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| __NOTOC__ | | __NOTOC__ |
| {{Adrenal insufficiency}} | | {{Adrenal insufficiency}} |
| {{CMG}}; {{AE}} {{Ayeesha}} | | {{CMG}}; {{AE}} {{Ayeesha}} |
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| | '''Synonyms and keywords:''' Addison's disease |
| ==[[Adrenal insufficiency overview|Overview]]== | | ==[[Adrenal insufficiency overview|Overview]]== |
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| ==[[Adrenal insufficiency epidemiology and demographics |Epidemiology and Demographics]]== | | ==[[Adrenal insufficiency epidemiology and demographics |Epidemiology and Demographics]]== |
| ==[[Adrenal insufficiency risk factors | Risk factors]] | | ==[[Adrenal insufficiency risk factors | Risk factors]]== |
| | | ==[[Adrenal insufficiency screening | Screening]]== |
| ==[[Adrenal insufficiency Clinical Presentation |Clinical Presentation]]== | | ==[[Adrenal insufficiency natural history, complications and prognosis | Natural History, Complications and Prognosis]]== |
| 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>:
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| *Fatigue and anorexia are the most common, seen in almost all cases. The fatigue worsens at night and with disease progression.
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| *Gastrointestinal symptoms include abdominal pain, nausea, vomiting, constipation, and diarrhea.
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| *Musculoskeletal symptoms include arthralgia, myalgia.
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| Signs and symptoms that are specific to primary adrenal insufficiency:
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| Salt craving, postural dizziness, Hypotension, weight loss, vitiligo, auricular calcification, postural hypotension.
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| Lab findings:
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| *Electrolytes: hyponatremia, hyperkalemia, hypercalcemia
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| *Hypoglycemia
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| *Azotemia
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| *Eosinophilia
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| *Anemia
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| 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.
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| Presentation:
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| Acute onset of Abdominal pain, nausea, vomiting, diarrhea, severe dehydration, dizziness, hypotension, shock, fever.
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| Labs: Hyponatremia, hyperkalemia, hypercalcemia, eosinophilia, hypoglycemia.
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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>
| | [[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]] |
| <ref>https://www.elsevier.es/index.php?p=revista&pRevista=pdf-simple&pii=S2173509314700698</ref>
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| #Prove the existence of [[adrenal insufficiency]] i.e. Syndromic Diagnosis.
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| #Determine the nature of [[adrenal insufficiency]] i.e. Primary, Secondary, Tertiary [[Adrenal insufficiency]] by identifying the location of the defect in the [[HPA]] axis.
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| #Determine the cause i.e. [[etiological]] diagnosis.
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| <font size="+1">'''Tests used in syndromic diagnosis''':</font>
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| '''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.
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| '''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.
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| '''Urine free [[cortisol]] measurement:''' Low sensitivity and therefore not useful in diagnostic confirmation.
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| '''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 –
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| {| class="wikitable"
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| |+
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| !Name of the test
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| !Insulin Hypoglycemia test
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| !ACTH stimulation test
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| !Low dose ACTH stimukation test
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| !Metyrapone stimulation
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| !Glucagon stimulation
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| |-
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| !Agent to be administered
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| |Regular insulin 0.1-1.15U/kg I.V
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| |Cosyntropin 250mcg I.V
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| |Consyntropin 1mcg I.V
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| |Metyrapone 30mg/kg P.O
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| |Glucagon 1mg I.M
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| |-
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| !Timing of sample collection
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| |0-30-45-60-90 min
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| |0-30-60 min
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| |0-30-60 min
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| |8 hours post metyrapone
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| |90-120-150-180-210-240min
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| |-
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| !Parameter Tested
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| |Plasma cortisol
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| |Plasma cortisol
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| |Plasma cortisol
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| |11 deoxycortisol
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| |Plasma cortisol
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| |-
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| !Comments
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| |Gold standard
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| |Safe
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| |Manual preparation
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| |Assesses whole HPA
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| |Less accurate
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| |}
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| Diagnostic algorithm:
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| {{familytree/start}}
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| {{familytree | | | | | | | | | | | | | | A01 | | | | | | | | | | |A01=[[Adrenal Insufficiency]] suspected}}
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| {{familytree | | | | | | | | | | | | | | |!| | | | | | | | | | | | | }}
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| {{familytree | | | | | | | | | | | | | | B01 | | | | | | | | | | |B01=Serum basal [[cortisol]]}}
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| {{familytree | | | | |,|-|-|-|-|-|-|-|-|-|+|-|-|-|-|-|-|-|-|.| | | | }}
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| {{familytree | | | | C01 | | | | | | | | C02 | | | | | | | C03 | | | |C01=<5 µg/dL|C02=5-18 µg/dL|C03=>18 µg/dL}}
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| {{familytree | | | | |!| | | | | | | | | |!| | | | | | | | |!| | | | }}
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| {{familytree | | | | D01 | | | | | | | | D02 | | | | | | | D03 | | |D01= Confirms [[Adrenal Insufficiency]]|D02=Dynamic tests|D03=Rules out [[Adrenal Insufficiency]]}}
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| {{familytree | | | | | | |,|-|-|-|-|-|-|-|^|-|-|-|-|-|-|-|.| | | | | | | }}
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| {{familytree | | | | | | |!| | | | | | | | | | | | | | | |!| | | | | | | | }}
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| {{familytree | | | | | | E01 | | | | | | | | | | | | | | E02 | | | | | |E01=Primary [[Adrenal Insufficiency]] suspected |E02= Secondary [[Adrenal Insufficiency]] suspected}}
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| {{familytree | | | | | | |!| | | | | | | | | | | | | | | |!| | | | | | }}
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| {{familytree | | | | | | F01 | | | | | | | | | | | | | | F02 | | | | | |F01=[[ACTH]] stimulation test|F02= [[ACTH]] stimulation test}}
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| {{familytree | | | | |,|-|^|-|.| | | | | | | | |,|-|-|-|-|+|-|-|-|-|.| | }}
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| {{familytree | | | | G01 | | G02 | | | | | | | G03 | | | G04 | | | G05 | | |G01= Serum cortisol <18 µg/dL|G02= Serum cortisol >18µg/dL|G03= Serum cortisol <18 µg/dL| G04= Serum cortisol 18-23µg/dL| G05= Serum cortisol >23 µg/dL}}
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| {{familytree | | | | |!| | | |!| | | | | | | | |!| | | | |!| | | | |!| | }}
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| {{familytree | | | | H01 | | H02 | | | | | | | H03 | | | H04 | | | H05 | |H01= Confirms [[Adrenal Insufficiency]]|H02= Rules out [[Adrenal Insufficiency]]|H03= Confirms [[Adrenal Insufficiency]]| H04= Indeterminate| H05= Rules out [[Adrenal Insufficiency]] }}
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| {{familytree | | | | | | | | | | | | | | | | | | | | | | |!| | | | | }}
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| {{familytree | | | | | | | | | | | | | | | | | | | | | | I01 | | | | |I01= Insulin hypoglycemic test}}
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| {{familytree | | | | | | | | | | | | | | | | | | | | |,|-|^|-|.| | | }}
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| {{familytree | | | | | | | | | | | | | | | | | | | | J01 | | J02 | | |J01= Serum cortisol <18µg/dL| J02= Serum cortisol >18µg/dL}}
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| {{familytree | | | | | | | | | | | | | | | | | | | | |!| | | |!| | }}
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| {{familytree | | | | | | | | | | | | | | | | | | | | K01 | | K02 | | |K01= Confirms [[Adrenal Insufficiency]]| K02= Rules out [[Adrenal Insufficiency]] }}
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| {{familytree/end}}
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| <font size="+1">'''Diagnosing the location of defect:'''</font>
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| {| class="wikitable"
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| |+
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| !
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| !Primary Adrenal Insufficiency
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| !Secondary Adrenal Insufficiency
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| |-
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| |Clinical
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| |Hyperpigmentation of skin and mucous membranes
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| |No hyperpigmentation
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| |-
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| |Labs
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| |Hyperkalemia, Hyponatremia
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| |Hyponatremia
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| |-
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| |ACTH
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| |Increased to two times upper limit of normal
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| |Normal or decreased
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| |}
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| ==Treatment== | | ==Treatment== |
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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>
| | [[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]] |
| <ref>https://www.elsevier.es/index.php?p=revista&pRevista=pdf-simple&pii=S2173509314700698</ref>
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| Management of adrenal insufficiency consists of glucocorticoid and mineralocorticoid replacement.
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| '''Glucocorticoid replacement therapy:'''
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| Given in patients with a confirmed diagnosis of adrenal insufficiency.
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| {| class="wikitable"
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| |Drug of choice
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| |Hydrocortisone. | |
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| |Dosage
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| |15-25 mg is given in two or three divided doses.
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| |-
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| |Dosing frequency
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| |Two divided doses – 2/3 of the total dose in the morning on awakening; 1/3 of the total dose in mid-afternoon
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| Three divided doses (10mg at 7 AM, 5mg at 12 PM, and 2.5-5mg at 4:30 PM. Avoid dosing after 6 PM
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| |-
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| |Alternate drugs | |
| |Cortisone acetate 20-25mg, Prednisone (3-5mg/day); Use of dexamethasone is not recommended
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| |Drug interactions
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| |Drugs increasing glucocorticoid dose requirement: Anticonvulsants like Barbiturates, Topiramate, Anti-tubercular drugs, Estrogens, Tamoxifen
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| Drugs decreasing glucocorticoid dose requirement: Licorice, Grapefruit juice, Colestipol
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| |-
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| |Monitoring
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| |Monitoring is done based on clinical improvement.
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| Symptoms that are suggestive of underdosing- Persistence or the incomplete resolution of fatigue, nausea, postural hypotension, myalgia.
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| Symptoms that are suggestive of overdosing - weight gain, edema, abdominal striae.
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| There is no role of measuring ACTH and serum cortisol levels.
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| |-
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| |Side effects
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| |Weight gain, edema, increased appetite, weight gain, osteoporosis, dyslipidemia, increased cardiovascular risk.
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| |}
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| '''Mineralocorticoid replacement therapy:'''
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| 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.
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| 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.
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| '''Treatment of acute adrenal crisis:'''
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| 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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