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 called 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

• In Europe and developed countries, autoimmunity is the predominant cause, accounting for approximately 85% of cases 1
• Historically, tuberculosis was the primary cause but has been surpassed by autoimmune adrenalitis, though tuberculosis still accounts for a significant proportion of cases globally 1, 3
• Other causes include adrenal hemorrhage (often associated with anticoagulants), metastatic neoplasms, genetic disorders such as adrenoleukodystrophy, and medications that inhibit steroidogenesis 4, 2

Clinical Presentation

• Symptoms develop insidiously over months to years, making early diagnosis challenging 1, 5
• Common symptoms include persistent fatigue, myasthenia (muscle weakness), unintentional weight loss, malaise, anorexia, and nausea 4, 3
• Salt craving is a characteristic symptom 1
• Hypotension and hyperpigmentation of the skin (especially in areas subjected to friction) are typical physical findings 4
• Neuropsychiatric manifestations including depression and psychosis can occur 4
• Symptoms usually do not occur until most of the adrenal gland has been destroyed 3

Laboratory Findings

• Hyponatremia is present in 90% of newly diagnosed cases 1
• Hyperkalaemia occurs in approximately 50% of cases 1
• Low serum cortisol with elevated plasma ACTH levels are characteristic 1

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
• The rapid ACTH stimulation test is useful for identifying adrenal insufficiency 3

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): PAI with hypoparathyroidism and chronic mucocutaneous candidiasis 1
• Autoimmune polyendocrine syndrome type-2 (APS-2): 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: hydrocortisone 15-25 mg per day in 2-3 divided doses 1
• Cortisone acetate: 25 mg daily (starting dose) in divided doses 6
• Dosage should be adjusted based on clinical assessment rather than laboratory values 1
• Fludrocortisone is preferably administered in conjunction with cortisone (10 mg to 37.5 mg daily in divided doses) or hydrocortisone (10 mg to 30 mg daily in divided doses) 7

Mineralocorticoid Replacement

• Fludrocortisone acetate is indicated as partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease 7
• The usual dose is 0.1 mg of fludrocortisone acetate daily, although dosage ranging from 0.1 mg three times a week to 0.2 mg daily has been employed 7
• If transient hypertension develops, the dose should be reduced to 0.05 mg daily 7

Adrenal Crisis Management

• 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, injury, or stress (surgery, infection, trauma) is essential 1, 5
• 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, 2
• Health-related quality of life is often reduced even with standard replacement therapy 2