Cushing's Disease and Diabetes

 
What is Cushing's
Cushing's Disease (or syndrome) occurs when the adrenal glands produce excess amounts of cortisol, also known as cortisone. Cushing's is also known as hyperadrenocorticism. Hyper = above normal; adreno = relating to the adrenal glands; corticism = relating to the cortex & cortisol production. So, Cushings is a disease of elevated cortisol production by the adrenal cortex.  Cushing's is much more common in dogs than in cats, so this page focuses on Cushings in dogs.

Dogs have two adrenal glands, which are are small pea-sized glands located next to the kidneys. The adrenal glands produce several types of hormones that are involved in regulating many of the body's processes including control of blood potassium and sodium concentrations, water metabolism, protein, fat and carbohydrate metabolism, stress response, regulation of blood pressure, and to a small extent sex hormone levels.

The outer portion of the adrenal gland is called the cortex and it produces corticosteroids (cortisol and corticosterone) and mineralocorticoids (aldosterone). Cortisol is involved in the metabolism of carbohydrates, fat, and protein. Aldosterone is involved in regulation of mineral and water balance. The inner portion of the adrenal gland is called the medulla and it produces epinepherine, which during a stress response, raises blood glucose levels, blood pressure, and cardiac output.

Production of cortisol by the adrenal gland is controlled by the pituitary gland, which is a small gland located at the base of the brain. The pituitary gland produces adrenocorticotropic hormone (ACTH) which stimulates the adrenal cortex to produce corticosteroids (cortisol). Additionally, the hypothalamus, a small structure in the brain, secretes corticotropin-releasing hromone (CRH) which signals the pituitary gland to produce ACTH. When enough cortisol is produced, it in turn goes back to the pituitary and hypothalamus and tells them to stop producing ACTH and CRH. In technical terms this is called a negative feedback system. The hypothalamus produces CRH which tells the pituitary gland to produces ACTH. The ACTH tells the adrenal glands to produce cortisol, which returns back to the hypothalamus and pituitary to turn off CRH and ACTH production.

Cushing's is one of the most common endocrine diseases of middle-aged and older dogs. Most dogs are 9-10 years old when diagnosed, but it can occur in younger dogs. Larger dogs and females tend to be more affected than smaller breeds or males.


Reasons why the balance between ACTH and cortisol can be upset:
  • Pituitary gland tumor- also called Pituitary Dependent Hyperadrenocorticism (PDH)– This is the most common type of Cushings and it is found in about 85% of all cases.  A tumor in the pituitary gland causes an increased production of ACTH, which in turn tells the adrenal cortex to produce more cortisol. The pituitary tumor can be very tiny or large and it can be benign or malignant.  Poodles, terriers, German shepherds, Dachshunds, beagles, and boxers are more commonly diagnosed with PDH than other breeds.
  • Adrenal gland tumor – A tumor in one or both adrenal glands can cause an excess production of corticosteroids, which causes Cushing’s. The tumor can be tiny or large and it can be benign or malignant.
  • Iatrogenic – Iatrogenic means the disease has resulted from a complication of medical treatment. When a dog is given corticosteroids to treat another medical condition such as allergies, the excess corticosteroids can overload the body and result in Cushing’s symptoms.

Clinical signs of Cushing's
Not all of these signs may be present, but as the disease progresses, they may become more pronounced or more signs may be seen. How common the sign is is shown for many of the items.

  • Increased appetite (polyphagia) - 80-95% will show this sign. 
  • Increased drinking (polydypsia) and urination urination (polyuria) - due to interference with production of antidiuretic hormone. 80-90%. 
  • Muscle weakness, lethargy, lack of activity - excess cortisol causes protein breakdown (catabolism) which leads to muscle weakness. 75-80% 
  • Obesity, bloated abdomen, and "potbelly" - due to an increase of fat in the abdomen, increase in liver size (hepatomegaly), cronically full bladder, stretching of the abdominal wall, and the abdominal well becoming weaker. 90-95% 
  • Panting - due to increased fat in the rib area (thorax), muscle weakness, and increased abdominal contents exerting pressure on the diaphragm. A "common" sign. 
  • Poor hair coat, thinning hair (usually on the sides), hair does not regrow . "Common". 
  • Skin infections - due to excess corticosteroids suppressing the immune system. 
  • Thin skin, flaky or greasy skin & bruising - many processes that control skin structure and health are effected. 
  • Fasting hyperglycemia (elevated blood glucose) - seen in 40-60% of dogs. 
  • Insulin resistance - seen in up to 85% of dogs

So as you can, some of the signs of diabetes and Cushing's are identical. 

Diagnosis and Testing
Diagnosis of Cushing’s can be complicated and difficult. It is important to determine the type of Cushings (adrenal, pituitary, or iatrogenic) so that the appropriate treatment can be undertaken. 

  • Routine lab tests are usually performed – complete blood count, biochemistry, urinalysis – and abnormalities in these tests may suggest Cushing’s.
  • An abdominal x-ray may show an enlarged liver or adrenal gland changes.
  • An abdominal ultrasound is often performed to evaluate liver and adrenal glands. 
  • A urine test measuring cortisol to creatinine ration is sometimes performed, but it is not a very specific test because many health problems can cause abnormal test results.  This is a screening test only – a negative result rules out Cushing’s.  A positive result does not confirm Cushing’s and more tests will need to be performed.
  • More definitive diagnostic testing  looks at adrenal gland function.  Cortisol levels in the blood are measured before and after a drug that would normally effect cortisol levels is given. Two commonly used tests are the ACTH stimulation test and the Low-dose dexamethasone suppression test. During the ACTH stimulation test, a pre-test blood sample is taken, then a dose of ACTH is given. After 2 hours, cortisol levels are measured again.  If the cortisol levels are higher than expected, Cushing’s may be diagnosed.  Dexamethasone is a cortisone-type drug that provides negative feedback on the pituitary gland to turn off ACTH production, and that in turn causes a decrease in adrenal cortisol production. In a normal animal (non-Cushing’s) a dip in cortisol would be seen 8 hours after giving dexamethasone. If a pituitary tumor exists, no drop in cortisol level is seen during the low-dose dexamethasone test. During a high-dose dexamethasone suppression test, cortisol levels will be suppressed in about 75% of dogs with PDH and will not be suppressed in the remaining 25% of dogs with PDH or in  100% of dogs with an adrenal tumor.
    For detailed information about the tests used to diagnose Cushing’s, see  http://www.marvistavet.com/html/confirming_cushing_s.html


Diabetic animals can pose a special problem when testing for Cushing's.
As you can see, diabetes and Cushing’s share many of the same signs (increased drinking, urination, eating, lethargy, enlarged liver). Uncontrolled diabetes can lead to complications that in turn cause increased cortisol levels and signs that are identical to Cushing’s.  Testing and diagnosis of Cushing’s in a non-diabetic dog can be complicated, and it can be extremely complicated in a dog that has diabetes.  The situation is even worse for a stressed or poorly controlled diabetic because stressed diabetics and Cushing’s dogs can have similar blood panel abnormalities and blood chemistry abnormalities.  Plasma ACTH levels, the ACTH stimulation test results, and low-dose dexamethasone suppression test results can be abnormal in a stressed DM dog; the high-dose dexamethasone suppression test  results can be abnormal in an unregulated DM dog.  There are clinical signs that help distinguish the two disease so your general vet and specialist must consider the “whole picture” of your dog’s physical condition and test results. 

Treatment
Cushings caused by a pituitary gland tumor (PDH). Surgery to remove a tumor in the pituitary gland is very risky and is rarely performed. Controlling the growth of the tumor may be attempted with radiation. Medication is used to control this type of Cushings.  

  • The drug most commonly used is o,p’DDD, also know as Lysodren or mitotane. This drug works by destroying the cortisol-producing cells in the adrenal cortex. Careful monitoring is required during treatment to be sure that too much drug is not given and too many adrenal cortex cells are not killed.  Too much drug would result in too little cortisol being produced (resulting in Addison’s disease, the opposite of Cushing’s).  Treatment involves an “induction” or “loading” phase where Lysodren is given on a daily basis. This loading phase rapidly brings the some of the Cushing’s symptoms under control. Owners are usually instructed to closely monitor their dog’s eating and drinking.  When drinking is normal (about 50-60 mL water per pound body weight per day) induction is complete and the “maintenance” phase begins.  In maintenance, Lysodren is given two to three times a week to keep the cortisol levels within acceptable levels.  ACTH stimulation tests are repeated every three to four months to ensure adequate control and dosing. 

  • Anipryl or L-deprenyl is another drug that is used to treat pituitary-dependent Cushing’s.  It was approved for use in the United States in 1997. Anipryl is used to treat cognitive dysfunction in dogs and has shown to be effective in clinical trials in controlling Cushing’s in about 70% of dogs. The drug works by influencing dopamine concentrations (a chemical used to by brain cells to communicate with each other), which in turn influences production of ACTH by the pituitary gland.  The effectiveness of this drug is controversial, but since the side effects are less severe than those of Lysodren, it is used in some dogs, especially those who are older or have multiple health problems. Anipryl does not involve an induction or loading phase.

  • Ketoconazole is another drug used to treat PDH or dogs who have adrenal gland tumors.  It works by blocking production of cortisol in the adrenal gland.  It has the potential to damage the liver.

Cushings caused by an adrenal gland tumor may be treated surgically or with Lysodren or Ketoconazole.  Surgery is difficult and may have many complications.  Removal of the adrenal gland may require life-long supplementation with glucocorticoids and mineralocorticoids (both normally produced by the adrenal gland).

Iatrogenic Cushing’s – treatment requires slowly discontinuing the cortisone that is being given.  This must be done in a controlled manner so that other problems do not occur.  The disease that is being treated with cortisone will probably recur. If damages has been done to the adrenal glands, that will need to be addressed.

Special considerations for treating diabetics
With a possible diabetic and/or Cushoid animal there are three different scenarios that can occur:

  • Your animal may be both diabetic and have Cushing's. As the Cushing's is brought under control your animal's insulin needs will be greatly reduced. Therefore it's very important to monitor your animal's blood glucose until the correct maintenance dose is determined so an overdose of insulin doesn't happen.  
    You can read Kiri's story - she lived with diabetes, Cushing's and hypothyroidism for over 6 years.
  • Your animal may only have Cushing's. The increased blood glucose levels may be a side effect of the Cushing's and once the Cushing's is brought under control there may be no need for insulin anymore.
  • Your animal may only be diabetic. The Cushing's tests may have been altered by one of the previously mentioned causes, resulting in false positive results.

Questions to ask your vet
With a diabetic it is very important to take every means possible to stabilize them on their insulin before a Cushing's test is even tried. Some questions to ask your vet:

  • If your animal is unregulated--ask your vet at what amount of insulin they would consider your animal to be needing to bring the glucose levels under control.
  • If your animal has only been on one type of insulin, are they willing to try another type.
  • Would a change in food, feeding schedule, or amount of food make a difference.

Resources and References

 

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Updated April 2006
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