What is the threshold for abnormal 8am cortisol levels in a general adult population?

Threshold for Abnormal 8am Cortisol

An 8am cortisol level below 500 nmol/L (18 μg/dL) in the presence of elevated ACTH is diagnostic of primary adrenal insufficiency, while levels above 386 nmol/L (14 μg/dL) effectively rule out adrenal insufficiency. 1, 2

Diagnostic Thresholds for Morning Cortisol

Upper Threshold (Ruling Out Adrenal Insufficiency)

• Morning cortisol >386 nmol/L (>14 μg/dL) effectively excludes adrenal insufficiency 1, 2
• Levels >300 nmol/L (10.9 μg/dL) make ACTH-cortisol insufficiency highly unlikely 2
• The normal reference range for healthy individuals is 138-635 nmol/L (5-23 μg/dL), with most values clustering between 276-552 nmol/L (10-20 μg/dL) 1, 2

Lower Threshold (Diagnosing Adrenal Insufficiency)

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 3, 1
• Cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH in acute illness raises strong suspicion of primary adrenal insufficiency 3, 1
• In critically ill patients, random cortisol <276 nmol/L (<10 μg/dL) suggests relative adrenal insufficiency 1

Critical Context for Interpretation

When Dynamic Testing is Required

• For equivocal morning cortisol values (between 250-500 nmol/L), a synacthen stimulation test is mandatory, with peak cortisol <500 nmol/L diagnostic of primary adrenal insufficiency 3, 1
• The European consensus emphasizes that treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures 3

Important Confounding Factors to Consider

• Exogenous steroid use (oral prednisolone, dexamethasone, inhaled fluticasone) can falsely lower cortisol levels and confound interpretation 3, 1, 2
• Oral contraceptives and estrogen therapy increase cortisol-binding globulin, falsely elevating total cortisol while free cortisol remains normal 1
• In acute illness or sepsis, a "normal" cortisol level may actually represent inadequate adrenal response for the stress state 1, 2

Assay-Specific Considerations

Modern Immunoassay Adjustments

The traditional 500 nmol/L (18 μg/dL) threshold was established with older polyclonal antibody assays. Newer monoclonal antibody-based assays (Roche Elecsys II, Abbott Architect) measure 30-40% lower cortisol concentrations than older assays 4, 5:

• For Abbott Architect assay: the adjusted threshold is approximately 351 nmol/L (12.7 μg/dL) 5
• For Roche Cortisol II assay: cortisol concentrations are comparable to LC-MS/MS but significantly lower than older assays 5
• Failure to use assay-specific cutoffs leads to overdiagnosis and unnecessary treatment 4, 5

Clinical Algorithm for 8am Cortisol Interpretation

1. If cortisol >386 nmol/L (>14 μg/dL): Adrenal insufficiency is effectively ruled out 1, 2

2. If cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH: Diagnostic of primary adrenal insufficiency in acute illness; initiate treatment immediately 3, 1

3. If cortisol 250-386 nmol/L (9-14 μg/dL): Proceed with synacthen stimulation test (0.25 mg); peak <500 nmol/L confirms adrenal insufficiency 3, 1

4. Always measure paired ACTH with morning cortisol: Elevated ACTH (>300 pg/mL) with inappropriately normal or low cortisol indicates primary adrenal insufficiency 3, 6

Common Pitfalls to Avoid

• Do not rely solely on a single 8am cortisol measurement when clinical suspicion is high—sensitivity is 100% but specificity only 33% at the 500 nmol/L cutoff 7
• Approximately 10% of patients with primary adrenal insufficiency present with normal basal cortisol concentrations but have clearly elevated ACTH, representing early Addison's disease 6
• In patients with hyperpigmentation, hyponatremia, hyperkalemia, or unexplained hypotension, pursue dynamic testing even if morning cortisol appears "normal" 3, 2
• Verify which cortisol assay your laboratory uses and apply the appropriate threshold—using outdated cutoffs with modern assays causes significant overdiagnosis 4, 5