When is plasma Adrenocorticotropic Hormone (ACTH) measurement recommended?

Plasma ACTH Measurement: Clinical Indications

Plasma ACTH measurement is primarily indicated when diagnosing suspected adrenal insufficiency (paired with serum cortisol) and when differentiating ACTH-dependent from ACTH-independent Cushing's syndrome after hypercortisolism has been confirmed. 1

Primary Indication: Diagnosis of Primary Adrenal Insufficiency

The diagnostic test for primary adrenal insufficiency should be paired measurement of serum cortisol and plasma ACTH. 1

When to Suspect and Measure:

• Consider in all patients presenting with unexplained collapse, hypotension, vomiting, or diarrhea 1
• Clinical suspicion increases with hyperpigmentation, hyponatremia, hyperkalemia, acidosis, or hypoglycemia 1

Diagnostic Thresholds for Primary Adrenal Insufficiency:

• Serum cortisol <250 nmol/L AND elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1
• Serum cortisol <400 nmol/L AND elevated ACTH in acute illness raises strong suspicion 1
• In equivocal cases, proceed to synacthen stimulation test (peak cortisol <500 nmol/L confirms diagnosis) 1

Critical Pitfall:

Treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures—give hydrocortisone first, then measure ACTH and cortisol 1

Secondary Indication: Differentiating Cushing's Syndrome Etiology

After confirming hypercortisolism with first-line tests (late-night salivary cortisol, 24-hour urinary free cortisol, or low-dose dexamethasone suppression test), measure morning (08:00-09:00h) plasma ACTH to determine if Cushing's syndrome is ACTH-dependent or ACTH-independent. 1, 2

Diagnostic Thresholds for Cushing's Syndrome:

• ACTH >5 ng/L (>1.1 pmol/L) indicates ACTH-dependent Cushing's syndrome 1, 2
• ACTH >29 ng/L (6.4 pmol/L) has 70% sensitivity and 100% specificity for Cushing's disease 1
• ACTH undetectable or very low (<5 ng/L) indicates ACTH-independent (adrenal) Cushing's syndrome 1, 2

Important Limitations:

Significant overlap exists between plasma ACTH levels in adrenal Cushing's syndrome and Cushing's disease—when ACTH levels are inconclusive (typically 5-29 ng/L), proceed to additional testing such as high-dose dexamethasone suppression test or CRH stimulation test 3

Tertiary Indication: Confirming Pituitary Origin in ACTH-Dependent Cushing's

When ACTH-dependent Cushing's is confirmed, CRH stimulation testing with ACTH measurement can help distinguish Cushing's disease from ectopic ACTH syndrome. 1, 2

CRH Test Criteria:

• ≥20% increase in cortisol from baseline supports pituitary origin (sensitivity 74-100%) 1, 2
• ACTH increase ≥43% at 15 minutes after CRH injection has positive likelihood ratio of 14.0, with 83% sensitivity and 94% specificity for Cushing's disease 4

When CRH Testing and Imaging Are Inconclusive:

Offer bilateral inferior petrosal sinus sampling (BSIPSS) with ACTH measurement to confirm central source of ACTH excess—central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after CRH or desmopressin confirms pituitary origin with 100% sensitivity 1, 2

Key Confounding Factors to Avoid

Medications That Interfere:

• Exogenous steroids (oral prednisolone, dexamethasone, inhaled fluticasone) confound interpretation of low cortisol levels 1
• Rule out exogenous glucocorticoid use before biochemical testing 2, 5

Physiologic States:

• In sepsis or acute illness, cortisol levels within normal range may be inappropriately low for disease state 1
• Confirm hypercortisolemia immediately prior to BSIPSS to ensure active disease phase in cyclical Cushing's disease 1, 2