Addison's Disease Management

Definition and Pathophysiology

• Addison's disease results from damage to the adrenal cortex, leading to inadequate production of cortisol and aldosterone, regardless of the underlying cause 1, 2
• The prevalence is approximately 10-15 per 100,000 population, making it a rare condition 1, 3
• In Europe, autoimmunity is the predominant cause (approximately 85% of cases), with other causes including tuberculosis, adrenal hemorrhage, and genetic disorders 1, 4

Clinical Presentation

• Symptoms develop insidiously over months to years and include salt craving 4
• Laboratory findings typically include hyponatremia (present in 90% of newly diagnosed cases) 3
• Laboratory findings typically include hyperkalaemia (in approximately 50% of cases) 3
• Laboratory findings typically include low serum cortisol and high plasma ACTH levels 2

Diagnosis

• The diagnosis of PAI follows a two-step approach 1, 3
• Paired measurement of serum cortisol and plasma ACTH is the initial diagnostic test 4
• Serum cortisol <250 nmol/L with elevated ACTH during acute illness is diagnostic 4
• 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 4

Associated Conditions

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

Treatment

• Patients with PAI require lifelong hormone replacement therapy with both glucocorticoids and mineralocorticoids to prevent potentially fatal adrenal crisis 5, 6
• Hydrocortisone (HC) or cortisone acetate (CA) are the preferred glucocorticoids 5, 6
• Typical dosing: HC: 15-25 mg per day in 2-3 divided doses 5, 6
• Dosage should be adjusted based on clinical assessment rather than laboratory values 5, 6

Management of Adrenal Crisis

• Adrenal crisis is a life-threatening emergency requiring immediate treatment 4, 7
• Treatment includes immediate administration of hydrocortisone 100 mg IV or IM, followed by 100 mg every 6-8 hours until recovery 4
• Rapid infusion of isotonic (0.9%) sodium chloride solution, initially at 1 L/hour until hemodynamic improvement 4

Patient Education and Follow-up

• Patients should wear a Medic Alert bracelet and carry a steroid card 5, 6
• Education on increasing steroid doses during illness or injury is essential 5, 6
• 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 4, 2

Prognosis

• With proper treatment, Addison's disease is a manageable chronic condition 1, 2
• However, premature death from adrenal crises remains a risk 1

Etiology of Adrenal Cortex Destruction in Addison’s Disease

Autoimmune Mechanisms

• In Western European populations, T‑ and B‑cell‑mediated autoimmunity accounts for roughly 85 % of Addison’s disease cases, making it the predominant pathogenic mechanism. [8][9]
• The majority of affected individuals develop circulating antibodies directed against 21‑hydroxylase, the key enzyme in adrenal steroid synthesis. 8

Infectious Causes

• Mycobacterium tuberculosis can infiltrate and impair both adrenal glands, leading to primary adrenal insufficiency. 8
• Bacterial pathogens such as Neisseria meningitidis and Haemophilus influenzae have been reported to cause adrenal destruction. 8
• Fungal infection with Pneumocystis carinii is a recognized, though rare, etiologic factor. 8
• Viral infections including HIV, herpes simplex virus, and cytomegalovirus can damage adrenal cortical tissue. 8

Hemorrhagic Destruction

• Antiphospholipid syndrome can precipitate adrenal hemorrhage and subsequent cortical loss. 8
• Complications of anticoagulant therapy (e.g., warfarin, heparin) are associated with adrenal hemorrhage. 8
• Disseminated intravascular coagulation (DIC) may lead to bilateral adrenal hemorrhage and insufficiency. 8

Genetic Disorders Affecting the Adrenal Cortex

• Congenital adrenal hyperplasia (enzyme‑deficiency forms) can result in adrenal cortical dysfunction and eventual insufficiency. 8
• Adrenoleukodystrophy, an X‑linked disorder affecting cerebral white matter, also involves adrenal cortical degeneration. 8
• Familial glucocorticoid deficiency (ACTH‑resistance syndrome) leads to isolated cortisol deficiency with adrenal atrophy. 8
• Mitochondrial disorders such as Kearns‑Sayre syndrome have been linked to adrenal insufficiency. 8

Infiltrative Processes

• Deposition diseases amyloidosis and hemochromatosis can infiltrate the adrenal cortex, impairing hormone production. 8
• Bilateral adrenal metastases or primary adrenal lymphoma may replace normal cortical tissue, causing insufficiency. 8

Iatrogenic Causes

• Certain medications that inhibit steroidogenesis—including ketoconazole, etomidate, mitotane, and metyrapone—can precipitate adrenal cortical failure. 8

Management of Primary Adrenal Insufficiency

Hormone Replacement

• Lifelong replacement with hydrocortisone (15–25 mg daily in divided doses) plus fludrocortisone (0.05–0.20 mg once daily) is required, and patients must have immediate access to emergency injectable hydrocortisone 100 mg for adrenal crisis. 10, 11
• Hydrocortisone or cortisone acetate are the preferred glucocorticoids because they most closely replicate physiological cortisol production, unlike synthetic alternatives that carry undesirable long‑term metabolic effects. 10, 11
• The total daily glucocorticoid dose should be 15–25 mg of hydrocortisone (or 20–30 mg of cortisone acetate), approximating the 5–10 mg/m² body‑surface‑area output of a normal adrenal gland. 10, 11
• The daily dose should be divided into 2–3 administrations, with the first dose taken immediately upon awakening and the last dose 4–6 hours before bedtime to simulate the natural circadian cortisol rhythm. 10, 11

Monitoring and Dose Adjustment

• Clinical assessment (symptom review, weight, blood pressure, electrolyte balance) is the primary tool for monitoring; plasma ACTH and serum cortisol levels are not useful for dose adjustment. 10, 11
• Signs of glucocorticoid over‑replacement include weight gain, insomnia, and peripheral edema. 10, 11
• Signs of under‑replacement include lethargy, nausea, poor appetite, weight loss, and increased or uneven skin pigmentation. 10, 11

Patient Education and Safety Measures

• Patients should be trained to self‑administer intramuscular hydrocortisone 100 mg for emergency use when vomiting prevents oral intake. 10, 11
• All patients must wear a Medic Alert bracelet or necklace and carry a steroid‑emergency card that states their diagnosis and need for immediate hydrocortisone. 10, 11
• Delays in emergency hydrocortisone administration can be fatal; many patients report having to argue with emergency‑department staff before receiving treatment. 10, 11

Drug Interactions

• CYP3A4 is the principal enzyme metabolizing hydrocortisone; concomitant medications that induce CYP3A4 (e.g., rifampin, phenytoin, carbamazepine) may require increased hydrocortisone doses. 10, 11
• CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) may necessitate hydrocortisone dose reduction. 10, 11

Dietary Management

• Many patients require increased dietary sodium chloride intake to compensate for renal sodium losses associated with mineralocorticoid deficiency. 10, 11