Cushing's Disease
J. Catharine Scott-Moncrieff, MA, MS, Vet MB, DACVIM, DECVIM, Purdue University
Todd Archer, DVM, MS, DACVIM (SAIM), Mississippi State University
Brittany Fright, RVT, Mississauga-Oakville Veterinary Emergency Hospital and Referral Group, Internal Medicine Department
Step 1: Overview
A Compass for Cushing’s: Demystifying Canine Hyperadrenocorticism
J. Catharine Scott-Moncrieff, MA, MS, Vet MB, DACVIM, DECVIMPurdue University, West Lafayette, Indiana
KEY POINTS
Absence of laboratory abnormalities does not rule out hyperadrenocorticism.
Clinical signs are the most important indicator of the diagnosis.
Each diagnostic test has strengths and weaknesses. Choosing the appropriate one is an individualized process.
VETORYL Capsules (trilostane) are veterinary-approved for the treatment of hyperadrenocorticism.
Active listening and then addressing client concerns or comments are key to successful diagnosis and treatment.
Monitoring needs to be shared by the client and veterinary team.
Clients will need support and encouragement to accept and comply with treatment recommendations.
Canine hyperadrenocorticism (Cushing’s syndrome) is the constellation of abnormalities resulting from excessive circulating concentrations of glucocorticoid hormones. (See Tables 1 and 2, in Step 2.) Cortisol is the most common secretory product of the adrenal gland in hyperadrenocorticism (HAC), although excessive secretion of other adrenal hormones such as sex hormones and mineralocorticoids has also been documented. Approximately 80% to 85% of cases of spontaneous canine HAC are due to an adrenocorticotropic hormone (ACTH) secreting pituitary tumor (pituitary dependent hyperadrenocorticism; PDH), with the remainder due to autonomous secretion of cortisol by an adrenocortical tumor (AT).
It is important to differentiate spontaneous HAC from iatrogenic HAC, which is caused by exogenous administration of glucocorticoids. Clinical signs of iatrogenic and spontaneous HAC cannot be distinguished so identification of iatrogenic HAC is based on a history of steroid administration and, if necessary, results of an ACTH stimulation test. HAC may interfere with the quality of life of both dog and owner. If left untreated, patients are also more susceptible to potentially life-threatening complications such as urinary tract infection, diabetes mellitus, and systemic hypertension. Although most of the current treatment options for canine HAC do not address the underlying abnormality (a benign pituitary tumor in 85% of spontaneous cases), appropriate treatment can resolve clinical signs and prevent complications.
Step 2: Diagnosis
Owner Observation & Testing
J. Catharine Scott-Moncrieff, MA, MS, Vet MB, DACVIM, DECVIMPurdue University, West Lafayette, Indiana
Diagnosis of HAC relies on the historical and physical examination findings, a laboratory minimum database (CBC, serum chemistry panel, urinalysis), and specific endocrine function tests. Not all dogs respond in the same way to high cortisol concentrations, so making a diagnosis of HAC may be challenging; a myriad of clinical signs may be observed. Although in severe cases the clinical signs are very characteristic, in others they may be more subtle with only one or two being present.
Signalment & Clinical Signs
HAC is typically a geriatric disease with a median age of 11 years; it is unlikely in a dog <6 years of age. Owner observations are very important for documenting the clinical signs of HAC because many may not be obvious in the examination room. Neurologic abnormalities from pituitary macrotumor syndrome may be very subtle (Table 1).
CLINICAL MANIFESTATIONS OF CANINE HAC1
Step 3: Treatment
Pinpointing Therapy
Todd Archer, DVM, MS, DACVIMAssociate Professor, Mississippi State University College of Veterinary Medicine
Treatment of canine hyperadrenocorticism (HAC) is directed at resolution of clinical signs, improvement in quality of life for the patient and owner, and reduction of risks associated with uncontrolled disease. These risks include recurrent secondary infections, diabetes mellitus, hypertension, calcinosis cutis, pancreatitis, and clot formation with pulmonary thromboembolism. Treatment should be instituted only in patients showing clinical signs, and even then a discussion should take place with each owner about the pros and cons.
If clinical signs are absent and only blood work values are consistent with Cushing’s disease, treatment is not indicated. Treatment options, protocols, and prognoses also vary depending on the type of HAC.
Adrenal Dependent HAC
Treatment for adrenal dependent HAC includes both surgical and medical options. While excision is the treatment of choice for adrenal tumors (AT) causing HAC, complication rates can be as high as 46% and mortality as high as 21%.1 Thus, adrenalectomy should be performed by only an experienced surgeon. If surgery successfully removes all tumor burden, it may be curative, but complications can be severe. When the owner does not want to pursue surgery or the AT is not surgically amenable, medical management is appropriate.
Pituitary Dependent HAC (PDH)
Treatment options for PDH are also surgery and medical management. At this time, medical management is preferred in the United States.2 Hypophysectomy is performed at Utrecht University and in limited centers in the United States. Trilostane, mitotane, selegiline, and ketoconazole are all choices for medical management, but trilostane and mitotane are most effective and commonly used. With trilostane or mitotane, dosage adjustments are based on ACTH stimulation testing results as well as the individual patient response to therapy. The author does not consider ketoconazole and selegiline good treatment options for canine hyperadrenocorticism.
Is Compounding Necessary?
The recent addition of a 5-mg VETORYL Capsule size provides more dosing options and makes compounding less necessary to fine-tune treatment. However, compounding may still be needed for some patients. In addition to VETORYL Capsules (available in 5-, 10-, 30-, 60-, and 120-mg sizes), trilostane is available from many veterinary compounding pharmacies that make their products from bulk ingredient or directly from VETORYL Capsules. A 2012 study4 of the trilostane concentration in products from 8 compounding pharmacies found a wide variation, ranging from 39% to 152.6% of the label claim. All batches compounded from VETORYL Capsules as well as the content in all proprietary VETORYL Capsules conformed to the acceptance criteria (90% to 105% of label claim), whereas 38% of batches ordered from compounding pharmacies failed to do so. This variation can play a critical role in the management of a patient. If a compounded product is needed, the author recommends having the pharmacy use only VETORYL Capsules.
Trilostane
Trilostane (VETORYL Capsules) is FDA-approved for the treatment of canine HAC. Median survival time for dogs with adrenal dependent HAC treated with trilostane and mitotane were 353 and 102 days respectively.3 Trilostane’s mechanism of action is competitive inhibition of 3β-hydroxysteroid dehydrogenase (3β-HSD). It reduces synthesis of cortisol, aldosterone, and adrenal androgens, and the effects appear to be reversible and dose dependent in most patients. Oral trilostane is rapidly absorbed, and absorption is enhanced when administered with food.
Initial dosage recommendations (2.2 to 6.7 mg/kg once a day) and protocols are the same for PDH and AT. In calculating dosages, round down and start at the lower end of the range. The author starts at an initial total daily dosage of 2-3 mg/kg/day. Once daily administration is recommended on the drug label. However, if clinical signs are not controlled for the full day, twice daily administration may be needed for optimum control. In diabetic patients, always use the twice-daily protocol to provide consistent therapy across a 12-hour interval.
If using a potassium-sparing diuretic or ACE inhibitor, hyperkalemia can develop. Side effects of trilostane are usually mild and can include lethargy, inappetence, and gastrointestinal upset within the first few days of treatment.
A rare life-threatening side effect of trilostane is acute adrenal necrosis with development of Addisonian crisis, which is caused by acute adrenal insufficiency resulting from cortisol deficiency with or without aldosterone deficiency. Dispense dexamethasone tablets (not prednisone, as it can cross-react with the cortisol assay for the ACTH stimulation test) at a dosage of 0.1 mg/kg for emergency use at home. If Addisonian crisis is suspected (patient is exhibiting vomiting, diarrhea, and collapse), the client should administer dexamethasone and immediately bring the patient to the clinic. An ACTH stimulation test will confirm whether Addisonian crisis has occurred.
Mitotane
Mitotane is an adrenocorticolytic agent. Thus, its effects may not be reversible. There are two consecutive phases of treatment: an initial loading phase and chronic maintenance. In the initial phase, the patient receives ~ 50 mg/kg/day to be divided and given twice daily with food. Once loading is successfully completed, the patient receives ~ 50 mg/kg/week, divided over several days.
Trilostane Cheat Sheet
How it works: Reversible inhibition of 3β-hydroxysteroid dehydrogenase (3β-HSD)
Starting dose: 2.2-6.7 mg/kg once a day
Monitoring: Recheck with testing 10-14 days after initiating therapy/dosage change
Upon disease control: Recheck with testing at 30 and 90 days; then every 3-6 months
Contraindications: • Primary hepatic disease • Renal insufficiency • Pregnancy Owners should not handle capsules if pregnant/trying to conceive.
Monitoring
Mitotane is an older drug whose use is decreasing with time, especially since it is not FDA-approved. Because of the critical nature of the induction phase and the potential serious side effects of therapy, mitotane involves significant monitoring, which is beyond the scope of this article.
With trilostane, the first recheck should be scheduled in 10 to 14 days after starting therapy. Trilostane should be given with food, including on the day of a recheck. The first and every recheck thereafter should include discussions with clients about clinical improvement and any side effects, as well as ACTH stimulation test results and electrolyte levels. The ACTH stimulation test should be performed 4 to 6 hours after dosing.
Most dogs will have demonstrated an improvement in clinical signs, such as a reduction in drinking, urinating, and appetite, at the first recheck. Some will not have yet realized the full effects of trilostane after two weeks of therapy; it may take a full month. If the ACTH stimulation test results are above the ideal range at the first recheck, an increase in dosage may not be indicated until 30 days after starting therapy. The first recheck can then ideally rule out overdosing.
Controlling the hypothalamic/pituitary/adrenal axis is essential. Post-ACTH stimulation test cortisol values should be within the range for well controlled patients, which varies depending on the reference used. The author uses between 1.5 and about 9 µg/dL. The key is resolution of clinical signs without excessive cortisol suppression. If a dosage adjustment is indicated, use a factor of 10% to 15%. Warn owners that it usually takes 2 to 3 dose adjustments to achieve control, and schedule a recheck in 10 to 14 days.
Once a patient is well managed, rechecks with ACTH stimulation and electrolyte testing should occur at 1 and 3 months, and then every 3 to 6 months as long as the disease is clinically well controlled. While there is no perfect schedule, the above schedule is referenced elsewhere.2 In patients in which once-a-day dosing achieves adequate ACTH stimulation test results but not control of clinical signs, or signs seem controlled during the day but not at night, change to twice-daily dosing, giving half the total daily dose in the morning and evening with meals.
Putting It All Together
When it comes to uncovering a pet suffering from Cushing’s disease, it is everyone’s job to ask appropriate questions and to actively listen to what the client says. Clients may bring in their older dog for a wellness exam, but when the receptionist asks about changes in the dog’s health or general behavior, they may reveal subtle clues suggesting Cushing’s disease. Often, clients brush these off as simply part of the dog getting older.
Once HAC has been diagnosed, emphasize the goals of management—ie, getting their dog back to normal. Stress how appropriate treatment will improve the clinical signs. Don’t assume clients will not pay for something; if they understand how it will improve quality of life for their dog and themselves, many are willing to do what it takes.
When the disease process is controlled, the patient’s clinical signs will begin to resolve. One of the main goals of treatment is getting life back to normal for both patient and owner. Everyone from the front desk to the exam room can contribute to this goal. Everyone should be listening to the client as he or she describes the dog’s clinical signs, response to therapy, and any complications that may occur. Hearing about the changes, no matter how subtle, is important for evaluating each patient, as an accurate patient evaluation is critical to determining the final dosage of medication for the individual patient. Titration of therapy over time is based on adequate resolution of clinical signs and laboratory testing (ACTH stimulation testing and monitoring of electrolytes).
It is also very important to stress up front that medical management is life-long, requiring rechecks in order to gain and maintain optimum control in the safest manner possible. This will require more checks early on and fewer as good control is achieved: Good client communication is imperative in achieving successful management. Taking time to explain the treatment process at the start will help eliminate owner frustration.
Step 4: Client Communication
Getting Clients to Say “YES!” to Treating Cushing’s Disease
Brittany Fright, RVTMississauga-Oakville Veterinary Emergency Hospital and Referral Group, Internal Medicine Department
You’ve just given a life-altering diagnosis to a valued client about a family member. The pet owner is likely to be overwhelmed at the moment and may have difficulty understanding and absorbing all of the information provided. In the fast-paced veterinary clinic, it can be hard to sit back and provide the thorough information and encouragement a client needs.
Moreover, clients may need time on their own—to go home, discuss the situation with family members, and digest the information they have been given. What your clients currently understand is that they have been living with some very troublesome clinical signs and you thankfully have an answer for them.
Gathering Information
Active listening and then responding to voiced concerns are critical to optimal management and client satisfaction. When probing for information that may point to HAC and educating clients about the illness and its management, several factors are important:
clinical signs of Cushing’s disease
side effects of medications
need for routine testing
client expectations.
The last point is probably the most important. Setting realistic expectations can mean all the difference in a client’s satisfaction with a pet’s care.
“Tuning in” to Clients
During conversations with owners of pets with HAC, listen carefully for key words or concepts to indicate they need more information/clarification on specific aspects of the disease and its management. Examples include:
Concerns over clinical signs
Financial constraints
Time commitment concerns with repeated monitoring
Misinformation obtained online
Time frame for improvement in clinical signs
Information regarding co-morbidities
Consistent, Positive Message
Communicating about HAC treatment and its chronicity is important and requires a solid team approach, ensuring everyone is on the same page in how we assist clients in making difficult decisions. The treatment options can often be seen as complex and expensive. You will need to stress to clients that this is a chronic illness, but that you will help them throughout the treatment process to make the best decisions for them and their pet.
For a variety of reasons, most practitioners will recommend medical treatment. This is where a team communication approach is most beneficial. From receptionist to technician to veterinarian, everyone needs to provide a consistent, positive message of encouragement and guidance. Receptionists are generally the first point of contact for pet owners and can gather relevant information about how the patient is doing when confirming appointments or checking patients in. Veterinary technicians have a more hands-on role in client communication and can be employed as “translators” between doctor and owner.
It is easy for us, exposed to this illness regularly, to underestimate the impact on pet owners of the uncontrollable appetite, accidents in the house, and change in appearance of their dog. These issues can take a toll on pet owners and the dog/owner bond. Our job as veterinary team members is to prevent this from happening. As a veterinary professional, you can involve your team by having them explain medication administration, monitoring, and possible side effects, including those that could indicate an Addisonian crisis. Adverse effects can be minimized by ensuring the medication is administered correctly, with a full meal. Side effects of trilostane and mitotane may also mimic those of Addisonian crisis. If they persist, new ones develop, or are immediately concerning, clients should be instructed to come in for an ACTH stimulation test immediately.
Monitoring
Clients should be prepared for the fact that it may take some time and repeated ACTH stimulation testing to determine optimum dosages. Explaining why we take a slow and steady approach to medication administration will offer clients peace of mind that their money is being spent in the best way possible and that we are always mindful of the patient’s well-being. Emphasize the success stories. It is not uncommon for clients to report their dog is acting like a goofy puppy again.