When Thomas Addison described the disease that now bears his name , bilateral adrenal destruction by tuberculosis was its most common cause. Now tuberculosis accounts for only 7 to 20 percent of cases; autoimmune disease is responsible for 70 to 90 percent, with the remainder being caused by other infectious diseases, replacement by metastatic cancer or lymphoma, adrenal hemorrhage or infarction, or drugs (table 1) [2-5]. Disseminated tuberculous or fungal infections are still a major cause of adrenal insufficiency in populations with a high prevalence of these diseases, but as tuberculosis has been better controlled, the overall incidence of Addison's disease has decreased . The prevalence of Addison's disease in Western countries has been estimated at 35 to 60 per million, but three studies indicate it may be as high as 144 per million [7-9].
This topic will review the major causes of primary adrenal insufficiency. Rarer causes are discussed separately. The rarer diseases, such as adrenal leukodystrophy/adrenal myeloneuropathy, are mostly inherited disorders that present in infancy or childhood. (See "Adrenoleukodystrophy" and "Unusual causes of adrenal insufficiency".)
Destruction of adrenal cortex — What long was termed "idiopathic" primary adrenal insufficiency is the result of an autoimmune process that destroys the adrenal cortex. There is evidence of both humoral and cell-mediated immune mechanisms directed at the adrenal cortex, often associated with autoimmune destruction of other endocrine glands (referred to as polyglandular autoimmune syndromes). Antibodies that react with several steroidogenic enzymes (most often 21-hydroxylase) and all three zones of the adrenal cortex are present in the serum of up to 86 percent of patients with autoimmune primary adrenal insufficiency (anti-21-OHase ), but only rarely in patients with other causes of adrenal insufficiency, or in normal subjects [9,10]. However, up to 10 percent of first-degree relatives of patients with autoimmune primary adrenal insufficiency express these antibodies and have an increased risk of developing adrenal insufficiency . (See "Pathogenesis of autoimmune adrenal insufficiency".)
Sex differences — Patients with autoimmune adrenal insufficiency as part of one of the polyglandular autoimmune syndromes are predominately female (70 percent). In contrast, patients with isolated autoimmune adrenal insufficiency are predominately male (71 percent) during the first two decades of life, are equally male and female in the third decade, and are predominately female (81 percent) thereafter . The explanation for these sex differences is unknown.
Early findings — The first evidence of autoimmune adrenal insufficiency is usually an increase in plasma renin activity in association with a normal or low serum aldosterone concentration, suggesting that the zona glomerulosa is involved initially [12,13]. Several months to years later, zona fasciculata dysfunction becomes evident, first by a decreasing serum cortisol response to corticotropin (ACTH) stimulation, later by increased basal serum ACTH concentrations, and finally by decreasing basal serum cortisol concentrations and symptoms [12,14].