Adrenal insufficiency in children
Introduction
Adrenal insufficiency is an uncommon but potentially serious condition. It can occur at any age, and the diagnosis may be obvious in some cases and subtle in others. Adrenal insufficiency may be an isolated problem or part of a more complex syndrome. It may present as a new finding or a complication of stress in a patient already receiving adrenal replacement therapy. In addition, patients who have discontinued high dose glucocorticoid therapy may have transient cortisol deficiency.
Primary adrenal insufficiency results from lack of both glucocorticoid (cortisol) and mineralocorticoid (aldosterone), due to disease intrinsic to the adrenal cortex. Central adrenal insufficiency is due to lack of adrenocorticotrophic hormone (ACTH) stimulation of an otherwise normal gland and involves lack of cortisol but normal aldosterone secretion.
Causes and clinical findings
 Primary adrenal insufficiency: Clinical findings in children with chronic primary adrenal insufficiency may be vague and can be categorized based on the specific hormones affected. (See Table 1.) It should be noted that adrenal androgen deficiency is manifested only in pubertal and postpubertal females, as the adrenals contribute very little to androgen production in males. Adrenal crisis results from marked adrenal insufficiency. In children, the predominant clinical features include hypotension leading to shock and classic electrolyte abnormalities. In addition, if the adrenal problem has been unrecognized, hyperpigmentation may be present. (See Table 2.) To minimize morbidity and mortality, prompt recognition and treatment of adrenal crisis is critical.
Adrenal crisis should be considered in the ill neonate, where it often goes unrecognized. It presents within the first few days to weeks of life with vomiting, lethargy and feeding difficulties. Congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency is the most common cause1, 2, although other forms of CAH as well as adrenal hypoplasia congenita and bilateral adrenal hemorrhage may be the cause. In girls, CAH is suggested by the presence of ambiguous genitalia. The etiology of primary adrenal insufficiency is classified based on pathophysiology. (See Table 3.) The major categories, in order of frequency, include steroidogenesis disorders (CAH, almost always 21-hydroxylase deficiency), adrenal damage (usually autoimmune, but sometimes infectious such as TB or HIV, or hemorrhage), peroxisomal disorders (ALD) and abnormal adrenal development1.
Central adrenal insufficiency: The signs and symptoms of secondary and tertiary adrenal insufficiency are caused by cortisol deficiency. (See Table 1, glucocorticoid deficiency.) Hypoglycemia is often the presenting symptom in infants. Aldosterone deficiency and thus salt loss is not seen, as the renin-angiotensin-aldosterone axis remains intact. There may be clinical manifestations of a pituitary or hypothalamic tumor (such as headache and visual field defects) or symptoms from other anterior pituitary hormone deficiencies.
Causes of central adrenal insufficiency (ACTH deficiency) may be congenital or acquired. (See Table 4.) The most common causes in pediatric practice are congenital hypopituitarism (defects in development of the pituitary gland, often associated with midline defects) or secondary to a brain lesion. In these situations there almost always is a combined pituitary hormone deficiency with lack of growth hormone, thyroid stimulating hormone and/or gonadotropins, and occasionally diabetes insipidus (posterior pituitary vasopressin deficiency).
Isolated ACTH deficiency is rare. (See Table 4.) The most common cause is transient ACTH deficiency after withdrawal of high-dose corticosteroid exposure.
Exogenous glucocorticoid therapy at pharmacologic (not replacement) doses for more than one month suppresses the hypothalamic-pituitary-adrenal axis. Withdrawal of glucocorticoids may cause symptoms of adrenal insufficiency due to an inadequate adrenal response, especially during periods of stress (such as surgery, major trauma or infection). Recovery of adrenal function occurs within six weeks in about half of the patients and within six months for almost all patients3. During this time period, exogenous glucocorticoid therapy should be given for stressful events. Although adrenal suppression is principally associated with oral or injected corticosteroids, it also can occur after the cessation of nasal spray, eyedrops, inhaled steroids4, or skin creams or lotions5. Prolonged maternal high dose glucocorticoid therapy, especially with dexamethasone, may suppress the fetal hypothalamic-pituitary-adrenal axis.
Diagnosis
Figure 1 outlines a diagnostic approach to patients with suspected adrenal insufficiency. After initial hormone levels and electrolytes are determined, stimulation tests may be used to evaluate adrenal response to ACTH (rapid IV ACTH stimulation test) and ACTH secretory ability (insulin-induced hypoglycemia, glucagon or metyrapone).
Additional testing is performed as needed to establish the disease underlying the adrenal insufficiency. In primary adrenal insufficiency, one may need to screen for other autoimmune endocrinopathies or for CAH. In central adrenal insufficiency or ACTH deficiency, other pituitary hormones may need to be assessed.
Treatment
Maintenance therapy
Glucocorticoids – Hydrocortisone is used for most infants and children because of its shorter duration of action and lower potency, allowing for titration to the optimal dose. Based on the estimates of the normal cortisol secretion rate, daily oral replacement dose is about 15-25 mg/m2/24 h administered every eight hours. In general, patients with central adrenal insufficiency require lower doses than those with primary adrenal insufficiency. Prednisolone or prednisone may be used, but they are about five times more potent than hydrocortisone (daily dose 3 to 5 mg/m2/24 h). They can be administered every 12 hours. Other more potent preparations, such as dexamethasone, are not often used for replacement therapy except in adults. (See Tables 5 and 6.) The glucocorticoid dose will need to be increased with a child's growth. Close follow-up of somatic growth (weight, bone age, and height and weight velocities) provide important guidelines for dose adjustments.
Mineralocorticoids – Patients with primary adrenal failure require mineralocorticoid replacement with 9-alpha-fluorocortisol. The usual daily dose is 0.1 mg, however higher doses are occasionally needed in infants or in patients treated with glucocorticoids that have little or no mineralocorticoid activity such as prednisolone, prednisone and dexamethasone. (See Table 6.) Infants younger than 1 year old may require sodium chloride supplementation at a dose of approximately 1 gram daily.
Stress therapy
Illnesses – Normal subjects increase their cortisol secretion with stress such as fever, illness, anesthesia, surgery and trauma. Patients with primary or central adrenal insufficiency therefore require higher doses of glucocorticoids when under such stresses. During conditions of moderate stress (severe upper respiratory infections), the dose should be double the glucocorticoid replacement dose. In major stress (such as temperature above 38° C and/or vomiting), the hydrocortisone dose should be increased to three to four times the normal replacement. Under stress conditions, infants and children frequently are unable to tolerate oral therapy. In such cases, parents often are advised to administer an intramuscular injection of hydrocortisone sodium succinate (SoluCortef®). Every patient should wear medical alert identification that indicates the diagnosis adrenal insufficiency.
Surgical procedures – Patients should receive an IV injection of SoluCortef at the induction of anesthesia. If the procedure lasts longer than 30 to 45 minutes, a continuous infusion of SoluCortef should follow and be maintained until the patient can return to oral therapy.
Adrenal crisis – The rapid recognition and prompt therapy of a salt-losing crisis are critical to survival. Electrolyte and fluid therapy must be instituted as soon as possible. The predominant manifestation of adrenal crisis is hypotension and shock, usually with hyponatremia and hyperkalemia due to mineralocorticoid deficiency. After obtaining blood samples to assess adrenal function, IV fluid (usually D5 NS without potassium) is given. Prompt treatment with IV SoluCortef is given at stress doses. It may be necessary to use specific treatment of the hyperkalemia if it is associated with EKG changes.
References
1. Perry R, Kecha O, Paquette J, et al. "Primary adrenal insufficiency in children: Twenty years experience at the Sainte-Justine Hospital, Montreal." J Clin Endocrinol Metab, 2005; 90:3243.
2. "Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology." J Clin Endocrinol Metab, 2002; 87:4048.
3. Donohoue PA. "The adrenal gland and its disorders." Principles and Practice of Pediatric Endocrinology, Kappy MS, Allen DB, Geffner ME, eds. Charles C. Thomas, Springfield, IL, 2005, p. 404.
4. Russell G. "Inhaled corticosteroids and adrenal insufficiency." Arch Dis Child, 2002; 87:455.
5. Levin C, Maibach HI. "Topical corticosteroid-induced adrenocortical insufficiency: Clinical implications." Am J Clin Dermatol, 2002; 3:141.
 Patricia Donohoue, MD, is a pediatric endocrinologist and program director of Endocrine at Children's Hospital of Wisconsin. She also is a professor and chief of Pediatrics (Endocrinology) at the Medical College of Wisconsin and a member of Children's Specialty Group.
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