Adrenal insufficiency is important to recognize because of its potentially life-threatening implications. Symptoms and signs of this disorder are varied and nonspecific. In infancy, these include lethargy, vomiting, poor appetite, and failure to thrive. Clinicians may mistake these problems for formula intolerance or inadequate lactation, or alternatively, primary infectious or gastrointestinal disorders. In older children, chronic fatigue, headache, gastrointestinal symptoms, salt craving and hyperpigmentation may be noted. Patients may undergo extensive evaluation before a diagnosis is made.

The adrenal glands, located at the upper pole of each kidney with a combined weight of 10 g in the adult, are composed of cortex and medulla. The adrenal cortex is the primary site of cortisol and aldosterone synthesis and a secondary site of sex hormone synthesis. The adrenal medulla is responsible for catecholamine synthesis, epinephrine, and norepinephrine, important in nervous system regulation. This section is restricted to discussion of adrenal cortical disease.

Glucocorticoids, such as cortisol, are essential for survi-val, mediating myriad developmental and physiologic processes. Some actions of cortisol include stimulating gluconeogenesis and glycogenolysis. By increasing cellular breakdown of sugars, protein, and fat, more substrate is provided for gluconeogenesis. Glucocorticoids also increase cellular resistance to insulin, thereby decreasing glucose uptake and use in peripheral tissues. The overall effect is to raise and maintain blood glucose levels, especially during stress (Pilkis & Granner, 1992). Thus, glucocorticoid deficiency may cause hypoglycemia.

Glucocorticoids also increase cardiac output and enhance vascular sensitivity to pressor hormones (Kelly, Mangos, Williamson, & Whitworth, 1998). Hence, glucocorticoid deficiency reduces cardiac output and may predispose the patient to heart failure and shock.

These problems are exacerbated by concomitant aldosterone deficiency. Aldosterone is essential for normal sodium homeostasis; deficiency of this hormone results in sodium loss through the kidney, colon, and sweat glands (Bonvalet, 1998).

Cortisol and aldosterone are synthesized from cholesterol in the adrenal cortex in several enzymatic steps (see Figure 47-1). Aldosterone synthesis differs from cortisol synthesis in that a specific 11β-hydroxylase isozyme (enzyme), termed aldosterone synthase, is used at the terminal step. Aldosterone synthesis is separately regulated, principally by the renin-angiotensin system. Cortisol synthesis is regulated primarily by pituitary adrenocorticotropic hormone (ACTH) and hypothalamic corticotropin-releasing hormone (CRH). Insufficient production of these tropic hormones or unresponsiveness to their actions results in select adrenocortical hormone deficiencies. Enzymatic blocks impairing cortisol synthesis or resistance to cortisol’s actions also presents as adrenal insufficiency (Speiser & White, 1998). Excessive ACTH secretion is a consequence of cortisol deficiency, causing both adrenal hyperplasia and hyperpigmentation. If aldosterone synthesis is blocked or if there is selective resistance to aldosterone action, sodium wasting and failure to thrive will result without complete adrenocortical insufficiency.

The exact overall incidence of adrenal insufficiency in childhood is unknown because of its multifactorial etiology. Secondary adrenal insufficiency due to pituitary failure is probably the most common cause and is a frequent cause of morbidity and mortality in children who have undergone treatment with cranial radiation, surgery, or exogenous glucocorticoids for extended periods. No data are available on
the prevalence and incidence of pituitary-induced adrenal failure. The epidemiology of classic CAH due to 21-hydroxylase deficiency (21-OHD) is approximately 1 in 10,000 to 1 in 15,000 live births (Pang & Shook, 1997). Primary adrenal insufficiency, Addison’s disease, is relatively rare in the pediatric population. The prevalence in Great Britain is 110 per million population of all ages, with more than 90% of cases attributed to autoimmune destruction of the adrenal cortex. A similar prevalence was found in Umbria, Italy (Laureti et al., 1999). The calculated incidence is approximately 5 to 6 per million population per year (Kong & Jeffcoate, 1994).

Physical examination can provide important clues that direct the clinician to appropriate laboratory diagnosis. In suspected adrenal insufficiency, as in the evaluation of any chronic childhood illness, careful review of linear growth and weight gain is critical to understanding the nature and chronicity of the problem.

This is a direct result of cosecretion of melanocyte-stimulating hormone with pro-opiomelanocortin, the precursor of ACTH. In the case of adrenal hemorrhage or tumor, a flank mass may be palpated on careful abdominal examination. Patients with global adrenocortical insufficiency chronically lacking adrenal androgens will often have sparse pubic and axillary hair. On the other hand, CAH patients produce excess androgens.

Relevant basic laboratory studies to confirm adrenal insufficiency include serum and urine electrolytes, glucose, early morning cortisol, ACTH, and plasma renin activity. One expects to find low serum (and high urine) sodium, high serum (and low urine) potassium with metabolic acidosis. There is an inappropriately low cortisol for the degree of ACTH elevation and high plasma renin activity. One should not attempt to restrict sodium intake in a patient with adrenal insufficiency, except under direct medical supervision, because this can provoke adrenal crisis. If central adrenal insufficiency is suspected, a low-dose cosyntropin stimulation test (1 μg intravenous [IV] bolus of ACTH 1-24) is the best way to assess the intactness of the HPA axis. Cortisol should rise after 30 to 60 minutes to a level greater than 15 to 20 μg/dL (Oelkers, 1996).

Classic, severely affected CAH patients usually have markedly elevated random basal serum 17-hydroxyprogesterones
in the range of greater than 10,000 to 20,000 ng/dL (New et al., 1983). Newborn screening programs are in effect in several states and rely primarily on filter paper determinations of blood 17-hydroxyprogesterone. The cost, sensitivity, specificity, and predictive values of these screening tests vary depending on the assay, the number of tests, and the established cut-off levels. Premature infants tend to have higher levels of 17-OHP than term infants and generate many false-positive results. Suggested weight-adjusted cut-offs range from 165 ng/mL in blood collected on filter paper for infants under 1300 g to 40 ng/mL for infants over 2200 g in Wisconsin (Allen et al., 1997); in Texas, cut-offs of 40 and 65 ng/mL are used for infants greater or less than 2500 g, respectively (Therrell et al., 1998). Because some radioimmunoassays cross-react with other steroids, positive screens should be confirmed. A more specific diagnostic test involving a complete profile of adrenocortical hormones before and 1 hour after high-dose cosyntropin stimulation (250 μg IV bolus) is obtained to distinguish CAH due to 21-hydroxylase deficiency from other forms of adrenal disease.

Radiographic imaging can be a helpful adjunct to biochemical testing in some types of adrenal insufficiency. Ultrasound is used in neonates with suspected adrenal hemorrhage; adrenal enlargement and inferior renal displacement may be detected. If done at 5-day intervals, ultrasound imaging may document changes in the lesion from solid to cystic to final calcification about a month later. Computed tomographic (CT) scan or magnetic resonance imaging is most sensitive for imaging adrenal pathology in older patients (Brant, 1999).

Prompt recognition of adrenal insufficiency is the key to a good outcome. Timely initiation of glucocorticoid replacement therapy is the most important factor.

Hydrocortisone has mineralocorticoid properties, and thus additional mineralocorticoid treatment is not immediately necessary. Drugs such as prednisone and dexamethasone do not possess significant mineralocorticoid activity and are not first-choice drugs for acute treatment (see Table 47-1). Because all patients in adrenal crisis and many with chronic adrenal insufficiency are dehydrated, isotonic fluid administration, in the form of a 20 mL/kg bolus of IV normal saline or lactated Ringer’s solution, is also required. Subsequent fluid replacement should be tailored to the individual patient’s needs, based on blood pressure, heart rate, mental status, and capillary refill.

Continued steroid treatment should be ordered for the acutely ill patient as IV hydrocortisone every 6 hours, at 3 mg/kg per day for the first 24 hours, representing a stress physiologic dose. Subsequently, the dose can be tapered until a reasonable maintenance dose is achieved. In children, the preferred maintenance cortisol replacement is hydrocortisone (which is the same as cortisol) in two or three divided doses totaling 0.3 mg/kg per day (or about 10 mg/m² per day), the basal physiologic dose. CAH patients often require higher doses of glucocorticoids, not to exceed 0.6 mg/kg per day (or about 20 mg/m² per day). A minimum dose of 6 mg/d of hydrocortisone (oral hydrocortisone cypionate, Cortef, suspension 10 mg/5 mL) in three divided doses is usually administered to infants with CAH.

The short half-life of hydrocortisone minimizes growth suppression and other adverse side effects of longer acting, more potent glucocorticoids, such as prednisone and dexamethasone. However, a single daily dose of a short-acting glucocorticoid is insufficient as replacement therapy and therefore a longer-acting steroid may be used in patients who cannot comply with a drug regimen requiring frequent dosing.

The following organizations provide information and support to patients and families with various adrenal disorders.