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Hyperadrenocorticism - Information and treatment updates
Hyperadrenocorticism, Cushing’s disease, is caused by either a pituitary brain tumor or an adrenal gland tumor in almost all cases. There may be a small percentage of dogs who have Cushing’s disease due to overstimulation of the pituitary gland by the hypothalamus but this is not a certainty at this time. Pituitary tumors are the most common cause of Cushing’s disease, accounting for 80 to 85% of the cases of Cushing’s disease
When there is a pituitary tumor it produces too much of the hormone that directs the adrenal glands to make cortisones. When there is an adrenal gland tumor it produces cortisone continuously without responding to the pituitary gland’s efforts to control the cortisone levels in the body. The end result of either process is the same, cortisol levels in the body rise beyond normal levels which leads to the clinical symptoms. In many texts a standard acronym for dogs with pituitary tumors causing Cushing’s disease is PDH, standing for pituitary dependent hyperadrenocorticism. For dogs with adrenal tumors the acronym most commonly used is ATH or adrenal tumor hyperadrenocorticism.
Cushing’s disease affects female dogs more commonly than male dogs. Approximately 60% of the dogs with Cushing’s disease are female. In addition, female dogs are also more likely to have an adrenal gland tumor causing the Cushing’s disease. Of dogs who have adrenal tumors about 65% are female.
Almost all dogs with Cushing’s disease are over 6 years of age and approximately 75% of dogs diagnosed with Cushing’s disease are over 9 years of age. It is important to remember this if a young dog is diagnosed with the disease. There are documented cases in young dogs, some under two years of age, but it is a rare finding. Almost all cats with Cushing’s disease are over 9 years of age.
PDH is a disease primarily of small dogs. About 75% of the cases of PDH occur in dogs weighing less than 20kg (44 lbs). Large breed dogs are less likely to develop Cushing’s disease overall but when they do develop it they have a higher incidence of adrenal gland tumors than smaller dogs with perhaps 20% of the cases of Cushing’s disease in larger dogs being adrenal in origin.
The symptoms of Cushing’s disease may include any of the following problems: increased drinking and urinating, increased appetite, panting, a pendulous appearance to the abdomen, increased susceptibility to urinary bladder and skin infections, decreased exercise tolerance, weight gain, hair loss (often in a symmetrical pattern), testicular atrophy, increased pigmentation of the skin, thinning of the skin (especially noticeable in cats), muscle weakness, calcium deposits in the skin (calcinosis cutis) or less commonly in internal organs and a bulging appearance to the eyes. Failure to regrow hair that has been shaved occurs with both hyperadrenocorticism and hypothyroidism fairly commonly.
It is very important to recognize that there are probably no dogs who have all the clinical signs when they are affected by Cushing’s disease. Most dogs probably have two to three symptoms and there are a number of dogs who have no clinical signs, or at least none that are recognized by their owners. Hyperadrenocorticism does not generally cause an obvious illness. Pets may seem normal except for the presence of a symptom such as increased thirst.
In cats the clinical signs can be so subtle that it is likely most cats with Cushing’s disease go undiagnosed and that the disorder is found only when there is a good reason other than clinical signs to look for it. The single most common reason that Cushing’s disease is diagnosed in cats is difficulty regulating insulin requirements in cats with diabetes. When it is very difficult to establish a maintenance dosage for insulin for a cat with diabetes there is a chance that Cushing’s disease is present, as well. This is how most cases of Cushing’s disease in cats have been discovered.
The most prevalent sign of Cushing’s disease in cats is probably thinning of the skin. This can be very noticeable in some cats as the skin develops an almost translucent appearance and just feels thin when touched. A small number of cats develop thinning of the skin to the point where it tears easily and these injuries prompt the diagnostic process necessary to identify the disease.
Unusual complications sometimes occur with Cushing’s disease in dogs, as well. A small number of dogs develop severe muscular weakness (myotonia) that usually affect the rear legs predominantly. This can lead to a stiff gait or to collapse of the rear limbs in some dogs. Facial paralysis seems to be due to Cushing’s disease in a small number of dogs. Just like cats, a few dogs with diabetes will be very hard to regulate on insulin unless concurrent Cushing’s disease is controlled.
Since Cushing’s disease is the overproduction of cortisone it is possible to create all the symptoms of the disease by giving doses of cortisones, such as prednisone. This occurs most commonly when prednisone is given on a daily basis or for very long periods of time on an every other day basis. When a pet is being given a cortisone containing medication and develops symptoms of Cushing’s disease it is referred to as iatrogenic Cushing’s disease. This is a very different problem than naturally occurring Cushing’s disease. The only time when this presents a serious diagnostic challenge is when the veterinarian has no idea that prednisone or other glucocorticoids are being administered.
Routine laboratory tests are not very helpful in diagnosing Cushing’s disease but they can give some hints that the disease is present. The most common routinely tested laboratory abnormality that veterinarians associate with Cushing’s disease is an increase in alkaline phosphatase levels. This is a very nonspecific test for Cushing’s disease but when there is a rise in the alkaline phosphatase levels it is necessary to at least think about the possibility that Cushing’s disease may be present.
Dogs with Cushing’s disease may have slightly elevated white blood cell counts. Usually this is due to rise in neutrophils. Blood sugar levels tend to be in the high normal to slightly higher than normal levels in dogs. This sign is less useful in cats because cats can elevate their glucose levels in response to stress, including the stress of veterinary visits and drawing blood. Sometimes blood urea nitrogen (BUN) and creatinine levels are decreased in dogs with Cushing’s disease. In most cases these values are normal, however.
The clinical syndromes caused by hypothyroidism and hyperadrenocorticism are similar enough that many dogs are tested for both diseases when either one is suspected. It is important to note that dogs who do have Cushing’s disease may have low thyroid hormone measurements due to the Cushing’s disease. This means that it is not uncommon for the lab values to indicate that both Cushing’s disease and hypothyroidism appear to be present when in fact the thyroid levels are low due to the Cushing’s disease and not because the dog actually has hypothyroidism. It can be very difficult to decide whether to treat a dog for hypothyroidism when it also has Cushing’s disease.
Diagnosing Cushing’s disease requires specialized testing. There are a number of options for testing dogs, all of which have some advantages and some disadvantages. At the present time the majority of endocrinologists seem to favor using the low dose dexamethasone suppression test (LDDS) over the ACTH response test but there is still some disagreement over this. The urine cortisol:creatinine ratio can be a useful screening test for Cushing’s disease but is not accurate enough to depend on for treatment decisions. To give you some idea of the relative accuracy of these tests it is necessary to discuss two values, sensitivity and specificity.
Sensitivity is the measurement of how likely a test is to be positive when a pet has a disease. A test that is 100% sensitive will always detect the disease. Another way to think of this is to consider the sensitivity as a measurement of how likely a negative result on a test is to be accurate. If a test is 100% sensitive then any negative result would be 100% accurate.
Specificity is the measurement of how accurately a positive test result identifies pets who actually have the disease. A test that is 80% specific will be accurate in identifying truly positive individuals 80% of the time. Or to look at it the other way, if the test is positive there is a 20% chance that the pet being tested doesn’t actually have the disease being tested for.
The specificity and sensitivity of the various tests for Cushing’s disease play a major role in determining the usefulness of each of the tests. The low dose dexamethasone suppression test is about 95% sensitive but is only about 70% specific. An ACTH response test is approximately 80% sensitive but the specificity of the test has been very variable in reported studies, with a low of 35% and a high of 80%. Urine cortisol:creatinine ratios are very sensitive for detecting the possibility of Cushing’s disease, probably at least 90% sensitive. This test has very low specificity, though. Only about 20 to 25% of dogs with abnormal cortisol:creatinine levels actually have Cushing’s disease. Some vets feel that this is still a useful screening test, on the theory that a negative result is very likely to be correct. This test is inexpensive compared to the other tests so even though further testing would need to be done to confirm a positive result it can still be viewed as a reasonable first step in the diagnostic process since a dog with a negative test result is unlikely to have Cushing’s disease.
It is possible to identify pituitary tumors with MRI or CT scans. This isn’t a very economical test and the sensitivity of the testing can be low when tumors are small. It is sometimes possible to identify adrenal tumors with ultrasound examination.
It is much harder to accurately diagnose Cushing’s disease in cats. There are several reasons for this but the one with the most impact on testing appears to be the ability of cats to produce high cortisol levels in response to stress. This ability makes it hard to get good results from tests that use cortisol levels to measure the response to ACTH or dexamethasone. Even though none of the tests work as well in cats as they do in dogs, there is general agreement that the urine cortisol:creatinine level and the LDDS tests probably work best at determining if Cushing’s disease is present. It is very important to note that the “low dose” dexamethasone test recommended for cats uses the dose of dexamethasone that is used for the “high dose” test in dogs. Failure to use this higher dose usually results in a meaningless test result.
In both dogs and cats it is important not only to show that Cushing’s disease is present but to take the next step and to determine whether the disease is caused by a pituitary gland tumor or by an adrenal gland tumor. This type of testing is in a transition state at the current time in veterinary medicine, at least in dogs.
In the past the best test for determining the underlying cause of Cushing’s disease was thought to be a test referred to as a high dose dexamethasone suppression test (HDDS). Using high doses of dexamethasone it is possible to fairly reliably suppress any effect of the pituitary gland on adrenal gland production of cortisols. Since it is possible to rule out PTH if suppression occurs, the only dogs who do not respond to the higher dose should be those with adrenal gland tumors. While the test doesn’t work quite that well in real life it was still the best test for differentiating between pituitary and adrenal origin Cushing’s disease until the advent of the newer imaging technologies.
It is usually possible to determine if the adrenal glands are enlarged by ultrasound examination and to visualize tumors if they are present in most dogs. If it has been demonstrated that Cushing’s disease is present this information can be used to determine if adrenal or pituitary origin Cushing’s disease is most likely. Ultrasonagraphy isn’t a very good initial test for Cushing’s disease because the changes may not be pronounced in the case of PDH and any tumor visualized may or may not be causing Cushing’s disease.
Computerized tomography (CT) or magnetic resonance imaging (MRI) can both be used to identify pituitary gland tumors if they are large enough. Many dogs do not have detectable tumors at the time of initial diagnosis but most dogs with PDH will eventually develop a tumor large enough to visualize by CT scan or MRI. This information applies about equally to dogs and cats, in general.
Some veterinarians opt not to try to differentiate between PDH and ATH based on testing. Insteady, they opt to treat for PDH first in all cases. If the response to treatment is not as good as they expect, they then make and effort to confirm that adrenal origin hyperadrenocorticism is present. This can be a reasonable choice as long as everyone is informed of the decision and the success or failure of treatment is monitored closely. It is not ideal but it meets the economic needs of some clients in a realistic manner.
The use of discrimination tests to differentiate between pituitary and adrenal origin Cushing’s disease in cats is not as well established. There is a protocol for doing a high dose dexamethasone suppression (HDDS) test using urine samples collected at home over the course of two or three days that looks like it may turn out to be the best test for discriminating between PDH and ATH in cats. Alternatively, MRI or CT scans may show pituitary gland tumors but this is not a very sensitive test.
At this point we have a patient who has clinical signs consistent with Cushing’s disease and who has laboratory results consistent with Cushing’s disease. In most cases we also have a pretty good idea whether the Cushing’s disease is caused by an adrenal gland tumor or by a pituitary brain tumor. It now becomes necessary to make treatment decisions based on the information that has been obtained.
The first question that has to be asked is whether treatment is even necessary. There is no well documented evidence that suggests that treatment for Cushing’s disease, with the exception of successful removal of solitary tumors, has an effect on life span after diagnosis. Therefore, medical treatment of Cushing’s disease can be viewed as optional if the clinical signs are not debilitating or causing significant interference with the pet’s life style and surgery is not an option. Most dogs and cats who are diagnosed with Cushing’s disease are brought to the veterinarian’s because their symptoms have become a problem but for those that aren’t it is reasonable to ask if treatment is necessary.
Surgical treatment for Cushing’s disease has always been an option for patients with adrenal gland tumors. There are a number of veterinarians who are comfortable attempting exploratory abdominal surgery and removing adrenal gland tumors. Until recently surgery was not considered to be an option for pituitary dependent Cushing’s disease in dogs and cats because the surgery was considered to be too risky or too expensive for veterinary medicine. Dr Meij at the Utrecht University in the Netherlands developed a technique for successfully removing pituitary gland tumors which is referred to as hypophysectomy. This surgery has survival rates comparable to medical treatment now and other institutions are starting to offer it as an alternative to medical treatment. I believe that most endocrinologists would agree that hypophysectomy is the preferred treatment for PDH when the pet owner can afford to pursue surgery and locating a surgical facility is not too difficult.
Despite the fact that removal of tumors from the adrenal gland has been a more widely available option there is some argument over whether it is the best approach to adrenal origin tumors, especially those that are suspected to have spread to other organs. Surgery of the adrenal gland carries significant risks and it is estimated that It is considered reasonable to use mitotane to treat adrenal tumors but the success rates are low in comparison to many surgical procedures, especially when malignant tumors are present. Overall the surgical success rate, defining 16 months of survival post-surgically as success, is about 50%. The success rate of medical therapy is almost identical when using the same criteria for success.
Treatment options for cats with either PDH or ATH origin Cushing’s disease are not as diverse. Cats do not respond very well to medical therapy for Cushing’s disease. Therefore, hypophysectomy is the preferred therapy. If that is not possible to arrange the other option to consider in a cat is surgical removal of both adrenal glands. This is a radical approach since it instantly produces hypoadrenocorticism (not enough production of cortisols) and this has to be managed very carefully to keep the patient alive. The mortality rate associated with surgery is about 50% within a few days to weeks of surgery but for cats who live through this initial period the surgery appears to work well.
While it is unusual, there have been some well documented cases of spontaneous remission from Cushing’s disease. This makes sense as spontaneous remission seems to occur with a number of cancers. It isn’t something you can count on, but if your pet seems to recover from previously diagnosed Cushing’s disease it is really possible that recovery is truly happening.
If surgery can not be considered there are medical treatment options. There are a number of medications that have been used to treat Cushing’s disease but the three most commonly used medications at the present time are selegiline (Anipryl Rx), mitotate (o,p’-DDD, Lysodren Rx) and trilostane (Vetoryl Rx, not approved at this time for use in the United States). Each of these drugs appears to have some advantages and disadvantages so it is generally necessary to tailor treatment to the specific needs of individual pets. It is important to recognize that medical treatment of Cushing’s disease controls the symptoms but does not address the underlying problem of a pituitary or adrenal gland tumor, with a few exceptions noted in the paragraphs that follow.
Selegiline is approved for the treatment of Cushing’s disease in dogs but it only works well in approximately 20% of dogs. In another 20% of dogs it works well enough that pet owners are satisfied with the choice of medication even though it doesn’t completely control symptoms of hyperadrenocorticism. Selegiline is considered to be a safe medication and it is easy to use because follow up laboratory testing is not nearly as important when using selegiline as when using mitotane or trilostane. For this reason a number of veterniarians will try selegiline first when treating a patient with uncomplicated Cushing’s disease, even though the odds are stronger that it won’t work. One reason this can be a good choice is the group of dogs who appear to have PDH that is due to overstimulation by the hypothalamus. Theoretically it is possible to actually cure this group using selegiline and some researchers believe they have seen this effect. If this does happen it happens for a very small and select group of patients but this still seems to justify trying selegiline when there are no major reasons not to.
Mitotane is a chemotherapeutic agent that specifically targets the adrenal glands. It works by destroying adrenal gland tissue, preventing the overproduction of cortisones by the adrenal glands. Since some adrenal gland function is necessary for survival, it is necessary to try to balance the amount of destruction that occurs against the need for cortisone in the body. In order to do this, it is necessary to run ACTH response tests frequently during the initial dosing period and then periodically while the dog is being given mitotane. It is hard to overemphasize the importance of this monitoring. There is a strong temptation to try to minimize testing due to the expense and inconvenience but patients treated with mitotane can die if too much adrenal tissue is damaged during the initial treatment stage or during maintenance therapy. It is absolutely critical for good lines of communication to exist between the veterinarian and pet owner when mitotane is being used. Do not leave your veterinarian’s office until you thoroughly understand exactly how your vet wants you to monitor your dog.
These are some things to consider when using mitotane:
When first stating mitotane the earliest indication it is working is a decrease in appetite. Any noticeable decrease in appetite, even just being slow to start eating, is sufficient change to alert your vet. Most veterinarians want you to stop the medication and schedule a recheck visit as soon as any decrease in appetite is noted.
Mitotane makes some dogs nauseous. Vomiting can be a sign of overdosage or of continuing the induction dose for too long, so you should discuss all instances of vomiting with your vet. If after doing so it seems likely that the medication is causing the vomiting rather than overdosage, splitting the daily dose up can help. Twice daily dosing with smaller amounts is often enough but the dose can be further divided if necessary. Giving the pills with food helps to alleviate this problem, as well.
Mitotane should not be started in a patient who is already vomiting, has diarrhea or seems to have a poor appetite.
If a patient who is on maintenance dosages of mitotane requires a planned surgery or if any other event occurs that causes significant sress it is best to put the dog on prednisone or other glucocorticoid medications for the stressful period. A few pets require cortisone supplementation every day while using mitotane but most do not.
Trilostane is approved for use in England but not in the United States. It is available in the U.S. through compounding pharmacies and can be imported legally as an experimental drug if proper procedures are followed. It works by inhibiting the production of cortisone in the adrenal gland by interfering with conversion of cortisone precursors into cortisone. In humans this effect seems to be variable but it is not known if there is a similar problem in dogs, yet. It is possible to evaluate the effect of trilostane using lab work and this is recommended. Trilostane is more expensive than mitotane but over time the lower laboratory follow-up requirements may make this expense easier to bear.
There are a number of possible complications of medical treatment of Cushing’s disease. The most significant of these is causing hypoadrenocorticism without noticing it. Even during the maintenance dosing it is critical to report changes in appetite, vomiting, diarrhea or marked decreases in water consumption to your veterinarian. Medical treatment often works for a while and then seems to stop working, necessitating adjustments in medication dosage or frequency of use. Some dogs who start out with just pituitary origin Cushing’s disease go on to develop adrenal tumors and this can complicate therapy. Obviously it is also possible for dogs with PDH to develop AT origin hyperadrenocorticism. If you keep in contact with your veterinarian and report changes as they occur, it is usually possible to work through complications and to continue to successfully treat pets with Cushing’s disease.
A number of people have asked if it is possible to combine medical therapies for Cushing’s disease in dogs but using mitotane or trilostane and selegiline as well. As far as I can tell there is no reason that selegiline can not be combined with these other medications. In a few instance in which I know this has been done the clients felt that they were receiving benefits from both drugs. It is possible that this is an effect that is independent of any effect that selegiline has on Cushing’s disease directly, though. Selegiline is also approved for use in “canine cognitive dysfunction” which is a senility problem in older dogs. It is likely that some dogs who seem to respond better to therapy with selegiline and another medication for Cushing’s disease actually has both problems, especially since both of these problems are common in older dogs.
In cats the major reason that Cushing’s disease is diagnosed is its adverse effect on the regulation of blood glucose in cats who have both diabetes and Cushing’s disease. It is unlikely that there would be nearly as much information on Cushing’s disease in cats if this link had not been uncovered. It is important to understand that this information doesn’t mean that all cats who are difficult to regulate on insulin have Cushing’s disease. It is more likely that there is a problem with insulin timing, dosage, type or use than that Cushing’s disease is present. However, if after careful review of injection procedures, insulin type, timing of insulin doses, diet and other factors there continues to be a problem with insulin regulation it makes sense to look for Cushing’s disease. Acromegaly, another hormonal disease, can also interfere with insulin regulation and must also be considered.
If medical or surgical treatment controls clinical signs, why do dogs and cats with Cushing’s disease die from the disease? The simplest answer to this question is that the population of dogs with Cushing’s disease can be said to have cancer in nearly 100% of cases and the cancer is not generally removed surgically. Eventually the cancer causes problems. This may be the strongest reason to opt for surgical treatment, especially for pituitary origin hyperadrenocorticism but the truth is that at the current time it is quite difficult to arrange for hypophysectomy because it is done by so few surgeons. In the future this is likely to change and surgery may become the most common treatment option. This may not cure all cases of PDH since there are some malignant tumors but it at least offers the hope of an actual cure.
There are other factors beside the underlying cancers that can lead to serious complications, as well. Some dogs with Cushing’s disease develop abnormal blood clotting, which can lead to pulmonary embolisms or problems in other areas of the body. High blood pressure (hypertension) is common in dogs with hyperadrenocorticism. Cushing’s disease complicates a number of other older age diseases, such as diabetes, skin infections, kidney or bladder infections and congestive heart failure. When these other conditions are present they tend to be much more difficult to manage in a patient with Cushing’s disease. Seizures and other neurologic signs can occur when pituitary tumors enlarge.
There are no specific dietary recommendation for pets with Cushing’s disease but it is theorized that they may do better on reduced fat diets since there is a strong tendency towards obesity in patients affected by Cushing’s disease. Some vets also favor the use of anti-oxidants such as fish oils in the diet, on the theory that controlling inflammation may help to slow the development of the underlying cancer.
Hyperadrenocorticism is a serious problem in older dogs and it is likely that over time we will continue to recognize it more and more in older cats, as well. It is a disorder that requires close communication between a veterinarian and pet owner during both the diagnostic and treatment periods. The importance of this communication can not be overstated so if your pet is diagnosed with Cushing’s disease make sure there is a veterinarian in the practice you chose to treat the disease who you are comfortable talking with and who you understand fully. Managing hyperadrenocorticism successfully can make a dog or cat feel much better, increasing the quality of their life. When it is caused by benign tumors that can be successfully removed there is a chance for a cure. As more veterinary facilities become experienced in hypophysectomy this should be come a more realistic option for many pets. Your vet can help you find a surgical facility capable of this surgery if you want to consider this option now rather than in the future.
Dr Mike Richards, DVM
Q: My 9 yr. old Russian Blue has been diagnosed with Cushing's Disease. I am trying to learn about as many options for treatment as possible. I realize that long term survival is probably not an option for him, however, I would like to keep him as healthy as possible for as long as possible. All suggestions and info I collect is passed on to my vet. -- Ann'a
A: Cushing's disease is pretty unusual in cats but it is being reported more often in the last few years than has previously been the case. It is most commonly recognized as a complication of feline diabetes when insulin resistance occurs. The most consistent medical treatment is probably metyrapone but ketaconazole and mitotane (Lysodren Rx) have also been used in cats with success in some cases. Adrenalectomy (removal of the adrenal gland) has been proposed as a possible treatment for hyperadrenocortism because medical treatment has been inconsistent. There appears to be a pretty high surgical risk, though. L-deprenyl has been used in dogs but I have no idea whether or not it has been tested in cats.
Good luck with this.
Mike Richards, DVM
Last edited 06/05/07