Cushing's Disease (hyperadrenocorticism) is a common condition in older dogs, often mistaken for the aging process itself. Dogs gain weight, lose hair, urinate in the house, and make owners begin to prematurely consider euthanasia. Yet Cushing's disease is treatable and that treatment can result in a longer, more comfortable life for the dog and its owner. Thus, it is important for the regular pet owner to learn the basic facts about Cushing's disease.
In health: In order to understand Cushing's disease, one needs to understand the basics of the negative feedback loop that operates in a normal, healthy dog. The pituitary gland, located at the base of the brain, produces ACTH (adrenocorticotrophic hormone), as directed by the hypothalamus (another part of the brain). This hormone is released into the bloodstream and stimulates the body's two adrenal glands, located near the kidneys, to secrete glucocorticoid (cortisone-like or cortisol) hormones into the bloodstream. Cortisol helps the body respond to stress. It is necessary for life and impacts a wide variety of bodily functions including blood sugar levels, fat metabolism, skeletal muscles, kidney function, nervous system, cardiovascular system, and immune response. ACTH/cortisol secretion is increased due to stress, including infection, pain, surgery, trauma, cold temperatures. When the blood cortisol levels are high enough, the pituitary stops secreting ACTH. When the blood cortisol levels dip low enough, the pituitary secretes more ACTH. The adrenals respond by secreting glucocorticoid hormones in response to the pituitary, just as the pituitary responds by secreting ACTH in response to the adrenals. The net effect is that a mildly fluctuating balance is achieved. This is an oversimplified picture of cortisol homeostasis in the healthy dog.
In Cushing's Disease: The feedback loop has gone awry in Cushing's disease for one of three reasons: a pituitary tumor, an adrenal tumor, or veterinary interference. The result is a chronic excess of blood cortisol. In effect, the dog is being poisoned with too much cortisol and cannot rely on its own feedback mechanism to regulate the blood cortisol level.
Pituitary Dependant 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.
Occasionally (10-15% of pituitary tumors) these tumors are larger and their size presents challenges of their own. Larger pituitary tumors (macroadenomas, over 1 centimeter in diameter) can place pressure on brain tissue and nerves, causing blindness, circling, seizures, or other neurological problems not directly related to hyperadrenocorticism. Some of these symptoms (e.g., incoordination) can resemble side-effects of medications used to treat Cushing's disease, further complicating diagnosis and treatment.
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).
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.
Causes/Predispositions: Given that tumor incidence increases with age and that tumors are the cause of Cushing's disease, it is logical that Cushing's disease is a problem seen most frequently in middle-aged or older dogs. The average canine Cushing's patient is 10 years old. I have seen literature stating that there is no difference between genders, as well as literature citing that females are more likely to become Cushingoid. Spayed/neutered dogs may have a slightly greater incidence of Cushing's, as well. Although all breeds are at risk, some breeds reported to be at greater risk include: poodle, Yorkshire terrier, beagle, Boston terrier, boxer, dachshund, German shepherd dog, golden retriever, Labrador retriever, Scottish terrier and terriers in general. Pituitary-dependent Cushing's is more common in small dogs, with 75% of cases being in dogs under 20 kilograms (44 pounds). Adrenal-based Cushing's cases, on the other hand, occur 50-55% of the time in dogs under 20 kilograms (44 pounds).
Symptoms: Symptoms of Cushing's disease can be vague and varied and tend to appear gradually and progressively. It is thus easy to mistake Cushing's disease for normal aging. Additionally, many of the clinical symptoms are not unique to Cushing's and could reflect a number of other health concerns.
The most common symptoms include:
• increased/excessive water consumption (polydipsia)
• increased/excessive urination (polyuria)
• urinary accidents in previously housetrained dogs
• increased/excessive appetite (polyphagia)
• appearance of food stealing/guarding, begging, trash dumping, etc.
• sagging, bloated, pot-bellied appearance
• weight gain or its appearance, due to fat redistribution
• loss of muscle mass, giving the appearance of weight loss
• bony, skull-like appearance of head
• exercise intolerance, lethargy, general or hind-leg weakness
• new reluctance to jump on furniture or people
• excess panting, seeking cool surfaces to rest on
• symmetrically thinning hair or baldness (alopecia) on torso
• other coat changes like dullness, dryness
• slow regrowth of hair after clipping
• thin, wrinkled, fragile, and/or darkly pigmented skin
• easily damaged/bruised skin that heals slowly
• hard, calcified lumps in the skin (calcinosis cutis)
• susceptibility to infections (especially skin and urinary)
• diabetes, pancreatitis, seizures
It is generally either the increased water intake and urination or the coat changes which prompt an owner to have their dog evaluated by the veterinarian, as these dogs don't appear suddenly and dramatically ill. It is estimated that 80-85% of Cushingoid dogs have increased water consumption, drinking from 2-10 times normal amounts (normal is considered 1 ounce of water drunk per pound of body weight per day). 85-100% of Cushingoid dogs have skin and coat changes. 80-90% of Cushingoid dogs have an increased appetite, and 90%-95% have a pot-bellied appearance. Considered a disease of middle and old age, dogs typically display symptoms at some point after 6 or 7 years of age. It is estimated that most dogs display some symptom(s) of the disease for one to six years before Cushing's is actually suspected and diagnosed. Certainly it is harder to ignore a dog that urinates throughout the house or a dog who is balding than it is to overlook an older dog who is gradually slowing down on walks.
Other indirect symptoms to consider are the disappearance of previous inflammatory conditions. Dogs with chronic allergies or arthritis may appear considerably better when they develop Cushing's, due to the heavy doses of cortisone they are giving themselves.
Illustration: These images show a healthy adult boxer dog, and the same dog several years later after he had been diagnosed with Cushing's disease. That is my dog, Dempsey. Click on a photo to compare enlarged images. One can observe changes that include muscle atrophy, coat dullness and loss of color, thinning hair especially over the ribcage, thin wrinkled skin, and pot belly. He weighs approximately the same in the first two photos, but the redistribution of weight is evident; he is bony along his head and spine, with fat being concentrated in his abdomen. The dog demonstrated some mild exercise intolerance and hind-end muscle weakness (refusing to jump into a car or onto a bed), and a previously existing left-shoulder limp disappeared.Additionally, this dog was drinking and urinating excessively and demonstrating a ravenous appetite. Yet he doesn't look like a sick dog. He simply looks like an old dog, and at 10 1/2, he is an old boxer indeed. It is easy to understand how Cushing's disease can be mistaken for nothing more than normal aging.
One month after beginning lysodren treatment, the dog's coat is vastly improved. He no longer has a sparse haircoat or thin, fragile skin. Even the color is brighter. His stance is steadier and more upright in his hind end. His muscle tone is better, including his abdominal region. Drinking and urination have abated to normal levels. His energy levels and playfulness have increased.
Diagnosis: Initially, Cushing's may be generally suspected based on the typical clinical picture described above: a middle-aged or older, potbellied, hungry, thirsty dog with a sparse haircoat. Routine bloodwork may reflect elevated liver enzymes (especially serum alkaline phosphatase), cholesterol, and blood glucose. Some white blood cells may be elevated (neutrofils), and others decreased (lymphocytes, esinophils). A urinalysis may reflect high levels of protein and low specific gravity (dilute urine). X-rays or ultrasound may show an enlarged liver or either enlarged or atrophied adrenals. 50% of adrenal tumors may appear mineralized. Although one could do a CT scan to search for a pituitary tumor, this is not a common diagnostic procedure. All of the above suggest the presence of Cushing's, but specific lab tests can help to further pinpoint a diagnosis. These tests include a urine cortisol/creatinine ratio test, an ACTH stimulation test, and low and high dose dexamethasone suppression tests. There is no single test to diagnose Cushing's, and Cushing's disease is often difficult to accurately diagnose.
Urine Cortisol/Creatinine Ratio Test: Considered a screening test, this cannot diagnose Cushing's, but it can rule it out. A urine sample is examined for the relative amounts of cortisol versus a normally excreted protein metabolite, creatinine (the latter is used to control for the degree of dilution of the urine). The greater the ratio, the higher the cortisol level. High cortisol in urine is suggestive of high cortisol in the bloodstream. Many conditions other than Cushing's disease can cause false positives, so this test is not considered diagnostic. Nonetheless, if the cortisol/creatinine ratio is okay, the dog is not likely to be Cushingoid, so this is a good screening test.
ACTH Stimulation Test: A blood sample is taken as a baseline. Then, a dog is given an injection of ACTH, the hormone which stimulates the adrenals to release cortisol. One to two hours later, blood cortisol levels are measured. Given that a dog with Cushing's has a constantly overworked, overproducing set of adrenals, the cortisol reserves are much greater, and the Cushingoid dog will be able to respond to the ACTH with greatly elevated cortisol output. This test doesn't differentiate between forms of Cushing's (adrenal vs. pituitary). It is considered diagnostic 80-95% of the time. Half of adrenal tumors will not respond on this test, and 15% of dogs with pituitary tumors will not respond. Nonetheless, it is an easy test and is often used along with a low dose dexamethasone suppression test to diagnose the presence of Cushing's disease. It is also used as a monitoring test for dogs who are being treated for Cushing's disease with Lysodren.
Low Dose Dexamethasone Suppression Test: This is considered the best test with an estimated 90-95% ability to diagnose Cushing's disease. A fasted dog has a blood sample taken as a baseline in the morning. A small amount of dexamethasone, a synthetic glucocorticoid, is injected, and follow-up blood samples are taken 4 hours and 8 hours later. A normal dog's body will perceive the presence of dexamethasone and suppress cortisol output throughout the test. Cushingoid dogs will not suppress blood cortisol in response to the dexamethasone injection, because their feedback mechanisms are not working properly as explained above. This test does not differentiate between forms of Cushing's disease (adrenal vs. pituitary), although it may be suggestive. Dogs who suppress at 4 hours and rebound at 8 hours usually have pituitary tumors.
High Dose Dexamethasone Suppression Test: Once a dog has been diagnosed as Cushingoid, 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 dex 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. The comfort of the patient should be the ultimate goal. In a dog with severe arthritis, for example, it may be more humane to allow him to remain Cushingoid than to treat the disorder. In general, surgery may be indicated for adrenal tumors. Chemotherapy in the form of Lysodren or Ketaconazole may be used to treat pituitary-dependent or adrenal-based Cushing's. And Anipryl may be tried to combat pituitary-dependent Cushing's. Treatment is best viewed as a means to improve quality of life, rather than increase lifespan, per se.
Surgery: If Cushing's disease is caused by an adrenal tumor, the logical approach is to surgically remove the tumor and the affected adrenal gland. These tumors tend not to recur on the remaining adrenal gland. In theory, this can cure adrenal-based Cushing's disease, and prognosis is very good for dogs with benign adrenal tumors. Dogs may be treated with ketoconazole prior to surgery to try to minimize the symptoms of Cushing's disease, as one significant symptom of Cushing's is delayed wound healing. There are high risks associated with adrenalectomies, and given that patients are often elderly dogs, this may deter an owner from pursuing this treatment route. 50% of adrenal tumors are malignant and may have already metastasized to liver or lungs by the time they are discovered. Most owners opt for non-surgical treatment.
Pituitary tumors are not removed surgically in veterinary medicine. These tumors tend to be very small and slow-growing and cause little or no damage on their own, aside from overstimulating the adrenal glands. With these canine patients, the symptoms themselves are treated and not the root cause.
Radiation: Pituitary macroadenomas may be treated with radiation in an attempt to shrink them and thus relieve the neurological symptoms caused by their presence and the pressure they place on brain tissue. Radiation involves thousands of dollars and repeated anesthesia, either of which may be difficult to justify with an elderly patient. Once the neurological symptoms abate, the dog would then be treated for hyperadrenocorticism itself.
Lysodren (Mitotane, o,p'-DDD): Lysodren is the drug of choice in treating pituitary-dependent Cushing's disease. It is also used, albeit with less effectiveness, in treating adrenal-based Cushing's. Lysodren selectively destroys adrenal cortex tissue, the cells that produce glucocorticoid hormones. An initial week or so of daily lysodren (a loading or induction phase) damages the adrenals enough to bring cortisol blood levels within normal ranges and make Cushingoid symptoms begin to abate. Thus, even though the pituitary may be secreting excess ACTH begging the adrenals to release more cortisol, they simply cannot respond in excess amounts. Dogs must then be maintained on once or twice a week lysodren dosages for the remainder of their life. Half of dogs will relapse and need another round of daily lysodren. Sometimes dogs fail to respond to lysodren either from the start or after having been on it for some time.
Lysodren is effective, yet it carries a great potential for serious side effects. If too much adrenal tissue is destroyed, a dog can be given permanent Addison's disease, hypoadrenocorticism (the opposite of Cushing's). This occurs inadvertently in approximately 5% of dogs given lysodren. A small minority of veterinary practitioners actually do this intentionally, and then they maintain the dog on daily medications for life. The risk of untreated Addison's is that a hypoadrenocorticoid dog can't manage stress the way a normal dog can, and can die from shock and heart failure. A normal body requires steroid hormones in order to survive.
More typically, a dog will experience a lysodren reaction in which cortisol levels are acutely too low. This occurs in approximately one third of canine patients and can be reflected in inappetence, vomiting, diarrhea, muscle weakness, wobbliness, lethargy, or even collapse and death. Less than 1% of dogs experience fatal complications. Owners must carefully monitor dogs taking lysodren and respond to such adverse reactions by stopping the lysodren and administering prednisone. Also, dogs on lysodren must receive periodic ACTH stimulation tests to monitor their blood cortisol levels. Thus, treating with lysodren requires a greater than average owner commitment to monitoring their dog.
Ketaconazole (Nizoral): This is considered in the treatment of dogs with either pituitary-dependent or adrenal-based hyperadrenocorticism who cannot tolerate lysodren or who do not respond to lysodren. Ketaconazole is an oral anti-fungal medication with the quirky side-effect of suppressing hormone production. That side-effect is sought-after when using Ketaconazole for treating Cushing's disease. This drug is given daily, and it can be prohibitively expensive to use. Approximately 20-25% of dogs do not respond to it. It has the advantage of being safer than lysodren, as it does not cause permanent adrenal tissue damage. Any effects it has on hormone production are fully reversible.
Anipryl (Deprenyl, Eldepryl, Selegiline): This is the most controversial of the drugs to treat Cushing's disease. Unlike the former, Anipryl does not affect the adrenal glands directly. First marketed for dogs as a psychotropic medication to help senile dogs think more clearly, Anipryl allegedly stabilizes the balance of brain chemicals. It reduces ACTH production by functionally increasing dopamine levels. 70-80% of Cushingoid dogs responded favorably to the drug in clinical trials, yet actual practicing veterinarians are skeptical of its effectiveness. One endocrinologist claimed that it is very effective for only about 15% of dogs with pituitary-dependent Cushing's. Others report a response rate closer to 40%. The effectiveness seems to be related to the specific location of the pituitary tumor itself. Anipryl is expensive and takes 1-3 months to evidence effects. Nonetheless, Anipryl is extremely safe and cannot cause Addison's disease. It's probably a good starting point for treating Cushing's. If it works, it works. If it doesn't, one can begin lysodren therapy. Anipryl has no effectiveness at all in treating adrenal-based tumors.
Vetoryl (Modrenal, Trilostane): This is a new British drug used to manage Cushing's disease. The drug works by interfering with cortisol synthesis to prevent excess cortisol production. It is not licensed in the United States at this time, but it can be obtained if one gets an FDA waiver. There seem to be many favorable reports of its effectiveness and safety.
Prognosis: Left untreated, Cushing's disease will progress. As excess cortisol is immunosuppressive, Cushingoid dogs are prone to various infections. They are also predisposed to developing hypothyroidism, pancreatitis, diabetes, seizures, hypertension, congestive heart failure, blood clots (thromboembolism), and liver and kidney failure. It should not go without noting that many of these dogs are at risk of early euthanasia due to incontinence resulting from increased water consumption.
The short-term prognosis is very good. Treated, one would expect symptoms of Cushing's to fully resolve over the course of 4-6 months. Excess drinking and urinating abate quickly. It may take several months for hair and coat improvement to be observed. Dogs generally are more comfortable after the disease is under control and may live happily for years.
Alternatively, some dogs become very uncomfortable if arthritis, allergies, or other inflammatory conditions are unmasked once the excess cortisol is removed, paradoxically reducing the animal's quality of life. Another consideration relates to pituitary tumors themselves. These tumors continue to be somewhat responsive to blood cortisol levels, so it is possible that controlling cortisol release at the adrenal level may hasten the growth of a pituitary tumor, as the pituitary tumor is no longer kept in partial check by excess cortisol levels. Neurologic signs from a pituitary macroadenoma may then present themselves.
The goal of treatment is to improve quality of life and perhaps lengthen life, but except in situations where an adrenal tumor can be completely removed or where a dog can be weaned off external sources of cortisone, Cushing's disease is not something from which a dog recovers. Cushing's disease is managed, not cured. Whether treated or not, most dogs will die within a few years of diagnosis, although not necessarily due to Cushing's iteself. Again, that is because most Cushing's patients are elderly and have concurrent health issues. Nonetheless, hyperadrenocorticism is a serious condition, and maintaining a dog with Cushing's disease requires vigilance and commitment on the part of the owner.
Bottom line: Cushing's disease is a common condition in older dogs and is often mistaken for signs of normal aging. Although most dogs with Cushing's disease cannot be cured, their quality of life (as well as the owner's quality of life) can be improved, and their lives may be extended with early intervention. It is often possible to successfully manage this disease for years. It thus behooves the pet owner to become familiar with the typical signs of Cushing's and the treatments available.
