Primary adrenal insufficiency

Primary adrenal insufficiency (also known as Addison disease) may present acutely or insidiously, with progressive substantial fatigue and generalized weakness associated with mucocutaneous hyperpigmentation, hypotension and/or postural hypotension, and salt craving.

Adrenocorticotropic hormone stimulation test is the definitive test to confirm or exclude the diagnosis of early primary adrenal insufficiency.

All patients require mineralocorticoid and glucocorticoid replacement therapy for life.

Use of a medical alert (bracelet or card) warning about their condition, and education on when to increase glucocorticoid replacement doses appropriately during surgery and during any stressful or infectious conditions, is vital to prevent potentially life-threatening adrenal crises.

Treatment complications arise from over-replacement of mineralocorticoid and/or glucocorticoid.

PAI was first described by Thomas Addison.[1]Kumar R, Wassif WS. Adrenal insufficiency. J Clin Pathol. 2022 Jul;75(7):435-42. https://jcp.bmj.com/content/75/7/435.long http://www.ncbi.nlm.nih.gov/pubmed/35534201?tool=bestpractice.com ​ PAI results from intrinsic diseases that affect the cortex of the adrenal glands, causing impairment in the synthesis and secretion of all steroids (glucocorticoids and/or mineralocorticoids) normally secreted by the three cortical layers.[2]Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880116 http://www.ncbi.nlm.nih.gov/pubmed/26760044?tool=bestpractice.com The main adrenal steroids that are deficient and also physiologically important include cortisol, aldosterone, and dehydroepiandrosterone (DHEA), as well as its sulfated conjugate, DHEA-S.[2]Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880116 http://www.ncbi.nlm.nih.gov/pubmed/26760044?tool=bestpractice.com

Cortisol deficiency in PAI reduces the feedback to the hypothalamic-pituitary axis and results in elevation of adrenocorticotropic hormone (ACTH) level; this enhances stimulation of the adrenal cortex.[2]Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880116 http://www.ncbi.nlm.nih.gov/pubmed/26760044?tool=bestpractice.com This is in contrast to central adrenal insufficiency, which occurs as a result of impaired ACTH secretion caused by pituitary (secondary) or hypothalamic (tertiary) diseases.[3]Husebye ES, Pearce SH, Krone NP, et al. Adrenal insufficiency. Lancet. 2021 Feb 13;397(10274):613-29. http://www.ncbi.nlm.nih.gov/pubmed/33484633?tool=bestpractice.com In most patients with central adrenal insufficiency, secretion of mineralocorticoids (aldosterone) is maintained.[4]Hahner S, Ross RJ, Arlt W, et al. Adrenal insufficiency. Nat Rev Dis Primers. 2021 Mar 11;7(1):19. http://www.ncbi.nlm.nih.gov/pubmed/33707469?tool=bestpractice.com [5]Crowley RK, Argese N, Tomlinson JW, et al. Central hypoadrenalism. J Clin Endocrinol Metab. 2014 Nov;99(11):4027-36. https://www.doi.org/10.1210/jc.2014-2476 http://www.ncbi.nlm.nih.gov/pubmed/25140404?tool=bestpractice.com

PAI in children is not specifically covered in this topic, but should prompt referral to a pediatric endocrinology specialist. Also not covered here is congenital adrenal hyperplasia, which includes diseases associated with deficiencies in any of the enzymes involved in adrenal steroid synthesis. See Congenital adrenal hyperplasia.