What is the recommended workup and acute and chronic management for a patient suspected of adrenal insufficiency?

Adrenal Insufficiency: Workup and Management

Diagnostic Workup

Obtain early morning (8 AM) serum cortisol and plasma ACTH as the first-line diagnostic tests, along with a basic metabolic panel to assess for hyponatremia and hyperkalemia. 1, 2

Initial Laboratory Interpretation

• Morning cortisol <250 nmol/L (<9 µg/dL) with markedly elevated ACTH (>300 pg/mL) is diagnostic of primary adrenal insufficiency and requires no further testing 1
• Morning cortisol >550 nmol/L (>18–20 µg/dL) effectively excludes adrenal insufficiency 1
• Morning cortisol between 5–18 µg/dL requires cosyntropin stimulation testing to definitively confirm or exclude the diagnosis 1, 2
• Low or inappropriately normal ACTH with low cortisol indicates secondary adrenal insufficiency 1, 2

Cosyntropin Stimulation Test Protocol

When morning cortisol is indeterminate, perform the high-dose test:

• Administer 0.25 mg (250 µg) cosyntropin IV or IM 1
• Measure serum cortisol at baseline, 30 minutes, and optionally 60 minutes 1
• Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency; peak >550 nmol/L (>18–20 µg/dL) excludes it 1
• The high-dose test is preferred over low-dose (1 µg) due to easier administration, comparable accuracy, and FDA approval 1

Etiologic Workup for Primary Adrenal Insufficiency

Once primary adrenal insufficiency is confirmed:

• Measure 21-hydroxylase autoantibodies first, as autoimmune adrenalitis accounts for ~85% of cases in Western populations 1
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative disease 1
• In males with negative autoantibodies, measure very long-chain fatty acids to screen for adrenoleukodystrophy 1

Critical Diagnostic Pitfalls

• Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—if the patient is clinically unstable with hypotension, altered mental status, or severe vomiting, give hydrocortisone 100 mg IV immediately and start 0.9% saline at 1 L/hour 1, 3
• Draw blood for cortisol and ACTH before treatment if possible, but do not wait for results 1, 3
• The absence of hyperkalemia does not exclude adrenal insufficiency—it is present in only ~50% of cases 1, 3
• Hyponatremia is present in 90% of newly diagnosed cases and can mimic SIADH; always exclude adrenal insufficiency before diagnosing SIADH 1
• Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound testing—wait until adequate washout before performing diagnostic tests 1

---

Acute Management: Adrenal Crisis

Adrenal crisis is a life-threatening emergency requiring immediate treatment without waiting for diagnostic confirmation.

Immediate Emergency Protocol (First Hour)

• Give hydrocortisone 100 mg IV bolus immediately upon clinical suspicion 4, 3
• Start 0.9% isotonic saline at 1 L over the first hour to address severe volume depletion 4, 3
• If IV access cannot be established rapidly, give hydrocortisone 100 mg IM as backup 3
• Obtain blood samples for cortisol, ACTH, electrolytes, creatinine, and glucose before treatment if feasible, but never delay therapy 4, 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 4, 3
• Administer a total of 3–4 L of 0.9% saline over 24–48 hours with frequent hemodynamic monitoring 4, 3
• Monitor serum electrolytes frequently to guide fluid management 4, 3
• Provide gastric stress-ulcer prophylaxis and low-dose heparin for DVT prophylaxis 4, 3
• Treat any precipitating infections with appropriate antimicrobial therapy 4, 3
• Admit patients with persistent hypotension to ICU or high-dependency unit 4, 3

Transition to Maintenance Therapy

• Taper parenteral glucocorticoids over 1–3 days to oral therapy once the precipitating illness resolves and the patient can tolerate oral intake 4, 3
• Resume oral hydrocortisone at double the usual maintenance dose for 48 hours after resuming oral intake 3
• Restart fludrocortisone only when hydrocortisone dose falls below 50 mg per day, as higher doses provide adequate mineralocorticoid activity 4, 3

Common Precipitating Factors

• Gastrointestinal illness with vomiting/diarrhea (most common trigger) 4, 3
• Any type of infection 4, 3
• Surgical procedures without adequate steroid coverage 4, 3
• Physical trauma or injuries 4, 3
• Medication non-compliance 3
• Starting thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies 4, 3

---

Chronic Maintenance Management

Glucocorticoid Replacement

The preferred regimen is hydrocortisone 15–25 mg daily in divided doses to approximate the normal diurnal cortisol rhythm. 4, 2

• Typical dosing schedule: 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5–5 mg at 4:00 PM 4
• Alternative regimens include 15+5 mg or 10+5+5 mg depending on individual response 1
• The first dose should be taken immediately upon waking; the last dose should be at least 6 hours before bedtime to avoid sleep disturbances 4
• Alternative glucocorticoids: cortisone acetate 25–37.5 mg daily in divided doses or prednisone 3–5 mg daily 4, 2
• Hydrocortisone is preferred over long-acting steroids because it allows recreation of the diurnal cortisol rhythm 1

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

• Fludrocortisone 50–200 µg once daily is required for all patients with primary adrenal insufficiency 4, 2
• Higher doses (up to 500 µg daily) may be needed in children, younger adults, or during the last trimester of pregnancy 4
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity 1, 4
• Patients should consume salt and salty foods without restriction 4
• Secondary adrenal insufficiency does not require fludrocortisone because the renin-angiotensin-aldosterone system remains intact 1, 3

Monitoring Replacement Adequacy

Monitoring should rely primarily on clinical assessment rather than serum cortisol or ACTH measurements. 1

• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss, morning symptoms, postural hypotension, salt craving 1, 4
• Signs of over-replacement: weight gain, insomnia, peripheral edema, hypertension 1
• Adjust timing of glucocorticoid dosing based on when symptoms occur during the day 1
• For morning nausea, consider waking earlier to take the first dose and then returning to sleep 1

Drug Interactions Affecting Hydrocortisone Requirements

• CYP3A4 inducers increase hydrocortisone clearance and may require higher doses: phenytoin, carbamazepine, phenobarbital, rifampin, other antituberculosis drugs 1, 4
• CYP3A4 inhibitors decrease hydrocortisone clearance and may require lower doses: grapefruit juice, licorice 1, 4
• Medications that interfere with fludrocortisone: diuretics, acetazolamide, NSAIDs 1

---

Stress Dosing and Prevention of Adrenal Crisis

Patient Education (Critical for Preventing Crisis)

All patients must be educated on stress dosing, as inadequate patient education is a frequent contributor to recurrent adrenal crises. 4, 5

• During minor illnesses with fever, double or triple the usual glucocorticoid dose 4, 2
• During severe illness with vomiting or inability to take oral medications, use parenteral hydrocortisone 100 mg IM immediately 4, 2
• Every patient should wear a medical alert bracelet or necklace indicating adrenal insufficiency 1, 4
• Provide a steroid emergency card at all times 4, 5
• Prescribe an emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1, 4, 5

Perioperative Stress Dosing

• Minor surgery: 100 mg hydrocortisone IM before anesthesia, then double oral dose for 24 hours 4
• Major surgery: 100 mg hydrocortisone IM before anesthesia, followed by 100 mg IM every 6 hours until able to take oral medications 4
• Continue stress-dose hydrocortisone throughout any surgical intervention without reduction 3
• Arrange endocrine consultation prior to surgery for stress-dose planning 1

Special Considerations

• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 1, 4, 3
• In patients with cirrhosis and refractory shock, consider screening for adrenal insufficiency or empiric hydrocortisone 50 mg IV q6h 1
• Patients on immune checkpoint inhibitors who develop hypophysitis are at particular risk of adrenal crisis, especially during rapid corticosteroid tapers 4, 3

---

Annual Follow-Up and Screening

• Assess health, well-being, weight, blood pressure, and serum electrolytes at least annually 1, 4
• Screen periodically for new autoimmune disorders, particularly hypothyroidism (TSH, FT4, TPO-Ab), diabetes, pernicious anemia (vitamin B12), and celiac disease (tissue transglutaminase 2 autoantibodies) 1, 4
• Monitor bone mineral density every 3–5 years to assess for complications of glucocorticoid therapy 1

---

Key Clinical Pearls

• Orthostatic hypotension is an early and cardinal feature of adrenal insufficiency, occurring before supine hypotension develops 3
• Hyperpigmentation of skin creases, scars, or mucous membranes strongly suggests primary adrenal insufficiency due to elevated ACTH 3
• Normal skin coloration favors secondary adrenal insufficiency, where ACTH production is low 3
• Persistent pyrexia may be due to adrenal insufficiency itself, not just infection—do not reduce steroid supplementation while the patient is febrile 3
• Even a mild upset stomach may precipitate an adrenal crisis, as patients cannot absorb their oral medication when they need it most 3
• Patients with confirmed adrenal insufficiency require lifelong hydrocortisone replacement therapy—never attempt to discontinue in patients with primary or secondary adrenal insufficiency from non-iatrogenic causes 1