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2/11/13

Dogs : Cushing's Disease (Hyperadrenocorticism)

This condition represents a classical excess in cortisone-type hormone circulation in the body. Both cats and dogs can be affected (though it is primarily a dog's disease) and the onset is insidious. We have assembled an information center to answer all your questions on this relatively common hormone imbalance.



1 Symptoms of Cushing's Syndrome
Cushing's syndrome (hyperadrenocorticism) is a chronically debilitating hormone imbalance that can affect many species, humans included. We will limit our discussion to dogs and cats, however. Cushing's syndrome, also called Cushing's disease, results from excessive cortisol in the bloodstream and the symptoms all stem from long-term over-exposure to this hormone.

Dogs
There are many clinical signs associated with Cushing’s syndrome (also called hyperadrenocorticism) in dogs. These signs usually come on gradually and, because of this slow onset, these changes are often written off as part of the normal aging process. The following list of common symptoms that an owner might observe in their pet at home is:
  • Drinking excessively
  • Urinating excessively
  • Incontinence 
Owners often notice that lately the water bowl must be filled more frequently than in the past. Some dogs are unable to hold their bladder all night and begin crying to go outside during the night when previously this was unnecessary.

Also, urinary tract infections may also be detected and true urine leaking may be observed.



How Much Water Consumption is Normal?
Each day a dog should drink about one cup of water for each ten pounds of body weight, though this can vary somewhat with environmental temperature and activity level. Dogs that truly have excessive water consumption will consume vastly more than this regularly.

Increased or even Ravenous Appetite

This symptom often leads dogs to beg incessantly or steal food from the garbage. It is important for an owner not to be fooled by the pet’s "good appetite": eating well is not necessarily a sign of normal health.

Pot-bellied Appearance
This symptom, seen in over 90% of Cushing’s syndrome dogs, results from hormonal redistribution of body fat plus a breakdown of abdominal musculature.

Muscle Weakness
Muscle protein is broken down in Cushing’s syndrome. The result may be seen as exercise intolerance, lethargy, reluctance to jump up on furniture or climb stairs.

Skin Disease
The classical signs of endocrine (hormonal) skin diseases are:
  • Hair loss on the main body sparing the head and legs
  • Thin, wrinkled skin with poor wound healing
  • Hair that does not grow back after clipping.
  • Blackheads and darkening of the skin, especially on the abdomen.
  • Persistent or recurring skin infections (especially if the dog is not itchy during times when the skin infection is cleared)
Another condition of the skin that may be observed is called calcinosis cutis, in which calcium deposits occur within the skin. These are raised, hard, almost rock-like areas that can occur almost anywhere on the body.

Some other notable findings might include: excessive panting and shortness of breath, infertility, extreme muscle stiffness (called pseudomyotonia - a very, very rare symptom in Cushing’s disease), and high blood pressure.

Aside from the symptoms described above, advanced untreated Cushing's disease puts a dog at risk for the following serious problems: 

Cats

In cats, the clinical features of Cushing’s disease are similar to those in the dog: excess water consumption, muscle wasting, pot-bellied appearance, thin coat, and skin abnormalities. Some cats develop a peculiar curling-in of their ear tips. An important difference to note is that while only 10% of dogs with Cushing’s disease develop diabetes mellitus, 80% of cats with Cushing’s disease develop diabetes mellitus. Diabetes in an animal with Cushing’s disease is difficult to control until the Cushing’s disease is controlled.

2 What Exactly is Cushing's Disease
Cushing’s syndrome is the resulting set of symptoms observed when the body is exposed to excess cortisone (or related hormones) over a long period of time. Cortisone, or more correctly cortisol, is a hormone produced by the adrenal glands, which are located atop the kidneys. Cortisol is stored in the adrenal gland and is released in times of stress where it helps our bodies prepare for a fight or flight situation. It adjusts the metabolism to expect physical exertion by mobilizing fat and sugar stores and retaining sodium and water. It puts us in a state of break down so that our stored resources can be used quickly. However, if the body is exposed to this hormone most of the time instead of during short stressful periods only, the state of break down becomes debilitating.

There are several mechanisms that can lead to Cushing’s syndrome and, as they are treated differently, it is important to determine which one is at work in a given animal.


In the normal body, the pituitary gland, located at the base of the brain, can detect when cortisol levels in the blood are declining. In response, the pituitary secretes a stimulating substance, called ACTH, which causes the adrenal gland to release more cortisol. When the pituitary gland detects that cortisol levels are again appropriate, it stops its stimulatory message.

You can think of the pituitary gland as a sort of a thermostat for cortisol. This raising and lowering of cortisol blood level is regulated throughout the day via ACTH secretion and occurs rapidly.

Pituitary-Dependent Cushing's Syndrome
This form of Cushing's disease accounts for 85% of dogs with Cushing's syndrome. Basically, the pituitary gland grows a small tumor. The tumor is generally too small to cause any trouble due to its size and it is generally a benign tumor. This tumor, however, over-produces ACTH, thus leading to over-stimulation and enlargement of both adrenal glands and an over-production of cortisone. Occasionally (10% of pituitary-dependent Cushing's dogs), these benign pituitary tumors are large enough to compress the brain. In these cases, neurological signs may be observed; these cases are unusual but very hard to treat (see section on macrotumors.)


Adrenal-Dependent Cushing's Syndrome
In 15% of dogs with Cushing's syndrome, an adrenal tumor is directly over-producing cortisone. The tumor is often large enough to see with radiographs or ultrasound and may be malignant. There is very little or no production of ACTH from the pituitary gland and as a result the opposite adrenal gland is usually atrophied/small.


Overuse of Cortisone-Type Hormones
Cortisone derivatives may well be the most over-used drugs in veterinary medicine. Their anti-inflammatory actions soothes such common maladies as allergic skin disease (especially flea allergic dermatitis) and degenerative arthritis. Relief is usually rapid and many owners find themselves requesting cortisone shots or pills over and over again. In time, Cushing's syndrome can result, not from any inherent disease in the pet's system but from the effects of the hormones given over the long term.

The pituitary gland perceives the high steroid levels yielded by the medication and does not send stimulation to the adrenal glands. In time, the adrenal glands atrophy and are not able to release cortisone on their own should they be required to do so. This effect lasts as long as a period of three months after the cortisone medication has been discontinued. To allow the adrenal to gradually recover, cortisone pills are usually prescribed in a decreasing dose, rather than a sudden stoppage; an owner should never discontinue the pills suddenly.

Commonly prescribed cortisone derivatives include: Vetalog, Azium, prednisone, prednisolone , dexamethasone, Depo-Medrol, triamcinolone and others. These medications have important parts to play in medicine but they must be respected and not used indiscriminately, nor discontinued suddenly after prolonged use.

3 Testing: Laboratory Hints Suggesting Cushing's Syndrome
When an animal is presented to the veterinarian for a potential clinical problem, an initial “data base” is collected in the form of a blood panel and urinalysis, and possibly a urine culture. There are some “tip offs” to Cushing’s syndrome which may be noted and added to the list of observed symptoms as evidence.

The Stress Leukogram

This term refers to the relative proportions of different types of white blood cells. There is a typical pattern produced by cortisol as the body responds to stress. This pattern is called a“stress leukogram.” If this pattern is seen in a patient that does not seem stressed, there is a possibility that an excess of cortisol is present.

Elevated Alkaline Phosphatase
Alkaline phosphatase (often abbreviated ALP or SAP) is one of the so-called “liver enzymes,” meaning that it is chiefly found in the liver. There is a form of this enzyme which is produced in very high levels in response to cortisol. This enzyme is not harmful in excess levels but since such marked increases in its levels are associated with cortisol, this would be a good hint that either this patient is taking cortisone type medications or has Cushing’s disease.

Elevated Cholesterol
This is a common finding in most endocrine diseases and, in this case, results from abnormal fat mobilization. High levels of circulating cholesterol may, as in humans, alter normal circulation and blood clotting.

Unconcentrated Urine and/or Bladder Infection
When a pet drinks excessive amounts of water, the extra water is passed as urine. As long as there is extra water, urine will be dilute. Because of the immunosuppression associated with Cushing’s disease, evidence of bacterial infection may be present as well or such evidence may be concealed by the dilution of the urine. Ideally urine should be cultured if it is too dilute to reliably detect white blood cells or blood. Recent studies have shown that 20% of dogs with Cushing’s disease have an inapparent bladder infection.

These classic laboratory findings complement the physical examination and may lead your veterinarian to recommend definitive testing for Cushing’s Syndrome.

Feline Cushing's Disease
In cats, laboratory findings turn out to be similar to those in dogs except that these changes are generally referrable to uncontrolled diabetes mellitus, a common but later change in feline Cushing’s disease. In early Cushing’s disease, cats may not show obvious blood test abnormalities. Classically, a cat with Cushing's disease will bruise easily after blood is taken and will have obviously thin skin.

It is important to realize that Cushing's disease is a very unusual reason for a cat to have uncontrollable diabetes mellitus. Most cats with uncontrollable diabetes mellitus have simpler explanations, such as poor insulin injection technique, incorrect insulin dose (usually overdose, as odd as that sounds), or a concurrent infection. It is important not to jump straight to Cushing's disease should a diabetic cat be difficult to regulate, and more obvious explanations should be first ruled out.

4 Testing: Confirming Cushing's Syndrome
Specific Tests to Confirm Cushing's Disease
Once there is reason to suspect Cushing's disease based on the history, physical examination, and initial laboratory testing, it is necessary to do specific testing to confirm it. There are several options. We will begin with dogs and then discuss cats.

CANINE CUSHING'S DISEASE TESTING
The Low Dose Dexamethasone Suppression Test(usually takes 8 hours in the hospital)

Dexamethasone is a cortisone-type hormone that is used therapeutically for numerous conditions. When given dexamethasone, the dog's pituitary gland will perceive that there is a steroid and shut off its stimulatory message to the adrenal glands. In the normal animal, this means that a drop in blood cortisol level will be seen 8 hours after a tiny dose of dexamethasone is given intravenously.

If there is a pituitary tumor, the pituitary is not about to shut off its stimulatory message and it ignores the dexamethasone. No drop in cortisol level is seen at the end of eight hours.

THIS TEST IS CURRENTLY CONSIDERED THE MOST ACCURATE

TO CONFIRM CUSHING'S DISEASE.
APPROXIMATELY 90% OF DOGS WITH CUSHING'S DISEASE
WILL TEST POSITIVE WITH IT.

To Run this Test
Ideally the low dose dexamethasone suppression test is run in the morning. A baseline cortisol level is measured, a low dose of dexamethasone is given intravenously, and blood samples are checked again in 8 hours. Sometimes a 4-hour sample is also drawn as the pattern of suppression over the entire 8 hours may help classify the type of Cushing's disease. The pet will require at least 8 hours in the hospital.

The ACTH Stim Test(Requires two hours in the hospital)

Central to the concept of Cushing's disease is the over-production of cortisol. It follows then that the adrenal glands of the Cushing’s patient would possess large amounts of stored hormone due to their chronic stimulation. We have been talking about the stimulatory message sent from the pituitary gland to the adrenal glands. This message consists of a hormone called Adrenocorticotrophic hormone or ACTH. In this test, a dose of ACTH is given to the patient. If a larger than expected rise in cortisol levels is measured in 2 hours, we may diagnose Cushing's syndrome.

To Run this Test
Ideally, the patient is fasted overnight and the test is performed in the morning between 8 a.m. and 10 a.m. A blood sample is drawn, a dose of ACTH is given, and two hours later a second blood sample is drawn.

When Would we Run this Test?

Given that the low dose dexamethasone suppression test is more accurate, when might we run this test instead? It turns out that this is the only test that can be used if the iatrogenic form of Cushing's disease is suspected. This test is also crucial in monitoring patients with Cushing's disease, depending on which medications are used. This test is more specific than the low dose dexamethasone suppression test, meaning that the strongly positive dogs definitely have Cushing's disease (false positives are unusual) but since it is not a very sensitive test, the University of California Veterinary School at Davis no longer recommends this test to determine whether or not a dog has Cushing's disease. As mentioned, this is the test that is used to monitor treatment, however, and a dog being treated for Cushing's disease will likely have many ACTH Stimulation tests ahead.

The Urine Cortisol/Creatinine Ratio

This is a screening test for Cushing's disease; a positive test here does NOT confirm Cushing's syndrome but a negative test DOES rule it out. In this test a single urine sample is collected to determine the relative amounts of cortisol and creatinine (creatinine is a protein metabolite that is excreted in urine constantly). If there is a high ratio - a relatively high amount of cortisol being excreted - further testing is in order. Ideally for this test the urine sample is collected at home so that cortisol secreted in response to the stress of visiting the vet's office does not interfere with results.

FELINE CUSHING'S DISEASE TESTING
The testing situation is somewhat different in cats.

The Urine Cortisol/Creatinine RatioWhile this test is of limited value in dogs, it is the preferred test in cats. The owner should bring urine samples collected first thing in the morning on three consecutive mornings. Having the sample collected at home removes the possibility of interference from vet visit-induced stress. The first two samples are used to determine if the cat has Cushing's disease and the ratios are averaged. On the second day, after the second sample is brought in, dexamethasone pills are given to the cat at home and the sample from the third day is used to determine the type of Cushing's disease the cat has.

Collecting a cat's urine at home is easier than it sounds. The cat is confined overnight and in the morning is allowed access to the litter box. The easiest way to collect the urine is to place a sheet of cellophane over the box. The cat will rumple this up a bit scratching around but only a small amount need be caught on the surface of the cellophane. A syringe can be used to suck up the sample and store it for transport to the veterinary clinic.

This test is sensitive in both dogs and cats, which means that a negative test can be considered a confirmed negative.

The Low Dose Dexamethasone Suppression Test
This test is performed similar to the way it is performed with dogs; however, the dose of dexamethasone required to test a cat is substantially higher as cats are more resistant to the effects of steroids. The test still requires 8 hours in the hospital and the cat should be relaxed and kept quiet during the stay. If the cat is the type to experience a great deal of stress in visiting the vet's office, consider the urine cortisol:creatinine ratio.

It is important to find a diagnosis of Cushing's disease but it is equally important to consider that successful treatment of Cushing's disease is about control of symptoms. If the symptoms do not warrant control, then treatment should be postponed until they are more severe. After it has been determined that a pet has Cushing's disease, it is important to determine the type of Cushing's disease (adrenal vs. pituitary tumor). The next section in this series reviews how this is done. Treatment options and prognosis are highly dependent on the type of Cushing's disease the pet has.

5 Classifying Cushing's Syndrome: Pituitary vs Adrenal
Adrenal or Pituitary Cushing's? Why do we Care?
Once a pet has been confirmed as having Cushing’s syndrome, the next step is to determine which form of Cushing’s syndrome the pet has since treatment is different for each form.
  • If an adrenal tumor is present, there is a 50% chance that it is a malignant tumor. Surgical exploration is generally warranted so that the tumor may be removed.
  • Adrenal tumors can be treated with medications just as pituitary tumors can be but the protocols are completely different so it is imperative that classification be complete.
So What Tests will Tell us What Type of Cushing's Syndrome is Present?
The Low Dose Dexamathasone Suppression Test If one is lucky, the same test used to determine if Cushing’s disease is present or not can also classify the Cushing’s disease so that no further tests are needed. If a 4-hour sample is drawn in addition to the pre-dexamethasone sample and the 8-hour sample, more information can be determined about the cortisol suppression pattern. Some patterns are characteristic of pituitary or adrenal Cushing’s disease. If your pet fits into this category, then no further testing is needed to classify the Cushing’s disease.

ImagingImaging such as ultrasound, MRI, CT scan, or nuclear medicine studies may be helpful in classifying Cushing’s syndrome. Probably ultrasound is the most readily available. If a Low Dose Dexamethasone Suppression test has confirmed Cushing’s syndrome but not confirmed which type, imaging of the adrenal glands can provide the information needed to complete classification. Two large or normal sized adrenal glands are typically present with the presence of a pituitary tumor as both adrenal glands will be equally stimulated by ACTH production. Other imaging results should be followed by either of the blood tests described below.

If one adrenal gland looks large and the other is not visible, an adrenal tumor may be suspected (remember, the non-tumorous gland will atrophy). In the event of an adrenal tumor, ultrasound is also helpful to determine the extent of tumor spread, which is crucial to deciding for or against surgical removal of the tumor.

The High Dose Dexamethazone Suppression Test This test is similar to the low dose dexamethasone suppression test except that a higher dose of dexamethasone is used and the patient having the test is already known to have Cushing’s disease through prior testing. In this case, a patient with a pituitary tumor will show suppression in circulating cortisol when exposed to the high dose of dexamethasone (though suppression does not occur with the low dose). If an adrenal tumor is present, suppression does not occur.

Engodenous ACTH Level This test is felt by many to be the most accurate method of classifying Cushing’s syndrome but the problem is that the test is technically challenging to run. Serum from the patient must be frozen when transported to the laboratory and may not thaw. The hormone ACTH is very fragile and may not survive the trip to the lab. The idea with this test is that a patient with a pituitary tumor will have high ACTH levels, as this is what the tumor is secreting. A patient with low or no measurable ACTH levels has an adrenal tumor as the pituitary is trying its best not to stimulate the over-active adrenal tumor.


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