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

From the Guidelines

Testing for adrenal insufficiency should typically involve a morning cortisol level followed by a high-dose ACTH stimulation test, as it is easier to perform and has comparable accuracy to the low-dose test, as suggested by the Society of Critical Care Medicine and European Society of Intensive Care Medicine in 2017 1. When evaluating patients for adrenal insufficiency, it is essential to consider the clinical context and presentation.

• A morning cortisol level between 6-8 AM can help identify patients with adrenal insufficiency, with levels below 5 mcg/dL suggesting insufficiency and levels above 15 mcg/dL generally ruling it out.
• For values between 5-15 mcg/dL, an ACTH stimulation test should be performed, which involves administering 250 mcg of synthetic ACTH and measuring cortisol levels 30 and 60 minutes after administration.
• A normal response is a cortisol level above 18-20 mcg/dL at either time point, while an inadequate response confirms adrenal insufficiency.
• Primary adrenal insufficiency can be distinguished from secondary insufficiency by measuring ACTH levels, which are elevated in primary disease, as noted in the 2021 ASCO guideline update 1 and the 2014 consensus statement on primary adrenal insufficiency 1.
• In critically ill patients, a random cortisol level below 10 mcg/dL or a delta cortisol less than 9 mcg/dL suggests critical illness-related corticosteroid insufficiency.
• Testing should ideally be performed before starting corticosteroid therapy, as exogenous steroids can suppress results. The high-dose ACTH test is preferred due to its ease of use and comparable accuracy to the low-dose test, as supported by a meta-analysis of 30 studies involving 1209 adults and 228 children 1.
• The task force suggested using the high-dose rather than the low-dose ACTH test for the diagnosis of CIRCI, owing to easier practical modalities and comparable accuracy.
• The likelihood ratio of a positive test was 9.1 and 5.9 for the high- and low-dose ACTH test, respectively, for adults, and 43.5 and 7.7, respectively, for children.
• Both tests had low sensitivity, as suggested by the suboptimal likelihood ratio of a negative test.

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 2.
• The adrenocorticotropic hormone (ACTH) stimulation test is commonly performed in patients suspected of having adrenal insufficiency when basal serum cortisol levels are inconclusive 2.
• 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 2.

Diagnostic Cutoffs for Adrenal Insufficiency

• The accurate interpretation of the cosyntropin (ACTH) stimulation test requires method- and assay-specific cutoffs of the level of cortisol 3.
• A study established thresholds for the level of cortisol specific to the Abbott Architect immunoassay, with an optimized threshold of 14.6 μg/dL at 60 minutes after stimulation (sensitivity, 92%; specificity, 96%) 3.
• The use of assay-specific cutoffs is essential for reducing misclassification and overtreatment in patients with suspected adrenal insufficiency 3.

Diagnosis and Management of Adrenal Insufficiency

• Adrenal insufficiency is the inadequate secretion of glucocorticoid and/or mineralocorticoid secretion from the adrenal cortex, and early detection and testing based on clinical suspicion may prevent subsequent presentation with adrenal crisis 4.
• A low baseline cortisol (often <100 nmol/L) alongside raised adrenocorticotropic hormone (ACTH) can be enough to diagnose primary adrenal insufficiency, while confirmatory testing can be done using the cosyntropin (Synacthen®) stimulation test or the insulin tolerance test 4.

Relationship between Morning Serum Cortisol and ACTH Test

• The mean basal morning cortisol level is highly correlated to peak cortisol response in the ACTH test (r = 0.7724, p < 0.0001) 5.
• A mean basal morning serum cortisol of > or = 300 nmol/L excluded the possibility of adrenal insufficiency, and a level of < 110 nmol/L suggested adrenal insufficiency 5.
• A study found that a morning serum cortisol cutoff of ≤323.3 nmol/L had a sensitivity of 87.7% and specificity of 46.1% for predicting central adrenal insufficiency diagnosed by insulin tolerance test 6.