Etiology
In developed countries, most cases of the disease (75% to 96%) are autoimmune in nature, with antibodies directed against 21-hydroxylase present in 80% to 90% of people, when known non-autoimmune causes have been excluded.[12] These antibodies are specific for primary adrenal insufficiency (PAI) disease and their presence in an otherwise healthy individual indicates an increased risk for the future development of PAI. Although PAI can present as an isolated event, it is often associated with other known endocrine disorders of similar etiology such as Hashimoto thyroiditis, Graves disease, type 1 diabetes mellitus, and premature gonadal failure (autoimmune polyglandular syndromes).[3][9] Similarly, patients with PAI disease are at an increased risk of developing other autoimmune diseases such as rheumatoid arthritis, Crohn disease, and celiac disease.[13] Tuberculosis continues to be a cause for PAI disease in countries where infection with that bacteria is still endemic or in people with previous exposure to tuberculosis.[14][15][16]
Less common causes of adrenal gland destruction include:
Infectious diseases, such as Pseudomonas aeruginosa and meningococcal infection, systemic fungal infections (e.g., histoplasmosis, paracoccidioidomycosis), and opportunistic infections secondary to HIV infection.
Infiltrative diseases (e.g., amyloidosis, hemochromatosis, xanthogranulomatosis, histiocytic disorders, sarcoidosis).[9]
Metastatic malignancies (e.g., lung, breast, kidney, colon, melanoma, and lymphoma).[9]
Hemorrhagic infarction of the adrenal glands, particularly in patients with antiphospholipid antibodies and in those receiving heparin or warfarin therapy.[9][17] The presentation in such patients is often acute and is associated with flank pain.
Surgical bilateral adrenalectomy for medical reasons (e.g., Cushing syndrome, bilateral pheochromocytoma).[9]
Use of some medications result in drug-induced PAI, such as drugs that inhibit cortisol production (e.g., etomidate, ketoconazole, metyrapone, aminoglutethimide, and mitotane) or that increase cortisol metabolism (e.g., phenytoin, phenobarbital, rifampin).[8][9][18][19] Immune checkpoint inhibitors may cause primary (adrenalitis) or secondary (hypophysitis) adrenal insufficiency. Adrenal autoantibodies have been detected in pembrolizumab-induced adrenal failure.[20]
Genetic conditions that interfere with cortisol synthesis or adrenal destruction (e.g., congenital adrenal hyperplasia, mitochondrial disorders, adrenoleukodystrophy, and adrenomyeloneuropathy) are more likely to be present and diagnosed in children.[9]
Pathophysiology
The clinical and biochemical manifestations of primary adrenal insufficiency result from decreased production of the main adrenal steroids (cortisol, aldosterone, and dehydroepiandrosterone [DHEA], as well as its sulfated conjugate, DHEA-S) and the compensatory rise in plasma adrenocorticotropic hormone.[2]
Decreased adrenal steroid secretion results from either destruction of the three layers of the adrenal cortex (the glomerulosa, fasciculata, and reticularis) or disruption of hormone synthesis.[4] Approximately 90% of the adrenal cortex needs to be destroyed to cause the clinical symptoms of adrenal insufficiency.[9] Destruction of the adrenal cortical layers can occur as a result of an autoimmune process (adrenalitis), infection (e.g., tuberculosis), infiltrating diseases (e.g., amyloidosis, hemochromatosis), or tumors (e.g., bilateral primary or metastatic tumors, or bilateral lymphoma).[4] Hemorrhage within the adrenals can similarly result in acute destruction of the adrenal cortex and may also cause destruction of the adrenal medulla.[21][22]
Classification
Types of adrenal insufficiency
Primary (adrenal): destruction or dysfunction of the adrenal gland resulting from intrinsic diseases of the adrenal cortex and leading to impairment in steroid hormone synthesis and secretion.[3]
Central: the term central adrenal insufficiency is often used to refer to hypocortisolemia secondary to a deficiency in adrenocorticotropic hormone (ACTH) secretion.[5]
Secondary (pituitary): inadequate pituitary ACTH release and subsequent production of cortisol and dehydroepiandrosterone (DHEA), as well as its sulfated conjugate DHEA-S. Intrinsic pituitary disease includes tumors, irradiation, and inflammation (hypophysitis).[3] The recent increase in the use of immunotherapy to treat different cancers was associated with higher risk of the development of hypophysitis.[6] The pituitary ACTH secreting cells (corticotrophs) are often affected by the immune hypophysitis, and their destruction as a result of the immune inflammatory process results in impairment of ACTH secretion and the development of central adrenal insufficiency.[7]
Tertiary (hypothalamus): inadequate hypothalamic corticotropin-releasing hormone and subsequent ACTH release. Diseases include inflammatory disease (e.g., tuberculosis, sarcoidosis), or tumors such as craniopharyngiomas. Hypothalamic suppression of ACTH secretion is caused by prolonged (more than 2 weeks) treatment with exogenous glucocorticoids. Subsequent glucocorticoid withdrawal is a common cause of tertiary adrenal insufficiency.[3] See our topic "Adrenal suppression" for more details.
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