Adrenal insufficiency: Difference between revisions
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==Diagnosis== | ==Diagnosis== | ||
[[Adrenal insufficiency diagnostic study of choice|Diagnostic study of choice]] | [[Adrenal insufficiency history and symptoms|History and Symptoms]] | [[Adrenal insufficiency physical examination|Physical Examination]] | [[Adrenal insufficiency laboratory findings|Laboratory Findings]] | [[Adrenal insufficiency electrocardiogram|Electrocardiogram]] | [[Adrenal insufficiency x ray|X-Ray Findings]] | [[Adrenal insufficiency echocardiography and ultrasound|Echocardiography and Ultrasound]] | [[Adrenal insufficiency CT scan|CT-Scan Findings]] | [[Adrenal insufficiency MRI|MRI Findings]] | [[Adrenal insufficiency other imaging findings|Other Imaging Findings]] | [[Adrenal insufficiency other diagnostic studies|Other Diagnostic Studies]] | [[Adrenal insufficiency diagnostic study of choice|Diagnostic study of choice]] | [[Adrenal insufficiency history and symptoms|History and Symptoms]] | [[Adrenal insufficiency physical examination|Physical Examination]] | [[Adrenal insufficiency laboratory findings|Laboratory Findings]] | [[Adrenal insufficiency electrocardiogram|Electrocardiogram]] | [[Adrenal insufficiency x ray|X-Ray Findings]] | [[Adrenal insufficiency echocardiography and ultrasound|Echocardiography and Ultrasound]] | [[Adrenal insufficiency CT scan|CT-Scan Findings]] | [[Adrenal insufficiency MRI|MRI Findings]] | [[Adrenal insufficiency other imaging findings|Other Imaging Findings]] | [[Adrenal insufficiency other diagnostic studies|Other Diagnostic Studies]] | ||
<font size="+2">[[Diagnosis]]</font>: | |||
The diagnosis of [[adrenal insufficiency]] is a three-step process that can be performed simultaneously or in sequential order. | |||
#Prove the existence of [[adrenal insufficiency]] i.e. Syndromic Diagnosis. | |||
#Determine the nature of [[adrenal insufficiency]] i.e. Primary, Secondary, Tertiary [[Adrenal insufficiency]] by identifying the location of the defect in the [[HPA]] axis. | |||
#Determine the cause i.e. [[etiological]] diagnosis. | |||
<font size="+1">'''Tests used in syndromic diagnosis''':</font> | |||
*'''Serum basal cortisol:''' As [[cortisol]] secretion follows a circadian rhythm with a nadir around midnight and peak between 6-8 AM, serum basal [[cortisol]] measurement should be taken between 8 AM-9 AM. Total [[serum]] [[cortisol]] is composed of the protein-bound fraction (90%) and free [[cortisol]] (10%) which is the biologically active form. Corticosteroid-binding [[globulin]] (CBG) is the major transporter for [[cortisol]]. Conditions that alter CBG also alter the total serum [[cortisol]], with no effect on free [[cortisol]]. Therefore caution has to be exercised while interpreting the levels of serum [[cortisol]] in conditions where CBG levels are altered. | |||
*'''Salivary [[cortisol]] levels:''' Salivary [[cortisol]] levels are measured at 8 am. Levels <0.18 µg/dL strongly predict adrenal insufficiency, whereas levels >0.58µg/L rule out adrenal insufficiency. The advantage of this test is that it is noninvasive so can be done by the patient at home and it only measures the free [[cortisol]] levels, so it’s not affected by changes in [[plasma proteins]]. The disadvantage is that it’s not a universally standardized test. | |||
*'''Urine free [[cortisol]] measurement:''' Low sensitivity and therefore not useful in diagnostic confirmation. | |||
'''Dynamic tests:''' They are used in patients with indeterminate levels of basal plasma cortisol i.e. in between 5 µg/dL to 10 µg/dL. The different typed of dynamic tests are as follows – | |||
==Treatment== | ==Treatment== | ||
Revision as of 10:58, 24 September 2020
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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]
Overview
Historical Perspective
Thomas Addison in 1885 first defined adrenal insufficiency as a disorder of impaired adrenocortical function leading to deficiency in glucocorticoids, mineralocorticoids, and adrenal androgens. Earlier salt supplementation was used in the treatment of adrenal insufficiency. Later Hench, Kendall, and Reichstein were awarded the 1950 Nobel Prize in Physiology or Medicine "for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects" which broadened the treatment options for adrenal insufficiency. The most common causes of primary adrenal insufficiency have been constantly evolving. In the 1920s, the most common cause of adrenal insufficiency was tuberculosis, whereas in the 1950s it is autoimmune polyglandular syndrome.
Classification
Adrenal insufficiency is classified based on the location of the pathology into: [1]. [2]
In Primary adrenal insufficiency, the pathology lies in the adrenal glands leading to decreased production of cortisol and aldosterone.The most common cause of primary adrenal insufficiency is autoimmune adrenalitis. In secondary adrenal insufficiency, the pathology lies in the pituitary gland leading to reduced ACTH production, whereas in tertiary adrenal insufficiency the pathology lies in the hypothalamus leading to reduced CRH production. The most common cause of tertiary adrenal insufficiency is chronic glucocorticoid therapy. Secondary and tertiary adrenal insufficiency together are categorised into central adrenal insufficiency. The following table summaries the causes of adrenal insufficiency.
| Causes of adrenal insufficiency | ||
|---|---|---|
| Primary adrenal insufficiency (Addison's disease) |
Secondary adrenal insufficiency | Tertiary adrenal insufficiency |
|
|
|
Pathophysiology
The pathogenesis of adrenal insufficiency varies based on the etiology as follows: [3]
Autoimmune adrenalitis: Humoral as well as cell mediated immune mechanisms attack various enzymes involved in the synthesis of adrenal cortical enzymes. Strong genetic association has bene seen with HLA DR3/DQ2 and DR4/DQ8. On gross anatomy the adrenal gland is atrophied with preservation of adrenal medulla. Histopathology shows lymphocytic infiltration with fibrosis of the parenchyma. The patients are asymptomatic until up to 90% of the cortex is destroyed. Autoantibodies against 21-hydroxylase, an essential enzyme required in the biosynthesis of steroid hormones of the adrenal cortex are seen. [4] [5]
- Isolated autoimmune adrenalitis accounts for 30-40% cases.
- Autoimmune Polyglandular Syndrome (APS) account for 60-70%. Which is further subclassified as follows:
Autoimmune Polyglandular Syndrome Type 1 (APS type 1): Exhibits autosomal recessive mode of inheritance. It is also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). Caused due to mutations in the autoimmune regulator gene (AIRE). Apart from adrenal insufficiency it presents with chronic mucocutaneous candidiasis, hypoparathyroidism, total alopecia.
Autoimmune Polyglandular Syndrome Type 2 (APS type 2): It is more common than APS type 1 and has polygenic inheritance. Strong association has been shown with HLA DR3 of MHC. Apart from adrenal insufficiency it presents with autoimmune thyroiditis, vitiligo, premature ovarian failure, type 1 diabetes mellitus, pernicious anemia.
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 phenotypic expression is variable and can present as pre-symptomatic, cerebral inflammatory demyelination, myelopathy, adrenal insufficiency. 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. [6] [7]
Chronic glucocorticoid use:
Secondary or Tertiary adrenal insufficiency induced by chronic use of glucocorticoids is the most common cause of adrenal insufficiency. HPA axis suppression has been reported with oral, inhaled, topical, injectable, intraarticular, intradermal, paraspinal, or rectal glucocorticoid preparations. Exogenous glucocorticoid use causes feedback inhibition of the HPA axis leading to reduced synthesis of CRH and ACTH by hypothalamus and pituitary. As a consequence of reduced ACTH, the adrenal cortex slowly loses the ability to synthesise cortisol. The mineralocorticoid synthetic function of the adrenal cortex is retained as it depends on RAAS. HPA axis function recovers quickly if glucocorticoids were used for less than 10-14 days. If glucocorticoids were used for >2weeks, weaning and assessment of HPA integrity are recommended. In some cases the HPA axis may remain suppressed for as long as 6-12 months after glucocorticoid withdrawal. [8] [9]
The other causes of adrenal insufficiency are due to the destruction of the adrenal, pituitary or hypothalamus due to various causes as mentioned in the table above.
Causes
Differentiating Xyz from other Diseases
Epidemiology and Demographics
Primary adrenal insufficiency is more common in women. It usually presents between the age group of 30-50. Secondary adrenal insufficiency is more common than primary and usually presents in the sixth decade of life.
Risk Factors
| Risk factors associated with increased risk of adrenal crisis | ||
|---|---|---|
| History | Drugs | Medical conditions |
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Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic study of choice | History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | X-Ray Findings | Echocardiography and Ultrasound | CT-Scan Findings | MRI Findings | Other Imaging Findings | Other Diagnostic Studies
The diagnosis of adrenal insufficiency is a three-step process that can be performed simultaneously or in sequential order.
- Prove the existence of adrenal insufficiency i.e. Syndromic Diagnosis.
- Determine the nature of adrenal insufficiency i.e. Primary, Secondary, Tertiary Adrenal insufficiency by identifying the location of the defect in the HPA axis.
- Determine the cause i.e. etiological diagnosis.
Tests used in syndromic diagnosis:
- Serum basal cortisol: As cortisol secretion follows a circadian rhythm with a nadir around midnight and peak between 6-8 AM, serum basal cortisol measurement should be taken between 8 AM-9 AM. Total serum cortisol is composed of the protein-bound fraction (90%) and free cortisol (10%) which is the biologically active form. Corticosteroid-binding globulin (CBG) is the major transporter for cortisol. Conditions that alter CBG also alter the total serum cortisol, with no effect on free cortisol. Therefore caution has to be exercised while interpreting the levels of serum cortisol in conditions where CBG levels are altered.
- Salivary cortisol levels: Salivary cortisol levels are measured at 8 am. Levels <0.18 µg/dL strongly predict adrenal insufficiency, whereas levels >0.58µg/L rule out adrenal insufficiency. The advantage of this test is that it is noninvasive so can be done by the patient at home and it only measures the free cortisol levels, so it’s not affected by changes in plasma proteins. The disadvantage is that it’s not a universally standardized test.
- Urine free cortisol measurement: Low sensitivity and therefore not useful in diagnostic confirmation.
Dynamic tests: They are used in patients with indeterminate levels of basal plasma cortisol i.e. in between 5 µg/dL to 10 µg/dL. The different typed of dynamic tests are as follows –
Treatment
Medical Therapy | Interventions | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies
References
- ↑ "Adrenal Insufficiency - Endotext - NCBI Bookshelf".
- ↑ Bornstein, Stefan R.; Allolio, Bruno; Arlt, Wiebke; Barthel, Andreas; Don-Wauchope, Andrew; Hammer, Gary D.; Husebye, Eystein S.; Merke, Deborah P.; Murad, M. Hassan; Stratakis, Constantine A.; Torpy, David J. (2016). "Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology & Metabolism. 101 (2): 364–389. doi:10.1210/jc.2015-1710. ISSN 0021-972X.
- ↑ "Adrenal Insufficiency - StatPearls - NCBI Bookshelf".
- ↑ 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.
- ↑ "Adrenal Insufficiency - StatPearls - NCBI Bookshelf".
- ↑ Berger J, Forss-Petter S, Eichler FS (March 2014). "Pathophysiology of X-linked adrenoleukodystrophy". Biochimie. 98: 135–42. doi:10.1016/j.biochi.2013.11.023. PMC 3988840. PMID 24316281.
- ↑ 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.
- ↑ "Glucocorticoid Therapy and Adrenal Suppression - Endotext - NCBI Bookshelf".
- ↑ Younes AK, Younes NK (2017). "Recovery of steroid induced adrenal insufficiency". Transl Pediatr. 6 (4): 269–273. doi:10.21037/tp.2017.10.01. PMC 5682381. PMID 29184808.
- ↑ Puar, Troy H.K.; Stikkelbroeck, Nike M.M.L.; Smans, Lisanne C.C.J.; Zelissen, Pierre M.J.; Hermus, Ad. R.M.M. (2016). "Adrenal Crisis: Still a Deadly Event in the 21st Century". The American Journal of Medicine. 129 (3): 339.e1–339.e9. doi:10.1016/j.amjmed.2015.08.021. ISSN 0002-9343.