Well, He Is Drinking a Lot

or

Hyperadrenocorticism in Canines

aka

Cushing's Disease

                                                                                                                                 By Beth A. Pelletier, DVM 

            Many dogs are overweight.  Many dogs drink a lot of water.  Many dogs pant excessively or have bad skin or aren't energetic.  However, no dog should have all of these signs - unless they have Cushing's disease!  Cushing's is caused by an excess of the stress hormone, cortisol in your dog's body.  A dog with hyperadrenocorticism may not exhibit all of the above signs but a combination of two or more of them will make your veterinarian suspicious that there is a hormonal imbalance in your pet.  Signs usually come on very gradually and may be very subtle, so they are easily overlooked.  The most common changes noted are a "pot-bellied" appearance (cortisol causes a redistribution of fat into the abdomen causing the belly to bulge out excessively) and increased thirst and urination.  Other possible signs include increased appetite, incontinence, or muscle weakness (manifesting as lethargy, exercise intolerance or reluctance to jump or climb).  Skin changes may be noted, such as hair loss, thin or wrinkled skin, delayed wound healing, persistent or recurrent infections, decreased fur re-growth after clipping, blackheads, darkened skin, or calcium deposits.  Invisible changes also occur with Cushing's, such as high blood pressure (hypertension).  These imperceptible changes may cause the most harmful effects in this disease.  Hypertension can lead to blood clots in the lungs (pulmonary thromboembolism), kidney damage and heart disease.  Diabetes mellitus and all of its consequences may also result from hyperadrenocorticism.  Cushing's disease is chronic and progresses slowly, so its diagnosis and treatment are not an emergency situation.  However, some of the problems mentioned above are quite serious and can be life threatening if left untreated. 

            Unfortunately, treatment has its own dangers and downsides, so we choose our candidates carefully.  If the case is severe enough to cause a decreased quality of life for your pet and yourself, it may be worth treating.  The problem with treatment is it may lead to the opposite problem: hypoadrenocorticism, aka Addison's disease.  An "Addisonian Crisis" results from too little cortisol in the blood and can be life threatening.  The pros and cons of treating must be weighed on an individual basis. Prior to treating however, we have to confirm the diagnosis.  Specific signs may make us suspicious, but diagnostics are the only way to prove the signs are due to hyperadrenocorticism.  Other diseases such as hypothyroidism can present very similarly to Cushing's, so they must be ruled out.

            The type of Cushing's must also be identified.  There are 2 types: pituitary-dependant hyperadrenocorticism (PDH) and adrenal tumor hyperadrenocorticism (ATH).  In PDH, the pituitary gland (located in the brain) is producing too much stimulating hormone (ACTH).  This hormone signals the adrenal glands (located near the kidneys) to produce cortisol.  In ATH, the adrenal glands are producing too much cortisol due to abnormal cells, without any help from the pituitary gland. The type of hyperadrenocorticism is important because it determines treatment. This can all be a little confusing, so CLICK HERE for a link to a page with three simple animations demonstrating normal pituitary-adrenal feedback and then the abnormal feedback loops in PDH and ATH.

            Let's take my friend, "Bo", as a case example.  Bo, a 13 year old beagle, came in for routine blood work prior to anesthesia for a growth removal.  Bo's owners had noticed some changes in him but passed them over as normal age-related developments.  Bo had gained some weight, but that could be explained by his voracious appetite and decreased energy.  He did a lot of panting and drank more water, which could be explained by the warmer weather.  On Bo's blood work however, we saw certain abnormal values that in conjunction with his pot belly and other signs made us highly suspicious of Cushing's disease.  So prior to his growth removal, we performed a simple, noninvasive test called a urine cortisol/creatinine ratio.  All that is required for this test is a urine sample that can be collected at home.  If the test is negative, the dog definitely does not have Cushing's.  If it is positive, the dog may have Cushing's (or he may have recently undergone a stressful event causing a temporary elevation in blood cortisol!).  Therefore, a positive result is indication for further testing.  Yes, it is a lot of testing, and this is just the beginning.

            Bo provided us with a urine sample (good boy) and it came back positive.  Further testing was recommended, but Bo's growth removal was a priority.  The surgery was performed and Bo went home to recover.  A few months later, Bo was back.  Since his initial testing, Bo's thirst and urination had gotten out of hand - to the point that he would drink his own urine (gross!).  With signs like that, Bo's owners were willing to pursue treatment if necessary.  Bo was hospitalized for one day so we could perform what is called a Low Dose Dexamethasone Suppression test or LDDS test.  This involves taking blood for a baseline cortisol level, then giving a supplemental steroid (Dexamethasone).  Additional blood samples are taken 4 hours and 8 hours after the steroid is given to determine the cortisol level at those time points.  If a dog has Cushing's, the cortisol level will stay high.  If he doesn't, the body's normal checks and balances detect the supplemental steroid and stop the body from producing its own steroid (cortisol).  This results in decreased cortisol levels at 4 and 8 hours. 

            In some cases, the LDDS test will also tell us the type of hyperadrenocorticism present.  If it does not clarify the type but confirms Cushing's, additional but similar testing will be necessary (a High Dose Dexamethasone Suppression Test or an ACTH level).

            Bo's LDDS test confirmed pituitary-dependent hyperadrenocorticism (meaning his pituitary was sending out too much ACTH to the adrenals which were then producting too much cortisol).  Once we had a diagnosis, the nitty gritty of treatment was tackled.  For PDH, there are a few options for treatment.  The oral medications mitotane and trilostane are the most commonly used and the least expensive treatment options.  Mitotane (trade name Lysodren) works by eroding the layers of the adrenal gland that produce cortisol.  Trilostane inhibits an enzyme that is necessary for cortisol production.  Both treatments require routine monitoring through careful observation at home and in-hospital blood tests to ensure the cortisol level does not get too low. 

            Adrenal tumor hyperadrenocorticism is less common but more tricky.  This type may be due to a malignant tumor, meaning it could spread to other organs through the blood or invade surrounding tissues as it grows, causing additional disease.  In dogs with ATH, 50% are malignant and 50% are benign.  A diagnosis of ATH is cause for performing chest radiographs to make sure metastases aren't present already. An abdominal ultrasound is also helpful to assess the tumor and determine if it could be removed surgically.  Mitotane can be used for ATH, either before or after surgery to remove excess adrenal tissue.

          After a few lengthy discussions with his owners, we decided to initiate treatment with mitotane (Lysodren).  Bo was started on an induction dose (which is much higher than the maintenance dose).  During induction, the drug is eroding layers of the adrenal gland, so there is less tissue present to produce cortisol.  This stage is continued until clinical signs resolve (decreased drinking, urinating, appetite and panting) or for a maximum of 9 days.  Most dogs respond within 9 days.  Once signs improve or on day 9, the drug is stopped and an adrenocorticotropic hormone (ACTH) stimulation test is performed as soon as possible.  The ACTH stimulation tells us if the cortisol levels are normal and if the body is responding appropriately to the stimulating hormone (ACTH).  If at any time a dog shows signs of too little cortisol (vomiting, anorexia, diarrhea, lethargy), the drug is stopped and a supplemental steroid (prednisone) is started.  Then, an ACTH stimulation test is performed.  It is very helpful to measure food and water consumption before induction and then daily during induction.  This allows you to have an objective assessment of whether or not thirst and appetite are decreasing.

            Bo did very well on the mitotane at home.  He returned on day 9 to have his ACTH stimulation test performed.  On that morning, his owners noted a decreased interest in his food and while in the hospital he vomited.  His owners had been called almost daily to check on Bo's progress and no prior evidence of low cortisol had been noted.  Bo was started on prednisone to prevent clinical signs of low cortisol (vomiting) while we waited 24 hours for the test results.  His pre-ACTH cortisol level was slightly low so he was maintained on prednisone while we decreased his mitotane to the maintenance dose of 3 treatments per week.  After a month on the maintenance dose, another ACTH stimulation test was run.  It showed that his maintenance doses of mitotane and prednisone were resulting in normal cortisol levels.  In addition, Bo was doing very well at home; he no longer had accidents in the house and didn't feel the need to drink his own urine (yay!). He no longer had a voracious appetite, had lost weight and was much more energetic.  Bo's owners will continue to monitor him closely at home.  A recheck ACTH stimulation test will be performed in 4 months, sooner if adverse effects are noted.

            As I mentioned above, not all dogs that technically have Cushing's disease require treatment.  However, if their clinical signs are severe, such as in Bo's case, or if secondary diseases are present (diabetes or hypertension), the treatment may be worth pursuing.  With an owner who is diligent in monitoring for adverse signs and is willing to return for follow up testing, the treatment can be very successful.  Each case must be handled on an individual basis.  If your dog is showing more than one of the suspicious signs, discuss options with your veterinarian.