Adrenal Insufficiency in Children

Background

• Adrenal insufficiency is a disorder resulting from the impaired production or action of glucocorticoids and/or mineralocorticoids normally synthesized by the adrenal cortex, and is characterized primarily by cortisol deficiency, with or without aldosterone deficiency.
• It is a potentially life-threatening condition because cortisol and aldosterone are central to energy, salt, and fluid homeostasis.
• Adrenal insufficiency can be caused by defects anywhere along the hypothalamic-pituitary-adrenal axis.
  • Primary adrenal insufficiency is due to impaired adrenal function, and is characterized by cortisol and/or aldosterone deficiency. Adrenal androgens may also be deficient.
  • Secondary adrenal insufficiency is due to inadequate pituitary secretion of adrenocorticotropic hormone (ACTH), and typically involves cortisol deficiency without aldosterone deficiency.
  • Tertiary adrenal insufficiency is due to inadequate hypothalamic secretion of corticotropin-releasing hormone (CRH) and consequent inadequate ACTH secretion.
• Common causes of adrenal insufficiency in children include congenital adrenal hyperplasia, other genetic disorders, autoimmune adrenalitis, and withdrawal of steroids after prolonged treatment.
• Adrenal insufficiency may present acutely with hypotension, shock, hypoglycemia, and/or electrolyte disturbances (adrenal crisis), or with insidious onset of nonspecific symptoms.

Evaluation

• Suspect adrenal insufficiency and perform diagnostic testing in children with otherwise unexplained volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, hypoglycemia, or chronic nonspecific symptoms such as fatigue, dizziness, or anorexia.
• Initial blood tests should include electrolytes, glucose, and pH.
• Measure basal and/or stimulated serum cortisol and plasma ACTH levels
  • Cortisol level during corticotropin stimulation test is generally preferred for diagnosis, but basal cortisol level is an option.
  • Low cortisol plus high ACTH suggests primary adrenal insufficiency. If not already done, perform corticotropin stimulation test to confirm diagnosis (Strong recommendation).
  • Low cortisol plus low or inappropriately normal ACTH suggests secondary or tertiary adrenal insufficiency.
• Measure aldosterone and renin levels to identify mineralocorticoid deficiency (Strong recommendation).
• Additional testing:
  • For suspected secondary or tertiary adrenal insufficiency, additional tests of hypothalamic-pituitary-adrenal axis function may be considered.
  • If etiology of primary or secondary/tertiary adrenal insufficiency is unclear, perform additional testing (for example blood tests for autoantibodies or other hormone deficiencies, imaging) to identify the underlying cause.

Management

• For severe adrenal insufficiency symptoms or adrenal crisis, give IV hydrocortisone immediately at appropriate stress dose prior to availability of diagnostic test results (Strong recommendation).
• For suspected acute adrenal insufficiency (adrenal crisis):
  • Give immediate hydrocortisone 50 mg/m² parenterally, followed by hydrocortisone 50-100 mg/m²/day by continuous IV or in divided doses every 6 hours (Strong recommendation).
  • Start appropriate fluid resuscitation (Strong recommendation).
  • Monitor for and correct hypoglycemia and hyperkalemia.
• Maintenance therapy:
  • Replacement therapy should be directed toward controlling symptoms at a dose that avoids adverse effects and allows adequate growth and pubertal development.
  • Provide glucocorticoid replacement therapy.
    • For primary adrenal insufficiency, consider hydrocortisone in 3-4 divided doses daily over other glucocorticoid therapies, and consider hydrocortisone 8 mg/m²/day orally as starting dose and adjust as needed (Weak recommendation).
    • For secondary and tertiary adrenal insufficiency, consider hydrocortisone 6-8 mg/m²/day orally and adjust as needed.
• In children with primary adrenal insufficiency and confirmed aldosterone deficiency, treatment should also include:
  • mineralocorticoid replacement therapy with fludrocortisone at starting dose 100 mcg/d orally (Strong recommendation)
  • sodium chloride supplementation in the newborn period and up to age 12 months (Strong recommendation)
• Stress dosing to prevent adrenal crisis:
  • Increasing glucocorticoid dosage in situations involving stressors known to increase cortisol requirements is useful to help prevent adrenal crisis.
  • Consider adjusting glucocorticoid dose based on illness severity or magnitude of stressor (Weak recommendation).
  • Options to consider may include doubling or tripling replacement dose and high-dose (50 mg/m²) parenteral hydrocortisone, depending on the specific stressor (Weak recommendation).
• Follow-up should include monitoring for symptoms or signs of over- and under-replacement of glucocorticoids and mineralocorticoids.