What is the pathophysiology of adrenal insufficiency?

Pathophysiology of Adrenal Insufficiency

Adrenal insufficiency is characterized by inadequate production of adrenocortical hormones (primarily cortisol, with or without aldosterone deficiency), resulting from dysfunction at the adrenal gland level (primary), pituitary level (secondary), or hypothalamic level (tertiary). 1

Types and Underlying Mechanisms

Primary Adrenal Insufficiency

• Direct damage to adrenal cortex causing deficiency of all adrenocortical hormones:
  • Autoimmune destruction (most common in developed countries)
  • Congenital adrenal hyperplasia
  • Infections (tuberculosis, fungal infections)
  • Pharmacological inhibition (e.g., high-dose azole antifungals)
  • Surgical removal of adrenal tissue 2

Secondary Adrenal Insufficiency

• Pituitary dysfunction leading to inadequate ACTH production:
  • Pituitary tumors
  • Pituitary hemorrhage
  • Inflammatory/infiltrative conditions (hypophysitis, sarcoidosis)
  • Surgery or radiation therapy
  • Medications suppressing ACTH (e.g., opioids) 2

Tertiary/Glucocorticoid-Induced Adrenal Insufficiency

• Hypothalamic dysfunction or exogenous glucocorticoid therapy:
  • Suppression of hypothalamic-pituitary-adrenal (HPA) axis
  • Occurs in approximately 7 in 1000 people on long-term oral corticosteroids
  • Can occur with any route of administration (oral, inhaled, topical, intranasal, intra-articular) 3, 2

Hormonal Pathways Affected

1. Glucocorticoid Pathway:

   • Cortisol deficiency affects metabolism, stress response, and immune function
   • Results in fatigue, weakness, weight loss, decreased appetite, hypoglycemia, and poor stress response 1, 4

2. Mineralocorticoid Pathway (primarily in primary adrenal insufficiency):

   • Aldosterone deficiency impairs sodium retention and potassium excretion
   • Leads to hyponatremia, hyperkalemia, and hypotension 1, 2

3. Adrenal Androgen Pathway:

   • Reduced production of dehydroepiandrosterone sulfate (DHEAS)
   • May contribute to decreased secondary sexual characteristics 1, 2

Pathophysiological Consequences

Circulatory Effects

• Reduced effective volemia
• Impaired adrenal perfusion
• Blunted vascular response to angiotensin II, norepinephrine, and vasopressin
• Worsened cardio-circulatory function 3

Metabolic Effects

• Impaired gluconeogenesis leading to hypoglycemia
• Altered protein and lipid metabolism
• Reduced stress response capacity 5, 4

Inflammatory Response

• Enhanced pro-inflammatory cytokine production
• Impaired adrenal steroidogenesis
• Increased susceptibility to infections and sepsis 3, 4

Laboratory Findings

• Primary AI: Low cortisol, high ACTH, low DHEAS, hyponatremia, hyperkalemia
• Secondary AI: Low cortisol, low/normal ACTH, low DHEAS, generally normal electrolytes 1, 2

Clinical Implications

The pathophysiological changes in adrenal insufficiency explain why patients are at high risk for adrenal crisis during stress, which can be life-threatening without prompt treatment. The disruption of normal cortisol production impairs the body's ability to respond to physiological stressors, leading to circulatory collapse, electrolyte abnormalities, and potentially death if untreated 1, 4.

Understanding these pathophysiological mechanisms is crucial for appropriate diagnosis, treatment, and prevention of complications in patients with adrenal insufficiency.