How to treat adrenal insufficiency with low cortisol levels?

Treatment of Adrenal Insufficiency ("Lazy Adrenal Gland")

All patients with confirmed adrenal insufficiency require lifelong glucocorticoid replacement therapy with hydrocortisone 15-25 mg daily in divided doses, and those with primary adrenal insufficiency additionally need fludrocortisone 50-200 µg daily for mineralocorticoid replacement. 1, 2

Diagnostic Confirmation Before Treatment

Before initiating treatment, confirm the diagnosis and type of adrenal insufficiency:

• Measure early morning (8 AM) serum cortisol and ACTH levels to distinguish primary from secondary adrenal insufficiency 1, 3
• Primary adrenal insufficiency: Low cortisol (<250 nmol/L or <9 µg/dL) with elevated ACTH 1, 2
• Secondary adrenal insufficiency: Low cortisol with low or inappropriately normal ACTH 3, 2
• If cortisol levels are intermediate (5-10 µg/dL): Perform ACTH stimulation test with 0.25 mg cosyntropin; peak cortisol <500-550 nmol/L (<18-20 µg/dL) at 30-60 minutes confirms adrenal insufficiency 1, 3, 2

Critical caveat: Never delay treatment in suspected acute adrenal crisis to perform diagnostic testing—draw blood for cortisol and ACTH, then immediately administer IV hydrocortisone 100 mg 1, 3, 4

Glucocorticoid Replacement Regimen

Standard Maintenance Therapy

• Hydrocortisone 15-25 mg daily in split doses is the preferred glucocorticoid because it recreates the diurnal cortisol rhythm 1, 4, 2
• Dosing schedule: First dose immediately upon waking, second dose 4-6 hours later, with the last dose at least 6 hours before bedtime 1
• Alternative regimen: Two-thirds of the total dose in the morning and one-third in the early afternoon 4
• Alternative agents: Prednisone 3-5 mg daily (equivalent to 15-25 mg hydrocortisone) can be used if adherence to multiple daily doses is problematic 4, 2

Important pitfall: Taking the morning dose too late can cause morning nausea and fatigue; consider waking earlier to take the first dose and then returning to sleep 3

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

• Fludrocortisone 0.05-0.2 mg daily as a single morning dose for patients with primary adrenal insufficiency 1, 5, 2
• Standard starting dose: 0.1 mg daily, with typical range of 50-200 µg 1, 5
• Titration: Adjust based on blood pressure, serum sodium, potassium, and plasma renin levels (target upper half of reference range) 4
• If hypertension develops: Reduce fludrocortisone dose but do not discontinue 1

Secondary adrenal insufficiency does NOT require mineralocorticoid replacement as the renin-angiotensin-aldosterone system remains intact 4, 2

Stress Dosing Guidelines

Minor Illness (Fever, Cold, Minor Infection)

• Double the usual daily hydrocortisone dose until recovery, continuing for 24-48 hours after symptoms resolve 4

Moderate Illness (Persistent Fever, Gastroenteritis)

• Triple the usual daily dose or use 2-3 times maintenance (hydrocortisone 30-50 mg total daily or prednisone 20 mg daily) 3, 4

Severe Illness, Trauma, or Adrenal Crisis

• Immediate IV or IM hydrocortisone 100 mg bolus without any delay 1, 3, 4
• Follow with hydrocortisone 100 mg IV every 6-8 hours until clinical recovery 1, 4
• Administer IV isotonic (0.9%) sodium chloride solution at 1 L/hour initially until hemodynamic improvement 1, 3
• Identify and treat the underlying precipitant (infection, trauma, surgery) 1

Perioperative Management

• Major surgery: Hydrocortisone 100 mg IV at induction, followed by continuous infusion of 200 mg/24 hours 4
• Continue IV hydrocortisone 200 mg/24 hours postoperatively while nil by mouth 4
• Transition to oral: Double the usual dose for 48 hours after uncomplicated recovery 4

Essential Patient Education and Safety Measures

Mandatory Requirements for All Patients

• Medical alert bracelet or necklace indicating adrenal insufficiency 1, 3, 4
• Steroid emergency card carried at all times 1
• Emergency injectable hydrocortisone kit (100 mg IM) with self-injection training 4, 2
• Written stress-dosing instructions detailing when and how to increase doses 4

Warning Signs of Adrenal Crisis

Educate patients to recognize: severe weakness, confusion, abdominal pain, persistent vomiting, and hypotension 4

Monitoring and Follow-Up

Annual Assessment

• Clinical evaluation: Health status, well-being, weight, blood pressure 1, 4
• Laboratory monitoring: Serum electrolytes (sodium, potassium) 1, 4
• Screen for new autoimmune disorders: Particularly hypothyroidism, diabetes, pernicious anemia, celiac disease 3, 4
• Bone mineral density: Every 3-5 years to assess for glucocorticoid-induced osteoporosis 1

Signs of Under-Replacement

• Lethargy, nausea, poor appetite, weight loss, morning fatigue, increased pigmentation (in primary AI) 3

Signs of Over-Replacement

• Weight gain, hypertension, hyperglycemia, osteoporosis, cushingoid features 1

Titrate to the lowest dose compatible with health and sense of well-being 1

Critical Pitfalls to Avoid

• Never use dexamethasone for long-term replacement in primary adrenal insufficiency as it lacks mineralocorticoid activity 4
• Never initiate thyroid hormone replacement before glucocorticoid replacement in patients with concurrent hypothyroidism and adrenal insufficiency, as this can precipitate adrenal crisis 3, 4
• Do not rely on electrolyte abnormalities alone for diagnosis—hyperkalemia is present in only 50% of primary AI cases 3
• Patients on chronic exogenous steroids (prednisolone ≥5 mg for ≥4 weeks) require perioperative stress dosing even without diagnosed adrenal insufficiency 4

Determining Etiology (After Treatment Initiated)

• Measure 21-hydroxylase (anti-adrenal) autoantibodies as first step—positive in ~85% of autoimmune Addison's disease in Western populations 1, 3
• If antibodies negative: Obtain CT imaging of adrenals to evaluate for hemorrhage, tumors, tuberculosis, or other structural causes 1, 3
• In male patients with negative antibodies: Assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 3