Cynthia R. Ward, VMD, PhD, DACVIM (SAIM)
Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
The adrenal cortex consists of distinct zones that secrete different hormones based upon enzymes available in that region. The zonae glomerulosa is responsible for the secretion of mineralocorticoids, and the zonae fasciculate and reticularis secrete glucocorticoids. The primary mineralocorticoid and glucocorticoid secreted in the dog are aldosterone and cortisol, respectively. Aldosterone secretion is primarily stimulated by activation of the renin-angiotensin system and hyperkalemia with only a small role of ACTH during severe volume depletion. Cortisol secretion from the adrenal gland is primarily regulated by the hypothalamic-pituitary-adrenal (HPA) axis with ACTH providing the primary control.
Primary hypoadrenocorticism results from destruction of the adrenal cortex such that cortisol and aldosterone are not able to be synthesized or secreted. This results in the classic presentation of hypoadrenocorticism, with the animal being severely volume depleted with an array of electrolyte abnormalities including hyperkalemia, hyponatremia, hypochloridemia, and hypercalcemia.
The hallmark of primary hypoadrenocorticism is the low sodium:potassium ratio (less than 25–27). The test used to diagnose primary hypoadrenocorticism is an ACTH stimulation test in which cortisol is measured pre- and post-synthetic ACTH (Cortrosyn®) administration.
Secondary hypoadrenocorticism or atypical hypoadrenocorticism disease or glucocorticoid-deficient hypoadrenocorticism results from a lack of ACTH. In humans, mutations resulting in CRH and ACTH deficiencies have been reported; however, in dogs, secondary hypoadrenocorticism is thought to result from a lack of ACTH due to pituitary failure. The failure of ACTH secretion has its primary effect on the zonae fasciculata and reticularis and thus spares the zona glomerulosa and aldosterone secretion. These dogs will maintain mineralocorticoid activity, but will be glucocorticoid deficient. In most dogs, the HPA axis is only evaluated by cortisol (glucocorticoid) measurement. The mineralocorticoid activity is estimated by evaluating Na and K concentrations. It has been shown that some dogs with normal serum Na and K concentrations are actually deficient in aldosterone. Conversely, some dogs may be hyponatremic with only glucocorticoid deficiency. Therefore, the lines have been blurred between primary and secondary hypoadrenocorticism in the absence of routine mineralocorticoid measurement. In order to fully determine aldosterone activity, it should be measured directly both before and after stimulation by ACTH, remembering that pharmacologic doses of ACTH (such as Cortrosyn® doses used in a stimulation test) will stimulate aldosterone secretion.
So, what distinguishes full-blown hypoadrenocorticism and glucocorticoid-deficient hypoadrenocorticism? In the latter case, the dog will only be cortisol deficient and will maintain mineralocorticoid activity. Clinical signs relate to glucocorticoid deficiency and will often be centered on gastrointestinal problems to include: vomiting, diarrhea, melena, hematemesis, hematochezia, weight loss, and generalized weakness. As with a full-blown Addisonian, the clinical signs may wax and wane. The dogs are generally not polyuric and polydipsic since aldosterone concentrations are normal. Clinical pathology abnormalities may include a mild normocytic, nonregenerative anemia; reverse stress leukogram (lack of neutrophilia, eosinophilia, lymphocytosis); and hypoglycemia. If significant blood loss has occurred, the anemia may be severe. Sodium and potassium concentrations are generally normal.
Glucocorticoid-deficient hypoadrenocorticism should be diagnosed with an ACTH stimulation test. Cortisol and aldosterone should be measured since Na and K are only rough estimates of mineralocorticoid activity. If aldosterone levels are low or approaching the low end of the normal range, the dog should be monitored closely for emerging mineralocorticoid deficiency. Diagnosis of glucocorticoid deficiency is based on resting cortisol levels lower than the normal range without a significant increase after ACTH administration. Using resting cortisol levels of >2 mcg/dL to rule out glucocorticoid-deficient hypoadrenocorticism has not been examined experimentally.
Since mineralocorticoid activity is not affected, only glucocorticoids need to be supplemented. Dexamethasone-SP may be used in an acute situation at a dose of 0.05–0.1 mg/kg. Dexamethasone has the advantage of being parenteral and also will not be read in the cortisol assay used for the ACTH stimulation test. After stabilization, the dog may be transitioned to prednisone at 0.2–0.4 mg/kg once per day. Often dogs will need a dose increase during stress. The dose should be titrated to the lowest that will maintain good quality of life for the dog.
Glucocorticoid doses should be adjusted based on clinical signs. Sodium/potassium levels should be monitored so that conversion to mineralocorticoid deficiency will not be missed.