Cushing's disease (hyperadrenocorticism) is a condition that results from the chronic overproduction of too much glucocorticoid in the body. In the normal dog, the pituitary gland produces a hormone called ACTH which stimulates the adrenal gland to produce the steroid hormone glucocorticoid which is necessary for the function of many systems in the body. If something goes wrong in the pituitary gland or adrenal gland and too much glucocorticoid is produced, then Cushing's disease develops This is a very complicated disease with a wide range of symptoms and causes. This article will try to give a concise description of the disease, its symptoms, how it’s diagnosed, and its treatment. 
Who gets hyperadrenocorticism? 

Cushing’s disease is considered a disease of middle age and older dogs and cats. It is much more common in dogs. The disease is similar in cats except that in cats up to 80% also have concurrent diabetes mellitus mellitus. This article will refer to the problem as it occurs in dogs. The usual age of contracting the disease is around six or seven years with a range of 2 to 16 years. There is equal distribution between males and females and there does not appear to be an increase of the disease in any one breed. 

Symptoms 

As a result of the chronically elevated glucocorticoids (steroids), the affected dogs develop a classic combination of dramatic clinical signs and lesions. The disease progresses slowly. A study showed that most dogs had at least one symptom of the disease from one to six years before the disease was diagnosed. Because the symptoms occur so gradually, the owner often attributes the changes to ‘old age’.

For dogs ultimately diagnosed with Cushing's disease, hair loss was one of the most common reasons the owners first brought their dog in for evaluation.

Increased Water Consumption and Urination: The most common symptom is increased consumption of water and resultant increased urination (polyuria/polydipsia). The dogs drink between 2 and 10 times the normal amount of water and the resultant increase in urination follows. This symptom is present in over 85% of all animals with Cushing’s disease. Previously housebroken animals may begin to have accidents because their bladders fill quickly with the overproduction of urine. 

Increase in Appetite: Increase in appetite (polyphagia) is another common clinical symptom that shows up in around 80% of the affected animals. Dogs may begin stealing food, getting into the garbage, begging continuously, and become very protective of their food. Despite having other symptoms, the owner may feel that the dog is okay because of it’s good appetite. 

Abdominal Enlargement: Abdominal enlargement is a common symptom in up to 80% of the affected dogs. The potbellied appearance is a result of the shifting of fat to the abdominal area and a weakening and wasting of muscle mass in the abdomen. 

Hair Loss and Thin Skin: 
 

Hair loss and thinning of the skin are also common symptoms in dogs with Cushing’s disease. It is estimated that between 50% and 90% of the affected animals develop these symptoms. Hair loss (alopecia) is one of the most common reasons that owners bring their dog in for evaluation. The hair loss usually starts over the areas of wear such as the elbows and progresses to the flanks and abdomen until eventually only the head and extremities have hair. The skin may also become thin and be easily damaged and slow to heal.

Increased panting or losses in reproductive ability are two other symptoms often noted with this disease. 

Cushing's Disease has two forms 

There are two different distinct forms of the disease. There is pituitary dependent hyperadrenocorticism (PDH) and there is an adrenal-based disease. 

Pituitary dependent hyperadrenocorticism : PDH involves the over secretion of ACTH, which is a hormone that stimulates the adrenal gland to produce glucocorticoids. The pituitary gland is most likely over producing ACTH because of a pituitary tumor. The PDH form of the disease is responsible for around 80% of the cases of canine Cushing’s disease. 

Adrenal-based hyperadrenocorticism: The adrenal-based form of the disease is usually a result of an adrenal tumor that causes an over secretion of glucocorticoids. Adrenal tumors are responsible for around 20% of the cases of Cushing’s disease. There is also a form of the disease called iatrogenic Cushing’s disease that occurs as a result of giving the animal high doses of steroids. In this form of the disease, symptoms of Cushing’s disease will go away once the steroids are discontinued. 

Diagnosis 
 

Cushing’s disease can present with a variety of symptoms and may also be involved with several different disease processes. Therefore it is recommended that any dog suspected of having Cushing’s disease should have a complete blood count, chemistry profile, and urinalysis performed as a routine part of the evaluation. In addition, abdominal x-rays may also be taken. There are several different tests that can be performed to get a definitive diagnosis of Cushing’s disease. Many times the veterinarian may perform more than one test to help confirm the diagnosis or to determine which form of the disease is present.

It is recommended that any dog suspected of having Cushing’s disease should have a complete blood count, chemistry profile, and urinalysis performed as a routine part of the evaluation.

ACTH stimulation test: The ACTH stimulation test is the most commonly used test by veterinarians to diagnose Cushing's disease. The test is safe, inexpensive and reliable. In this test the dog is given an injection of ACTH. Dogs that have either the pituitary or the adrenal form of the disease will respond to the ACTH by producing glucocorticoids and we can measure a greatly elevated level of blood cortisol after the injection. This test does not differentiate between the two forms of Cushing's disease. In addition, other diseases or certain medications may cause an increase in blood cortisol after the injection of ACTH so this test result needs to be interpreted along with other laboratory results. 

Low Dose Dexamethasone Suppression Test: The low dose dexamethasone suppression test is an excellent test to diagnose Cushing’s disease. When given low doses of dexamethasone normal dogs show a marked decrease in blood cortisol levels when tested 8 hours later. Dogs with Cushing’s disease do not have a decrease in cortisol level after being given dexamethasone. This test does not distinguish between the two forms of the disease. 

The ACTH stimulation test and low doses dexamethasone suppression test are often used in conjunction to diagnose Cushing's disease in dogs. 

High Dose Dexamethasone Suppression Test: Once the diagnosis of Cushing's disease is made, the high-dose dexamethasone suppression test is used to distinguish between the two forms of the disease. Dogs with pituitary dependent Cushing’s disease will show a decrease in circulating blood cortisol when given a high dose of dexamethasone. Dogs with adrenal based Cushing’s disease will not show a decrease when given the high dose of dexamethasone. This test is used after Cushing’s disease has already been confirmed through other diagnostic testing. 

These test are the ones most commonly performed, however there are several other tests available and new developments in diagnostics of this disease are made every year. 

Treatment 

Treatment consists of several different options. Depending on the type of disease, surgery can be performed. If an adrenal tumor is identified then surgical removal may be a viable option. There are several different forms of tumors that can invade the adrenal gland and their treatment will be based on the particular tumor type. There are a few surgeons that have successfully performed surgery to remove the affected pituitary gland in the pituitary form of the disease. However this is a very specialized procedure and is not commonly performed in the pituitary form of the disease. 
 

Non surgical treatment is the most often used treatment for most cases of canine Cushing’s disease. About 80 % of the cases of Cushing’s disease in the dog are of the pituitary type and since both the adrenal and the pituitary type will respond effectively to some of the oral treatments, many veterinarians don't perform the diagnostics necessary to distinguish between the two different forms. There are currently three different oral medications being used to treat canine Cushing’s disease.

Non surgical treatment is the most often used treatment for most cases of canine Cushing’s disease.

Lysodren: Until recently, Lysodren (mitotane) was the only treatment available for pituitary dependent Cushing’s disease. It is convenient to use and is relatively inexpensive and is still probably the most widely used treatment. The downside of this drug is that it can have some serious side effects and regular blood-monitoring tests need to be performed as long as the animal is on the drug. 

The use of lysodren is considered a form of chemotherapy. It works by eroding the layers of the adrenal gland that produces the corticosteroid hormones. As the number of corticosteroid-producing cells is reduced, even though the pituitary gland continues to produce excess ACTH the adrenal gland is less able to respond, so the amount of glucocorticoid being produced is reduced. The problems arise when too much of the adrenal cortex is killed off. The animals may then need to be placed on prednisone, either short or long term. The Lysodren is initially given daily while the animal is being monitored for a decrease in the symptoms (water consumption, appetite). When the symptoms begin to subside the dose is changed to once weekly. If the symptoms haven't decreased by the 9th day an ACTH challenge test is performed to determine if the drug is working. It may then be continued and rechecked every 8 days until the results are achieved. If the dog becomes lethargic, vomits or has diarrhea, or if the treatment doesn't work by 30 days, then the treatment plan is re-evaluated. If treatment is successful then all symptoms should be resolved within 4 to 6 months. A certain percentage of dogs will relapse and need to undergo the daily therapy again at some point in their lives. 

Ketoconazole: Ketoconazole is an oral antifungal agent that has been used extensively since the mid 80s. One of the side effects of ketoconazole is that it interferes with the synthesis of steroid hormones. It therefore gained some popularity as a treatment for Cushing’s disease. However with the advent of the newer drug L-deprenyl (Anipryl) it is rarely used anymore. 

L-deprenyl (Anipryl): L-deprenyl (Anipryl) is the newest drug available for the treatment of canine Cushing’s disease and is currently the only drug approved and licensed for use to treat Cushing’s disease in the dog. Anipryl works to inhibit the overproduction of ACTH by the pituitary gland. For this reason it only works on cases of pituitary dependent Cushing's disease. However since over 80% of all cases of Cushing’s disease are pituitary dependent it has become a popular choice in the treatment of this disease. Some of the advantages of this drug are that it doesn't produce nearly as many unwanted side effects and the risk of destroying too much of the adrenal gland doesn't occur. In addition, monitoring of the adrenal gland and the resulting blood tests are not as necessary because it doesn't affect the adrenal gland directly. Some disadvantages are that it is more expensive then Lysodren and doesn't have any effect on the adrenal based disease. This product is currently being widely used and because of its safety and effectiveness is rapidly becoming the drug of first choice for the treatment of this disease. 

Summary 

Cushing’s disease is a disease that affects middle age to older dogs. The affected animal has a characteristic presentation including increased water consumption and resulting increased urination, increased appetite, hair loss and a pot bellied appearance. There are several diagnostic tests available. There are also several new treatment options available that make this disease much more treatable than it was only a few years ago.
 

References

Bonagura, J. Kirks Current Veterinary Therapy XII. Saunders. Philadelphia, PA; 2000. 
Bonagura, J. Kirks Current Veterinary Therapy XIII. Saunders. Philadelphia, PA; 1995. 
Ettinger, S. Textbook of Veterinary Internal Medicine. Saunders. Philadelphia, PA; 1989.