What is the pathophysiology of Addison’s disease?

Pathophysiology of Addison's Disease

Mechanism of Adrenal Cortex Destruction

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 pathophysiology centers on disruption of the hypothalamic-pituitary-adrenal (HPA) axis, which triggers a cascade of hormonal deficiencies with life-threatening consequences 2:

Cortisol Deficiency

• Loss of cortisol production impairs regulation of metabolism, immune function, and stress responses 2
• The body loses its ability to mount appropriate physiological responses to illness, injury, or physical stress 1
• Cortisol deficiency leads to the insidious symptoms of fatigue, weakness, weight loss, and hypotension that develop over months to years 1, 3

Aldosterone Deficiency

• Mineralocorticoid loss causes dysregulation of sodium and potassium homeostasis 2
• Sodium wasting and potassium retention result in hyponatremia (present in 90% of newly diagnosed cases) and hyperkalemia (in approximately 50% of cases) 1, 4
• Volume depletion from sodium loss produces hypotension and dehydration 2
• Mineralocorticoid deficiency may predominate or persist independently of glucocorticoid function in some patients, challenging the traditional view of uniform adrenal destruction 5

Compensatory ACTH Elevation

• As the adrenal cortex fails, plasma ACTH levels rise markedly in an attempt to stimulate remaining functional tissue 1, 4
• Elevated ACTH causes the characteristic hyperpigmentation of skin creases, scars, and mucous membranes seen in primary adrenal insufficiency 1
• This compensatory mechanism distinguishes primary from secondary adrenal insufficiency, where ACTH is low 4

Etiologic Mechanisms of Adrenal Destruction

Autoimmune Adrenalitis (85% of Cases in Europe)

• T- and B-cell-mediated autoimmunity is the predominant pathogenic mechanism in Western populations, accounting for roughly 85% of cases 1
• The majority of affected individuals develop circulating antibodies against 21-hydroxylase, the key enzyme in adrenal steroid synthesis 1, 3
• Autoimmune destruction has historically been considered irreversible, though emerging evidence suggests heterogeneity with potential for partial recovery of glucocorticoid function while mineralocorticoid deficiency persists 5, 3

Infectious Causes

• Mycobacterium tuberculosis can infiltrate and impair both adrenal glands, leading to primary adrenal insufficiency 1, 2
• Bacterial pathogens such as Neisseria meningitidis and Haemophilus influenzae cause adrenal destruction 1
• Fungal infection with Pneumocystis carinii and viral infections (HIV, herpes simplex, cytomegalovirus) can damage adrenal cortical tissue 1

Hemorrhagic Destruction

• Antiphospholipid syndrome can precipitate adrenal hemorrhage and subsequent cortical loss 1
• Complications of anticoagulant therapy (warfarin, heparin) are associated with adrenal hemorrhage 1, 6
• Disseminated intravascular coagulation may lead to bilateral adrenal hemorrhage and insufficiency 1

Genetic Disorders

• Congenital adrenal hyperplasia (enzyme-deficiency forms) results in adrenal cortical dysfunction 1
• Adrenoleukodystrophy, an X-linked disorder, involves adrenal cortical degeneration alongside cerebral white matter damage 1, 2
• Familial glucocorticoid deficiency (ACTH-resistance syndrome) and mitochondrial disorders such as Kearns-Sayre syndrome cause adrenal insufficiency 1

Infiltrative and Neoplastic Processes

• Deposition diseases including amyloidosis and hemochromatosis infiltrate the adrenal cortex, impairing hormone production 1
• Bilateral adrenal metastases or primary adrenal lymphoma may replace normal cortical tissue 1, 2

Iatrogenic Causes

• Medications that inhibit steroidogenesis—including ketoconazole, etomidate, mitotane, and metyrapone—can precipitate adrenal cortical failure 1, 6
• Adrenalectomy directly removes hormone-producing tissue 2

Critical Clinical Implications

Progressive Nature with Variable Patterns

• The disease typically progresses from an ACTH-driven compensated phase to overt adrenal insufficiency requiring lifelong hormone replacement 5, 3
• However, the natural history may be more heterogeneous than traditionally thought, with potential for complete or partial recovery of glucocorticoid secretion in some cases 5
• Recovery of zona fasciculata function (cortisol production) may occur independently from zona glomerulosa function (aldosterone production), explaining cases of isolated mineralocorticoid deficiency 5

Life-Threatening Consequences

• Without adequate cortisol and aldosterone, patients cannot mount appropriate responses to physiological stress 1, 2
• Adrenal crisis represents acute decompensation with hypotension, shock, severe vomiting, altered mental status, and potential death if untreated 1, 4
• The insidious onset and nonspecific symptoms frequently lead to delayed diagnosis or misdiagnosis as CNS infections, renal tubular acidosis, or other conditions 7, 6

Requirement for Lifelong Replacement

• The pathophysiological deficits necessitate lifelong glucocorticoid and mineralocorticoid replacement therapy to prevent fatal adrenal crisis 1, 2
• Replacement aims to emulate physiological hormone secretion patterns and restore metabolic, immune, and cardiovascular homeostasis 3