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Canine Cushing’s Syndrome

In 1932, Dr. Harvey Cushing diagnosed 12 humans with a disorder that was characterized by excess cortisol secretion. On the human side, “Cushing’s Syndrome” is an inclusive term that refers to all causes of excess cortisol secretion, and “Cushing’s Disease” is a term that refers exclusively to cases associated with pituitary-dependent disease. We tend to call everything “Cushing’s Disease” although the more appropriate term would be Canine Cushing’s Syndrome or CCS.

Don’t you just love those trivial little facts? I know I do. So, now that I started with trivial semantics, we will talk this week about Cushing’s Syndrome. In case you are wondering, I will come back to diabetes mellitus to finish it later, but I will be speaking at the annual Oklahoma Veterinary Medical Association meeting in a little over a week. This lets me get myself mentally prepared for my talk.

You may be asking – what is Cushing’s Syndrome? Well, there are several disease syndromes that are caused by over-production of endogenous cortisol (steroids). The most common clinical signs include marked increases in water consumption and urine output, increased appetite, abdominal enlargement, bilaterally symmetrical alopecia (hair loss) or poor hair re-growth following shaving, panting, and lethargy.

diagram of how the pituitary-adrenal axis works in normal dogs, dogs with pituitary-dependent hyperadrenocorticism, and dogs with a functioning adrenocortical tumor

Now, to understand Cushing’s Syndrome, we have to talk a little bit about the pathophysiology of this disease. In the normal pituitary-adrenal axis, the pituitary gland in the brain produces ACTH. This hormone stimulates the adrenal glands (in the abdomen near the kidneys) to produce cortisol. Cortisol has a negative feedback effect on the pituitary gland. Every mammal must have cortisol in order to have normal GI function, but too much cortisol causes clinical abnormalities.

With pituitary-dependent disease (PDH), the pituitary gland has a tumor (most are small and microscopic in size although approximately 10% are large and are known as macroadenomas), and this tumor oversecretes ACTH. This stimulates the adrenal glands to overproduce cortisol, leading to clinical signs. This whole system can still shut itself off properly, but it requires more cortisol to decrease ACTH production.

With an adrenal tumor (AT), one (or very rarely both) adrenal gland develops a tumor. The tumor secretes cortisol autonomously as the pituitary gland is not secreting any ACTH. The gland opposite the cancerous one is small, and it will not be producing any hormone, which is important to our discussion later.

CT image of a right adrenal tumor

Before we embark upon diagnosing Cushing’s Syndrome, we want to make sure that a dog is actually exhibiting clinical signs of disease. If typical clinical signs are seen, we will then start the diagnostic work-up with a CBC, serum chemistry profile, and a urinalysis. The CBC will often have what we call a “stress leukogram.” That is a fancy term to say that certain cell lines are higher than normal while others are lower than normal. Some dogs will have an elevated red blood cell count, but that doesn’t happen consistently. The serum chemistry profile most frequently shows an elevated alkaline phosphatase, which is a liver enzyme. In fact, if the alkaline phosphatase is normal, a dog has less than a 10% chance of having CCS. Blood glucose concentrations can be mildly increased, and some dogs will have concurrent diabetes mellitus and CCS. A urinalysis most frequently reveals dilute urine, but these dogs are at increased risk of urinary tract infection, too.

Multiple tests can be used to obtain a diagnosis of CCS. The easiest screening test is a urine cortisol:creatinine ratio. Owners need to catch a first morning urine sample (I actually like first morning urines from 3 consecutive days), and then, we run the test, looking for excess cortisol in the urine. If the test is negative, we have completely ruled-out CCS since this test is extremely sensitive. However, if the test is positive, we need to proceed with additional testing. One of the traditional screening tests is an ACTH stimulation test. This is easy for the dogs, as it is a one-hour test. We measure a baseline cortisol, give ACTH which stimulates production of cortisol, and one hour later, we measure another cortisol level. In theory, dogs with CCS will over-secrete cortisol. This is a nice, quick test, but unfortunately, it is only abnormal in 80-85% of dogs with CCS. Another test is a low-dose dexamethasone suppression test. To perform this test, we measure a baseline cortisol, administer dexamethasone which does not cross-react with the cortisol assay, and cortisol levels are then measured 3 and 8 hours later. In a dog with a normal pituitary-adrenal axis, cortisol secretion will be shut down for more than 8 hours following dexamethasone administration. In dogs with CCS, cortisol either never decreases, or it decreases but rises above normal by 8 hours. This test is abnormal in 85-90% of dogs with CCS, but it is a long test during which a dog can’t be fed. In addition, they must be fasted for 12 hours before the test to have accurate results.

In addition to a blood test consistent with CCS, I recommend an imaging study. An abdominal ultrasound examination can be performed to evaluate the adrenal glands. Alternatively, a CT examination can be performed to look at the adrenal glands and the brain, which helps rule-out large pituitary tumors.

CT image of a pituitary macroadenoma

Once the diagnosis has been made, we need to consider treatment options. With PDH, medical management is the treatment of choice unless a dog has a large pituitary tumor which can potentially be treated with radiation therapy. With ATs, we always start with medical management so that the atrophied adrenal gland can begin secreting cortisol pre-operatively, and if possible, we will remove the tumor surgically once the dog is stable. Some ATs cannot be surgically excised, and those dogs are also treated medically.

The two drugs used most frequently to treat CCS are Lysodren® (mitotane) and Vetoryl® (trilostane). Lysodren works by partially destroying the adrenal gland, and after the initial induction phase of therapy, the amount of drug used for maintenance therapy drops off precipitously (this helps keep drug costs down). Trilostane works by blocking the production of adrenal steroids. In theory, it should be safer since it shouldn’t affect the adrenal tissue, but in reality, it can also cause destruction of the adrenal glands, leading to marked underproduction of steroids, collapse, and/or death.

With either drug, an ACTH stimulation test is used to assess response to therapy, and the first recheck is usually performed within 7-14 days after initiating therapy. Tests will be repeated regularly (usually every 3 months) thereafter to evaluate cortisol levels and adjust drug doses.

CT image of a left adrenal tumor with calcification

Canine Cushing’s Syndrome is a very manageable disease. However, it is not an inexpensive disease to either diagnose or manage. The drugs can be quite dangerous, and as an internist, I will almost never treat a dog without overt clinical abnormalities unless it is a dog with a high risk of developing a secondary problem (for example, miniature schnauzers are a breed at increased risk of developing diabetes mellitus, and we would likely treat this breed’s CCS sooner rather than later).

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