What is the best way to diagnose adrenal insufficiency?

Diagnosing Adrenal Insufficiency

The most definitive diagnostic approach for adrenal insufficiency is paired measurement of serum cortisol and plasma ACTH, followed by a synacthen (tetracosactide) stimulation test in equivocal cases. 1

Initial Diagnostic Evaluation

Clinical Suspicion

Consider adrenal insufficiency in patients with:

• Unexplained collapse, hypotension, vomiting, or diarrhea
• Hyperpigmentation (in primary adrenal insufficiency)
• Hyponatremia, hyperkalemia, acidosis, hypoglycemia
• Recent discontinuation of long-term steroid therapy
• Fatigue, anorexia, weight loss, nausea, and weakness 1, 2

Laboratory Testing Algorithm

1. First-line testing:

   • Paired morning (8 AM) serum cortisol and plasma ACTH 1
   • Electrolytes (sodium, potassium, chloride, bicarbonate) 3

2. Interpretation of first-line results:

   • Primary adrenal insufficiency:

     • Low cortisol (<250 nmol/L or <5 μg/dL) with elevated ACTH 1, 2
     • Often accompanied by hyponatremia and hyperkalemia

   • Secondary adrenal insufficiency:

     • Low cortisol with low or normal ACTH 2
     • Typically normal electrolytes

3. Equivocal cases requiring further testing:

   • Intermediate cortisol values (250-400 nmol/L)
   • Discordant clinical picture and laboratory results

Confirmatory Testing

Synacthen (ACTH Stimulation) Test

• Procedure: Administer 0.25 mg synacthen (tetracosactide) IM or IV, measure serum cortisol at baseline, 30 and/or 60 minutes 1
• Interpretation:
  • Normal response: Peak cortisol >500-550 nmol/L
  • Diagnostic of adrenal insufficiency: Peak cortisol <500 nmol/L 1
• Caution: May give false normal results in recent onset secondary adrenal insufficiency 4

Additional Testing for Secondary Adrenal Insufficiency

• Insulin tolerance test (gold standard but more risky) 5
• Metyrapone test (alternative when insulin tolerance test is contraindicated) 6

Special Considerations

Steroid-Induced Adrenal Insufficiency

• Common in patients who have recently tapered or discontinued supraphysiological doses of glucocorticoids 2
• AM cortisol levels may be unreliable in patients on corticosteroids 3
• Gradual tapering of steroids is essential to prevent adrenal insufficiency (reduce by no more than 2.5-5 mg every 1-2 weeks) 3

Acute Adrenal Crisis

• Important: Treatment should never be delayed by diagnostic procedures if adrenal crisis is suspected 1
• Immediately administer IV hydrocortisone 100 mg and isotonic saline 1, 3
• Obtain blood samples for cortisol and ACTH before starting treatment if possible

Etiological Evaluation

After confirming adrenal insufficiency, determine the etiology:

1. Measure 21-hydroxylase (anti-adrenal) autoantibodies (for autoimmune adrenal insufficiency) 1
2. If antibodies are negative:
   • CT imaging of adrenals
   • In males, test very long-chain fatty acids for adrenoleukodystrophy 1
3. Consider APS-1 (Autoimmune Polyendocrine Syndrome type 1) in children and young adults with PAI and other manifestations like hypoparathyroidism and candidiasis 1

Common Pitfalls to Avoid

• Delayed diagnosis: Non-specific symptoms often lead to delayed recognition; maintain high clinical suspicion
• Premature exclusion: Normal electrolytes do not rule out adrenal insufficiency
• Medication interference: Exogenous steroid use (including inhaled steroids like fluticasone) may confound interpretation of cortisol levels 1
• Timing errors: Cortisol has diurnal variation; morning samples are essential
• Initiating thyroid replacement before cortisol replacement: Can precipitate adrenal crisis in patients with multiple hormone deficiencies 3

Patient Education and Follow-up

• All diagnosed patients should:
  • Wear medical alert identification
  • Carry a steroid alert card
  • Receive education on managing illness and stress (doubling doses during illness)
  • Have emergency injectable hydrocortisone available 1, 3
• Annual follow-up should include assessment of well-being, weight, blood pressure, electrolytes, and screening for other autoimmune disorders 1