What is Addison's disease, including its pathophysiology?

Addison's Disease: Pathophysiology and Management

Addison's disease (primary adrenal insufficiency) is a rare but potentially life-threatening endocrine disorder requiring lifelong steroid replacement therapy with both glucocorticoids and mineralocorticoids to prevent adrenal crisis and maintain normal physiological function. 1, 2

Pathophysiology

Addison's disease occurs due to destruction of the adrenal cortex, resulting in insufficient production of essential hormones:

• Glucocorticoids (cortisol): Regulates metabolism, stress response, and immune function
• Mineralocorticoids (aldosterone): Controls sodium retention and potassium excretion
• Adrenal androgens: Contributes to secondary sexual characteristics

Causes

1. Autoimmune adrenalitis: Most common cause in developed countries (>80% of cases)

   • Characterized by autoantibodies against adrenal tissue
   • Often associated with other autoimmune conditions

2. Infectious causes:

   • Tuberculosis (historically common, still significant in developing regions)
   • Fungal infections
   • HIV-related infections

3. Other causes:

   • Adrenal hemorrhage (especially with anticoagulant use)
   • Metastatic cancer
   • Genetic disorders (adrenoleukodystrophy in males)
   • Medications (checkpoint inhibitors, drugs affecting glucocorticoid metabolism)

Disease Progression

The disease typically develops gradually as the adrenal cortex is progressively destroyed. Symptoms usually don't appear until >90% of the adrenal tissue has been damaged 3.

Clinical Presentation

Common Symptoms and Signs

• Constitutional: Fatigue, weakness, malaise, anorexia, weight loss
• Gastrointestinal: Nausea, vomiting, abdominal pain
• Cardiovascular: Hypotension, orthostatic symptoms
• Skin changes: Hyperpigmentation (hallmark finding) affecting:
  • Skin creases
  • Pressure points
  • Mucosal surfaces
  • Scars
• Electrolyte disturbances:
  • Hyponatremia
  • Hyperkalemia
• Musculoskeletal: Myopathy, muscle weakness 4

Laboratory Findings

Parameter	Finding	Explanation
Sodium	Low	Aldosterone deficiency
Potassium	High/Upper normal	Aldosterone deficiency
Morning cortisol	Low	Cortisol deficiency
ACTH	High	Compensatory increase
Renin	High	Compensatory increase
Aldosterone	Low	Adrenal failure

Diagnosis

The diagnosis is established through a combination of clinical features and laboratory tests:

1. Initial testing:

   • Serum electrolytes
   • Morning cortisol level
   • ACTH level

2. Confirmatory testing:

   • Rapid ACTH stimulation test (gold standard)
   • Measure cortisol before and after synthetic ACTH administration
   • Inadequate cortisol response confirms diagnosis

3. Etiology determination:

   • 21-hydroxylase antibodies (for autoimmune cause)
   • Very long-chain fatty acids (for adrenoleukodystrophy in males)
   • Imaging studies when indicated

Management

Hormone Replacement Therapy

1. Glucocorticoid replacement:

   • Hydrocortisone is preferred (mimics physiologic cortisol)
   • Typical dosage: 15-25 mg daily in divided doses
   • Common regimen: 2/3 of dose in morning, 1/3 in afternoon
   • Cortisone acetate is an alternative option 1

2. Mineralocorticoid replacement:

   • Fludrocortisone: 0.1 mg daily (range 0.05-0.2 mg)
   • Adjust based on blood pressure, electrolytes, and symptoms 5

3. Salt supplementation:

   • Additional sodium chloride intake often required

Monitoring and Dose Adjustment

• Clinical assessment is the primary method for dose adjustment
• Signs of under-replacement: Fatigue, nausea, poor appetite, weight loss, increased pigmentation
• Signs of over-replacement: Weight gain, insomnia, peripheral edema
• Laboratory monitoring: Electrolytes, plasma renin activity

Stress Dosing and Emergency Management

• Stress dosing required during:

  • Acute illness with fever
  • Trauma
  • Surgery
  • Severe emotional stress

• Adrenal crisis management:

  • Immediate hydrocortisone 100 mg IV bolus
  • Followed by 100-300 mg/day as continuous infusion or divided doses
  • Rapid IV isotonic saline administration
  • Treat underlying precipitating factors 2

Patient Education (Critical)

• Emergency preparedness:

  • Injectable hydrocortisone for emergency use
  • Medical alert bracelet/card
  • Education on stress dosing 1, 2

• Regular follow-up:

  • Annual consultation to assess replacement adequacy
  • Monitor for complications and comorbidities

Prognosis

With proper treatment and education, patients with Addison's disease can lead normal lives with good quality of life. However, the condition requires lifelong management and vigilance to prevent potentially fatal adrenal crises 3.

Common Pitfalls

1. Delayed diagnosis due to nonspecific symptoms
2. Inadequate stress dosing during illness or procedures
3. Failure to recognize adrenal crisis which can be fatal
4. Insufficient patient education about emergency management
5. Inappropriate glucocorticoid dosing leading to under or over-replacement