Hyperadrenocorticism in dogs: keys to diagnosis
Introduction
Hyperadrenocorticism (HAC), also known as Cushing’s syndrome, is one of the most common endocrine disorders in older dogs, but it can be very hard to diagnose2. There aren’t any diagnostic tests with 100% sensitivity/specificity, so the diagnosis is generally made on the basis of the clinical picture, the results of various adrenal function tests and imaging tests.2 Several risk factors have been reported, including advanced age and breed, such as for Bichon Frisé or Miniature Poodle.8 In addition, some studies have suggested that the prevalence is higher among females and after sterilisation.9
Hyperadrenocorticism in dogs: pathophysiology
Hyperadrenocorticism in dogs is the result of chronic overproduction of cortisol. Cortisol is required in the right amounts by a healthy body, but excessive quantities lead to numerous alterations, some of which are very serious and affect patient quality of life. In most cases, the increased cortisol level is caused by a functioning pituitary tumour HAC (PTHAC) or an adrenal tumour HAC (ATHAC), although there are other causes, such as exogenous corticosteroid administration (iatrogenic) or food-dependent7 ectopic ACTH secretion.2
In dogs, HAC is usually caused by a functioning adenoma of the pituitary gland (80–85% of cases) that produces autonomous ACTH secretion, bilateral adrenocortical hyperplasia and excessive and chronic glucocorticoid secretion. ATHAC accounts for the other 15–20% of cases and these are usually due to a cortisol-secreting adrenal tumour, generally unilateral. The excess cortisol exerts a negative feedback mechanism on ACTH secretion, causing atrophy of the cortisol-secreting cells in the contralateral gland and the nonneoplastic cells in the affected gland.2 Although rare (5%), patients can have both types of HAC simultaneously.8
In addition, the term occult or atypical HAC has been coined to refer to dogs with a history, physical examination and clinicopathological alterations compatible with HAC, but with normal adrenal function test results. In any case, it has not yet been fully clarified whether this type of HAC exists as an independent entity or corresponds to patients with mild or early forms of HAC.3,4
Clinical picture
A medical history and physical exam compatible with hyperadrenocorticism are the main indication for specific diagnostic tests. The early detection of these clinical signs not only helps improve the patient’s response to treatment and quality of life, but also increases the chances of making a good diagnosis with the tests currently available.
The clinical signs of HAC are usually chronic and progressive and stem from the increase in protein catabolism and gluconeogenic and lipolytic activity, and from the anti-inflammatory and immunosuppressive effects associated with the excess of corticosteroids.
The most common signs are:
- Polyuria/polydipsia (82–91%)
- Polyphagia (46–57%)
- Pendulous abdomen (67–73%)
- Hepatomegaly (50–67%)
- Muscle weakness (7–14%)
- Systemic hypertension (31–86%)
As well as cutaneous signs, typically alopecia, thin skin with poor healing, pyoderma and calcinosis cutis.2,4
Diagnosis
Certain clinicopathological disorders often occur in dogs with HAC and may suggest its existence. The most common haematological disorders include:
- Eosinopaenia (54–81%)
- Lymphopaenia (14–79%)
- Monocytosis (30%)
- Erythrocytosis (9–17%)
- Thrombocytosis (37–78%)
With respect to the blood chemistry, common findings include:
- High alkaline phosphatase levels (76–100%)
- ALT (80–95%)
- High pre- and post-prandial bile acids (11–37%)
- Cholesterol (73–90%)
- Glucose (20–57%)
- Low urea
Urinalysis usually shows a urine specific gravity of < 1.015, coupled with proteinuria (62–80%) and bacteriuria.2
When is adrenal function testing recommended?
Adrenal function tests are recommended in the following situations:
- Patients with a history and physical exam results compatible with HAC
- Presence of a macroscopic pituitary tumour or adrenal mass
- Diabetic patients with an unexplained poor response to high doses of insulin
- Systemic hypertension of unknown aetiology5
Two basic steps should be remembered when conducting diagnostic tests for HAC:
- Perform screening tests that confirm or rule out the disease (low-dose dexamethasone suppression test, ACTH stimulation, UC:C ratio).
- Having confirmed the diagnosis of hyperadrenocorticism, the second step involves testing to differentiate between pituitary or adrenal tumour hyperadrenocorticism (high-dose dexamethasone suppression, imaging or endogenous ACTH tests) as several important factors, such as the treatment of choice, differ between the two forms.
Adrenocortical function tests
A dynamic assessment of adrenal function is required to confirm the presence and origin of HAC, as isolated measurements of cortisol are of no diagnostic value in HAC because of the pulsatile nature of its secretion.5
The most used diagnostic tests in clinical practice include dexamethasone suppression, ACTH stimulation and urine cortisol:creatinine ratio.
- Urine cortisol:creatinine (UC:C) ratio: this is used as a screening test because it has a very high sensitivity of > 98%. However, it has a very low specificity. This means a UC:C within the normal range can be used to rule out HAC, but a value above the reference range is not necessarily diagnostic of HAC as many other diseases will also return a high UC:C ratio.4
- ACTH stimulation: this is the test of choice in cases of iatrogenic HAC, in dogs treated with corticosteroids and to monitor the response to medical treatment. It is easy to perform and only takes a few hours to complete. However, it has a lower sensitivity than other screening tests, especially in dogs with adrenal masses. Nevertheless, it has a greater specificity and is therefore recommended over the low-dose dexamethasone suppression test in dogs given phenobarbital or which have a concurrent disease. But it should not be used to differentiate between types of HAC.4
- Testing adrenal function in dogs using dexamethasone: dexamethasone can be used to help diagnose HAC in dogs thanks to its capacity to suppress hypothalamic–pituitary–adrenal axis activity.5,6
Low-dose suppression test
Start with a dexamethasone suppression test at low doses. It is considered a screening test because it has a high sensitivity (85–100%), i.e., it detects Cushing’s syndrome in most dogs, but a low specificity (44–73%), i.e., patients without Cushing’s syndrome may also return a positive result. Besides being used to rule out HAC in dogs, this test can also differentiate between cases of pituitary and adrenal tumour HAC in some patients. Given these characteristics and benefits, some authors consider it the test of choice for the diagnosis of HAC. As mentioned above, no test is perfect, so the recommendation is to perform a complete diagnostic protocol. Said protocol should include:
- Drawing a blood sample to determine basal cortisol
- Administering dexamethasone (0.01–0.015 mg/kg/IV)
- Drawing blood samples at 4 (t4) and 8 (t8) hours
Prior fasting is not considered essential, but dogs should not be fed during the test.4,5
A recent study reviewed the different response patterns and interpretation of the results for this test:6
- Complete suppression (healthy dogs): t4 and t8 cortisol below or very close to the laboratory limit of detection (cut-off) (< 1–1.5 μg/dL)
- Lack of suppression (compatible with HAC): t4 and t8 cortisol > cut-off and < 50% reduction in basal cortisol
- Partial suppression (suggests HAC, to be interpreted with other findings): t4 and t8 cortisol > cut-off but one or both times < 50% of basal cortisol.
- Escape (t4 < 1 μg/dL, t8 > 1 μg/dL) and reverse patterns (t4 > cut-off, t8 < cut-off). Perform additional tests. Although an escape pattern (defined as t4 < 1.4 μg/dL and t8 > t4) has been considered as an indicator of pituitary tumour HAC,4,5 a recent study found patients with nonadrenal disease who also presented an escape pattern.6
High-dose dexamethasone suppression test
Once HAC has been confirmed, the high-dose dexamethasone suppression test can help establish its origin.
The protocol is the same as for the low-dose test, but the high dose of dexamethasone in dogs is 0.1 mg/kg/IV.
In dogs with a confirmed diagnosis of HAC, values below cut-off at 4 and 8 hours or > 50% suppression correspond to a pituitary tumour in approximately 75% of patients.5
Treatment
There is almost certainly no perfect treatment for HAC, as the disease is highly variable in terms of its severity and the underlying causes. Therefore, every patient should be assessed carefully and their type of medication and dosage should be individualised.6
Various drugs have been proposed, including (but not limited to) trilostane, mitotane, ketoconazole and selegiline. Surgical procedures (unilateral adrenalectomy and transsphenoidal hypophysectomy) are used to a lesser extent. Other modalities will probably be more appropriate in the future, including radiation therapy for large pituitary tumours.10
Conclusions
In addition to its therapeutic utility, dexamethasone can be used to assess adrenal function in dogs with suspected HAC, as well as to confirm its origin. However, it should be noted that there is no single test that confirms the diagnosis of HAC with 100% reliability. As such, it may be necessary to combine various techniques to reach an accurate diagnosis.
