What is the recommended approach for testing adrenal insufficiency?

Testing for Adrenal Insufficiency

The diagnostic approach begins with paired measurement of early morning (8 AM) serum cortisol and plasma ACTH, followed by cosyntropin stimulation testing when results are equivocal. 1

Initial Diagnostic Testing

Morning Laboratory Assessment

• Obtain early morning (approximately 8 AM) serum cortisol and plasma ACTH simultaneously as the initial diagnostic tests 1, 2
• Measure serum electrolytes (sodium, potassium), as hyponatremia occurs in 90% of cases and hyperkalaemia in approximately 50% 1
• Check DHEAS levels, which are typically low in primary adrenal insufficiency 1, 2

Interpretation of Morning Cortisol and ACTH

Primary Adrenal Insufficiency:

• Serum cortisol <250 nmol/L (<9 mcg/dL) with elevated ACTH in acute illness is diagnostic 1
• Serum cortisol <140 nmol/L (<5 mcg/dL) with elevated ACTH confirms the diagnosis 2, 3
• Serum cortisol 140-400 nmol/L (5-14.5 mcg/dL) with elevated ACTH raises strong suspicion and requires confirmatory testing 1

Secondary Adrenal Insufficiency:

• Serum cortisol 140-280 nmol/L (5-10 mcg/dL) with low or low-normal ACTH suggests secondary causes 2, 1
• Low cortisol with low ACTH distinguishes secondary from primary adrenal insufficiency 1

Confirmatory Testing: Cosyntropin Stimulation Test

When to Perform

• Required when morning cortisol levels are equivocal (between 140-500 nmol/L or 5-18 mcg/dL) 1, 4
• Used to confirm diagnosis when clinical suspicion remains despite intermediate baseline values 5, 3

Test Protocol

Adult Dosing:

• Administer 0.25 mg (250 mcg) cosyntropin intravenously or intramuscularly 4

Pediatric Dosing:

• 0.125 mg for patients birth to <2 years of age 4
• 0.25 mg for patients 2-17 years of age 4

Sample Collection:

• Obtain baseline serum cortisol immediately before cosyntropin administration 4
• Collect serum cortisol at exactly 30 and 60 minutes post-injection 4

Interpretation

• Peak serum cortisol <500 nmol/L (<18 mcg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency 1, 6
• Peak cortisol ≥500 nmol/L (≥18 mcg/dL) indicates normal adrenal function 1, 6

Critical Pre-Test Considerations

Medication Management

Stop these medications on the day of testing to avoid false results 1, 4:

• Glucocorticoids (except dexamethasone if diagnosis unclear) 1, 4
• Spironolactone 1, 4
• Long-acting glucocorticoids require cessation for a longer period before testing 4

Stop estrogen-containing medications 4-6 weeks before testing, as they elevate cortisol-binding globulin and falsely increase total cortisol levels 1

Factors Affecting Accuracy

• Conditions altering cortisol-binding globulin (pregnancy, oral contraceptives) may require salivary cortisol testing instead 3
• Use of inhaled steroids (fluticasone) or oral prednisolone can confound interpretation 1
• Time of day affects results; testing should be standardized to morning hours 5
• Newer highly specific cortisol assays have lower diagnostic cut-off points 3

Clinical Context for Testing

When to Suspect Adrenal Insufficiency

Consider testing in patients presenting with 1:

• Unexplained collapse, hypotension, or shock
• Persistent vomiting or diarrhea
• Hyperpigmentation (primary AI only)
• Hyponatremia, hyperkalaemia, acidosis, or hypoglycemia
• Fatigue (50-95% of cases), nausea/vomiting (20-62%), anorexia/weight loss (43-73%) 2

Specific Clinical Scenarios

• Glucocorticoid-induced AI: Suspect in patients who recently tapered or discontinued supraphysiological glucocorticoid doses 2
• Immune checkpoint inhibitor therapy: Requires close monitoring as emerging cause of both primary and secondary AI 3
• Acute illness with suspected adrenal crisis: Never delay treatment for diagnostic testing; treat immediately with IV hydrocortisone 100 mg and obtain cortisol/ACTH samples before first dose if possible 1

Common Pitfalls to Avoid

• Never delay emergency treatment in suspected acute adrenal crisis to perform diagnostic testing 1, 7
• Do not rely solely on hyponatremia and hyperkalaemia, as the classic combination is present in only about 50% of cases 1
• Avoid interpreting cortisol levels without considering medications affecting cortisol or cortisol-binding globulin 1, 4
• Do not use the cosyntropin test as initial screening; start with morning cortisol and ACTH 1, 2
• Be aware that patients on chronic glucocorticoids will have low morning cortisol due to iatrogenic secondary AI, not true adrenal insufficiency requiring different management 1