Initiation of cortisol replacement therapy with a glucocorticoid (such as hydrocortisone) and mineralocorticoid (such as fludrocortisone) is the most appropriate next step in management. This patient has symptoms consistent with adrenal insufficiency (fatigue, unintentional weight loss, nausea, and vomiting); her family history of autoimmune disorders, hyperpigmentation noted on physical examination, and hyperkalemia on laboratory testing suggest primary adrenal failure. Patients with primary adrenal failure frequently have increased pigmentation over the extensor surfaces and buccal mucosa due to the excessive secretion of melanocyte-stimulating hormone, which shares a common precursor with adrenocorticotropic hormone (ACTH). Hyperkalemia occurs due to deficiency of aldosterone. The diagnosis of adrenal insufficiency is made by documenting an inappropriately low serum cortisol level. An early morning serum cortisol level that is less than 3 µg/dL (82.8 nmol/L) in the setting of signs and symptoms of cortisol deficiency is diagnostic of this disorder. Treatment should not be withheld while awaiting further diagnostic testing since adrenal insufficiency is a potentially life-threatening condition that may result in hemodynamic instability. Treatment of primary adrenal failure requires both glucocorticoid and mineralocorticoid replacement. Hydrocortisone or another long-acting agent with primarily glucocorticoid activity should be given along with a mineralocorticoid agent such as fludrocortisone.

The synthetic ACTH (cosyntropin) stimulation test is extremely sensitive for detecting either primary or secondary adrenal insufficiency. In patients with nondiagnostic basal cortisol values (4-12 µg/dL [110.4-331.2 nmol/L]), stimulation testing with synthetic ACTH is indicated. A normal response is a peak serum cortisol greater than 20 µg/dL (552 nmol/L). ACTH stimulation testing is not needed if the early morning serum cortisol level is unequivocally low, as in this patient.

Measurement of the plasma ACTH level is used to differentiate primary adrenal failure from other causes of low cortisol. In primary adrenal failure, the plasma ACTH level is typically significantly elevated (200 pg/mL [44 pmol/L]) and would confirm the diagnosis. However, withholding therapy while awaiting diagnostic confirmation would not be appropriate because of the potential life-threatening nature of primary adrenal failure.

Although prednisone is an acceptable agent for glucocorticoid replacement, it has almost pure glucocorticoid activity and would not be an appropriate single agent for treatment of primary adrenal failure in which replacement of both glucocorticoid and mineralocorticoid is required.