What is Addison's disease?

What is Addison's Disease?

Addison's disease is a rare endocrine disorder caused by damage to the adrenal cortex, resulting in inadequate production of cortisol and aldosterone, which requires lifelong hormone replacement therapy to prevent potentially fatal adrenal crisis. 1

Definition and Epidemiology

• Addison's disease (primary adrenal insufficiency) occurs when the adrenal cortex fails to produce sufficient glucocorticoids (cortisol) and mineralocorticoids (aldosterone), regardless of the underlying cause 1
• The prevalence is approximately 10-15 per 100,000 population, making it a rare condition 1
• In Europe, autoimmunity accounts for approximately 85% of cases, with other causes including tuberculosis, adrenal hemorrhage, and genetic disorders 1

Pathophysiology

• The disease disrupts the hypothalamic-pituitary-adrenal (HPA) axis, leading to cortisol deficiency which is critical for regulating metabolism, immune function, and stress responses 2
• Aldosterone deficiency causes dysregulation of sodium and potassium homeostasis, resulting in hypotension and dehydration 2
• The adrenal cortex also produces androgens (DHEA and androstenedione), and their loss leads to androgen deficiency, particularly clinically significant in women 3

Clinical Presentation

• Symptoms develop insidiously over months to years and are often nonspecific, including persistent fatigue, malaise, anorexia, unintentional weight loss, nausea, diarrhea, joint and back pain 1, 2, 4
• Salt craving is a characteristic symptom 1
• Orthostatic hypotension is common 4
• Hyperpigmentation of the skin occurs, especially in sun-exposed areas, palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa 4
• Neuropsychiatric manifestations including depression and psychosis can occur 2

Laboratory Findings

• Hyponatremia is present in 90% of newly diagnosed cases 1
• Hyperkalaemia occurs in approximately 50% of cases 1
• Low serum cortisol and high plasma ACTH levels are characteristic 1
• Low DHEAS, androstenedione, and testosterone levels indicate androgen deficiency 3

Diagnosis

• The diagnosis follows a two-step approach: 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 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

Associated Conditions

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

Treatment

Maintenance Therapy

• Patients require lifelong hormone replacement therapy with both glucocorticoids and mineralocorticoids to prevent potentially fatal adrenal crisis 1
• Hydrocortisone (HC) or cortisone acetate (CA) are the preferred glucocorticoids 1
• Typical dosing: hydrocortisone 15-25 mg per day in 2-3 divided doses 1
• Fludrocortisone 0.1 mg daily is the standard mineralocorticoid replacement (dosage ranging from 0.1 mg three times a week to 0.2 mg daily has been employed) 5
• Dosage should be adjusted based on clinical assessment rather than laboratory values 1

Adrenal Crisis Management

• Adrenal crisis is a life-threatening emergency requiring immediate treatment with 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

Androgen Replacement

• For female patients with persistent lack of libido and/or low energy despite optimized glucocorticoid and mineralocorticoid replacement, a 6-month trial of DHEA replacement (25-50 mg daily) can be offered 3
• Evidence for benefit from DHEA replacement remains weak and inconsistent across studies 3

Patient Education and Monitoring

• 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
• Annual follow-up should include assessment of health and well-being, measurement of weight and blood pressure, monitoring of serum electrolytes, screening for development of new autoimmune disorders, and 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, and mortality in patients with PAI is still increased despite available therapy 1, 6