Testing for Addison's disease

Testing for Addison's disease

Gender, age and breed are key determining factors in diagnosing hypoadrenocorticism
Jan 01, 2009

Dr. J. Catharine Scott-Moncrieff lectured at the 2008 American College of Veterinary Internal Medicine Forum on diagnostic testing for canine hypoadrenocorticism. Here are some relevant points from that lecture:

Hypoadrenocorticism, or Addison's disease, results from failure of the adrenal glands to secrete glucocorticoids (primarily cortisol) and mineralocorticoids (primarily aldosterone). Most cases of hypoadrenocorticism are from primary adrenal failure, resulting in deficiency of usually both cortisol and aldosterone from the adrenal cortex. Rarely, Addison's disease may be due to pituitary dysfunction, resulting in a failure of ACTH secretion and pure glucocorticoid deficiency (secondary adrenal failure). In secondary hypoadrenocorticism, mineralocorticoid secretion is expected to be normal.


Because most cases of hypoadrenocorticism either don't result in a necropsy or are successfully treated, the underlying cause usually is not known in individual animals. Primary adrenal failure is suspected to be immune-mediated in most cases. Other causes of primary hypoadrenocorticism include granulomatous destruction or hemorrhagic infarction of the adrenal gland, adrenalitis, neoplasia, amyloidosis and necrosis.

Immune-mediated destruction of the adrenal gland may occur together with other immune-mediated endocrine disorders, such as hypothyroidism, diabetes mellitus and hypoparathyroidism. Destructive lesions in the hypothalamus or pituitary from neoplasia, inflammation or trauma may cause secondary hypoadrenocorticism. Idiopathic ACTH deficiency also may occur.

Primary adrenal failure may be caused by a number of drugs, including mitotane, trilostane and ketoconazole. Adrenal suppression caused by ketoconazole and trilostane is reversible in most cases, but adrenal failure caused by mitotane may be permanent.

Administration of glucocorticoid drugs may cause secondary adrenal failure. After corticosteroid administration (topical, oral or injectable), suppression of ACTH production from the pituitary gland occurs within a few days, resulting in secondary adrenal atrophy. How long the adrenal axis is suppressed depends on the potency and half-life of the administered glucocorticoid. Long-acting depot drugs are the most potent adrenal suppressants and can cause suppression for five to six weeks or longer.


Seventy percent of dogs diagnosed with hypoadrenocorticism are female, and most are young to middle-aged (average being 4 to 5 years). The disease is heritable in the standard Poodle, Bearded Collie, Portuguese Water Dog and the Nova Scotia Duck Tolling Retriever. In these breeds, no obvious sex predisposition is evident. In the standard poodle, Portuguese Water Dog and Nova Scotia Duck Tolling Retriever, the disease appears to be inherited as an autosomal recessive trait. Incidence of hypoadrenocorticism in the Nova Scotia Duck Tolling Retriever is estimated to affect 1.4 percent of the population, while in the standard Poodle 8.6 percent in one study were affected.

History and physical exam

Clinical signs may be acute or gradual in onset, and they often wax and wane. Owners may not realize how long their dog has been ill until treatment results in a dramatic improvement in activity level. Because 85 percent to 90 percent of adrenal reserve must be depleted before clinical signs are observed, it may require a stressful event to trigger clinical illness. Clinical signs may be vague and rarely are pathognomonic. Anorexia, vomiting, lethargy/depression, weakness, weight loss, diarrhea, shaking/shivering, polyuria, polydipsia and abdominal pain may be observed. Most of these clinical signs can occur due to glucocorticoid deficiency alone.

If mineralocorticoids also are deficient, the clinical signs tend to be more severe, and polyuria, polydipsia, hypovolemic shock, collapse and dehydration often are present. Less common clinical signs include acute gastrointestinal hemorrhage and seizures due to hypoglycemia or electrolyte derangement. The physical examination may be normal or may reveal lethargy, weakness, dehydration, bradycardia, weak pulses, decreased capillary refill time and other evidence of hypovolemic shock.

Clinical pathology

Complete blood count may reveal a nonregenerative normocytic normochromic anemia, or the hematocrit may be increased due to dehydration. Eosinophilia, neutrophilia or lymphocytosis occurs in only 20 percent to 30 percent of dogs with hypoadrenocorticism, but lack of a stress leukogram in a dog with systemic illness is common.

A serum chemistry profile may reveal hyponatremia, hypochloremia, hyperkalemia, hypercalcemia and hyperphosphatemia. These changes occur due to aldosterone deficiency with a resultant failure of the kidneys to conserve sodium. This is accompanied by profound fluid loss, shift of potassium ions to the extracellular compartment, pre-renal azotemia due to decreased renal perfusion and hypovolemia. A mild to moderate metabolic acidosis also may occur because lack of aldosterone impairs renal tubular hydrogen ion secretion.

Other serum chemical abnormalities that may occur in dogs with hypoadrenocorticism include hypoalbuminemia, hypocholesterolemia, hypoglycemia and increased liver enzymes. Specific gravity of the urine is commonly less than 1.030 due to loss of the normal medullary concentration gradient and impaired water reabsorption by the renal collecting tubules. The changes on the minimum data base in dogs with hypoadrenocorticism may initially mimic other disorders such as renal failure, hepatic disease, gastrointestinal disease or insulinoma.

Serum electrolyte abnormalities

Most dogs with hypoadrenocorticism have the classic electrolyte changes of hyponatremia and hyperkalemia due to aldosterone deficiency. It is now recognized, however, that a subset of dogs with hypoadrenocorticism does not have the classic electrolyte changes typically observed in dogs with hypoadrenocorticism.

In a retrospective study of dogs with hypoadrenocorticism, 24 percent lacked hyponatremia and hyperkalemia. In a study of 25 Nova Scotia Duck Tolling Retrievers, 32 percent lacked electrolyte abnormalities at the time of diagnosis. Reasons for normal electrolytes include secondary hypoadrenocorticism from decreased ACTH secretion, selective destruction of the zona fasiculata and reticularis or early-stage disease in which there has not yet been complete destruction of the zona glomerulosa.

Dogs with glucocorticoid-deficient hypoadrenocorticism tend to be older, have a longer duration of clinical signs and are more likely to be anemic, hypoalbuminemic and hypocholesterolemic.

It is important to recognize that an absence of the characteristic electrolyte changes does not exclude a diagnosis of hypoadrenocorticism. Conversely, reliance on measurement of electrolytes alone for diagnosis of hypoadrenocorticism can be misleading, because there are many other causes of these electrolyte changes.