What is the diagnosis and treatment for a patient with suspected adrenal insufficiency?

Diagnosis and Treatment of Adrenal Insufficiency

Immediate Clinical Decision-Making

If you suspect adrenal crisis (unexplained collapse, severe hypotension, vomiting, altered mental status), give IV hydrocortisone 100 mg immediately and 0.9% saline at 1 L/hour—never delay treatment for diagnostic testing. 1, 2, 3

Diagnostic Approach

Step 1: Initial Laboratory Testing

Obtain paired early morning (8 AM) serum cortisol and plasma ACTH as your first-line diagnostic test 1, 2, 4:

• Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH = diagnostic of primary adrenal insufficiency 1, 2
• Basal cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH = strong suspicion of primary adrenal insufficiency 1, 2
• Low cortisol with low or inappropriately normal ACTH = secondary adrenal insufficiency 2, 4
• Intermediate cortisol (140-400 nmol/L or 5-14.5 μg/dL) = proceed to cosyntropin stimulation test 2, 3

Also check: basic metabolic panel (sodium, potassium, glucose), as hyponatremia is present in 90% of cases and hyperkalemia in only 50% 1, 2, 5.

Step 2: Cosyntropin (Synacthen) Stimulation Test

When to perform: Intermediate morning cortisol values or when diagnosis remains uncertain 1, 2, 3

Protocol 1, 2:

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration
• Peak cortisol <500 nmol/L (<18 μg/dL) = diagnostic of adrenal insufficiency
• Peak cortisol >550 nmol/L (>18-20 μg/dL) = normal, excludes adrenal insufficiency

Critical pitfall: Do not perform this test in patients currently taking hydrocortisone, prednisone, or other corticosteroids—these suppress the HPA axis and cause false-positive results 2. If you must treat suspected adrenal crisis but want to preserve diagnostic testing capability, use dexamethasone 4 mg IV instead of hydrocortisone, as it does not interfere with cortisol assays 2, 3.

Step 3: Determine Etiology

For primary adrenal insufficiency (high ACTH, low cortisol) 2, 3:

• Measure 21-hydroxylase autoantibodies first—autoimmunity causes ~85% of cases in Western populations
• If antibodies negative, obtain CT imaging of adrenals to evaluate for hemorrhage, metastatic disease, tuberculosis, or structural abnormalities

For secondary adrenal insufficiency (low ACTH, low cortisol) 2:

• Obtain pituitary MRI to evaluate for tumors, hemorrhage, or infiltrative disease
• Check other pituitary hormones (TSH, LH, FSH, prolactin, IGF-1)

Treatment

Acute Adrenal Crisis (Life-Threatening Emergency)

Immediate management 1, 2, 3, 6:

1. IV hydrocortisone 100 mg bolus immediately
2. 0.9% saline infusion at 1 L/hour (minimum 2L total)
3. Continue hydrocortisone 100 mg IV every 6-8 hours until stable
4. Draw blood for cortisol and ACTH before treatment if possible, but never delay treatment for testing

Chronic Maintenance Therapy

Glucocorticoid replacement (all patients) 2, 3, 4:

• Hydrocortisone 15-25 mg daily in divided doses (typical: 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) to mimic physiological cortisol rhythm
• Alternative: Prednisone 3-5 mg daily (single morning dose)
• Avoid dexamethasone for chronic replacement 2

Mineralocorticoid replacement (primary adrenal insufficiency only) 2, 3, 4:

• Fludrocortisone 0.05-0.2 mg daily (typical starting dose 0.1 mg)
• Titrate based on blood pressure (supine and standing), salt cravings, and absence of peripheral edema 2
• Secondary adrenal insufficiency does NOT require mineralocorticoid replacement 2

Critical pitfall: When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone to prevent precipitating adrenal crisis 2.

Stress Dosing and Patient Education

All patients must receive 2, 3, 4:

• Medical alert bracelet or necklace indicating adrenal insufficiency
• Injectable hydrocortisone 100 mg IM emergency kit with self-injection training
• Education on doubling or tripling daily dose during fever, illness, or physical stress
• Written instructions on when to use emergency injection (severe vomiting, inability to take oral medication, severe illness)

Stress dosing guidelines 2:

• Minor stress (mild illness, dental work): Double usual daily dose for 1-2 days
• Moderate stress (fever >38°C, gastroenteritis): Triple usual daily dose or hydrocortisone 50-75 mg daily
• Major stress (surgery, severe illness): Hydrocortisone 100-150 mg daily IV/IM in divided doses

Monitoring and Follow-Up

Primary adrenal insufficiency 2, 3:

• Annual screening for associated autoimmune conditions: thyroid function, fasting glucose, complete blood count, vitamin B12, tissue transglutaminase antibodies (celiac disease)
• Monitor for signs of over-replacement (weight gain, hypertension, hyperglycemia) or under-replacement (fatigue, hypotension, weight loss)

Medications that increase hydrocortisone requirements 2: anti-epileptics, rifampin, phenytoin, carbamazepine, topiramate

Medications that decrease hydrocortisone requirements 2: grapefruit juice, liquorice (avoid these)

Key Clinical Pearls

• Hyponatremia is present in 90% of cases but hyperkalemia in only 50%—absence of hyperkalemia does not exclude diagnosis 1, 2, 5
• Hyperpigmentation, salt craving, and hyperkalemia suggest primary adrenal insufficiency 2, 5
• Hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 2
• Patients taking ≥20 mg/day prednisone for ≥3 weeks who develop unexplained hypotension should be presumed to have adrenal insufficiency 2, 5
• Morning nausea and lack of appetite often indicate glucocorticoid under-replacement—consider earlier morning dosing 2
• Persistent hypotension despite adequate glucocorticoid replacement in primary adrenal insufficiency requires optimization of fludrocortisone dosing (may need up to 500 mcg daily in young adults) 2