Diseases of the Adrenal Gland

Chapter 33 Diseases of the Adrenal Gland

Peter P. Kintzer, Mark E. Peterson

HYPOADRENOCORTICISM IN DOGS AND CATS

Hypoadrenocorticism is an endocrinopathy characterized by a deficiency of glucocorticoid and/or mineralocorticoid secretion from the adrenal cortex. Spontaneous hypoadrenocorticism is uncommon in dogs and is rare in cats.

Etiology

Primary Adrenocortical Insufficiency

Primary adrenocortical insufficiency (Addison disease) is the result of atrophy or destruction of all layers of the adrenal cortex, usually resulting in glucocorticoid and mineralocorticoid deficiency. Potential causes include the following:

• Idiopathic (probably immune mediated).
• 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.
• Granulomatous (fungal) adrenalitis, neoplasia, hemorrhage (very rare).

Secondary Hypoadrenocorticism

Secondary hypoadrenocorticism is due to deficient pituitary adrenocorticotropic hormone (ACTH) secretion resulting in inadequate glucocorticoid production, while mineralocorticoid secretion is preserved. Potential causes include the following:

• Abrupt withdrawal of long-term and/or high-dose glucocorticoid administration
• Megestrol acetate (Ovaban, Schering Plough) therapy in cats
• Lesions of the hypothalamus or pituitary gland (e.g., tumors)
• Idiopathic ACTH deficiency (rare)

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.
• Sex: Female dogs are at an increased risk of developing naturally occurring primary hypoadrenocorticism (71% females in one study). No sex predilection has been reported in cats.

Clinical Signs

No historical or clinical finding or set of clinical signs is pathognomonic for hypoadrenocorticism, and most clinical signs occur frequently in various other more common disorders. The severity and duration of clinical signs vary greatly among patients. A high index of suspicion is needed to recognize some cases of hypoadrenocorticism.

Acute Hypoadrenocorticism

• History consistent with chronic hypoadrenocorticism preceding the acute addisonian crisis
• Weakness and depression progressing to collapse
• Slow capillary refill time, weak pulses progressing to hypovolemic shock
• Bradycardia and hypothermia
• Cardiac arrhythmias (secondary to electrolyte abnormalities, acidosis, azotemia, and poor perfusion)

Chronic Hypoadrenocorticism

• Anorexia, vomiting, and diarrhea.
• Muscle weakness, lethargy, and depression.
• Weight loss, dehydration, shaking, polydipsia, polyuria, melena, abdominal pain, and hair loss may be present.
• Waxing and waning course.
• Previous response of clinical signs to administration of fluids and/or glucocorticoids.
• Exacerbation of clinical signs associated with “stress.”

Diagnosis

History and Clinical Signs

A high index of suspicion is necessary because both history and clinical signs are nonspecific and seen with many other more common disorders such as the following:

• Gastrointestinal disorders
• Primary renal failure
• Other causes of acute collapse or episodic weakness (cardiovascular disease, neuromuscular disease, and metabolic disorders)

Hemogram

• Absolute eosinophilia and lymphocytosis are present in some cases.
• High hematocrit and total plasma protein may occur secondary to dehydration.
• Mild anemia is present in some cases.

Serum Biochemical and Electrolyte Abnormalities

Key Point

Hyperkalemia and hyponatremia are seen in the vast majority of animals with primary hypoadrenocorticism, but do not rely on these abnormalities for definitive diagnosis as they can also be seen in other more common diseases.

• 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.
• Secondary hypoadrenocorticism is usually associated with normal serum electrolyte concentrations, but hyponatremia can occur.
• 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.
• Hypoglycemia (rare) may occur secondary to decreased gluconeogenesis and glycogenolysis.
• Metabolic acidosis is not uncommon, especially in an addisonian crisis.

Urine-Specific Gravity

Urine-specific gravity is below 1.030 in over half of cases despite prerenal azotemia. This decreased urine-concentrating ability is probably due to medullary washout secondary to renal sodium wasting and decreased medullary blood flow.

Electrocardiographic Abnormalities

Electrocardiographic (ECG) changes are primarily attributable to hyperkalemia. Although electrocardiography can be of value in estimating the degree of hyperkalemia, these ECG abnormalities may correlate poorly with serum potassium concentrations because of the effects that other serum electrolyte abnormalities, metabolic acidosis, and impaired tissue perfusion have on the cardiac conduction system.

• Widening and flattening of P waves; increased duration of the PR interval
• Increased T wave amplitude
• Decreased amplitude and prolongation of QRS complexes
• Bradycardia
• Sinoatrial standstill (absence of P waves)
• Ventricular premature contractions, atrial fibrillation, and heart block

Radiographic Findings

• Microcardia, microhepatica, and hypoperfusion of lungs (as manifestations of hypovolemia)
• Megaesophagus (rare)

Adrenocorticotropic Hormone Stimulation Test

Definitive diagnosis of hypoadrenocorticism requires demonstration of inadequate adrenal reserve by use of the ACTH stimulation test. This test measures the relative “thickness” of the adrenal cortex.

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.
• In cats, obtain a plasma or serum sample for cortisol determination before and 1 and 2 hours after IM injection of 2.2 U/kg of ACTH gel.

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.
• Dexamethasone and desoxycorticosterone pivalate (DOCP) do not interfere with the cortisol assay (see “Treatment”); however, dexamethasone is a potent steroid and suppresses the pituitary-adrenal axis.

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

Key Point

Collect proper blood and urine samples and perform necessary diagnostic testing before instituting therapy.

The ACTH stimulation test (preferably using synthetic ACTH administered IV) can be performed simultaneously with initial therapy if dexamethasone is used for glucocorticoid replacement because it does not interfere with the cortisol assay. ACTH stimulation testing using ACTH gel should not be performed on dehydrated, hypovolemic, or hypotensive patients, since impaired absorption of the gel may result in erroneous results. Alternatively, testing can be performed after initial stabilization. If prednisone, prednisolone, or hydrocortisone is being administered, these are discontinued and the glucocorticoid supplementation is changed to dexamethasone for at least 24 hours before the ACTH stimulation test is done.

Acute Hypoadrenocorticism

This is a medical emergency requiring immediate intervention.

• Correct hypotension and hypovolemia.
• Improve vascular integrity.
• Provide an immediate source of rapid-acting glucocorticoid.
• Correct electrolyte imbalance and acidosis.
• 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.
• A rapid-acting parenteral mineralocorticoid formulation is no longer available. However, begin oral supplementation with fludrocortisone (Florinef, Squibb) immediately if the animal is not vomiting.

Acidosis

• Correct mild to moderate acidosis with parenteral fluid therapy (0.9% NaCl solution).
• 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.
• Correction of acidosis also drives extracellular potassium into cells, thereby reducing hyperkalemia.

Other Supportive Care as Needed

• Correct hypothermia.
• Treat symptomatic hypoglycemia with a slow IV bolus of 1.5 ml/kg of 50% dextrose and 2.5% to 5% dextrose added to the IV fluids if needed.

Chronic Hypoadrenocorticism

Animals with chronic disease generally do not require aggressive therapy; however, parenteral fluid therapy and parenteral glucocorticoid supplementation may initially be indicated in some cases. Dogs and cats with primary hypoadrenocorticism require lifelong glucocorticoid and mineralocorticoid replacement therapy and sometimes the addition of salt to the diet. Animals with documented secondary hypoadrenocorticism require glucocorticoid replacement only.

Hypovolemia

• Give 0.9% NaCl solution, 60 to 80 ml/kg/day IV, for initial correction of hypovolemia.
• Decrease fluid volume over 48 to 96 hours based on return of clinical and laboratory parameters to normal.

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.
• Side effects are rare.
• Fludrocortisone acetate (Florinef, Squibb)
• Give an initial dosage of 0.01 to 0.02 mg/kg/day PO.
• Monitor serum electrolytes, BUN, and creatinine every 1 to 2 weeks until stabilized in the normal range, then reevaluate every 3 to 4 months.
• Adjust dose by 0.05 to 0.1 mg/day based on serum electrolyte concentrations.
• 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.
• Side effects include polyuria, polydipsia, polyphagia, and weight gain.
• Development of side effects, relative resistance to the drug, or financial considerations may necessitate a change to DOCP.

Glucocorticoid Supplementation

Many patients require glucocorticoid supplementation in addition to mineralocorticoid therapy to prevent signs of glucocorticoid deficiency or to control persistent mild azotemia. Use one of the following:

• Prednisone or prednisolone, 0.2 mg/kg/day PO.
• Cortisone acetate, 1 mg/kg/day PO.
• Give 2- to 10-fold higher glucocorticoid doses for brief periods of stress, surgery, or illness.

Sodium Chloride Therapy

• NaCl, 1 to 5 g daily, may be beneficial in some patients to help normalize serum sodium concentration.
• NaCl supplementation may have a sparing effect on the required fludrocortisone dose needed occasionally in dogs.

HYPERADRENOCORTICISM IN DOGS

Spontaneous hyperadrenocorticism (Cushing’s syndrome) is a collection of clinical and biochemical abnormalities caused by chronic overproduction of cortisol by the adrenal cortices.

Etiology

Hyperadrenocorticism can be pituitary dependent, secondary to cortisol-secreting adrenocortical neoplasia, or iatrogenic.

Pituitary-Dependent Hyperadrenocorticism

This is the most common cause of naturally occurring hyperadrenocorticism in dogs, accounting for 85% to 90% of cases. The excessive secretion of ACTH from pituitary corticotroph hyperplasia, microadenoma, macroadenoma, or (very rarely) adenocarcinoma results in bilateral adrenocortical hyperplasia.

Cortisol-Secreting Adrenocortical Tumors

These tumors are responsible for approximately 10% to 15% of dogs with spontaneous Cushing’s syndrome. About half of adrenocortical tumors are benign and half are malignant.

Iatrogenic Hyperadrenocorticism

Excessive or prolonged administration of corticosteroids can cause iatrogenic hyperadrenocorticism.

• Clinical signs and physical examination findings are similar to those seen in the natural disease.
• Endogenous ACTH production is suppressed, resulting in atrophy of the adrenal cortices.

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).
• Sex: No sex predilection is seen in dogs with pituitary-dependent hyperadrenocorticism. In contrast, two-thirds of dogs with adrenal tumors are female.

Clinical Signs

Key Point

Dogs with hyperadrenocorticism usually develop clinical signs that reflect dysfunction of many organ systems, although in some dogs only one or a few clinical signs may predominate.

General Appearance

• Pendulous, distended, or “pot-bellied” abdomen
• Haircoat changes reflecting hair loss
• Muscle atrophy and weakness

Integument

• Hair loss ranging from a thinning of the coat to bilaterally symmetric alopecia
• Thin hypotonic skin susceptible to bruising
• Hyperpigmentation
• Seborrheic changes
• Secondary pyoderma and Malassezia dermatitis

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.
• Glomerulopathy and associated proteinuria may occur.
• Testicular atrophy and female infertility (anestrus) can occur secondary to low concentrations of pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) caused by negative feedback from high circulating cortisol concentrations.

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.
• Pulmonary thromboembolic disease, a rare complication of hyperadrenocorticism, can cause moderate to severe respiratory distress and sometimes is fatal.

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).
• Hypertension may occur.

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.
• Muscle weakness is quite common and results from muscle wasting secondary to the catabolic effects of glucocorticoid excess.

Gastrointestinal System

• Polyphagia is common.
• Hepatomegaly is often detected.
• Pancreatitis secondary to excess cortisol levels is occasionally seen.

Diagnosis

History

Common owner complaints include polyuria and polydipsia, polyphagia, hair loss, weight gain, lethargy, and weakness. Determine recent corticosteroid administration (including eye, ear, and topical preparations).

Physical Examination

Perform a careful examination to determine the clinical signs listed on the previous page.

Key Point

The most important diagnostic procedures for hyperadrenocorticism are a careful and complete history and physical examination.

Routine Laboratory Testing

• The hemogram may reveal a stress leukogram and mild erythrocytosis.
• Up to 80% of dogs with hyperadrenocorticism have high serum alkaline phosphatase activity, composed primarily of the steroid-induced isoenzyme.
• Elevated serum cholesterol concentration is common.
• 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.
• Urinalysis often reveals a low specific gravity (<1.020).
• Proteinuria is occasionally seen. A urine protein-to-creatinine ratio >3.0 is usually due to glomerular disease or urinary tract infection.

Radiography

• Hepatomegaly is common.
• Approximately one-third of adrenal tumors are mineralized and, therefore, detectable on abdominal radiographs.
• Mineralization of bronchial walls is an occasional incidental finding.
• Pulmonary metastasis is rarely detected in some dogs with adrenal carcinoma.

Ultrasonography

Ultrasonography is more sensitive than radiography for imaging the adrenal glands and is a recommended part of the workup of all dogs with hyperadrenocorticism. This is a very user-dependent technique.

• 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.
• In dogs with adrenal neoplasia, evaluate the liver for metastasis and the caudal vena cava for tumor thrombus.

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.
• CT and MRI are the most accurate and reliable methods for imaging the adrenal glands, followed by ultrasonography and then radiography. With CT or MRI, the location of the adrenal tumor and evidence of metastasis can be identified in most dogs.

Pituitary-Adrenal Function Tests

Basal Serum Cortisol Concentration

Basal serum (or plasma) cortisol concentrations cannot be used to diagnose hyperadrenocorticism because of significant overlap among dogs with hyperadrenocorticism, dogs with non-adrenal illness, and normal dogs.

Adrenocorticotropic Hormone Stimulation Test

This is an adrenal function test that measures the relative “thickness” of the adrenal cortex. Therefore, the ACTH stimulation test is the best test to differentiate spontaneous from iatrogenic hyperadrenocorticism.

• 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).
• Dogs with iatrogenic hyperadrenocorticism have a “blunted” or no response to ACTH administration.

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Aug 27, 2016 | Posted by in SMALL ANIMAL | Comments Off on Diseases of the Adrenal Gland

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