What is the purpose and interpretation of the Adrenocorticotropic Hormone (ACTH) stimulation test in diagnosing adrenal insufficiency or Addison's disease?

ACTH Stimulation Test: Purpose and Interpretation

The ACTH stimulation test is the gold standard confirmatory test for diagnosing adrenal insufficiency when basal cortisol levels are inconclusive, with a peak cortisol <500 nmol/L (<18 μg/dL) at 30 or 60 minutes diagnostic of adrenal insufficiency. 1, 2

Test Purpose and Indications

The ACTH stimulation test (also called cosyntropin or Synacthen test) serves to:

• Confirm or exclude adrenal insufficiency when morning cortisol levels are neither clearly normal (>500 nmol/L) nor clearly diagnostic (<250 nmol/L) 1
• Differentiate between primary and secondary adrenal insufficiency by evaluating the adrenal gland's capacity to respond to ACTH stimulation 3
• Rule out adrenal insufficiency before diagnosing SIADH, as both conditions present with identical hyponatremia patterns in 90% of newly diagnosed adrenal insufficiency cases 1

Standard Test Protocol

Dosing and Administration

• Adults: Administer 0.25 mg (250 μg) cosyntropin intramuscularly or intravenously 1, 2
• Pediatric patients (2-17 years): 0.25 mg 2
• Pediatric patients (<2 years): 0.125 mg 2

Timing and Sampling

• Obtain baseline serum cortisol before cosyntropin administration 1, 2
• Measure serum cortisol at 30 and/or 60 minutes after administration 1, 2
• The test can be performed at any time of day, though morning testing is preferred but not mandatory 1
• Simultaneously obtain baseline ACTH before cosyntropin to help differentiate primary from secondary adrenal insufficiency 1

Interpretation of Results

Diagnostic Thresholds

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

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary Adrenal Insufficiency (Addison's Disease):

• Peak cortisol <500 nmol/L with elevated ACTH 1
• Often accompanied by hyponatremia (90% of cases) and hyperkalemia (50% of cases) 1
• Both glucocorticoid and mineralocorticoid deficiency present 1

Secondary Adrenal Insufficiency:

• Peak cortisol <500 nmol/L with low or inappropriately normal ACTH 1, 3
• Aldosterone production remains intact (controlled by renin-angiotensin system, not ACTH) 3
• Only glucocorticoid deficiency present 3

Critical Pre-Test Considerations

Medications That Must Be Stopped

• Glucocorticoids and spironolactone: Stop on the day of testing 2
• Long-acting glucocorticoids: May require longer discontinuation period 2
• Estrogen-containing drugs: Stop 4-6 weeks before testing, as they elevate cortisol-binding globulin and falsely increase total cortisol levels 1, 2
• Exogenous steroids (prednisolone, inhaled fluticasone): Can suppress the HPA axis and confound results 1

Exception for Emergency Situations

• If adrenal crisis is suspected and you need to treat immediately but still want diagnostic testing later: Use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1
• Never delay treatment of suspected acute adrenal insufficiency for diagnostic procedures 1, 2

High-Dose vs Low-Dose Testing

The high-dose (250 μg) test is recommended over the low-dose (1 μg) test due to:

• Comparable diagnostic accuracy (likelihood ratios: high-dose 9.1 vs low-dose 5.9 in adults) 1, 4
• Easier practical administration without requiring bedside dilution 1
• FDA approval and standardized protocol 1, 2
• Established reference ranges 3

The low-dose test requires dilution of commercial preparation at bedside, making it less practical for routine clinical use 1. While some older literature suggested the low-dose test might be more sensitive for secondary adrenal insufficiency 5, recent meta-analyses show similar diagnostic accuracy between both doses 4.

Common Pitfalls and How to Avoid Them

Do Not Rely on Electrolytes Alone

• Hyperkalemia is absent in 50% of primary adrenal insufficiency cases 1
• Hyponatremia can be indistinguishable from SIADH without specific adrenal testing 1
• 10-20% of patients may have normal electrolytes at presentation 1

Conditions Affecting Cortisol-Binding Globulin

• Low CBG (cirrhosis, nephrotic syndrome): Falsely lowers total cortisol levels 2
• High CBG (pregnancy, estrogen therapy): Falsely elevates total cortisol levels 2
• Consider measuring CBG levels when these conditions are present to ensure accurate interpretation 2

Timing Considerations

• The test can be performed during high-dose glucocorticoid therapy within the first 3 days after initiation, but results become unreliable after 96 hours 6
• In acute illness, basal cortisol <250 nmol/L with elevated ACTH is diagnostic without requiring stimulation testing 1

Clinical Context for Test Interpretation

The ACTH stimulation test has:

• High specificity (adequate to rule in adrenal insufficiency when positive) 4
• Lower sensitivity (suboptimal for ruling out adrenal insufficiency when negative, particularly for secondary AI) 4
• Positive likelihood ratio: 9.1 for high-dose test in adults 4
• Negative likelihood ratio: 0.39 for high-dose test in adults (meaning a negative test does not completely exclude secondary AI) 4

Therefore, always integrate test results with clinical presentation and pre-test probability of adrenal insufficiency 7. If clinical suspicion remains high despite a borderline or negative test, consider insulin tolerance testing (the true gold standard) or empiric treatment 1, 7.