Diagnosis of Canine Hypercortisolism

Introduction

Hypercortisolism is a common endocrinopathy in dogs and is also referred to as Cushing’s disease or syndrome. A change in nomenclature has been recommended and hypercortisolism is the recommended term rather than hyperadrenocorticism.
Hypercortisolism is typically a slowly progressive disorder of older dogs occurring
more frequently in small rather than large dogs. Diagnosis of hypercortisolism can vary
from straight forward to difficult but it is rarely urgent so there is time to consider signs,
plan tests, interpret results and consider treatment plan.

Spontaneous hypercortisolism in dogs is caused by a pituitary tumour (micro or
macroadenoma) or an adrenal tumour (adenoma or carcinoma). In people, disease
can occur due to extra pituitary excretion of ACTH, but this has not been well
documented in dogs and there are a small number of dogs reported to have hypercortisolism associated with eating (rare). Hypercortisolism associated with a pituitary tumour is more common than adrenal tumours particularly in small dogs.
Large dogs, however, may have an equal chance of having an adrenal or pituitary
tumour. Some dogs can have both adrenal and pituitary tumours. Exogenous glucocorticoids can result in iatrogenic hypercortisolism and clinical signs like those of dogs with spontaneous disease.

Typical clinical signs of hypercortisolism can include;

Metabolic: Polyuria, polydipsia, polyphagia, lethargy

Body shape change: pot belly, redistribution of fat to shoulders and rump, hepatomegaly.

Dermatologic: alopecia, thin skin, comedones, coat colour change, widening of scars, calcinosis cutis, pyoderma.

Musculoskeletal: laxity of tendons and ligaments, muscle wastage, myotonia.

Panting.

Neurological signs can occur in dogs with large or expanding pituitary masses.

Hypertension.

Not all dogs develop all signs but to make a diagnosis of hypercortisolism dogs should
have some signs.

Diagnosis of Hypercortisolism

Like many other diseases diagnosis of hypercortisolism involves combining clinical signs and examination with laboratory tests and diagnostic imaging. There are really no shortcuts to make a diagnosis because appropriate treatment requires confirmation of disease and determination of the site of the lesion. Treatment, whether surgical or medical is expensive, potentially life threatening and should only be embarked upon following sound diagnosis.

Clinical signs and findings have been mentioned already, it is worthwhile noting that
large breed dogs can look less typically cushingoid.

Laboratory diagnosis of hypercortisolism:

Routine haematology, biochemistry and urinalysis are corner stones in the diagnosis
of hypercortisolism and will increase suspicion of the disease when performed in a
dog with suggestive clinical signs. Common changes include;

Haematology- stress leucogram, thrombocytosis, high reference interval or increased
red cell numbers.

Biochemistry- increased liver enzyme activities (ALP higher than ALT), hypercholesterolaemia, hypertriglyceridaemia, moderate bile acid increase, mild hyperglycaemia.

Urinalysis- Urine SG is typically <1.030, proteinuria, UTI (may have no signs and no
pyuria).

Confirmatory tests are undertaken when there is a high index of suspicion following clinical examination and routine laboratory testing. It does not seem appropriate to embark on expensive further testing in a dog with no clinical signs and limited routine laboratory test changes e.g. increased ALP activity alone.

ACTH Stimulation/Response tes

This test is used to help confirm hypercortisolism and is useful as a starting point of
therapy. This test is easy and quick to perform, it is specific (95%) but is less sensitive.
See table for how to perform the test. This is the test of choice when considering
iatrogenic hypercortisolism.

Low Dose Dexamethasone Suppression Test (LDDS)

A useful test to confirm diagnosis and may differentiate between adrenal and pituitary disease. This test takes 8 hours to perform and is sensitive but lacks specificity. It is a useful test to exclude hypercortisolism, but positive results can occur with other illness and stress. See table for how to perform test.

Urinary cortisol to creatinine ratio (UCCR)

A test that is used to screen for hypercortisolism but cannot differentiate between pituitary and adrenal gland disease when used in this format. The test is sensitive but lacks specificity. Urine must be collected at home, when the dog has not been to the clinic for at least 3 days and is not stressed. It is recommended to collect the first urine of the day (morning). A negative result makes hypercortisolism very unlikely.

Endogenous ACTH

Measurement of endogenous ACTH can be useful to distinguish between adrenal and pituitary gland disease following diagnosis of hypercortisolism. Dogs with hypercortisolism due to adrenal gland neoplasia should have very low eACTH and dogs with pituitary gland disease would be expected to have high reference interval or increased eACTH. The limitation of this test is that there are stringent sample handling requirements (see brochure), diagnostic imaging may provide the same answer. eACTH is not useful to confirm diagnosis of hypercortisolism due to its episodic secretion. It may be useful in cases where there are adrenal and pituitary masses.

Diagnostic Imaging

Abdominal ultrasound

Performing abdominal ultrasound is crucial in the diagnosis of hypercortisolism. These are often older animals and the potential for co-morbidities cannot be underestimated. Abdominal ultrasound allows for full investigation of the abdomen to eliminate the possibility of other disease that can mimic hypercortisolism e.g. liver disease, to look for co-morbidities e.g. kidney disease or neoplasia and to screen for diseases that can occur in association with hypercortisolism such as gall bladder mucocoele. With pituitary gland disease it is expected that there is bilateral adrenomegaly and typically with adrenal gland disease there is unilateral enlargement with atrophy of the contralateral gland. Adrenal gland masses can abut and invade the vena cava resulting in massive haemorrhage and thrombosis.

Computed Tomography

CT of the head is useful to confirm the presence of a pituitary mass or to determine its
size in the presence of neurological signs. This is an expensive test and is not routine
in the work up of dogs with hypercortisolism but does have its merits. CT of the
abdomen and chest would be considered for surgical planning and to screen for
metastasis in dogs with adrenal gland neoplasia.

Frequently asked questions?

What is the best test to diagnose hypercortisolism?

     Unfortunately, there is no easy answer as there is no gold standard test that will diagnose hypercortisolism. The most straight forward diagnoses are in dogs with typical clinical signs that have routine clinicopathological changes suggestive of hypercortisolism and an ACTH stimulation test, low dose dexamethasone suppression and diagnostic imaging confirm the diagnosis and localise the lesion.

I have a case with high ALP but no signs or other clinicopathological changes, does it have hypercortisolism?

     This is a slowly progressive disease, and dogs should have consistent clinical signs prior to the undertaking of investigations, otherwise what are you treating? Increased ALP activity alone is not toxic to dogs. Wait and see what happens and if signs develop then investigate as appropriate.

Can synthetic ACTH be given intramuscularly?

     Yes, synthetic ACTH can be given intramuscularly, but it stings! Synthetic ACTH should
be given intravenously in dehydrated or collapsed animals e.g. Addisonian crisis as it may not be absorbed well otherwise. Dogs with hypercortisolism are typically well hydrated and not collapsed.

Should a dog undergoing LDDS be fasted?

     Fasting may be a stressor for some dogs, during a LDDS test stress should be kept to a minimum. Feeding a small volume of low-fat food may prevent a dog becoming overly stressed and avoiding this influence on the results. If fasting is necessary, feed after the 3 hour sample as there are 5 hours until the next sample is taken.

Can ACTH stim and BAST be performed on the same day?

     Why would this be necessary? Two separate diseases are being investigated and hypercortisolism will cause some increase in bile acids meaning results may not be clear. If it is necessary to do so 3 blood samples will be required, start with basal cortisol, give ACTH, take second sample 1 hour later and then feed the dog. Use the second sample for post ACTH cortisol and pre-prandial bile acids. Take post prandial bile acid sample 2 hours later.

Can other diagnostic tests such as imaging be performed on the same day?

     Other tests can be performed on the same day as ACTH stimulation test and LDDS but only after these tests have been completed. Do not perform ACTH stimulation test and LDDS on the same day. They can be performed on consecutive days.

Can I sedate a dog to perform ACTH stimulation test or LDDS?

     No, this is not recommended during the investigation of hypercortisolism as the stress may influence the results. If a dog has hypoadrenocorticism stress will not influence its ability to produce cortisol and ACTH stimulation test can be performed with sedation (the dogs are usually so sick it is not required).

My patient is receiving steroids, and I want to test for hypercortisolism, do I need to
stop the medication? 

     Even small doses of glucocorticoids can cause signs of iatrogenic hypercortisolism. An ACTH stimulation test can be performed if the dog has not received steroids for 24 hours (the assay can measure the exogenous steroid in some cases) to see if there is either a poor or blunted response. If there is a poor/blunted response following ACTH administration this suggests iatrogenic hypercortisolism, an excessive response could suggest hypercortisolism.

I have done all the routine tests for hypercortisolism but cannot confirm its presence, what will I do?

     This is very uncommon. Does the dog look like it has hypercortisolism and have appropriate signs? Have you ruled out other differential diagnoses? If this is the case, consider urine cortisol to creatinine ratio and potentially followed by advanced imaging (CT scan of the brain) and pair it with eACTH. If this is not possible but you are convinced by the appearance and signs that the dog has the disease a well planned and monitored treatment trial could be considered. Trilostane is not a benign medication and definitive goals such as resolution of Pu/Pd and improvement of appearance should be defined.

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