What is Addison's disease?

Addison's Disease Definition

Addison's disease is a rare endocrine disorder resulting from damage to the adrenal cortex, leading to inadequate production of cortisol and aldosterone, regardless of the underlying cause. 1

Epidemiology and Etiology

• The prevalence of Addison's disease is approximately 10-15 per 100,000 population, making it a relatively rare condition 1
• In Europe, autoimmune adrenalitis is the predominant cause (approximately 85% of cases) 1, 2
• Other causes include:
  • Tuberculosis and other infectious agents 1, 3
  • Adrenal hemorrhage 1, 3
  • Metastatic neoplasms 3
  • Genetic disorders such as adrenoleukodystrophy 1, 3
  • Iatrogenic causes including medications that inhibit steroidogenesis 3, 4

Pathophysiology

• The disease involves disruption of the hypothalamic-pituitary-adrenal (HPA) axis 3
• Cortisol deficiency affects metabolism, immune function, and stress responses 3
• Aldosterone deficiency leads to dysregulation of sodium and potassium homeostasis, causing hypotension and dehydration 3

Clinical Presentation

• Symptoms typically develop insidiously over months to years 1, 5
• Common manifestations include:
  • Persistent fatigue and weakness 3, 5
  • Unintentional weight loss 3, 5
  • Hypotension, especially orthostatic 5
  • Hyperpigmentation of the skin, particularly in sun-exposed areas, palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa 3, 5
  • Salt craving 1
  • Gastrointestinal symptoms such as anorexia and diarrhea 5
  • Neuropsychiatric manifestations including depression and psychosis 3

Laboratory Findings

• Hyponatremia (present in 90% of newly diagnosed cases) 1
• Hyperkalemia (in approximately 50% of cases) 1
• Low serum cortisol and high plasma ACTH levels 1

Diagnosis

• Diagnosis follows a two-step approach 1:
  1. Initial diagnostic test: Paired measurement of serum cortisol and plasma ACTH 1
  2. Serum cortisol <250 nmol/L with elevated ACTH during acute illness is diagnostic 1
• In equivocal cases, a synacthen (tetracosactide) stimulation test is performed (0.25 mg IM or IV), with peak serum cortisol <500 nmol/L confirming the diagnosis 1
• Measurement of basal plasma cortisol alone is an insensitive screening test 5

Associated Conditions

• Approximately half of patients with autoimmune primary adrenal insufficiency have other co-existing autoimmune diseases 1
• These combinations are classified into polyendocrine syndromes 1:
  • Autoimmune polyendocrine syndrome type-1 (APS-1): Primary adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis 1
  • Autoimmune polyendocrine syndrome type-2 (APS-2): Primary adrenal insufficiency with primary hypothyroidism and other autoimmune conditions 1

Treatment

• Patients with primary adrenal insufficiency require lifelong hormone replacement therapy with both glucocorticoids and mineralocorticoids to prevent potentially fatal adrenal crisis 1, 6
• Glucocorticoid replacement:
  • Hydrocortisone (HC) or cortisone acetate (CA) are the preferred glucocorticoids 1
  • Typical dosing: HC 15-25 mg per day in 2-3 divided doses 1, 7
  • Dosage should be adjusted based on clinical assessment rather than laboratory values 1
• Mineralocorticoid replacement:
  • Fludrocortisone is indicated as partial replacement therapy for primary and secondary adrenocortical insufficiency 6
  • The usual dose is 0.1 mg daily, although dosage ranging from 0.1 mg three times a week to 0.2 mg daily may be employed 6
  • If transient hypertension develops, the dose should be reduced to 0.05 mg daily 6

Management of Adrenal Crisis

• Adrenal crisis is a life-threatening emergency requiring immediate treatment 1
• Treatment includes:
  • Immediate administration of hydrocortisone 100 mg IV or IM, followed by 100 mg every 6-8 hours until recovery 1
  • Rapid infusion of isotonic (0.9%) sodium chloride solution, initially at 1 L/hour until hemodynamic improvement 1

Patient Education and Follow-up

• Patients should wear a Medic Alert bracelet and carry a steroid card 1
• Education on increasing steroid doses during illness or injury is essential 1, 2
• Annual follow-up should include:
  • Assessment of health and well-being 1
  • Measurement of weight and blood pressure 1
  • Monitoring of serum electrolytes 1
  • Screening for development of new autoimmune disorders 1
  • Assessment for complications of glucocorticoid therapy 1

Prognosis

• With proper treatment, Addison's disease is a manageable chronic condition 1
• However, premature death from adrenal crises remains a risk 1, 4
• Many patients on standard replacement therapy complain of fatigue, weariness, and reduced stress tolerance 7
• Health-related quality of life is often reduced despite treatment 4