Should I obtain a morning plasma ACTH level in a patient with a serum cortisol of 5 µg/dL to determine the cause of adrenal insufficiency?

Should You Order Morning Plasma ACTH in a Patient with Serum Cortisol of 5 µg/dL?

Yes, you should absolutely obtain a morning plasma ACTH level in this patient, as a cortisol of 5 µg/dL (138 nmol/L) falls in the indeterminate zone that requires ACTH measurement to distinguish primary from secondary adrenal insufficiency and guide appropriate treatment. 1

Why ACTH Measurement is Essential at This Cortisol Level

A morning cortisol of 5 µg/dL is neither diagnostic nor exclusionary for adrenal insufficiency:

• Morning cortisol <3 µg/dL is virtually diagnostic of adrenal insufficiency 2
• Morning cortisol >14 µg/dL (>386 nmol/L) effectively rules out adrenal insufficiency 3
• Your patient's value of 5 µg/dL falls squarely in the 5-18 µg/dL range that requires additional investigation 2

The Critical Diagnostic Role of ACTH

ACTH measurement is the definitive test to determine the etiology of confirmed adrenal insufficiency:

• Primary adrenal insufficiency: Low cortisol with high ACTH (>5 ng/L), often accompanied by hyponatremia and hyperkalemia 1
• Secondary adrenal insufficiency: Low cortisol with low or inappropriately normal ACTH 1, 4

This distinction is crucial because treatment differs significantly:

• Primary adrenal insufficiency requires both glucocorticoid AND mineralocorticoid replacement (hydrocortisone plus fludrocortisone) 1
• Secondary adrenal insufficiency requires only glucocorticoid replacement, as the renin-angiotensin-aldosterone system remains intact 1

Optimal Timing and Collection Protocol

Collect the ACTH sample in the morning (08:00-09:00h) simultaneously with cortisol:

• ACTH follows a circadian rhythm with peak levels in the morning 4
• Morning collection provides standardized comparison with established reference ranges 4
• No fasting is required for ACTH measurement 4
• Ensure the patient is not on exogenous steroids, as these suppress ACTH and confound interpretation 1, 3

Diagnostic Thresholds for ACTH Interpretation

Once you have the ACTH level:

• ACTH >5 ng/L (>1.1 pmol/L) with low cortisol indicates primary adrenal insufficiency 1, 4
• ACTH low or inappropriately normal with low cortisol indicates secondary adrenal insufficiency 1
• In acute illness, basal cortisol <250 nmol/L (<9 µg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency 1

Next Steps After ACTH Measurement

If ACTH confirms adrenal insufficiency, proceed with confirmatory testing:

• Cosyntropin stimulation test (0.25 mg IM or IV) with cortisol measured at 30 and 60 minutes is the gold standard 1
• Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency 1
• Peak cortisol >550 nmol/L (>18-20 µg/dL) excludes adrenal insufficiency 1

For primary adrenal insufficiency (high ACTH), determine etiology:

• Measure 21-hydroxylase autoantibodies (positive in ~85% of autoimmune cases in Western populations) 1
• If autoantibodies are negative, obtain adrenal CT to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1

Critical Pitfall to Avoid

Never delay treatment if the patient is clinically unstable with suspected adrenal crisis:

• Unexplained hypotension, collapse, vomiting, or diarrhea warrant immediate IV hydrocortisone 100 mg plus 0.9% saline infusion at 1 L/hour 1
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay treatment for diagnostic procedures 1
• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases, but absence of hyperkalemia cannot rule out the diagnosis (present in only ~50% of cases) 1