Snapshot A 25-year-old man presents to the clinic for an annual check-up. He is otherwise healthy and has no significant concerns. Basic laboratory studies demonstrate a sodium level of 129 mg/dL and potassium level of 5.9 mg/dL. A physical examination demonstrates hyperpigmentation of the oral mucosa. Review of systems were positive for generalized fatigue, 5-lbs unintentional weight loss, and some headaches. Introduction Clinical definition disorder characterized by the loss of adrenal gland function leading to the deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens can be either acute or chronic depending of the etiology Epidemiology demographics autoimmune causes (which accounts for 70-90% of cases in the U.S.) occur predominantly within the female population risk factors other autoimmune endocrinopathies Pathogenesis any process that damages the adrenal cortices and leads to a deficiency of aldosterone, catecholamines, and cortisol autoimmune adrenalitis (Addison disease) most common cause in the U.S. both humoral and cell-mediated immune mechanisms against the adrenal cortex a small percentage of patients may have polyglandular autoimmune syndrome infectious adrenalitis tuberculosis (most common cause in the developing world) disseminated fungal infections (e.g., histoplasmosis) HIV infection hemorrhagic infarction Waterhouse-Friderichsen syndrome associated with meningococcemia (Neisseria meningitidis) anticoagulant drug or heparin therapy (e.g., heparin-induced thrombocytopenia) metastatic disease commonly associated with lung, breast, and melanoma cancers Associated conditions approximately 1/2 of patients with autoimmune adrenal insufficiency have other autoimmune endocrine disorders (e.g., hypothyroidism) Presentation Symptoms fatigue weight loss nausea/vomiting abdominal pain muscle/joint pain salt craving adrenal crisis Physical exam skin and mucosal hyperpigmentation (if longstanding) due to increased production of proopiomelanocortin (POMC), a prohormone that is cleaved into ACTH and melanocyte-stimulating hormone (MSH) hypotension auricular-cartilage calcification vitiligo Imaging Computed tomography (CT) may demonstrate bilateral adrenal injury, hemorrhage, or infarction Studies Serum cortisol concentration (e.g., morning serum cortisol) best initial test low serum cortisol (e.g., < 5 ug/dL) strongly suggests adrenal insufficiency Plasma ACTH concentration best initial test but often not quickly available high plasma ACTH concentration with low serum cortisol suggests primary adrenal insufficiency ACTH stimulation test will have low response to ACTH stimulation Plasma aldosterone and renin levels will have low aldosterone and high renin levels Chemistry panel hyperkalemia hyponatremia Differential Secondary adrenal insufficiency distinguishing factors will not have hyperpigmentation on physical examination will have low levels of ACTH Treatment Glucocorticoid replacement therapy e.g., hydrocortisone or dexamethasone stress doses indicated at times of stress (e.g., surgery) significant adverse effects with chronic use (e.g., osteoporosis) Mineralcorticoid replacement therapy e.g., fludrocortisone prevents sodium loss, intravascular volume depletion, and hyperkalemia Androgen replacement therapy e.g., dehydroepiandrosterone (DHEA) appears to improve mood and psychological well-being adverse effects include hirsutism, acne, and increased sweating/odor Complications Adrenal crisis medical emergency managed with schedule IV glucocorticoid