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, also known as primary adrenal insufficiency (PAI), 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
• Recent data suggest the prevalence is increasing, partly due to iatrogenic causes including novel anti-cancer checkpoint inhibitors and other medications 2

Causes and Pathophysiology

• In Europe and developed countries, autoimmunity is the predominant cause, accounting for approximately 85% of cases 1
• Other causes include tuberculosis, adrenal hemorrhage, metastatic neoplasms, genetic disorders (such as adrenoleukodystrophy), and medications that inhibit steroidogenesis 3, 2
• The pathophysiology involves disruption of the hypothalamic-pituitary-adrenal (HPA) axis, with cortisol deficiency affecting metabolism, immune function, and stress responses, while aldosterone deficiency causes dysregulation of sodium and potassium homeostasis 3
• The adrenal cortex also produces androgens (DHEA and androstenedione), and their loss leads to androgen deficiency, particularly clinically significant in women 4

Clinical Presentation

• Symptoms develop insidiously over months to years and are often nonspecific, including persistent fatigue, myasthenia (muscle weakness), unintentional weight loss, hypotension, and salt craving 1, 3
• Hyperpigmentation of the skin, especially in areas subjected to friction, is a characteristic finding 3
• Neuropsychiatric manifestations can occur, including depression and psychosis 3
• Laboratory findings typically include hyponatremia (present in 90% of newly diagnosed cases), hyperkalaemia (in approximately 50% of cases), low serum cortisol, and high plasma ACTH levels 1
• Low DHEAS, androstenedione, and testosterone levels indicate androgen deficiency 4

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 Autoimmune Conditions

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

Treatment

Patients require lifelong hormone replacement therapy with both glucocorticoids and mineralocorticoids to prevent potentially fatal adrenal crisis. 1

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
• Dosage should be adjusted based on clinical assessment rather than laboratory values 1

Mineralocorticoid Replacement

• Fludrocortisone acetate is indicated as partial replacement therapy for primary adrenocortical insufficiency in Addison's disease 5
• The usual dose is 0.1 mg daily, although dosage ranging from 0.1 mg three times a week to 0.2 mg daily has been employed 5
• If transient hypertension develops, the dose should be reduced to 0.05 mg daily 5

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 4
• DHEA replacement should be guided by monitoring serum DHEAS, androstenedione, and testosterone levels, with target hormone levels maintained in the normal range 4
• The evidence for benefit from DHEA replacement remains weak and inconsistent across studies, and long-term safety data are lacking, requiring cautious use. 4, 6

Management of Adrenal Crisis

Adrenal crisis is a life-threatening emergency requiring immediate treatment. 1

• 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 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 therapies 1, 2
• Health-related quality of life is often reduced even with standard replacement therapy 2