How do you diagnose adrenal insufficiency?

Diagnosing Adrenal Insufficiency

The diagnosis of adrenal insufficiency requires measuring early-morning (8 AM) serum cortisol and ACTH levels, followed by confirmatory testing with a cosyntropin (Synacthen) stimulation test when initial results are inconclusive. 1

Initial Diagnostic Approach

Clinical Suspicion

• Look for characteristic symptoms:
  • Fatigue (50-95% of cases)
  • Nausea and vomiting (20-62%)
  • Anorexia and weight loss (43-73%)
  • Hypotension
  • Hyperpigmentation (in primary adrenal insufficiency)
  • Salt craving 2

First-line Laboratory Tests

1. Early morning (8 AM) serum cortisol:

   • <5 μg/dL (<138 nmol/L): Highly suggestive of adrenal insufficiency
   • 5-10 μg/dL (138-276 nmol/L): Intermediate, requires further testing

   • 10 μg/dL (>276 nmol/L): Usually rules out adrenal insufficiency 2

2. ACTH level:

   • High ACTH + Low cortisol = Primary adrenal insufficiency
   • Low/normal ACTH + Low cortisol = Secondary adrenal insufficiency 1

3. Basic metabolic panel:

   • Hyponatremia
   • Hyperkalemia (in primary adrenal insufficiency)
   • Hypoglycemia 1

Confirmatory Testing

Cosyntropin (Synacthen) Stimulation Test

• Gold standard for diagnosing primary adrenal insufficiency
• Procedure:
  1. Measure baseline cortisol
  2. Administer cosyntropin 250 μg IV/IM
  3. Measure cortisol at 30 and 60 minutes post-administration
• Interpretation:
  • Normal response: Peak cortisol >18-20 μg/dL (>500-550 nmol/L)
  • Abnormal response: Failure to reach threshold indicates adrenal insufficiency 1, 2

Special Considerations for Secondary Adrenal Insufficiency

• Standard cosyntropin test may yield false-negative results in recent onset (<4 weeks) secondary adrenal insufficiency
• Alternative tests:
  • Insulin tolerance test (gold standard for secondary adrenal insufficiency)
  • Metyrapone test 3

Distinguishing Primary vs. Secondary Adrenal Insufficiency

Feature	Primary	Secondary
ACTH level	High	Low/normal
Electrolytes	↓Na, ↑K	Usually normal
Hyperpigmentation	Present	Absent
Mineralocorticoid deficiency	Present	Absent
21-OH antibodies	Often positive	Negative
Associated conditions	Other autoimmune disorders	Pituitary/hypothalamic disorders [1]

Additional Testing Based on Suspected Etiology

For Primary Adrenal Insufficiency

• 21-hydroxylase antibodies (21OH-Ab): Positive in autoimmune adrenal insufficiency
• Adrenal CT scan: For non-autoimmune causes (tuberculosis, hemorrhage, infiltration)
• Very long-chain fatty acids: To screen males for adrenoleukodystrophy
• Tuberculosis testing: Quantiferon test, PCR 4

For Secondary Adrenal Insufficiency

• Pituitary MRI: To evaluate for tumors, hemorrhage, or infiltrative disease
• Other pituitary hormone testing: To assess for hypopituitarism 1

Common Pitfalls to Avoid

1. Delaying treatment in suspected adrenal crisis: Administer hydrocortisone 100 mg IV immediately, followed by IV saline infusion, without waiting for test results 1, 5

2. Missing secondary adrenal insufficiency: Standard cosyntropin test may be falsely normal; consider insulin tolerance test or metyrapone test when clinical suspicion is high 3

3. Starting thyroid hormone replacement before corticosteroids: In patients with both hypothyroidism and adrenal insufficiency, always start corticosteroids first to prevent precipitating adrenal crisis 1

4. Inadequate follow-up: Regular monitoring of clinical status, electrolytes, and medication adjustments is essential 1

5. Failure to educate patients: All diagnosed patients need education on stress dosing, emergency management, and medical alert identification 1

By following this systematic approach to diagnosis, adrenal insufficiency can be identified promptly, allowing for appropriate treatment and prevention of potentially life-threatening adrenal crisis.