What Cortisol Level is Considered Low in nmol/L?
A morning cortisol <250 nmol/L with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency, while levels <100 nmol/L strongly suggest adrenal dysfunction regardless of clinical context. 1, 2
Diagnostic Thresholds for Low Cortisol
Definitive Low Cortisol Levels
- Basal cortisol <100 nmol/L strongly suggests adrenal insufficiency and has a 93.2% positive predictive value for confirming the diagnosis, making further dynamic testing often unnecessary in the appropriate clinical context 3, 4, 5
- Basal cortisol <250 nmol/L with elevated ACTH in the presence of acute illness is diagnostic of primary adrenal insufficiency 1, 2
- Morning cortisol <275 nmol/L (<10 μg/dL) is concerning and warrants further investigation with ACTH stimulation testing 6
Intermediate Range Requiring Further Testing
- Cortisol levels between 100-450 nmol/L fall into an indeterminate zone where ACTH stimulation testing is mandatory to definitively rule in or rule out adrenal insufficiency 3, 5
- Basal cortisol <400 nmol/L with elevated ACTH in acute illness raises strong suspicion of primary adrenal insufficiency and requires confirmatory testing 1, 2
- For patients with known pituitary disease, basal cortisol <214 nmol/L has 85% sensitivity and 71% specificity for adrenal insufficiency 3
Levels That Effectively Rule Out Adrenal Insufficiency
- Basal cortisol ≥450 nmol/L has a 98.7% negative predictive value to rule out adrenal insufficiency, potentially obviating the need for formal ACTH testing 5
- Cortisol >375 nmol/L provides 95% specificity for ruling out adrenal insufficiency in the general population 3
- For patients with pituitary disease, cortisol >330 nmol/L gives 95% specificity for excluding adrenal insufficiency 3
Critical Context for Interpretation
Timing and Clinical Setting Matter
- These thresholds apply specifically to morning (8 AM) cortisol measurements taken in a physically unstressed state 4, 7
- In critically ill patients with treatment-insensitive hypotension, total cortisol levels <10 μg/dL (276 nmol/L) or delta cortisol <9 μg/dL (248 nmol/L) after ACTH stimulation define critical illness-related corticosteroid insufficiency (CIRCI) and are associated with poorer outcomes 8
Important Caveats
- The absence of hyperkalemia cannot rule out adrenal insufficiency, as it is present in only ~50% of cases, while hyponatremia is present in 90% of newly diagnosed cases 1, 6
- A single low cortisol value between 100-200 nmol/L should be repeated within a month, as this significantly improves diagnostic categorization 4
- Exogenous steroids including prednisone, dexamethasone, and inhaled fluticasone suppress the HPA axis and confound cortisol measurements, making interpretation unreliable in patients actively taking corticosteroids 1, 6
Assay-Specific Considerations
Modern Assay Adjustments
- The traditional 500 nmol/L (18 μg/dL) peak cortisol threshold for ACTH stimulation testing was established using older immunoassays 9
- When using newer, more specific assays like Roche Cortisol II or LC-MS/MS, the equivalent threshold drops to approximately 351-368 nmol/L (12.7-13.3 μg/dL) 9
- Failure to adjust diagnostic thresholds for newer assays can lead to overdiagnosis of adrenal insufficiency by up to 140% 9
Clinical Action Points
When to Treat Immediately Without Testing
- If a patient presents with unexplained hypotension, collapse, or gastrointestinal symptoms suggestive of adrenal crisis, immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion without waiting for cortisol results 1, 6
- Treatment of suspected acute adrenal insufficiency should never be delayed for diagnostic procedures 8, 1