What does an elevated Adrenocorticotropic hormone (ACTH) level indicate?

Elevated ACTH Levels: Diagnostic Implications and Clinical Approach

Elevated levels of ACTH indicate that excessive cortisol secretion is not coming from the adrenal gland but rather from pituitary tumors (usually benign) or ectopic tumors in the lung, thyroid, pancreas, or bowel. 1

Primary Diagnostic Considerations

• Elevated ACTH with hypercortisolism suggests ACTH-dependent Cushing syndrome, most commonly Cushing disease (pituitary origin) or ectopic ACTH syndrome 1
• Normal or elevated ACTH with low cortisol indicates primary adrenal insufficiency (Addison's disease) 1
• ACTH levels are typically measured in the morning (08:00-09:00h) when interpreting results 1

ACTH-Dependent Cushing Syndrome

Differential Diagnosis:

• Cushing disease (pituitary adenoma):

  • Most common cause of ACTH-dependent Cushing syndrome
  • ACTH is detectable (>5 ng/l or >1.1 pmol/l) 1
  • Shows >20% increase in cortisol during CRH stimulation test 1

• Ectopic ACTH syndrome:

  • Sources include tumors in lung, thyroid, pancreas, or bowel 1
  • Often associated with higher ACTH levels than pituitary sources 1
  • May not respond to dexamethasone suppression 1

Diagnostic Algorithm:

1. Confirm hypercortisolism first using:

   • 24-hour urinary free cortisol (UFC) 1
   • Late-night salivary cortisol 1
   • Low-dose dexamethasone suppression test 1

2. Determine ACTH dependency:

   • Measure morning plasma ACTH level 1
   • ACTH >5 ng/l (>1.1 pmol/l) confirms ACTH-dependent Cushing syndrome 1

3. Differentiate pituitary from ectopic source:

   • CRH stimulation test: >20% increase in cortisol suggests pituitary origin 1
   • Pituitary MRI (preferably 3T) to identify adenoma 1
   • Bilateral inferior petrosal sinus sampling (BIPSS) if MRI is negative or equivocal 1
     • Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin and ≥3:1 after stimulation confirms pituitary source 1

Primary Adrenal Insufficiency

• Characterized by high ACTH and low cortisol levels 1
• Associated with hyponatremia, hyperkalemia, and orthostatic hypotension 1
• Diagnosis confirmed by paired measurement of serum cortisol and plasma ACTH 1
• ACTH levels may be markedly elevated (>200 pg/ml) 1, 2

Clinical Pitfalls and Caveats

• ACTH measurement alone is insufficient for diagnosis and must be interpreted alongside cortisol levels 3
• There is considerable overlap in ACTH concentrations between pituitary and ectopic sources of Cushing syndrome 3
• ACTH can be released in a pulsatile or cyclical manner, potentially leading to variable results 4
• Measurement of ACTH precursors (POMC, pro-ACTH) may help distinguish ectopic ACTH syndrome (markedly elevated) from pituitary Cushing disease 5
• Isolated ACTH deficiency can occur as an immune-related adverse event in patients receiving immune checkpoint inhibitors 6
• False positives/negatives can occur with dynamic testing, necessitating multiple diagnostic approaches 1

Treatment Implications

• For pituitary adenomas causing Cushing disease:

  • Transsphenoidal surgery is first-line treatment 1
  • Medical management with ketoconazole (400-1200 mg/day) if surgery is contraindicated 1

• For ectopic ACTH-producing tumors:

  • Surgical removal of the primary tumor when possible 1
  • Bilateral adrenalectomy or medical management if primary tumor is unresectable 1

• For primary adrenal insufficiency:

  • Replacement therapy with glucocorticoids (hydrocortisone 10-20 mg morning, 5-10 mg afternoon) 1
  • Mineralocorticoid replacement with fludrocortisone (0.1 mg/day) 1