Cushings disease

What is the best test for diagnosing spontaneous Cushings disease in the dog? Our lab recommends the low dose dexamethasone suppression test as the best initial test, unless the dog has recently received exogenous steroids of any form including topicals, is receiving anti-convulsant therapy or has severe non-adrenal illness (e.g. diabetes mellitus, renal failure, etc.). If any of these situations are present, the test of choice is the ACTH stimulation test.

What is the best test for diagnosing spontaneous Cushings disease in the cat? The test of choice is the high dose dexamethasone suppression test. See section on Evaluation of Adrenal Function (NOTE: This test should never be used to diagnose Cushings in the dog, only to differentiate between pituitary and adrenal-dependent disease).

What is the best test for diagnosing spontaneous Cushings disease in the horse? The test of choice is a dexamethasone suppression test, but the protocol is very different from that used in the dog or cat. (See section on Evaluation of Adrenal Function).

Which adrenal test should I use in a ferret suspect on having Cushing's disease? Recent evidence shows that ferrets do not get "classic" cortisol-dependent Cushings disease. The syndrome of alopecia and pot belly associated with an adrenal tumor is most likely due to excess secretion of estradiol in combination with other steroids besides cortisol. Performance of a low dose dexamethasone suppression or ACTH stimulation test is not recommended.

Which test do I use in other species? It is best to contact one of the DVMs in the laboratory at the time of the test to get current recommendations. If nothing else, it is often useful to test another normal individual along with the patient.

Where do I get ACTH? How should it be administered? ACTH gel is difficult to obtain. One source is Rhone-Poulenc Rorer, Collegeville, PA who sell H.P. Acthar gel at 80 USP units/ml. We have encountered some vials of ACTH gel that seem to lack activity (e.g., A.C.T.H., repository corticotropin injection, distributed by Austin, division of Vetoquinol Canada, Joliette, Canada). We recommend use of synthetic ACTH called cosyntropin (or Cortrosyn). Cosyntropin can be obtained from a pharmacy or through Henry Schien (see below) and is manufactured by Organon, Inc. It costs approximately $140.00 for 10 vials. Each vial contains 250 micrograms of ACTH as a powder that must be reconstituted. The dose for dogs is 5 micrograms/kg IV (maximum dose 250 micrograms) and for cats is 125 mg/cat IV. For both dogs and cats, collect a blood sample before the ACTH injection (the pre-sample) and then collect one post-ACTH sample one hour later. Once the ACTH is reconstituted, it can be stored in the refrigerator for up to 4 months. Each vial of synthetic ACTH costs about $14.00 and one vial supplies enough ACTH to perform response tests in 5 dogs weighing 22 pounds (10 kg). Therefore, the actual cost of ACTH per test in dogs of this size is about $3.00.

Cortrosyn is available through Henry Schien at 1-800-872-4346, order number 7579460, at a cost of $131.00 for 10 ampules.

I didn't get a sample exactly at the required time after ACTH administration. Can I send in a 90 or 120 minute sample? Yes, a sample collected up to 120 minutes in the dog is probably O.K. A 90 minute sample in the cat is also probably O.K.

How long should I wait after a dose of prednisone to do an ACTH response or dexamethasone suppression test? The answer has two parts. First, prednisone, prednisolone and hydrocortisone cross-react in the cortisol assay, so wait at least 24 hours after administration of one of these drugs before performing eithe test. Dexamethasone, methylprednisolone and triamcinolone do not cross-react. Any steroid, however, can suppress the adrenal gland. If an animal has been receiving any form of steroid, even topically, for weeks to months, either test can be altered due to feedback effects. The time needed for withdrawal and recovery of the pituitary-adrenal axis depends on the duration of treatment and form of steroid used. Steroid therapy can cause clinical signs of Cushing's disease (iatrogenic) and can also cause atrophy of the adrenal cortex. This can be diagnosed using the ACTH response test.

How long should I wait between doing a dexamethasone suppression test and an ACTH stimulation test? Assuming the dexamethasone suppression is a low dose test, wait at least 48 hours. If it is high dose, wait at least 5 days (except if you are doing a combination test and the ACTH follows the high dose of dexamethasone by 4 hours).

What is the combination test? The combination test is an injection of a high dose dexamethasone suppression and ACTH stimulation. It can be used to diagnose Cushings and, if the dog has Cushings, potentially to differentiate between adrenal and pituitary-dependent.

What does the urinary cortisol:creatinine ratio (UCCR) tell me? This test can be used to tell if a dog does NOT have Cushings syndrome. Very near 100% of dogs with spontaneous Cushings have an elevated UCCR. However, most dogs with an elevated UCCR do not have Cushings. If the UCCR is normal, the dog most likely does not have Cushings. If the ratio is elevated, it is possible that the dog has Cushings. A more specific test such as the low dose dexamethasone suppression or ACTH stimulation must be done to determine if Cushings is truly present or not.

What form of dexamethasone do I use for a dexamethasone suppression test? Any form of dexamethasone or dexamethasone sodium phosphate can be used, but the dose must be based on the amount of active dexamethasone in solution. The dexamethasone can be give IV or IM, although our lab prefers the IV route.

I think I gave the dexamethasone out of the vein. What should I do? It would be best to wait 48 hours after a low dose, or 72 hours after a high dose, and repeat the test.

The dose of dexamethasone is very small for this dog. What should I do? It is important to dose the dog accurately. Dilute the dexamethasone 1 to 10 (e.g. 0.2 ml of dexamethasone into 1.8 ml of sterile saline or sterile water) and administer the diluted dexamethasone.

Do I need to fast a dog before an ACTH stimulation or dexamethasone suppression test? Fasting is not absolutely necessary, but dogs should be calm during the test. Very excessive lipemia may affect cortisol assay results.

Can I do any other diagnostic tests when I am testing for Cushings? It is best to minimize handling of the dog. Radiographs would best not be done. In a diabetic, blood glucose should be monitored during the test. Hypoglycemia is an extremely potent stimulator of ACTH release, and hypoglycemia during either the ACTH stimulation or any dexamethasone suppression test (i.e. low or high dose) could result in a false positive.

I am screening a dog for Cushings disease. If the result of an ACTH response test or low dose dexamethasone suppression test is NORMAL, does this rule out Cushings disease 100% of the time? Neither test is 100%. The low dose dexamethasone suppression is about 90-95% sensitive and the ACTH stimulation test is about 85% sensitive. In other words, the low dose dexamethasone will be normal in 5-10% of Cushings patients and the ACTH stimulation will be normal in about 15% of Cushings patients. If a test you do is normal and you are still very suspicious that the dog has Cushings, then do another screening test.

I am screening a dog for Cushings disease. If the result of an ACTH stimulation or low dose dexamethasone suppression test is POSITIVE for Cushings, how confident can I be in making the diagnosis? This is a difficult question. If the dog has the classic signs and laboratory abnormalities and no non-adrenal illness, you can be confident in the diagnosis. If non-adrenal illness is present, the waters are muddier. In one study of ill dogs not even suspected of having Cushings, about 50% had an abnormal low dose dexamethasone suppression and about 15% had an abnormal ACTH stimulation. That means if non-adrenal illness is present, the low dose dexamethasone has about a 50% false positive rate and the ACTH stimulation has about a 15% false positive rate. In that situation, the complete clinical picture has to be taken into account and a judgment made.

What are the tests available to differentiate between pituitary and adrenal dependent Cushings in a dog? The high dose or ultra high dose dexamethasone suppression test or an endogenous ACTH level. About 75% of dogs can be differentiated using the high dose dexamethasone suppression. If the dog suppresses, the diagnosis is pituitary-dependent. If there is no suppression, then the dog could still have either form of Cushings and an endogenous ACTH level should be submitted. In other words, the results of the high dose dexamethasone suppression test can only identify dogs with pituitary-dependent Cushings. If cortisol levels are not suppressed by a high dose of dexamethasone in a dog with confirmed Cushings, the odds of pituitary-dependent versus adrenal-dependent Cushings are 50:50.

What do I need to do to submit an endogenous ACTH? The complete protocol is in Evaluation of Adrenal Function. ACTH may be degraded in blood once a sample is drawn, so there are some special handling instructions.

Why should I differentiate the Cushings into adrenal or pituitary before I begin treatment? There are a few reasons. If the dog does have adrenal-dependent Cushings, then adrenalectomy is an option. Even if medical therapy is going to be used in either case, knowing the type provides valuable information to the owner on prognosis, follow-up and cost. The prognosis with adrenal tumors is worse. Adrenal tumors are more difficult to treat with Lysodren, so the owners should be warned that there may be numerous visits required until the dog is controlled and the cost for Lysodren could be high. Lastly, if the dog does not respond well to Lysodren and differentiation is desired later, interpreting the results of tests after Lysodren has been administered can be extremely difficult.

Therapy for Cushings Disease

What is the best test for monitoring a dog on Lysodren or ketoconazole therapy? The ACTH stimulation test.

How can L-deprenyl be used to treat Cushings disease? L-deprenyl has recently been approved in Canada for the treatment of canine pituitary-dependent Cushings disease. Very little has been published to date on its efficacy. It works by increasing dopamine levels; increased dopamine levels may decrease ACTH secretion in a percentage of pituitary adenomas. A recent report indicated that in approximately 50 dogs with pituitary-dependent Cushings treated for 6 months, 60-80% improved in such areas as polyuria/polydipisia, hair loss, abdominal size and skin thickness. How many dogs returned to normal was not reported. No side effects or drug interactions were noted, so L-deprenyl would be safe to try. However, Lysodren is probably the much more effective treatment.

I am currently inducing a Cushingoid dog on Lysodren. It presented with anorexia, depression, and vomiting, looking like it had Addisons. I did an ACTH stimulation test, but, surprisingly, its values were within the desired range. What should I do? The clinical signs could be either directly due to the Lysodren or to "glucocorticoid withdrawal". If the signs are due to the Lysodren and the dog is ready to be placed on maintenance therapy, the reduction in dose will most likely eliminate the signs. Glucocorticoid withdrawal is a problem recognized in people due to a sudden lowering of cortisol concentrations. Even though the dog's measured values were in the normal range, its body may be dependent on the much higher levels present in Cushings disease. The body will readjust to the lowered cortisol levels, but in the meantime, supplementation may be helpful. In this case, the dose of prednisone required is a physiologic dose (0.1 mg/lb once daily). In the acute situation, where the dog is showing clinical signs, a one time higher dose of 0.5 mg/lb may be helpful. The dog should be quickly weaned off the physiologic dose of prednisone.

Should I use glucocorticoids during the loading phase with Lysodren therapy? Not all endocrinologists agree on the answer to this question. However, we recommend that a physiologic dose of prednisone (0.1 mg/lb/day) be given during the loading phase to prevent signs of glucocorticoid withdrawal. Glucocorticoid administration is not required during maintenance Lysodren therapy if the cortisol values pre and post ACTH administration are in the ideal range.

Addisons Disease
What is the preferred test to diagnose Addisons disease? The ACTH stimulation test is the only test to diagnose Addisons disease.

What do you recommend for the treatment of Addisons disease? Refer to a recent Current Veterinary Therapy for a complete description. Maintenance treatment requires a mineralocorticoid, either fludrocortisone acetate (0.0125 mg/kg daily as a starting dose) or desoxycorticosterone pivalate (DOCP, 2.2 mg/kg IM every 25-30 days). The drug dosages need to be monitored and tailored to the dog. Approximately 50% of Addisonian dogs do not require glucocorticoid replacement (e.g. prednisone). If glucocorticoids are required, the dose is 0.2 mg/kg/day of prednisone or prednisolone.

Where can I get DOCP? DOCP is available through Novartis (formerly Ciba-Geigy) at 1-800-332-2761.DOCP costs $74 for a 100 mg vial. The shelf-life of DOCP is usually long (e.g. 18-24 months from purchase).

Guidelines for monitoring response to Lysodren or ketoconazole therapy
NOTE: These guidelines apply only to Lysodren or ketoconazole therapy. For L-deprenyl, the preferred test for monitoring response is the low dose dexamethasone suppression.
Periodic ACTH stimulation testing is recommended in all dogs with Cushings disease treated with either Lysodren or ketoconazole.

General Guildelines for ACTH Response Testing.

1. Monitoring Lysodren therapy: ACTH stimulation testing is recommended after the initial induction period (7-10 d of daily Lysodren). If additional induction phases are required, an ACTH stimulation should be done at the end of each phase. Once the dog is on maintenance, an ACTH stimulation should be done 3 months and 6 months later. Periodic retests at 6 month intervals are recommended, if the patient is responding well to treatment (earlier if not).

2. Monitoring ketoconazole therapy: The initial dose of ketoconazole is 5 mg/kg bid for 7 days. If there are no adverse effects, the dose is increased to 10 mg/kg bid and an ACTH stimulation should be done after 14 days. If cortisol levels are not within the ideal range, the dose should be increased to 15 mg/kg and an ACTH stimulation again done after 14 additional days. The ACTH stimulation test should begin within 1-3 hours of the last dose of ketoconazole.

3. "Ideal" values: in a Cushings dog receiving either Lysodren or ketoconazole are pre-ACTH cortisol, 30-100 nmol/L and post-ACTH cortisol, 30-110 nmol/L. In other words, we like to see measurable cortisol levels which do not rise above 110 nmol/L after ACTH.

Interpretation of specific results with the ACTH stimulation test during therapy with Lysodren

At completion of induction therapy (daily loading therapy):
1. If both cortisols (pre and post ACTH) are between 30 and 110 nmol/L, go to maintenance therapy.

2. If both cortisols (pre and post ACTH) are above 110 nmol/L, continue daily Lysodren and repeat ACTH stimulation in 5 days. Continue daily therapy until cortisols are between 30 and 110 nmol/L.

3. If both cortisols (pre and post ACTH) are below 30 nmol/L, stop Lysodren, wait 3 weeks, retest with ACTH stimulation and start maintenance when cortisols increase into 30-110 nmol/L range. Dog may require glucocorticoid supplementation, especially if stressed. Also, monitor Na/K to see if Addisons is present.

During maintenance therapy:
1. If both cortisols (pre and post ACTH) are between 30 and 110 nmol/L, continue as is.

2. If both cortisols (pre and post ACTH) are below 30 nmol/L, stop Lysodren, retest with ACTH stimulation at 3-4 week intervals until cortisols increase into 30-110 nmol/L range, then resume maintenance. Dog may require glucocorticoid supplementation, especially if stressed. Also, monitor Na/K to see if Addisons is present.

3. If both cortisols (pre and post ACTH) are well above 110 nmol/L, re-initiate loading Lysodren at 50 mg/kg on a daily basis for 5 days. Retest with ACTH stimulation after 5 days to see if cortisols have dropped, and continue daily Lysodren until they do. Once cortisols are between 30 and 110 nmol/L, restart weekly maintenance at a dose 50% above that used previously.

4. If both cortisols (pre and post ACTH) are slightly above 110 nmol/L, increase weekly Lysodren dose by 25% and retest with ACTH stimulation in 4-6 weeks.