Cushing's disease: an update!
Since I graduated in 1980, veterinary medicine has expanded in knowledge and diagnostic capabilities. As a result of increased awareness and screening, canine Cushing’s disease (hyperadrenocorticism or HAC) is being diagnosed (and over diagnosed) in a large number of dogs. What do we really know about canine Cushing’s disease? What clinical sign(s) are pathognomonic and which are suggestive of the disorder? How is Cushing’s best diagnosed, treated, and monitored? What happens if we elect not to treat? The answers to these questions follow.
Dr. Doreen Houston with grandson Bennett
In about 85-90% of dogs, Cushing’s disease is caused by bilateral adrenocortical hyperplasia as a result of a pituitary tumour (adenoma or carcinoma) producing too much adrenocorticotrophic hormone (ACTH), which causes the adrenal gland to overproduce steroid hormones. Pituitary dependent hyperadrenocorticism (PDH) affects primarily older, female, small breed dogs such as the Miniature Poodle, Dachshund, Boxer, Boston terrier, and Beagle. Adrenal tumours (ATs) affect primarily large breed, female dogs.
Clinical signs
Only one is really pathognomonic for the disorder and that is calcinosis cutis. If present, it is highly likely the dog has Cushing’s disease. On the other hand, the following clinical signs may or may not be related to the disorder:
- Polyuria, polydipsia, polyphagia
- Panting
- Pendulous abdomen (redistribution of body fat, muscle catabolism, thin skin, big liver)
- Hair thinning and hair loss
- Muscle weakness
- Lethargy
- Skin hyperpigmentation, comedones, bruising
- Facial nerve palsy
- CNS disturbance with larger tumours (e.g. seizures, behavioural change)
- Recurrent infections
- Reproductive abnormalities (clitoral hypertrophy, testicular atrophy, anestrus)
- Predisposition to proteinuria (microalbuminuria in association with systemic arterial hypertension can lead to secondary renal disease)
Diagnosis
There is a need to have a high index of suspicion, based on clinical signs, before screening a dog for HAC. Ensure the dog is not on any form of steroid medication. Findings on CBC, biochemistry, and urinalysis may include:
- Neutrophilia, eosinopenia, and lymphopenia
- Elevated serum alkaline phosphatase (SAP), cholesterol, ALT, glucose (lots of reasons other than HAC for these changes)
- Inappropriate (<1.025) urine specific gravity (USG) on first morning sample
Although a number of screening tests are available, the ACVIM Consensus group in 2012 recommended the Low Dose Dexamethasone Suppression (LDDS) as the test of choice; it is diagnostic in approximately 95% of cases. A baseline serum cortisol sample is collected, 0.01-0.015 mg/kg dexamethasone sodium phosphate is administered, and serum cortisol samples collected at 4 and 8 hours post dexamethasone administration. In normal dogs, cortisol suppresses to < 1.0 ug/dl or < 30 mmol/L at 8 hours. Dogs with HAC are more resistant to steroid suppression; lack of adequate suppression at 8 hours is diagnostic for Cushing’s disease. Some dogs with pituitary-dependent HAC may exhibit suppression at 4 hours followed by escape at 8 hours, thus it is critical to obtain both the 4- and 8-hour samples.
Other screening tests
- Urinary cortisol-creatinine ratio test – many false positive results
- Measurement of 17OHP – no longer recommended
- Adrenocorticotropic hormone (ACTH) stimulation test – used to diagnose iatrogenic Cushing’s disease (dog receiving steroids who becomes Cushingoid), to monitor response to therapy, and to diagnose Addison’s disease (hypo ACTH)
Differentiating tests to know if PDH or AT
- High dose dexamethasone suppression test (0.1-1 mg/kg IV)
- Measurement of endogenous ACTH
- Abdominal ultrasound, CT, or MRI of the adrenal and/or pituitary gland
Treatment with mitotane (Lysodren®) or trilostane (Vetoryl®)
Don’t treat based on abnormal lab results if there are no clinical signs! Prior to initiating therapy, recommend that the owner monitor and record water consumption and appetite over a 3-5 day period in the home environment. The treatments recommended should result in a drop in water consumption to approximately 60 ml/kg/day (in dogs with PU/PD) and may result in a drop in appetite. It is critical the owner be aware when these changes occur and call immediately. Any vomiting, diarrhea, or listlessness should also prompt a call.
Mitotane (Lysodren®)
This drug causes destruction of the cortisol-producing areas of the adrenal gland. The goals of therapy are to eliminate clinical signs and have the pre- and post-ACTH plasma cortisol values within the normal resting range (< 4.0-6.0ug/dl) or < 100 nmol/L). The induction dose is 25 mg/kg PO q 12 hours (50 mg/kg/day) until the owner reports changes in water consumption or appetite as above. This generally takes 7-28 days (average 12). An ACTH stimulation test is performed at this time, or if no changes are noted by the owner, every 7 days until the basal and post ACTH cortisol concentrations are within the desired range. It is important to maintain daily contact with the owner. The maintenance dose is 50 mg/kg/week (divided into 2-3 doses [e.g. Monday, Thursday, and Saturday]).
Note: If any side effects are detected or if low basal or post-ACTH cortisol concentration develops after the initial treatment period, stop the Lysodren®, and check electrolytes and renal values. Most often, physiologic dosages of prednisone (0.2 mg/kg) are needed until serum cortisol returns to the basal reference range. If adverse clinical signs were caused by a low circulating cortisol concentration, maintenance dosages of mitotane can usually be restarted in 2-4 weeks.
Trilostane (Vetoryl®)
Trilostane is a synthetic, orally active steroid analogue that competitively inhibits 3β hydroxysteroid dehydrogenase, the enzyme that is critical for synthesis of cortisol. The European label directions (2-10 mg/kg once daily) differ from North American ones (2.2-6.7 mg/kg/day). Several endocrinologists recommend starting at 1 mg/kg q 12 hours and titrating upward depending on response to therapy.
Administer trilostane for 10 days and then perform an ACTH stimulation test. Regardless of whether the dog is on once a day or twice a day trilostane, the ACTH stimulation test is performed 4-6 hours post-pill. If the serum cortisol is > 50 and < 200 nmol/L (2-7 µg/dl) and the dog is clinically improved, continue with the same dose. If the dog is still showing dramatic clinical signs of HAC and if post ACTH cortisol concentration is markedly elevated, increase the dose by 25%. Don’t change the dose if the dog is clinically doing well. If the dog is not well or the serum cortisol is < 50 nmol/L (< 2µg/dl), stop the trilostane and provide supportive care. Repeating the ACTH stimulation test 14 days later will confirm if the dog is Addisonian or not. If not, a lower dose of trilostane (50-75% of previous dose) is recommended.
Monitoring
The ACTH stimulation test and electrolytes, BUN, and creatinine should be performed at 3-4, 6, and 12 weeks and then every 6 months (as with Lysodren). Make sure the owner has given trilostane the day the ACTH stimulation test is performed! The goal is to have the post ACTH stimulation value between 40-150 nmol/L.
Why choose trilostane over mitotane?
- Intolerance or fear of mitotane
- No induction protocol with trilostane
- It is a daily drug, which some owners prefer vs. trying to remember which days to give Lysodren
- Longer survival time reported with trilostane (708 days with trilostane vs. 662 days with mitotane in one study but really not a significant difference)
BUT…it is more expensive than mitotane, must be given more frequently, and can have similar side effects!
The risks of not treating include:
- Euthanasia (owners do not tolerate dogs urinating in the house)
- Problems regulating diabetes mellitus
- Thromboembolism
- Increased incidence of infections
- Systemic hypertension
- Glomerular nephropathy
Prognosis:
Most do well for another 2-4 years.
This article is based on a presentation given by Dr. Houston at the NBVMA/EVTA Conference, held in New Brunswick.CVT
