Causes of Adrenal Insufficiency
Chronic glucocorticoid therapy is the most common cause of adrenal insufficiency you will encounter in clinical practice, affecting approximately 7 in 1,000 people on long-term corticosteroids—roughly 100 times more prevalent than intrinsic adrenal disease. 1, 2, 3
Primary Adrenal Insufficiency (Adrenal Gland Failure)
Primary adrenal insufficiency results from direct destruction or dysfunction of the adrenal cortex, causing deficiency of all adrenocortical hormones—glucocorticoids, mineralocorticoids, and androgens. 1
Most Common Causes in Adults:
- Autoimmune adrenalitis (Addison's disease) accounts for approximately 85% of cases in Western Europe, confirmed by positive 21-hydroxylase autoantibodies. 2
- Infectious causes including tuberculosis and fungal infections. 3
- Pharmacological inhibition from high-dose azole antifungal therapy. 3
- Surgical removal of adrenal cortical tissue. 3
Most Common Causes in Children:
- Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the leading cause, occurring in 1 in 10,000-15,000 live births and accounting for approximately 70% of pediatric cases. 2, 4
Secondary Adrenal Insufficiency (Pituitary/Hypothalamic Failure)
Secondary adrenal insufficiency results from ACTH deficiency due to pituitary pathology, or CRH deficiency from hypothalamic disease. Crucially, aldosterone production remains intact because the renin-angiotensin system is preserved. 1, 2
Major Causes:
- Pituitary tumors and their treatment (surgery, radiation). 3, 5
- Pituitary hemorrhage or infarction. 3, 5
- Infiltrative conditions including hypophysitis, sarcoidosis, and hemochromatosis. 3, 5
- Medications suppressing ACTH production, particularly opioids. 3
- Congenital causes in children including developmental disorders of the hypothalamus and pituitary, or combined pituitary hormone deficiencies from transcription factor mutations. 2, 4
Tertiary/Iatrogenic Adrenal Insufficiency (Exogenous Glucocorticoid-Induced)
This is the single most common form of adrenal insufficiency overall and the type you will most frequently encounter. 1, 2, 3
Critical Threshold for HPA Axis Suppression:
- Adults: Prednisolone ≥5 mg daily (or equivalent) for ≥1 month. 1
- Children: Hydrocortisone-equivalent dose of 10-15 mg/m² daily for ≥1 month. 1
All Routes of Administration Can Cause Suppression:
- Oral glucocorticoids. 1
- Inhaled corticosteroids (even at recommended doses, in a dose-dependent manner). 1, 6
- Topical corticosteroids. 1
- Intranasal corticosteroids. 1
- Intra-articular corticosteroid injections. 1
Clinical Significance and Mortality Risk
The stakes are high: mortality risk is 2.19-fold higher in men and 2.86-fold higher in women with adrenal insufficiency, with adrenal crisis occurring 6-8 times per 100 patient-years. 1, 2 Mortality from adrenal crisis itself occurs at approximately 0.5 per 100 patient-years. 1, 2, 7
Common Precipitants of Adrenal Crisis:
- Acute gastrointestinal illness (vomiting, diarrhea). 7
- Febrile infections. 1, 7
- Surgical procedures without adequate stress-dose coverage. 1, 7
- Medication errors or omissions during hospitalization. 1
Critical Pitfall to Avoid
Never delay treatment with intravenous hydrocortisone 100 mg and physiologic saline if acute adrenal crisis is suspected—there are no long-term adverse consequences of short-term glucocorticoid administration, but untreated crisis can be fatal. 1, 2, 7 If feasible, obtain blood samples for cortisol and ACTH before treatment, but do not postpone therapy while awaiting results. 7
Recognition Challenge:
The most commonly missed diagnosis is glucocorticoid-induced adrenal insufficiency in patients who have recently tapered or discontinued supraphysiological glucocorticoids. 3 Inhaled corticosteroids are particularly underrecognized as a cause because they were historically thought to be safe at recommended doses—this is incorrect. 1, 6