How should suspected adrenal insufficiency be evaluated?

Testing for Adrenal Insufficiency

The diagnostic approach begins with early morning (8 AM) serum cortisol and plasma ACTH measurements, followed by a cosyntropin stimulation test when initial results are indeterminate. 1, 2

Initial Diagnostic Workup

Morning cortisol and ACTH levels are the first-line tests:

• Draw blood at approximately 8 AM for serum cortisol and plasma ACTH 1, 2
• Include a basic metabolic panel (sodium, potassium, CO2, glucose) to assess for hyponatremia and hyperkalemia, though hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases 1, 3
• Measure DHEAS to help distinguish primary from secondary adrenal insufficiency 2

Interpretation of morning cortisol levels:

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1
• Cortisol <100 nmol/L (<3.6 μg/dL) alongside raised ACTH can be sufficient to diagnose primary adrenal insufficiency without further testing 4
• Cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH suggests secondary adrenal insufficiency 1
• Cortisol ≥300 nmol/L (≥10.8 μg/dL) excludes adrenal insufficiency in non-acute cases 5, 6
• Cortisol levels between 110-300 nmol/L require confirmatory testing with cosyntropin stimulation 5, 6

Cosyntropin (ACTH) Stimulation Test

When morning cortisol is indeterminate (typically 5-18 μg/dL), proceed with the cosyntropin stimulation test, which is the gold standard for confirming adrenal insufficiency. 1, 2

Test protocol:

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM 1, 7
• Obtain baseline serum cortisol before administration 1
• Measure serum cortisol at 30 and/or 60 minutes post-administration 1
• The test can be performed at any time of day, though morning is preferred 1

Interpretation:

• Peak cortisol <500 nmol/L (<18 μg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal and excludes adrenal insufficiency 1
• The high-dose (250 mcg) test is preferred over the low-dose (1 mcg) test due to easier administration, comparable diagnostic accuracy, and FDA approval 1

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency:

• Low cortisol with high ACTH 1, 2
• Often accompanied by hyponatremia and hyperkalemia (though hyperkalemia present in only ~50% of cases) 1, 3
• Low DHEAS levels 2

Secondary adrenal insufficiency:

• Low cortisol with low or inappropriately normal ACTH 1, 2
• Hyponatremia without hyperkalemia 1
• Low or low-normal DHEAS levels 2

Special Diagnostic Considerations

Adrenal insufficiency vs. SIADH:

• The cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolar hyponatremia, as both conditions present with nearly identical laboratory findings 1
• Both show euvolemic hypo-osmolar hyponatremia with inappropriately high urine osmolality and elevated urinary sodium 1
• Adrenal insufficiency must be excluded before diagnosing SIADH 1

Critical pitfalls to avoid:

• Never delay treatment of suspected acute adrenal crisis for diagnostic testing—if the patient is clinically unstable with unexplained hypotension, collapse, or gastrointestinal symptoms, immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion 1, 3, 2
• Do not rely on electrolyte abnormalities alone—hyponatremia is present in 90% of cases, but hyperkalemia occurs in only ~50% 1, 3
• Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound testing—hold hydrocortisone for 24 hours before testing, and avoid diagnostic testing until other corticosteroids have been discontinued with adequate washout time 1
• If you must treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1
• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic due to cross-reactivity with therapeutic steroids 1

Etiologic Workup After Diagnosis

For confirmed primary adrenal insufficiency:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies, as autoimmunity accounts for ~85% of cases in Western populations 1
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, or other structural causes 1
• In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1

For confirmed secondary adrenal insufficiency:

• Evaluate for pituitary or hypothalamic disorders through MRI imaging and assessment of other pituitary hormone deficiencies 1
• Consider medication history, particularly opioids and other drugs that suppress corticotropin production 2