CLASSIFYING CUSHING'S DISEASE
ADRENAL OR PITUITARY CUSHINGS?
Once a pet has been confirmed as having Cushing’s syndrome, the next step is to determine which form of Cushing’s syndrome the pet has since treatment and prognosis are very different for each form. As described, there are two forms, commonly abbreviated PDH and AT. PDH stands for "pituitary dependent hyperadrenocorticism" and, as mentioned, accounts for 85% of canine and feline Cushing's patients. In PDH, there is a pituitary tumor, often extremely small, causing over stimulation of the adrenal glands. AT simply stands for "adrenal tumor." Adrenal tumors can be benign or malignant (for more details, click here). Testing to determine the type or form of Cushing's disease is called discriminatory testing. This type of testing is done AFTER the diagnosis of Cushing's disease has already been made. Here are some issues and concerns where the type of Cushing's disease present becomes an important matter:
Approximately 85% of Cushing's patients will have pituitary dependent disease while approximately 15% will have adrenal tumors.
SO WHAT TESTS WILL TELL US WHAT TYPE OF CUSHING’S SYNDROME IS PRESENT?
THE LOW DOSE DEXAMETHASONE SUPPRESSION TEST
If one is lucky, the same test used to determine if Cushing’s disease is present can also classify the Cushing’s disease so that no further tests are needed. To get the information needed, a 4-hour sample is drawn in addition to the pre-dexamethasone sample and the 8-hour sample. If the cortisol level suppresses to a level below 50% of baseline at 4 hours, only to escape to a level high enough to indicate a positive result, only a pituitary tumor is possible. While pituitary tumors do not always show this kind of classic suppression at four hours, adrenal tumors never do. If suppression is seen in the 4-hour sample, further testing is not needed, though this is the only pattern that is distinctive enough to obviate further testing. Approximately, 60% of patients with pituitary tumors can be identified with the Low Dose Dexamethasone Suppression test.
THE HIGH DOSE DEXAMETHASONE SUPPRESSION TEST
This test is similar to the low dose dexamethasone suppression test except that a higher dose of dexamethasone is used and the patient having the test is already known to have Cushing’s disease through prior testing. The idea behind this test is that a patient with a pituitary tumor will show suppression in circulating cortisol when exposed to the high dose of dexamethasone (though suppression does not occur with the low dose). If an adrenal tumor is present, suppression does not occur. Unfortunately, the theory does not hold well enough to make this a reliable test; a full 20-30% of pituitary tumors will fail to suppress even with the high dose of dexamethasone. Further, this test cannot identify patients with adrenal tumors; it is able to confirm about 70-80% of patients with pituitary disease. The remaining patients will need further testing.
ENDOGENOUS ACTH LEVEL
This test is felt by many to be the most accurate method of classifying Cushing’s syndrome but the problem is that the test is technically challenging to run. Serum from the patient must be frozen when transported to the laboratory and must not thaw. The hormone ACTH is very fragile and may not survive the trip to the lab. The idea with this test is that a patient with a pituitary tumor will have high ACTH levels, as this is what the tumor is secreting. A patient with low or no measurable ACTH levels has an adrenal tumor as the pituitary is trying its best not to stimulate the over-active adrenal tumor.
Fundamental to discerning pituitary dependent Cushing's syndrome from adrenal tumor is the size and shape of the adrenal glands. With pituitary dependent disease both adrenal glands are being over stimulated so they should both be symmetrical in size and shape and most likely enlarged. With an adrenal tumor, one gland will be severely atrophied and possibly undetectable while the other one is enlarged and possibly misshapen. This dichotomy makes imaging of the adrenal glands an accurate way to distinguish types of Cushing's syndrome. Ultrasound, MRI, or CT scan can be used, however, ultrasound is the most readily available and least costly. In one study, ultrasound was able to correctly identify adrenal tumors in 86% of cases. Sedation is generally not needed for abdominal ultrasound whereas, CT and MRI require general anesthesia and usually referral to some type of specialty clinic.
An added benefit of imaging, includes looking for evidence of malignancy should an adrenal tumor be identified. Malignant tumors tend to invade the vena cava, the largest vein in the body. Ultrasound has been found to be extremely accurate in evaluating for this complication. Imaging also allows for measurements of the adrenal glands to be taken. Glands that measure >4 cm in length are highly suspicious of being malignant.
It is important to note that ultrasound can never be used to make the initial diagnosis of Cushing’s syndrome as there is too much variability in the size of normal adrenal glands. When it comes to gaining information about a patient’s Cushing’s syndrome, imaging is best used on patients already known to have Cushing’s syndrome for whom classification is needed.
IS IT REASONABLE TO “PLAY THE ODDS” AND NOT DO FURTHER TESTING?
Since 85% of canine patients with Cushing’s syndrome have a pituitary tumor, it is not unreasonable to “play the odds” and treat for a pituitary tumor. The risks in doing so is that if the patient does not readily respond to medication is will be impossible to know if the medication dose simply needs adjustment or if the patient has an adrenal tumor and a completely different treatment is needed. A great deal of time and effort could be wasted by pursuing the wrong therapy.
For the cat with Cushing’s syndrome the methods that can be reliably used to distinguish pituitary from adrenal disease are: high dose dexamethasone suppression testing, endogenous ACTH and imaging.
HIGH DOSE DEXAMETHASONE SUPPRESSION TEST
The feline high dose dexamethasone suppression test is the same as the canine version of the test except that even higher dexamethasone doses must be used. If the cortisol levels suppress in response to the injection of dexamethasone then only a pituitary tumor is possible. If the cortisol levels do not suppress, however, then no conclusion can be drawn as 50% of feline pituitary tumors will not suppress. This can be a frustrating situation but since the test is non-invasive, it is worth a try to confirm a pituitary tumor in this way.
As with dogs, this test is very accurate in distinguishing pituitary-dependent from adrenal Cushing's syndrome but the problem is transport and sample stability. ACTH is a delicate hormone and the sample must be frozen all the way to the lab with no thawing out. The idea is that the patient with pituitary disease will have a very high level of ACTH while the adrenal patient will have none or very little. Obviously, if there is a transport problem the results can falsely indicate an adrenal tumor where there is none.
When it comes to using imaging to distinguish pituitary from adrenal Cushing’s syndrome the rules for cats are the same as those for dogs. A cat with pituitary disease will have both adrenal glands approximately the same size, possibly both of them clearly larger than what would be considered normal. If there is an adrenal tumor, one gland will be large (the one with the tumor) while the other is very small (atrophied). Ultrasound is probably the least invasive and least complicated method of distinguishing adrenal from pituitary disease in cats and has the added benefit of screening for local tumor spread.
Page last updated: 2/20/2020