What is the appropriate evaluation and initial management for suspected primary adrenal insufficiency (Addison disease)?

Evaluation and Initial Management of Addison Disease

In suspected primary adrenal insufficiency, immediately obtain paired morning cortisol and plasma ACTH levels, then perform a cosyntropin (ACTH) stimulation test (250 mcg) as the gold standard confirmatory test—but if the patient is acutely ill with suspected adrenal crisis, start IV hydrocortisone 100 mg immediately after drawing labs without waiting for results. 1

Clinical Recognition

Maintain high suspicion in patients presenting with:

• Classic symptoms: Fatigue, anorexia, weight loss, orthostatic hypotension, nausea, salt craving, hyperpigmentation (especially in skin creases, scars, and mucous membranes)
• Laboratory clues: Hyponatremia (present in 90% of cases), hyperkalemia (50% of cases), hypoglycemia (especially children), mild hypercalcemia (10-20%), eosinophilia, lymphocytosis 2
• High-risk populations: Patients with other autoimmune diseases (type 1 diabetes, autoimmune thyroid disease, vitiligo), unexplained TSH elevation (4-10 IU/L range), or on medications that induce AI (ketoconazole, mitotane, etomidate) 1

Critical pitfall: Hyponatremia and hyperkalemia together are NOT reliable markers—sodium is often only marginally reduced and potassium is normal in half of patients at diagnosis. Don't wait for the "classic" electrolyte pattern. 2

Diagnostic Algorithm

Step 1: Initial Screening (When Patient is Stable)

• Morning (8 AM) plasma cortisol AND ACTH (paired sample)
  • Cortisol <250 nmol/L (<9 mcg/dL) with elevated ACTH = diagnostic of primary AI in acute illness 2
  • Cortisol <400 nmol/L (<14.5 mcg/dL) with elevated ACTH = strong suspicion, proceed to confirmatory testing 2
  • Normal cortisol range does NOT exclude AI if inappropriately low for stress state 2

Step 2: Confirmatory Testing

Cosyntropin (ACTH) stimulation test is the gold standard with superior sensitivity and specificity compared to basal levels 1:

• Administer 250 mcg cosyntropin (tetracosactide) IM or IV
• Measure cortisol at baseline, 30 and 60 minutes
• Peak cortisol <500 nmol/L (<18 mcg/dL) = diagnostic of PAI 2

Important consideration: In pregnancy, interpret results carefully as cortisol levels physiologically increase; the test remains safe to perform 1

Step 3: Establish Etiology

Once PAI is confirmed:

1. 21-hydroxylase (anti-adrenal) autoantibodies first—autoimmune is the most common cause 2
2. If antibodies negative: Order CT imaging of adrenals to evaluate for infiltration, hemorrhage, metastases, or infection 2
3. In males with negative antibodies: Measure very long-chain fatty acids to exclude adrenoleukodystrophy 2
4. In children/young adults: Consider autoimmune polyendocrine syndrome type 1 (APS-1) if hypoparathyroidism or chronic candidiasis present 2

Immediate Management for Suspected Adrenal Crisis

Never delay treatment for diagnostic testing when adrenal crisis is suspected (shock, severe hypotension, volume depletion, unexplained collapse) 1, 2:

1. Draw blood for cortisol and ACTH immediately (before any steroid administration if possible)
2. Start IV hydrocortisone 100 mg bolus, then 100 mg every 6-8 hours 2
3. Aggressive IV fluid resuscitation: 0.9% normal saline at 1 L/hour initially until hemodynamic improvement 2
4. Identify and treat precipitant: Most commonly infection (GI infections, fever) or medication non-adherence 3, 4

Chronic Replacement Therapy

Once diagnosis is confirmed and patient is stable:

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg/day in 2-3 divided doses (highest dose upon waking, last dose ≥6 hours before bedtime) 1, 2
• Alternative: Cortisone acetate 20-35 mg/day in divided doses 1
• Children: Hydrocortisone 8 mg/m²/day (or 6-10 mg/m²) 1, 5
• Avoid dexamethasone due to difficulty with dose titration and Cushingoid side effects 1

Mineralocorticoid Replacement (Primary AI Only)

• Fludrocortisone 50-100 mcg daily (range 50-200 mcg), single morning dose 1, 2
• Higher doses may be needed in children, young adults, and third trimester pregnancy (up to 500 mcg) 2
• Unrestricted salt intake is essential—advise patients to eat salty foods liberally 2
• Avoid potassium-containing salt substitutes, liquorice, and grapefruit juice (potentiate mineralocorticoid effects) 2

Monitoring

• Clinical assessment: Weight, postural blood pressure, energy levels, salt craving, signs of glucocorticoid excess 1
• Labs: Serum electrolytes, blood pressure monitoring 2
• Do NOT use hormonal monitoring (cortisol levels) to adjust glucocorticoid doses—adjust based on clinical response only 1
• Screen annually for associated autoimmune diseases, especially thyroid disease (up to 50% develop another autoimmune disorder) 6

Essential Patient Education

All patients must receive 2:

• Steroid emergency card and medical alert identification jewelry
• Injectable hydrocortisone kit for self/family administration (100 mg IM)
• Stress dosing education: Double or triple oral dose during minor illness (fever, GI infection); seek emergency care if unable to tolerate oral medications
• Recognition of adrenal crisis symptoms and when to use emergency injection

Common pitfall: The most frequent precipitants of adrenal crisis are GI infections with vomiting (preventing oral medication absorption) and fever—patients must understand to increase doses proactively and seek help early. 3, 4