Probably one of the most confusing endocrine disorders is hyperadrenocorticism or Cushing’s disease. Trying to diagnose and treat animals with this disorder can sometimes be frustrating, but if a clinical approach is taken, it can be much easier and more rewarding.
Cushing’s disease is caused by a hyperfunctioning adrenal cortex that is producing excessive cortisol. The production of cortisol is regulated by the hypothalamus and pituitary gland. Normally, in response to stressful situations, the pituitary gland produces ACTH that in turn causes the adrenal cortex to produce cortisol. The production of cortisol, in turn, causes a negative feedback on the pituitary, thus decreasing the amount of ACTH produced. In other words, by producing increasing amounts of cortisol, the cortisol actually turns off more production, keeping things in balance. This negative feedback loop controls the amount of cortisol produced.
Cushing’s disease is caused by the adrenal cortex over-producing cortisol. There can be two causes of the excessive production. The most common cause (about 90% of the time) is due to a small tumor of the pituitary gland called a pituitary microadenoma. These tumors typically do not get larger than 0.8 to 1 cm in size and usually do not cause any neurologic signs due to the tumor size. Since most of the time these tumors remain small, the clinical signs they cause are all due to the stimulation of the adrenal cortex and the production of excessive cortisol. On rare occasions, these tumors can get larger (over 1cm), and are called pituitary macroadenomas. These larger tumors do have the potential to cause neurologic signs compatible with a brain tumor. Both types of tumors produce excessive amounts of ACTH, and with that, increased cortisol. This excess of cortisol is what causes the clinical signs of Cushing’s disease.
The other type of Cushing’s disease is caused by a primary tumor in the adrenal cortex that directly produces cortisol. These dogs have normal pituitary glands. It is not nearly as common as the pituitary dependent types and occurs about 10% of the time.
Dogs with Cushing’s disease have clinical signs due to the chronically elevated cortisol levels in their circulation. Cortisol is the natural “prednisone” of the body. Too much cortisol causes the same things one would see with a dog receiving prednisone. They commonly will be polyuric, polyphagic and polydipsic. Many dogs will pant a lot, have a “pot belly,” (distended abdomen appearance) and a thinning hair coat. Some dogs get chronic skin or urinary tract infections due to suppression of the immune system by increased cortisol.
Diagnosing Cushing’s disease
Clinical signs are the most important thing in diagnosing Cushing’s disease.
Cushing’s should be thought of as a clinical illness, not something that you just diagnose based on lab testing. If you think a dog has Cushing’s, then most likely he does. The converse is also true. If you don’t think a dog has it, you are probably correct.
The most common laboratory abnormality is a high Alkaline Phosphatase (ALK Phos) enzyme. Oftentimes it is extremely elevated (in the thousands) especially relative to the other liver enzymes. About 90% of dogs with Cushing’s have an increased ALK Phos. Other common abnormalities include a stress leukogram, high cholesterol, hypertension, UTIs, and a modest proteinuria.
There are many tests that are used to diagnose Cushing’s and I think this creates much of the confusion regarding the disease. There are tests that just establish the diagnosis, and then others used to determine if the condition is pituitary or adrenal in origin. Tests that establish a diagnosis include: the low dose dexamethasone suppression test (LDD), ACTH stimulation test, and the urine cortisol Creatinine ratio. Most people consider the LDD test the best test in diagnosing or ruling out Cushing’s disease. The biggest issue with the test is that it takes 8 hours and 3 blood samples (initial cortisol, and a 4 and 8-hour sample), so the test essentially takes all day. The ACTH stim test is advantageous because it only takes an hour and is easier to perform. The ACTH stim does have more false negatives than the LDD, so a negative result may need to be interpreted with some caution. Probably the simplest screening test is the urine cortisol Creatinine ratio. This test only requires a single urine sample collected at home. The sample must be collected at home because the stress of the dog coming into the hospital for urine collection can impact the results. False positives on the test are very common. But, if the test is negative, it is pretty accurate at saying the dog does not have Cushing’s. If the test is positive, it just means that the dog MIGHT have Cushing’s. So the usefulness of this test is in ruling Cushing’s out.
The real key (and probably the most confusing part), in all of the Cushing’s diagnostic tests, is remembering to correlate your test results with your clinical impression. If you really think the dog has Cushing’s, but he tests negative on one of the tests, then do the other one. If the second test comes back positive, the dog likely has the condition. The converse is also true: If you really do not think the dog has Cushing’s (but it needs to be ruled out), and the dog tests negative then the dog probably does not have it, and I would look for another diagnosis.
Establishing the type of Cushing’s
Once the diagnosis of Cushing’s is established, the type (pituitary disease, or an adrenal tumor) of Cushing’s needs to be determined. Occasionally the results of the LDD will come back where there is enough suppression of cortisol to diagnose pituitary disease, but many times additional tests are needed. These include the high dose dexamethasone suppression test (HDD), ACTH level and diagnostic imaging. The HDD test is similar to the LDD, but ten times the dose of dexamethasone is given. The theory is that the higher dose of dexamethasone will suppress cortisol secretion from the pituitary, but not from an adrenal tumor. The reality of the test is about 10% of dogs with pituitary disease still do not suppress on this test….so a positive HDD (cortisol does not suppress appropriately on post samples) does not really tell you what you have. On the other hand, a negative test (cortisol suppresses) is very useful and tells you that you have pituitary disease, as an adrenal tumor should not show cortisol suppression from this dose of dexamethasone.
Another way to figure out the type of Cushing’s disease is with an ACTH level. This test works under the premise that a dog with pituitary disease will be producing a lot of ACTH (as it is directly produced by the pituitary), causing the level to be increased. Conversely, if the dog has an adrenal tumor, the cortisol produced by the adrenal tumor would suppress the secretion of ACTH by the pituitary by negative feedback, so the ACTH level would be low. Unfortunately, as with so many “gray areas in trying to diagnose Cushing’s, many times the value comes back as more in the middle range and is not diagnostic.
Currently, the best way of determining if the dog has pituitary vs. adrenal Cushing’s probably is with diagnostic imaging. A skilled ultrasonographer can visualize the adrenal glands and determine if they are both symmetrically enlarged (pituitary disease) or if there is an adrenal tumor on one (or occasionally both) adrenal gland(s). A CT or MRI can also identify adrenal masses, but the added expense for these diagnostics are usually not required.
Treatment of Pituitary based Cushing’s
Finally, after establishing a diagnosis, treatment is considered. Dogs with pituitary disease are usually treated medically. Most veterinarians are now using trilostane as the first line of therapy. Trilostane works by selectively blocking the production of cortisol from the adrenal glands. It does not damage adrenal tissue; it just blocks the cortisol that is being overproduced. There is a large variation in the Trilostane dose that is required to control the cortisol secretion and thus clinical signs associated with the disease. Typically one starts at the low end of the dose (1-2mg/kg SID to BID) and works up from there. After about a week or two of therapy, the 1-hour ACTH stim is done to assess if the dog’s cortisol levels are appropriate. The owner is also questioned to see if the clinical signs have improved or resolved. If the dog is doing well and the cortisol levels are now in the normal range, then the dog can be rechecked in several months. If the clinical signs have not improved much and the levels are still high, then the dose is increased (usually about 50% higher), and the process repeats with another ACTH stim 1-2 weeks later.
The biggest side effect of Trilostane is an increase in serum potassium as the production of aldosterone by the adrenal glands can also be suppressed along with the cortisol. This is usually not a clinical issue but should be expected on lab work. When monitoring ACTH stims, an electrolyte panel should be checked as well to make sure the potassium is not getting too elevated. The worst potential side effect of Trilostane is acute adrenal necrosis. Dogs present just like an acute Addisonian crisis and require emergency treatment. Thankfully this is a rare and idiosyncratic occurrence.
Sometimes the dog’s clinical signs have improved significantly, but the stim is still somewhat elevated. In these cases, I like to go by the clinical impression (i.e. believe the dog, not the test results). I probably would not increase the Trilostane dose here and just follow up in the future.
Many people use Trilostane SID, but I find that BID treatment usually produces the best clinical outcome. Trilostane has a short half-life so the ACTH stim for monitoring therapy should be done about 3-6 hours post-pill.
Another drug used to treat this disorder is Lysodren. Lysodren is a cytotoxic drug that causes a selective necrosis of the cell producing cortisol in the adrenal cortex. There are more side effects associated with its usage, but if closely monitored it is still quite safe and very effective. Still, it has fallen a bit out of favor with most veterinarians recently. The drug is given as a daily “loading” dose. Once the cortisol levels have normalized, the total daily loading dose (a single daily dose) is divided and given just twice a week.
Ketoconazole, another enzyme blocker, and Anipryl, a MOA inhibitor have also been used but with much more limited success.
Treatment of Adrenal-based Cushing’s
Treating an adrenal tumor is usually a surgical issue, but there are times when surgery may not be indicated. Each patient is an individual and many factors should be taken into consideration before surgery. Surgery may not be the option for patients that are too old and frail or dogs with too many concurrent illnesses. A CT scan of the abdomen may show that the tumor would be difficult or impossible to remove, or it could show metastatic lesions. Finally, an adrenalectomy is a very expensive procedure and owners may decline it for financial reasons. If surgery is not an option for a patient, one can still consider medical management with the medicines described above. Actually, many dogs have improved quality and quantity of life with medical treatment of adrenal tumors, so treatment should not be discounted just on the basis of an “aggressive” or non-resectable tumor.
When surgery is being considered, I always recommend a CT or MRI first to best assess the likelihood of surgical success and to rule out metastatic disease.
If everything looks good for surgery, it is highly advisable that these cases be handled at a facility that has boarded surgeons, 24-hour post-op monitoring, and ideally an anesthesiologist. Removing an adrenal tumor is not a simple surgery, and may cause significant intra-op and post-op complications. Bleeding problems, blood pressure issues, and infections are not uncommon issues that may need to be addressed. When the cases are selected appropriately and the proper care is in place, these patients can do very well and have excellent outcomes. Recently, we have even started to remove certain adrenal tumors via laparoscopy, and have had very good results.
The final point on treating animals with Cushing’s is perhaps the most important. What do you do with an asymptomatic dog that you have diagnosed as having Cushing’s disease? For example, a dog presents for pre-dental bloodwork and we find a very elevated ALK Phos. We test him for Cushing’s and he comes back positive. The dog has no signs of Cushing’s and feels fine. Should we treat this asymptomatic dog? If we remember back to the beginning that Cushing’s is a clinical disease we have our answer. If there are no signs of Cushing’s, the dog is not clinical. The patient may become clinical down the road or may not. Treating a dog with no clinical signs is generally not recommended. These dogs should be followed and monitored, but there is no evidence that treating asymptomatic dogs increases longevity.
How about when we do an abdominal ultrasound and find an incidental adrenal mass? This is not exactly as clear-cut, but many times these incidental findings are not going to become problems, as many of them are non-functional adrenal adenomas. Getting a good history from the owner, checking the blood pressure (in case the adrenal tumor is a pheochromocytoma) would certainly be prudent before recommending surgery. If there are no clinical or pathologic signs, it may just be best to monitor the mass over time with ultrasounds to make sure it is not growing excessively.
Historically, treating Cushing’s has been thought of as “difficult”. Some veterinarians have experienced cases of dog’s cortisol levels falling too rapidly or getting too low with treatment resulting in an Addisonian crisis. These drug-induced emergencies are rare especially if the patients are followed closely.
Most dogs with Cushing’s disease do very well and respond to treatment, significantly improving the quality of their lives. It is a disease that can be confusing, but if one remembers that it is a clinical issue and not a laboratory issue, it can be very rewarding to treat…or even, not to treat.
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