What is Addison's disease?

Addison's Disease: Definition, Diagnosis, and Management

Addison's disease, also called primary adrenal insufficiency (PAI), is a rare but serious endocrine disorder characterized by insufficient production of glucocorticoid and mineralocorticoid hormones by the adrenal cortex, which can be life-threatening if untreated. 1

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
• The prevalence is approximately 10-15 per 100,000 population, making it a rare condition 1
• In Europe, autoimmunity is the predominant cause (approximately 85% of cases), with other causes including tuberculosis, adrenal hemorrhage, and genetic disorders 1

Clinical Presentation

• Symptoms develop insidiously over months to years and include 1, 2:

  • Fatigue and weakness
  • Weight loss
  • Hypotension (particularly orthostatic)
  • Hyperpigmentation of skin, especially in sun-exposed areas, palmar creases, frictional surfaces, recent scars, and oral mucosa
  • Nausea, poor appetite, and sometimes vomiting
  • Salt craving

• Laboratory findings typically include 1:

  • Hyponatremia (present in 90% of newly diagnosed cases)
  • Hyperkalaemia (in approximately 50% of cases)
  • Low serum cortisol and high plasma ACTH levels
  • Increased plasma renin activity with low aldosterone levels

Diagnosis

The diagnosis of PAI follows a two-step approach 1:

1. Assessment of adrenal cortex function:

   • 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

2. Determination of etiology:

   • Measurement of 21-hydroxylase (anti-adrenal) autoantibodies to identify autoimmune etiology 1
   • If antibodies are negative, CT imaging of the adrenals is recommended 1
   • In male patients, very long-chain fatty acids should be measured to check for adrenoleukodystrophy 1

Associated Conditions

• Approximately half of patients with autoimmune PAI have other co-existing autoimmune diseases 1:

  • Autoimmune thyroid disease
  • Autoimmune gastritis with vitamin B12 deficiency
  • Type 1 diabetes mellitus
  • Premature ovarian insufficiency
  • Vitiligo and celiac disease

• 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 with PAI 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
  • CA: 25-37.5 mg per day in divided doses 1
  • First dose upon awakening and last dose at least 4-6 hours before bedtime 1
• Dosage should be adjusted based on clinical assessment rather than laboratory values 1
• Signs of over-replacement: weight gain, insomnia, peripheral edema 1
• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss, increased pigmentation 1

Mineralocorticoid Replacement

• Fludrocortisone 0.1 mg daily is the standard dose, though ranging from 0.05-0.2 mg may be needed 3
• Dosage should be adjusted based on blood pressure, serum electrolytes, and plasma renin activity 3
• Patients should be advised to consume salt and salty foods freely 1

Management of Adrenal Crisis

• Adrenal crisis is a life-threatening emergency requiring immediate treatment 1
• Treatment includes:
  • 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
  • Identification and treatment of the underlying precipitant (often infection) 1

Patient Education and Follow-up

• 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
• Training in intramuscular administration of hydrocortisone during acute adrenal crisis is crucial 1
• Annual follow-up should include 1:
  • Assessment of health and well-being
  • Measurement of weight and blood pressure
  • Monitoring of serum electrolytes
  • Screening for development of new autoimmune disorders
  • Assessment for complications of glucocorticoid therapy, including bone mineral density every 3-5 years

Prognosis

• With proper treatment, Addison's disease is a manageable chronic condition 1
• However, premature death from adrenal crises remains a risk 1, 4
• Quality of life and ability to work may be reduced in many patients despite treatment 1, 4