What are the diagnostic tests for adrenal insufficiency (Addison's disease)?

From the Guidelines

Testing for adrenal insufficiency should initially involve evaluating ACTH and cortisol levels, as well as a basic metabolic panel, and considering an ACTH stimulation test for indeterminate results, as recommended by the American Society of Clinical Oncology 1.

Diagnostic Approach

When suspecting adrenal insufficiency, the following steps should be taken:

• Evaluate ACTH (AM) and cortisol level (AM) to assess adrenal function.
• Perform a basic metabolic panel (Na, K, CO, glucose) to identify any electrolyte imbalances or other metabolic disturbances.
• Consider an ACTH stimulation test for indeterminate results, which is the gold standard for diagnosing adrenal insufficiency, as supported by the Society of Critical Care Medicine and European Society of Intensive Care Medicine 1.

Interpretation of Test Results

• A normal response to the ACTH stimulation test is a peak cortisol level above 18-20 mcg/dL, while lower values suggest adrenal insufficiency.
• ACTH levels should be measured simultaneously to distinguish between primary (high ACTH) and secondary (low/normal ACTH) insufficiency.
• Morning cortisol levels can serve as an initial screening tool, with levels below 3 mcg/dL strongly suggesting insufficiency and levels above 15 mcg/dL typically ruling it out.

Additional Considerations

• Patients should temporarily discontinue glucocorticoids before testing when possible, as these medications can suppress results.
• Testing should be conducted in the morning when cortisol levels are naturally highest, and patients should be well-hydrated and not acutely ill, as stress can affect cortisol levels and potentially mask insufficiency.
• The diagnosis of primary adrenal insufficiency requires two steps: assessing adrenal cortex function and establishing the aetiology, as outlined in the consensus statement on the diagnosis, treatment, and follow-up of patients with primary adrenal insufficiency 1.

From the FDA Drug Label

Cosyntropin for injection is indicated, in combination with other diagnostic tests, for use as a diagnostic agent in the screening of adrenocortical insufficiency in adults and pediatric patients. Stimulated plasma cortisol levels of less than 18 mcg/dL at 30- or 60-minutes post cosyntropin for injection are suggestive of adrenocortical insufficiency.

Testing for Adrenal Insufficiency using cosyntropin (IV) involves:

• Administering 0.25 mg of cosyntropin by intravenous or intramuscular injection
• Obtaining blood samples for baseline serum cortisol and again at 30 and 60 minutes after administration
• Interpreting plasma cortisol levels, with values less than 18 mcg/dL at 30 or 60 minutes suggestive of adrenocortical insufficiency 2

From the Research

Testing for Adrenal Insufficiency

• Adrenal insufficiency is a rare disease characterized by cortisol deficiency, and its evaluation can be challenging due to the rarity of the disease and limitations in biochemical assessment 3.
• The adrenocorticotropic hormone (ACTH) stimulation test is commonly performed in patients suspected of having adrenal insufficiency when basal serum cortisol levels are inconclusive 3.
• Recent literature has evaluated the impact of technical aspects such as time of day, type of assay, and sample source used for cortisol measurement on the clinical value of the ACTH stimulation test 3.

Diagnostic Tests

• Morning serum cortisol examinations and short ACTH tests are popular screening tests for unstressed patients suspected of having adrenal insufficiency 4.
• The mean basal morning cortisol level is highly correlated to the peak cortisol response in the ACTH test, and a mean basal morning serum cortisol of ≥300 nmol/L excludes the possibility of adrenal insufficiency 4.
• A rapid cosyntropin stimulation test offers a simple means for detecting adrenal insufficiency, while assessment of suspected hypercortisolism is more difficult due to fluctuating cortisol levels 5.

Predictive Value of Basal Cortisol Levels

• Basal cortisol levels can predict adrenal insufficiency in cosyntropin testing, with a basal cortisol level ≥450 nmol/L having a negative predictive value of 98.7% to rule out adrenal insufficiency 6.
• A basal cortisol level ≤100 nmol/L has a positive predictive value of 93.2% to rule in adrenal insufficiency 6.
• Morning serum cortisol level can predict central adrenal insufficiency diagnosed by insulin tolerance test, with a cutoff of ≤126.4 nmol/L having a sensitivity of 13.8% and specificity of 98.7% 7.

Diagnostic Accuracy

• The diagnostic accuracy of basal cortisol levels can help guide clinicians in determining when formal ACTH testing can be omitted, reducing expenses and simplifying test protocols 6.
• A morning serum cortisol cutoff of ≤323.3 nmol/L has a sensitivity of 87.7% and specificity of 46.1% for predicting central adrenal insufficiency 7.
• A new diagnostic flow-chart for central adrenal insufficiency has been proposed based on morning serum cortisol cutoffs 7.