What is the recommended diagnostic work‑up and acute and chronic management for a patient with suspected adrenal insufficiency?

Diagnostic Work-Up and Management of Adrenal Insufficiency

Immediate Recognition and Emergency Treatment

If you suspect acute adrenal crisis—defined by unexplained hypotension, collapse, severe vomiting, altered mental status, or shock—administer hydrocortisone 100 mg IV bolus immediately plus 0.9% saline 1 L over the first hour without waiting for any laboratory confirmation. 1, 2, 3 Draw blood for cortisol, ACTH, electrolytes, glucose, creatinine, and BUN before giving hydrocortisone if feasible, but never delay treatment. 1, 2, 3

Critical Pitfall

Treatment delay increases mortality; over 70% of adrenal insufficiency cases are diagnosed during acute hospital admission where symptoms overlap with other conditions and the diagnosis is easily missed. 4 Never postpone glucocorticoid therapy for diagnostic procedures when adrenal crisis is clinically suspected. 1, 2, 3

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Diagnostic Work-Up for Stable Patients

Step 1: Early Morning (8 AM) Hormonal Assessment

Obtain fasting early-morning serum cortisol, plasma ACTH, and DHEAS simultaneously. 1, 5

Interpretation thresholds:

• Morning cortisol <250 nmol/L (<9 µg/dL) with markedly elevated ACTH (>300 pg/mL) = diagnostic of primary adrenal insufficiency; no further testing needed. 1, 2
• Morning cortisol >550 nmol/L (>18–20 µg/dL) = excludes adrenal insufficiency. 1, 2
• Morning cortisol 250–550 nmol/L (9–20 µg/dL) = indeterminate; proceed to cosyntropin stimulation test. 1, 5
• Low or inappropriately normal ACTH with low cortisol = secondary adrenal insufficiency. 1, 5

Step 2: Cosyntropin (Synacthen) Stimulation Test

Protocol: 1, 2

• Administer 0.25 mg (250 µg) cosyntropin IV or IM
• Measure serum cortisol at baseline, 30 minutes, and optionally 60 minutes
• Peak cortisol <500 nmol/L (<18 µg/dL) = confirms adrenal insufficiency
• Peak cortisol >550 nmol/L (>18–20 µg/dL) = excludes adrenal insufficiency

Important considerations:

• The high-dose (250 µg) test is preferred over low-dose (1 µg) due to easier administration, comparable accuracy, and FDA approval. 1
• Hold hydrocortisone for 24 hours before testing; other steroids require longer washout. 1
• If you must treat suspected crisis but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 1

Step 3: Distinguish Primary vs. Secondary Adrenal Insufficiency

Primary adrenal insufficiency features: 1, 2

• High ACTH (>300 pg/mL) with low cortisol
• Hyponatremia (90% of cases) plus hyperkalemia (~50% of cases)
• Hyperpigmentation of skin creases, scars, mucous membranes
• Salt craving
• Low DHEAS

Secondary adrenal insufficiency features: 1, 5

• Low or inappropriately normal ACTH with low cortisol
• Hyponatremia without hyperkalemia (mineralocorticoid function preserved)
• Normal skin color (no hyperpigmentation)
• May have other pituitary hormone deficiencies

Critical pitfall: The absence of hyperkalemia does not exclude primary adrenal insufficiency—it occurs in only ~50% of cases. 1, 2, 3

Step 4: Etiologic Work-Up for Primary Adrenal Insufficiency

1. Measure 21-hydroxylase autoantibodies (positive in ~85% of autoimmune Addison's disease in Western populations). 1, 2
2. If antibodies are negative, obtain CT scan of adrenals to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative disease. 1, 2
3. In males with negative antibodies, measure very-long-chain fatty acids to screen for adrenoleukodystrophy. 1

Step 5: Basic Metabolic Panel

Check sodium, potassium, glucose, creatinine, BUN, and calcium. 1 Expect hyponatremia (90%), hyperkalemia (~50%), mild hypercalcemia (10–20%), and prerenal azotemia. 2, 3

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Acute Management of Adrenal Crisis

First Hour Emergency Protocol

1. Hydrocortisone 100 mg IV bolus immediately 1, 2, 3
2. 0.9% saline 1 L IV over first hour 1, 2, 3
3. If IV access unavailable, give hydrocortisone 100 mg IM 3

Ongoing Management (First 24–48 Hours)

• Continue hydrocortisone 200 mg per 24 hours as continuous IV infusion (preferred) or 50 mg IV/IM every 6 hours. 3
• Administer total 3–4 L isotonic saline over 24–48 hours with frequent hemodynamic monitoring. 3
• Monitor serum electrolytes frequently to guide fluid management. 3
• Provide gastric stress-ulcer prophylaxis and low-dose heparin. 3
• Treat precipitating infections promptly with appropriate antimicrobials. 3, 6
• Frequent blood glucose monitoring, especially in children. 3
• Admit to ICU or high-dependency unit if persistent hypotension or severe presentation. 3

Do not add separate mineralocorticoid (fludrocortisone) during acute crisis—high-dose hydrocortisone provides adequate mineralocorticoid activity. 3

Transition to Maintenance Therapy

• Taper parenteral glucocorticoids over 1–3 days once precipitating illness permits oral intake. 3
• Resume oral hydrocortisone at double the usual dose for 48 hours after resuming oral intake. 3
• Restart fludrocortisone only when hydrocortisone dose falls below 50 mg per day. 3

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Chronic Maintenance Therapy

Glucocorticoid Replacement

Preferred regimen: Hydrocortisone 15–25 mg daily in divided doses (typically 10 mg at 7:00 AM, 5 mg at 12:00 PM, 2.5–5 mg at 4:00 PM). 1, 2, 5

Alternative regimens: 1, 2

• Cortisone acetate 25–37.5 mg daily in divided doses
• Prednisone 3–5 mg daily (for select patients with marked energy fluctuations)

Avoid dexamethasone for chronic replacement. 1

Mineralocorticoid Replacement (Primary AI Only)

Fludrocortisone 50–200 µg daily (typical starting dose 0.05–0.1 mg daily). 1, 2, 5 Adjust based on:

• Salt cravings
• Orthostatic blood pressure
• Peripheral edema
• Plasma renin activity

Unrestricted sodium salt intake is essential. 1

Secondary adrenal insufficiency does not require fludrocortisone because aldosterone production is preserved. 3

Monitoring Adequacy of Replacement

Do not rely on serum cortisol or ACTH measurements—use clinical assessment. 1

Signs of under-replacement: 1

• Lethargy, fatigue
• Morning nausea, poor appetite
• Weight loss
• Orthostatic hypotension

Signs of over-replacement: 1

• Weight gain
• Insomnia
• Peripheral edema

Practical tip: Have patients wake earlier to take first hydrocortisone dose, then return to sleep—this relieves morning nausea and lack of appetite. 1

Drug Interactions Requiring Dose Adjustment

Increase hydrocortisone dose if taking: 1

• CYP3A4 inducers: phenytoin, carbamazepine, phenobarbital, rifampin, antituberculosis drugs

Decrease hydrocortisone dose if consuming: 1

• Grapefruit juice
• Licorice

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Stress Dosing and Prevention of Adrenal Crisis

Sick Day Rules

Minor illness with fever: Double or triple usual glucocorticoid dose. 2, 6

Moderate stress (e.g., outpatient procedures): Hydrocortisone 30–50 mg total daily or prednisone 20 mg daily. 1

Major stress (e.g., major surgery): Hydrocortisone 100–150 mg daily. 1

Severe vomiting or inability to take oral medications: Use emergency injectable hydrocortisone 100 mg IM immediately and seek medical care. 2, 6

Patient Education and Safety Measures (Mandatory)

1. Wear medical alert bracelet or necklace indicating adrenal insufficiency. 1, 2, 5
2. Carry steroid emergency card at all times. 6
3. Prescribe emergency injectable hydrocortisone 100 mg IM kit with self-injection training. 2, 5
4. Educate on warning signs of impending crisis: severe weakness, confusion, persistent vomiting, hypotension. 1
5. Instruct to double/triple dose during illness and use injectable if unable to take oral medications. 2, 6

Critical pitfall: Inadequate patient education and failure to increase glucocorticoid dose during illness are the most frequent contributors to recurrent adrenal crises. 3, 6

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Annual Monitoring and Screening

• Assess health, well-being, weight, blood pressure 1
• Serum sodium, potassium, glucose, HbA1c, CBC 2
• Thyroid function tests (TSH, FT4, TPO antibodies) 1, 2
• Vitamin B12 levels 1, 2
• Screen for celiac disease if frequent diarrhea (tissue transglutaminase antibodies, total IgA) 1
• Bone mineral density every 3–5 years 1

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Special Situations

Glucocorticoid-Induced Adrenal Insufficiency

Do not attempt diagnostic testing while patient is on corticosteroids or immediately after stopping—this yields false-positive results reflecting expected HPA suppression. 1, 4 Wait until corticosteroid treatment is ready to be discontinued with adequate washout time (hydrocortisone 24 hours; prednisone longer). 1

For long-term steroid exposure, consult endocrinology for recovery and weaning protocol using hydrocortisone rather than attempting abrupt discontinuation. 1

Concurrent Hypothyroidism

Start glucocorticoid replacement several days before initiating thyroid hormone to prevent precipitating adrenal crisis. 1, 2, 3

Pregnancy and Labor

Administer hydrocortisone 100 mg IM at onset of labor, then continue 200 mg per 24 hours IV infusion (or 50 mg IM every 6 hours) until after delivery. 3

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Common Precipitating Factors for Adrenal Crisis

• Gastrointestinal illness with vomiting/diarrhea (most common) 3, 6
• Any infection 3, 6
• Surgical procedures without adequate steroid coverage 3, 6
• Physical trauma or injuries 3, 6
• Medication non-compliance 3, 6
• Myocardial infarction 3
• Severe allergic reactions 3
• Chronic under-replacement with fludrocortisone plus low salt intake 3
• Starting thyroid hormone before adequate glucocorticoid replacement 3