What is the diagnostic approach for adrenal insufficiency?

Diagnostic Approach for Adrenal Insufficiency

First-Line Screening Test

Obtain an early morning (8 AM) serum cortisol and plasma ACTH simultaneously as your initial diagnostic test. 1, 2, 3 This paired measurement can often establish the diagnosis without further testing and should be performed before any dynamic testing. 2

Interpreting Morning Cortisol Results

The morning cortisol level determines your next step:

• Cortisol <250-275 nmol/L (<9-10 μg/dL): Highly suggestive of adrenal insufficiency, proceed directly to treatment if clinically indicated 1, 4

  • If ACTH is elevated: diagnostic of primary adrenal insufficiency 1, 2
  • If ACTH is low or inappropriately normal: indicates secondary adrenal insufficiency 1, 3

• Cortisol 250-400 nmol/L (9-14.5 μg/dL): Indeterminate zone—proceed to cosyntropin stimulation test 1, 2

• Cortisol >400-550 nmol/L (>14.5-20 μg/dL): Generally excludes adrenal insufficiency in stable patients 1

Critical caveat: Morning cortisol alone has limited predictive value and should not be used in isolation to exclude adrenal insufficiency. 5 The test performs best in morning samples from outpatients; afternoon samples and inpatient samples are less reliable. 4

Confirmatory Testing: Cosyntropin Stimulation Test

When to Perform

Perform the cosyntropin (Synacthen) stimulation test when: 1, 2

• Morning cortisol is in the indeterminate range (250-400 nmol/L)
• Clinical suspicion remains high despite normal morning cortisol
• You need definitive confirmation before committing to lifelong therapy

Test Protocol (FDA-Approved)

Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously. 1, 6 The high-dose test is preferred over low-dose (1 mcg) testing due to easier administration, comparable diagnostic accuracy, and FDA approval. 1

Timing of blood draws: 1, 6

• Baseline (pre-injection)
• 30 minutes post-injection
• 60 minutes post-injection (optional but recommended)

Interpreting Results

• Peak cortisol <500-550 nmol/L (<18-20 μg/dL): Diagnostic of adrenal insufficiency 1, 2, 3
• Peak cortisol >550 nmol/L (>20 μg/dL): Normal response, excludes adrenal insufficiency 1, 2

Critical Medication Considerations

Stop these medications before testing to avoid false results: 1, 6

• Glucocorticoids and spironolactone: Stop on the day of testing 1, 6
• Long-acting glucocorticoids (e.g., dexamethasone): Stop for a longer period before testing 1, 6
• Estrogen-containing medications: Stop 4-6 weeks before testing, as they elevate cortisol-binding globulin and falsely elevate total cortisol levels 1
• Inhaled steroids (e.g., fluticasone): Can suppress the HPA axis and confound results 1

Emergency Situations: Never Delay Treatment

If you suspect acute adrenal crisis (hypotension, collapse, vomiting, altered mental status), give IV hydrocortisone 100 mg immediately—do NOT wait for test results. 1, 2, 3 Mortality is high if untreated. 1

Special Scenario: Treating Before Confirming Diagnosis

If you must treat emergently but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone. 1, 2 Dexamethasone does not interfere with cortisol assays, allowing you to perform the cosyntropin test afterward. 1

Before giving hydrocortisone, draw blood for cortisol and ACTH if the patient is stable enough for a 2-minute delay. 1, 2

High-Risk Clinical Scenarios Requiring Immediate Testing

Suspect adrenal insufficiency in: 1, 2

• Any patient taking ≥20 mg/day prednisone (or equivalent) for ≥3 weeks who develops unexplained hypotension 1, 2
• Vasopressor-resistant hypotension in critically ill patients 1
• Unexplained collapse with hypotension, vomiting, or diarrhea 1, 2
• Profound fatigue with hyponatremia (present in 90% of cases) 1, 2

Important: Hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases, so its absence does NOT rule out the diagnosis. 1, 2 Do not rely on electrolyte abnormalities alone. 1

Distinguishing Primary from Secondary Adrenal Insufficiency

Once adrenal insufficiency is confirmed, the ACTH level distinguishes the type: 1, 3

Primary adrenal insufficiency: 1, 3

• High ACTH with low cortisol
• Often accompanied by hyponatremia and hyperkalemia (though hyperkalemia only in ~50%)
• Requires both glucocorticoid AND mineralocorticoid replacement

Secondary adrenal insufficiency: 1, 3

• Low or inappropriately normal ACTH with low cortisol
• May have other pituitary hormone deficiencies
• Requires glucocorticoid replacement only (mineralocorticoid function preserved)

Etiologic Workup After Diagnosis

For primary adrenal insufficiency: 1

1. Measure 21-hydroxylase autoantibodies first (autoimmunity causes ~85% of cases in Western populations) 1
2. If antibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1
3. In males with negative antibodies, consider measuring very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 1

For secondary adrenal insufficiency: 1

• Evaluate for pituitary/hypothalamic pathology with MRI
• Assess other pituitary hormone axes

Common Pitfalls to Avoid

1. Do not delay treatment for testing in unstable patients—this is the most critical error and can be fatal. 1, 2

2. Do not rely on electrolytes alone—10-20% of patients have normal electrolytes at presentation. 1

3. Do not use afternoon cortisol samples in inpatients—they are unreliable for screening. 4

4. When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days BEFORE thyroid hormone replacement to prevent precipitating adrenal crisis. 1

5. Do not assume normal cortisol excludes the diagnosis in patients on exogenous steroids—they may have iatrogenic secondary adrenal insufficiency that becomes apparent only after steroid withdrawal. 1, 3