Adrenal insufficiency pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayeesha Kattubadi, M.B.B.S[2]


It is thought that adrenal insufficiency is the result of multiple etiologies like autoimmune adrenalitis, X-linked adrenoleukodystrophy, chronic glucocorticoid use, adrenal hemoorage etc. The pathophysiology depends on each etiological subtype.



Adrenal insufficiency arises due to the deficiency of adrenocortical hormones.The normal physiology of adrenocortical hormone production can be understood as follows: The adrenal cortex is divided into three zones from outside to inside as - Zona glomerulosa, zona fasciculata and zona reticularis which are responsible for the production of streroidogenic hormones like mineralocorticoid, glucocorticoid and androgens respectively. [1]


The pathophysiology of adrenal insufficiency depends on the etiological subtype.

Autoimmune adrenalitis: Both humoral and cell-mediated immune mechanisms attack enzymes involved in adrenocortical hormone synthesis. Autoantibodies against 21-hydroxylase, an enzyme required in the biosynthesis of adrenocortical hormones can be found. The patients remain asymptomatic until 90% of the cortex is destroyed. It can present as isolated autoimmune adrenalitis in 30-40% of cases or as an autoimmune polyglandular syndrome in 60-70% of cases. The autoimmune polyglandular syndrome in subclassified as autoimmune polyglandular syndrome type 1(APS type 1) and autoimmune polyglandular syndrome type 2 (APS type 2) [2] [3]

X-linked Adrenoleukodystrophy(X-ALD): X-ALD occurs due to mutations in the peroxisomal ATP-binding cassette (ABC) transporter encoded by the ABCD1 gene. Disruption of this transport protein leads to the accumulation of Very Long Chain Fatty Acids (VLCFA). Male patients usually present in childhood or adolescence, whereas heterozygous females present between 40-50 years. The lifetime prevalence of adrenal insufficiency is 80% in males, with the highest risk being in the first decade. Adrenal Insufficiency is extremely rare in females. [4] [5]

Chronic glucocorticoid use: Chronic use of glucocorticoids can cause secondary or tertiary adrenal insufficiency and is the most common cause of adrenal insufficiency. Exogenous glucocorticoid use causes feedback inhibition of the HPA axis leading to reduced synthesis of CRH and ACTH by the hypothalamus and pituitary. As a consequence of reduced ACTH, the adrenal cortex slowly loses the ability to synthesize cortisol. The mineralocorticoid synthetic function of the adrenal cortex is retained as it depends on RAAS. HPA axis is usually suppressed when glucocorticoids were used for >2weeks. In some cases, the HPA axis may remain suppressed for as long as 6-12 months after glucocorticoid withdrawal. HPA axis can be suppressed with oral, inhaled, topical, injectable, intraarticular, intradermal, paraspinal, or rectal glucocorticoid preparations. [6] [7]


Autoimmune adrenalitis: Genes involved in the pathogenesis of autoimmune adrenalitis include HLA DR3/DQ2 and DR4/DQ8.

  • The autoimmune polyglandular syndrome type 1 is transmitted in an autosomal recessive pattern. Gene involved in the pathogenesis is the autoimmune regulator gene (AIRE).
  • The autoimmune polyglandular syndrome type 2 shows a polygenic inheritance. A strong association has been shown with HLA DR3 of MHC.

X-linked adrenoleukodystrophy: Genes involved in the pathogenesis of X-ALD include the ABCD1 gene which causes an alteration in peroxisomal ATP-binding cassette (ABC) transporter.

Associated Conditions

Autoimmune adrenalitis:

X-linked Adrenoleukodystrophy: Apart from presenting as adrenal insufficiency it is also associated with cerebral inflammatory demyelination, myelopathy.

Gross Pathology

On gross pathology, the adrenal gland is atrophied in autoimmune adrenalitis. Autopsy findings show a decrease in the size and weight of the gland. In addition there may be hyperpigmentation of the gland. [8]

Microscopic Pathology

On microscopic histopathological analysis, infiltration of the adrenal cortex with chronic inflammatory cells like lymphocytes is a characteristic finding in autoimmune adrenalitis. The adrenal cortex can be atrophied with the preservation of the medulla. [8]


  1. "StatPearls". 2020. PMID 30725945.
  2. "StatPearls". 2020. PMID 28722862.
  3. Erichsen, Martina M.; Løvås, Kristian; Skinningsrud, Beate; Wolff, Anette B.; Undlien, Dag E.; Svartberg, Johan; Fougner, Kristian J.; Berg, Tore J.; Bollerslev, Jens; Mella, Bjarne; Carlson, Joyce A.; Erlich, Henry; Husebye, Eystein S. (2009). "Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry". The Journal of Clinical Endocrinology & Metabolism. 94 (12): 4882–4890. doi:10.1210/jc.2009-1368. ISSN 0021-972X.
  4. Huffnagel, Irene C; Laheji, Fiza K; Aziz-Bose, Razina; Tritos, Nicholas A; Marino, Rose; Linthorst, Gabor E; Kemp, Stephan; Engelen, Marc; Eichler, Florian (2019). "The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration". The Journal of Clinical Endocrinology & Metabolism. 104 (1): 118–126. doi:10.1210/jc.2018-01307. ISSN 0021-972X.
  5. Berger J, Forss-Petter S, Eichler FS (2014). "Pathophysiology of X-linked adrenoleukodystrophy". Biochimie. 98: 135–42. doi:10.1016/j.biochi.2013.11.023. PMC 3988840. PMID 24316281.
  6. Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K; et al. (2000). "Endotext". PMID 25905379.
  7. Younes, Areej K.; Younes, Noor K. (2017). "Recovery of steroid induced adrenal insufficiency". Translational Pediatrics. 6 (4): 269–273. doi:10.21037/tp.2017.10.01. ISSN 2224-4336.
  8. 8.0 8.1 Kemp WL, Koponen MA, Meyers SE (2016). "Addison Disease: The First Presentation of the Condition May be at Autopsy". Acad Forensic Pathol. 6 (2): 249–257. doi:10.23907/2016.026. PMC 6506997 Check |pmc= value (help). PMID 31239896.

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