Normal ACTH Cutoff Values
The normal reference range for plasma ACTH is approximately 10-60 pg/mL (2.2-13.3 pmol/L) when measured in the morning (08:00-09:00h), with values >5 pg/mL considered detectable and values <5 pg/mL suggesting ACTH suppression. 1, 2
Clinical Context for ACTH Interpretation
The interpretation of ACTH levels depends critically on the clinical scenario and must be paired with cortisol measurements:
Normal Baseline Values
- Morning ACTH levels in healthy individuals range from 12-186 pg/mL (mean approximately 23 pg/mL in younger adults and 17.5 pg/mL in elderly subjects) 3, 4
- ACTH exhibits diurnal variation with highest levels in early morning (0400-0800h) and lowest levels in evening (1600-2200h), with evening values often <10-34 pg/mL 3
- Timing is critical: ACTH should be measured at 08:00-09:00h for standardization and comparison with established reference ranges 1
Diagnostic Thresholds in Disease States
For diagnosing ACTH-dependent Cushing's syndrome:
- ACTH >5 pg/mL indicates detectable ACTH and suggests ACTH-dependent disease with high certainty 1, 2
- ACTH >29 pg/mL has 70% sensitivity and 100% specificity for Cushing's disease (pituitary source) in the presence of confirmed hypercortisolism 1, 5
- Patients with untreated Cushing's disease typically have ACTH levels of 65-220 pg/mL 3
For diagnosing ACTH-independent Cushing's syndrome:
- ACTH <5 pg/mL or undetectable levels suggest adrenal source of cortisol excess 1, 2
- In adrenal tumors causing Cushing's syndrome, ACTH is typically suppressed and non-stimulatable 6
For diagnosing adrenal insufficiency:
- ACTH >200 pg/mL strongly suggests primary adrenal insufficiency (Addison's disease), with levels ranging from 223-1226 pg/mL in untreated patients 3
- In primary adrenal insufficiency with acute illness, plasma ACTH is clearly increased while serum cortisol is low 7
- ACTH <5 pg/mL or undetectable suggests secondary (pituitary) or tertiary (hypothalamic) adrenal insufficiency 3
Critical Pairing with Cortisol
ACTH must always be interpreted alongside cortisol levels to determine the appropriateness of the pituitary-adrenal response 7:
- In primary adrenal insufficiency: Low cortisol (<250 nmol/L or <9 μg/dL) + elevated ACTH is diagnostic 7
- In secondary adrenal insufficiency: Low cortisol + inappropriately normal or low ACTH indicates pituitary/hypothalamic dysfunction 7
- In Cushing's syndrome: Elevated cortisol + ACTH >5 pg/mL indicates ACTH-dependent disease 1, 2
Important Clinical Caveats
- Assay-specific differences exist: Different immunoassays may yield different absolute values, though relative interpretations remain consistent 8, 9
- Stress and illness can elevate ACTH appropriately; a cortisol level within the normal range may be inappropriately low for the degree of stress (such as in sepsis), even when ACTH is not markedly elevated 7
- Exogenous steroids (prednisolone, dexamethasone, inhaled fluticasone) suppress ACTH and confound interpretation 7
- Sample handling: ACTH is unstable and requires immediate processing on ice with EDTA tubes to prevent degradation 1
- Cyclical Cushing's syndrome can produce variable ACTH levels, requiring confirmation of hypercortisolemia immediately prior to ACTH measurement 1