How should glucocorticoid deficiency be diagnosed and managed?

Glucocorticoid Deficiency: Diagnosis and Management

Diagnosis

Measure early-morning (approximately 8 AM) serum cortisol, ACTH, and DHEAS to diagnose adrenal insufficiency, and if cortisol levels are intermediate (5-10 µg/dL), perform a cosyntropin stimulation test (250 µg) with cortisol measurement at 30 and 60 minutes—a peak cortisol >550 nmol/L (approximately 20 µg/dL) excludes the diagnosis. 1, 2, 3

Diagnostic Approach by Clinical Presentation

Acute presentation (suspected adrenal crisis):

• Draw blood for cortisol and ACTH immediately, but never delay treatment while awaiting results 1, 4
• Administer hydrocortisone 100 mg IV bolus and 0.9% saline 1 L over the first hour without waiting for diagnostic confirmation 1, 4
• Clinical features include hypotension (often <90/60 mmHg), dehydration, nausea/vomiting, abdominal pain, altered mental status, and muscle pain 1, 4
• Laboratory findings typically show hyponatremia (90% of cases), hyperkalemia (50%), increased creatinine from prerenal azotemia, and hypoglycemia (especially in children) 1, 4, 5

Chronic presentation:

• Morning cortisol <5 µg/dL with elevated ACTH and low DHEAS indicates primary adrenal insufficiency 2, 3
• Morning cortisol 5-10 µg/dL with low or low-normal ACTH suggests secondary or glucocorticoid-induced adrenal insufficiency 2, 6
• Nonspecific symptoms include fatigue (50-95%), nausea/vomiting (20-62%), anorexia and weight loss (43-73%), and hyperpigmentation (primary only) 1, 2, 5

Etiologic Workup

After confirming adrenal insufficiency, determine the underlying cause:

• Test for 21-hydroxylase autoantibodies (21OH-Ab)—positive in ~85% of autoimmune Addison's disease in Western Europe 1, 4, 3
• If 21OH-Ab negative, obtain CT scan of adrenals to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative processes 1, 4
• Measure very long chain fatty acids (VLCFA) if adrenoleukodystrophy is suspected 1, 4
• Screen for associated autoimmune conditions, particularly thyroid disease (measure TSH, FT4, TPO-Ab annually) 1

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Management of Chronic Glucocorticoid Deficiency

Glucocorticoid Replacement

Prescribe hydrocortisone 15-25 mg daily divided into 2-3 doses (typically 10 mg + 5 mg + 2.5-5 mg at 07:00,12:00, and 16:00), with the first dose immediately upon awakening and the last dose at least 6 hours before bedtime. 1, 2, 3

Alternative regimens include:

• Cortisone acetate 25-37.5 mg daily in divided doses (12.5 mg + 12.5 mg + 6.25 mg) 1
• Prednisolone 4-5 mg once daily (reserved for select patients with marked energy fluctuations or compliance issues) 1
• Pediatric dosing: hydrocortisone 6-10 mg/m² body surface area daily 1, 3

Common pitfall: Avoid dexamethasone for routine replacement—it lacks mineralocorticoid activity and has an excessively long half-life 1, 4

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

Add fludrocortisone 50-200 µg (0.05-0.2 mg) once daily in the morning for all patients with primary adrenal insufficiency. 1, 7, 2, 3

• Higher doses (up to 500 µg daily) may be needed in children, younger adults, or during the third trimester of pregnancy 1, 7
• Instruct patients to consume salt and salty foods without restriction and avoid potassium-containing salt substitutes 1, 7
• Monitor for adequacy by checking blood pressure (supine and standing) and plasma renin activity (aim for upper normal range) 7, 8

Critical warning: Under-replacement with mineralocorticoids is common and predisposes to recurrent adrenal crises—postural hypotension is an early warning sign 7, 8

Monitoring Glucocorticoid Replacement

Base dose adjustments primarily on clinical assessment rather than laboratory tests, as plasma ACTH and serum cortisol are not useful for monitoring replacement therapy. 1

Signs of over-replacement:

• Weight gain, insomnia, peripheral edema 1

Signs of under-replacement:

• Lethargy, nausea, poor appetite, weight loss, increased or uneven pigmentation 1

When to consider cortisol day curves:

• Suspected malabsorption or rapid cortisol clearance 1
• Measure serum or salivary cortisol before dose and at 2,4, and 6 hours post-dose 1

Drug Interactions

Increase hydrocortisone dose when patients take medications that accelerate cortisol clearance: 1, 4

• Anti-epileptics/barbiturates
• Antituberculosis drugs (rifampin)
• Topiramate
• Etomidate

Decrease hydrocortisone dose with:

• Grapefruit juice
• Licorice 1

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Management of Adrenal Crisis

Immediate Emergency Treatment (First Hour)

Administer hydrocortisone 100 mg IV bolus immediately, then infuse 0.9% isotonic saline 1 L over the first hour—this provides both glucocorticoid and mineralocorticoid activity by saturating 11β-hydroxysteroid dehydrogenase type 2. 1, 4, 9

• If IV access is unavailable, give hydrocortisone 100 mg IM 1, 4
• Draw blood for cortisol, ACTH, electrolytes, creatinine, and glucose before treatment if feasible, but never delay therapy 1, 4

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. 1, 4

• Infuse a total of 3-4 L isotonic saline or 5% dextrose-in-saline over 24-48 hours with frequent hemodynamic monitoring 1, 4
• Admit patients with persistent hypotension to ICU or high-dependency unit 1, 4
• Provide gastric stress ulcer prophylaxis and low-dose heparin 1, 4
• Treat precipitating infections promptly with antimicrobials 1, 4
• Monitor blood glucose frequently, especially in children 4

Do not add fludrocortisone during acute crisis—high-dose hydrocortisone (≥50 mg/day) provides adequate mineralocorticoid effect 1, 7, 4, 8

Transition to Maintenance Therapy

Taper parenteral glucocorticoids over 1-3 days to oral therapy once the precipitating illness permits oral intake. 1, 4

• Resume fludrocortisone only when hydrocortisone dose falls below 50 mg/day 1, 7, 4, 8
• Double the usual oral hydrocortisone dose for 48 hours after resuming oral intake following uncomplicated recovery 4

Common Precipitating Factors

Gastrointestinal illness with vomiting/diarrhea is the most common trigger (patients cannot absorb oral medication when they need it most). 1, 4

Other triggers include:

• Any type of infection 1, 4
• Surgery without adequate steroid coverage 1, 4
• Physical trauma or injuries 1, 4
• Medication non-compliance 1, 4
• Myocardial infarction, severe allergic reactions 4
• Starting thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies 7, 4

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Stress Dosing and Patient Education

Sick Day Rules

Instruct all patients to double or triple their oral hydrocortisone dose during minor illnesses (fever, infection, injury) and to use parenteral hydrocortisone 100 mg IM during severe illness or inability to take oral medications. 1, 4, 2, 10

Surgical and Procedural Stress Dosing

For major surgery, administer hydrocortisone 100 mg IV at induction, then 200 mg per 24 hours as continuous infusion or 50 mg IV/IM every 6 hours until the patient can tolerate oral intake. 1, 4

• For minor procedures (body surface surgery), continue usual oral dose with possible modest increase 1
• For laparoscopic day-case surgery, consider a 23-hour observation protocol 1

Obstetric Management

Give hydrocortisone 100 mg IM at the onset of labor, then continue 200 mg per 24 hours IV infusion (or 50 mg IM every 6 hours) until after delivery. 1, 4

• Fludrocortisone dose may need to increase (up to 500 µg daily) during the third trimester due to progesterone's antimineralocorticoid effects 1, 7

Essential Patient Safety Measures

All patients must: 1, 2, 10, 3

• Wear medical alert jewelry (bracelet or necklace)
• Carry a steroid emergency card
• Have injectable hydrocortisone 100 mg IM kit at home with family member trained in administration
• Receive education on recognizing adrenal crisis symptoms and when to seek emergency care

Critical pitfall: Many patients are discharged with inadequate education about sick day rules—do not assume competency 1, 4

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Annual Follow-Up

Review patients at least annually with assessment of: 1

• Weight, blood pressure (supine and standing), and general well-being
• Serum sodium, potassium, and creatinine
• Thyroid function (TSH, FT4, TPO-Ab) to screen for autoimmune thyroid disease
• Plasma glucose and HbA1c
• Bone mineral density every 3-5 years to monitor for glucocorticoid-induced osteoporosis 1

Investigate recurrent crises by evaluating for: 1, 4

• Chronic under-replacement with fludrocortisone
• Low salt intake
• Poor medication compliance
• Underlying psychiatric disorders

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Special Populations

Glucocorticoid-Induced Adrenal Insufficiency

Suspect this diagnosis in patients who have recently tapered or discontinued supraphysiological glucocorticoid doses—approximately 50% have adrenal insufficiency during ongoing treatment or initially after withdrawal. 2, 6

• Morning cortisol 5-10 µg/dL with low or low-normal ACTH suggests the diagnosis 2, 6
• Perform cosyntropin stimulation test if morning cortisol is intermediate 2, 6
• Treatment principles follow those for secondary adrenal insufficiency (glucocorticoid replacement only, no mineralocorticoid) 2, 6

Pediatric Considerations

Use hydrocortisone 6-10 mg/m² body surface area daily in children, with more frequent blood glucose monitoring during illness or crisis. 1, 4, 3

• Initial fluid bolus for adrenal crisis: 10-20 mL/kg normal saline (maximum 1,000 mL) 4
• Higher fludrocortisone doses (up to 500 µg daily) may be needed 1, 7