Chapter 33 Diseases of the Adrenal Gland
HYPOADRENOCORTICISM IN DOGS AND CATS
Etiology
Primary Adrenocortical Insufficiency
• Iatrogenic, which can result from mitotane therapy of hyperadrenocorticism in dogs. Mineralocorticoid concentrations remain normal in most dogs, and the glucocorticoid deficiency is usually transient (weeks to months). However, permanent iatrogenic Addison disease can occur.
Signalment
• Age: Most dogs and cats are young to middle-aged, but can range in age from 6 months to over 10 years.
• Breed: In dogs, any breed can be affected, but Great Danes, Portuguese water dogs, rottweilers, standard poodles, West Highland white terriers, and Wheaton terriers appear to be at an increased risk of developing naturally occurring primary hypoadrenocorticism. No breed predilection has been reported in cats.
Clinical Signs
Diagnosis
Serum Biochemical and Electrolyte Abnormalities
• Hyperkalemia and a Na+/K+ ratio of less than 27 is present in 95% of cases of primary hypoadrenocorticism.
• Occasionally, primary hypoadrenocorticism may be associated with normal serum electrolyte concentrations (atypical primary hypoadrenocorticism). Repeated determinations may be necessary to demonstrate the typical electrolyte abnormalities in some animals with primary hypoadrenocorticism.
• Iatrogenic hypoadrenocorticism caused by mitotane or ketoconazole therapy is usually associated with normal serum electrolyte concentrations.
• Azotemia is common (>80%) in primary hypoadrenocorticism and may also occur in secondary hypoadrenocorticism.
• Hypercalcemia is seen in 30% of affected dogs and cats, possibly due to decreased renal calcium excretion.
Adrenocorticotropic Hormone Stimulation Test
Intravenous Procedure
• In dogs and cats, obtain a plasma or serum sample for cortisol determination before and 1 hour after IV injection of 5 μg/kg of the synthetic ACTH, cosyntropin (Cortrosyn, Amstar). Once reconstituted, the solution appears to be stable for at least 4 weeks if refrigerated. Alternatively, the remaining solution can be aliquoted and frozen. This method is recommended. Availability and backorder issues, however, may preclude use of this product.
Intramuscular Procedures
• Alternatively, in dogs, obtain a plasma or serum sample for cortisol analysis before and 2 hours after IM injection of 2.2 U/kg of ACTH gel. Acthar Gel (80 U/ml, Questcor Pharmaceuticals) is available but is very expensive. ACTH gel (usually 40 U/ml) is available from various compounding pharmacies. The bioavailability and reproducibility of these various formulations have not been stringently evaluated. Therefore, it may be prudent to assess the activity of each new vial by performing an ACTH stimulation test on a normal dog.
Interpretation
• Dogs and cats with hypoadrenocorticism show a blunted or absent cortisol response to ACTH administration.
• Primary hypoadrenocorticism: Basal and post-ACTH cortisol concentrations are usually <1 μg/dl (30 nmol/L).
• Secondary hypoadrenocorticism: The serum cortisol response to exogenous ACTH is blunted; however, post-ACTH concentrations of cortisol may be as high as 3.0 μg/dl (85 nmol/L) in some cases.
• False elevations of cortisol concentrations may occur after administration of prednisone, prednisolone, cortisone, or fludrocortisone because these cross-react on the cortisol radioimmunoassay. Discontinue these drugs 24 to 48 hours prior to the test.
Plasma Concentration of ACTH
Plasma concentration of ACTH is high (>500 pg/ml) in dogs and cats with primary hypoadrenocorticism and very low or undetectable with secondary hypoadrenocorticism. This assay is available at several diagnostic laboratories. Contact the appropriate laboratory for collection, shipping, and handling instructions (e.g., see www.ahdl.msu.edu for the Diagnostic Laboratory of Michigan State University).
Treatment
Acute Hypoadrenocorticism
This is a medical emergency requiring immediate intervention.
• Following stabilization of the acute addisonian crisis, institute long-term mineralocorticoid and glucocorticoid replacement therapy as described for treatment of chronic hypoadrenocorticism.
Hypovolemia and Hyponatremia
• Infuse 0.9% NaCl solution at a dosage of 60 to 80 ml/kg/hr IV over the first 1 to 2 hours, then gradually reduce the rate to the maintenance requirement, depending on patient response. Monitor urine output. Administer a colloid if necessary to address the hypovolemia and hypotension (uncommon).
• Administer dexamethasone sodium phosphate, 2 to 4 mg/kg IV, or prednisolone sodium succinate, 15 to 20 mg/kg IV. Repeat in 2 to 6 hours as needed. Glucocorticoid supplementation is gradually tapered to a maintenance dose of prednisone (0.2 mg/kg/day) over the following 3 to 5 days as the patient’s condition improves.
Hyperkalemia
• Hyperkalemia associated with hypoadrenocorticism can often be successfully treated with parenteral fluid therapy (0.9% NaCl solution) only.
• For severe hyperkalemia causing life-threatening bradyarrhythmias and sinoatrial standstill, more aggressive therapy is indicated. Administer short-acting insulin (e.g., regular insulin) and dextrose IV (first choice), sodium bicarbonate, or calcium salts.
Acidosis
• Treat severe acidosis (pH < 7.1) with serum bicarbonate. Give 25% of the calculated bicarbonate deficit over the first 6 to 8 hours of therapy if the serum bicarbonate concentration is <12 mEq/L. It is unusual for additional bicarbonate administration to be needed.
Chronic Hypoadrenocorticism
Mineralocorticoid Supplementation
Use one of the following treatment protocols:
• DOCP (Percorten-V, Novartis)
• DOCP is a long-acting injectable mineralocorticoid; give it initially at 2.2 mg/kg IM or SQ, every 4 weeks. A dosage interval of 3 to 4 weeks is effective in most cases.
• Percorten-V is approved by the Food and Drug Administration (FDA) for treatment of primary hypoadrenocorticism in dogs.
• Monitor serum electrolytes, blood urea nitrogen (BUN), and creatinine every 1 to 2 weeks until stabilized in the normal range to ensure an appropriate dose and duration of action; reevaluate every 3 to 6 months during long-term therapy.
• Less than 10% of dogs require a dose greater than 2.2 mg/kg. Dose less than 2.2 mg/kg may be sufficient in some cases. If financial constraints are present, gradually reduce to the lowest effective dose while monitoring serum electrolyte concentrations.
• Fludrocortisone acetate (Florinef, Squibb)
• Monitor serum electrolytes, BUN, and creatinine every 1 to 2 weeks until stabilized in the normal range, then reevaluate every 3 to 4 months.
• Average dose to control the disease is 0.02 to 0.03 mg/kg/day; very few animals can be controlled on less than 0.01 mg/kg/day.
HYPERADRENOCORTICISM IN DOGS
Etiology
Signalment
• Age: Spontaneous hyperadrenocorticism is primarily a disease of middle-aged to older dogs but can be seen in dogs ranging from 6 months to 20 years of age.
• Breed: All breeds can be affected. Poodles, dachshunds, Boston terriers, and boxers appear to be at greater risk of developing pituitary-dependent hyperadrenocorticism. Adrenal tumors are more common in larger dogs (>20 kg).
Clinical Signs
Urinary and Reproductive Systems
• Polyuria and polydipsia are seen in up to 90% of dogs with hyperadrenocorticism. Glucocorticoids decrease the renal tubular reabsorption of water by increasing the glomerular filtration rate and renal blood flow and by inhibiting the action of antidiuretic hormone (ADH) at the tubular level.
• Urinary tract infection can occur secondary to the immunosuppressive effects of cortisol excess. The typical signs of pollakiuria, hematuria, and stranguria may be minimal in some dogs as a result of the anti-inflammatory action of cortisol.
Respiratory System
• Excessive panting is quite common and is attributed to decreased pulmonary compliance, respiratory muscle weakness, pulmonary hypertension, or the direct effects of cortisol on the respiratory center.
Endocrine System
• Some dogs with hyperadrenocorticism develop diabetes mellitus and the associated clinical signs of polyuria, polydipsia, weight loss, and polyphagia.
• The hallmark of steroid-induced diabetes is the development of insulin resistance, defined clinically as persistent hyperglycemia despite insulin doses of >2.5 U/kg per injection.
• Cortisol antagonizes the actions of insulin by interfering with its action at the cellular level (receptor and postreceptor effects).
Central Nervous System and Neuromuscular System
• Lethargy is the most common central nervous system (CNS) disturbance. Lethargy may be associated with high concentrations of ACTH or the effects of excessive cortisol on cerebral enzymes and on neurotransmitter synthesis.
• CNS signs of circling, seizures, behavior change, and depression to obtundation may be caused by the local compressive effects of a large, expanding pituitary tumor.
Diagnosis
Physical Examination
Perform a careful examination to determine the clinical signs listed on the previous page.
Routine Laboratory Testing
• Up to 80% of dogs with hyperadrenocorticism have high serum alkaline phosphatase activity, composed primarily of the steroid-induced isoenzyme.
• Increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations are common.
• Mild hyperglycemia is common. Overt diabetes mellitus (glucose >250 mg/dl) occurs in up to 10% of dogs with untreated hyperadrenocorticism.
Radiography
• Approximately one-third of adrenal tumors are mineralized and, therefore, detectable on abdominal radiographs.
Ultrasonography
• Bilateral adrenomegaly is found in most dogs with pituitary-dependent hyperadrenocorticism. The maximal adrenal diameter (thickness) is considered the best indicator of adrenal size (reference value for healthy dogs <7.4 mm); however, this lacks sensitivity and specificity as a definitive test because of overlap in adrenal size among healthy dogs, dogs with non-adrenal disease, and dogs with pituitary-dependent hyperadrenocorticism.
• An adrenal mass is usually readily identified in dogs with adrenal neoplasia. The contralateral adrenal is atrophied and unlikely to be found. Bilateral adrenal tumors are very rare.
Computed Tomography and Magnetic Resonance Imaging
• Pituitary tumors >1 cm in diameter (macroadenomas or macroadenocarcinomas) are relatively easy to define with these imaging techniques.
• Pituitary microadenomas may be identified if they are ideally positioned or approach 1 cm in diameter. magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT) for imaging pituitary microadenomas.
Pituitary-Adrenal Function Tests
Adrenocorticotropic Hormone Stimulation Test
• Intravenous procedure
• Obtain a serum sample for cortisol determination before and 1 hour after IV injection of 5 μg/kg of the synthetic ACTH, cosyntropin (Cortrosyn, Amstar). Once reconstituted, the solution appears to be stable for at least 4 weeks if refrigerated. Alternatively, the remaining solution can be aliquoted and frozen. This method is recommended. Availability and backorder issues, however, may preclude use of this product.
• Intramuscular procedure
• Obtain a serum sample for cortisol analysis before and 2 hours after IM injection of 2.2 U/kg ACTH gel. Acthar Gel (80 U/ml, Questcor Pharmaceuticals) is available but is very expensive. ACTH gel (usually 40 U/ml) is available from various compounding pharmacies. The bioavailability and reproducibility of these various formulations has not been stringently evaluated. Therefore, it may be prudent to assess the activity of each new vial by performing an ACTH stimulation test on a normal dog.
• Interpretation
• Of the dogs with pituitary-dependent hyperadrenocorticism, 75% to 90% demonstrate an exaggerated cortisol response to exogenous ACTH. A post-ACTH cortisol concentration of more than 20 μg/dl (550 nmol/L) is consistent with hyperadrenocorticism.
• Approximately 50% of dogs with adrenocortical tumors show an exaggerated cortisol response, whereas the remainder have a normal response. Some dogs with adrenal carcinoma have extremely high post-ACTH cortisol concentrations (>50 μg/dl or >1500 nmol/L).
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