Diagnosis of Hyperadrenocorticism

Sandy May BVSc (Hons),MMed Vet (Clin Path)

Vetdiagnostix. Cape Town Branch. Tel: 021 910 2243

Hyperadrenocorticism (HAC) occurs as a result of hyperplasia or neoplasia (Adrenal dependent hyperadrenocorticism – ADH) of the zona fasiculata of the adrenal cortex resulting in overproduction of cortisol.

Hyperplasia of the adrenal gland results  from an adenoma of the pars distalis or pars intermedia of the pituitary gland (pituitary dependent hyperadrenocorticism – PHD).

Serum cortisol has a negative feedback effect on the production of ACTH and CRH by the pituitary and the hypothalamus. ACTH also has a negative feedback effect on the hyopthalamus. In dogs the secretion of ACTH is pulsatile with 6-12 peaks in a day.5

Any breed can develop hyperadrenocorticism but in general middle aged to older small breed dogs develop PDH and older large breed dogs develop ADH.

The most common clinical signs associated with hyperadrenocorticism include polydipsia and polyuria, polyphagia, pattern alopecia (bilaterally symmetrical affecting flanks, ventral abdomen, neck and perineum), muscle weakness, thinning of skin, abnormal fat distribution with pendulous abdomen and hypertension. Rarer signs include calcinosis cutis and neurological signs.

Typical clinicopathological abnormalities include an increase in alkaline phosphate (ALP) activity in 85% of dogs. Synthesis of this enzyme is induced by cortisol in the dog. There may be mild hyperglycaemia.  Hypercholesterolaemia and hypertriglyceridaemia are usually present.

The RCC, Hb and PCV/ Ht. may be slightly elevated Thrombocytosis may be present and the characteristic stress leukogram of mature neutrophilia, lymphopaenia and monocytosis is present.

Urine SG is <1.015 and usually in the hyposthenuric range. Proteinuria is frequently present and urinary tract infection is frequently found.

Specific diagnostic tests:

  • Urine cortisol:creatinine ratio
  • ACTH stimulation test
  • Dexamethasone suppression test
  • Endogenous ACTH

 

A. Urine cortisol: creatinine ratio

The urine cortisol: creatinine ratio (UCCR) has a high sensitivity for HAC but low specificity. The normal reference range is <10 (<10 x 10-6 – convention is to express this as 10), which effectively rules out a diagnosis of HAC. The test has a good negative predictive value.

Due to the effect of stress the test only becomes more reliable when the cut-off is set at >100 (90% probability of PDH). Thus a high ratio does not confirm HAC and further discriminating tests need to be done.

The cortisol and creatinine concentrations are measured on the same urine sample and the ratio is calculated as follows:

Cort: Creat  =  urine cortisol concentration (nmol/l)

urine creatinine concentration (µmol/l)

 

B. ACTH stimulation test

The method for the ACTH stimulation test in dogs is as follows:1

  • The test can be started at any time of day
  • Collect a blood sample for the basal cortisol concentration
  • Inject 250µg of synthetic ACTH i.v or i.m. (125ug  synthacten IM is effective)
  • Collect a second sample 60 mins later.

Interpretation:

The baseline cortisol concentration is irrelevant

  • A post stimulation concentration of >600nmol/l is consistent with a diagnosis of a diagnosis of HAC in a dog with typical clinical signs and showing no evidence of other clinical disease.
  • This test reliably identifies approximately 84% of dogs with PDH and 51% of dogs with ADH2

Advantages:

  • The biggest advantage of this test is its ability to  distinguish between iatrogenic and spontaneous HAC3
  • It can be used to monitor response to treatment
  • It is quick to perform
  • It provides baseline information for treatment

Disadvantage

  • It does not distinguish between PDH and ADH
  • It is not very sensitive in detecting HAC caused by adrenal neoplasia

 

C. Dexamethasone suppression tests:

Low dose Dexamethasone suppression test (LDDST)

The low dose dexamethasone suppression test is an alternative to the ACTH stimulation test for the diagnosis of HAC.

Method:

  • Collect a blood sample for the basal cortisol concentration
  • Inject 0.01 mg/kg dexamethasone iv
  • Collect samples at 4 (-6) and 8 hours post-dexamethasone injection.

Interpretation (Figure 1)

  • A normal response is suppression to below 40 nmol/l
  • A complete lack of response could be consistent with PDH or ADH
  • In most PDH cases, there will be suppression to below 40 nmol/l at 4-6 hours and “escape” at 8 hours with an increase in cortisol concentrations.

Advantages

  • The sensitivity is higher than the ACTH stimulation test (90-95%), thus fewer cases will be missed.
  • It has an almost 100% sensitive with adrenal neoplasia and 90 -95% sensitivity for PDH

Disadvantages

  • The specificity however is  very low if measured in sick dogs ( 44%- 73%) – thus a  ≅ 50% chance of false positives in non-adrenal illness. 5
  • The test takes a long time (8h)
  • It does not distinguish between iatrogenic and spontaneous HAC.

High Dose Dexamethasone Suppression Test

This is NOT a screening test. It is used for discriminating between pituitary-dependent and adrenal-dependent hyperadrenocorticism. It has become less frequently used since ultrasound is available in most practices.

Method:1,3 

  • Collect a blood sample for the basal cortisol concentration
  • Inject 0.1 mg/kg dexamethasone iv
  • Collect  samples at 6 and 8 hours post-dexamethasone.

Interpretation:

No suppression is consistent with ADH. The neoplastic cells function autonomously and are not subject to feedback suppression.

Suppression to below 40 nmol/l is consistent with PDH.

 

D. Endogenous ACTH

This is the preferred test for HAC in horses but has not been used extensively in dogs.

Method:

The sampling conditions are very specific.

  • The blood should be taken into chilled EDTA-aprotinin tubes, placed immediately on iced and separated immediatly refrigerated centrifuge.4
  • The plasma should be transferred into a PLASTIC tube and immediately frozen and sent to the laboratory frozen.

Interpretation3

  • Normal dogs have an ACTH concentration of 3-10 pmol/l
  • Dogs with PDH have concentration> 6.2 pmol/l
  • Dogs with ADH have undetectable concentrations.

Advantages

  • Single blood sample
  • Easy discrimination between ADH and PDH

Disadvantages

  • Specific sampling conditions
  • Overlap between normal dogs and those with PDH

 

Summary:

  • The urine cortisol: creatinine ratio is a good screening test but it cannot be used as a diagnostic test. It has a good negative predictive value
  • The ACTH stimulation test and LDDST are most frequently used to diagnose HAC, but patients must be carefully selected to avoid false positives.
  • The LDDST is more sensitive if an adrenal tumour is suspected.
  • The high dose dexamethasone test and endogenous ACTH can be used to distinguish PDH from ADH but are rarely used.

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