What is the diagnostic approach for adrenal insufficiency?

Diagnostic Approach for Adrenal Insufficiency

Initial Clinical Recognition

Suspect adrenal insufficiency in any patient presenting with unexplained collapse, hypotension, vomiting, diarrhea, or fatigue, particularly when accompanied by hyponatremia. 1

Key clinical features that increase suspicion include:

• Hyperpigmentation (in primary adrenal insufficiency) 1
• Hyponatremia (present in 90% of cases) 1, 2
• Hyperkalaemia (only in ~50% of cases—absence does NOT rule out adrenal insufficiency) 1, 2
• Hypoglycemia, acidosis 1
• Recent glucocorticoid use (≥20 mg/day prednisone or equivalent for ≥3 weeks) 2

Critical pitfall: Never delay treatment of suspected acute adrenal crisis for diagnostic testing—if the patient is unstable, give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour. 1, 2

Step 1: First-Line Laboratory Testing

Obtain early morning (8 AM) paired measurements of serum cortisol and plasma ACTH as the initial diagnostic test. 1, 2, 3

Additional baseline labs to order:

• Serum sodium, potassium, glucose (to assess for characteristic electrolyte abnormalities) 2
• DHEAS (low in primary adrenal insufficiency) 1, 3
• Plasma renin activity (elevated in primary adrenal insufficiency) 1

Interpretation of Morning Cortisol and ACTH:

Primary adrenal insufficiency:

• Serum cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic in acute illness 1, 2
• Serum cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion in acute illness 1

Secondary adrenal insufficiency:

• Low cortisol (140-275 nmol/L or 5-10 μg/dL) with low or inappropriately normal ACTH 2, 3

Rule-out threshold:

• Morning cortisol >360 nmol/L (>13 μg/dL) reliably rules out adrenal insufficiency 4

Important caveat: Exogenous steroids (prednisolone, dexamethasone) and inhaled steroids (fluticasone) can confound cortisol interpretation. 1

Step 2: Confirmatory Testing with ACTH Stimulation Test

For equivocal morning cortisol results (between 250-360 nmol/L), perform the cosyntropin (Synacthen) stimulation test. 1, 2

Test Protocol:

Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously. 1, 5

• For pediatric patients <2 years: use 0.125 mg 5
• For pediatric patients 2-17 years: use 0.25 mg 5

Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration. 1, 2, 5

Interpretation:

• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>20 μg/dL) is normal 2, 3

Critical consideration: The high-dose (250 mcg) test is preferred over the low-dose (1 mcg) test due to easier administration, comparable diagnostic accuracy, and FDA approval. 2 The low-dose test requires bedside dilution, making it impractical for routine use. 2

Pre-Test Medication Management:

Stop glucocorticoids and spironolactone on the day of testing. 5

• Long-acting glucocorticoids require longer discontinuation periods 5
• Estrogen-containing drugs should be stopped 4-6 weeks before testing (elevate cortisol-binding globulin, falsely elevating total cortisol) 5

Exception: If you need to treat suspected adrenal crisis but still want to perform confirmatory testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as it does not interfere with cortisol assays. 2

Step 3: Etiologic Workup (After Confirming Diagnosis)

For Primary Adrenal Insufficiency:

Measure 21-hydroxylase (anti-adrenal) autoantibodies first—autoimmunity accounts for ~85% of primary adrenal insufficiency in Western populations. 1, 2

If autoantibodies are negative:

• Obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, fungal infections, or other structural causes 1, 2
• In male patients, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 2

For Secondary Adrenal Insufficiency:

Evaluate for pituitary pathology (tumors, hemorrhage, hypophysitis, sarcoidosis) and medication causes (opioids, checkpoint inhibitors). 3

Special Diagnostic Scenarios

Distinguishing Adrenal Insufficiency from SIADH:

Both conditions present with euvolemic hypo-osmolar hyponatremia and can be clinically indistinguishable. 2 The absence of hyperkalemia cannot rule out adrenal insufficiency. 2 Perform the cosyntropin stimulation test to definitively exclude adrenal insufficiency before diagnosing SIADH. 2

Alternative Testing Method:

Home waking salivary cortisone sampling has 95% sensitivity and specificity for diagnosing adrenal insufficiency and may be used as an alternative screening tool when clinic attendance is difficult. 6 However, this is not yet standard practice and requires specialized laboratory capabilities. 6

Common Pitfalls to Avoid

• Do not rely solely on electrolyte abnormalities—10-20% of patients have normal electrolytes at presentation, and hyperkalemia occurs in only ~50% of cases 1, 2
• Do not wait for test results if adrenal crisis is suspected—mortality is high if untreated 2
• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before thyroid hormone replacement to prevent precipitating adrenal crisis 2
• Remember that vasopressor-resistant hypotension may be the only presenting sign in critically ill patients 2