What is the diagnostic workup for adrenal insufficiency in a patient with chronic fatigue, weight loss, hyperpigmentation, salt craving, hyponatremia, hyperkalemia, orthostatic hypotension, and a history of autoimmune disease, tuberculosis, adrenal surgery, or chronic glucocorticoid use?

Diagnostic Workup for Adrenal Insufficiency

Draw an early-morning (8 AM) serum cortisol and plasma ACTH immediately, and if the patient is hemodynamically unstable with suspected adrenal crisis, administer 100 mg IV hydrocortisone and 0.9% saline at 1 L/hour without waiting for laboratory confirmation. 1

Initial Laboratory Evaluation

Baseline Hormone Assessment

• Obtain early-morning (approximately 8 AM) serum cortisol and plasma ACTH as the first-line diagnostic tests 1, 2
• Measure dehydroepiandrosterone sulfate (DHEAS) to help differentiate primary from secondary adrenal insufficiency 2
• Obtain a basic metabolic panel to assess for hyponatremia (present in ~90% of cases) and hyperkalemia (present in only ~50% of cases) 1, 3

Interpretation of Baseline Results

• Morning cortisol <250 nmol/L (<9 µg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 3
• Morning cortisol 250–400 nmol/L (9–14 µg/dL) with elevated ACTH raises strong suspicion and warrants confirmatory testing 1
• Morning cortisol <250 nmol/L with low or inappropriately normal ACTH suggests secondary adrenal insufficiency 3
• Morning cortisol 140–275 nmol/L (5–10 µg/dL) with low ACTH is indicative of secondary adrenal insufficiency 3

Confirmatory Testing: Cosyntropin Stimulation Test

When to Perform

• The cosyntropin stimulation test is the gold standard when baseline cortisol levels are indeterminate (between 9–14 µg/dL) 1, 4
• This test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolar hyponatremia before diagnosing SIADH 3

Test Protocol

• Administer 0.25 mg (250 µg) cosyntropin intramuscularly or intravenously 1, 4
• For pediatric patients: 0.125 mg for age <2 years; 0.25 mg for age 2–17 years 4
• Obtain baseline serum cortisol before cosyntropin administration 1, 4
• Measure serum cortisol at exactly 30 and 60 minutes after cosyntropin administration 1, 4

Interpretation of Results

• Peak cortisol <500 nmol/L (<18 µg/dL) at 30 or 60 minutes confirms adrenal insufficiency 1, 3, 4
• Peak cortisol >550 nmol/L (>18–20 µg/dL) is considered normal and excludes adrenal insufficiency 1, 3

Critical Medication Considerations Before Testing

• Stop glucocorticoids (hydrocortisone, prednisone, prednisolone) on the day of testing to avoid false-negative results 1
• Stop spironolactone on the day of testing because it can falsely elevate cortisol levels 1, 4
• Stop estrogen-containing drugs 4–6 weeks before testing because they increase cortisol-binding globulin and falsely elevate total cortisol 4
• Long-acting glucocorticoids may need to be stopped for a longer period before testing 4
• If you must treat before testing, use dexamethasone 4 mg IV instead of hydrocortisone because it does not interfere with cortisol assays 1, 3

Etiologic Workup After Confirming Primary Adrenal Insufficiency

First-Line Etiology Testing

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmune adrenalitis accounts for ~85% of primary adrenal insufficiency in Western populations 1, 3

If Autoantibodies Are Negative

• Obtain adrenal CT imaging to evaluate for hemorrhage, metastatic disease, tumors, tuberculosis, fungal infections, or other structural abnormalities 1, 3
• In male patients with negative antibodies, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 1, 3

Additional Laboratory Findings That Support the Diagnosis

• Hyponatremia (serum sodium <134 mEq/L) is present in ~90% of newly diagnosed cases 1, 3
• Hyperkalemia occurs in only ~50% of cases; its absence does not exclude adrenal insufficiency 1, 3
• Mild hypercalcemia occurs in 10–20% of patients 1
• Anemia, mild eosinophilia, and lymphocytosis are common hematologic findings 1
• Elevated liver transaminases are frequently observed 1
• Plasma renin activity is typically elevated in primary adrenal insufficiency 1
• TSH may be modestly elevated (4–10 IU/L) due to loss of cortisol-mediated inhibition 1

Differentiating Primary from Secondary Adrenal Insufficiency

Primary Adrenal Insufficiency

• High ACTH with low cortisol pattern 3
• Both glucocorticoid and mineralocorticoid deficiency (hyponatremia + hyperkalemia) 1, 3
• Hyperpigmentation of skin creases, scars, or mucous membranes due to elevated ACTH 1
• Salt craving is a clinical clue 3
• Orthostatic hypotension from mineralocorticoid deficiency 1

Secondary Adrenal Insufficiency

• Low or inappropriately normal ACTH with low cortisol pattern 3
• Glucocorticoid deficiency only; mineralocorticoid function preserved 3
• Normal skin coloration (no hyperpigmentation) because ACTH is low 1
• Hyponatremia without hyperkalemia 3
• May have additional pituitary hormone deficiencies 3

Critical Pitfall: Distinguishing from SIADH

• Before diagnosing SIADH, adrenal insufficiency must be excluded because both present with euvolemic hyponatremia, serum sodium <134 mEq/L, plasma osmolality <275 mOsm/kg, inappropriately high urine osmolality, and elevated urinary sodium 1, 3
• The cosyntropin stimulation test is required to rule out adrenal insufficiency in patients with hypo-osmolar hyponatremia 1, 3
• Treatment differs critically: adrenal insufficiency requires glucocorticoid replacement, whereas SIADH requires fluid restriction 1, 3

Emergency Management Considerations

When to Treat Immediately Without Waiting for Testing

• In hemodynamically unstable patients with suspected adrenal crisis, give 100 mg IV hydrocortisone immediately and start 0.9% saline at 1 L/hour; do not wait for laboratory confirmation 1, 5
• Draw baseline serum cortisol and plasma ACTH before hydrocortisone if feasible, but treatment must not be delayed 1
• Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—mortality is high if untreated 1, 3

High-Risk Clinical Scenarios Requiring Immediate Treatment

• Unexplained collapse, hypotension, and gastrointestinal symptoms (vomiting or diarrhea) 3
• Any patient taking ≥20 mg/day prednisone or equivalent for ≥3 weeks who develops unexplained hypotension 3
• Vasopressor-resistant hypotension in critically ill patients 3

Common Diagnostic Pitfalls to Avoid

• Do not rely on electrolyte abnormalities alone to make or exclude the diagnosis—hyperkalemia is present in only ~50% of cases, and 10–20% of patients have mild hypercalcemia at presentation 1, 3
• Do not attempt diagnostic testing in patients actively receiving corticosteroids, as HPA-axis suppression yields falsely low cortisol results 1, 3
• Do not check morning cortisol in patients on corticosteroids—the assay measures both endogenous cortisol and therapeutic steroids with variable cross-reactivity 3
• Wait until corticosteroids have been discontinued with adequate washout time before performing definitive HPA axis testing 3
• For patients on long-term steroids, consult endocrinology for a recovery and weaning protocol using hydrocortisone rather than attempting abrupt discontinuation and early testing 3