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{{Adrenal insufficiency}}
{{Adrenal insufficiency}}
{{CMG}}; {{AE}} {{Ayeesha}}
{{CMG}}; {{AE}} {{Ayeesha}}  
 
'''Synonyms and keywords:''' Addison's disease
==[[Adrenal insufficiency overview|Overview]]==
==[[Adrenal insufficiency overview|Overview]]==


==[[Adrenal insufficiency historical perspective|Historical Perspective]]==
==[[Adrenal insufficiency historical perspective|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 <ref name="pmid25905309">{{cite journal| author=Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K | display-authors=etal| title=Endotext | journal= | year= 2000 | volume=  | issue=  | pages=  | pmid=25905309 | doi= | pmc= | url= }} </ref> <ref name="BornsteinAllolio2016">{{cite journal|last1=Bornstein|first1=Stefan R.|last2=Allolio|first2=Bruno|last3=Arlt|first3=Wiebke|last4=Barthel|first4=Andreas|last5=Don-Wauchope|first5=Andrew|last6=Hammer|first6=Gary D.|last7=Husebye|first7=Eystein S.|last8=Merke|first8=Deborah P.|last9=Murad|first9=M. Hassan|last10=Stratakis|first10=Constantine A.|last11=Torpy|first11=David J.|title=Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline|journal=The Journal of Clinical Endocrinology & Metabolism|volume=101|issue=2|year=2016|pages=364–389|issn=0021-972X|doi=10.1210/jc.2015-1710}}</ref> :
*'''[[Primary adrenal insufficiency]]'''
*'''[[Secondary adrenal insufficiency]]'''
*'''Tertiary [[adrenal insufficiency]]'''


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.
==[[Adrenal insufficiency classification|Classification]]==
{| class="wikitable"
|+
! colspan="3" |<font size="+2">Causes of [[adrenal insufficiency]]
|-
|'''<font size="+1">[[Primary adrenal insufficiency]]'''<br>'''([[Addison's disease]])'''
|'''<font size="+1">[[Secondary adrenal insufficiency]]'''
|'''<font size="+1">[[Tertiary adrenal insufficiency]]'''
|-
|
*'''[[Autoimmune]]:'''
**Sporadic
**[[Autoimmune polyendocrine syndrome type 1]]<br>(APS type 1)
**[[Autoimmune polyendocrine syndrome type 2]]<br>(Schmidt's syndrome)
*'''[[Infections]]:'''
**[[Tuberculosis]],
**[[Fungal infections]],
**[[Cytomegalovirus]],
**[[HIV]]
*'''[[Adrenal]] [[Metastasis]]'''
*'''[[Adrenal]] infiltration'''
*'''[[Adrenal hemorrhage]]:'''
**[[Waterhouse-Friderichsen syndrome]],
**Drugs - Anticoagulants- [[Heparin]], [[Warfarin]])
*'''[[Adrenoleukodystrophy]]'''
*'''Congenital adrenal hypoplasia'''
*'''Bilateral adrenelectomy'''
 
|
*'''[[Pituitary]] [[tumors]]'''
*'''[[Iatrogeneic]]:'''
**[[Pituitary]] [[surgery]],
**[[Pituitary]] [[radiation]]
*'''[[Granulomatous diseases]]:'''
**[[Tuberculosis]]
**[[Sarcoidosis]]
**[[Histiocytosis]]
**[[Wegener's granulomatosis]]
*'''[[Metastasis]]'''
*'''[[Pituitary apoplexy]]'''
*'''[[Sheehan's syndrome]]'''<br>(Peripartum pituitary necrosis)
*'''[[Genetic]]:'''
**Isolated [[ACTH]] deficiency,
**Multiple pituitary hormone deficiencies
*'''Trauma'''
|
*'''[[Glucocorticoid]] therapy'''
*'''[[Cushing's syndrome]]'''<br>(Excess endogenous [[glucocorticoid]] production)
*'''Drugs:'''
**[[Mifepristone]]
**[[Chlorpromazine]]
**[[Imipramine]]
*'''[[Hypothalamic]] tumors'''<br>(Primary and metastatic)
*'''[[Iatrogenic]]:'''
**[[Hypothalamic]] [[surgery]]
**[[Hypothalamic]] [[radiation]]
*'''[[Granulomatous diseases]]:'''
**[[Tuberculosis]]
**[[Sarcoidosis]]
**[[Histiocytosis]]
**[[Wegener's granulomatosis]]
*'''Trauma'''
 
|}


==[[Adrenal insufficiency pathophysiology|Pathophysiology]]==
==[[Adrenal insufficiency pathophysiology|Pathophysiology]]==


The [[pathogenesis]] of [[adrenal insufficiency]] varies based on the [[etiology]] as follows:
==[[Adrenal insufficiency differential diagnosis|Differential diagnosis]]==
 
<font size="+1">'''[[Autoimmune adrenalitis]]'''</font> <ref> {{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK441832/ |title=Adrenal Insufficiency - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}} </ref> <ref name="ErichsenLøvås2009">{{cite journal|last1=Erichsen|first1=Martina M.|last2=Løvås|first2=Kristian|last3=Skinningsrud|first3=Beate|last4=Wolff|first4=Anette B.|last5=Undlien|first5=Dag E.|last6=Svartberg|first6=Johan|last7=Fougner|first7=Kristian J.|last8=Berg|first8=Tore J.|last9=Bollerslev|first9=Jens|last10=Mella|first10=Bjarne|last11=Carlson|first11=Joyce A.|last12=Erlich|first12=Henry|last13=Husebye|first13=Eystein S.|title=Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry|journal=The Journal of Clinical Endocrinology & Metabolism|volume=94|issue=12|year=2009|pages=4882–4890|issn=0021-972X|doi=10.1210/jc.2009-1368}}</ref>: 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. 
 
*'''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]].
 
<font size="+1">'''[[X linked Adrenoleukodystrophy(X-ALD)]]'''</font>  <ref>{{cite journal |vauthors=Berger J, Forss-Petter S, Eichler FS |title=Pathophysiology of X-linked adrenoleukodystrophy |journal=Biochimie |volume=98 |issue= |pages=135–42 |date=March 2014 |pmid=24316281 |pmc=3988840 |doi=10.1016/j.biochi.2013.11.023 |url=}} </ref> <ref name="HuffnagelLaheji2019">{{cite journal|last1=Huffnagel|first1=Irene C|last2=Laheji|first2=Fiza K|last3=Aziz-Bose|first3=Razina|last4=Tritos|first4=Nicholas A|last5=Marino|first5=Rose|last6=Linthorst|first6=Gabor E|last7=Kemp|first7=Stephan|last8=Engelen|first8=Marc|last9=Eichler|first9=Florian|title=The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration|journal=The Journal of Clinical Endocrinology & Metabolism|volume=104|issue=1|year=2019|pages=118–126|issn=0021-972X|doi=10.1210/jc.2018-01307}}</ref> : 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.
 
<font size="+1"> '''[[Chronic glucocorticoid use]]'''</font> <ref>{{cite journal |vauthors=Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland HJ, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, Nicolaides NC, Pavlaki AN, Maria Alexandra MA, Chrousos GP |title= |journal= |volume= |issue= |pages= |date= |pmid=25905379 |doi= |url=}}</ref> <ref>{cite journal |vauthors=Younes AK, Younes NK |title=Recovery of steroid induced adrenal insufficiency |journal=Transl Pediatr |volume=6 |issue=4 |pages=269–273 |date=October 2017 |pmid=29184808 |pmc=5682381 |doi=10.21037/tp.2017.10.01 |url=}}</ref>:
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.
 
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.
 
==[[Adrenal insufficiency causes|Causes]]==
 
==[[Adrenal insufficiency differential diagnosis|Differentiating Xyz from other Diseases]]==
 
==[[Adrenal insufficiency epidemiology and demographics|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.
 
 
==[[Adrenal insufficiency risk factors|Risk Factors]]==
 
 
{| class="wikitable"
|+
! colspan="2" |Risk factors associated with increased risk of adrenal crisis
!
|-
|'''History'''
|'''Drugs'''
|'''Medical conditions'''
|-
|
*<nowiki>Prior history of [[adrenal crisis}}</nowiki>
*Known case of [[adrenal insufficiency]]
|
*Suppression of [[HPA]] axis by exogenous [[steroids]]
*Increased risk of adrenal [[hemorrhage]] by [[anticoagulants]]
*Increased cortisol metabolism by [[Levothyroxine]], [[Phenytoin]], [[Phenobarbitol]]
*Decreased production of cortisol by [[Ketoconazole]], [[Etomidate]]
|
*[[Thyrotoxicosis]]
*[[Diabetes insipidus]]
*[[Diabetes mellitus]]
*[[Pregnancy]]
|}
 
==[[Adrenal insufficiency screening|Screening]]==


==[[Adrenal insufficiency natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
==[[Adrenal insufficiency epidemiology and demographics |Epidemiology and Demographics]]==
==[[Adrenal insufficiency risk factors | Risk factors]]==
==[[Adrenal insufficiency screening | Screening]]==
==[[Adrenal insufficiency natural history, complications and prognosis | Natural History, Complications and Prognosis]]==


==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>:
==Treatment==
 
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>
[[Adrenal insufficiency medical therapy|Medical Therapy]] | [[Adrenal insufficiency surgery|Surgery]] | [[Adrenal insufficiency primary prevention|Primary Prevention]] | [[Adrenal insufficiency secondary prevention|Secondary Prevention]] | [[Adrenal insufficiency cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Adrenal insufficiency future or investigational therapies|Future or Investigational Therapies]]
 
*'''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 –
{| class="wikitable"
|+
!Name of the test
!Insulin Hypoglycemia test
!ACTH stimulation test
!Low dose ACTH stimukation test
!Metyrapone stimulation
!Glucagon stimulation
|-
!Agent to be administered
|Regular insulin 0.1-1.15U/kg I.V
|Cosyntropin 250mcg I.V
|Consyntropin 1mcg I.V
|Metyrapone 30mg/kg P.O
|Glucagon 1mg I.M
|-
!Timing of sample collection
|0-30-45-60-90 min
|0-30-60 min
|0-30-60 min
|8 hours post metyrapone
|90-120-150-180-210-240min
|-
!Parameter Tested
|Plasma cortisol
|Plasma cortisol
|Plasma cortisol
|11 deoxycortisol
|Plasma cortisol
|-
!Comments
|Gold standard
|Safe
|Manual preparation
|Assesses whole HPA
|Less accurate
|}
 
==Treatment==
[[Adrenal insufficiency medical therapy|Medical Therapy]] | [[Adrenal insufficiency interventions|Interventions]] | [[Adrenal insufficiency surgery|Surgery]] | [[Adrenal insufficiency primary prevention|Primary Prevention]] | [[Adrenal insufficiency secondary prevention|Secondary Prevention]] | [[Adrenal insufficiency cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Adrenal insufficiency future or investigational therapies|Future or Investigational Therapies]]


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Latest revision as of 15:26, 21 January 2021

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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]

Synonyms and keywords: Addison's disease

Overview

Historical Perspective

Classification

Pathophysiology

Differential diagnosis

Epidemiology and Demographics

Risk factors

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

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