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Primary AI results from congenital or acquired adrenal gland dysfunction. Secondary and tertiary AI result from pituitary or hypothalamic underfunction, respectively. Glucocorticoid deficiency impairs gluconeogenesis and glycogenolysis, and decreases the sensitivity of the vascular system to angiotensin II and norepinephrine, resulting in hypoglycemia, tachycardia, and mild hypotension. Aldosterone deficiency causes decreased sodium retention by the kidney, osmotic diuresis, hyponatremia, hypovolemia, and dehydration. In addition, it causes a decreased distal renal tubular exchange of potassium and hydrogen ions for sodium ions, leading to hyperkalemia and acidosis. Androgen deficiency in primary AI leads to ambiguous genitalia and underdeveloped secondary sexual characteristics in prepubertal children. In addition, in primary AI, the lack of negative feedback from cortisol on the anterior pituitary causes oversecretion of ACTH and propiomelanocortin that in turn stimulate skin hyperpigmentation (Fig. 77-1).
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Etiology and Epidemiology
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One of the most common causes of AI in North America is the abrupt withdrawal of glucocorticoids while on chronic treatment.1 Children, who have been on glucocorticoid therapy for 2 to 4 weeks, tend to have prolonged suppression of the hypothalamopituitary axis leading to secondary AI after treatment is stopped.2 The most common cause of primary AI in children is CAH, with an incidence of 1 in 10,000 to 18,000 live births.3 In long-term studies of children with AI, most have primary AI and, of these, approximately 72% are found to have CAH.4,5
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CAH results from a deficiency in the enzymatic activity of one of the enzymes in the cortisol biosynthetic pathway, the commonest being 21-hydroxylase deficiency. Mortality for CAH is five times that of the general population. This has improved with the present recommendation for universal screening of newborns.6,7 Other rarer forms of congenital primary AI are congenital adrenal hypoplasia, adrenal aplasia or hemorrhage associated with a traumatic delivery,8 familial isolated glucocorticoid deficiency, the “triple A syndrome,” consisting of AI, alacrima, and achalasia of the esophagus, and adrenoleukodystrophy (ALD) (Table 77-1).
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Acquired causes of primary AI in children are less common than congenital disorders and result from autoimmune, infectious, infiltrative, hemorrhagic, or ablative disorders of the adrenal cortex. Granulomatous, degenerative, or storage diseases that involve the adrenal gland, such as tuberculosis, histoplasmosis, or lysosomal acid lipase deficiency (Wolman disease), also cause acquired primary AI. The most common cause of this is autoimmune adrenalitis, which accounts for 80% of all cases. Catecholamine resistant shock and low plasma cortisol levels may indicate acute AI in fulminating sepsis or meningococcemia.9–11
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Secondary AI that is not due to pharmacologic glucocorticoid withdrawal can result from any process that interferes with the pituitary's ability to secrete ACTH, such as tumors, craniopharyngioma, infections, infiltrative diseases of the pituitary, lymphocytic hypophysitis, head trauma, and intracranial aneurysms (Table 77-1). Most of these coexist with other pituitary hormone deficiencies and there is history of pituitary insult or abnormality of the hypothalamopituitary axis on MRI.12