What are the causes of hypocortisolism (adrenal insufficiency) in adults and children?

Causes of Hypocortisolism (Adrenal Insufficiency)

Hypocortisolism is classified into three categories based on anatomic location: primary (adrenal gland pathology), secondary (pituitary dysfunction), and tertiary/iatrogenic (hypothalamic or exogenous glucocorticoid-induced suppression). 1

Primary Adrenal Insufficiency

Primary adrenal insufficiency results from direct adrenal gland pathology, causing deficiency of both cortisol and aldosterone. 1

In Adults:

• Autoimmune adrenalitis (Addison's disease) is the most common cause, accounting for approximately 85% of cases in Western Europe, confirmed by positive 21-hydroxylase autoantibodies (21OH-Ab). 2
• Infectious causes include tuberculosis, HIV-related infections, and fungal infections. 2, 3
• Infiltrative diseases such as metastatic cancer, sarcoidosis, and hemochromatosis. 3
• Adrenal hemorrhage or infarction from trauma or thrombotic events. 2, 3
• Pharmacological inhibition from high-dose azole antifungal therapy. 3
• Surgical adrenalectomy (bilateral). 3

In Children:

• Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common cause, occurring in 1 in 10,000-15,000 live births and accounting for approximately 70% of pediatric cases. 1, 4
• Adrenoleukodystrophy (ALD) is the most common non-CAH genetic cause in children. 4
• Familial glucocorticoid deficiency from mutations in MC2R or MRAP genes. 4, 5
• Adrenal hypoplasia congenita due to DAX-1 (NR0B1) gene mutations. 4, 5
• IMAGE syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia, genital abnormalities) from CDKN1C gain-of-function mutations. 5
• MIRAGE syndrome from SAMD9 mutations. 5
• Triple A syndrome (Allgrove syndrome). 4
• Nonclassic forms of STAR and CYP11A1 deficiency presenting with delayed-onset adrenal insufficiency. 5
• Sphingosine-1-phosphate lyase-1 (SGPL1) deficiency, a newly recognized sphingolipidosis. 5

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency results from ACTH deficiency due to pituitary pathology, with preserved aldosterone production. 1

Causes:

• Pituitary tumors (adenomas, craniopharyngiomas). 3
• Pituitary hemorrhage or infarction (Sheehan syndrome, apoplexy). 3
• Inflammatory/infiltrative conditions including hypophysitis, sarcoidosis, and hemochromatosis. 3
• Pituitary surgery or radiation therapy. 3
• Medications suppressing ACTH such as chronic opioid therapy. 3
• Congenital causes in children including developmental disorders of the hypothalamus and pituitary, or combined pituitary hormone deficiencies from transcription factor mutations. 1, 6
• Brain tumors and their treatment in children. 1

Tertiary/Iatrogenic Adrenal Insufficiency

Glucocorticoid-induced adrenal insufficiency is the most common form overall, affecting approximately 7 in 1,000 people prescribed long-term oral corticosteroids—roughly 100 times more prevalent than intrinsic adrenal disease. 1, 3

Causes:

• Exogenous glucocorticoid therapy via any route: oral, inhaled, topical, intranasal, or intra-articular administration. 1
• Inhaled corticosteroids commonly suppress the HPA axis even at recommended doses in a dose-dependent manner. 1
• Abrupt withdrawal of supraphysiological glucocorticoid doses. 3

Common Pediatric Conditions Requiring Glucocorticoids:

Children receiving glucocorticoids for asthma, renal disease, juvenile chronic arthritis, inflammatory bowel disease, and Duchenne muscular dystrophy are at significant risk. 1

Critical Clinical Pitfall

Never delay treatment with intravenous hydrocortisone and physiologic saline if acute adrenal crisis is suspected, as mortality occurs in 0.5 per 100 patient-years, with adrenal crisis incidence of 6-8 events per 100 patient-years. 2, 7 The mortality risk is 2.19-fold higher in men and 2.86-fold higher in women with adrenal insufficiency. 1

Diagnostic Approach by Etiology

When evaluating a patient with confirmed adrenal insufficiency, measure 21-hydroxylase autoantibodies first in young females and adults to identify autoimmune etiology. 2 If negative, obtain CT imaging of the adrenals to identify structural abnormalities, tumors, calcifications, or hemorrhage. 2 In children with negative autoimmune workup, consider genetic testing for CAH, ALD, and other monogenic causes, as specific diagnosis has implications for monitoring associated features and family counseling. 4, 5