How is adrenal insufficiency diagnosed?

Diagnostic Approach to Adrenal Insufficiency

The most definitive diagnostic test for adrenal insufficiency is paired measurement of morning serum cortisol and plasma ACTH, followed by an ACTH stimulation test (cosyntropin test) when results are equivocal. 1

Initial Evaluation

Clinical Features Suggesting Adrenal Insufficiency

• Unexplained collapse, hypotension, vomiting, diarrhea
• Hyperpigmentation (in primary adrenal insufficiency)
• Hyponatremia, hyperkalemia, acidosis, hypoglycemia
• Fatigue, weight loss, anorexia
• Salt craving (in primary adrenal insufficiency)

First-Line Testing

1. Morning serum cortisol (8am-12pm) with paired ACTH measurement 2, 1

   • Morning cortisol <275 nmol/L (<10 μg/dL) with elevated ACTH suggests primary adrenal insufficiency 3
   • Morning cortisol <275 nmol/L with low/normal ACTH suggests secondary adrenal insufficiency 3
   • Morning cortisol >500 nmol/L (>18 μg/dL) effectively rules out adrenal insufficiency 1
   • Intermediate values (275-500 nmol/L) require confirmatory testing

2. Basal cortisol (9am-1pm) can be used when morning sampling isn't possible:

   • <85 nmol/L is highly specific (99.7%) for adrenal insufficiency 4

   • 350 nmol/L effectively rules out adrenal insufficiency (sensitivity 98.9%) 4

Confirmatory Testing

ACTH Stimulation Test (Cosyntropin Test)

• Gold standard for diagnosing primary adrenal insufficiency 1, 5

• Procedure:

  1. Stop interfering medications:
     • Glucocorticoids and spironolactone on day of testing
     • Long-acting glucocorticoids for longer period
     • Estrogen-containing drugs 4-6 weeks before testing 5
  2. Obtain baseline serum cortisol
  3. Administer cosyntropin:
     • Adults: 0.25 mg IV or IM 5
     • Children <2 years: 0.125 mg IV or IM
     • Children 2-17 years: 0.25 mg IV or IM 5
  4. Measure serum cortisol at 30 and 60 minutes post-administration 5

• Interpretation:

  • Peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 2, 1
  • In primary adrenal insufficiency: low cortisol with elevated ACTH
  • In secondary adrenal insufficiency: low cortisol with low/normal ACTH 1, 6

Insulin Tolerance Test (ITT)

• Gold standard for diagnosing secondary adrenal insufficiency 7, 8
• Tests the entire hypothalamic-pituitary-adrenal axis
• Reserved for cases where secondary adrenal insufficiency is suspected but ACTH stimulation test is normal 7
• Contraindicated in patients with seizure disorders, cardiovascular disease, or elderly patients

Additional Testing to Determine Etiology

For Primary Adrenal Insufficiency

1. 21-hydroxylase (anti-adrenal) autoantibodies - to identify autoimmune etiology 2
2. If antibodies negative:
   • CT imaging of adrenal glands
   • In males: very long-chain fatty acids to check for adrenoleukodystrophy 2
   • Consider infectious causes (TB, fungal)

For Secondary Adrenal Insufficiency

1. MRI of pituitary/hypothalamus - to identify tumors, hemorrhage, infiltrative conditions
2. Other pituitary hormone testing - to identify panhypopituitarism

Important Considerations

Diagnostic Pitfalls

• Medication effects:

  • Glucocorticoids and spironolactone may falsely elevate cortisol levels 5
  • Estrogen-containing drugs increase cortisol binding globulin, affecting total cortisol levels 5
  • Opioids can suppress corticotropin production 6

• Timing considerations:

  • Morning samples are most reliable 1
  • Afternoon samples may be used in outpatients but have different cutoff values 3

Emergency Situations

• Never delay treatment of suspected acute adrenal insufficiency for diagnostic testing 2, 1
• In acute illness with suspected adrenal crisis:
  • Cortisol <400 nmol/L with elevated ACTH strongly suggests primary adrenal insufficiency 2
  • Immediate treatment with hydrocortisone 100mg IV bolus and fluid resuscitation is indicated 1

By following this diagnostic algorithm, clinicians can efficiently diagnose adrenal insufficiency and initiate appropriate treatment to prevent potentially life-threatening adrenal crisis.