Cushing’s Disease (Hyperadrenocorticism)
A summary of the causes, diagnosis and treatment of a common endocrine disease in dogs
-Robin K. Nelson, DVM
Cushing’s disease is a health condition that occurs when the adrenal glands overproduce cortisol, the body’s main stress hormone. The seriousness of the disease varies greatly depending on its duration and the degree of cortisol excess. Considered to be one of the most common endocrine disorders in dogs, there is no known genetic basis and questionable prevalence regarding its occurrence.
The medical term for Cushing’s disease is hyperadrenocorticism or HAC. Besides cortisol, the adrenal glands, situated above both kidneys, produce several other vital substances that regulate a variety of body functions necessary to sustain life.
Adrenal Gland function and Control
A dog’s hypothalamic-pituitary-adrenal axis is a complex set of influences and interactions that provide a balance of positive and negative feedbacks to maintain normal cortisol levels in the dog’s body. When the body is stressed, a positive feedback is sent to the brain to initiate release of cortisol. The anterior pituitary gland in the brain triggers the release of adrenocorticotropic hormone (ACTH) to the adrenal cortex. Within the adrenal cortex, the zona fasciculata releases cortisol. When cortisol levels in the dog’s body are high, they act as negative feedback on the pituitary gland decreasing ACTH and cortisol release.
Causes of Cushing’s Disease
Pituitary-Dependent Hyperadrenocorticism (PDH)
PDH involves a tumor of the pituitary gland in the brain that secretes too much Adrenocorticotropic Hormone or ACTH causing excess cortisol production by the adrenal glands. This form makes up about 80–85% of Cushing’s disease cases. The often-small tumor secretes an excess of ACTH causing bilateral (both sides) enlargement of the adrenal glands and excessive secretion of cortisol.
Adrenal-Dependent Hyperadrenocorticism (ADH)
ADH involves a functional tumor of the adrenal gland. This less common form of hyperadrenocorticism accounts for 15–20% of the cases. With ADH, the adrenal tumor is usually unilateral (one side) and solitary. In PDH and ADH, the tumors in either the pituitary gland or the adrenal gland do not respond to the negative or positive feedback of the adrenocortical axis thereby disrupting the delicate balance needed to maintain normal cortisol levels in the body.
Iatrogenic Hyperadrenocorticism
Iatrogenic Hyperadrenocorticism results from excessive oral or topical administration of prescribed glucocorticoids.
At risk Dogs
Both ADH and PDH seem to have a predilection for older dogs, with increased odds past the age of 12. Though any breed of dog can develop Cushing’s disease in either form, ADH tends to occur in middle to large breed dogs and seems to show a predisposition for females 60–65% of the time.
PDH occurs more commonly in small dogs particularly Dachshunds, Beagles, Miniature Poodles, Yorkshire terriers, Boston terriers, and Miniature Schnauzers.
Signs and Symptoms
Regardless of type, clinical signs of Cushing’s disease are essentially the same. Symptoms are often mistaken for common signs of aging. Owners usually notice increased appetite, increased water consumption, and increased urination. Common signs and symptoms are known as “the 7 P’s.” Dogs with Cushing’s disease may also show heat intolerance, lethargy or lack of activity, muscle weakness and atrophy, recurrent urinary tract infections, alopecia (hair loss), thin, fragile skin, bruising, and secondary demodicosis (mange) .
Uncommon clinical manifestations of Cushing’s disease include hypertension, bronchial calcification, polyneuropathies, behavioral changes-suggesting an enlarging brain tumor, pulmonary thromboemboli (blood clots in the lungs), central blindness, and prostatomegaly (enlarged prostate) in castrated male dogs.
Symptoms and Signs of Cushing’s Disease- Seven P’s
· Polydipsia-increased water consumption
·Polyuria-increased urination
· Polyphagia-increased appetite
· Pot-bellied appearance
· Panting
· Increased pigmentation
· Pyoderma (skin disease with pus)
Diagnosis
Any patient suspected of Cushing’s disease needs to be assessed through a detailed history and physical examination and preliminary lab work including a complete blood count (CBC), serum chemistry profile, and urinalysis. Findings consistent with canine HAC suggest further endocrine testing is needed to arrive at a specific diagnosis of Cushing’s disease.
Laboratory Abnormalities in Cushing’s Disease
Platelets: 75–80% of dogs have increased number of platelets
Liver enzymes (changes in blood flow cause liver cells to leak enzymes)
-Cortisol-induced increase in ALP is the most common abnormality seen in 85–90% of cases. Increases can be severe (as high as 10 times normal).
-Increases in ALT are usually mild
Blood glucose (cortisol affects sugar formation and utilization)
-Usually see mild elevations in blood glucose
-Some dogs develop diabetes mellitus
Cholesterol: approximately 90% of dogs with HAC have hypercholesterolemia
Urine concentration
-Dilute urine common (cortisol prevents water reabsorption by kidneys)
-Specific gravity (measure of concentration) is usually <1.025 and urine is pale
-Cause of increased water consumption necessary to maintain hydration
Although most dogs with Cushing’s disease will have one or more abnormalities on CBC and serum chemistry profiles, the condition should still be included on the differential list in any dog with polydipsia, polyuria, and dilute urine, even with normal CBC and chemistry profile results.
Cushing’s disease can be a diagnostic and treatment challenge. Adrenal function testing can be very confusing and frustrating. A veterinarian needs to prove the presence of HAC prior to beginning treatment.
A dog should be as stable as possible for testing. Concurrent diseases such as ear infections, hot spots, and diabetes may interfere with proper interpretation of lab results. Diagnosing Cushing’s disease can be quite expensive. The differential diagnoses which must be ruled out prior to treatment include hypothyroidism, sex hormone dermatopathy, Alopecia X, renal (kidney) disease and hepatopathies or liver conditions. Unfortunately, there is not a 100% accurate test to prove hyperadrenocorticism, and repeat testing is often necessary.
Three adrenal function SCREENING tests are available:
- The urine cortisol:creatinine ratio (UC:CR) is a very sensitive test and should be performed to rule out HAC. It provides a cortisol measurement over time. A urine sample is collected by the owner at home to avoid stress-related cortisol elevations caused by hospitalization.
If the UC:CR is normal, the patient does not have Cushing’s Disease.
If the UC:CR is elevated, results from other screening tests are necessary to diagnose the disease.
2. The low dose dexamethasone suppression test or LDDST is usually the “go to” test. Cortisol is measured before and four and eight hours after IV administration of a low dose of dexamethasone (type of cortisone). In a normal patient, the hypothalamic-pituitary-adrenal axis feedback mechanism should be suppressed below the normal range for 8 hours by the dexamethasone injection. The dog with HAC will show lack of suppression at the 8 hour time point. The LDDST can also serve as a differentiating test suggesting whether the HAC is pituitary or adrenal dependent.
If the 4-hour cortisol measurement is suppressed below normal or by 50% of the baseline and the 8 hour cortisol is not suppressed, it is indicative of PDH.
3. The ACTH Stimulation test is less affected by stress and recommended in dogs with significant concurrent diseases like diabetes. The test looks for excess cortisol secretion from hypertrophied adrenal glands (PDH) and adrenal tumors (ADH) in response to ACTH administration. Serum cortisol is measured before and 60 minutes after an IV injection of Cortrosyn. Post ACTH cortisol levels above the normal range is diagnostic for HAC, but this result can also occur with nonadrenal illness.
Dogs with Iatrogenic Cushing’s disease will have little to no increase in cortisol after ACTH administration. This test cannot distinguish between PDH and ADH. The ACTH Stimulation test is used to monitor therapy.
Determining where the disease is located- adrenal gland versus the pituitary gland-can direct therapy as well as predict cost of treatment, time of resolution of clinical signs, and help explain any neurological or abdominal signs consistent with tumor enlargement.
Tests to DIFFERENTIATE between PDH and ADH
1. The LDDS test, successful in separating out 65% of dogs with HAC.
2. The High Dose Dexamethasone Suppression test works under the theory that a high dose of steroid can suppress ACTH secretion from a pituitary tumor. In an ADH patient, no suppression is noticed because ACTH is already suppressed via the negative feedbacks from high cortisol levels from the adrenal tumor.
3. Endogenous plasma ACTH measurement is the most sensitive differentiating test, but sample handling is exacting and crucial to avoid erroneous results. If an adrenal tumor is present, the concentration of endogenous (within the body) ACTH is very low due to negative feedback inhibition of ACTH release. With pituitary-dependent hyperadrenocorticism, the endogenous ACTH can be elevated, may be within the reference interval, or may even be a little below normal.
4. Abdominal ultrasound and other “imaging” can be very helpful in identifying an adrenal tumor (indicating ADH) or bilateral adrenal hyperplasia (enlargement) suggesting PDH. Abdominal imaging may also identify other abdominal diseases and potential adrenal tumor invasion of the liver or vascular structures. CT and MRI of the brain may detect pituitary macroadenomas.
Treatment
Not all dogs with Cushing’s disease need to be treated at the time of diagnosis. The benefits of treatment in dogs without significant clinical signs or complications must be weighed with the potential complications and cost of treatment.
Pituitary gland tumor
The location of the tumor dictates treatment. Most dogs with Cushing’s disease have a pituitary-gland tumor. Removing pituitary tumors in people is routine, but this surgical technique is still in its infancy in dogs. Radiation of the tumor is a developing option, but several months of treatment may be necessary for improvement in clinical signs. Most dogs with PDH are treated with Mitotane (Lysodren) or Trilostane (Vetoryl). These two drugs selectively destroy or inhibit part of the adrenal cortex so even though the pituitary tumor continues to secrete ACTH, cortisol levels remain normal. Guidelines must be followed closely because effective treatment depends on consistent and regular administration of oral medication. Careful monitoring is necessary to ensure that the drugs don’t destroy all the cortex and that cortisol stays at a defined level. Dogs on long-term treatment should have an examination and ACTH response test every 3–4 months. Sometimes gradually increasing amounts of drug are required to maintain adequate clinical remission.
Adrenal gland tumor
Adrenal-based Cushing’s disease is rare, more concerning, and best treated with surgery. Approximately one half of adrenal tumors are malignant, growing aggressively and metastasizing quickly. Unfortunately, surgical excision is complicated and often unlikely to be curative.
Additional medication
Ketoconazole, an oral antifungal, and L-depranyl (selegiline), a monoamine oxidase inhibitor typically used for canine cognitive disorders, have also been used to treat Cushing’s disease. These drugs are less effective, but sometimes preferred because their mechanism of action lowers the cortisol slowly. They may be used in instances where close monitoring is not possible.
Once treatment is initiated, symptoms should begin to noticeably resolve. A dog on medication should drink less water and the frustrating polyuria should improve.
Prognosis
Owners need to be aware of the likelihood of lifelong therapy. Many geriatric dogs with Cushing’s disease die of unrelated causes brought on by aging. Cost of medication and constant veterinary check-ups and testing can be difficult to afford. Survival time, estimated to be two years on average, is probably a direct effect of concurrent diseases and the complications common to HAC patients. Approximately 15–20% of PDH patients exhibit neurological signs due to their pituitary tumor increasing in size over time. Over 80% of untreated HAC patients become hypertensive and 5–10% of dogs additionally have diabetes.
Cushing’s disease is a complicated condition to understand and often presents diagnostic and treatment dilemmas. The diagnosis is challenging for dog owners, but understanding the disease and having an understanding veterinarian are helpful in making decisions.
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