone also results in hydrogen ion retention and a
mild acidosis. Albumin (protein), cholesterol and glucose
levels tend to be low, while liver enzymes may be elevated.
One study showed that 24%
of dogs diagnosed with Addison’s did not have classic electrolyte
abnormalities, and the percentage may be higher in some breeds.
These atypical cases may be due to secondary Addison’s –
affecting only the pituitary or hypothalamus – or occur because
the areas of the adrenal glands producing glucocorticoids only or
primarily have been affected. While some cases of atypical
Addison’s go on to include diminished mineralocorticoid
production, by no means all of them will. Dogs with atypical
Addison’s tend to be older, have had a longer duration of symptoms
prior to diagnosis, and be low in protein and cholesterol.
A sodium:potassium ratio
of less than 27 or 28 is strongly indicative of Addison’s disease,
but it is only useful in dogs with mineralocorticoid involvement.
In these cases it is a powerful diagnostic tool, but not absolutely
accurate (~95%). Care should be taken particularly in cases in which
one electrolyte is significantly affected (high potassium, low
sodium) while the other is well within the normal range or even high
normal for sodium). In cases of atypical Addison’s the
sodium:potassium ratio is generally completely normal, and levels of
sodium and potassium well with reference ranges.
Imaging is of little
value. In typical Addison’s you will generally see a smaller
than normal heart and liver and narrowing of cardiac blood vessels.
The adrenal glands may also appear small, but this is subjective.
Elevated potassium will produce characteristic changes in the EKG,
but are not diagnostic. A basal cortisol of <2
micrograms/dl is 100% predictive of Addison’s but not diagnostic.
To diagnose Addison’s you need an ACTH stimulation test. In
this test the dog’s basal serum cortisol is measured. He is
then injected with a dose of synthetic ACTH and the level of
cortisol is recorded again an hour later. (One dose of
dexamethasone can have been administered prior to the test if
necessary to treat a dog in crisis.) In dogs with Addison’s
(typical or atypical) pre and post cortisol levels are usually less
than 1 mcg/dl, but should definitely be below the lab’s reference
range. This range can vary depending upon the laboratory doing the
testing, but is usually <5mcg/dl. Inadequate response will
also be seen in dogs that have been treated for Cushing’s or with
glucocorticoids. Some dogs with sex-hormone secreting adrenal
tumors may also fail to respond. The ACTH hormone is not
terrifically stable, and loss of activity of the ACTH used may lead
to a false diagnosis. A borderline post ACTH level of cortisol
should be retested in four to eight weeks to see if the dog was in
the early stages of adrenal failure.
In cases of atypical
Addison’s, measuring serum ACTH can determine whether the disease
is adrenal (primary, normal ACTH levels) or secondary (pituitary,
subnormal levels). The former are more likely to progress to
full-blown Addison’s disease, and electrolyte levels should be
tested at regular intervals. In one study of 11 dogs with
atypical Addison’s, only one developed mineralocorticoid
deficiency although 9 of the 11 had primary (adrenal) disease,
however. Measuring plasma aldosterone does not appear to be
helpful in reaching a diagnosis or distinguishing different types of
Addison’s disease.
Treating Atypical
Addison’s disease: Conservatively between 5 and 10% of dogs
with primary hypoadrenocorticism only have a glucocorticoid
deficiency. Symptoms tend to be relatively mild and in most
cases look like a gastrointestinal upset with weight loss, vomiting,
loss of appetite, and – especially in small lean dogs – low
blood sugar. The ACTH stimulation test should be run in any
dog with vague waxing and waning clinical signs, general malaise and
weight loss. If the ACTH stimulation test result is consistent with
Addison’s but sodium and potassium levels are normal – atypical
Addison’s – glucocorticoid supplementation should be given as
0.2 to 0.4 mg/kg prednisolone a day, and electrolyte levels and
general health should be monitored every three to four months for a
year. If sodium or potassium concentrations or both become
abnormal the disease has probably progressed to typical Addison’s.
Some veterinarians advocate measuring serum aldosterone
concentrations pre and post ACTH stimulation for confirmation, but
this test is not yet widely available, and has not proven
particularly accurate. Atypical Addisonians should not receive
mineralocorticoids.
Treating an Addisonian
Crisis: During an Addisonian crisis time is of the essence.
If Addison’s disease is suspected in a previously undiagnosed dog
in extremis, blood and urine samples should be collected for a
complete blood count, serum biochemistry, serum cortisol and
urinalysis prior to any treatment. The dog is then given
synthetic ACTH for the ACTH stimulation test, and blood collected an
hour later for cortisol evaluation. (If synthetic ACTH is not
available it is more important to stabilize the dog, and run this
test later.) During the hour, shock doses of 0.9% sodium
chloride (fluids) are given to resolve the loss of blood volume and
blood pressure. The glucocorticoid dexamethasone is given
intravenously (as it doesn’t affect the ACTH stim test result as
oral prednisone or prednisolone would). The dog should be kept
warm to prevent or resolve hypothermia.
Mineralocorticoids are also given. It is preferable to give
desoxycorticosterone pivalate (DOCP, Percorten V) intramuscularly.
Even given daily Percorten does not produce adverse effects in
healthy dogs, and so it can safely be given in suspected cases of
Addisonian crisis even if this proves not to be the problem.
(Giving the drug subcutaneously is contraindicated in dehydrated
dogs, which dogs in Addisonian crisis typically are, due to poor
absorption.) Florine-f – fludrocortisone acetate – may be
substituted if Percorten is not available. It has both
mineralocorticoid and glucocorticoid activity, but has to be given
orally and dogs in Addisonian crisis usually have significant
gastrointestinal upset – vomiting, gastric bleeding – limiting
assimilation. Percorten also corrects electrolyte
abnormalities better than Florine-f. After one or two hours
replacement fluids are reduced to maintenance levels. If the
dog has not responded well within 24 hours, the diagnosis should be
reevaluated.
Maintenance therapy:
Electrolyte levels of dogs treated with DOCP should be checked 2
weeks after the initial dose, and then at weekly intervals.
This is necessary to determine the appropriate dose between DOCP
injections. Once either potassium rises above laboratory
normals of sodium drops below the laboratory reference range, or
both, it is time for the next shot. This interval can range
from every two to every 8 weeks. Novartis, the manufacturer of
Percorten, recommends an initial dose of 1mg/lb body weight, but I
find most dogs of Beardie size or larger do well with an initial
dose of 0.5 mg/lb. If electrolyte levels are still normal
after four weeks an even smaller dose can be given the next time.
Maintenance doses can be given either subcutaneously or
intramuscularly, so owners should be able to give the shots
themselves to lower their costs once the dog is stabilized.
While Florine-f can be used for maintenance treatment, it does not
stabilize sodium and potassium concentrations as effectively as
Percorten and is more expensive for dogs weighing more than 25 lbs.
With stable dogs it is only necessary to recheck electrolytes every
four to six months or if the dog becomes ill. Because Percorten has
no glucocorticoid activity it is necessary to give prednisolone (Beardies
tolerate the artificial drug better than prednisone) at a dose of
2.5 or 5 mg every day or every other day. The dose must be
increased if the dog is stressed or if a stressful situation is
anticipated. In this case increase the prednisolone dose two
or three days before the anticipated stress – travel, visitors,
hospitalization, etc.
While Addison’s is not a
disease anyone would wish for, most dogs are well maintained and can
expect a fairly normal life span and other diseases are usually
responsible for their deaths. Owners become especially keyed
into their dogs and recognize situations that cause their dog stress
and tweak drug doses accordingly. One of the biggest risks now
seems to be that anytime the dog appears not to be functioning
optimally owners increase medication dose, often without consulting
their veterinarian. This response seems to be encouraged by
the Internet Addison’s groups. As a result I have seen a lot
of dogs over-medicated several fold. If your dog is taking
more than the recommended dose of either Percorten or Florine-f
(0.015-0.2 mg/kg/day, although I have maintained Addisonian Beardies
well on doses as low as 0.1 mg a day), do consider the possibility
that your dog is being over-medicated. Fortunately, there is
less risk of this happening if the dog is getting Percorten
injections.
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A grateful thank you to
Linda Aronson, DVM for the use of this article
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