What is the pathophysiology of Addison disease?

Pathophysiology of Addison Disease

Primary Mechanism of Adrenal Cortical Failure

Addison disease results from destruction or dysfunction of the adrenal cortex, leading to inadequate production of cortisol, aldosterone, and adrenal androgens, regardless of the underlying cause. 1

The pathophysiology centers on disruption of the hypothalamic-pituitary-adrenal (HPA) axis due to loss of functional adrenal cortical tissue 2:

• Cortisol deficiency impairs regulation of metabolism, immune function, and stress responses 2
• Aldosterone deficiency causes dysregulation of sodium and potassium homeostasis, resulting in hypotension and dehydration 2
• Loss of negative feedback from cortisol leads to compensatory elevation of ACTH and melanocyte-stimulating hormone, producing the characteristic hyperpigmentation 3

Etiologic Mechanisms of Adrenal Destruction

Autoimmune Adrenalitis (Most Common in Western Populations)

In Western Europe and the United States, T- and B-cell-mediated autoimmunity accounts for approximately 85% of Addison disease cases, making it the predominant pathogenic mechanism 1, 4:

• The immune system erroneously attacks and destroys adrenal cortical cells through lymphocytic and plasma cell infiltration 4
• Circulating antibodies against 21-hydroxylase (the key enzyme in adrenal steroid synthesis) are present in more than 90% of autoimmune cases at diagnosis 1, 4
• The adrenal glands become sclerotic and reduced in volume as cortical tissue is progressively replaced by inflammatory infiltrate 4

Infectious Causes

Mycobacterium tuberculosis can infiltrate and impair both adrenal glands, accounting for 10-15% of cases in developed countries 1, 2:

• Tuberculosis was historically the leading cause before the antibiotic era 1
• Other infectious agents include bacterial pathogens (Neisseria meningitidis, Haemophilus influenzae), fungal infection (Pneumocystis carinii), and viral infections (HIV, herpes simplex virus, cytomegalovirus) 1

Hemorrhagic Destruction

Bilateral adrenal hemorrhage can precipitate acute adrenal insufficiency through 1:

• Antiphospholipid syndrome precipitating adrenal hemorrhage 1
• Complications of anticoagulant therapy (warfarin, heparin) 1
• Disseminated intravascular coagulation (DIC) 1
• Severe stress, trauma, or coagulopathies 2

Genetic Disorders

Several inherited conditions affect adrenal cortical function 1:

• Congenital adrenal hyperplasia (enzyme-deficiency forms, most common in children—72% of pediatric cases) 1, 4
• Adrenoleukodystrophy (X-linked disorder affecting cerebral white matter and adrenal cortex) 1, 2
• Familial glucocorticoid deficiency (ACTH-resistance syndrome) 1
• Mitochondrial disorders such as Kearns-Sayre syndrome 1

Infiltrative and Neoplastic Processes

Replacement of normal cortical tissue occurs in 1:

• Bilateral adrenal metastases or primary adrenal lymphoma 1
• Deposition diseases: amyloidosis and hemochromatosis 1

Iatrogenic Causes

Medications that inhibit steroidogenesis can precipitate adrenal cortical failure, including ketoconazole, etomidate, mitotane, and metyrapone 1, 2:

• Bilateral adrenalectomy (surgical removal) 2

Hormonal Consequences and Laboratory Manifestations

The destruction of adrenal cortical tissue produces characteristic hormonal patterns 5:

• Cortisol levels decrease while ACTH levels markedly increase due to loss of negative feedback 5, 3
• Plasma renin activity increases in response to aldosterone deficiency 4
• Hyponatremia develops in approximately 90% of newly diagnosed cases due to aldosterone deficiency and cortisol-mediated impaired free water excretion 6, 5
• Hyperkalemia occurs in about 50% of patients at diagnosis due to aldosterone deficiency 6, 5

Clinical Pitfall

The clinical manifestations of Addison disease are often insidious and nonspecific, progressing over months to years, which frequently results in delayed diagnosis or misdiagnosis as other conditions such as CNS infections, chronic fatigue syndrome, or psychiatric disorders 2, 7, 8. The absence of hyperkalemia cannot exclude the diagnosis, as it is present in only approximately 50% of cases 6, 5.