hyperadrenocorticism

• This is more common in middle aged to older dogs and is more likely to occur in the female
• Clinical signs include…

  • Polydipsia, Polyuria
  • Secondary diabetes insipidus
  • Polyphagia
  • Muscle wasting and weakness (pot-belly, panting)
  • Skin thinning, calcinosis cutis, pigmentation, bruising
  • Symmetrical hair loss
  • Reproductive dysfunction
• Radiography is not commonly done for diagnosis but you would see..

  • Abdominal radiographs
  • Good contrast
  • Hepatomegaly
  • Pot-bellied appearance
  • Calcinosis cutis
  • Distended bladder
  • Thoracic radiographs
  • Tracheal and bronchial wall mineralisation
  • Pulmonary metastasis
  • Osteoporosis
• The risk of false positives is higher in sick animals
• what would you expect on haematology with a dog with hyperadrenocorticism?

  • Stress leukogram
  • Neutrophilia (mature)
  • Lymphopenia
  • Monocytosis
  • Absolute eosinopenia
• Extreme bile acid abnormalities indicates liver disease but mild-moderate indicates HAC
• what would you expect in biochemistry with a dog with HAC?

  • Increased alkaline phosphatase activity
  • There is a steroid induced isoform in the dog
  • Increased ALT activity
  • Hyperglycaemia
  • Hepatic gluconeogenesis
  • Insulin insensitivity
  • Elevated phosphorus due to the steroid effect on bone turnover
  • Increased cholesterol and triglyceride
  • Mildly abnormal bile acids
• what would you expect to see on urinalysis in a dog with HAC?

  • a urine specific gravity less than 1.030 despite often mild dehydration
  • Mild glucosuria in some cases
  • Proteinuria in some cases
  • Positive urine culture
• The process of diagnosis includes…

  • Low-dose dexamethasone
  • ACTH response
  • Urinary cortisol : creatinine ratio
  • Steroid induced alkaline phosphatase
• To perform a low-dose dexamethasone test, give 0.01 to 0.015 mg/kg dexamethasone (Azium) IV. Then sample at 0, 3 to 6 and 8 hours. The 8 hour cortisol result greater than 30 -40 nmol/L is a positive test result. However, this test can give false positive results and the risk increases the more unwell the animal is. Ideally, perform this test when you are highly suspicious of HAC.
• which test is more specific ACTHstim or LDDT?

  ACTH
• which test is more sensitive ACTHstim or low-dose dexamethasone?

  LDDT
• Which diagnostic test can help differentiate between ADH and PDH?

  Low dose dexamethasone
• In the case of a normal dog, when we inject dexamethasone it causes suppression of pituitary secretion of ACTH through negative feedback which in turn reduces cortisol produced by the adrenals. As a consequence measured cortisol is suppressed at 8 hours.
• In pituitary-dependent Cushing’s disease there isn’t effective negative feedback from dexamethasone on ACTH and therefore there is only a slight reduction or no reduction at all and consequently, there is only a small or no reduction in cortisol. This can result in a flat line cortisol response or a partial lowering of cortisol which then is not maintained for the full 8 hours of the test.
• In the case of adrenal-dependent disease ACTH production is already suppressed by negative feedback. When inject dexamethasone it cannot suppress ACTH any further such that it remains low and unchanged. That unchanging ACTH means there is no change in cortisol during the course of the test.
• both adrenal dependent disease and some cases of pituitary dependent disease can results in a “flat-line response” with the low-dose dexamethasone test. We use a rule of thumb of 50% suppression from baseline for determining whether we can be confident in a pituitary origin.
• the ACTH response test is often used to monitor therapy as this test measures adrenocortical reserve. To perform give 0.25 mg Synacthen IV/IM or 5mg/kg IV/IM. Samples at 0 and 1 hour and a 1 hour cortisol value greater than 500-600nmol/L are positive

  • Subnormal responses suggest exogenous steroid
• An injection of ACTH presents a massive stimulation to the adrenal glands to produce cortisol. When adrenal cortical mass is larger, a higher than normal cortisol output can be expected.
• While the process of differentiation includes…

  • Dexamethasone suppression (low, high and mega)
  • Low dose dexamethasone - sufficient suppression for differentiation in 60% of positive LDDST
  • Endogenous ACTH
  • Imaging (US, CAT, MRI)
  • This is seen as the easier, simpler and more direct route to differentiate
• label the image

  A) pituitary

  B) adrenal

  
• Symmetrically enlarged and normal conformation adrenals are seen in which HAC type?

  pituitary
• One enlarged gland and one atrophied adrenal gland are seen in which HAC type?

  adrenal
• DM can occur with HAC. Diabetes alone will have high ALKP, ALT and cholesterol with PU/PD (just like HAC) so you cannot rely on usual evidence and hence need to find something that is not expected in the regular diabetic e.g., hair loss, thin skin bruising at venipuncture or a persistent high insulin requirement. If they need more insulin than the typical diabetic then this supports a HAC diagnosis in the diabetic dog. In these cases, treat the DM first as this provides data on the insulin requirement and improves confidence in the positive endocrine diagnostic tests.
• medical therapy for HAC includes...

  • Trilostane (Licenced)
  • Mitotane (opDDD; Lysodren) – not licenced for animals (special import scheme)
  • Selegiline (not effective in the majority, but possibly can be used and effective in combination with trilostane)
• Trilostane is a modified steroid, it selectively and reversibly inhibits the enzyme system 3 beta hydroxysteroid isomerase, thus blocking the production of cortisol, corticosterone and aldosterone. When used to treat hyperadrenocorticism, it reduces the production of glucocorticoid and mineralocorticoid steroids in the adrenal cortex. Circulating concentrations of these steroids are thus reduced. Trilostane also antagonises the activity of exogenous adrenocorticotrophic hormone (ACTH).

  • Trilostane binds to the enzyme (3BHSD) inhibiting conversion
• Trilostane therapy is reversible as once it is removed the conversion starts again as there is no competitive inhibitor. With this therapy, despite treating the HAC, the adrenal glands can get bigger during the first part of the treatment. Be sure to avoid Aggressive therapy as this can leads to more complete inhibition of cortisol causing a greater loss of negative feedback on pituitary mass which results in increased ACTH output/pituitary mass enlargement and adrenal stimulation/enlargement. As a result you will need a higher dose requirement and result in spiralling dose requirements
• When you give once a day it causes a massive drop in cortisol as seen by the purple line. You do not want to completely reduced cortisol levels as you need to preserve mineralocorticoid function.

  • Plan to allow some negative feedback to mitigate increases in pituitary ACTH output and/or mass enlargement in PDH
  • The pathway is the same as the one aldosterone uses

  By the 24 hour mark you are starting to get close to the original cortisol levels and hence need another dose - this is how dosing once a day (SID) works.