Addison's disease: pathophysiology, clinical presentation, and management

Addison's Disease

Etiology

Addison's disease is a chronic disorder of the adrenal cortex resulting in decreased production of glucocorticoids, mineralocorticoids, and androgens. There is increased secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland. Histologic examination of adrenal glands from patients with autoimmune adrenal insufficiency reveals fibrosis with a mononuclear cell infiltrate, plasma cells, and rare germinal centers. The most common cause of primary adrenal insufficiency in developed countries is autoimmunity (70% to 90%), with tuberculosis the second most common cause (10% to 20%). Addison disease can be present in 3 clinical forms: part of syndromes termed APS-1 and autoimmune polyendocrine syndrome type 2 (APS-2) and as an isolated disease. Adrenal autoantibodies are generally of the IgG class, and less frequently of the IgA and the IgM class. Antibodies directed against antigens other than P450 cytochrome enzymes have been found in some patients with isolated Addison's disease. Another study found antibodies of the IgG type directed against the ACTH receptor on adrenal cells, which blocked ACTH-induced cortisol secretion as well as ACTH-induced DNA synthesis in these cells. This was the case in 74% and 80% respec- tively, of the Addisonian patients studied, and was found in none of the healthy control subjects. This blocking effect was lost at higher titres of IgG concentration. This indicates that humoral immunity rather than cellular immunity is involved in Addison's disease.

Clinical Symptoms and Diagnosis

The diagnosis of Addison disease is made in symptomatic patients with high levels of ACTH and a deficiency of cortisol or when serum cortisol levels do not increase after an ACTH stimulation test in the presence of increased basal ACTH levels; 21-hydroxylase autoantibodies are usually (>90%) present. The clinical manifestations are subtle (weakness, fatigue, anorexia, orthostasis, nausea, myalgias, and salt craving), and a high index of suspicion is necessary to diagnose adrenal insufficiency before an adrenal crisis. Screening patients with type 1A diabetes, hypoparathyroidism, and polyendocrine autoimmunity for 21-hydroxylase autoantibodies is recommended. If present, yearly monitoring with an ACTH stimulation test is performed to allow early diagnosis and prevent an adrenal crisis. Forty percent to 50% of patients with Addison disease will have another autoimmune disease, necessitating lifelong monitoring for associated autoimmune conditions.

Treatment/Medications