What are the characteristics of Addison's disease?

Characteristics of Addison's Disease

Addison's disease is a rare endocrine disorder characterized by inadequate production of cortisol and aldosterone due to damage to the adrenal cortex, with a prevalence of 10-15 per 100,000 population, primarily presenting with fatigue, hyperpigmentation, hypotension, and electrolyte disturbances. 1

Definition and Pathophysiology

• Addison's disease (primary adrenal insufficiency) results from damage to the adrenal cortex leading to inadequate production of cortisol and aldosterone 1
• In Europe, autoimmunity is the predominant cause (approximately 85% of cases), with other causes including tuberculosis, adrenal hemorrhage, and genetic disorders 1
• The main autoimmune mechanism involves destruction of adrenal cortical cells by an autoreactive process directed against the steroid-synthesizing enzyme 21-hydroxylase 2

Clinical Presentation

Common Symptoms

• Symptoms develop insidiously over months to years and include: 3, 1
  • Fatigue and weakness
  • Unintentional weight loss
  • Anorexia
  • Salt craving
  • Nausea and vomiting
  • Abdominal pain
  • Muscle and joint pain

Physical Signs

• Hyperpigmentation of the skin, especially in sun-exposed areas, palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa 4, 5
• Hypotension, often orthostatic 3
• Vitiligo and other signs of autoimmune disease may be present 1

Laboratory Findings

• Hyponatremia (present in 90% of newly diagnosed cases) 3, 1
• Hyperkalaemia (in approximately 50% of cases) 3, 1
• Low serum cortisol and high plasma ACTH levels 3
• Increased plasma renin activity with low serum aldosterone 3
• Mild to moderate hypercalcemia may be present in 10-20% of patients 3
• Mild eosinophilia, lymphocytosis, and increased liver transaminases may be observed 3
• Children, but rarely adults, may present with hypoglycemia 3

Diagnosis

• The diagnosis follows a two-step approach: first assessing adrenal cortex function, then establishing etiology 3, 1
• Paired measurement of serum cortisol and plasma ACTH is the initial diagnostic test 1
• Serum cortisol <250 nmol/L with elevated ACTH during acute illness is diagnostic of primary adrenal insufficiency 3, 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 3, 1
• Treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures 3

Etiology

• The etiology should be determined starting with measurement of 21-hydroxylase (anti-adrenal) autoantibodies 3
• If antibodies are negative, CT imaging of the adrenal glands is recommended to demonstrate tumors or calcifications typical of tuberculosis 3
• Males should be screened for adrenoleukodystrophy by measuring very long-chain fatty acids 3
• Autoimmune polyendocrine syndrome type-1 (APS-1) should be considered in children and young persons presenting with PAI and other manifestations (e.g., hypoparathyroidism and candidiasis) 3, 1

Associated Conditions

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

Treatment

• Patients require lifelong hormone replacement therapy with both glucocorticoids and mineralocorticoids 3, 1
• Hydrocortisone (HC) or cortisone acetate (CA) are the preferred glucocorticoids, taken in 2-3 divided doses 3, 6
• Typical dosing: HC 15-25 mg per day or CA 20-30 mg per day, with the largest dose in the morning 1, 6
• Fludrocortisone is used for mineralocorticoid replacement 7
• Increased sodium chloride intake is often needed to compensate for renal loss 3
• Dosage adjustment is based on clinical assessment rather than laboratory values 3, 6
• Signs of over-replacement include weight gain, insomnia, and peripheral edema 3, 6
• Signs of under-replacement include lethargy, nausea, poor appetite, weight loss, and increased pigmentation 3, 6

Management of Adrenal Crisis

• Adrenal crisis is a life-threatening emergency requiring immediate treatment 1, 6
• Treatment includes immediate administration of hydrocortisone 100 mg IV or IM, followed by 100 mg every 6-8 hours until recovery 1, 2
• Rapid infusion of isotonic (0.9%) sodium chloride solution is essential 1

Patient Education and Follow-up

• All patients should wear a Medic Alert bracelet and carry a steroid card 3, 1, 6
• Education on increasing steroid doses during illness or injury is essential 3, 1
• Annual follow-up should include assessment of well-being, weight, blood pressure, serum electrolytes, and screening for development of new autoimmune disorders 1, 6

Prognosis

• With proper treatment, Addison's disease is a manageable chronic condition 1
• However, premature death from adrenal crises remains a risk without proper management 1
• Neuropsychiatric manifestations including depression and psychosis can occur and impact quality of life 8