What causes adrenal insufficiency in adults and children?

Causes of Adrenal Insufficiency

Adrenal insufficiency has three major causes: exogenous glucocorticoid therapy (the most common, affecting 7 in 1,000 people), autoimmune destruction of the adrenal glands (primary adrenal insufficiency), and pituitary/hypothalamic disorders causing ACTH deficiency (secondary adrenal insufficiency). 1, 2

Tertiary Adrenal Insufficiency (Iatrogenic/Glucocorticoid-Induced) - Most Common

This is the most common cause encountered in clinical practice, occurring approximately 100 times more frequently than intrinsic adrenal or pituitary disease. 1, 2

• Any route of glucocorticoid administration can suppress the hypothalamic-pituitary-adrenal (HPA) axis: oral, inhaled, topical, intranasal, and intra-articular. 1, 3, 2

• Threshold doses that cause HPA suppression:

  • Adults: prednisolone ≥5 mg daily (or equivalent) for ≥1 month 1, 3
  • Children: hydrocortisone-equivalent dose of 10-15 mg/m² daily for ≥1 month 1

• Inhaled corticosteroids, previously considered safe, commonly cause HPA axis suppression in a dose-dependent manner, even at recommended doses. 1, 3, 2

• Common clinical scenarios include children receiving glucocorticoids for asthma, renal disease, inflammatory bowel disease, juvenile chronic arthritis, and Duchenne's muscular dystrophy. 1, 2

• Drug-induced secondary adrenocortical insufficiency may persist for months after discontinuation of therapy. 4

Primary Adrenal Insufficiency

Primary adrenal insufficiency results from destruction or dysfunction of the adrenal gland itself, causing deficiency of both cortisol AND aldosterone. 1, 2, 5

In Adults:

• Autoimmune adrenalitis (Addison's disease) is the most common cause in Western populations, accounting for approximately 85% of cases, characterized by autoantibodies. 2, 5, 6

• Other causes include:

  • Tuberculosis and fungal infections 5
  • Pharmacological inhibition (e.g., high-dose azole antifungal therapy) 5
  • Adrenal hemorrhage or infarction 7
  • Infiltrative diseases (e.g., sarcoidosis, hemochromatosis) 7
  • Surgical removal of adrenal cortical tissue 5

In Children:

• Congenital adrenal hyperplasia (particularly 21-hydroxylase deficiency) is the most common inherited cause, occurring in 1 in 15,000 live births. 1, 2, 7

• Other congenital causes include adrenal hypoplasia and genetic mutations affecting adrenal development. 7

• Primary adrenal insufficiency affects 1 in 8,000-10,000 children overall. 1

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency results from pituitary ACTH deficiency, causing cortisol deficiency but preserved aldosterone production (since the renin-angiotensin system remains intact). 1, 3, 2

In Adults:

• Pituitary tumors are the most frequent cause 6, 8

• Other causes include:

  • Pituitary hemorrhage (apoplexy) 5
  • Inflammatory or infiltrative conditions (hypophysitis, sarcoidosis, hemochromatosis) 5
  • Pituitary surgery or radiation therapy 5
  • Medications that suppress corticotropin production (e.g., opioids) 5, 9

In Children:

• Congenital causes include developmental disorders of the hypothalamus and pituitary, particularly mutations in essential transcription factors causing combined pituitary hormone deficiencies. 1, 2, 7

• Acquired causes include brain tumors and their treatment, affecting approximately 1 in 10,000 children. 1, 2

• ACTH-secreting pituitary adenomas (corticotroph adenomas) account for 55% of pituitary adenomas in children aged 0-11 years and 30% in those aged 12-17 years. 3

Clinical Significance and Mortality

• Patients with adrenal insufficiency face significantly elevated mortality risk: risk ratio 2.19 for men and 2.86 for women, primarily from cardiovascular, infectious, and malignant diseases. 1, 2

• Adrenal crises occur at 6-8 episodes per 100 patient-years, with 8.6% of patients reporting previous crises caused by inadequate glucocorticoid coverage during hospitalization or surgery. 1, 2

• Two patients died during adrenal crisis in a prospective 2-year follow-up study of 423 patients. 1

• Patients with comorbidities (asthma, diabetes) and those with mineralocorticoid or vasopressin dependency are more vulnerable to adrenal crisis. 1