What lab tests are recommended for a patient suspected of having adrenal stress, considering their past medical history and potential for endocrine disorders?

Laboratory Testing for Adrenal Stress (Adrenal Insufficiency)

For suspected adrenal insufficiency, obtain morning (8:00-9:00 AM) serum cortisol and plasma ACTH levels as the essential first-line tests, followed by a cosyntropin stimulation test if initial results are indeterminate. 1, 2

Initial Diagnostic Workup

Essential First-Line Tests

• Morning serum cortisol (8:00-9:00 AM) is the most critical initial test, as cortisol follows a diurnal rhythm with highest levels in the morning 1, 2
• Plasma ACTH (measured simultaneously with morning cortisol) determines whether adrenal insufficiency is primary (high ACTH, low cortisol) or secondary (low ACTH, low cortisol) 3, 1, 2
• Basic metabolic panel (sodium, potassium, glucose) should be obtained to assess for hyponatremia (present in 90% of cases) and hyperkalemia (present in only ~50% of primary adrenal insufficiency cases) 2

Interpretation of Initial Results

• Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in the presence of acute illness is diagnostic of primary adrenal insufficiency 2
• Basal cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion of primary adrenal insufficiency 2
• Morning cortisol ≥300 nmol/L (≥10.8 μg/dL) excludes adrenal insufficiency in most cases 4
• Morning cortisol <110 nmol/L (<4 μg/dL) strongly suggests adrenal insufficiency 4
• Morning cortisol between 110-300 nmol/L (4-10.8 μg/dL) requires cosyntropin stimulation testing for definitive diagnosis 4

Cosyntropin (ACTH) Stimulation Test

When to Perform

The cosyntropin stimulation test is indicated when morning cortisol levels are indeterminate (between 4-10.8 μg/dL) or when clinical suspicion remains high despite borderline normal cortisol levels 2, 5

Test Protocol

• Administer 0.25 mg (250 mcg) cosyntropin intravenously or intramuscularly 5
• Obtain baseline serum cortisol immediately before administration 5
• Measure serum cortisol at exactly 30 and 60 minutes post-administration 5
• Test should preferably be performed in the morning, though not strictly required 2

Interpretation Criteria

• Peak cortisol <500 nmol/L (<18 μg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency 2, 5
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 2
• Note: Newer specific cortisol assays (LC-MS/MS, specific immunoassays) may use lower cutoffs of 14-15 μg/dL instead of the historical 18 μg/dL threshold 6

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary Adrenal Insufficiency Pattern

• High ACTH with low cortisol is the hallmark finding 1, 2
• Hyponatremia plus hyperkalemia suggests primary adrenal insufficiency (mineralocorticoid deficiency) 2
• Additional testing: Measure 21-hydroxylase autoantibodies to identify autoimmune etiology (accounts for ~85% of cases in Western populations) 2
• If autoantibodies negative: Obtain adrenal CT imaging to evaluate for hemorrhage, tumors, tuberculosis, or other structural causes 2

Secondary Adrenal Insufficiency Pattern

• Low or inappropriately normal ACTH with low cortisol indicates pituitary/hypothalamic dysfunction 3, 1, 2
• Hyponatremia without hyperkalemia suggests secondary adrenal insufficiency (mineralocorticoid function preserved) 2
• Additional testing: Evaluate other pituitary hormones (TSH, free T4, LH, FSH, testosterone/estrogen) and consider pituitary MRI 3

Additional Tests for Primary Adrenal Insufficiency

• Plasma renin activity (PRA) and aldosterone levels should be measured to assess mineralocorticoid deficiency 7
• Elevated PRA with low aldosterone confirms mineralocorticoid deficiency requiring fludrocortisone replacement 7

Critical Pitfalls to Avoid

Medication Interference

• Stop glucocorticoids and spironolactone on the day of testing, as they cause falsely elevated cortisol levels 5
• Long-acting glucocorticoids (e.g., dexamethasone) may need to be stopped for longer periods before testing 5
• Stop estrogen-containing drugs 4-6 weeks before testing, as they increase cortisol-binding globulin and falsely elevate total cortisol levels 5
• Hydrocortisone must be held for 24 hours before testing; other steroids require longer washout periods 2

Clinical Considerations

• Never delay treatment for diagnostic testing if adrenal crisis is suspected—immediately administer IV hydrocortisone 100 mg and 0.9% saline 2
• Do not rely on electrolyte abnormalities alone—hyperkalemia is absent in 50% of primary adrenal insufficiency cases 2
• Morning cortisol measurements are unreliable in patients actively taking corticosteroids due to assay cross-reactivity 2
• Measure cortisol-binding globulin levels if cirrhosis, nephrotic syndrome, or other conditions affecting binding proteins are present 5

Special Populations

• Patients on chronic corticosteroids: Wait until treatment is discontinued with adequate washout time before attempting diagnostic testing 2
• Suspected cyclic Cushing's disease: Confirm active hypercortisolism immediately before performing diagnostic procedures 1
• Critically ill patients: Basal cortisol <250 nmol/L with elevated ACTH is diagnostic without need for stimulation testing 2

Diagnostic Algorithm Summary

1. Obtain morning (8 AM) cortisol and ACTH as initial screening 1, 2
2. If cortisol <250 nmol/L with high ACTH: Diagnose primary adrenal insufficiency 2
3. If cortisol <400 nmol/L with low ACTH: Suspect secondary adrenal insufficiency 2
4. If cortisol 110-300 nmol/L: Perform cosyntropin stimulation test 4
5. If cortisol ≥300 nmol/L: Adrenal insufficiency excluded in most cases 4
6. For confirmed primary AI: Measure 21-hydroxylase antibodies and consider adrenal CT if negative 2
7. For confirmed secondary AI: Evaluate other pituitary hormones and obtain pituitary MRI 3