What is the diagnostic approach for adrenal insufficiency?

Diagnostic Approach for Adrenal Insufficiency

The diagnostic approach for adrenal insufficiency should begin with paired measurement of morning serum cortisol and plasma ACTH levels, followed by ACTH stimulation testing in equivocal cases. 1

Initial Clinical Suspicion

Adrenal insufficiency should be suspected in patients presenting with:

• Unexplained collapse, hypotension, vomiting, or diarrhea
• Hyperpigmentation (in primary adrenal insufficiency)
• Laboratory abnormalities:
  • Hyponatremia (present in 90% of new cases)
  • Hyperkalaemia
  • Metabolic acidosis
  • Hypoglycemia (more common in children)
  • Mild hypercalcemia (10-20% of cases)
  • Anemia, eosinophilia, lymphocytosis, elevated liver enzymes 1

Diagnostic Algorithm

Step 1: Initial Laboratory Testing

• Measure early morning (8 AM) serum cortisol and plasma ACTH levels 1, 2
• Assess basic metabolic panel (sodium, potassium, bicarbonate, glucose) 1

Step 2: Interpretation of Initial Results

• Primary adrenal insufficiency:

  • Low morning cortisol (<5 μg/dL or <140 nmol/L)
  • Elevated ACTH
  • Hyponatremia and hyperkalemia (due to aldosterone deficiency) 1, 2

• Secondary adrenal insufficiency:

  • Low morning cortisol
  • Low or inappropriately normal ACTH
  • Typically normal electrolytes (aldosterone production usually intact) 2

Step 3: Confirmatory Testing

• ACTH stimulation test (cosyntropin/synacthen test):

  • Administer 0.25 mg cosyntropin IV or IM for adults and children ≥2 years
  • Use 0.125 mg for children <2 years 3
  • Obtain serum cortisol levels at baseline, 30 minutes, and 60 minutes after administration 3
  • A peak serum cortisol <500 nmol/L (18 μg/dL) confirms adrenal insufficiency 1

• Important considerations:

  • Stop glucocorticoids and spironolactone on the day of testing
  • Long-acting glucocorticoids require longer washout periods
  • Estrogen-containing medications should be stopped 4-6 weeks before testing 3

Step 4: Determining Etiology

• For primary adrenal insufficiency:

  • Measure 21-hydroxylase (anti-adrenal) autoantibodies
  • If antibodies are negative, perform adrenal CT imaging to evaluate for:
    • Metastasis
    • Hemorrhage
    • Infection (tuberculosis, fungal)
  • In male patients with negative antibodies, measure very long-chain fatty acids to check for adrenoleukodystrophy 1

• For secondary adrenal insufficiency:

  • Evaluate pituitary function with additional hormone testing
  • Consider pituitary MRI 2

Special Considerations

Acute Adrenal Crisis

• Critical point: Treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures 1
• In acute settings with suspected adrenal crisis:
  • Serum cortisol <250 nmol/L with increased ACTH is diagnostic of primary adrenal insufficiency
  • Serum cortisol <400 nmol/L with increased ACTH raises strong suspicion 1
  • Immediately administer IV hydrocortisone 100 mg and isotonic saline 1

Common Pitfalls

1. Medication interference:

   • Exogenous glucocorticoids can suppress the HPA axis and confound test results
   • Estrogens increase cortisol-binding globulin, affecting total cortisol levels 1, 3

2. Timing issues:

   • Failure to obtain morning cortisol samples (cortisol has diurnal variation)
   • Incorrect timing of samples during ACTH stimulation test 3

3. Interpretation challenges:

   • Secondary adrenal insufficiency may yield false normal results on ACTH stimulation test
   • In such cases, insulin tolerance test or metyrapone test may be required 4

4. Emerging causes:

   • Immune checkpoint inhibitor therapy is an increasingly recognized cause of both primary and secondary adrenal insufficiency requiring close monitoring 5

By following this systematic diagnostic approach, clinicians can accurately diagnose adrenal insufficiency and initiate appropriate treatment to prevent life-threatening adrenal crisis and improve patient outcomes.