What is the treatment for Addison's disease?

Addison's Disease: Clinical Overview

Definition and Epidemiology

Addison's disease is primary adrenal insufficiency caused by destruction of the adrenal cortex, resulting in deficient production of cortisol and aldosterone, requiring lifelong hormone replacement therapy to prevent fatal adrenal crisis. 1

• Prevalence is approximately 10-15 per 100,000 population 1
• Autoimmunity accounts for ~85% of cases in Europe, with tuberculosis, adrenal hemorrhage, and genetic disorders comprising the remainder 1
• The disease destroys the adrenal cortex regardless of underlying etiology 1

Clinical Presentation

Symptoms develop insidiously over months to years, making diagnosis challenging and often delayed. 1

Key clinical features include:

• Salt craving (pathognomonic feature) 1
• Persistent fatigue and myasthenia 2
• Unintentional weight loss 2
• Hypotension 2
• Hyperpigmentation of skin, especially in friction areas 2
• Neuropsychiatric manifestations including depression and psychosis 2

Laboratory abnormalities:

• Hyponatremia (present in 90% of newly diagnosed cases) 1, 3
• Hyperkalemia (approximately 50% of cases) 1, 3
• Low serum cortisol with markedly elevated plasma ACTH 1, 3
• Mild hypercalcemia, anemia, eosinophilia, lymphocytosis may be present 3
• Hypoglycemia in children (rare in adults) 3

Diagnosis

The diagnostic approach follows a two-step process: initial paired cortisol/ACTH measurement, followed by cosyntropin stimulation testing in equivocal cases. 1, 3

Initial Testing

• Measure serum cortisol and plasma ACTH simultaneously 1, 3
• Serum cortisol <250 nmol/L with elevated ACTH during acute illness is diagnostic 1

Confirmatory Testing

• Cosyntropin (synacthen/tetracosactide) stimulation test: 0.25 mg IM or IV 1, 3
• Measure cortisol at baseline, 30 minutes, and/or 60 minutes 3
• Peak serum cortisol <500 nmol/L (or failure to exceed 550 nmol/L) confirms diagnosis 1, 3

Etiologic Diagnosis

• 21-hydroxylase autoantibodies should be first test to establish autoimmune cause 3
• If negative, pursue CT imaging of adrenals, interferon-ω antibodies, and very long-chain fatty acid measurement 3

Critical caveat: If adrenal crisis is suspected, never delay treatment for diagnostic testing—collect blood samples before hydrocortisone administration if possible, but immediate treatment takes absolute priority. 3

Treatment

All patients require lifelong dual hormone replacement with both glucocorticoids and mineralocorticoids. 1, 4

Glucocorticoid Replacement

Hydrocortisone is the first-line glucocorticoid, administered in 2-3 divided doses daily to mimic natural cortisol rhythm. 4

• Standard dosing: 15-25 mg hydrocortisone daily in divided doses 1, 4
• First dose immediately upon waking, last dose at least 6 hours before bedtime 4
• Alternative: Cortisone acetate can be used 1
• Pediatric dosing: 6-10 mg/m² body surface area 4
• Adjust based on clinical assessment, NOT laboratory values 1

Mineralocorticoid Replacement

Fludrocortisone 50-200 μg (0.05-0.2 mg) once daily replaces aldosterone deficiency. 4, 5

• FDA-approved dosing: 0.1 mg daily (range 0.1 mg three times weekly to 0.2 mg daily) 5
• Children and younger adults may require higher doses 4
• If essential hypertension develops, reduce dose but do not discontinue completely 4
• Patients should consume salt freely and avoid licorice and grapefruit juice 4

Dose Adjustments for Special Situations

During minor illness or stress, double or triple oral glucocorticoid dose. 4

Surgery and procedures:

• Major surgery: 100 mg hydrocortisone IM before anesthesia 4
• Continue IV or IM hydrocortisone with increased oral doses perioperatively 4

Pregnancy:

• Small adjustments to both medications may be needed, particularly third trimester 4
• Parenteral hydrocortisone required during delivery 4

Exercise:

• Unaccustomed intense or prolonged exercise may require increased hydrocortisone and salt intake 4

Management of Adrenal Crisis

Adrenal crisis is a life-threatening emergency requiring immediate aggressive treatment without delay. 1, 4

Immediate interventions:

• Hydrocortisone 100 mg IV or IM immediately, then 100 mg every 6-8 hours until recovery 1, 4
• Rapid infusion of isotonic (0.9%) saline at 1 L/hour initially until hemodynamic improvement 1, 4
• Typically 3-4 L given over 24-48 hours 4
• Identify and treat underlying precipitant (infection most common) 4

Associated Autoimmune Conditions

Approximately 50% of patients with autoimmune Addison's disease have coexisting autoimmune disorders. 1

Polyendocrine syndromes:

• APS-1: PAI + hypoparathyroidism + chronic mucocutaneous candidiasis 1
• APS-2: PAI + primary hypothyroidism + other autoimmune conditions 1

Patient Education and Monitoring

All patients must receive comprehensive education on emergency management and wear medical alert identification. 4

Essential patient education:

• Wear Medic Alert bracelet and carry steroid emergency card 1, 4
• Education on dose adjustments during illness or injury 1, 4
• Training on emergency injectable hydrocortisone use 4
• When to seek immediate medical attention 4

Annual Follow-up Requirements

Patients require at least annual monitoring with specific assessments. 1, 4

Monitoring includes:

• Assessment of general health, well-being, weight, and blood pressure 1, 4
• Serum electrolytes (sodium and potassium) 1, 3
• Screening for new autoimmune disorders, particularly hypothyroidism 1, 4, 3
• Assessment for complications of glucocorticoid therapy 1
• Bone mineral density every 3-5 years 4
• Thyroid function tests, plasma glucose, HbA1c, complete blood count, vitamin B12 3

Prognosis

With proper treatment, Addison's disease is manageable as a chronic condition, but premature death from adrenal crisis remains a persistent risk. 1