Causes of Elevated ACTH
Elevated ACTH levels indicate ACTH-dependent disease, which is caused by either a pituitary adenoma (Cushing's disease, 75-80% of cases) or ectopic ACTH secretion from tumors such as neuroendocrine tumors, lung carcinoids, or other malignancies. 1
Primary Causes of Elevated ACTH
ACTH-Dependent Cushing's Syndrome
Pituitary Source (Cushing's Disease)
- Pituitary corticotroph adenomas account for 75-80% of ACTH-dependent cases in children/adolescents and 49-71% in adults 1
- Microadenomas (≤2 mm diameter) represent 98% of pediatric cases and are frequently too small to detect on MRI 1
- Macroadenomas are rare, occurring in only 2-5% of pediatric cases versus 10% in adults 2
- Any ACTH level >5 ng/L (>1.1 pmol/L) indicates ACTH-dependent disease 1
- ACTH levels >29 ng/L have 70% sensitivity and 100% specificity for diagnosing Cushing's disease 1
Ectopic ACTH Secretion
- Neuroendocrine tumors (particularly bronchial carcinoids, thymic carcinoids, pancreatic NETs) ectopically produce ACTH 3
- These tumors typically show very high ACTH levels (mean 0.42 ± 0.07 mU/100 ml in one series) compared to pituitary sources 4
- Some ectopic tumors co-secrete both CRH and ACTH, creating a positive feedback loop that further amplifies ACTH production 3
- Ectopic sources often present with profound hypokalemia and markedly elevated urinary free cortisol 1
Physiologic Mechanism
Loss of Normal Feedback Inhibition
- In Cushing's disease, the pituitary adenoma loses normal cortisol-mediated negative feedback, resulting in autonomous ACTH secretion despite elevated cortisol 1
- The normal circadian rhythm of ACTH/cortisol is lost, with persistently elevated morning levels rather than the normal peak-and-nadir pattern 1
Iatrogenic ACTH Elevation
- Adrenal steroidogenesis inhibitors (metyrapone, ketoconazole, osilodrostat) block cortisol synthesis, removing cortisol's negative feedback on the pituitary 5
- This causes compensatory ACTH elevation as the pituitary attempts to restore cortisol levels 5
- With these medications, significantly elevated ACTH may indicate tumor growth and requires MRI monitoring 6
Diagnostic Approach to Elevated ACTH
Initial Classification
- Morning (08:00-09:00h) plasma ACTH measurement is the optimal time for diagnostic interpretation due to circadian rhythm 1
- ACTH >5 ng/L confirms ACTH-dependent disease (rules out adrenal adenoma) 1
- ACTH >29 ng/L strongly suggests pituitary source over ectopic 1
Localization of ACTH Source
- Pituitary MRI is the next step for ACTH-dependent disease, though sensitivity is only 63% for microadenomas 1
- If MRI shows adenoma ≥10 mm, proceed directly to surgery 1
- If MRI is normal or shows lesion <6 mm, bilateral inferior petrosal sinus sampling (BIPSS) is required to distinguish pituitary from ectopic sources 1
- BIPSS criteria: central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH/desmopressin confirms pituitary source with 96-100% sensitivity 1
Ectopic Source Evaluation
- If BIPSS suggests ectopic source or clinical features suggest ectopic (very high cortisol, profound hypokalemia), perform neck-to-pelvis thin-slice CT 1
- 68Ga-DOTATATE PET imaging can localize neuroendocrine tumors not visible on conventional imaging 1
Critical Pitfalls to Avoid
- Do not confuse ACTH-dependent with ACTH-independent disease: Only adrenal adenomas show suppressed/undetectable ACTH with elevated cortisol 1
- Do not measure ACTH in the afternoon: Physiologically lower afternoon levels do not correspond to established diagnostic thresholds 1
- Do not interpret ACTH levels in patients on exogenous steroids: These suppress ACTH and confound interpretation 1
- Monitor for tumor growth with steroidogenesis inhibitors: Significant ACTH elevations during treatment may indicate progressive tumor growth requiring MRI 6
- Recognize dual CRH/ACTH secretion: Some ectopic tumors co-secrete both hormones, creating particularly severe hypercortisolism 3