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Diagnosis and monitoring of hyperadrenocorticism – General Guidelines

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. Pituitary tumours secrete ACTH which 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.
  • Differentiating pituitary dependent hyperadrenocorticism from adrenal tumours with the high dose dexamethasone suppression test or an endogenous ACTH assay. This step is not always needed.

 Refer to each individual test listing for test protocols.

 Low Dose Dexamethasone Suppression Test

Dogs

The low dose dexamethasone suppression test 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 secretion.

It has greater sensitivity than the ACTH stimulation test (i.e. there will be fewer false negatives) but lower specificity (there will be more false positives). Combined data from studies shows:

For pituitary dependent hyperadrenocorticism

  • Using <40 nmol/L as the cut-off, 94% of cases failed to suppress
  • Using <50% of baseline as the cut-off, 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 (NB. These dogs were not suspected of having hyperadrenocorticism)

For healthy dogs

  • 100% suppressed at 4 and 8 hours

Test interpretation:

Suppression is defined as cortisol <40 nmol/L, or < 50% of the baseline at 8 hours. Pituitary-dependent hyperadrenocorticism (PDH) may show a decrease of cortisol to <40 nmol/L at 3 hours, and subsequent escape from suppression to >40 nmol/L at 8 hours. Absence of this pattern does not allow differentiation between PDH and adrenocortical tumors.

The low dose dexamethasone suppression test 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

 Cats

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 AP and ALT concentrations compared to dogs. Urine is not often dilute and the cats are rarely PU/PD.

The dexamethasone suppression test is better than both the ACTH stimulation test and urinary cortisol:creatinine ratio as a screening test, but is not very effective as a discrimination test for diagnosing Cushing's disease.

For diagnosis of feline Cushing's disease the 3-4 hour sample is not needed, but it may be useful for differentiation of pituitary dependent Cushing's from adrenal tumours. The dexamethasone suppression test can differentiate between pituitary dependent hyperadrenocorticism and adrenal tumours in up to 60% of cases. Two different protocols are described, one carried out in the clinic and one carried out at home by the owners (using the urine cortisol:creatinine test). 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.

 

ACTH Stimulation Test

Dogs

The ACTH stimulation test is a useful screening test for hyperadrenocorticism, but is not as sensitive as the low dose dexamethasone suppression test (there will be more false negatives with the ACTH stimulation test compared with the low dose dexamethasone suppression test). 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 nonadrenal illness give an exaggerated response

This test is diagnostic for hypoadrenocorticism and for iatrogenic hyperadrenocorticism, and is the test of choice for monitoring the effectiveness of treatment for hyperadrenocorticism. The test can be carried out at any time of the day without any special preparation.

Test interpretation (dogs):

  • Post-ACTH cortisol values >550 nmol/L usually indicate hyperadrenocorticism.
  • 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 signify cant 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, 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.

Cats

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. It is recommended by some authors that the ACTH stimulation test should not be used to diagnose Cushings in cats.

Test interpretation (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

The UCCR is a useful screening test for canine hyperadrenocorticism as a low (normal) result makes Cushing's unlikely (approximately 90% sensitivity). It is 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). 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: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.

Test interpretation:

  • Ratio < 10 x 106 Cushings ruled out
  • Ratio 10 – 15 x 106 Equivocal result, retest
  • Ratio > 10 x 106 Cushings 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.

Test interpretation:

  • Approximately 60% of dogs with pituitary adenomas have a cortisol < 50% of the baseline and approximately 40% of animals have cortisol concentrations < 40 nmol/L.
  • Approximately 25% of dogs with pituitary adenoma do not suppress.
  • 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

 

Monitoring of hyperadrenocorticism

The ACTH stimulation test is currently the only test suitable for monitoring therapy for hyperadrenocorticism.

Target cortisol values for Cushingoid dogs being treated with mitotane or ketoconazole are 30-100 nmol/L for both the baseline and post ACTH samples.

For dogs on trilostane therapy the ACTH stimulation test should be performed 4 hours after the morning dose and interpreted in the light of the clinical history, physical exam, haematology and biochemistry electrolytes) results. Current recommendations are│

  • If the post-ACTH cortisol concentration is <50 nmol/L, the trilostane is stopped for 7 days and then re-introduced at a lower dose.
  • If the post-ACTH cortisol concentration is 50 - 250 nmol/L, and clinical signs show significant improvement then continue on the current dose.
  • Monitor those with values between 200 - 250 nmol/L for clinical signs of recurrence.
  • If the post-ACTH cortisol concentration is >250 nmol/L, increase the morning dose
  • If after at least 28 days of therapy, clinical signs show very little or no improvement, concurrent illness is ruled out and the post-ACTH cortisol concentration is >200 nmol/L, increase the dose
  • If an ACTH stimulation test is performed at times other than 4 to 6 hours after trilostane, then the current recommendation is that the post-ACTH cortisol concentration falls between 50 - 250 nmol/L
    • Reference: Vetoryl. Treatment and Monitoring of Hyperadrenocorticism. Dechra Veterinary Products May 2007.