Cushing's syndrome

Cushing’s syndrome is the umbrella term for a range of clinical syndromes that is caused by a chronic excess of glucocorticoid activity, which can be due to a range of endogenous or exogenous steroid hormones.

Comments:
• ALIVE discourages the use of the term Cushing’s disease or hyperadrenocorticism for the umbrella term of this clinical syndrome.
• ALIVE recognises the possibility of pre-clinical or subtle presentations associated with high cortisol concentrations/ hypercortisolism.
• ALIVE also recognises that demonstrable hypercortisolism is not always associated with or does not always lead to Cushing’s syndrome.

Excessive glucocorticoid activity due to cortisol.

A clinical syndrome in which a dog or cat appears to have Cushing’s syndrome, yet the results of dynamic testing of pituitary-adrenal function fall into appropriate (normal) reference intervals. Testing requires a normal dexamethasone suppression test (based on blood or urine estimates of corticoid activity) and a normal ACTH stimulation test. Subdiagnostic Cushing’s syndrome has previously been referred to as Atypical or Occult Cushing’s/Hyperadrenocorticism.

Comments:
ALIVE emphasises that measurement of basal urinary corticoid:creatinine ratio (UCCR) and endogenous ACTH is not a dynamic test of pituitary-adrenal function.

Naturally-occurring Cushing’s syndrome

Pituitary-dependent hypercortisolism (PDH)
Hypercortisolism due to dysregulated ACTH secretion by the pituitary. This is generally associated with pituitary neoplasia or hyperplasia.

ALIVE criteria for the diagnosis of PDH are: 
• Identification of a set of clinical features attributable to Cushing’s syndrome including supportive history, physical examination findings and clinicopathologic test results.
• AND demonstration of an excess of cortisol through dynamic testing of pituitary-adrenal function; dynamic testing of pituitary-adrenal function includes a dexamethasone suppression test based on blood or urine or an ACTH stimulation test.
• AND ACTH-dependence originating from the pituitary is proven through at least one clear differentiation test result which includes the following:
- a characteristic suppression of a LDDST using blood
- a characteristic suppression of a HDDST using blood
- a characteristic suppression of a HDDST combined with UCCR measurement.
- absence of suppressed endogenous ACTH concentration
- absence of an ultrasound examination characteristic of a glucocorticoid-secreting adrenal tumour using ALIVE methodology
- characteristic changes of pituitary morphology on CT or MRI using ALIVE methodology.

Comments:
• All diagnostic test methodology needs to comply with ALIVE guidelines (see diagnostic test definitions for more information)
• ALIVE emphasises that measurement of basal UCCR and endogenous ACTH is not a dynamic test of pituitary-adrenal function.
• Lack of suppression in response to dexamethasone is not confirmation of ADH.
• Employed cortisol assays should be validated and subjected to quality control; usually this means tests should be run by reference laboratories and not performed in-house to be reliably accurate.
• As there are other diseases that can cause similar clinical signs and false positive test results for Cushing’s syndrome, it is important that, as part of the diagnostic approach, these conditions are excluded (e.g. diabetes mellitus, hypercalcemia, liver insufficiency).
• It is accepted that the range of clinical signs of hypercortisolism and what is considered a satisfactory demonstration of cortisol excess varies between individual animals and clinicians.

Naturally-occurring Cushing’s syndrome

A rare form of ACTH-dependent hypercortisolism associated with uncontrolled secretion of ACTH from a non-pituitary site, usually a carcinoid (a malignant tumor of neuroendocrine origin).

ALIVE criteria for the diagnosis of PDH due to ectopic ACTH secretion are:
• Clinical signs of Cushing’s syndrome
• AND lack of cortisol suppression in response to dexamethasone
• AND markedly increased endogenous ACTH concentration
• AND marked bilateral adrenal enlargement -AND pituitary imaging within normal limits
• AND the identification of a non-pituitary tumor and resolution of ACTH excess after removal of the tumor.

Comments:
• Severe hypokalemia has, thus far, been a typical clinicopathologic finding.
• The lungs and pancreas should be evaluated for the presence of the ACTH-secreting tumor; a tumor may not be found as they can be very small.

Naturally-occurring Cushing’s syndrome

A clinical syndrome in which the findings of Cushing’s syndrome are due to excess secretion of ACTH yet an excess of cortisol cannot be proven.

ALIVE criteria for the diagnosis of ACTH-dependent subdiagnostic Cushing’s syndrome are:
• Clinical signs of Cushing’s syndrome
• AND other causes of the clinical signs have been eliminated
• AND normal results of all dynamic tests of pituitary-adrenal function
• AND endogenous ACTH concentration is not suppressed
• AND results of abdominal imaging are not characteristic of a glucocorticoid-secreting adrenal tumour using ALIVE criteria.

Comments:
• Such cases may be due to inaccuracy of current reference interval limits.
• If these criteria are met, the recommendation is to retest for Cushing’s syndrome in 2-3 months' time if clinical signs persist.
• ALIVE is aware of the use of treatment trials to aid in diagnosis in such situations, especially when pet owners are not coping with the clinical signs or the welfare of the patient is at risk.
• ALIVE emphasises that treatment trials can pose significant risks, should not replace the above diagnostic criteria and, if considered, should only be undertaken when euthanasia is being considered or the patient’s welfare is thought to be at significant risk if treatment is being postponed.
• Additionally, any treatment trial should only be conducted in a cautious, well-educated, well-monitored and supervised manner.

Naturally-occurring Cushing’s syndrome

Hypercortisolism due to unregulated cortisol secretion by the adrenal cortex. This is generally associated with adrenal neoplasia or hyperplasia.

ALIVE criteria for the diagnosis of ADH are:
• Identification of a set of clinical features attributable to Cushing’s Syndrome including supportive history, physical examination findings and clinicopathologic test results.
• AND demonstration of an excess of cortisol through dynamic testing of pituitary-adrenal function; dynamic testing of pituitary-adrenal function can include a dexamethasone suppression test based on blood or urine or an ACTH stimulation test.
• AND ACTH-independence confirmed by at least one clear differentiation test result which includes the following:
- suppressed endogenous ACTH concentration
- an ultrasound examination characteristic of a glucocorticoid-secreting adrenal tumour using ALIVE criteria
- characteristic changes of adrenal morphology on ultrasound, CT or MRI using ALIVE methodology.

Comments:
• All diagnostic test methodology needs to comply with ALIVE guidelines (see diagnostic test definitions for more information).
• ALIVE emphasises that measurement of basal UCCR and endogenous ACTH is not a dynamic test of pituitary-adrenal function.
• Lack of suppression in response to dexamethasone is not confirmation of ADH.
• Employed cortisol assays should be validated and subjected to quality control; usually this means tests should be run by reference laboratories and not performed in-house to be reliably accurate.
• As there are other diseases that can cause similar clinical signs and false positive test results for Cushing’s syndrome, it is important that, as part of the diagnostic approach, these conditions are excluded.
• The range of clinical signs of hypercortisolism and what is considered a satisfactory demonstration of cortisol excess varies between individual animals and clinicians.

Naturally-occurring Cushing’s syndrome

A form of ACTH-independent hypercortisolism caused by excess cortisol secretion due to aberrant expression of receptors in the adrenal cortex. A subtype of aberrant adrenal expression is food-dependent hypercortisolism, due to receptors for gastrointestinal hormones. Presence of receptors for gastric inhibitory polypeptide (GIP) is the only aberrant expression currently demonstrated in dogs. In this form of Cushing’s syndrome, food ingestion induces GIP release from the small intestine, which binds to its receptor in the adrenal gland, and causes excess cortisol secretion.

ALIVE criteria for the diagnosis of the food-dependent form of aberrant adrenal receptor expression are:
• Clinical signs of Cushing’s syndrome.
• AND normal results of dynamic testing of pituitary-adrenal function.
• AND suppressed endogenous ACTH concentration.
• AND increased UCCR after ingestion of a meal.
• AND no evidence of one adrenal gland being smaller than normal
• AND pituitary imaging within normal limits
• AND supportive octreotide test, where ocreotide administration prevents food-induced cortisol elevation

Naturally-occurring Cushing’s syndrome

A clinical syndrome in which the findings of Cushing’s syndrome are due to secretion by an adrenal tumor of a non-cortisol hormone that has glucocorticoid activity, e.g. corticosterone, progesterone.

ALIVE criteria for the diagnosis of ACTH-independent subdiagnostic Cushing’s syndrome require:
• Clinical signs of Cushing’s syndrome
• AND normal or below normal results of dynamic testing of pituitary-adrenal function
• And ONE of the following:
- results of abdominal imaging characteristic of a glucocorticoid-secreting
- adrenal tumour using ALIVE criteria
- suppressed endogenous ACTH concentration.

Comments
If these criteria are fulfilled, identification of the hormone(s) being secreted by the adrenal tumour is not necessary for effective clinical management.

A form of Cushing’s syndrome caused by chronic administration of systemic or topical glucocorticoids.

ALIVE criteria for the diagnosis of iatrogenic Cushing’s syndrome are:
• A history of receiving, or having recently received, chronic exogenous glucocorticoid therapy
• AND lack of cortisol secretion as demonstrated by an ACTH stimulation test
• AND resolution of clinical signs with withdrawal of the exogenous glucocorticoids.

Comments
A similar syndrome can be caused by administration of exogenous progestinsSudden cessation of exogenous glucocorticoids should be avoided given the risk of hypoadrenocorticism.

To optimise quality of life, to eliminate clinical signs, and to reduce long-term complications and mortality. These are achieved by eliminating the source of either ACTH or autonomous adrenal hormone excess, or at least, controlling excess adrenal hormone secretion. Treatment ideally should be considered only if there are clinical signs consistent with naturally-occurring Cushing’s syndrome and when the disease is confirmed by endocrine testing.

Comments:
Differentiating between forms of naturally-occurring Cushing’s syndrome is highly desirable in order to optimise management strategies and prognosticate. Latrogenic glucocorticoid excess is treated by gradual cessation of exogenous glucocorticoid administration.

Proposed score 2
• Range total score: 0-15
• Treatment aim: lowest score possible without unacceptably high risk of hypoadrenocorticism