What is the pathophysiology of Addison's disease?

Pathophysiology of Addison's Disease

Addison's disease results from destruction of the adrenal cortex, leading to inadequate production of cortisol and aldosterone, with the underlying mechanism involving progressive loss of adrenocortical cells that prevents adequate hormone synthesis regardless of the cause. 1

Mechanism of Adrenal Cortex Destruction

The pathophysiology centers on damage to the adrenal cortex—the outer region of the adrenal glands responsible for steroid hormone synthesis. 2 This destruction occurs through several distinct mechanisms:

Autoimmune Destruction (Most Common in Western Countries)

• T and B cell-mediated autoimmunity against adrenocortical cells is the predominant mechanism in approximately 85% of cases in Western Europe. 3
• The immune system erroneously attacks and destroys adrenal cortical cells through autoimmune adrenalitis. 2, 4
• Most patients develop circulating antibodies against 21-hydroxylase (21OH-Ab), the key steroidogenic enzyme. 3, 5
• Symptoms typically develop insidiously over months to years as progressive cortical destruction occurs. 5
• Clinical manifestations usually do not appear until most of the adrenal gland has been destroyed. 6

Non-Autoimmune Mechanisms

Infectious causes include:

• Mycobacterium tuberculosis infiltration and impairment of the adrenal glands 3, 2
• Bacterial infections (meningococcus, Haemophilus influenzae) 3
• Fungal infections (Pneumocystis carinii) 3
• Viral infections (HIV, herpes simplex, cytomegalovirus) 3

Hemorrhagic destruction occurs through:

• Antiphospholipid syndrome 3
• Anticoagulant therapy complications 3
• Disseminated intravascular coagulation 3
• Severe stress, trauma, or coagulopathies 2

Genetic disorders affecting adrenal function:

• Congenital adrenal hyperplasia 3
• Adrenoleukodystrophy (X-linked condition affecting cerebral white matter and adrenal cortex) 3, 2
• Familial glucocorticoid deficiency (ACTH resistance syndrome) 3
• Mitochondrial disorders (Kearns-Sayre syndrome) 3

Infiltrative processes:

• Amyloidosis, hemochromatosis 3
• Bilateral adrenal metastasis or lymphoma 3

Iatrogenic causes:

• Surgical removal (adrenalectomy) 2
• Medications inhibiting steroidogenesis (ketoconazole, etomidate, mitotane, metyrapone) 3, 2

Hormonal Consequences and HPA Axis Disruption

The destruction of adrenal cortex disrupts the hypothalamic-pituitary-adrenal (HPA) axis, resulting in three critical hormone deficiencies: 2

Cortisol Deficiency

• Loss of glucocorticoid production impairs regulation of metabolism, immune function, and stress responses. 2
• Serum cortisol levels decrease while plasma ACTH levels markedly increase due to loss of negative feedback. 1, 7
• The elevated ACTH drives the characteristic hyperpigmentation seen in primary adrenal insufficiency. 7

Aldosterone Deficiency

• Mineralocorticoid loss causes dysregulation of sodium and potassium homeostasis. 2
• Results in excessive sodium loss in urine and impaired free water clearance, leading to hyponatremia (present in 90% of newly diagnosed cases). 1, 7
• Causes hyperkalemia in approximately 50% of cases due to impaired renal potassium excretion. 1, 7
• Leads to dehydration and hypotension, including orthostatic hypotension. 7, 2
• Elevated plasma renin activity reflects the mineralocorticoid deficiency. 7

Adrenal Androgen Deficiency

• Depletion of DHEAS, androstenedione, and testosterone occurs. 7
• The clinical significance of this androgen deficiency remains incompletely understood. 8

Clinical Pitfall

A critical understanding is that symptoms do not manifest until most of the adrenal gland has been destroyed 6, which explains the insidious nature of symptom development and frequent diagnostic delays. 7 The progressive nature of cortical destruction means patients may have subclinical disease for extended periods before presenting with overt adrenal insufficiency or acute crisis.