Introduction
This page summarizes the complex
disease know as Cushing's disease, also know as hyperadrencorticism.
It is a disease that occurs from the overproduction of cortisone by
the adrenal glands
Anatomy
The adrenal glands are small paired glands buried
in fat in the front of each kidney. Even though these glands are
small, the cortisol they secrete, along with their other functions,
have great significance to normal physiology.
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.
Cortex
This is the section that produces the
glucocorticoid cortisol. Cortisol has large effects on
carbohydrate and protein metabolism.
Medulla
This consists of the very center of
the adrenal gland. It secretes hormones commonly known as
epinephrine or adrenaline.
Physiology
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 a profound
effect on the body. They also 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 a
summary of adrenal hormone physiology is presented.
The adrenal glands secrete several important
hormones, most of which originate from cholesterol. The most
important hormone secreted in relation to Cushing's is called
cortisol.
Cortisol, also commonly known by the slang term
"steroids", 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 kidney system.
Stress will increase the level of this hormone in
the bloodstream. This includes surgery, infection, fever, and
hypoglycemia (low blood sugar). The level of this hormone continually
fluctuates in the bloodstream depending on physiologic needs. This
continual fluctuation adds to the difficulty of diagnosing Cushing's,
which you will learn about soon.
To control the level of these hormones, the hypothalamus and
pituitary gland in the brain secrete chemicals into the bloodstream. One of
these chemicals is called adrenocorticotrophic hormone (ACTH). It is the amount
of ACTH circulating in the blood stream that tells the adrenal glands 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 ACTH secreted.
This allows the body to precisely refine the levels of cortisol, and change
cortisol levels rapidly due to changing physiologic needs.
Cause
Pituitary Dependent
(PD)
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 adrenal glands respond to this excess ACTH
by 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.
Non-Pituitary Dependent
(aT)
In up to 15% of Cushing's there
is an actual tumor of one of the adrenal glands (sometimes both
are involved). It enlarges and secretes excess cortisol in the
bloodstream.
The benign version of this
tumor occurs 50% of the time, and is called an adenoma. The
malignant version, which occurs the other 50% or the time, is
called an adenocarcinoma. It can spread from the adrenal gland to
the liver, lung, kidney, and lymph nodes.
Iatrogenic
Long term use of supplemental cortisone, in oral, injectable,
or even topical form, might cause an animal to have the symptoms of Cushing's
disease. A common supplemental cortisone is called prednisone. The blood level
of cortisone that results from this supplemental use will cause the adrenal
glands to shrink in size. This is because 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 it is being
introduced into its body, not because the adrenal glands are overproducing
it.
Symptoms
Some dogs with Cushing's disease
show the classic symptoms, while other show only a few vague
symptoms. The classic symptoms are:
Polyphagia- excess
appetite.
Polyuria/polydypsia (PU/PD)-
This is excess urinating and excess drinking of water. Several
other important diseases cause these symptoms also, notably liver
disease, kidney
disease pyometra,
and diabetes
mellitus (sugar
diabetes).
Pot bellied abdomen.
Thin skin and usually
symmetrical hair loss along the trunk. The hair might grow in
lighter in color or even be hyperpigmented. Secondary skin
infections are common.
Other symptoms could include
lethargy, muscle wasting, poor appetite, weakness, and behavioral
changes.
Diagnosis
Cushing's disease has a large
effect on the skin. Many skin conditions have similar symptoms, so
numerous diseases have to be kept in mind when making a diagnosis.
These include hypothyroidism,
skin
allergies,
sarcoptic
mange, demodectic
mange, and
Ringworm.
A thorough
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
so that we do not overlook some of the diseases that are also encountered in
pets as they age.
1.
Signalment
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
Cushing's:
- Yorkshire Terrier
- Poodle
- Beagle
- Boston Terrier
- Boxer
- Dachshund
Females and males get it at about the same
frequency, neutered pets might be at higher risk of
Cushing's.
2. History
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
more.
Other findings include skin
infections that recur after antibiotic therapy is stopped. Some
dogs might be itchy if a skin infection is present.
3. Physical Exam
Routine physical exam findings might
include:
Pot bellied abdomen
An enlarged liver (hepatomegaly) might be palpated, along
with smaller muscle mass in general.
Bruising might be seen under the skin or
when a blood sample is obtained.
Hair loss that is symmetrical and calcium
deposits under the skin.
Blood pressure might be elevated.
4. Diagnostic
Tests
Several tests are used as an
aid in making this diagnosis. Each test has its advantages and
disadvantages.
Blood
Panel
A CBC (complete
blood cell) and biochemistry panel should be run on every dog 8 years of
age or more, especially if they have any of the symptoms of Cushing's.
The CBC might show an increased WBC (white
blood cell count). The biochemistry
panel might show an elevated alkaline phosphatase (Alk
Phos). This is an enzyme that is located in the bile production area of
the liver. The excess cortisol influences this enzyme, although other diseases
can cause this elevation also.Cholesterol,
red blood cells, blood glucose, and liver enzyme tests might also be elevated.
If a thyroid
test is run also, it might be
low or borderline normal.
This dog has a high Alk
Phos. Some dogs 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.
BUN is usually low, not high, in Cushing's Disease, so this pet might
also be dehydrated or have kidney
disease at the same time.
Urinalysis
This test is not as
important in Cushing's disease as it is in other diseases,
especially kidney disease. 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.
This
urinalysis of this Cushing's dog shows a low specific
gravity and excess protein, but the glucose in normal
and there is no sign of an infection.
Radiography
Radiography might be of
value if the adrenal glands are calcified (might occur with an
adrenal tumor), otherwise the adrenals do not show up on a
radiograph. an enlarged liver 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.
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 can not be
seen since it is not calcified.
The liver (L) might be enlarged, although
this enlargement can be found in other diseases, especially
liver cancer.
Ultrasound
This test can be highly
beneficial in this diagnosis. The adrenal glands can be
measured, and their internal architecture can be
analyzed.
This
adrenal gland measures 1.9 cm by 0.9 cm, so it is a
little enlarged. In this dog it was due to pituitary
dependent Cushing's.
Screening Tests
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 know as the hypothalmic-pituitary-adrenal
axis. The first goal is to determine if Cushing's Disease exists. after
this is achieved, the next step is to determine if it is pituitary dependent
(PD) or an adrenal tumor (AT).
Urine cortisol:creatine
ratio
In this test the level of cortisol in the
urine is measure, and used as an indication of the cortisol
level in the bloodstream. Creatinine is measured to adjust
for different levels of urine dilution. Our kidney
page has more information on
creatinine. It is used 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. If the test comes back normal, then it is unlikely that
Cushing's is present.
ACTH Stimulation
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 dog.
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.
Low Dose Dexamethasone Suppression Test
(LDDS)
This is also a good test when the
history, physical exam, and routine blood panel and
urinalysis are consistent with Cushing's. It only works in
dogs because cats get a significant number of false
positives.
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.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.
Here is the
results on a dog that we suspected of having
Cushing's. What is your diagnosis in this
case?
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.
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
of life.
Underlying problems need identification and
treatment. If your dog is hypothyroid
the problem needs to be corrected with supplemental soloxine. Skin
infections and internal organ problems like kidney
disease need treatment for a successful
Cushing's outcome. Urinary tract infections need to be cleared up
with the use of antibiotics, and underlying diabetes
mellitus needs to be regulated with
insulin. 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 drugs have been used over
the years to treat this disease. The 3 most common and effective ones
will be described.
Pituitary Dependent (PD)
L-Deprenyl (anipryl)
This drug should be considered first in the treatment of
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 is given daily for 2 months, with the
dose increased if the symptoms don't diminish. Side effects are
negligible. 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. This
drug should not be used if your pet is being treated for
Demodex
with Mitaban, or with antidepressant medications or Prozac.
Mitotane (o,p'-DDD)
This drug, know by the trade name of
Lysodren, selectively destroys part of the adrenal gland. This
limits the amount of cortisol that the adrenal gland secrete
can secrete. Pets that are on insulin for diabetes mellitus
need to have their insulin dose adjusted downwards when given
mitotane. It should be administered with meals to enhance its
absorption.
Side effects can occur with this
drug:
- lethargy
- vomiting
- diarrhea
- poor appetite
- weakness
- incoordination
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 the use of mitotane. We will give
you cortisone pills to give at home if side effects are severe
enough.
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. Dogs
with this problem have to be put on supplemental prednisone
for the rest of their lives.
2. It is not uncommon for relapses of
Cushing's to occur within 12 months, even while on the
maintenance therapy.
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.
Ketaconazole
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 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 give every 12 hours for the rest of the dogs life. This is a
more expensive proposition than mitotane.
Iatrogenic
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 cortisone 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
common.
Feline Cushing's
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. The disease follow a similar
pattern in cats and dogs with a few notable exceptions:
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.
Sometimes the skin is easily bruised and torn.
This is called the fragile skin syndrome.
This
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
mats.
They do not routinely show any changes on a regular
blood panel or urinalysis. If the alkaline phosphatase is high it is usually
due to liver changes from unregulated diabetes mellitus.
The ACTH stimulation test is used but 2 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.
The LDDS test is used but the dexamethasone
that is injected needs to be given at a higher dose.
Medical therapy is generally unrewarding 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 for the rest of
its life. Unfortunately, cats with Cushing's can be poor
anesthetic
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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