How should I evaluate cortisol for suspected adrenal insufficiency or Cushing's syndrome?

Evaluating Cortisol for Suspected Adrenal Insufficiency or Cushing's Syndrome

Initial Diagnostic Approach

For suspected adrenal insufficiency, obtain a morning (8 AM) serum cortisol and plasma ACTH simultaneously as your first-line test, followed by a cosyntropin stimulation test if results are indeterminate. 1, 2

Adrenal Insufficiency Evaluation

Morning Cortisol and ACTH Interpretation:

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency—no further testing needed 1, 2
• Cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion and requires confirmatory cosyntropin testing 1
• Low cortisol with low or inappropriately normal ACTH indicates secondary adrenal insufficiency 1
• Cortisol >550 nmol/L (>18-20 μg/dL) effectively excludes adrenal insufficiency 1

Cosyntropin Stimulation Test Protocol:

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM 1, 2, 3
• Measure serum cortisol at baseline, exactly 30 minutes, and 60 minutes post-administration 1, 3
• Peak cortisol <500 nmol/L (<18 μg/dL) at either 30 or 60 minutes confirms adrenal insufficiency 1, 2, 3
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 1

Cushing's Syndrome Evaluation

For suspected Cushing's syndrome, start with late-night salivary cortisol (LNSC) and/or 24-hour urinary free cortisol (UFC), with the 1 mg dexamethasone suppression test (DST) as an alternative if LNSC is not feasible. 4

Screening Test Selection:

• LNSC ≥2 measurements on consecutive days is preferred for ease of patient collection 4
• UFC averaged over 2-3 collections provides reliable screening 4
• 1 mg DST is useful in shift workers but should be avoided in women on estrogen-containing oral contraceptives 4
• Measuring dexamethasone level along with morning cortisol after 1 mg dexamethasone improves test interpretability 4

If adrenal tumor-related Cushing's is suspected, start with DST rather than LNSC, as LNSC has lower specificity in these patients 4

Critical Pitfalls to Avoid

Testing Interference

Never attempt cortisol testing in patients actively taking corticosteroids—this will yield false results showing "adrenal insufficiency" that simply reflects expected HPA suppression. 1

• Patients on prednisone, prednisolone, hydrocortisone, or inhaled fluticasone will have suppressed morning cortisol due to iatrogenic secondary adrenal insufficiency 1
• Stop glucocorticoids and spironolactone on the day of cosyntropin testing as they falsely elevate cortisol levels 3
• Stop estrogen-containing drugs 4-6 weeks before testing as they increase cortisol-binding globulin and falsely elevate total cortisol 3
• Wait until the patient has been weaned off corticosteroids before performing definitive HPA axis testing 1

Clinical Context Errors

Do not rely on electrolyte abnormalities alone to diagnose or exclude adrenal insufficiency:

• Hyponatremia is present in 90% of newly diagnosed cases 1, 2
• Hyperkalemia occurs in only ~50% of cases—its absence does not rule out adrenal insufficiency 1, 2
• Hyponatremia plus hyperkalemia suggests primary adrenal insufficiency, while hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 1

Adrenal insufficiency must be excluded before diagnosing SIADH, as both conditions present with euvolemic hypo-osmolar hyponatremia and similar laboratory findings. 1

Emergency Management

Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—mortality is high if untreated. 1, 2

• If clinically unstable with unexplained hypotension, collapse, or GI symptoms: give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour 1, 2
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 1
• If you need to treat but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone—dexamethasone does not interfere with cortisol assays 1

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency:

• High ACTH with low cortisol 1, 2
• Both glucocorticoid and mineralocorticoid deficiency 1
• Hyperpigmentation due to elevated ACTH 2
• Salt craving is a clinical clue 1

Secondary adrenal insufficiency:

• Low or inappropriately normal ACTH with low cortisol 1
• Glucocorticoid deficiency only (mineralocorticoid function preserved) 1
• No hyperpigmentation 1
• May have additional pituitary hormone deficiencies 1

Etiologic Workup After Diagnosis

For confirmed primary adrenal insufficiency:

• Measure 21-hydroxylase autoantibodies first—autoimmunity accounts for ~85% of cases in Western populations 1, 2
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, or other structural causes 1, 2
• In males with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1

For confirmed secondary adrenal insufficiency:

• Evaluate for pituitary lesions with MRI 1
• Screen for other pituitary hormone deficiencies 1