Cushing's Disease (also know as
hyperadrenocorticism- Cushing's is easier to pronounce so stick with
that word) results when the adrenal glands secrete an excess amount
of cortisone. It is the most common endocrinopathy (hormone disease)
encountered in older dogs. This disease is the exact opposite of
another endocrine problem in dogs called addison's disease
This detailed page will emphasize
Cushing's disease in dogs, with an explanation of how it differs from
cats at the end. This is a complex disease that does not lend itself
to a simple explanation or an easy diagnosis. You might want to go to
the bathroom before attempting this page! We have a summary
page on Cushing's if the
explanation on this page is too detailed for your needs.
Several medical terms and abbreviations relate
directly to Cushing's:
cortisone produced by the adrenal glands
size of an organ
exogenous cortisone- supplemental
hypertrophy- increased size of an
mostly cortisol, and a small amount of
affects sodium and potassium
hypoglycemia- low blood glucose
iatrogenic- caused by something a
person does as opposed to happening naturally.
adrenalectomy- surgery to remove
the adrenal gland.
adrenomegaly- enlarged adrenal
anabolic steroid- testosterone and
catabolic steroid- cortisol and
The adrenal glands are small paired glands buried
in fat in the front of each kidney. Even though they are small, the
cortisol they secrete, along with their other functions, have great
significance to normal physiology.
arrows point to the paired adrenal glands in front of
each kidney. The extensive blood supply to the kidneys
and adrenal glands is apparent.
This is a picture of an
adrenal gland (arrow) that is buried in fat near the
kidney (K). It is from a ferret that has an adrenal gland
tumor, so the adrenal gland is inflamed and easily
visualized. This is not necessarily the case in dogs and
cats that have adrenal gland tumors.
The internal architecture of the adrenal gland is
made up of several distinct zones.
The cortex of the adrenal gland is made up of 3
This is the outer layer of the adrenal gland. This section
secretes the mineralcorticoid aldosterone. Aldosterone is vital to proper
sodium and potassium regulation.
This is the next layer as you go inward, and
produces the glucocorticoid cortisol. The cells in this area
are the ones that cause Cushing's.
As we continue inward we come across this section that
secretes the sex hormones known as androgens (male sex hormones), estrogen
(female sex hormones), and sex steroids. These are usually secreted in such
small amounts as to be of no major significance in healthy animals.
This consists of the very center of
the adrenal gland. It secretes hormones called catecholamines.
The two important ones are epinephrine (adrenaline) and
These tiny organs have a profound influence on
many internal organs. The hormones they secrete work in unison with
other internal organs, particularly the liver, and have an enormous
effect on physiology. These hormones interact with many other
hormones that have the opposite effect, usually in some type of
feedback mechanism that is monitored by the brain. This interaction
is complex, so only a summary of adrenal hormone physiology is
The adrenal glands secrete several important
hormones, most of which are synthesized from cholesterol. We will
explain 3 of them; cortisol, aldosterone, and epinephrine:
Cortisol is a hormone that is essential for
life. Cortisol maintains a normal blood glucose level, facilitates
metabolism of fat, and supports the vascular and nervous systems.
It affects the skeletal muscles, the red blood cell production
system, the immune system, and the kidneys.
It is considered a "catabolic steroid". This
means it takes amino acids from the skeletal muscles and with help
from the liver converts them to glycogen, the storage form of
glucose. These functions are the exact opposite of "anabolic
steroids", the drugs that weight lifters take to increase muscle
mass. The end result of this is an increase in the level of
glucose in the bloodstream. The hormone called insulin has the
opposite effect on blood glucose, adding to the complexity of this
system. You can learn more about insulin by going to our
The level of cortisol in the bloodstream
continually fluctuates as physiologic needs vary. Surgery,
infection, fever, and hypoglycemia (low blood sugar). will cause
cortisol to increase. This continual fluctuation adds to the
difficulty of diagnosing Cushing's.
To control the level of cortisol the
hypothalamus and pituitary gland in the brain secrete chemicals
into the bloodstream called releasing factors. In the case of the
adrenal glands , the hypothalamus secretes a hormone called
corticotropin releasing hormone (CRH). It goes to the pituitary
gland and stimulates it to release a hormone called
adrenocorticotrophic hormone (aCTH). It is the amount of aCTH
circulating in the blood stream that tells the adrenal glands
(specifically, the cells at the zona fasciculata) how much
cortisol to secrete. There is a negative feedback loop that allows
the hypothalamus and pituitary gland to refine precisely how much
cortisol circulates in the bloodstream. The more cortisol secreted
by the adrenal glands, the less CRH and aCTH secreted. This allows
the body to precisely refine the level of cortisol, and to change
the level rapidly due to changing physiologic needs.
Numerous internal organs are affected by
Cortisol is needed for proper muscle action,
yet too much can cause the muscles to atrophy (shrink). This is
due to their catabolic effect. This means that they literally
cause the body to use the amino acids in the muscle fibers to
increase the blood glucose (sugar) level. Cortisol does this in
a complex mechanism that involves the liver. The end result is
the muscles become smaller. When this occurs at the abdominal
muscles the abdomen appears pot bellied.
Bone is made up of a protein matrix and
calcium, both of which are affected by cortisol. Excess
cortisol affects the protein matrix, decreases calcium
absorption from the intestines, and increases calcium excretion
by the kidneys. Skeletal mass decreases and bones become
It causes atrophy of hair follicles and
sebaceous glands, which leads to alopecia (hair loss). Elastic
tissue under the skin is also affected, leading to thinner skin
and adding to the pendulous abdomen. The disruption in the
elastic tissue of the skin can also cause calcium changes in
the skin. This might lead to areas where calcium builds up in
small nodules. In cats the skin changes can become severe, and
are called the fragile skin syndrome.
Cortisol is required for maintaining the integrity of the
lining of blood vessels. An excess will lead to thinning of these walls
and the potential for rupture. The end result is a hematoma. Cortisol also
increases the number of circulating red blood cells and helps maintain blood
Central Nervous System (CNS)
Cortisol is necessary for the normal
maintenance of brain functions. It can interfere with sleep and
change the mood. You might notice these effects if your dog has
Cushing's or is given supplemental cortisone for treatment of a
Excess cortisol will increase the workload
on the liver
as it converts amino acids to glycogen. Pets with Cushing's
will commonly have an enlarged liver, known as hepatomegaly.
You will be shown a picture of an enlarged liver on an x-ray in
the diagnosis section.
An increase of cortisol increases the blood flow (also
called GFR-glomerular filtration rate) to the kidneys. This will result
in an increase in the amount of water and waste products filtered by the
kidneys. Our kidney
disease page has more details. This is one of
the reasons why dogs with Cushing's drink and urinate excessively (PU/PD),
and urinate a dilute urine.
This is one of the more profound functions
of cortisol. It decreases the inflammatory process and helps
minimize an over reaction of the immune system to foreign
bodies or infections. Unfortunately, it also suppresses the
immune system to the point that the body has a hard time
mounting a proper response. The body is more susceptible to
infections, especially those caused by bacteria.
Aldosterone is the principal mineralcorticoid secreted by
the adrenal glands. This hormone is secreted as a response from the kidneys
when fluid volume in the bloodstream is decreasing. It involves other hormones
called renin and angiotensin. The end result is an increase in sodium in the
bloodstream, with a corresponding increase in blood volume and blood
pressure. This hormone also interacts with and
affects potassium levels. To further complicate the picture, ACTH also has
an affect here, just like it does with cortisol.
This part of adrenal gland physiology is not
significantly altered in Cushing's. addison's disease, which is
the production of too little cortisone, has a greater affect on
This compound, technically called a
neurotransmitter, also has hormone-like properties. It is a very
powerful chemical that effects all organ systems. It acts very
rapidly, with effects remaining only for a short period of time.
It is the primary reason the body has the ability to respond to an
emergency. This physiologic mechanism is also known as the "flight
or fight" response.
Upon stimulation of the central nervous system (ex.-fear
or pain), the adrenal medulla is stimulated to secrete epinephrine into the
bloodstream. We are all familiar with what happens next. The pupils dilate,
the heart rate and blood pressure increase, and the palms get sweaty. Internally,
the body is increasing the blood glucose level, the breathing passages are
opened up, more red blood cells are secreted into the circulation, blood is
shunted away from the skin and other internal organs, and blood flow is increased
to the brain and skeletal muscles. All of this has the effect of bringing
the brain and skeletal muscles extra glucose and oxygen, and accounts for
the extra boost of awareness and energy we all feel at this time.
Up to 90% of all Cushing's cases in dogs
fall into this category. The pituitary gland is invaded with a slow growing
cancer called an adenoma. This causes it to secrete an excess amount of ACTH.
The cells in the zona fasciculata area
of the adrenal glands respond to this excess ACTH
by hypertrophying (enlarging) and secreting excess cortisol. It is this excess
of cortisol that is circulating in the bloodstream that causes the symptoms
we see in this disease.
This pituitary gland tumor can
remain slow growing and not effect the pet any more than inducing
Cushing's disease. In 10-20% of these tumors they enlarge to the
point that they will cause significant neurologic symptoms.
Unfortunately, some of these neurologic symptoms mimic those seen
as side effects to the medication used to treat
tumors are best diagnosed using an MRI (magnetic
resonance imaging). This boxer has a large white tumor in
Non-Pituitary Dependent (AT)
In up to 15% percent of Cushing's there is
an actual tumor of one of the adrenal glands (sometimes both are involved).
The tumor enlarges and secretes excess cortisol in the bloodstream. This excess
cortisol is monitored by the hypothalamus and pituitary in the negative feedback
mechanism, causing them to secrete less ACTH.
Less ACTH in
the bloodstream will cause the other adrenal (if it does not also have a tumor)
to atrophy (shrink).
The benign version of this
tumor occurs 50% of the time, and is called an adenoma. The
malignant version, which occurs the other 50% of the time, is
called an adenocarcinoma. It can invade the primary vein returning
blood back to the heart (called the vena cava), and spread from
the adrenal gland to the liver,
lung, kidney, and lymph nodes.
The white arrow points to a very small
and normal adrenal gland in a ferret. A
lobe of the liver has been pulled to the left (forward) so that you
can see the adrenal gland. The dark blue structure running horizontally
is the vena cava as it courses past the liver towards the heart. The
close proximity of the adrenal to the vena cava and liver shows how
easily a malignant tumor here can spread into the bloodstream and lodge
elsewhere in the body.
chest radiograph follows the vena cava (arrows) as it
continues from the liver to the heart. Unfortunately, the
heart unwittingly can now pump cancerous tissue to the
rest of the body.
are a common problem in ferrets.
The adrenal tumor in this case does not secrete excess cortisol, so technically
the disease is not called Cushing's. The tumor causes an excess secretion of
sex hormones, causing a different set of symptoms when compared to the dog and
Exogenous (external or
supplemental) use of cortisone is very common in medicine. It is a
highly beneficial drug used to treat a wide variety of diseases.
In some cases it is used as an emergency drug to literally save a
life. Cortisone is beneficial in several disease
- Immune system
- Neoplasia (cancer)
- Cerebral edema (brain swelling)
Long term use of cortisone, in oral, injectable, or even
topical form, might cause an animal to have the symptoms of Cushing's disease.
It all depends on the type of cortisone used, the dose it is used at, and
the duration of use. As a general rule, once the original symptoms of the
disease are treated with cortisone, we recommend decreasing its use, stopping
its use, or finding an alternative drug. Sometimes this is not feasible though.
The level of cortisone that results from this exogenous use
will cause the adrenal glands to atrophy. The negative feedback loop tells
the brain there is plenty of cortisol in the bloodstream, so the pituitary
secretes less ACTH. The pet has the symptoms of Cushing's because cortisone
is being introduced into its body, not because the adrenal glands are producing
it in excess amounts.
Exogenous cortisone goes by several names. They
come in injectable, oral, and topical forms, and tend to be more
potent than the cortisol that is naturally produced by the adrenal
glands.Some of the more common ones
Ectopic ACTH Syndrome
This is a rare version of
Cushing's that does not fall into any of the above categories. It
can be found in association with cancer in the dog.
Some dogs with Cushing's disease
show the classic symptoms, while other show only a few vague
symptoms. The classic symptoms are:
(PU/PD)- This is excess urinating and excess drinking of water. It
is one of the first signs of the disease, and usually precedes the
other symptoms by a significant period of time. Several other
important diseases cause these symptoms also, notably liver
Pot bellied abdomen to the
point a dog might look pregnant. It is due to hepatomegaly and
abdominal muscle weakness.
Thin skin and usually
symmetrical hair loss along the trunk. The hair might grow in
lighter in color or lose its luster. It might not grow in well at
all. Calcium deposits under the skin, called calcinosis cutis,
occur on occasion. Secondary skin infections are common also. The
skin might also be hyperpigmented.
Muscle wasting over the head,
shoulders, thighs, and pelvis.
Other occasional symptoms
- Pruritis (itchy skin)- due
to secondary bacterial, fungal, or parasitic
- Panting- due to affects on
the lungs or the respiratory center in the brain
- Anorexia (poor appetite)
- Straining to urinate or blood in urine due
to urinary tract infection or bladder
- Irregular heat cycles in female
- Testicular atrophy in males and clitoral
enlargement in females
- Emesis (vomiting) due to
- Ataxia (incoordination),
blindness, circling, and seizures due to a large pituitary tumor or spread
of a malignant adrenal tumor
- Lameness due to a ruptured cruciate
approach is needed for a correct
diagnosis of Cushing's. In every disease we encounter we follow the tenet's
of the diagnostic approach to ensure that we make an accurate diagnosis, and
also so that we do not overlook some of the diseases that are common in pets
as they age.
Diagnosing some cases of Cushing's
is straightforward, especially if the disease has been present for a
significant amount of time before a diagnosis is made. These are the
pets that have the classic symptoms noted above, and fit the pattern
found during a physical exam and routine blood samples. The adrenal
screening tests are used to verify the diagnosis.
Some dogs have the normal symptoms
of Cushing's, but routine blood sampling does not bear this out. In
these cases some of the more specialized tests like ultrasound and
adrenal screening tests are needed to make the diagnosis.
Cushing's tends to be a problem
that affects older dogs, usually greater than 10 years of age. The
disease tends to have a slow and gradual onset, so the early
symptoms are easily missed.
Several canine breeds are prone to getting
- Yorkshire Terrier
- Boston Terrier
Females and males get it at about the same
frequency, neutered pets might be at higher risk of
Cushing's disease is suspected
in any pet that has some of the symptoms described above,
particularly the skin symptoms and the PU/PD. It is important to
remember that some dogs do not show any symptoms early in the
course of the disease. This is another reason for yearly exams and
blood and urine samples in dogs and cats 8 years of age or
Other historical findings
include skin infections that recur after antibiotic therapy is
stopped. Some dogs have a history of pruritis (itchiness) if
pyoderma is present.
A history of poorly
controlled diabetes mellitus might also clue us in to Cushing's.
3. Physical Exam
Routine physical exam findings might
Pot bellied abdomen
The abdomen of this dachshund is pot bellied due to
Cushing's. It could also have been due to fluid buildup from cancer
or heart disease. An enlarged liver from a disease other than Cushing's
can cause this also.
nodes due to secondary bacterial infections or
spread of an adrenal tumor.
An enlarged liver (hepatomegaly) might be palpated, along
with smaller muscle mass (atrophy) in general.
Bruising (hematoma) might be observed under
the skin, or when a blood sample is obtained.
Skin infections and wounds that do not heal
or recur after antibiotics are stopped.
Hair loss (alopecia) that is symmetrical,
along with thin skin, poor hair coat, and calcium deposits
under the skin. Many
skin conditions have similar symptoms, so numerous diseases
have to be kept in mind. They
Blood pressure might be elevated. This might
cause a detached retina, picked up by an ophthalmic
Heart disease, initially noted with the
stethoscope as an increased heart rate, an irregular heart
rate, or a murmur.
Several tests are used as an
aid in making this diagnosis. Each test has its advantages and
usually negative in Cushing's, although demodex
is possible as a secondary problem due to the immunosupression
effect of cortisol.
a CBC (complete blood count)
and biochemistry panel should be run on every dog 8 years of
age or more, especially if they have any of the symptoms of
The CBC might show an increase in the number
of red blood cells (RBC's).
It might also show an
increased WBC (white blood cell count), called leukocytosis.
When these white blood cells are broken down, there are usually
more neutrophils (neutrophilia), less lymphocytes
(lymphopenia), and less eosinophils (eosinopenia). These white
blood cell abnormalities can also be caused by the "stress
response". It is due to excess epinephrine and cortisol
secreted in response to the actual process of taking the blood
sample (those people that have passed out when their blood was
taken are an extreme example of this). The excess cortisol
secreted by the adrenals in the stress response is temporary,
and part of normal physiology. It is not caused by Cushing's
Cholesterol, blood glucose, and liver enzyme
tests (ALT) might be elevated in Cushing's. If a thyroid
test is run it might be low or
An elevated alkaline
phosphatase (Alk Phos) is a consistent finding in Cushing's. This is an
enzyme that is located in the bile production area of the liver. The excess
cortisol influences this enzyme, although growing animals, fractures, obstructions
of the bile ducts, liver disease, drugs, pets with diabetes mellitus, and
pets with cancer can all cause an elevated Alk Phos.A
significantly increased Alk Phos alerts us to keep Cushing's in our tentative
This dog has a mildly elevated liver
enzyme test and mildly elevated Alk Phos. If the signalment, history,
and physical exam do not make us suspect Cushing's we probably will
not proceed to adrenal screening tests. This dog should be examined,
and the blood should be checked every 3-6 months to see if these abnormalities
This dog has a normal liver test but
a higher Alk Phos than the dog above. Some dogs even go much higher
than this, especially if the disease has been present for a long period
of time. This dog needs further diagnostic tests if there are any other
Cushing's symptoms present also. Note the 3 arrows on the bottom that
point to Cholesterol, Bun, and Creatinine. Cholesterol is usually high,
but BUN is usually low, not high, in Cushing's Disease. The high BUN
and creatinine could indicate that this pet might be dehydrated, or
even have kidney
disease in addition to Cushing's.
A normal specific
gravity in a dog should be around 1.025, and there should be no or minimal
protein, glucose, WBC's, or bacteria, as a general rule. In Cushing's the
specific gravity of the urine might be low, the protein might be elevated,
and a urinary tract infection might be present because of excess glucose
in the urine.
urinalysis of a Cushing's dog shows a low specific
gravity and excess protein, but the glucose is normal
and there is no sign of an infection.
This test can give us an idea that Cushing's
is the cause of a skin problem. Many of the changes that are
noted microscopically when evaluating the biopsy are also seen
in other diseases, so it is not specific for Cushing's. In
spite of this fact, skin biopsies give us a large amount of
information in skin conditions.
Radiography might be of
value if the adrenal glands are calcified (happens in up to 50%
of adrenal tumors), otherwise the adrenals do not show up on a
radiograph. Hepatomegaly can be seen on the radiograph, along
with problems associated with other diseases in pets this age,
so a radiograph can be highly beneficial to help rule them out.
Radiography might also show osteoporosis (poor bone density)
and calcification of soft tissue, both of which could be due to
In this lateral
view (laying on its side) of the abdomen, the kidney (K)
closest to the arrow is the right kidney. The arrow
points to where the right adrenal gland is located,
although it cannot be seen since it is not calcified. The
whitish area between the K's is normal, and is caused by
the effect of the 2 kidneys as they
This is a
VD (ventral-dorsal, or laying on its back) view of a dog.
The left kidney (K) is labeled, and the arrow points to
where the left adrenal gland is located. There is some
calcification in this radiograph, but it is not at the
adrenal gland. Can you see it?
The liver (L) might be enlarged
(hepatomegaly), although this enlargement can be found in
other diseases, especially liver cancer and diabetes
This test can be highly
beneficial in this diagnosis. The adrenal glands can be
measured, and their internal architecture (called parenchyma)
can be analyzed. It is not feasible to visualize all of the
distinct different zones of the adrenal gland though. Other
internal organs are also checked, giving us a substantial
amount of information from just one test.
adrenal gland measures 1.9 cm by 0.9 cm, so it is a
little enlarged (hypertrophied).
dog also had an enlarged spleen (splenomegaly) with a
mass in the center of the spleen
final report summarized the problems:
This is the most reliable way to confirm
a diagnosis of Cushing's disease. These tests evaluate the interactions
that are occurring between the hypothalamus, the pituitary gland, and the
adrenal gland. The interaction between these glands is known as the hypothalmic-pituitary-adrenal
axis. The first goal is to determine if Cushing's disease exists. The next
step is to determine if it is pituitary dependent (PD) or non-pituitary
dependent (an adrenal tumor- AT).
You might want to go back to the Cause
Section above for a review before
Testing this axis is not as easy as it
sounds. The mammalian body is a dynamic system with thousands of chemical
reactions and interactions occurring simultaneously. Also,
levels of cortisol are in a continual state of flux. Because of this there
are inherent limitations with laboratory testing.
The normal values in animals
calculated by a particular lab are called reference values.
They reflect 95% of the population, statistically the same
thing as the values that fall under the bell shaped curve. Not
every animal falls perfectly into this range, so there is
always a degree of interpretation needed in determining whether
a value is abnormal or not. Eventually, it boils down to a
determination of probabilities.
Two important concepts of
laboratory testing relate directly to Cushing's:
The sensitivity of a test refers to the
ability of that test to detect diseased patients. A
Cushing's test that is 95% sensitive will diagnose Cushing's in 95% of
all dogs with Cushing's disease. 5% of the dogs in this scenario will
have Cushing's, even though their screening test for Cushing's says they
don't have the disease.
The specificity of a test refers to the
ability of the test to detect only diseased patients. A
Cushing's test that is 95% specific means that 95% of the time if the
test is positive for Cushing's, the animal really does have Cushing's.
This means that 5% of the time the test will say an animal has Cushing's
disease when in reality it does not.
Animals that do
not have Cushing's disease might show up positive on these tests, while
others that have the disease might be negative on these tests. Many times
we have to play the odds based on probabilities. Due to this limitation
in testing we recommend using these tests in combination, and repeating
them if they do not give clear cut answers.
These tests sometimes come back as positive
for Cushing's when in reality other diseases are affecting the cortisol
level. Some of these diseases (called non adrenal illness) include liver
disease, chronic kidney disease, urinary tract infection, skin diseases,
and uncontrolled diabetes mellitus. Also,
cortisone and anticonvulsants can give false positives.
The most common screening
tests are as follows. If you make it through this next section
then you should give yourself a pat on the back. You might just
want to go right to a summary
of these tests.
Urine cortisol:creatine ratio
In this test the level of cortisol in the
urine is measured and used as an indication of the ortisol
level in the bloodstream. Creatinine is measured to adjust
for different levels of urine dilution. Our kidney
page has more information on
This test is useful as a screening tool
when our differential diagnosis (you know what that means
because you read the Diagnostic
Process page) does not put
Cushing's on the top of the list. For example, we might use
it in a pet that has PU/PD, but not the other signs of
Cushing's. It works in both dogs and cats.
This test is easy to perform because all
that is needed is a urine sample. We recommend you obtain
this sample at home in the morning just after your pet wakes
up. Bring it to us immediately for analysis by our lab.
Obtaining it at home will minimize the stress of a car ride
and a visit to our hospital, both of which will normally
increase the level of cortisol in the bloodstream (remember
the stress response?), thus affecting this test.
A high level of cortisol in the sample is suggestive
of Cushing's. Unfortunately, up to 80% of dogs that don't have Cushing's
will also have an increased level. This means that the specificity is
low. A cortisol:creatinine ratio test that is high needs one of the other
screening tests to determine if Cushing's is indeed present. If the test
comes back normal, then it is unlikely that Cushing's is present.
This test checks for Cushing's and
addison's disease. Some experts recommend this as the best
general test for a diagnosis of Cushing's. It is also used
to monitor therapy on pet that is on medication for
When a dog or cat is given ACTH by an injection the adrenal
glands are stimulated to produce cortisol. By measuring this cortisol
with a blood sample we can determine what reserve the adrenal glands have
in the production of cortisol.
This is the ACTH we inject. It is given at a specific
dose depending on the weight of the pet.
This test is very specific for Cushing's, so false
positives are rare compared to other screening tests. It is not as sensitive
as other screening tests, particularly the LDDS test. For this reason it
is sometimes used in combination with the LDDS test.
This is the only test that can distinguish between iatrogenic
and naturally occurring Cushing's. It is the only test that gives reliable
results for a dog that has been on cortisone recently. It does not distinguish
between pituitary dependent (PD) and non-pituitary dependent (AT-adrenal
A blood sample is taken to measure the resting cortisol
level before ACTH is given. Two hours after the ACTH injection is given
a blood sample is taken again to measure the level of cortisol. This two
hours gives the ACTH injection time to stimulate the adrenal glands to
In the dog, if the second test of cortisol is much higher
than the first, it is suggestive of Cushing's 80-95% of the time. It does
not necessarily tell us if it is PD or AT, because this exaggerated response
will occur in 85% of PD Cushing's, and also 50% of those with AT Cushing's.
This test is not as reliable in cats, only 51% of cats with Cushing's
will show an exaggerated response.
If there is a reduced level of cortisol
on the second blood sample then either the dog has addison's
disease or iatrogenic Cushing's. This reduced response also
occurs in dogs that are receiving Mitotane or Ketaconazole
therapy for Cushing's.
Between 5% and 20% of dogs that have Cushing's (either
PD or AT) will not show the exaggerated response expected with this disease.
If we suspect Cushing's in these dogs then the test should be repeated
at a later date or the LDDS test should be performed.
Low Dose Dexamethasone Suppression Test
This is also a good test when the history, physical exam,
and routine blood panel and urinalysis are consistent with Cushing's.
It might also help differentiate between PDH and AT, but that is better
determined by the HDDS test (High Dose Dexamethasone Suppression test).
It only works in dogs because cats get a significant number of false positives.
It is sensitive for Cushing's because 85%
to 100% of the time it finds a Cushing's disease that is
present. Its specificity is low though, meaning it might
come back as positive for Cushing's between 44% and 73% of
the time when the dog does not have Cushing's.
This dose of dexamethasone (which is a version of cortisone)
suppresses the adrenal gland from producing cortisol in normal dogs, but
not those with Cushing's. It achieves this suppression by interfering
with the negative feedback mechanism. The dexamethasone is monitored by
the brain as an excess of cortisone in the bloodstream, so less ACTH is
secreted, and therefore less cortisol is secreted by the adrenal gland.
In this test an injection of Dexamethasone is given and
cortisol levels are measured at 4 hours and 8 hours after the injection.
Like the ACTH stimulation test, a pre-injection blood sample is taken
to measure the resting cortisol level.
In interpreting this test we look at the 8 hour sample
first. At this time cortisol levels should be below the baseline level
obtained before the injection. If not, then a diagnosis of PD or AT Cushing's
is made, or there is a false positive result. If the 4 hour or 8 hour
cortisol test result is less than 50% of the normal resting cortisol,
then a diagnosis of PD Cushing's or false positive is made. If the 4 hour
or 8 hour cortisol test result is greater than 50% of the normal resting
cortisol, then a diagnosis of Cushing's is made or there is a false positive.
In this last scenario it cannot be determined if the Cushing's is PD or
If the 4 or 8 hour samples show
suppression when compared to the normal resting cortisol
level then there is no Cushing's disease, or else there is a
Here are the
LDDS test results on a dog that we suspected of having
Cushing's. What is your diagnosis in this
High Dose Dexamethasone Suppression Test
This test is not used as a routine
screening test. It comes into play when a dog already has
Cushing's and you want to be certain that it is not that
occasional case that is an adrenal tumor.
The protocol for this test is similar to the LDDS test,
except of course, a higher dose of dexamethasone is injected. A dog with
an adrenal tumor does not suppress cortisol levels from the baseline sample.
Summary of Cushing's
In some dogs with Cushing's the excess
cortisol that circulates in the blood stream will spill over
into the urine. If this test is positive then a dog might
have Cushing's. If it is negative, there is a good chance it
does not have Cushing's.
A positive on this test gives a reasonably good chance
that a dog has Cushing's. It will not catch all dogs with Cushing's, so
a dog with a negative test might still have the disease.
This test will catch most dogs that have the disease.
A negative on this test means that most likely the dog does not have Cushing's.
A positive on this test indicates that a dog might have Cushing's.
See how easy that was!
5. Response to
One of the tenets of the
process is whether or
not a treatment that is instituted actually corrects the problem.
This usually applies to Cushing's. You should note significantly
less PU/PD, improved skin, and a more active pet if the treatment
This disease tends to occur in
older dogs that commonly have other problems. Some dogs die of other
diseases before the symptoms of Cushing's become a significant
problem. Treating Cushing's does not necessarily give your pet a
longer life. The goal of therapy is to give your pet a better quality
Underlying problems need identification and
treatment. If your dog is hypothyroid
the problem needs to be corrected with supplemental soloxine.
Internal organ problems like kidney
disease need treatment for a successful
Cushing's outcome. Urinary tract and skin infections need to be
cleared up with the use of antibiotics, and underlying
mellitus needs to be regulated with
Some dogs with large tumors of the pituitary gland
might initially respond to medical therapy for pituitary dependent
Cushing's. The Cushing's symptoms, especially neurologic, might recur
as the tumor progresses.
Several different treatment modalities have been
developed for Cushing's:
Pituitary Dependent (PD)
This drug should be considered first in the
treatment of PD Cushing's. It works only for PD Cushing's. It
is used for Parkinson's disease in people and is also used to
treat canine cognitive dysfunction (CD). This is helpful
because one medication can be used to successfully treat 2
diseases that occur in older dogs.
It affects the hypothalamus and its interaction with the
pituitary gland in relation to a chemical called dopamine. There are minimal
side effects, especially when compared to the other drugs used to treat
Cushing's. ACTH testing is of no value to monitor effectiveness since the
drug does not act on either the pituitary or the adrenal gland.
It is given daily for 2 months, with the dose increased
if the symptoms don't diminish. The majority of PD Cushing's dogs will show
an improvement in symptoms within the first 2 months. If there is no improvement
within one month after the dose is increased then concurrent illnesses need
to be looked for. If they do not exist then therapy with mitotane should
be instituted. Anipryl drug should not be used if your pet is being treated
with Mitaban, or with antidepressant medications or Prozac.
This drug, know by the trade name of
Lysodren, selectively destroys the zona fasciculata and
reticularis, effectively limiting the amount of cortisol that
these areas of the adrenal gland can secrete. Pets that are on
insulin for diabetes mellitus need to have their mitotane and
insulin doses adjusted downwards. It should be administered
with meals to enhance its absorption.
This drug is first administered at a loading
dose for 7-10 days.
Side effects are not uncommon:
- emesis (vomiting)
- anorexia (poor appetite)
- ataxia (incoordination)
Side effects are due to the cortisol level
being reduced below normal levels. Even if the cortisol level
does not go below normal levels, a rapid decrease in elevated
cortisol levels to the normal range can still cause these
You need to closely observe your pet when it
is on mitotane for any of the above side effects. If they occur
you are to immediately stop medicating and call us. We will
already have given you prednisone pills to give at home if side
effects are significant.
After 7-10 days of loading dose the cortisol levels are
assessed with the ACTH stimulation test. Do not give your pet any supplemental
cortisone on the day of testing. The pre and post cortisol levels should
be normal. If they are, then we will continue to use mitotane at a weekly
maintenance dose to prevent the problem from recurring again. Once your
pet gets to this point it is rare to need any supplemental cortisone pills.
Two long term effects can occur while on
mitotane maintenance therapy:
1. The Mitotane can be so effective
that the adrenal glands do not produce enough cortisol for
normal physiology. This is called iatrogenic
hypoadrenocorticism. In these dogs we stop all mitotane
therapy and use supplemental prednisone. Sometimes this side
effect is permanent, and your dog needs to be on
supplemental prednisone the rest of its life.
2. It is not uncommon for relapses of
Cushing's to occur within 12 months, even while on the
maintenance therapy. These dogs are again given a loading
dose of mitotane, then converted to maintenance dose when
cortisol levels are normal.
Both of these effects emphasize the need for continual
monitoring of your pet. This means close observation at home and ACTH stimulation
tests every 3-6 months.
We have a complete page explaining Anipryl.
This is a drug routinely used to control fungal infections.
It has a different mechanism of action than mitotane. It inhibits cortisol
production in dogs and humanoids by preventing enzyme pathways from functioning
properly. Ketaconazole works for PD and AT Cushing's. It is not as common
to use as the previous 2 drugs.
It needs to be given at a test dose initially to watch
for anorexia or emesis. If tolerated well, a loading dose is given for 7-10
days. After an ACTH test to determine if the cortisol is in the normal range,
the drug is given every 12 hours for the rest of the dogs life. This is
a more expensive proposition than mitotane.
Surgery to remove both adrenal glands can also be used.
It is an involved endeavor performed at a specialized surgical hospital.
Post operative complications are common, and these pets need lifetime prednisone
replacement therapy. As a result, this treatment is not commonly utilized.
Recurrence of the symptoms of PD Cushing's
after initiation of therapy might be an indication of a large
pituitary tumor. MRI is recommended to identify this type of
tumor. Radiation therapy is recommended to prevent further
progression of symptoms. Unfortunately, there are very few
specialty radiation centers that can perform this procedure.
This form of Cushing's is the easiest to treat
since we are not giving a medication but taking one away. In most
cases the elimination of exogenous cortisone will return your pet
to normal function, although this might take several months. Some
of the skin changes might take longer, and may not even return
completely to normal. In some cases we use a decreasing dose of
supplemental prednisone for several weeks to give the adrenal
glands time to resume normal production of cortisol.
Adrenal Tumor (AT)
The surgery to remove the cancerous adrenal
gland is called an adrenalectomy. It is a specialized surgery that
is not routinely performed. Post operative complications are
Because the remaining adrenal gland is atrophied the dog
needs to be supplemented with prednisone until the gland returns to normal
function. ACTH tests are done every few months to determine when the gland
is functioning normally, which can take up to 12 months.
Adrenal tumors can also be treated with mitotane at high
doses and for a long period of time. Side effects are common at this dose,
and relapses can occur. These dogs will also need to be on supplemental prednisone
for the rest of their lives.
Cushing's in cats is rare compared to dogs. One
reason is because they tend to be more resistant to higher levels of
cortisol, especially if iatrogenic. Most feline Cushing's occurs in
females. It can affect the ability to control the blood sugar level
in cats with diabetes mellitus concurrently.
Cats do not show as much PU/PD as dogs do,
unless they have diabetes
mellitus concurrently. Most cats are
presented in a more advanced state of Cushing's disease because
the early symptom of PU/PD is not observed. They might also have
hepatomegaly, weight gain, pot-bellied appearance, and muscle
Sometimes the skin is easily bruised and torn.
This is called the fragile skin syndrome.
picture is from an older cat that was at the groomer to
be clipped. The skin literally peeled off like wet tissue
paper when the groomer attempted to clip some
Cats do not routinely show any changes on a
regular blood panel or urinalysis. The most consistent finding on
a blood panel is hyperglycemia. an elevated alkaline phosphatase
occurs in only a minority of cases. Oftentimes the elevated
alkaline phosphatase is due to liver changes from unregulated
The urine cortisol:creatine ratio test is
helpful in cats, especially since it is a relatively stress free
test compared to blood sampling. If the test is normal then there
is much less of a chance that Cushing's is present. It the test is
elevated it might be Cushing's, but there are also other
situations that cause this elevation.
The ACTH stimulation test is used, but two blood samples
need to be analyzed at 30 and 60 minutes, instead of the 1 sample at 2 hours
for the dog. This is because the increase in cortisol is variable in the cat.
False negatives are common. False positives occur in stressed cats or those
with non adrenal illness.
The LDDS test is used but the dexamethasone that is injected
needs to be given at a higher dose. This test, when used in conjunction with
the ACTH stimulation test, is one of the best ways to diagnose Cushing's in
The HDDS test to differentiate PD from AT has not been refined
to the point that is of diagnostic value.
In general, results of these tests can be
variable, and must be interpreted in conjunction with the history
and clinical findings. In light of the fact that Cushing's is
uncommon in cats, these tests need careful
If the above tests suggest Cushing's then radiology can be
helpful since up to 30% of feline adrenal tumors are mineralized. Other radiographic
findings include hepatomegaly and obesity. Ultrasonic evidence of an enlarged
adrenal gland (especially if unilateral) or changes in internal adrenal architecture
is strong evidence of an adrenal tumor (AT).
Adrenal tumors occur in about 20% of feline Cushing's. They
can be malignant or benign.
Medical therapy is generally unrewarding.
Ketaconazole can be used, but the effects are variable, and side
effects can occur. Mitotane might help, along with metyrapone.
Metyrapone may be more helpful as a presurgical stabilization
prior to surgery. Anipryl has not been used in cats.
Surgery is needed to remove one of the adrenal
glands if the gland has a tumor, and both glands if the problem is
PD. If both glands are removed the cat has to be on supplemental
cortisone and mineralcorticoids for the rest of its life. Some
cats with concurrent diabetes mellitus will no longer have the
disease when their adrenal tumor is removed.
Unfortunately, cats with Cushing's can be poor
risks due to diabetes
mellitus and fragile skin. When this
occurs we sometimes will use medical therapy to help control the
problem and make our patient a better anesthetic risk.
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