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«David Bruyette, DVM, DACVIM VCA West Los Angeles Animal Hospital 1818 South Sepulveda Blvd Los Angeles, CA 90025 David.Bruyette 1. ...»

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Diagnosis and Treatment of

Hyperadrenocorticism in Dogs

David Bruyette, DVM, DACVIM

VCA West Los Angeles Animal Hospital

1818 South Sepulveda Blvd

Los Angeles, CA 90025

David.Bruyette@vcahospitals.com

1. Introduction

A. Cushing's syndrome refers to all causes of hyperadrenocorticism

with overproduction of cortisol.

1. ACTH-dependent

A. Cushing's disease: Pituitary hypersecretion of ACTH which

results in bilateral adrenal hyperplasia (90% of cases)

B. Ectopic ACTH production: Non-pituitary tumors secreting ACTH resulting in bilateral adrenal hyperplasia. Has not been completely documented in dogs or cats.

2. ACTH independent A. Adrenocortical adenoma or carcinoma: Hypersecretion of cortisol with atrophy of normal adrenal and suppressed ACTH concentrations (10% of cases).

3. Iatrogenic A. Excessive or prolonged administration of glucocorticoids.

Clinically indistinguishable from natural disease. Results in adrenal atrophy and suppressed ACTH levels.

2. Signalment A. Poodles, Dachshunds, Schnauzers, Boston Terriers, Boxers.

B. Middle to old age. Average 12 years; range 6 months to 17 years.

C. No sex predilection.

D. Rare in cats. Usually seen with insulin resistant diabetes mellitus and/or cats with severe dermal atrophy/ulceration.

3. Clinical Signs A. PU / PD B. Pendulous, "pot-bellied abdomen": Due to muscle catabolism by glucocorticoids and hepatomegaly.

C. Bilaterally symmetric alopecia: Head and extremities spared.

D. Thin skin E. Muscle weakness and muscle atrophy; cruciate ruptures F. Mineralization of skin (calcinosis cutis) G. Hyperpigmentation: ACTH similar to MSH, co-existing hypothyroidism, chronic skin irritation.

H. Reproductive abnormalities

1. Anestrus

2. Clitoral hypertrophy

3. Testicular atrophy

4. Perianal adenomas in females and neutered males.

I. Respiratory signs

1. Panting: Pulmonary hypertension and decreased compliance, primary CNS disturbance, pulmonary mineralization.

2. Dyspnea: Rare; seen with pulmonary thromboembolism and concurrent congestive heart failure.

J. Central nervous system

1. Seen with large pituitary tumors (macroadenomas). Present at time of diagnosis or following therapy for Cushing's disease as microscopic pituitary tumors enlarge into macroadenomas.

2. Signs due to compression/invasion of pituitary and/or

hypothalamus:

A. Seizures B. Pacing C. Lethargy D. Inappetence E. Behavior change F. Head pressing G. Circling

4. Diagnosis of Hyperadrenocorticism A. History and clinical signs B. R/O iatrogenic disease with questions concerning current or past medications. These medications can include oral, ophthalmic, otic, and topical medications. Make sure the owner tells you about everything and anything that went on or in their pet.

–  –  –

2. Tests to differentiate PDH from AT (performed after confirming diagnosis of hyperadrenocorticism).

A. High-dose dexamethasone suppression test

–  –  –

Testing Protocols These are suggested protocols that are used in the evaluation of patients with hyperadrenocorticism. You must use the protocol and normal values from the laboratory to whom you are submitting samples to properly evaluate endocrine tests.

–  –  –

C. Hyperadrenocorticism if post-cortisol 20 ug/dl (530 nmol/L)

2. Low-Dose Dexamethasone Suppression Test A. 8 A.m: Baseline serum cortisol. Administer 0.01 mg/kg dexamethasone sodium phosphate (0.015 mg/kg dexamethasone) IV.

B. 12 p.m: Collect 4 hour post-dexamethasone cortisol.

C. 4 p.m: Collect 8 hour post-dexamethasone cortisol.

D. In normal animals cortisol suppresses to less than 1.0 ug/dl (27.5 mmol/L) at 8 hours.

E. 50% or greater suppression at either 4 or 8 hours together with lack of suppresion at 8 hours is diagnostic for PDH and additional tests are not necessary.

3. Urine Cortisol/Creatinine Ratio A. First morning urine sample is preferred. Sample should be obtained at home. Requires 1 – 2 mls.

B. Stable at room temperature or refrigerated for 3 days.

C. Normal range 2.8 - 4.8. A normal result effectively rules-out hyperadrenocorticism, an abnormal result should be confirmed with a LDDS or ACTH stimulation test.

Differentiating PDH From AT

1. Low-Dose Dexamethasone Suppression Test

–  –  –

1. Owners assess water consumption and appetite at home for 3-5 days.

2. Begin Lysodren at 25 mg/kg PO BID.

3. When water consumption or appetite starts to decrease or following seven consecutive days of therapy (which ever occurs first) the medication is discontinued and an ACTH response test is performed.

4. If an adequate response to therapy is seen (pre and post cortisols within the resting range) maintenance therapy is begun. If an adequate response has not been seen, daily therapy is continued until clinical signs improve or for an additional 7 days and another ACTH stimulation test is performed.

5. If adverse reactions are noted at any time during therapy (reduction in appetite, anorexia, vomiting, diarrhea) therapy should be discontinued and the animal brought in as soon as possible for evaluation. Electrolytes, BUN, and an ACTH stimulation test should be performed. If the animal can not be brought in within the next 12-24 hours, replacement doses of steroids (0.25 mg/kg/day of prednisone) are started and the animal is seen at the earliest possible time. Owners should have 5 mg prednisone tablets at home for emergency use.





Maintenance Therapy

–  –  –

2. Watch for clinical signs of returning hyperadrenocorticism.

3. ACTH stimulation test in 4 weeks then every 3-4 months.

4. Electrolytes every 3-4 months. Even though the zona glomerulosa is fairly resistant to the effects of o,p'-DDD, mineralocorticoid deficiency can occur (see treatment for hypoadrenocorticism).

–  –  –

Another protocol that has been used with o,p'-DDD in the management of Cushing's disease is total adrenal ablation. In this protocol, Lysodren is administered at 100 mg/kg/day divided BID for 30 days. Supplemental cortisone acetate (2 mg/kg divided BID) and fludrocorticone tablets (0.1 mg/10 # once a day) are begun beginning on day 1 of Lysodren therapy. The diet is supplemented with 1-5 grams of NaCl per day. One week after the induction phase with o,p'-DDD, the dose of cortisone is reduced to 1 mg/kg/day. Electrolytes and an ACTH stimulation test are performed at the end of the induction period, every six months, and at any time the animal demonstrates signs compatible with either hyperadrenocorticism or hypoadrenocorticism. While this form of therapy may be effective in the management of canine hyperadrenocorticism, is does require close patient monitoring and life-long daily therapy. Close attention must be paid to these animals during times of stress and episodes of nonadrenal illness.

2. Medical therapy (con't)

–  –  –

C. l-Deprenyl (Anipryl) l-Deprenyl (Anipryl) is a selective monoamine oxidase-B inhibitor (MAO-B) that is currently approved for the treatment of Parkinson's disease in man and PDH and cognitive dysfunction in the dog. There are several reasons why dopamine depletion and monoamine oxidase inhibitors may play a role in the pathogenesis and treatment of canine PDH. First dopamine concentrations are decreased in canine patients with PDH. Secondly, PDH is a geriatric disease and it is known that the concentration of MAO-B increases with age. Together these events lead to further functional dopamine depletion. Thirdly, treatment with dopamine agonists (man, dog, horses) has been beneficial in some patients with PDH. Dopamine affects the HPA axis primarily through tonic inhibition of ACTH release from the pars intermedia (PI). Based on previous studies, approximately 30% of cases of PDH in the dog arise from adenomas or adenomatous hyperplasia in the PI. In addition, it appears that dopamine depletion also play a role in enhancing corticotropin releasing hormone (CRH) mediated ACTH release. In the dog, treatment with the dopamine antagonist domperidone results in enhanced CRH mediated ACTH release. This suggests that dopamine depletion can impact ACTH release from both the PI and pars distalis (PD) and that dopamine depletion may play a role in the pathogenesis of canine PDH. MAO-B can be effectively and irreversibly inhibited in the dog with chronic, daily oral administration of l-deprenyl with few adverse side effects. Therapy with l-deprenyl has recently been shown to be effective in 4 studies involving 125 dogs with PDH. The drug was administered once a day. Efficacy of therapy was evaluated on the basis of reversal of clinical signs and normalization or a return toward normal in the low dose dexamethasone suppression test. Seventy-five percent of the dogs treated with 1.0 or 2.0 mg/kg, were considered treatment successes based on clinical and biochemical criteria.

–  –  –

6. Management of Diabetes and Hyperadrenocorticism As the clinical signs of diabetes mellitus and hyperadrenocorticism are similar, clinical suspicion of hyperadrenocorticism is usually made based on physical examination findings and the occurrence of insulin resistance. The diagnosis of hyperadrenocorticism in a diabetic patient can be difficult. Unregulated or poorly regulated diabetic dogs can have exaggerated cortisol responses to ACTH, an elevated urine cortisol/creatinine ratio, and an abnormal LDDS test, without having hyperadrenocorticism. While well regulated diabetics have normal ACTH response tests, most ACTH response tests on diabetic dogs are being performed because of difficulties with glucose regulation. If you have a diabetic animal in which you suspect hyperadrenocorticism it is probably best to institute insulin therapy (even if it requires high doses) in order to regulate the diabetes. Once an adequate response to insulin therapy has been observed (based on clinical signs and serial blood sugars) adrenal function tests can then be performed. Prior to initiating Lysodren, insulin therapy is reduced to 0.5 to 1.0 U/kg BID.

This will help avoid the occurrence of ketoacidosis while helping to prevent severe hypoglycemic reactions that may occur as insulin requirements decrease. Owners are asked to monitor urine sugars 2-3 times a day and if negative readings are obtained the dose of insulin is reduced by 25%. One-third of treated dogs may be able to discontinue insulin therapy entirely following successful management of the hyperadrenocorticism.

A. Start daily Lysodren at 25 mg/kg/day.

B. Insulin requirements may change rapidly. Owner should monitor urine samples 2-3 times a day for glucose. With negative results, insulin dose is lowered 25% at next injection.

C. Cortisol causes insulin antagonism so with resolution of

hyperadrenocorticism:

–  –  –

D. Aside from starting with a decreased dose, the protocol is the same as that used for treating PDH without diabetes.

7. Prognosis A. Most dogs with PDH live normal lives (average 2.2 years, but remember most are geriatric to begin with.)

–  –  –

Trilostane Therapy Of Canine Hyperadrenocorticism

INTRODUCTION

Canine hyperadrenocorticism (HAC) has been most commonly treated with the adrenolytic drug o, p'-DDD (mitotane). However, it is well recognised that mitotane has several side effects, is associated with a high frequency of relapses and is not without risk to owners. Other drugs such as ketoconazole and l-deprenyl (selegeline) have also been investigated for the treatment of HAC. Recently it has been suggested that trilostane was an effective treatment for canine hyperadrenocorticism. Several workers in the field have subsequently used trilostane in canine pituitary dependent and adrenal dependent hyperadrenocorticism, in feline hyperadrenocorticism and in equine Cushing's syndrome. Trilostane is a synthetic, orally active steroid analogue. It can act as a competitive inhibitor of the 3ß hydroxysteroid dehydrogenase enzyme system and thereby inhibit the synthesis of several steroids, including cortisol and aldosterone. This blockade is reversible and seems to be dose-related.

Use in humans

In humans, trilostane has been mainly used for Cushing's syndrome. However the clinical response was rather disappointing with only few patients showing clinical improvement. Decreases in cortisol levels and in blood pressure were even less common. Other conditions in humans treated with trilostane are Conn's disease (primary aldosteronism) and advanced breast cancer. In humans, trilostane is given orally at a dose of 60 mg four times daily for three days with adjustment according to the patient's response. Usually a final dose of 120-480 mg daily in divided doses is required with a maximal dose of 960 mg recommended. Uncommon dose-related side effects of trilostane in humans include flushing, nausea and vomiting, diarrhoea, rhinorhoea and palatal oedema. Acute addisonian episodes have also been reported.

CLINICAL STUDIES

Canine pituitary dependent hyperadrenocorticism (PDH) The efficacy and safety of trilostane in the treatment of canine PDH were evaluated in a multicentre study at the Royal Veterinary College in London, the Veterinary Teaching Hospital in Dublin and Small Animal Hospital in Glasgow. Seventy-eight dogs with confirmed PDH were treated with trilostane for up to 3 years. The starting dose varied from 1.8 to 20 mg/kg (mean = 5.9 mg/kg).

Trilostane appeared to be well tolerated by almost all dogs with only 2 dogs developing signs and biochemical evidence of hypoadrenocorticism. One of these dogs recovered with appropriate therapy. The other died despite withdrawal of trilostane and administration of appropriate therapy. A further two dogs died within one week of starting trilostane but in neither case could a direct link with the trilostane therapy be established. The low prevalence of side effects compared favourably to those reported with mitotane.



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