TABLE 2

Acquired causes of primary adrenal insufficiency

Category and cause		Key features^{^a}
Autoimmune (most common)	Sporadic (from affected 21-hydroxylase enzyme)	40% of autoimmune cases,¹² common in patients age 30–50²⁵
	Autoimmune polyglandular syndrome type 1^{^b}	Hypoparathyroidism, chronic mucocutaneous candidiasis, Addison disease, other autoimmune diseases such as pernicious anemia, alopecia (5% to 10%)¹⁷
	Autoimmune polyglandular syndrome type 2^{^b}	Autoimmune thyroid disease, type 1 diabetes, vitiligo, premature gonadal failure (60%)¹⁷
Infection	Tuberculosis	Most common cause in countries where tuberculosis is prevalent An extra-adrenal primary lesion is usually present Antitubercular medications do not reverse destruction¹⁸
Infection	Disseminated histoplasmosis, paracoccidioidomycosis, human immunodeficiency virus or acquired immunodeficiency syndrome, cytomegalovirus, tertiary syphilis	Extremely rare, extra-adrenal manifestations are seen first
Injury	Bilateral adrenal hemorrhage due to sepsis	Classically with disseminated meningococcemia, but can also occur with Pseudomonas aeruginosa, Streptococcus pneumoniae, or Staphylococcus aureus sepsis¹⁹
	Bilateral adrenal hemorrhage due to anticoagulation	Rarely occurs with systemic anticoagulation Usually within the first 2 weeks of therapy²⁰
	Infarction due to antiphospholipid antibody syndrome	Bilateral venous thrombosis Affects more men than women Antibodies target lipid-rich cells in the adrenal gland²¹
	Physical trauma
Metastases	In decreasing order: lung, breast, melanoma, stomach²²	Adrenal glands are prone to metastasis due to relatively rich blood supply Mere presence of metastasis does not cause adrenal insufficiency; severe destruction (> 90%) of the adrenal cortex is necessary
Acquired adrenal dysgenesis	Secondary to adrenocorticotropic hormone deficiency; can also be congenital	Hypotrophy of adrenal cortex, adrenal insufficiency, hypogonadism, especially in males due to reduction in adrenal androgens¹
Iatrogenic	Surgical bilateral adrenalectomy	Usually performed in the setting of Cushing disease or bilateral pheochromocytoma
Iatrogenic	Drugs	See Table 3
Infiltrative	Hemochromatosis, sarcoidosis, amyloidosis	Extensive infiltration of adrenal cortex results in dense fibrosis and deficiency of cortisol and aldosterone²⁴

↵^aNot all listed primary adrenal conditions necessarily present with both glucocorticoid and mineralocorticoid deficiency.
↵^bFrom major histocompatibility complex class II mutations plus environmental triggers such as mental stress, viral infections, drugs.