Cushing’s Disease
Spontaneous hyperadrenocorticism in dogs and cats, aka Cushing’s Disease, is a result of an overproduction of glucocorticoids (aka cortisol). There are 3 possible causes for this biochemical abnormality: pituitary-dependent hyperadrenocorticism, adrenocortical tumors, and iatrogenic hyperadrenocorticism.
Pituitary-dependent hyperadrenocorticism is the most common cause of this disorder, being responsible for almost 85% of cases in dogs. It is specific to the overproduction of the hormone ACTH usually from a pituitary microadenoma (a tumor that is less than 10 mm in diameter). The pituitary microadenoma causes bilateral adrenocortical hyperplasia which leads to an excessive secretion of cortisol in the body.
Adrenocortical neoplasia, or tumors, are responsible for about 15% of spontaneous hyperadrenocorticism cases in dogs. About 50% of these tumors are benign.
Iatrogenic hyperadrenocorticism can happen from excessive exposure to corticosteroids through prolonged administration.
Spontaneous hyperadrenocorticism is a disease of middle-aged to older dogs and cats but can be diagnosed as early as 6 months. Poodles, dachshunds, Boston Terriers, and boxers are predisposed but any dog breed can be affected. There are no breed predilections with cats. There are no sex predilections found in dogs with pituitary-dependent hyperadrenocorticism, but 70% of cases with adrenal tumors have been found to be in female dogs.
Clinical Signs
Dogs and cats with hyperadrenocorticism usually develop clinical signs that reflect dysfunction of many organ systems, but some dogs may only experience one clinical symptom. A dog with hyperadrenocorticism may appear distended or “pot-bellied,” have bilaterally symmetric alopecia with a dull and dry hair-coat, have thin skin, hyperpigmentation, muscle atrophy and testicular atrophy.
Polyuria (increase in urination) and polydipsia (increase in thirst) are seen in majority of cases of dogs with hyperadrenocorticism. This is because glucocorticoids decrease the renal tubular reabsorption of water by increasing glomerular filtration rate and renal blood flow. They also inhibit the action of antidiuretic hormone (ADH) at the tubular levels. Lower urinary tract infections can be seen as well from cortisol excess. In contrast to dogs with the disease, the cause of polyuria and polydipsia in cats appears to be primarily the result of a hyperglycemic osmotic diuresis secondary to diabetes mellitus.
Excessive panting is quite commonly seen as well and can be due to decreased pulmonary compliance, pulmonary hypertension, or the direct effects of cortisol on the respiratory center. Very rarely, severe respiratory distress from pulmonary thromboembolic disease can be a complication of hyperadrenocorticism.
Dogs with hyperadrenocorticism can develop diabetes mellitus and its associated clinical signs of polyuria, polydipsia, weight loss, and polyphagia (increase in hunger). The hallmark of steroid-induced diabetes is the development of insulin resistance, which is clinically defined as persistent hyperglycemia despite insulin doses (>2.5 U/kg/administration). Diabetes can be developed from hyperadrenocorticism because cortisol antagonizes the actions of insulin by interfering with its action at the cellular level (diabetes means a lack of insulin!). Overt diabetes mellitus occurs in 10% of dogs with hyperadrenocorticism. The majority of cats (almost 80%) with hyperadrenocorticism have concurrent diabetes mellitus.
Normally, when under stress, cortisol’s principal function is to inhibit the effect of insulin and provide the body with glucose instead via gluconeogenesis in the liver. Insulin regulates the amount of glucose in the blood produced by the pancreas. Excess of cortisol over a long period of time consistently produces glucose, which leads to an increase in blood sugar levels and can eventually make the whole body insulin resistant. The pancreas is unable to keep up with the high demand of insulin which keeps glucose levels high and cells can’t get the sugar they need. This cycle continues through a negative feedback loop.
Lethargy is the most common symptom linked to the dog’s central nervous system. It may be due to the high levels of ACTH or the effects of excessive cortisol on cerebral enzymes and neurotransmitters. A large pituitary tumor can have compressive effects that can lead to severe symptoms like seizures, circling, and behavior changes. Muscle weakness is commonly seen due to the catabolic effects of glucocorticoid excess.
Diagnosis
Bloodwork can show high serum alkaline phosphatase activity and is seen in 85% of dogs with hyperadrenocorticism. High serum cholesterol concentrations and alanine transferase (SGPT)activity with mild elevations in blood glucose are commonly seen as well. Urinalysis often reveals urine of low specific gravity (<1.020) and proteinuria (increased level of protein in urine) is not uncommon but severe proteinuria is usually related to glomerular disease or urinary tract infections. Severe hyperglycemia and glycosuria are seen in up to 80% of cases in cats. Hypercholesterolemia is commonly seen with cats as well. In contrast to dogs, high serum alkaline phosphatase is not a consistent finding in cats with hyperadrenocorticism.
Radiography can show hepatomegaly (abnormally enlarged liver) but may not show clear evidence of adrenal tumors. These are best diagnosed through ultrasound or CT. CT is the most accurate and reliable method to image adrenal glands. The location of the tumor and evidence of metastasis can be identified with CT.
Basal serum cortisol concentrations are not useful in diagnosing hyperadrenocorticism because of constant fluctuation throughout the day. An ACTH Stimulation Test, like that used to help diagnose Addison’s disease, is the most commonly used adrenal function test. Because it measures the “thickness” of the adrenal cortex, it is the best test to differentiate between spontaneous from iatrogenic hyperadrenocorticism. Of dogs with pituitary-dependent hyperadrenocorticism, 85% show an exaggerated cortisol response to exogenous ACTH (>20 ug/dl whereas normal is 6–17 mg/dl). Approximately 70% of cats with naturally occurring hyperadrenocorticism show an exaggerated cortisol response (>15 ug/dl) to exogenous ACTH. 50% of dogs with adrenal tumors show an exaggerated cortisol response. Dogs with iatrogenic hyperadrenocorticism have a “blunted” response or no response to ACTH administration.
A Low-Dose Dexamethasone Suppression Test is useful to confirm the diagnosis of hyperadrenocorticism. The overall sensitivity for diagnosing approaches 90%. Protocol requires a serum sample to be collected before and 4 and 8 hours after administration (IV or IM) of dexamethasone. In general, serum cortisol concentrations of normal dogs fall below 1 ug/dl by 4 hours after administration of dexamethasone and remain suppressed for the entire 8-hour period of the test. In contrast, cortisol concentrations in most dogs with hyperadrenocorticism remain above 1 ug/dl during the 8-hour testing period. A third of dogs will show an “escape” pattern from suppression, where serum cortisol concentrations will fall below 1 ug/dl by 4 hours after administration of dexamethasone and rise above 1 ug/dl by hour 8 of the test.
This test has not been standardized for diagnosis of hyperadrenocorticism in cats and is not recommended.
Endogenous Plasma ACTH concentration test and a High-Dose Dexamethasone Suppression Test are useful in differentiating between pituitary-dependent hyperadrenocorticism from adrenocortical tumors. An endogenous plasma ACTH concentration test is more reliable in distinguishing between the two, but the test is very expensive and the specifics of sample handling are difficult for most practitioners. A high-dose dexamethasone test follows the same protocol as the low-dose test but administers a higher concentration of dexamethasone (0.1–1.0 mg/kg where as low-dose is 0.015 mg/kg). Dogs with adrenal tumors secrete autonomosly and do not show feedback suppression of cortisol after administration of a high dose of dexamethasone. Of dogs with pituitary-dependent hyperadrenocorticism, 85% show adequate feedback suppression of cortisol after administration.
In contrast to most dogs with pituitary-dependent hyperadrenocorticism, the majority of cats fail to show adequate cortisol suppression after high-dose dexamethasone suppression testing. Therefore, this test cannot readily differentiate between pituitary-dependent hyperadrenocorticism from adrenal tumors in cats. It is the preferred method of screening for hyperadrenocorticism in cats though.
Treatment
When selecting treatment, efficacy, cost (including monitoring), and risk of adverse effects need to be considered. Regular patient evaluations are necessary as well. The goal of therapy is to achieve subclinical hypoadrenocorticism whereby both basal and post-ACTH cortisol concentrations are within the normal basal cortisol range.
Mitotane is a drug most frequently used in the treatment of hyperadrenocorticism in dogs. It is an adrenolytic agents that causes selective necrosis of the zona fasciculata and zona reticularis of the adrenal cortex. It directly suppresses the adrenal cortex and alters the peripheral metabolism of steroids and inhibits cells of the adrenal cortex and their production of cortisol by covalently bonding to adrenal proteins. The administration protocol involves an initial induction phase that uses a daily dosage for induction of remission, followed by a maintenance phase that uses a dosage once or twice weekly. A glucocorticoid like Prednisone during the induction phase helps prevent the development of adverse effects secondary to hypoadrenocorticism. The effectiveness of therapy is best monitored using the ACTH stimulation test.
Mitotane (Lysodren) requires experienced hands. Its variability in intestinal absorption, long half-life, and cytotoxic effects can be problematic, and deciding to switch from the induction phase to the maintenance phase can be difficult. Clients have to be prompt in identifying changes in thirst and appetite to prevent overdose. It can be used for long term suppression of hyperadrenocorticism but the onset of action is slower and monitoring for side effects is necessary. Mitotane is not recommended in cats because of poor tolerance and lack of efficacy.
Trilostane (Vetoryl) is an antiadrenal that produces suppression of the adrenal cortex by inhibiting enzymatic conversion of steroids by 3-beta-hydroxysteroid dehydrogenase/delta-ketostoid isomerase, thus inhibiting synthesis of adrenal steroids. It has more predictable pharmacokinetics and is not directly cytotoxic. The daily medication cost is more expensive than mitotane but the monitoring expenses are less than that of mitotane.
When therapeutic concentrations of trilostane are present, cortisol synthesis decreases. It preferentially inhibits cortisol synthesis and does not effect aldosterone synthesis (this may be due to a different absorption sensitivity to trilostane or different cellular uptake in the zona glomerulosa). Results also show resolution of polyuria and polydipsia with general improvement showing within 7 days of administration. Trilostane is administered orally and is rapidly absorbed; it undergoes hepatic metabolism so caution is recommended for patients with liver dysfunction or renal insufficiency.
Surgical adrenolectomy is the most successful means of treating hyperadrenocorticism in cats. Medical therapy has been disappointing; but metyrapone, an enzyme inhibitor that blocks adrenal synthesis of glucocorticoids, has been used with mixed results. Some cats treated with this agent have showed clinical improvement without developing side effects.
References:
“Adrenal Gland: Canine Hyperadrenocorticism.” Saunders Manual of Small Animal Practice, by Stephen J. Birchard and Robert G. Sherding, Saunders Elsevier, 1994, pp.240–246.
Aronson, Dina. “Cortisol — Its Role in Stress, Inflammation, and Indications for Diet Therapy.” Today’s Dietitian, Nov. 2009, www.todaysdietitian.com/newarchives/111609p38.shtml.
Cook, Audrey K. “Trilostane: A Therapeutic Consideration for Canine Hyperadrenocorticism.” dvm360.Com, 16 July 2014, veterinarymedicine.dvm360.com/trilostane-therapeutic-consideration-canine-hyperadrenocorticism.