The sometimes tricky art of diagnosing hyperadrenocorticism in dogs

1. Introduction

• Cushing's syndrome refers to all causes of hyperadrenocorticism with overproduction of cortisol.
• ACTH-dependent
• Cushing's disease: Pituitary hypersecretion of ACTH which results in bilateral adrenal hyperplasia (90% of cases)

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

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

• Iatrogenic
• Excessive or prolonged administration of glucocorticoids. Clinically indistinguishable from natural disease. Results in adrenal atrophy and suppressed ACTH levels.

2. Signalment

• Poodles, Dachshunds, Schnauzers, Boston Terriers, Boxers.

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

• No sex predilection.

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

3. Clinical signs

• PU / PD

• Pendulous, "pot-bellied abdomen": Due to muscle catabolism by glucocorticoids and hepatomegaly.

• Bilaterally symmetric alopecia: Head and extremities spared.

• Thin skin

• Muscle weakness and muscle atrophy; cruciate ruptures

• Mineralization of skin (calcinosis cutis)

• Hyperpigmentation: ACTH similar to MSH, co-existing hypothyroidism, chronic skin irritation.

• Reproductive abnormalities
• Anestrus

• Clitoral hypertrophy

• Testicular atrophy

• Perianal adenomas in females and neutered males.

• Respiratory signs
• Panting: Pulmonary hypertension and decreased compliance, primary CNS disturbance, pulmonary mineralization.

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

• Central nervous system
• 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.

• Signs due to compression/invasion of pituitary and/or hypothalamus:

• Seizures
• Pacing

• Lethargy

• Inappetence

• Behavior change

• Head pressing

• Circling

4. Diagnosis of Hyperadrenocorticism

• History and clinical signs

• 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.

• Laboratory data
• Hemogram
• Polycythemia (PCV 45-55%)

• Stress leukogram
• Lymphopenia

• Eosinopenia

• Neutrophilia (mature)

• Biochemistry profile
• Elevations in:
• Serum alkaline phosphatase (SAP)

• Cholesterol

• Serum alanine aminotransferase (ALT)

• Fasting blood glucose: Diabetes in 5-10%.

• Thyroid function tests
• T3 and T4 basal levels are generally decreased.

• Response to TSH parallels normal.

• Secondary to negative feedback of cortisol on pituitary.

• 80% have a normal fT4ED

• Does not require thyroid supplementation.

• Blood pressure: 50 – 80% are hypertensive, cause unknown.
• Recent study demonstrated normal or decreased levels of atrial natriuretic factor (ANF) in dogs with hyperadrenocorticism. Argues against hypervolemia as the etiology of the hypertension.

• Urinalysis
• Decreased urine specific gravity.

• Proteinuria

• Radiographic abnormalities
• Thoracic films
• Bronchial calcification

• Metastases from adrenal adenocarcinoma

• Abdominal films
• Hepatomegaly

• Osteopenia

• 50% of adrenal tumors are visualized as soft tissue or calcified masses.

• Subcutaneous calcification

• Adrenal function tests
• Three tests used to diagnose hyperadrenocorticism. They do not differentiate between PDH or AT.
• ACTH stimulation test
• Look for exaggerated cortisol response in response to ACTH.

• See protocols at the end of this discussion.

• Diagnostic in 85% of pituitary-dependent cases (PDH)

• Diagnostic in 70% of adrenal tumors (AT)

• Overall accuracy 80-85 %

• A suppressed response to ACTH in animals with clinical signs of hyperadrenocorticism suggests iatrogenic disease.

• Low-dose dexamethasone suppression test
• Low doses of dexamethasone inhibit ACTH release from the pituitary via negative feedback and decrease plasma cortisol concentrations in normal dogs.

• Dogs with Cushing's are more resistant to steroid suppression. Therefore, lack of suppression following dexamethasone = hyperadrenocorticism.

• Diagnostic in 95% of PDH

• Diagnostic in 100% of AT

• Overall 90-95%
• May also be used to distinguish PDH from AT (see below)

• See protocols

• Urine cortisol/creatinine ratio
• Assessment of cortisol production and excretion rate.

• Sensitivity of this test is greater than that of the LDDS (some animals with clinical signs of hyperadrenocorticism may have normal LDDS response tests but elevated urine cortisol to creatinine ratios). Used as a screening test.

• Test is easy to perform.

• As with all adrenal function tests, elevated results may occur in animals with non-adrenal disease.

• Positive tests confirmed with a LDDS.

• Must be performed on urine obtained at home, preferably in the AM

• Tests to differentiate PDH from AT (performed after confirming diagnosis of hyperadrenocorticism).
• High-dose dexamethasone suppression test
• With PDH, a high dose of dexamethasone results in a decrease in ACTH release from the pituitary and a decrease in plasma cortisol.

• With AT, the tumor secretes cortisol autonomously thereby suppressing ACTH production. With low ACTH concentrations already present, dexamethasone has no effect on plasma cortisol.

• 70% of patients with PDH suppress plasma cortisol to less than 50% of the pre-treatment value.

• 100% of patients with AT do not suppress.

• Therefore: Suppression = PDH; Lack of suppression = Inconclusive

• See protocol

• Endogenous ACTH concentration
• PDH: Levels normal or high

• AT: Levels low to undetectable

• Contact lab regarding sample handling and collection. Use of the preservative (Aprotinin)  allows for greater utilization of this test.

• Excellent method to differentiate PDH from AT.

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.

• ACTH Stimulation Test
• Synthetic ACTH (Cortrosyn) 5 ug/kg IV or IM; collect serum at 0 and 1 hour, or

• ACTH gel (Acthar) 2.2 U/kg IM; collect serum at 0 and 2 hours.

• Hyperadrenocorticism if post-cortisol > 20 ug/dl (530 nmol/L)

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

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

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

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

• 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.

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

• Stable at room temperature or refrigerated for 3 days.

• 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

• Low-Dose Dexamethasone Suppression Test
• See above.

• High-Dose Dexamethasone Suppression Test
• 8 a.m: Obtain serum cortisol. Administer 0.1 mg/kg dexamethasone sodium phosphate (0.15 mg/kg dexamethasone) IV.

• 4 p.m: Collect post-dexamethasone cortisol.

• Suppression defined as greater than a 50% reduction of cortisol.

• Suppression = PDH, non-suppression = Inconclusive

• Endogenous ACTH Concentration
• Check with lab on sample collection and handling.

• Normal: 20-100 pg/ml (4.4-22.0 pmol/L)

• PDH: 40-500 pg /ml (8.8-110 pmol/L)

• AT: < 20 pg/ml (<4.4 pmol/L)