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==[[Adrenal insufficiency overview|Overview]]==
 
==[[Adrenal insufficiency overview|Overview]]==
  
[[Adrenal Insufficiency]] is a clinical state where there is reduced production of adrenocortical [[hormones]]. The adrenal cortex is divided into three zones- [[zona glomerulosa]], [[zona fasciculata]], and [[zona reticularis]] producing [[mineralocorticoids]], [[glucocorticoids]], and [[androgens]] respectively. [[Adrenal Insufficiency]] causes [[glucocorticoid]] and [[mineralocorticoid]] deficiency. It is classified as primary, secondary, and tertiary. Its presentation depends on the rapidity and degree of hormone depletion. It can present acutely as [[adrenal crisis]], especially when the body is under stress due to [[infections]], trauma, etc. If it presents chronically it is called [[Addison disease]]. The mainstay of treatment includes replacement therapy with [[glucocorticoids]] i.e [[hydrocortisone]]. Whereas, primary adrenal insufficiency requires additional [[mineralocorticoid]] replacement as well.  
+
[[Adrenal Insufficiency]] is a clinical state where there is reduced production of adrenocortical [[hormones]]. The adrenal cortex is divided into three zones- [[zona glomerulosa]], [[zona fasciculata]], and [[zona reticularis]] producing [[mineralocorticoids]], [[glucocorticoids]], and [[androgens]] respectively. [[Adrenal Insufficiency]] causes [[glucocorticoid]] and [[mineralocorticoid]] deficiency. It is classified as primary, secondary, and tertiary. Its presentation depends on the rapidity and degree of hormone depletion. It can present acutely as [[adrenal crisis]], especially when the body is under stress due to [[infections]], trauma, etc. If it presents chronically it is called [[Addison disease]]. The mainstay of treatment includes replacement therapy with [[glucocorticoids]] i.e [[hydrocortisone]]. Whereas, primary adrenal insufficiency requires additional [[mineralocorticoid]] replacement as well. <ref>{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK441832/+ |title=Adrenal Insufficiency - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
  
 
==[[Adrenal insufficiency historical perspective|Historical Perspective]]==
 
==[[Adrenal insufficiency historical perspective|Historical Perspective]]==
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==[[Classification]]==
 
==[[Classification]]==
  
'''[[Adrenal insufficiency]]''' is classified based on the location of the [[pathology]] into:  
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'''[[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]]'''
 
*'''[[Primary adrenal insufficiency]]'''
 
*'''[[Secondary adrenal insufficiency]]'''
 
*'''[[Secondary adrenal insufficiency]]'''
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The [[pathogenesis]] of [[adrenal insufficiency]] varies based on the [[etiology]] as follows:  
 
The [[pathogenesis]] of [[adrenal insufficiency]] varies based on the [[etiology]] as follows:  
  
<font size="+1">'''[[Autoimmune adrenalitis]]'''</font> : 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.   
+
<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.
 
*'''Isolated autoimmune adrenalitis''' accounts for 30-40% cases.
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'''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]].  
 
'''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>   : 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.
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<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> :
+
<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.  
 
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.  
  
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==[[Adrenal insufficiency epidemiology|Epidemiology]]==
 
==[[Adrenal insufficiency epidemiology|Epidemiology]]==
  
The most common cause of adrenal insufficiency is glucocorticoid-induced adrenal insufficiency. The most common cause of primary adrenal insufficiency varies based on geography. In the developed world, Tuberculosis was the most common cause, whereas, since the 1950s, the incidence of autoimmune adrenalitis is rising. The autoimmune polyglandular syndrome shows a female: male preponderance of 2:1, usually presenting in the age group of 30-50 years. In developing countries, Tuberculosis remains the most common cause.    
+
The most common cause of adrenal insufficiency is glucocorticoid-induced adrenal insufficiency. The most common cause of primary adrenal insufficiency varies based on geography. In the developed world, Tuberculosis was the most common cause, whereas, since the 1950s, the incidence of autoimmune adrenalitis is rising. The autoimmune polyglandular syndrome shows a female: male preponderance of 2:1, usually presenting in the age group of 30-50 years. In developing countries, Tuberculosis remains the most common cause. <ref name="BensingHulting2016">{{cite journal|last1=Bensing|first1=Sophie|last2=Hulting|first2=Anna-Lena|last3=Husebye|first3=Eystein S|last4=Kämpe|first4=Olle|last5=Løvås|first5=Kristian|title=MANAGEMENT OF ENDOCRINE DISEASE: Epidemiology, quality of life and complications of primary adrenal insufficiency: a review|journal=European Journal of Endocrinology|volume=175|issue=3|year=2016|pages=R107–R116|issn=0804-4643|doi=10.1530/EJE-15-1242}}</ref> <ref name="ChabreGoichot2017">{{cite journal|last1=Chabre|first1=Olivier|last2=Goichot|first2=Bernard|last3=Zenaty|first3=Delphine|last4=Bertherat|first4=Jérôme|title=Group 1. Epidemiology of primary and secondary adrenal insufficiency: Prevalence and incidence, acute adrenal insufficiency, long-term morbidity and mortality|journal=Annales d'Endocrinologie|volume=78|issue=6|year=2017|pages=490–494|issn=00034266|doi=10.1016/j.ando.2017.10.010}}</ref> <ref>{{cite book | last = Melmed | first = Shlomo | title = Williams textbook of endocrinology | publisher = Elsevier | location = Philadelphia, PA | year = 2020 | isbn = 9780323555968 }}</ref> <ref>{{cite book | last = Gardner | first = David | title = Greenspan's basic & clinical endocrinology | publisher = McGraw-Hill Medical | location = New York | year = 2011 | isbn = 9780071622431 }}</ref>
  
 
==[[Adrenal insufficiency Clinical Presentation |Clinical Presentation]]==
 
==[[Adrenal insufficiency Clinical Presentation |Clinical Presentation]]==
The presentation of adrenal insufficiency is non-specific and depends on the extent of loss of adrenal hormones. Common symptoms that are seen in [[Adrenal insufficiency]]   :
+
The presentation of adrenal insufficiency is non-specific and depends on the extent of loss of adrenal hormones. Common symptoms that are seen in [[Adrenal insufficiency]] <ref name="ChansonGuignat2017">{{cite journal|last1=Chanson|first1=Philippe|last2=Guignat|first2=Laurence|last3=Goichot|first3=Bernard|last4=Chabre|first4=Olivier|last5=Boustani|first5=Dinane Samara|last6=Reynaud|first6=Rachel|last7=Simon|first7=Dominique|last8=Tabarin|first8=Antoine|last9=Gruson|first9=Damien|last10=Reznik|first10=Yves|last11=Raffin Sanson|first11=Marie-Laure|title=Group 2: Adrenal insufficiency: screening methods and confirmation of diagnosis|journal=Annales d'Endocrinologie|volume=78|issue=6|year=2017|pages=495–511|issn=00034266|doi=10.1016/j.ando.2017.10.005}}</ref> <ref>{{cite journal |vauthors=Pazderska A, Pearce SH |title=Adrenal insufficiency - recognition and management |journal=Clin Med (Lond) |volume=17 |issue=3 |pages=258–262 |date=June 2017 |pmid=28572228 |pmc=6297573 |doi=10.7861/clinmedicine.17-3-258 |url=}}</ref> <ref>{{cite book | last = Melmed | first = Shlomo | title = Williams textbook of endocrinology | publisher = Elsevier | location = Philadelphia, PA | year = 2020 | isbn = 9780323555968 }}</ref>:
 
 
 
*Fatigue and anorexia are the most common, seen in almost all cases. The fatigue worsens at night and with disease progression.
 
*Fatigue and anorexia are the most common, seen in almost all cases. The fatigue worsens at night and with disease progression.
 
*Gastrointestinal symptoms include abdominal pain, nausea, vomiting, constipation, and diarrhea.
 
*Gastrointestinal symptoms include abdominal pain, nausea, vomiting, constipation, and diarrhea.
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Salt craving, postural dizziness, Hypotension, weight loss, vitiligo, auricular calcification, postural hypotension.
 
Salt craving, postural dizziness, Hypotension, weight loss, vitiligo, auricular calcification, postural hypotension.
 
Lab findings:
 
Lab findings:
 
 
*Electrolytes: hyponatremia, hyperkalemia, hypercalcemia
 
*Electrolytes: hyponatremia, hyperkalemia, hypercalcemia
 
*Hypoglycemia
 
*Hypoglycemia
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*Anemia
 
*Anemia
  
Adrenal Crisis  : About 50% of people with undiagnosed adrenal insufficiency present with adrenal crisis. It is also known as the Addisonian crisis. A life-threatening emergency arising due to an acute deficiency of adrenal cortisol. The mortality rate is 0.5/100 patients/year. It is often triggered by an acutely stressful event like infection, surgery, dehydration, etc.  
+
Adrenal Crisis <ref>{{cite journal |vauthors=Elshimy G, Alghoula F, Jeong JM |title= |journal= |volume= |issue= |pages= |date= |pmid=29763143 |doi= |url=}}</ref> <ref name="pmid28722962">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume= | issue=  | pages=  | pmid=28722962 | doi= | pmc= | url= }} </ref>: About 50% of people with undiagnosed adrenal insufficiency present with adrenal crisis. It is also known as the Addisonian crisis. A life-threatening emergency arising due to an acute deficiency of adrenal cortisol. The mortality rate is 0.5/100 patients/year. It is often triggered by an acutely stressful event like infection, surgery, dehydration, etc.  
 
Presentation:
 
Presentation:
 
Acute onset of Abdominal pain, nausea, vomiting, diarrhea, severe dehydration, dizziness, hypotension, shock, fever.
 
Acute onset of Abdominal pain, nausea, vomiting, diarrhea, severe dehydration, dizziness, hypotension, shock, fever.
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==Diagnosis==
 
==Diagnosis==
 
The diagnosis of [[adrenal insufficiency]] is a three-step process that can be performed simultaneously or in sequential order. <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>
 
The diagnosis of [[adrenal insufficiency]] is a three-step process that can be performed simultaneously or in sequential order. <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>
 
+
<ref>https://www.elsevier.es/index.php?p=revista&pRevista=pdf-simple&pii=S2173509314700698</ref>
  
 
#Prove the existence of [[adrenal insufficiency]] i.e. Syndromic Diagnosis.
 
#Prove the existence of [[adrenal insufficiency]] i.e. Syndromic Diagnosis.
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!ACTH stimulation test
 
!ACTH stimulation test
 
!Low dose ACTH stimukation test
 
!Low dose ACTH stimukation test
!Metyrapone stimulation
+
!Metyrapone stimulation  
 
!Glucagon stimulation
 
!Glucagon stimulation
 
|-
 
|-
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|Cosyntropin 250mcg I.V
 
|Cosyntropin 250mcg I.V
 
|Consyntropin 1mcg I.V
 
|Consyntropin 1mcg I.V
|Metyrapone 30mg/kg P.O
+
|Metyrapone 30mg/kg P.O  
 
|Glucagon 1mg I.M
 
|Glucagon 1mg I.M
 
|-
 
|-
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|-
 
|-
 
!Parameter Tested
 
!Parameter Tested
|Plasma cortisol
+
|Plasma cortisol  
 
|Plasma cortisol
 
|Plasma cortisol
 
|Plasma cortisol
 
|Plasma cortisol
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|Manual preparation
 
|Manual preparation
 
|Assesses whole HPA
 
|Assesses whole HPA
|Less accurate
+
|Less accurate  
 
|}
 
|}
 
Diagnostic algorithm:
 
Diagnostic algorithm:
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|+
 
|+
 
!
 
!
!Primary Adrenal Insufficiency
+
!Primary Adrenal Insufficiency  
!Secondary Adrenal Insufficiency
+
!Secondary Adrenal Insufficiency  
 
|-
 
|-
 
|Clinical
 
|Clinical
 
|Hyperpigmentation of skin and mucous membranes
 
|Hyperpigmentation of skin and mucous membranes
|No hyperpigmentation
+
|No hyperpigmentation  
 
|-
 
|-
 
|Labs
 
|Labs
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|Hyponatremia
 
|Hyponatremia
 
|-
 
|-
|ACTH
+
|ACTH  
 
|Increased to two times upper limit of normal
 
|Increased to two times upper limit of normal
 
|Normal or decreased
 
|Normal or decreased
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<font size="+1">Treatment of adrenal insufficiency:</font> <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>
 
<font size="+1">Treatment of adrenal insufficiency:</font> <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>
 
+
<ref>https://www.elsevier.es/index.php?p=revista&pRevista=pdf-simple&pii=S2173509314700698</ref>
  
 
Management of adrenal insufficiency consists of glucocorticoid and mineralocorticoid replacement.
 
Management of adrenal insufficiency consists of glucocorticoid and mineralocorticoid replacement.

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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

Adrenal Insufficiency is a clinical state where there is reduced production of adrenocortical hormones. The adrenal cortex is divided into three zones- zona glomerulosa, zona fasciculata, and zona reticularis producing mineralocorticoids, glucocorticoids, and androgens respectively. Adrenal Insufficiency causes glucocorticoid and mineralocorticoid deficiency. It is classified as primary, secondary, and tertiary. Its presentation depends on the rapidity and degree of hormone depletion. It can present acutely as adrenal crisis, especially when the body is under stress due to infections, trauma, etc. If it presents chronically it is called Addison disease. The mainstay of treatment includes replacement therapy with glucocorticoids i.e hydrocortisone. Whereas, primary adrenal insufficiency requires additional mineralocorticoid replacement as well. [1]

Historical Perspective

In 1885, Thomas Addison 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. Hench, Kendall, and Reichstein were awarded the Nobel Prize in Physiology or Medicine in 1950 "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 cause of primary adrenal insufficiency has been changing. In the 1920s, the most common cause of Adrenal Insufficiency was Tuberculosis, since the 1950s it has been autoimmune polyglandular syndrome.

Classification

Adrenal insufficiency is classified based on the location of the pathology into [2] [3] :

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:

Autoimmune adrenalitis [4] [5]: 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.

X linked Adrenoleukodystrophy(X-ALD) [6] [7] : 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.

Chronic glucocorticoid use [8] [9]: 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.

Differential diagnosis

Addison's disease differential diagnosis

Epidemiology

The most common cause of adrenal insufficiency is glucocorticoid-induced adrenal insufficiency. The most common cause of primary adrenal insufficiency varies based on geography. In the developed world, Tuberculosis was the most common cause, whereas, since the 1950s, the incidence of autoimmune adrenalitis is rising. The autoimmune polyglandular syndrome shows a female: male preponderance of 2:1, usually presenting in the age group of 30-50 years. In developing countries, Tuberculosis remains the most common cause. [10] [11] [12] [13]

Clinical Presentation

The presentation of adrenal insufficiency is non-specific and depends on the extent of loss of adrenal hormones. Common symptoms that are seen in Adrenal insufficiency [14] [15] [16]:

  • Fatigue and anorexia are the most common, seen in almost all cases. The fatigue worsens at night and with disease progression.
  • Gastrointestinal symptoms include abdominal pain, nausea, vomiting, constipation, and diarrhea.
  • Musculoskeletal symptoms include arthralgia, myalgia.

Signs and symptoms that are specific to primary adrenal insufficiency: Salt craving, postural dizziness, Hypotension, weight loss, vitiligo, auricular calcification, postural hypotension. Lab findings:

  • Electrolytes: hyponatremia, hyperkalemia, hypercalcemia
  • Hypoglycemia
  • Azotemia
  • Eosinophilia
  • Anemia

Adrenal Crisis [17] [18]: About 50% of people with undiagnosed adrenal insufficiency present with adrenal crisis. It is also known as the Addisonian crisis. A life-threatening emergency arising due to an acute deficiency of adrenal cortisol. The mortality rate is 0.5/100 patients/year. It is often triggered by an acutely stressful event like infection, surgery, dehydration, etc. Presentation: Acute onset of Abdominal pain, nausea, vomiting, diarrhea, severe dehydration, dizziness, hypotension, shock, fever. Labs: Hyponatremia, hyperkalemia, hypercalcemia, eosinophilia, hypoglycemia.

Diagnosis

The diagnosis of adrenal insufficiency is a three-step process that can be performed simultaneously or in sequential order. [3] [19]

  1. Prove the existence of adrenal insufficiency i.e. Syndromic Diagnosis.
  2. Determine the nature of adrenal insufficiency i.e. Primary, Secondary, Tertiary Adrenal insufficiency by identifying the location of the defect in the HPA axis.
  3. 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. Serum cortisol level <5µg/dL confirms the presence of adrenal insufficiency. 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 18 µg/dL. The different typed of dynamic tests are as follows –

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

Diagnostic algorithm:

 
 
 
 
 
 
 
 
 
 
 
 
 
Adrenal Insufficiency suspected
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum basal cortisol
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<5 µg/dL
 
 
 
 
 
 
 
5-18 µg/dL
 
 
 
 
 
 
>18 µg/dL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirms Adrenal Insufficiency
 
 
 
 
 
 
 
Dynamic tests
 
 
 
 
 
 
Rules out Adrenal Insufficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Adrenal Insufficiency suspected
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary Adrenal Insufficiency suspected
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACTH stimulation test
 
 
 
 
 
 
 
 
 
 
 
 
 
ACTH stimulation test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum cortisol <18 µg/dL
 
Serum cortisol >18µg/dL
 
 
 
 
 
 
Serum cortisol <18 µg/dL
 
 
Serum cortisol 18-23µg/dL
 
 
Serum cortisol >23 µg/dL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirms Adrenal Insufficiency
 
Rules out Adrenal Insufficiency
 
 
 
 
 
 
Confirms Adrenal Insufficiency
 
 
Indeterminate
 
 
Rules out Adrenal Insufficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Insulin hypoglycemic test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum cortisol <18µg/dL
 
Serum cortisol >18µg/dL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirms Adrenal Insufficiency
 
Rules out Adrenal Insufficiency
 
 


Diagnosing the location of defect:

Primary Adrenal Insufficiency Secondary Adrenal Insufficiency
Clinical Hyperpigmentation of skin and mucous membranes No hyperpigmentation
Labs Hyperkalemia, Hyponatremia Hyponatremia
ACTH Increased to two times upper limit of normal Normal or decreased

Treatment

Treatment of adrenal insufficiency: [3] [20]

Management of adrenal insufficiency consists of glucocorticoid and mineralocorticoid replacement.

Glucocorticoid replacement therapy: Given in patients with a confirmed diagnosis of adrenal insufficiency.

Drug of choice Hydrocortisone.
Dosage 15-25 mg is given in two or three divided doses.
Dosing frequency Two divided doses – 2/3 of the total dose in the morning on awakening; 1/3 of the total dose in mid-afternoon

Three divided doses (10mg at 7 AM, 5mg at 12 PM, and 2.5-5mg at 4:30 PM. Avoid dosing after 6 PM

Alternate drugs Cortisone acetate 20-25mg, Prednisone (3-5mg/day); Use of dexamethasone is not recommended
Drug interactions Drugs increasing glucocorticoid dose requirement: Anticonvulsants like Barbiturates, Topiramate, Anti-tubercular drugs, Estrogens, Tamoxifen

Drugs decreasing glucocorticoid dose requirement: Licorice, Grapefruit juice, Colestipol

Monitoring Monitoring is done based on clinical improvement.

Symptoms that are suggestive of underdosing- Persistence or the incomplete resolution of fatigue, nausea, postural hypotension, myalgia.

Symptoms that are suggestive of overdosing - weight gain, edema, abdominal striae.

There is no role of measuring ACTH and serum cortisol levels.

Side effects Weight gain, edema, increased appetite, weight gain, osteoporosis, dyslipidemia, increased cardiovascular risk.

Mineralocorticoid replacement therapy: Mineralocorticoids are given only in patients with primary adrenal insufficiency. A synthetic mineralocorticoid, 9 α-fludrocortisone is used in a dose of 0.05-0.2 mg/day in the morning. Dosage adjustments have to be made based on the clinical picture. Symptoms and signs of underdosing include hypovolemia, orthostatic hypotension, hyperkalemia, hyperuricemia, increased plasma renin activity. Symptoms and signs of overdosing include hypertension, hypokalemia, edema. If a patient on fludrocortisone develops hypertension, reduce the dose. If the blood pressure remains elevated, start an antihypertensive medication, and continue fludrocortisone.

The use of dehydroepiandrosterone (DHEA) is not routinely recommended. A six-month trial of DHEA can be considered in patients with significant impairment in quality of life, decreased libido, women, depressed mood despite glucocorticoid and mineralocorticoid therapy. If there is no improvement at the end of six months, its use has to be discontinued. DHEA is contraindicated in people with breast and prostate cancer.

Treatment of acute adrenal crisis: In patients suspected of having adrenal insufficiency, hydrocortisone 100mg IV/IM given immediately followed by a continuous infusion of 200mg in the next 24 hours. Alternately prednisolone can be used. Intravenous fluid replacement with 0.9% NS is also recommended to maintain blood pressure.

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