Hyperadrenocorticism may arise either from an adenoma usually involving the pars distalis and very occasionally the pars intermedia of the pituitary gland, or an adenoma or carcinoma of the adrenal gland. Hormones, usually ACTH from the pituitary gland, then cause hyperplasia of the adrenal glands. Functional adrenal tumours secrete excessive amounts of cortisol independent of pituitary control.
The diagnosis of hyperadrenocorticism generally involves three steps.
- Clinical examination and general blood tests, which are used to rule in/out other possible differentials.
- Carrying out one or more of the screening tests for hyperadrenocorticism. These are the low dose dexamethasone suppression test, the ACTH stimulation test, or the urinary cortisol:creatinine ratio. These tests should not be used when there is concurrent illness because of the effects on cortisol production. Testing should wait until the animal is otherwise well.
- Differentiating pituitary dependent hyperadrenocorticism from adrenal tumours involves imaging and/or a high dose dexamethasone suppression test. The endogenous ACTH assay is not available for dogs in New Zealand.
Monitoring of hyperadrenocorticism when on therapy.
Traditionally this has involved using the ACTH stimulation test. In April 2018 for those animals on Vetoryl® a single cortisol measurement on a sample taken before the Vetoryl is given has been proposed by some endocrinologists (see below). Refer to each individual test listing for test protocols.
Low dose dexamethasone suppression test – dogs (LDDST)
The LDDST is considered to be the most reliable screening and diagnostic test for hyperadrenocorticism. In normal dogs and cats dexamethasone suppresses ACTH secretion which reduces cortisol production and release.
It has slightly greater sensitivity than the ACTH stimulation test (i.e. there will be fewer false negatives) but there will be more false positives (it has lower specificity). Combined data from studies shows:
For pituitary dependent Hyperadrenocorticism:
- Using <40 nmol/L as the cut-off, then 94% of cases failed to suppress
- Using <50% of baseline as the cut-off, then 77% of cases failed to suppress
For adrenal tumours:
- 100% of cases failed to suppress regardless of criteria
For dogs with non-adrenal illness
- 55% failed to suppress at 8 hours (Note: these dogs were not suspected of having hyperadrenocorticism)
For healthy dogs
- 100% suppressed at 4 and 8 hours
Suppression is defined as a level <40 nmol/L or a > 50% decrease in cortisol at 8 hours. Pituitary-dependent hyperadrenocorticism (PDH) may show a decrease of cortisol to <40 at 3/4 hours, and subsequent escape from suppression to >40 at 8 hours. In about 60% of cases of hyperadrenocorticism the low dose test will differentiate between PDH and adrenal tumours. The remaining 40% which do not show this pattern could be due to PDH or an adrenocortical tumours.
In cats the LDDST is better than both the ACTH stimulation test and urinary cortisol to creatinine ratio as a screening test.
The LDDST is of no value for diagnosing hypoadrenocorticism, iatrogenic hyperadrenocorticism or for monitoring response to treatment.
False positives (lack of suppression) can occur with:
- Non-adrenal illness such as diabetes mellitus, renal failure, liver disease; clinically ill animals with concurrent disease should be treated before testing for Cushing’s. The more severe the non-adrenal illness, the greater the likelihood of having exaggerated cortisol results.
- Exogenous glucocorticoid drugs such as prednisolone which will be measured as cortisol by the assay
- Bathing, hospitalisation or other stress-inducing procedure
- Anticonvulsant medication
ACTH stimulation test
This is a useful screening test for hyperadrenocorticism but not quite as sensitive as the low dose dexamethasone screening test (there will be more false negatives with the ACTH stimulation test compared with the LDDST). Combined data from a number of studies shows that:
- 30% of dogs with pituitary tumours give an exaggerated response on the ACTH stimulation test while 30% give a borderline response.
- 60% of dogs with an adrenal tumour give an exaggerated response
- 15% of dogs with non-adrenal illness give an exaggerated response
This test is diagnostic for hypoadrenocorticism and for iatrogenic hyperadrenocorticism and is the test of choice for monitoring effectiveness of treatment of hyperadrenocorticism. The test can be carried out at any time of the day without any special preparation.
- Post-ACTH cortisol values >550/600 nmol/L usually indicate hyperadrenocorticism. The higher the value the more convincing the diagnosis if the clinical signs fit.
- Post-ACTH cortisol values of 470-550 nmol/L are equivocal.
- Post-ACTH cortisol values <470 nmol/L suggest normal adrenocortical function.
Note that in 15% of pituitary-dependent hyperadrenocorticism (PDH) cases and almost 50% of cases due to adrenocortical neoplasia there is no significant elevation of Post-ACTH cortisol values. Failure of cortisol levels to increase significantly in a dog with typical clinical and laboratory features of Cushing’s syndrome does not eliminate this syndrome from the diagnosis. Cortisol values in dogs with iatrogenic hyperadrenocorticism mimic those with hypoadrenocorticism.
Anticonvulsant therapy (phenobarbitone, primidone, and phenytoin) may cause an elevated post-ACTH cortisol value. Non-adrenal illness that causes stress, such as diabetes mellitus and renal failure, may also result in an exaggerated response to ACTH.
Hyperadrenocorticism is a rare disease in cats. It is most commonly seen in insulin resistant diabetics and associated with hyperglycaemia but can be a difficult diagnosis to confirm. Like all endocrine disease, it should be diagnosed first on the basis of clinical signs. Very few cats with Cushing’s have increased serum ALP and ALT concentrations compared to dogs. Urine is not often dilute and the cats are rarely PU/PD.
The peak increase in cortisol after ACTH administration occurs more rapidly in cats than dogs. The sensitivity is low and affected animals often have normal results and it is recommended by some authors that the ACTH stimulation test should not be used to diagnose Cushing’s in cats.
- Post-ACTH cortisol values >420 nmol/L indicate hyperadrenocorticism.
- Post-ACTH cortisol values between of 360 and 420 nmol/L are equivocal.
- Post-ACTH cortisol values <360 nmol/L suggest normal adrenocortical function.
Urinary Cortisol:Creatinine Ratio
This is a useful screening test for canine hyperadrenocorticism as a low (normal) result makes it unlikely (approximately 90% sensitivity). It is therefore useful in those cases where hyperadrenocorticism is unlikely but needs to be definitely excluded. The test has low specificity, (there are a lot of false positives) so that further tests are needed to confirm that a high result is due to hyperadrenocorticism. It is thought that the test has similar sensitivity and specificity in cats but there are few published reports.
The urinary cortisol to creatinine ratio may be used as a screening test on urinary samples collected at home by the owners. Patients with suspicious results may then be tested with the low dose dexamethasone test.
- Ratio <10 x 106 Cushing’s ruled out
- Ratio 10–15 x 106 equivocal result, retest
- Ratio >15 x 106 Cushing’s may be present
High Dose Dexamethasone Suppression Test in Dogs
This test is used to help determine if the hyperadrenocorticism is pituitary dependent or due to an adrenal tumour. It should be used only after a diagnosis of hyperadrenocorticism has been made, using either the low dose dexamethasone test or ACTH stimulation tests. The high dose dexamethasone suppression test has no value in cases of hypoadrenocorticism or iatrogenic hyperadrenocorticism. This test is gradually being phased out by clinicians in favour of the more specific endogenous ACTH assay.
Suppression is defined as a concentration of cortisol at 4 or 8 hours that is < 50% of the baseline cortisol concentration, or a cortisol concentration at 4 or 8 hours that is < 40 nmol/l.
In dogs, 25% of animals with pituitary adenoma do not suppress, approximately 60% of animals with pituitary adenomas have a cortisol < 50% of the baseline and approximately 40% of animals have cortisol concentrations < 40 nmol/l. Failure of suppression does not allow differentiation between PDH and adrenal tumours.
Dogs with adrenal tumours do not suppress; both 3 and 8 hour cortisol values are >50% of the baseline value
High dose dexamethasone test in cats
Two different protocols are described, one carried out in the clinic and one carried out at home by the owners.
Suppression is described as a ratio that is < 50% of the baseline. Cats that suppress have pituitary adenoma; cats that do not suppress may have either pituitary adenoma or an adrenal tumour.
Monitoring of hyperadrenocorticism
For dogs on Mitotane or ketoconazole target cortisol values are 30-100 nmol/L for both the baseline and post ACTH samples.
For dogs on trilostane (Vetoryl) therapy, the ACTH stimulation test has traditionally been used. This test is carried out 4 hours after the morning dose and interpreted in the light of the clinical history, physical exam, haematology and biochemistry electrolytes results. The tablet must be given with food. An algorithm on how to interpret the result is available on the Dechra website.
In April 2018 a monitoring method has been introduced by Dechra in conjunction with Dr Ian Ramsay, University of Glasgow which involves a single cortisol measured on a sample taken pre Vetoryl tablet. To be able to use this method there are strict criteria which must be met with regards the health of the dogs and their demeanour – i.e. calm, not stressed, well in themselves etc. The information on when to use this test and its interpretation is available here.