What is the workup for adrenal insufficiency?

Diagnostic Workup for Adrenal Insufficiency

The diagnostic workup for adrenal insufficiency should begin with morning ACTH and cortisol levels, followed by an ACTH stimulation test for indeterminate results, with additional testing guided by the suspected etiology. 1, 2

Initial Laboratory Evaluation

First-line Testing

• Morning hormone measurements (between 7-9 AM) 2:
  • Serum cortisol (AM)
  • Plasma ACTH (AM)
  • Basic metabolic panel (sodium, potassium, CO2, glucose)

Interpretation of Initial Results

• Diagnostic cortisol thresholds:
  • Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH: strongly suggestive of primary adrenal insufficiency 1, 2
  • Morning cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH: raises strong suspicion for primary adrenal insufficiency 2
  • Random cortisol <150 nmol/L with symptoms: indicates need for hydrocortisone replacement 2

Confirmatory Testing

ACTH Stimulation Test (Gold Standard)

• Procedure: Administer 250 μg synthetic ACTH (cosyntropin/Synacthen) and measure cortisol at:
  • Baseline
  • 30 minutes
  • 60 minutes
• Interpretation: Peak cortisol <500 nmol/L (18 μg/dL) confirms adrenal insufficiency 2, 3

Differential Diagnosis Testing

For Primary Adrenal Insufficiency

• Autoimmune etiology:

  • 21-hydroxylase (21OH) antibodies 1
  • If 21OH-Ab negative, consider non-autoimmune causes 1

• Imaging:

  • Adrenal CT scan to evaluate for:
    • Metastasis
    • Hemorrhage
    • Calcifications (typical of tuberculosis)
    • Infiltrative disorders 1

• Additional testing (based on clinical suspicion):

  • Very long-chain fatty acids (for adrenoleukodystrophy in males) 1
  • Tuberculosis testing (Quantiferon, culture, PCR) 1

For Secondary Adrenal Insufficiency

• Pituitary evaluation:
  • MRI of the brain with pituitary/sellar cuts 1, 2
  • Additional pituitary hormone testing:
    • TSH and Free T4
    • LH, FSH
    • Testosterone (males) or estradiol (premenopausal females) 1

Distinguishing Primary from Secondary Adrenal Insufficiency

Laboratory Pattern

• Primary adrenal insufficiency:

  • Low cortisol
  • High ACTH
  • Possible electrolyte abnormalities (hyponatremia, hyperkalemia)
  • Low DHEAS 4

• Secondary adrenal insufficiency:

  • Low cortisol
  • Low or inappropriately normal ACTH
  • Normal electrolytes (typically)
  • Low DHEAS 4

Special Considerations

Adrenal Crisis

• If adrenal crisis is suspected, never delay treatment for diagnostic procedures 1
• Immediate treatment with:
  • IV hydrocortisone 100 mg
  • IV normal saline (at least 2L)
  • Evaluation for precipitating causes (e.g., infection) 1

Medication Interference

• Exogenous steroid use (including inhaled steroids) may confound interpretation of cortisol levels 1
• Opioids can suppress ACTH production 4

Common Pitfalls

• Waiting for laboratory confirmation before treating suspected adrenal crisis
• Failing to consider adrenal insufficiency in patients with non-specific symptoms (fatigue, nausea, weight loss)
• Not testing for adrenal insufficiency before initiating thyroid hormone replacement in patients with multiple endocrine abnormalities 2
• Misinterpreting cortisol levels in patients already on corticosteroid therapy 1

Follow-up After Diagnosis

• Evaluate for precipitating cause of crisis (if applicable)
• Endocrine consultation
• Initiate appropriate hormone replacement therapy:
  • Glucocorticoid replacement (hydrocortisone 15-25 mg daily in divided doses) 4
  • Mineralocorticoid replacement (fludrocortisone 0.05-0.2 mg daily) for primary adrenal insufficiency 5, 4
• Patient education on stress dosing and adrenal crisis prevention 2
• Medical alert bracelet 1, 2

By following this systematic approach to the workup of adrenal insufficiency, clinicians can efficiently diagnose this potentially life-threatening condition and initiate appropriate treatment to reduce morbidity and mortality.