Pathophysiology

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Primary adrenal insufficiency, also known as Addison's disease, occurs when the adrenal glands are unable to produce cortisol. It occurs from destruction of the adrenal cortex, usually from an autoimmune process. In general, the clinical manifestations are observed when destruction of the cortex exceeds 90%4 Signs and symptoms of adrenal insufficiency reflect the disturbance of normal physiologic carbohydrate, fat, and protein homeostasis caused by inadequate cortisol production and inadequate cortisol action. Primary adrenal insufficiency usually develops gradually. Patients may remain asymptomatic in the early stages, with signs and symptoms present only during times of physiologic stress. Persistent signs and symptoms of hypocortisol-ism typically occur with disease progression. Additionally, primary adrenal insufficiency may be accompanied by a reduction in aldosterone and androgen production. See Clinical Presentation and Diagnosis of Chronic Adrenal Insufficiency and Clinical Presentation and Diagnosis of Acute Adrenal Insufficiency (Adrenal Crisis) text-boxes.

FIGURE 45-2. Adrenal steroid synthesis. The adrenal cortex consists of three histologically distinct zones: The zona glomerulosa, zona fasciculata, and an innermost layer called the zona reticularis. Each zone is responsible for production of different hormones. (17, 17-hydroxylase; 3B-HSD, 3j#-hy-droxysteroid dehydrogenase; 21, 21a-hydroxylase; 17, 20, 17, 20-lyase; 11B, ^-hydroxylase; AS, aldosterone synthase; DHEA, dehydroepiandrosterone; DHEA-S, sulfated form of dehydroepiandros-terone.)

FIGURE 45-2. Adrenal steroid synthesis. The adrenal cortex consists of three histologically distinct zones: The zona glomerulosa, zona fasciculata, and an innermost layer called the zona reticularis. Each zone is responsible for production of different hormones. (17, 17-hydroxylase; 3B-HSD, 3j#-hy-droxysteroid dehydrogenase; 21, 21a-hydroxylase; 17, 20, 17, 20-lyase; 11B, ^-hydroxylase; AS, aldosterone synthase; DHEA, dehydroepiandrosterone; DHEA-S, sulfated form of dehydroepiandros-terone.)

Secondary adrenal insufficiency occurs as a result of a pituitary gland dysfunction, whereby decreased production and secretion of ACTH leads to a decrease in cortisol synthesis. Tertiary adrenal insufficiency is a disorder of the hypothalamus that results in decreased production and release of CRH, which in turn decreases pituitary ACTH production and release. In contrast to Addison's disease (i.e., primary adrenal insufficiency), aldosterone production is unaffected in the secondary and tertiary forms of the disease. Chronic adrenal insufficiency often has a good prognosis if diagnosed early and treated appropriately.

Acute adrenal insufficiency (i.e., adrenal crisis) results from the body's inability to sufficiently increase endogenous cortisol during periods of excessive physiologic stress. Adrenal crisis can occur when patients with chronic adrenal insufficiency do not receive adequate glucocorticoid replacement during stressful conditions such as those experienced during surgery, infection, acute illness, invasive medical procedures, or trauma. Acute adrenal insufficiency can also result from bilateral adrenal infarction due to hemorrhage, embolus, sepsis, or adrenal vein thrombosis. Additionally, abrupt discontinuation or rapid tapering of glucocorticoids, given chronically in supraphysiologic doses, may lead to adrenal crisis. This condition results from prolonged suppression of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent adrenal gland atrophy and hypocortisolemia. Other drugs associated with adrenal insufficiency include those that inhibit production (e.g., ketoconazole) or increase metabolism (e.g., the cytochrome P-450 subfamily IIIA polypeptide 4 [CYP450 3A4] inducer rifampin) of cortisol.4 Regardless of etiology, patients experiencing an adrenal crisis require immediate glucocorticoid treatment because manifestations such as circulatory collapse can lead to life-threatening sequelae.

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