Hyperadrenocorticism

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Cushing's disease (hyperadrenocorticism) in dogs 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 glucocorticoid hormones 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.

Cushing's disease brought about by an adrenal tumor is commonly seen in the Toy Poodle, German Shepherd Dog, Dachshund, Labrador Retriever, and some Terrier breeds. The pituitary dependent form is commonly seen in the Poodle, Dachshund, Beagle, German Shepherd Dog, Boston Terrier, and Boxer.

A sex predilection for females is seen in some dogs with hyperadrenocorticism secondary to adrenal tumors. The most common clinical signs are polydipsia (PD), polyuria (PU), polyphagia, heat intolerance, lethargy, abdominal enlargement or “potbelly,” panting, obesity, muscle weakness, and recurrent urinary tract infections. Dermatologic manifestations are numerous and often include truncal alopecia, thin skin, phlebectasias, comedones, bruising, cutaneous hyperpigmentation, calcinosis cutis, pyoderma, dermal atrophy, secondary demodicosis, and seborrhea. Cutaneous mineralization (calcinosis cutis) is a characteristic although infrequent finding in dogs. Although mineral deposition may occur anywhere in the skin, the dorsal midline, ventral abdomen, and inguinal region are affected most frequently. 

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.

Numerous mineral crystals are deposited along collagen and elastin fibers in the dermis and outer subcutis and may protrude through the atrophic and thinned epidermis. In less severe cases, the epidermis remains intact and appears irregularly elevated by the firm, opaque, white deposits of mineral. A narrow rim of hyperemia and foreign-body granulomatous inflammation often surrounds the areas of mineralization. The mineral deposits occur despite normal blood calcium and phosphorus levels probably because of the gluconeogenic and protein catabolic actions of cortisol. Mineralization may also occur in other tissues of the body, most frequently the airways and blood vessels.

Mineralization of skin

Increased Water Consumption and Urination: The most common symptom is increased consumption of water and the resultant increased urination (polyuria/polydipsia). The dogs drink between two and ten 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.

Types of hyperadrenocorticism

The most common cause of Cushing's disease is a microscopic, benign pituitary tumor (microadenoma) which oversecretes ACTH and ignores the adrenals' response. 50% of pituitary tumors are less than 3mm in diameter. The dog's pituitary keeps cranking out ACTH, causing the adrenals to keep cranking out cortisol, yet the pituitary does not respond to the elevated blood cortisol levels by stopping its release of ACTH. 85% of Cushing's cases are pituitary dependent. Dogs with pituitary dependent hyperadrenocorticism tend to have two very large adrenal glands, as both are constantly working to keep up production of excess cortisol.

2. Adrenal-based Hyperadrenocorticism

Alternatively, there may be an adrenal tumor responsible for secreting too much cortisol. 50% of these are benign (adenomas), and 50% are malignant (adenocarcinomas) and are inclined to spread to the lungs and liver. Again, the interplay between pituitary and adrenal messages is lost, and the tumor keeps secreting too much cortisol irrespective of what the brain is telling it. 15% of Cushing's cases are adrenal-based. In these dogs, one adrenal gland tends to be extremely enlarged (due to the tumor and the overproduction of cortisol that goes with it), and the other tends to be extremely small (to try to compensate for the overactive larger one

3. Iatrogenic Hyperadrenocorticism

The third cause of Cushing's is one that we can create ourselves if we give a dog too much external glucocorticoid, especially for chronic conditions like allergies. We essentially do what the adrenal tumor would do by flooding the dog's body with an excess of corticosteroid. Although both the adrenals and pituitary will attempt to respond to our interference by cutting ACTH and cortisol secretion, if we continue to bombard the dog's body with too much glucocorticoid, symptoms of Cushing's disease will result. The reason dogs are given tapering doses or every-other-day doses of steroids like prednisone is to avoid this consequence. Dogs with this form of Cushing's tend to have two very small, atrophied adrenal glands. Nonetheless, if iatrogenic (veterinary-induced) hyperadrenocorticism develops, it is fully reversible. The external source of steroid is slowly withdrawn to allow the adrenals to "wake up" and resume functioning.

Diagnosis

1. Urine Cortisol:Creatinine Ratio

In this test, the owner generally collects a urine sample at home (where the animal is not stressed). The sample is sent by the veterinarian to a special laboratory for testing. Most dogs with Cushing's disease have an abnormal result. However, there are other diseases that can also cause abnormal results. So if this test is abnormal, further diagnostic testing should be performed. 

2. Low dose dexamethasone test (LDDT)

The low-dose dexamethasone suppression (LDDS) test is the screening test of choice for hyperadrenocorticism in dogs. It is sensitive; only 5% of dogs with hyperadrenocorticism exhibit suppressed cortisol concentrations at 8 hr. In addition, 30% of dogs with PDH exhibit suppression at 3 or 4 hr followed by “escape” of suppression at 8 hr—this pattern is diagnostic for PDH. The major disadvantage of the LDDS test is the lack of specificity in dogs with nonadrenal illness (diabetes mellitus, chronic renal disease, liver disease); these dogs should be treated for the nonadrenal illness and stabilized before the LDDS test is performed.

Steps:

2. ACTH test

This is another test that is commonly used in the diagnosis of Cushing's disease today. It will not distinguish between the two types of hyperadrenocorticism, but it may aid in the diagnosis in difficult cases. It is also used to evaluate the effectiveness of therapy. 

3. High dose dexamethasone test (HDDT)

Once a dog has been diagnosed as Cushing disease, this test can be used to differentiate between forms of Cushing's. Similar to the low dose dex test, a fasted dog has a baseline blood sample taken in the morning. The dog is then given a large dose of dexamethasone. Blood samples are taken 4 hours and 8 hours later. A dog with an adrenal tumor will not suppress at all. His adrenal tumor simply doesn't "care" about the level of blood cortisol; it keeps pumping out cortisol. A dog with a pituitary tumor still has some limited ability to respond to feedback and thus should respond to a high dose of dexamethasone with a suppressed cortisol level. Approximately 15%-20% of dogs with pituitary tumors will not suppress on a high dose dexa test; these dogs generally have large macroadenomas.

Treatment

Treatment depends on the type of Cushing's disease, as well as on the overall health of the canine patient. As many dogs with Cushing's are elderly and may have concurrent health problems, treatment can be complicated. This is a serious illness for which there is no known cure. Dogs require life long treatment. Monitoring is required through periodic blood tests.

Cushing's is very rare in cats and is usually the result of insulin resistance in a cat with Diabetes Mellitus. Diagnosis is similar to the dog and treatment is usually surgical removal of the adrenal glands. Medical therapy is usually not effective in cats.

Mitotane (Lysodrane)

• Selectively destroys glucocorticoids secreating cells in adrenal cortex 
• Initial dose: 40-50mg/kg bid until both basal and post ACTH cortisol level are in ideal range. 
• Maintain therapy with 50mg/kg/week 
• Monitor the cortisol level by using ACTH test  If cortisol level is <1µg/dL, stop mitotane and administer prednisolone (0.1mg/kg)

Ketoconazole (oral antifungal)

• Inhibits enzymes responsible for cortisol synthesis 
• Administer 10-20 mg/kg q12h 
• Monitor the cortisol level by using ACTH test 
• Side effect: Vomitting, diarrhea, lethargy 

Trilostane

Trilostane is a newer treatment that is used to treat some dogs with Cushing's disease. It is more expensive, but may be an alternative treatment for dogs with adrenal tumors. As with Lysodren, the dog is reexamined repeatedly during the initial phase of treatment, and ACTH stimulation tests are performed. In many cases, after several months of therapy the dose needs to be increased.

**Cushing’ disease may predispose the animal with diabetes mellitus due to high glucose in the blood. If this occurs, treatment for diabetes should be initiated.

Guarded: The average life span with medical treatment is about 2 years, although longer survival is possible. Glucocorticoids reduce inflammation and suppress the immune system and predispose to other ailments such as Diabetes Mellitus, urinary tract infection, kidney disease, hypertension and pancreatitis.

Sources: Mercks Veterinary Manual 10th ed, http://www.kateconnick.com/library/cushingsdisease.html, Pet care suite 101: Cushing's disease in a dog