How to Check Cortisol in Addison Disease
The diagnosis of Addison disease (primary adrenal insufficiency) requires paired measurement of morning (8 AM) serum cortisol and plasma ACTH, with a high-dose cosyntropin stimulation test (250 mcg) performed when baseline values are equivocal. 1, 2
Diagnostic Algorithm
Step 1: Initial Screening - Morning Cortisol and ACTH
- Draw blood at 8 AM for simultaneous measurement of:
- Serum cortisol
- Plasma ACTH
Interpretation of baseline values:
- Cortisol <140 nmol/L (5 μg/dL) + ACTH >2× upper limit of normal → Confirms primary adrenal insufficiency 1
- Cortisol <250 nmol/L + elevated ACTH in acute illness → Diagnostic of primary AI 2
- Cortisol 250-400 nmol/L + elevated ACTH in acute illness → Strong suspicion, proceed to stimulation test 2
- Cortisol >332 nmol/L (12 μg/dL) → Rules out adrenal insufficiency, no further testing needed 3
- Cortisol <96 nmol/L → Highly predictive of inadequate adrenal reserve 3
Step 2: Cosyntropin Stimulation Test (When Baseline is Equivocal)
Perform high-dose (250 mcg) cosyntropin test:
- Administer 250 mcg cosyntropin (tetracosactide) IV or IM
- Measure cortisol at baseline and 30 minutes post-injection 1
- The 30-minute time point is validated and preferred over 60 minutes 1
Diagnostic cutoffs:
- Peak cortisol <500 nmol/L (18 μg/dL) → Confirms primary adrenal insufficiency 2
- With newer immunoassays, a cutoff of ≥14.6 μg/dL may be more appropriate 4
Step 3: Confirm Mineralocorticoid Deficiency
Simultaneously measure plasma renin and aldosterone to assess for mineralocorticoid deficiency, which may be the earliest or only manifestation in evolving Addison disease 1
- Elevated renin + low/normal aldosterone → Suggests primary AI 1, 5
- This is particularly important as mineralocorticoid deficiency may predominate early in disease 1
Critical Pitfalls to Avoid
Never delay treatment for diagnostic testing in suspected acute adrenal crisis 2. Draw baseline cortisol and ACTH, then immediately start hydrocortisone.
ACTH assay variability: Different assays have significant analytical bias 1. The guideline recommends ACTH >2× upper limit of normal, though some patients may have values only slightly above the reference range 1.
Low-dose (1 mcg) cosyntropin test: While potentially more sensitive for secondary AI, it adds no additional sensitivity or specificity for primary AI compared to the high-dose test 1. Use the standard 250 mcg dose for practical reasons.
Timing matters: The 30-minute cortisol measurement is validated and preferred over the traditional 60-minute timepoint 1.
Confounding factors: Exogenous steroids (oral prednisolone, dexamethasone, inhaled fluticasone) can confound interpretation of low cortisol levels 2.
Additional Diagnostic Considerations
Plasma ACTH concentration >300 ng/L (66 pmol/L) provides maximal adrenal stimulation, so a low cortisol with this ACTH level is highly predictive of primary AI 1. An elevated ACTH with normal-range cortisol can indicate early-stage disease 1.
In children under 2 years, the circadian cortisol rhythm is not established until after 4 months of age, making the Synacthen test the only feasible diagnostic test 6.