What is the diagnostic and treatment approach for Addison's disease?

Diagnostic and Treatment Approach for Addison's Disease

Initial Diagnostic Workup

The diagnosis of Addison's disease requires measurement of serum cortisol and ACTH levels, with confirmation by cosyntropin stimulation testing when necessary, followed by etiologic determination through 21-hydroxylase antibody testing. 1

First-Line Laboratory Tests

• Measure serum cortisol and ACTH simultaneously as the cornerstone diagnostic tests, typically showing low or inappropriately normal cortisol with markedly elevated ACTH 1
• Check serum electrolytes: hyponatremia is present in approximately 90% of newly diagnosed cases, and hyperkalemia occurs in about 50% of patients at diagnosis due to aldosterone deficiency 1
• Additional supportive findings include mild to moderate hypercalcemia, anemia, mild eosinophilia, lymphocytosis, and elevated liver transaminases 1
• In children specifically, check for hypoglycemia, which is rare in adults 1

Confirmatory Testing

• Perform a cosyntropin (synacthen) stimulation test when partial adrenal insufficiency is suspected or results are equivocal by administering 0.25 mg cosyntropin intramuscularly or intravenously 2, 1
• Measure serum cortisol at baseline, 30 minutes, and/or 60 minutes after administration 2, 1
• A normal response requires cortisol to exceed 550 nmol/L at either the 30 or 60-minute mark 2, 1

Critical Caveat for Acute Presentations

• If there is clinical suspicion of impending acute adrenal crisis, immediately administer intravenous hydrocortisone and 0.9% saline infusion without waiting for diagnostic procedures 2, 1
• Secure blood samples for cortisol and ACTH measurement prior to treatment if possible, but never delay treatment 2, 1
• The diagnosis can always be established later, even after treatment has commenced 2

Etiologic Diagnosis

Primary Etiologic Test

• Assay 21-hydroxylase autoantibodies (21OH-Ab) as the first test to establish an autoimmune cause, which accounts for approximately 85% of cases in Western Europe after excluding congenital adrenal hyperplasia 2, 1
• If 21OH-Ab is positive, further etiologic evaluation is generally not necessary 2

When 21OH-Ab is Negative

• Perform CT imaging of the adrenal glands to demonstrate tumors or calcifications typical of tuberculosis 2, 1
• In males, screen for adrenoleukodystrophy by measuring very long-chain fatty acids (VLCFA) 2, 1
• Consider testing for interferon omega or IL-22 autoantibodies if APS-1 is suspected (particularly in young patients with hypoparathyroidism, candidiasis, dental enamel dysplasia, keratitis, autoimmune hepatitis, malabsorption, or premature ovarian insufficiency) 2
• Note that 21OH-Ab are often absent in children and the elderly, who may have genetic causes or tuberculosis/hemorrhage/malignant disorders respectively 2

Treatment Approach

Standard Maintenance Therapy

The standard treatment consists of lifelong hormone replacement with oral hydrocortisone (15-25 mg daily in 2-3 divided doses) and fludrocortisone (50-200 μg once daily), with dose adjustments during illness, stress, or surgery to prevent potentially fatal adrenal crisis. 3

Glucocorticoid Replacement

• Hydrocortisone is the first-line glucocorticoid replacement, administered in divided doses (typically 2-3 times daily) to mimic the natural cortisol rhythm 3
• Give the first dose immediately after waking and the last dose at least 6 hours before bedtime 3
• Start with 15-25 mg of hydrocortisone daily, using the lowest effective dose to minimize side effects while maintaining well-being 3
• In children, dose hydrocortisone at 6-10 mg/m² of body surface area 3
• Per FDA labeling, hydrocortisone is preferably administered in conjunction with fludrocortisone at 10-30 mg daily in divided doses 4

Mineralocorticoid Replacement

• Administer fludrocortisone at 50-200 μg (0.05-0.2 mg) once daily to replace aldosterone 3, 4
• Children and younger adults may require higher doses of fludrocortisone 3
• If essential hypertension develops, reduce the fludrocortisone dose but do not completely discontinue 3
• Advise patients to consume salt and salty foods freely and to avoid licorice and grapefruit juice 3

Management of Adrenal Crisis

• Immediately treat adrenal crisis with 100 mg IV or IM hydrocortisone, followed by 100 mg every 6-8 hours until recovery 3
• Administer isotonic (0.9%) saline at an initial rate of 1 L/hour until hemodynamic improvement, with 3-4 L typically given over 24-48 hours 3
• Identify and treat the underlying precipitant of the crisis (e.g., infection) 3

Dose Adjustments for Special Situations

• During minor illness or stress, patients should double or triple their oral glucocorticoid dose 3
• For major surgery, give 100 mg hydrocortisone IM before anesthesia 3
• During pregnancy, make small adjustments to hydrocortisone and fludrocortisone doses, particularly in the third trimester, with parenteral hydrocortisone during delivery 3
• For unaccustomed intense or prolonged exercise, increase hydrocortisone and salt intake 3

Monitoring and Follow-Up

Annual Clinical Assessment

• Review patients at least annually with assessment of general health and well-being, measurement of weight, blood pressure, and serum electrolytes 5, 3
• Weight and blood pressure at each visit detect signs of over-replacement or under-replacement 5
• Check serum sodium and potassium annually to detect hyponatremia or hyperkalemia, which may indicate glucocorticoid under-replacement or fludrocortisone excess 5
• Assess energy levels, morning nausea, appetite, and timing of symptom patterns to guide dose adjustments 5

Mineralocorticoid Monitoring

• Guide fludrocortisone dosing by blood pressure, serum electrolytes, and assessment of salt cravings, with a typical dose range of 50-200 µg daily 5

Screening for Associated Conditions

• Perform thyroid function testing periodically, as autoimmune hypothyroidism is common in patients with autoimmune Addison's disease 5, 3
• Screen for other autoimmune disorders, including diabetes mellitus, pernicious anemia, and celiac disease, particularly in patients with autoimmune etiology 5

Bone Health Monitoring

• Assess bone mineral density every 3-5 years to monitor for glucocorticoid-induced osteoporosis 5, 3

Important Monitoring Limitations

• Serum cortisol levels are not useful for monitoring adequacy of replacement therapy, as hydrocortisone produces highly variable peaks and troughs throughout the day 5
• ACTH levels do not guide dose adjustments in established Addison's disease, as they remain elevated regardless of replacement adequacy 5

Patient Education Requirements

• All patients must receive education on dose adjustments during illness, use of emergency injectable hydrocortisone, and when to seek medical attention 3
• Patients should recognize signs of under-replacement and over-replacement, and understand stress dosing protocols 5, 3
• Patients must wear medical alert identification (bracelet/necklace) and carry an emergency steroid card 5, 3
• Patients should carry emergency injectable hydrocortisone 5