What is the pathophysiology of Addison's disease?

Pathophysiology of Addison's Disease

Addison's disease (primary adrenal insufficiency) is primarily caused by autoimmune adrenalitis resulting in progressive destruction of the adrenal cortex, leading to deficiencies in glucocorticoids, mineralocorticoids, and adrenal androgens, which manifests clinically once approximately 90% of adrenal tissue has been destroyed. 1

Etiology

The causes of primary adrenal insufficiency include:

1. Autoimmune adrenalitis - Now the most common cause in developed countries 1
2. Infectious causes - Tuberculosis (historically the leading cause, still significant in some regions) 2
3. Neoplastic disorders affecting the adrenal glands
4. Genetic disorders affecting adrenal function
5. Iatrogenic causes - Including:
   • Adrenal hemorrhage associated with anticoagulants
   • Drugs affecting glucocorticoid synthesis or metabolism
   • Immune checkpoint inhibitors 3

Pathophysiological Process

Adrenal Cortex Destruction

• The disease process targets the adrenal cortex, which is responsible for producing three main classes of hormones:

  • Glucocorticoids (cortisol)
  • Mineralocorticoids (aldosterone)
  • Adrenal androgens (DHEA and androstenedione)

• In autoimmune adrenalitis, the body produces antibodies against adrenal tissue, most commonly against 21-hydroxylase (21OH-Ab), a key enzyme in steroid hormone synthesis 4

• The destruction is progressive, with clinical symptoms typically not appearing until approximately 90% of the adrenal cortex has been destroyed

Hormonal Imbalance

1. Glucocorticoid Deficiency:

   • Reduced cortisol production disrupts glucose metabolism
   • Impairs stress response
   • Affects energy levels and immune function
   • Leads to increased ACTH production through negative feedback disruption

2. Mineralocorticoid Deficiency:

   • Reduced aldosterone leads to sodium loss and potassium retention
   • Results in volume depletion and hypotension
   • Causes electrolyte imbalances (hyponatremia, hyperkalemia)

3. Adrenal Androgen Deficiency:

   • Reduced DHEA and androstenedione
   • May contribute to fatigue, reduced libido, and loss of axillary/pubic hair in women

Compensatory Mechanisms

• The pituitary gland responds to low cortisol by increasing ACTH production
• Elevated ACTH stimulates melanocortin receptors, leading to hyperpigmentation of the skin
• The renin-angiotensin system is activated in response to volume depletion and hypotension

Clinical Manifestations Related to Pathophysiology

Early/Chronic Manifestations

• Fatigue and weakness - Due to cortisol deficiency and electrolyte imbalances
• Hyperpigmentation - Due to elevated ACTH levels stimulating melanocortin receptors
• Orthostatic hypotension - Due to volume depletion from aldosterone deficiency
• Salt craving - Compensatory response to sodium loss
• Gastrointestinal symptoms (nausea, anorexia, diarrhea) - Due to cortisol deficiency
• Hypoglycemia - Due to impaired gluconeogenesis from cortisol deficiency
• Weight loss - Due to fluid loss, decreased appetite, and metabolic changes 1, 5

Adrenal Crisis

• Represents acute, severe adrenal insufficiency
• Characterized by:
  • Hypotension/shock
  • Severe dehydration
  • Hypoglycemia
  • Fever
  • Electrolyte abnormalities
  • Can be life-threatening if not treated promptly 1

Laboratory Findings Reflecting Pathophysiology

• Elevated ACTH - Due to loss of negative feedback from cortisol
• Low morning serum cortisol - Due to adrenal cortex destruction
• Hyponatremia - Due to aldosterone deficiency causing sodium loss
• Hyperkalemia - Due to aldosterone deficiency causing potassium retention
• Elevated plasma renin activity - Compensatory response to volume depletion 6

Associated Autoimmune Conditions

• Up to 50% of patients with autoimmune adrenalitis develop other autoimmune disorders during their lifetime 1
• Common associations include:
  • Autoimmune thyroid disease
  • Type 1 diabetes
  • Vitiligo
  • Pernicious anemia
  • Celiac disease

Diagnostic Considerations

The diagnosis is confirmed by demonstrating inadequate cortisol response to ACTH stimulation, with elevated baseline ACTH levels indicating primary (rather than secondary) adrenal insufficiency 6.

Morning serum cortisol thresholds:

• <110 nmol/L (<4 μg/dL): Suggests adrenal insufficiency
• ≥300 nmol/L (≥10.8 μg/dL): Typically excludes adrenal insufficiency
• 110-300 nmol/L: Further testing required 6