Short ACTH stimulation test for adrenal reserves of cortisol, not adrenal function

The classical description of Addison's disease in a 15-year-old girl1 is a timely reminder of this well-known but uncommon disorder. In their description of the investigative work-up and discussion, Chantelle Barnard and associates1 imply that the short adrenocorticotropin hormone (ACTH) stimulation test is diagnostic of primary adrenal insufficiency. This is a common misapprehension.

In the test, an intravenous (or intramuscular) injection of 250 μg of synthetic ACTH (tetracosactrin) results in release of preformed cortisol from adrenal stores, which is measured in the serum 30 (and/or 60) minutes later and compared with the baseline concentration. An abnormal response (a serum cortisol peak below 550 nmol/L or an increment of less than 200 nmol/L from baseline or both) identifies adrenal insufficiency but cannot distinguish Addison's disease (primary adrenal failure) from secondary hypo-adrenalism. In pituitary disease (ACTH deficiency), for instance, the result of the test may be abnormal because of reduced stores of cortisol, even though the adrenal glands themselves have normal biosynthetic and secretory function. In this situation, a prolonged ACTH stimulation test using 1 mg depot tetracosactrin, with serial measurements of serum cortisol concentrations over 24 hours, would allow sufficient time for the otherwise healthy adrenal glands to mount an adequate cortisol response, whereas the test result would be abnormal in Addison's disease (particularly in preclinical disease, in which the result of the shorter test may be normal).

As the authors correctly point out, the hyperpigmentation seen in Addison's disease reflects increased ACTH and melanocyte-stimulating hormone due to dysinhibition of the hypothalamic–pituitary axis, which is in turn a result of low circulating cortisol concentrations. This is a relatively specific sign, and there is therefore little doubt that the hypoadrenalism in the patient described was due to primary adrenal failure. However, an elevated plasma ACTH concentration at baseline reliably distinguishes between primary and secondary causes and would have provided incontrovertible evidence of Addison's disease,2 besides being far simpler than the prolonged ACTH stimulation test.