Adrenal Insufficiency

Primary adrenal insufficiency results in deficiencies of cortisol, aldosterone, and adrenal androgens, whereas central insufficiency causes only isolated cortisol deficiency. Autoimmune adrenalitis is the most common cause of primary adrenal insufficiency in the United States; exogenous glucocorticoid (GC) therapy is the most common cause of central/secondary adrenal insufficiency due to suppression of endogenous CRH and ACTH production. Patients treated with supraphysiologic GC for <3 weeks will not have suppression of the HPA axis, and GC tapering is not necessary. Patients with >3 weeks of GC therapy will require tapering to allow for recovery of the HPA axis. Chronic suppression (>1 year) of the HPA axis by exogenous GC therapy may eventually lead to atrophy of the zonae fasciculata and reticularis, which requires lifelong daily GC replacement therapy.

Diagnosis

The presentation of adrenal insufficiency may be acute or slowly progressive and should be suspected in patients with suggestive signs and symptoms and those at increased risk. Acute adrenal crisis (often presenting with shock) most commonly occurs in patients with primary adrenal insufficiency who have concurrent illness or stress, such as surgery or trauma, due to the loss of both GC and aldosterone production. Adrenal crisis is unlikely in patients with secondary insufficiency due to the intact renin-angiotensin system, although milder clinical findings of adrenal insufficiency may occur due to the inability to produce adequate GC under stressful situations. Following discontinuation of long-term GC therapy, patients are vulnerable for adrenal insufficiency for up to 1 year. Other settings associated with adrenal insufficiency include sepsis, autoimmune disease, adrenal hemorrhage/infarction, granulomatous disease (tuberculosis or sarcoidosis), AIDS, and, rarely, pituitary/hypothalamic disease (see Hypothalamic and Pituitary Disorders) (Table 1).

Unexplained weight loss, anorexia, weakness, nausea, abdominal pain, arthralgias, fatigue, and malaise should be observed in most patients with adrenal insufficiency. Orthostatic hypotension and salt craving can be prominent in primary insufficiency due to aldosterone deficiency leading to profound volume depletion. In secondary insufficiency, there may be a small decrease in blood pressure (BP) due to the loss of the slight vasoconstrictive effect of cortisol. Hyperpigmentation is often present in primary insufficiency due to elevated ACTH levels. Hyperkalemia, hyponatremia, and azotemia are often found in primary insufficiency, while hypoglycemia and eosinophilia may be present in both (Table 2).

Measuring a random or morning cortisol level will not detect insufficiency. A cosyntropin (ACTH) stimulation test establishes the diagnosis of adrenal insufficiency. Cortisol and ACTH values are obtained at baseline and at 30 and 60 minutes following administration of cosyntropin. A rise of serum cortisol by ≥18 µg/dL (496.6 nmol/L) rules out adrenal insufficiency. However, these values may not apply to critically ill patients who have low concentrations of albumin and cortisol-binding globulin due to the false lowering of the total cortisol level; in these patients, serum free cortisol concentrations should be measured.

To distinguish primary from secondary adrenal insufficiency, plasma ACTH and cortisol levels should be measured at 8 AM. In primary adrenal insufficiency, ACTH is elevated by >100 pg/mL (22 pmol/L), while ACTH is low or inappropriately normal in central adrenal insufficiency. A pituitary magnetic resonance imaging (MRI) scan should be obtained in secondary insufficiency, and other pituitary axes, such as thyroid and reproductive function, should be assessed.

Therapy

If acute adrenal crisis is suspected, serum ACTH and cortisol levels should be obtained immediately. While awaiting results, high-dose GC and large-volume intravenous saline should be given. Dexamethasone is the preferred GC therapy because it does not interfere with serum cortisol assays. For less critically ill patients, oral GC should be promptly administered for primary or secondary adrenal insufficiency; delay is potentially life threatening. Fludrocortisone is required in primary but not secondary insufficiency, but stress dosing is not required; in the acute phase, intravenous saline is required because several days of therapy are necessary for the effects of fludrocortisone to be seen. Mild stress (eg, fever or gastroenteritis) requires doubling or tripling of the daily GC dose, and severe illness requires hospitalization for high-dose intravenous GC therapy. Oral GC used for daily replacement therapy are prednisone, hydrocortisone, and dexamethasone (Table 3).

Follow-Up

Patients are advised to wear a medical alert bracelet indicating their diagnosis, and they need to understand and be able to articulate how to increase their GC dose during illness. Adequacy of GC replacement is assessed by looking for signs and symptoms of cortisol insufficiency (under-replacement), such as afternoon fatigue, weight loss, or malaise, or Cushing syndrome (over-replacement), such as weight gain, hyperglycemia, or hypertension. Adjustment of the replacement mineralocorticoid dose is based on the plasma renin activity (PRA) or the patient's symptoms. Patients experiencing lightheadedness upon standing or who are orthostatic on examination may need more fludrocortisone, whereas patients with peripheral edema or increased BP may need less. Mineralocorticoid replacement does not need to be increased for acute illness.