Primary adrenal insufficiency is due to failure of the adrenal gland, whereas secondary adrenal insufficiency is due to failure of ACTH production or release.
Addison's disease occurs when >90% of adrenal tissue is destroyed. The most common cause is autoimmune destruction (alone, or as part of type I or type II polyglandular autoimmune syndromes). Tuberculosis used to be the leading etiology. Other granulomatous diseases (histoplasmosis, coccidioidomycosis, cryptococcosis, sarcoidosis), bilateral adrenalectomy, bilateral tumor metastases, bilateral hemorrhage, CMV, HIV, amyloidosis, and congenital diseases (some types of congenital adrenal hypoplasia, adrenal hypoplasia congenita, and adrenoleukodystrophy) are additional etiologies.
Manifestations include fatigue, weakness, anorexia, nausea and vomiting, weight loss, abdominal pain, cutaneous and mucosal pigmentation, salt craving, hypotension (especially orthostatic), and, occasionally, hypoglycemia. Routine laboratory parameters may be normal, but typically serum Na is reduced and serum K increased. Extracellular fluid depletion accentuates hypotension. In secondary adrenal insufficiency, pigmentation is diminished and serum potassium is not elevated. Serum Na tends to be low because of hemodilution stemming from excess vasopressin secreted in the setting of cortisol deficiency.
The best screening test is the cortisol response 60 min after 250 µg ACTH (cosyntropin) IV or IM. Cortisol levels should exceed 18 µg/dL 30-60 min after the ACTH. If the response is abnormal, then primary and secondary deficiency may be distinguished by measurement of aldosterone from the same blood samples. In secondary, but not primary, adrenal insufficiency, the aldosterone increment from baseline will be normal (≥5 ng/dL). Furthermore, in primary adrenal insufficiency, plasma ACTH is elevated, whereas in secondary adrenal insufficiency, plasma ACTH values are low or inappropriately normal. Pts with recent onset or partial pituitary insufficiency may have a normal response to the rapid ACTH stimulation test. In these pts, alternative testing (metyrapone test or insulin tolerance testing) can be used for diagnosis.
| TREATMENT | ||
Addison's DiseaseHydrocortisone, at 15-25 mg/d divided into 2/3 in the morning and 1/3 in the afternoon, is the mainstay of glucocorticoid replacement. Some pts benefit from doses administered three times daily, and other glucocorticoids may be given at equivalent doses. Mineralocorticoid supplementation is usually needed for primary adrenal insufficiency, with administration of 0.05-0.1 mg fludrocortisone PO qd and maintenance of adequate Na intake. Doses should be titrated to normalize Na and K levels and to maintain normal blood pressure without postural changes. Measurement of plasma renin levels may also be useful in titrating the dose. Mineralocorticoid replacement is not needed in pts with secondary adrenal insufficiency. All pts with adrenal insufficiency should be instructed in the parenteral self-administration of steroids and should be registered with a medical alert system. During periods of intercurrent illness, the dose of hydrocortisone should be doubled. During adrenal crisis, high-dose hydrocortisone (10 mg/h continuous IV or 100-mg bolus IV three times a day) should be administered along with normal saline. Thereafter, if the pt is improving and is afebrile, the dose can be tapered by 20-30% daily to usual replacement doses. |
Isolated aldosterone deficiency accompanied by normal cortisol production occurs with hyporeninism, as an inherited aldosterone synthase deficiency, postoperatively following removal of aldosterone-secreting adenomas (transient), and during protracted heparin therapy. Hyporeninemic hypoaldosteronism is seen most commonly in adults with diabetes mellitus and mild renal failure; it is characterized by mild to moderate hyperkalemia. This is usually a benign condition that can be managed by observation. If needed, oral fludrocortisone (0.05-0.15 mg/d PO) restores electrolyte balance if salt intake is adequate. In pts with hypertension, mild renal insufficiency, or congestive heart failure, an alternative approach is to reduce salt intake and to administer furosemide.