Cushing’s syndrome, or hyperadrenocorticism, is a relatively common endocrine condition in middle-aged and older dogs (Bennaim et al., 2019). While one study estimated the annual prevalence of Cushing’s as 0.17 percent in primary care (Schofield et al., 2022), such statistics are limited by a lack of widespread screening – partially due to the lack of a definitive diagnostic test. This can make a diagnosis of Cushing’s syndrome a challenge despite its widely recognised clinical signs.
Causes of hyperadrenocorticism
Cushing’s syndrome is the result of excessive corticosteroid levels. Iatrogenic Cushing’s syndrome, however, is the result of excessive corticosteroid administration and should respond to gradual tapering of steroid medications. Spontaneous Cushing’s syndrome is the result of a functional pituitary or adrenal tumour, which causes cortisol production to break free from the negative feedback usually exerted by the hormone cortisol on the hypothalamic–pituitary–adrenal axis.
1) Pituitary-dependent hyperadrenocorticism
Typically caused by functional microadenomas of corticotropic cells, pituitary-dependent hyperadrenocorticism (PDH) accounts for up to 85 percent of Cushing’s cases (Sanders et al., 2018). It is characterised by excessive adrenocorticotropic hormone (ACTH) production and bilateral adrenocortical hyperplasia.
2) Adrenal-dependent hyperadrenocorticism
Adrenal-dependent hyperadrenocorticism (ADH) is less common, accounting for up to 20 percent of spontaneous Cushing’s syndrome cases (Sanders et al., 2018). This form is independent of pituitary control, instead resulting from an adrenal tumour.
Distinguishing between adrenocortical adenomas and carcinomas is difficult, but the two are thought to occur with approximately equal frequency
Distinguishing between adrenocortical adenomas and carcinomas is difficult, but the two are thought to occur with approximately equal frequency (Mooney et al., 2012). Bilateral tumours are rare, and the contralateral, unaffected gland is typically atrophied in response to low ACTH levels.
Signalment
Cushing’s syndrome most commonly affects middle-aged and older dogs, with the prevalence increasing with age and weight over breed average (Schofield et al., 2022). Suggested breed predispositions include the Bichon Frise, Dachshunds(O’Neill et al., 2016), Miniature Schnauzers and Miniature Poodles (Hoffman et al., 2018), while Border Collies and Labrador Retrievers are less likely to be affected (O’Neill et al., 2016).
History and clinical signs
Steroid hormones exert widespread effects, affecting many body systems. The classic presentation of a “Cushingoid” dog – a pendulous abdomen, alopecia and polydipsia – is more common in smaller breeds, while larger patients may more often show fewer signs. Where limited signs are present, they usually include either polyuria and polydipsia or skin changes and alopecia (Behrend et al., 2013).
Common clinical signs of Cushing’s disease include:
- Polydipsia and polyuria (in 82 to 91 percent of cases (Bennaim et al., 2019))
- Polyphagia
- Pendulous abdominal enlargement (“pot belly”)
- Skin thinning, scaliness and coat changes
- Calcinosis cutis
- Poor wound healing
- Hepatomegaly
- Muscle wastage
- Lethargy and exercise intolerance
- Reproductive changes (anoestrus, testicular atrophy)
Affected dogs may also present with poorly controlled diabetes mellitus, incontinence, spontaneous thromboembolism due to hypercoagulability or lameness due to ligament laxity and tearing (Behrend et al., 2013).
Diagnosing Cushing’s syndrome
Diagnosis is based on specific testing, although the following supportive findings are commonly identified (Behrend et al., 2013):
- Marked elevation in alkaline phosphatase (ALP)
- Mild to moderate increase in alanine aminotransferase (ALT)
- A “stress leukogram”
Other potential changes include:
- Thrombocytosis and mild erythrocytosis
- Hypercholesterolaemia and hypertriglyceridaemia
- Hyperglycaemia
- A urine specific gravity of 1.018 to 1.020 or lower
- Proteinuria
Urinary tract infections (UTIs) are common in affected dogs but frequently cause no clear clinical signs or changes on a basic urinalysis. Culture and sensitivity should be considered for definitive exclusion.
Diagnostic tests
No single test is definitive, so they should be interpreted in context; appropriate pre-diagnostic screening for Cushing’s syndrome can ensure high prevalence in tested populations, increasing test accuracy (Behrend et al., 2013). There are three main tests available: urine cortisol:creatinine ratio (UCCR), the ACTH stimulation test and the low-dose dexamethasone suppression test (LDDST).
Appropriate pre-diagnostic screening for Cushing’s syndrome can ensure high prevalence in tested populations, increasing test accuracy
Urine cortisol:creatinine ratio
UCCR is most useful for excluding hyperadrenocorticism in cases unlikely to be positive. This is because the diagnostic sensitivity of UCCR is estimated to be 75 to 100 percent (Behrend et al., 2013; Bennaim et al., 2019), so false negatives are relatively rare. However, false positives are not uncommon, so further testing is required for confirmation.
Urine samples should be collected in a low-stress environment.
ACTH stimulation test
The ACTH stimulation test relies on blood samples taken pre- and post-dosing with an ACTH analogue to assess adrenocortical reserve. This is the gold standard for diagnosing iatrogenic Cushing’s syndrome, in which plasma cortisol will not rise post-ACTH administration. In dogs with spontaneous Cushing’s, it will rise excessively due to overproduction by the adrenal gland(s).
The test’s specificity is high (59 to 93 percent), but its sensitivity for spontaneous Cushing’s syndrome ranges from 57 to 95 percent(Behrend et al., 2013); this is higher for dogs with PDH and lower for ADH.
ACTH stimulation tests can be useful for treatment monitoring.
Low-dose dexamethasone suppression test
A low dose of dexamethasone in a healthy animal causes negative feedback on the pituitary and hypothalamus, resulting in a reduction in ACTH production. This subsequently causes a greater than 50 percent reduction in cortisol after eight hours.
In dogs with ADH, suppressing ACTH production has no significant impact on cortisol production. In dogs with PDH, the pituitary is desensitised to negative feedback, so a mild reduction in cortisol levels may be seen. If cortisol levels are suppressed by over 50 percent at any point in a dog with Cushing’s syndrome, PDH is confirmed; however, the absence of significant suppression is not a reliable indicator of ADH.
The LDDST has a reported sensitivity of 85 to 100 percent but has a specificity of only 44 to 73 percent and cannot be used for monitoring treatment (Behrend et al., 2013).
What test should I use to diagnose Cushing’s disease?
The 2012 ACVIM consensus statement advises the use of the LDDST as the screening test of choice for spontaneous Cushing’s syndrome and the ACTH stimulation test for iatrogenic cases (Behrend et al., 2013). Patients with a suggestive presentation but multiple negative tests may benefit from retesting three to six months later if their signs progress.
Patients with a suggestive presentation but multiple negative tests may benefit from retesting three to six months later if their signs progress
Differentiating PDH from ADH
ACTH assays are one of the most reliable ways to discriminate between PDH and ADH. However, ACTH release can be pulsatile, resulting in some values within the reference range in cases of PDH (Behrend et al., 2013). Abdominal ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) can also reliably identify adrenal tumours.
Treatment of spontaneous Cushing’s syndrome
PDH typically requires lifelong medication – while treatments like hypophysectomy and radiotherapy exist, they are not widely available and come with significant risks (Mooney et al., 2012; Sanders et al., 2018). Bilateral adrenalectomy is another option but is potentially high-risk (see below) and necessitates lifelong management of iatrogenic hypoadrenocorticism. The treatment of choice for hyperadrenocorticism is, therefore, trilostane. Trilostane is a synthetic steroid analogue that lacks hormonal activity and acts as a competitive inhibitor of 3 β-hydroxysteroid dehydrogenase in the adrenal cortex, blocking the production of glucocorticoids and, to a lesser extent, mineralocorticoids and sex hormones.
Clinical signs like polydipsia often resolve over a few days, while skin changes can take months. As Cushing’s syndrome predisposes dogs to concurrent conditions such as diabetes mellitus and UTIs(Hoffman et al., 2018), further testing should be carried out in patients with refractory clinical signs. Unmasking conditions such as chronic kidney disease should also be considered.
Are there any adverse effects?
Adverse effects are reported in approximately 15 percent of dogs (Mooney et al., 2012), with figures ranging from 0 to 40 percent(Lemetayer and Blois, 2018). These are typically mild but range from diarrhoea and lethargy to, though rarely, ataxia or muscle tremors. Isolated case reports have linked trilostane to adrenal necrosis or sudden death (Reusch et al., 2007).
Close monitoring is advisable in the form of monitoring clinical signs, physical examinations, bloodwork and cortisol measurement
Overdoses tend not to be lethal, with clinical signs of hypoadrenocorticism rare; however, close monitoring is advisable in the form of monitoring clinical signs, physical examinations, bloodwork and cortisol measurement. These may also help to detect other conditions unmasked by treatment, including renal disease and arthritis. While ACTH stimulation tests have traditionally been used, new evidence suggests that pre-trilostane cortisol levels may be a better monitoring method (Macfarlane et al., 2016).
Limited data exists examining the effects of trilostane treatment on adrenal tumours. While it has been suggested that the progression of adrenal neoplasia in these patients may contribute to subsequent morbidity and mortality(Arenas et al., 2014), further research is needed in this area.
Surgical management
If the adrenal tumour can be entirely excised, ADH may be cured. However, while studies are limited, adrenalectomy is reported to have high morbidity and mortality, and these dogs are frequently poor surgical candidates (Degasperi and Dupré, 2016; Mooney et al., 2012). ADH can alternatively be managed similarly to PDH with trilostane.
Adrenalectomy is reported to have high morbidity and mortality, and these dogs are frequently poor surgical candidates
Summary
There is no single definitive diagnostic test for Cushing’s syndrome. Instead, clinicians must combine suggestive signalment, history and clinical signs with biochemical parameters and selected tests to arrive at a diagnosis.
Ensuring a high prevalence of Cushing’s in tested patient populations gives the greatest likelihood of accurate results. With this in mind, the most recent ACVIM consensus statement recommends more widespread use of the LDDST where there is a strong suspicion of Cushing’s syndrome.
Appropriate treatment of Cushing’s syndrome can result in a fair to good prognosis, with a reported median survival time of 14 months for medically managed ADH and up to 30 months for dogs with PDH (Alenza et al., 2006; Arenas et al., 2014; Fracassi et al., 2015).
