Laboratory Workup After Suppressed Cortisol
When a suppressed cortisol level is identified, the essential next step is to measure ACTH to distinguish between primary adrenal insufficiency (elevated ACTH) and secondary/central adrenal insufficiency (low or inappropriately normal ACTH). 1
Immediate Diagnostic Algorithm
Step 1: Measure ACTH
- ACTH level is the critical discriminating test that determines the etiology and guides all subsequent workup 1
- Draw ACTH simultaneously with or immediately after confirming low cortisol (ideally at 8-9 AM) 2
- Elevated ACTH with low cortisol = Primary adrenal insufficiency 1
- Low or inappropriately normal ACTH with low cortisol = Secondary (central) adrenal insufficiency 1, 2
Step 2: If Primary Adrenal Insufficiency (High ACTH)
After establishing primary adrenal insufficiency, immediately assess for mineralocorticoid deficiency: 1
- Plasma renin (expect elevated) 1
- Aldosterone (expect low) 1
- Electrolytes (sodium, potassium) - hyponatremia is common; hyperkalemia suggests mineralocorticoid deficiency 1
Step 3: If Secondary Adrenal Insufficiency (Low/Normal ACTH)
Evaluate for other pituitary hormone deficiencies: 2, 3
- TSH and free T4 - to assess for central hypothyroidism 2
- LH, FSH, and testosterone (males) or estradiol (females) - to assess for hypogonadism 2
- Prolactin - may be elevated with pituitary stalk compression or low with panhypopituitarism 2
- IGF-1 - to screen for growth hormone deficiency in appropriate candidates 2
- Electrolytes - hyponatremia can occur but hyperkalemia does NOT occur in secondary adrenal insufficiency 1
Additional Contextual Testing
When Cortisol Level is Borderline (5-18 μg/dL or 138-500 nmol/L)
Perform dynamic testing to confirm or exclude adrenal insufficiency: 1
- ACTH stimulation test (Synacthen test) using 250 μg (or 125 μg in children <2 years) 1
- Measure cortisol at 30 and 60 minutes post-injection 1
- Peak cortisol <18 μg/dL (500 nmol/L) confirms adrenal insufficiency 1
If ACTH Stimulation Test is Normal but Clinical Suspicion Remains High
Consider insulin-induced hypoglycemia test or metyrapone test - particularly if: 1
- ACTH insufficiency is recent (<4 weeks post-pituitary surgery or trauma) 1
- Partial ACTH insufficiency is suspected 1
- Other anterior pituitary deficiencies are present 1
Critical Pitfalls to Avoid
- Do NOT use urinary free cortisol to diagnose adrenal insufficiency - it lacks sensitivity for this purpose 1
- Do NOT use random cortisol levels - timing matters; 8-9 AM cortisol is essential 2
- Hyperkalemia excludes secondary adrenal insufficiency - its presence indicates primary adrenal insufficiency or another cause 1
- In acute/emergency situations with cortisol <18 μg/dL (500 nmol/L), start hydrocortisone replacement immediately without waiting for additional testing 1
- Certain conditions elevate cortisol (estrogen therapy, pregnancy, acute illness) - use higher diagnostic thresholds and incorporate ACTH/renin levels in interpretation 1
Special Populations
Post-Surgical or Post-Cushing's Syndrome
- Start hydrocortisone replacement perioperatively in patients after surgery for Cushing's syndrome or cortisol-secreting adrenal tumors 1
- Confirm or exclude diagnosis later with appropriate testing 1