What are the diagnostic criteria and treatment options for adrenal insufficiency?

Diagnosing Adrenal Insufficiency

Obtain an early morning (8 AM) serum cortisol and plasma ACTH as your first-line diagnostic test, and if the morning cortisol is <250 nmol/L (<9 μg/dL) with elevated ACTH in the setting of acute illness, this is diagnostic of primary adrenal insufficiency without need for further testing. 1, 2

Initial Diagnostic Workup

Morning cortisol and ACTH measurements:

• Draw blood at approximately 8 AM for serum cortisol, plasma ACTH, and DHEAS 1, 3
• Simultaneously obtain a basic metabolic panel (sodium, potassium, CO2, glucose) to assess for electrolyte abnormalities 1
• Critical interpretation thresholds:
  • Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH = diagnostic of primary adrenal insufficiency 1, 2, 3
  • Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH = suggestive of secondary adrenal insufficiency 1, 3
  • Morning cortisol >400 nmol/L (>14.5 μg/dL) effectively rules out adrenal insufficiency 1

Key electrolyte patterns to recognize:

• Hyponatremia is present in 90% of newly diagnosed cases and is the most common finding 1, 2
• Hyperkalemia occurs in only ~50% of cases, so its absence does NOT rule out adrenal insufficiency 1, 2
• Some patients (10-20%) may have mild hypercalcemia or completely normal electrolytes 1

Confirmatory Testing: Cosyntropin Stimulation Test

When to perform the test:

• Use this test when morning cortisol values are intermediate (140-400 nmol/L or 5-14.5 μg/dL) 1, 2
• Also indicated when clinical suspicion remains high despite borderline morning cortisol 1

Test protocol (per FDA label):

• Adults: Administer 0.25 mg (250 mcg) cosyntropin IV or IM 4
• Pediatric dosing:
  • Birth to <2 years: 0.125 mg 4
  • 2-17 years: 0.25 mg 4
• Obtain baseline serum cortisol, then measure cortisol at exactly 30 and 60 minutes post-administration 1, 4

Interpretation:

• Peak cortisol <500 nmol/L (<18 μg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency 1, 2, 4
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is considered normal and rules out adrenal insufficiency 1, 2

Important medication considerations before testing:

• Stop glucocorticoids and spironolactone on the day of testing (they falsely elevate cortisol levels) 4
• Long-acting glucocorticoids may need to be stopped for a longer period 4
• Stop estrogen-containing drugs 4-6 weeks before testing (they elevate cortisol-binding globulin and total cortisol) 4
• Inhaled steroids like fluticasone can suppress the HPA axis and confound results 1

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency pattern:

• Low cortisol + high ACTH 1, 3
• Low DHEAS 3
• Both glucocorticoid AND mineralocorticoid deficiency (hyponatremia + hyperkalemia when present) 1

Secondary adrenal insufficiency pattern:

• Low cortisol + low or inappropriately normal ACTH 1, 3
• Low or low-normal DHEAS 3
• Glucocorticoid deficiency only (mineralocorticoid function preserved) 1
• May have additional pituitary hormone deficiencies 1

Etiologic Workup After Diagnosis

For confirmed primary adrenal insufficiency:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as 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, fungal infections, 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:

• Obtain MRI of the pituitary to evaluate for tumors, hemorrhage, inflammatory conditions (hypophysitis, sarcoidosis), or infiltrative disease 3
• Assess other pituitary hormone axes 1

Critical Pitfalls to Avoid

NEVER delay treatment for diagnostic testing in suspected adrenal crisis:

• If a patient presents with unexplained collapse, hypotension, vomiting/diarrhea, or profound fatigue, treat immediately 1, 2
• Give IV hydrocortisone 100 mg bolus immediately, followed by 100 mg every 6-8 hours 1, 2
• Infuse 0.9% saline at 1 L/hour 1, 2
• Draw blood for cortisol and ACTH before treatment if possible, but do NOT delay treatment to obtain these samples 1, 2

Special scenario—if you need to treat but want to preserve diagnostic testing:

• Use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1, 2
• This allows you to perform cosyntropin stimulation testing later 1, 2

High-risk populations requiring heightened suspicion:

• Any patient taking ≥20 mg/day prednisone (or equivalent) for ≥3 weeks who develops unexplained hypotension 1, 2
• Patients with vasopressor-resistant hypotension despite adequate fluid resuscitation 1
• Critically ill patients with cirrhosis and refractory shock 1

Do not rely solely on electrolyte abnormalities:

• Between 10-20% of patients have normal electrolytes at presentation 1
• The absence of hyperkalemia does NOT exclude adrenal insufficiency 1, 2

Special Diagnostic Consideration: Differentiating from SIADH

When evaluating hypo-osmolar hyponatremia:

• Adrenal insufficiency must be excluded BEFORE diagnosing SIADH, as both present with euvolemic hypo-osmolar hyponatremia 1
• Both conditions show serum sodium <134 mEq/L, plasma osmolality <275 mOsm/kg, inappropriately high urine osmolality, and elevated urinary sodium 1
• The standard 0.25 mg cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in this setting 1
• This distinction is crucial because treatment differs dramatically: adrenal insufficiency requires glucocorticoid replacement, while SIADH requires fluid restriction 1

Treatment Based on Diagnosis

Maintenance therapy for confirmed adrenal insufficiency:

• Glucocorticoid replacement (all patients): Hydrocortisone 15-25 mg daily OR prednisone 3-5 mg daily 1, 3
• Mineralocorticoid replacement (primary AI only): Fludrocortisone 50-200 mcg daily 1, 3

Critical patient education requirements:

• All patients need education on stress dosing during acute illness 1, 2
• Prescribe injectable hydrocortisone 100 mg IM for emergency self-administration 3
• Patients should wear a medical alert bracelet 1, 2
• Arrange endocrine consultation prior to surgery or procedures for stress-dose planning 1

Important sequencing consideration:

• When treating secondary adrenal insufficiency with concurrent hypothyroidism, start corticosteroids several days BEFORE initiating thyroid hormone replacement to prevent precipitating adrenal crisis 1

Annual screening for associated conditions (primary AI):

• Thyroid function, plasma glucose, complete blood count, vitamin B12, and tissue transglutaminase antibodies 2