Background
In 1855, Thomas Addison first described adrenal insufficiency, which was subsequently named after him. The basis of Addison disease has dramatically changed since its initial description. Originally, the disease usually resulted from an infection of the adrenal gland; the most common infection was tuberculosis, which is still the predominant cause of Addison disease in developing countries. Currently, in developed countries, Addison disease most commonly results from nonspecific autoimmune destruction of the adrenal gland.
Pathophysiology
Adrenal insufficiency can manifest as a defect anywhere in the hypothalamic-pituitary-adrenal axis. Primary adrenal insufficiency is a result of destruction of the adrenal cortex. The zona glomerulosa, the outer layer of the adrenal gland, produces aldosterone. Cortisol is produced in both the zona fasciculata and the zona reticularis, the middle and innermost layers of the adrenal gland, respectively. Dehydroepiandrosterone is produced in the zona reticularis.
Clinical findings are noted after 90% of the adrenal cortex has been destroyed. Precipitating events are multifactorial and include autoimmune, infectious (eg, mycobacterial, fungal), neoplastic (eg, primary, metastatic), traumatic, iatrogenic (eg, surgery, medication), vascular (eg, hemorrhage, emboli, thrombus), and metabolic (eg, amyloidosis) events. With the destruction of the adrenal cortex, feedback inhibition of the hypothalamus and anterior pituitary gland is interrupted, and corticotropin is secreted continuously. Corticotropin and melanocyte-stimulating hormone (MSH) are both components of the same progenitor hormone. When corticotropin is cleaved from the prohormone, MSH is concurrently released. The increased MSH level results in a characteristic bronze hyperpigmentation. Hyperpigmentation is generally noted in primary adrenal insufficiency associated with increased levels of corticotropin and MSH.
Epidemiology
Frequency
United States
The reported incidence of Addison disease is 5 or 6 cases per million population per year, with a prevalence of 60-110 cases per million population.
Mortality/Morbidity
The mortality rate for Addison disease is 1.4 deaths per million cases per year. This estimate is outdated because the incidence of tuberculosis-related Addison disease was greater when these data were compiled than it is now. A Swedish study reported that the relative rate of death in Addison disease patients was 2-fold higher than in background patients.[1] Malignancy, infectious diseases, and cardiovascular events were the responsible causes of this higher mortality rate. Diabetes mellitus was noted in 12% of this population, but it contributed only a small amount to the overall higher mortality rate.
Sex
The male-to-female ratio is 1:1.5-3.5.
Age
Addison disease can occur in persons of any age; however, it is most common in people aged 30-50 years. The expression of adrenal cortex antibodies (ACAs) in patients without symptoms of Addison disease represents a significant risk of progression to adrenal insufficiency. The risk varies with age; children have a high risk of progression compared with adults, in whom the expression of ACAs represents a 30% risk of progression to Addison disease.
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