What is the significance of an Adrenocorticotropic Hormone (ACTH) level of 5.0?

ACTH Level of 5.0 pg/mL: Clinical Significance and Diagnostic Approach

An ACTH level of 5.0 pg/mL is at the lower limit of detectability and requires immediate correlation with a simultaneous morning cortisol level to determine if secondary adrenal insufficiency is present, which would be life-threatening if untreated. 1

Immediate Diagnostic Interpretation

• Any ACTH level >5 ng/L (approximately 5 pg/mL) is considered detectable and suggests ACTH-dependent pathology if cortisol is elevated, but when cortisol is low, this borderline ACTH level indicates secondary (central) adrenal insufficiency. 1

• The critical distinction depends entirely on the simultaneous morning (8-9 AM) cortisol level: 2, 3

  • If morning cortisol is <10 μg/dL (<275 nmol/L) with ACTH of 5.0, this indicates secondary adrenal insufficiency requiring urgent endocrine evaluation 3
  • If cortisol is elevated with ACTH of 5.0, this represents the lower range of ACTH-dependent Cushing's syndrome 1

Clinical Context Matters

• In patients on immune checkpoint inhibitors, an ACTH of 5.0 with low cortisol strongly suggests isolated ACTH deficiency as an immune-related adverse event, which can present with fatigue, anorexia, hyponatremia, and hyperkalemia. 2, 4

• In patients taking exogenous corticosteroids (including inhaled fluticasone), ACTH will be suppressed and cortisol will be low due to iatrogenic secondary adrenal insufficiency, making the diagnosis of pathologic adrenal insufficiency challenging. 2

• Look for associated electrolyte abnormalities: hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases, though absence of hyperkalemia does not rule out the diagnosis. 3

Required Immediate Workup

• Measure simultaneous morning (8-9 AM) cortisol, basic metabolic panel (sodium, potassium, CO2, glucose), and consider ACTH stimulation testing if results are indeterminate. 2, 3

• If morning cortisol is <10 μg/dL with ACTH of 5.0, proceed with low-dose (1 microgram) ACTH stimulation test, which has superior diagnostic accuracy for secondary adrenal insufficiency compared to the standard 250 microgram test. 5

• A peak cortisol <18 μg/dL (<500 nmol/L) after ACTH stimulation confirms adrenal insufficiency. 3

Distinguishing Primary vs. Secondary Adrenal Insufficiency

• Primary adrenal insufficiency shows high ACTH (typically >29 pg/mL) with low cortisol, while secondary shows low or inappropriately normal ACTH (≤5-10 pg/mL) with low cortisol. 2, 1

• An ACTH of 5.0 with low cortisol definitively indicates secondary (central) adrenal insufficiency, requiring evaluation of other pituitary hormones (TSH, free T4, LH, FSH, testosterone/estradiol) to assess for hypopituitarism. 2

• Consider brain MRI with pituitary cuts if multiple pituitary hormone deficiencies are present or if the patient has new severe headaches or vision changes. 2

Urgent Management if Adrenal Insufficiency Confirmed

• For severe symptoms (hypotension, altered consciousness, inability to perform activities of daily living): administer IV hydrocortisone 100 mg immediately with at least 2 liters of normal saline without waiting for test results. 2, 3

• For moderate symptoms: initiate stress-dose corticosteroids at 2-3 times maintenance (hydrocortisone 20-30 mg morning, 10-20 mg afternoon), then taper to maintenance over 5-10 days. 2

• Maintenance therapy: hydrocortisone 10-20 mg orally every morning, 5-10 mg in early afternoon, or prednisone 5-10 mg daily. 2

• Fludrocortisone (0.1 mg/day) is NOT needed in secondary adrenal insufficiency, only in primary adrenal insufficiency where mineralocorticoid deficiency occurs. 2

Critical Pitfalls to Avoid

• Never delay treatment in symptomatic patients waiting for confirmatory testing—empiric stress-dose corticosteroids can be life-saving. 2, 3

• If diagnosis is uncertain and stimulation testing will be needed, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 2

• Always start corticosteroids several days before initiating thyroid hormone replacement in patients with multiple pituitary deficiencies to prevent precipitating adrenal crisis. 2

• All patients with confirmed adrenal insufficiency require education on stress dosing and a medical alert bracelet. 2

• Obtain endocrine consultation prior to any surgery or procedure for stress-dose planning. 2

Alternative Diagnostic Considerations

• In the context of suspected Cushing's syndrome, an ACTH of 5.0 would be inappropriately low if cortisol is elevated, suggesting ACTH-independent (adrenal) Cushing's syndrome requiring adrenal CT imaging. 1

• Plasma dehydroepiandrosterone sulfate (DHEAS) levels are typically low in ACTH deficiency and can provide supportive diagnostic evidence. 6