What are the etiologies of adrenal insufficiency in adults and how should they be evaluated?

Determining Etiology of Adrenal Insufficiency in Adults

Begin etiologic evaluation by measuring serum 21-hydroxylase (anti-adrenal) autoantibodies immediately after confirming the diagnosis, as autoimmunity is the most common cause in adults. 1

Algorithmic Approach to Etiologic Diagnosis

Step 1: Distinguish Primary from Secondary Adrenal Insufficiency

The initial diagnostic workup should have already established whether you're dealing with primary or secondary AI based on ACTH levels:

• Primary AI: Low cortisol + elevated ACTH (plus hyperkalemia, elevated renin, low aldosterone, low DHEAS)
• Secondary AI: Low cortisol + low or inappropriately normal ACTH 2

Step 2: For Primary Adrenal Insufficiency - Follow This Sequence

First-line test: Anti-21-hydroxylase antibodies 1

• If positive: Autoimmune adrenalitis confirmed (most common cause in adults, accounting for 82-144 per million prevalence) 2
• Screen for autoimmune polyendocrine syndromes:
  • Check for associated conditions: type 1 diabetes, autoimmune thyroid disease, vitiligo, pernicious anemia 1
  • In children/young adults with hypoparathyroidism or chronic mucocutaneous candidiasis, test for APS-1 using anti-interferon omega antibodies or AIRE gene mutation analysis 1

If antibodies are negative: Obtain adrenal CT imaging 1, 2

• Look for: bilateral adrenal calcifications (tuberculosis), hemorrhage, metastases, infiltrative disease, adrenal masses
• Tuberculosis and fungal infections remain important causes, particularly in endemic areas 3

In male patients specifically: Measure very long-chain fatty acids (VLCFA) 1, 2

• Essential to exclude adrenoleukodystrophy, particularly in young males
• This is a critical step that should not be omitted in the male population

Step 3: For Secondary Adrenal Insufficiency - Systematic Evaluation

First: Rule out iatrogenic causes 2

• Most common: Corticosteroid-induced suppression (prevalence 150-280 per million) 2
  • Any glucocorticoid formulation: oral, inhaled (especially fluticasone), topical, intra-articular 4
  • Duration >3 weeks increases risk 2
  • Recent cessation of glucocorticoid therapy is the most frequent cause 2
• Previous treatment for Cushing's syndrome
• Medications: opioids, checkpoint inhibitors, megestrol acetate 3

Second: Obtain pituitary MRI with contrast 2

• Evaluate for: pituitary adenomas, craniopharyngiomas, hemorrhage (Sheehan syndrome), infiltrative disease (sarcoidosis, hemochromatosis, hypophysitis)
• Assess other pituitary hormone axes for combined deficiencies

Third: Assess for hypothalamic pathology

• History of cranial radiation
• Infiltrative diseases
• Traumatic brain injury

Common Pitfalls to Avoid

1. Don't skip VLCFA testing in males - Adrenoleukodystrophy can present initially as isolated adrenal insufficiency before neurological symptoms develop 1

2. Don't assume negative antibodies rule out autoimmunity early in disease - Antibodies may become positive over time; consider repeat testing if clinical suspicion remains high

3. Don't forget drug-induced causes - Azole antifungals (especially high-dose ketoconazole), mitotane, etomidate, and drugs that increase cortisol metabolism (phenytoin, carbamazepine, rifampin) can cause or unmask AI 3

4. Don't overlook bilateral adrenal metastases - Particularly in patients with known malignancy (lung, breast, melanoma, lymphoma) 2

5. In glucocorticoid-induced AI: Patients using multiple glucocorticoid formulations simultaneously, high-dose inhaled/topical steroids >1 year, or concomitant CYP3A4 inhibitors are at particularly high risk 4

Special Populations

Pregnant women: The diagnosis is particularly challenging due to overlapping symptoms and physiological cortisol elevation, but untreated AI carries high maternal mortality. Maintain high clinical suspicion and proceed with paired cortisol/ACTH and cosyntropin testing when indicated 3

Children: Genetic causes predominate, especially congenital adrenal hyperplasia. In neonates presenting with ambiguous genitalia, hypoglycemia, or salt-wasting, immediately evaluate for enzyme defects 2

The French consensus 2 and European guidelines 1 are concordant on this systematic approach, with the 2018 French guidelines providing the most recent algorithmic framework for both adult and pediatric populations.