Addison's disease medical therapy: Difference between revisions

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{{CMG}} ; {{AE}} {{ADG}}
{{CMG}} ; {{AE}} {{ADG}}
==Overview==
==Overview==
The mainstay of treatment for Addison disease is corticosteroid replacement, if there is persistent mineralocorticoid deficiency, it should be combined with fludrocortisone.
The mainstay of treatment for Addison disease is [[Corticosteroid medications|corticosteroid replacement]], if there is persistent [[Mineralocorticoid|mineralocorticoid deficiency]], it should be combined with [[fludrocortisone]].


==Medical therapy==
==Medical therapy==
The mainstay of treatment for Addison's disease is pharmacotherapy which is replacement of deficient hormones. Medical management of Addison's disease can be discussed under two categories
The mainstay of treatment for Addison's disease is [[pharmacotherapy]] which is replacement of deficient hormones. Medical management of Addison's disease can be discussed under two categories:<ref name="pmid27810905">{{cite journal |vauthors=Gan EH, Pearce SH |title=MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addison's disease |journal=Eur. J. Endocrinol. |volume=176 |issue=3 |pages=R123–R135 |year=2017 |pmid=27810905 |doi=10.1530/EJE-16-0581 |url=}}</ref><ref name="pmid25138826">{{cite journal |vauthors=Inder WJ, Meyer C, Hunt PJ |title=Management of hypertension and heart failure in patients with Addison's disease |journal=Clin. Endocrinol. (Oxf) |volume=82 |issue=6 |pages=789–92 |year=2015 |pmid=25138826 |doi=10.1111/cen.12592 |url=}}</ref><ref name="pmid24766944">{{cite journal |vauthors=Tucci V, Sokari T |title=The clinical manifestations, diagnosis, and treatment of adrenal emergencies |journal=Emerg. Med. Clin. North Am. |volume=32 |issue=2 |pages=465–84 |year=2014 |pmid=24766944 |doi=10.1016/j.emc.2014.01.006 |url=}}</ref><ref name="pmid24755997">{{cite journal |vauthors=Napier C, Pearce SH |title=Current and emerging therapies for Addison's disease |journal=Curr Opin Endocrinol Diabetes Obes |volume=21 |issue=3 |pages=147–53 |year=2014 |pmid=24755997 |doi=10.1097/MED.0000000000000067 |url=}}</ref><ref name="pmid24031090">{{cite journal |vauthors=Grossman A, Johannsson G, Quinkler M, Zelissen P |title=Therapy of endocrine disease: Perspectives on the management of adrenal insufficiency: clinical insights from across Europe |journal=Eur. J. Endocrinol. |volume=169 |issue=6 |pages=R165–75 |year=2013 |pmid=24031090 |pmc=3805018 |doi=10.1530/EJE-13-0450 |url=}}</ref><ref name="pmid23177474">{{cite journal |vauthors=Napier C, Pearce SH |title=Autoimmune Addison's disease |journal=Presse Med |volume=41 |issue=12 P 2 |pages=e626–35 |year=2012 |pmid=23177474 |doi=10.1016/j.lpm.2012.09.010 |url=}}</ref><ref name="pmid22907517">{{cite journal |vauthors=Quinkler M |title=[Addison's disease] |language=German |journal=Med Klin Intensivmed Notfmed |volume=107 |issue=6 |pages=454–9 |year=2012 |pmid=22907517 |doi=10.1007/s00063-012-0112-3 |url=}}</ref>
*Acute management ( Addison's crisis)
*Acute management ( Addison's crisis)
*Chronic management   
*Chronic management   
===Acute management ===
===Acute management ===
The main stay of treatment includes glucocorticosteroids and supportive therapy
The main stay of treatment includes [[Corticosteroids|glucocorticosteroids]] and supportive therapy.
====Goals====
====Goals====
*Normalization of blood pressure and volume status
*Normalization of [[blood pressure]] and volume status.
*Supplementation of adequate glucocorticoids plus mineralocorticoid.
*Supplementation of adequate [[glucocorticoids]] plus [[mineralocorticoid]].
*When arrhythmias occur, or when potassium levels exceed 6.5 mmol/l, emergency lowering of potassium levels is mandated. Several agents are used to lowering potassium levels. The choice depends on the degree and cause of the hyperkalemia and other aspects of the patient's condition.
*When [[arrhythmias]] occur, or when [[potassium]] levels exceed 6.5 mmol/l, emergency lowering of potassium levels is mandated. Several agents are used to lowering [[potassium]] levels. The choice depends on the degree and cause of the [[hyperkalemia]] and other aspects of the patient's condition.


====Supportive therapy====
====Supportive therapy====
*Maintain airway, breathing, and circulation, and refer immediately to tertiary care center for intravenous corticosteroids.
*Maintain [[airway]], [[breathing]], and [[circulation]], and refer immediately to tertiary care center for intravenous [[corticosteroids]].
*If the patient has pre filled syringes (emergency kit) and presents with Addisonian crisis while far from a hospital, an intramuscular injection should be given and the patient transferred to the nearest emergency room for intravenous normal saline and intravenous hydrocortisone.
*If the patient has pre filled syringes (emergency kit) and presents with Addisonian crisis while far from a hospital, an [[intramuscular]] injection should be given and the patient transferred to the nearest emergency room for intravenous [[normal saline]] and [[Hydrocortisone|intravenous hydrocortisone]].
*Normal saline 0.9% or 5% dextrose in normal saline should be administered to correct hypotension and dehydration.
*[[Normal saline]] 0.9% or 5% [[dextrose]] in [[normal saline]] should be administered to correct [[hypotension]] and [[dehydration]].
*It is usually necessary to administer 1 L rapidly and a further 2 to 4 L over the first 24 hours, to correct hypotension.
*It is usually necessary to administer 1 L rapidly and a further 2 to 4 L over the first 24 hours, to correct [[hypotension]].
*Careful monitoring of BP, fluid status, and serum sodium and potassium levels should be maintained.
*Careful monitoring of blood pressure, fluid status, and serum [[sodium]] and [[potassium]] levels should be maintained.


===Pharmocotherapy===
===Pharmacotherapy===
*Dexamethasone should be given to patients with suspected Addisonian crisis prior to any laboratory measurements.
*[[Dexamethasone]] should be given to patients with suspected Addisonian crisis prior to any laboratory measurements.
*Intravenous hydrocortisone is used to treat Addisonian crisis following dexamethasone.
*Intravenous [[hydrocortisone]] is used to treat Addisonian crisis following [[dexamethasone]].
*In addition, fludrocortisone is needed for mineralocorticoid replacement.
*In addition, [[fludrocortisone]] is needed for [[mineralocorticoid]] replacement.
====Adult====
====Adult====
:*Preferred regimen (1): Dexamethasone IV 2-8 mg/dose q12h followed by a Oral 0.5 mg maintenance dose.
:*Preferred regimen (1): [[Dexamethasone]] IV 2-8 mg/dose q12h followed by an oral 0.5 mg maintenance dose.
:*Preferred regimen (1): Hydrocortisone 100 mg bolus immediately; followed by either 100 mg q8h '''(or)''' 300 mg q24 by continuous infusion for 2 to 3 days; then 100 to 150 mg q24h and taper to 75 mg/d before switching to oral maintenance dose
:*Preferred regimen (1): [[Hydrocortisone]] 100 mg bolus immediately; followed by either 100 mg q8h '''(or)''' 300 mg q24 by continuous infusion for 2 to 3 days; then 100 to 150 mg q24h and taper to 75 mg/d before switching to oral [[maintenance dose]]
:**Note: Maintenance dose 10 mg in the morning, 5 mg around noon, and 5 mg in the afternoon '''(or)''' 10 to 15 mg in the morning and 5 to 10 mg in the afternoon.
:**Note: [[Maintenance dose]] 10 mg in the morning, 5 mg around noon, and 5 mg in the afternoon '''(or)''' 10 to 15 mg in the morning and 5 to 10 mg in the afternoon.
====Pediatric====
====Pediatric====
:Preferred regimen (1): Hydrocortisone 1 to 2 mg/kg/dose bolus immediately; followed by 25 to 150 mg/d, given in divided doses every 6 to 8 hours (in infants and young children)or150 to 250 mg/d given in divided doses every 6 to 8 hours (in older children).
:* Preferred regimen (1): [[Hydrocortisone]] 1 to 2 mg/kg/dose bolus immediately; followed by 25 to 150 mg/d, given in divided doses every 6 to 8 hours (in infants and young children)or150 to 250 mg/d given in divided doses every 6 to 8 hours (in older children).
===Management of Hyperkalemia===
* [[Calcium]] supplementation ([[calcium gluconate]] 10% (10ml), preferably through a [[central venous catheter]] as the [[calcium]] may cause [[phlebitis]]) does not lower [[potassium]] but decreases [[myocardium|myocardial]] excitability, protecting against life threatening [[arrhythmias]].
* [[Insulin]] (e.g. [[intravenous injection]] of 10-15u of (short acting) [[insulin]] (e.g. Actrapid) {along with 50ml of 50% dextrose to prevent [[hypoglycemia]]}) will lead to a shift of [[potassium]] ions into cells, secondary to increased activity of the [[sodium-potassium ATPase]].
* [[Bicarbonate]] therapy (e.g. 1 [[ampule]] (45mEq) infused over 5 minutes) is effective in cases of [[metabolic acidosis]].  The [[bicarbonate]] ion will stimulate an exchange of cellular H<sup>+</sup> for Na<sup>+</sup>, thus leading to stimulation of the [[sodium-potassium ATPase]].
* [[Salbutamol]] ([[albuterol]], [[Ventolin]]<sup>®</sup>) is a β<sub>2</sub>-selective [[catecholamine]] that is administered by [[nebulizer]] (e.g. 10-20 mg).  This [[drug]] promotes movement of [[potassium]] into [[cells]], lowering the blood levels.
* [[Polystyrene sulfonate]] (Calcium Resonium, [[Kayexalate]]) is a binding resin that binds [[potassium]] within the [[Intestines|intestine]] and removes it from the [[body]] by [[defecation]]. [[Calcium]] Resonium (15g three times a day in water) can be given by [[mouth]]. [[Kayexalate]] can be given by [[mouth]] or as an [[enema]]. In both cases, the resin absorbs [[potassium]] within the [[Intestines|intestine]] and carries it out of the body by [[defecation]]. This [[medication]] may cause [[diarrhea]].
* [[Refractory]] or severe cases may need [[dialysis]] to remove the [[potassium]] from the [[circulation]].
* Preventing recurrence of [[hyperkalemia]] typically involves reduction of [[dietary]] [[potassium]], removal of an offending [[medication]], and/or the addition of a [[diuretic]] (such as [[furosemide]] (Lasix<sup>®</sup>) or [[hydrochlorothiazide]]).
* [[Patiromer]] [[anion]] is a [[potassium]] binding ion cation exchange polymer that increases the [[gastrointestinal]] excretion of [[potassium]] (it is available in 8.4, 16.8, and 25.2 grams of powder in packets to be administered once daily).  [[Patiromer]] should not be used as an [[emergency]] treatment for life-threatening [[hyperkalemia]] because of its delayed onset of action.
 
===Chronic management===
===Chronic management===
The main stay of treatment includes glucocorticosteroids and mineralocorticoids.
The main stay of treatment includes [[Glucocorticosteroid|glucocorticosteroids]] and [[mineralocorticoid]]<nowiki/>s.
====Goals====
====Goals====
*Adequate daily supplementation of glucocorticoid and mineralocorticoid to mimic normal physiology. This should aim to maintain normal blood pressure, blood glucose, and fluid volume, and instill a sense of well-being in the patient
*Adequate daily supplementation of [[glucocorticoid]] and [[mineralocorticoid]] to mimic normal physiology. This should aim to maintain normal [[blood pressure]], [[blood glucose]], and fluid volume, and instill a sense of well-being in the patient
*Advise patients on medication for minor illness (febrile illness or emesis) to double or triple their usual dose of glucocorticoid. In case of severe illness, they should inject themselves with a large dose of glucocorticoid and seek immediate medical attention
*Advise patients on [[medication]] for minor illness (febrile illness or emesis) to double or triple their usual dose of [[glucocorticoid]]. In case of severe illness, they should inject themselves with a large dose of [[glucocorticoid]] and seek immediate medical attention
*If patients are monitored to normalize ACTH level, they are almost invariably overtreated with glucocorticoid resulting in iatrogenic Cushing syndrome. Monitoring is primarily based on clinical features
*If patients are monitored to normalize [[Adrenocorticotropic hormone|ACTH]] level, they are almost invariably overtreated with [[glucocorticoid]] resulting in iatrogenic [[Cushing's syndrome|Cushing syndrome]]. Treatment monitoring is primarily based on clinical features.
*Ensure that patients are aware that they must be vigilant in maintaining their therapeutic regimen
*Ensure that patients are aware that they must be vigilant in maintaining their therapeutic regimen.
====Precautions====
====Precautions====
*All patients with known Addison disease should have an emergency plan in place for corticosteroid supplementation (oral or intramuscular), to be implemented if significant illness occurs
*All patients with known Addison disease should have an emergency plan in place for [[Corticosteroid medications|corticosteroid supplementation]] (oral or intramuscular), to be implemented if significant illness occurs.
*Immediate action is needed for the signs of Addisonian crisis in a known Addison disease patient
*Immediate action is needed for the signs of Addisonian crisis in a known Addison disease patient
*If the patient has pre filled syringes (emergency kit) and presents with Addisonian crisis while far from a hospital, an intramuscular injection should be given and the patient transferred to the nearest emergency room for intravenous normal saline and intravenous hydrocortisone.
*If the patient has pre filled syringes (emergency kit) and presents with Addisonian crisis while far from a hospital, an intramuscular injection should be given and the patient transferred to the nearest emergency room for intravenous [[normal saline]] and [[Hydrocortisone|intravenous hydrocortisone]].
*In an undiagnosed patient who requires immediate corticosteroid treatment, dexamethasone may be given as it does not interfere with ACTH stimulation testing.
*In an undiagnosed patient who requires immediate [[corticosteroid]] treatment, [[dexamethasone]] may be given as it does not interfere with [[Adrenocorticotropic hormone|ACTH]] stimulation testing.
====Pharmacotherapy====
====Pharmacotherapy====
'''Glucocorticosteroid'''
'''Glucocorticosteroid'''
:*Preferred regimen (1): cortisone 10 to 37.5 mg q12h orally given in 2 divided doses with two-thirds of the total dose given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.) or
:*Preferred regimen (1): [[Cortisone]] 10 to 37.5 mg q12h [[Orally ingested|orally]] given in 2 divided [[doses]] with two-thirds of the total [[dose]] given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.)  
:*Preferred regimen (2): hydrocortisone : 15-30 mg/day orally given in 2 divided doses with two-thirds of the total dose given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.) or
:*Preferred regimen (2): [[Hydrocortisone]] : 15-30 mg/day orally given in 2 divided [[doses]] with two-thirds of the total [[dose]] given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.)  
:*Preferred regimen (3): dexamethasone : 0.25 to 0.75 mg orally once daily  
:*Preferred regimen (3): [[Dexamethasone]] : 0.25 to 0.75 mg orally once daily  
:*Preferred regimen (4): prednisone : 2.5 to 5 mg orally once daily
:*Preferred regimen (4): [[Prednisone]] : 2.5 to 5 mg orally once daily
'''Mineralocorticosteroid''''  
'''Mineralocorticosteroid''''  
:*Preferred regimen (1): fludrocortisone : 0.1 to 0.2 mg orally once daily
:*Preferred regimen (1): [[Fludrocortisone]] : 0.1 to 0.2 mg orally once daily
mild-to-moderate stress:
mild-to-moderate stress:
:*Alternative regimen (1): cortisone 50-100 mg/day orally given in 2 divided doses with two-thirds of the total dose given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.) for 3 days
:*Alternative regimen (1): [[Cortisone]] 50-100 mg/day [[Orally ingested|orally]] given in 2 divided [[doses]] with two-thirds of the total [[dose]] given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.) for 3 days
:*Alternative regimen (2): hydrocortisone 30-90 mg/day orally given in 2 divided doses with two-thirds of the total dose given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.) for 3 days
:*Alternative regimen (2): [[Hydrocortisone]] 30-90 mg/day [[Orally ingested|orally]] given in 2 divided [[doses]] with two-thirds of the total [[dose]] given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.) for 3 days
:*Alternative regimen (3): dexamethasone 0.50 to 2.25 mg orally once daily for 3 days
:*Alternative regimen (3): [[Dexamethasone]] 0.50 to 2.25 mg [[Orally ingested|orally]] once daily for 3 days
:*Alternative regimen (4): prednisone 5-15 mg orally once daily for 3 days
:*Alternative regimen (4): [[Prednisone]] 5-15 mg [[Orally ingested|orally]] once daily for 3 days
'''Severe stress'''  
'''Severe stress'''  
:*Alternative regimen (5): hydrocortisone sodium succinate 100 mg intravenously every 6-8 hours
:*Alternative regimen (5): [[Hydrocortisone]] sodium succinate 100 mg [[intravenously]] every 6-8 hours
===Women with decreased libido===
===Women with decreased libido===
====Androgen replacement====
====Androgen replacement====
*The ovaries and the adrenals are the main source of androgens in women.
*The [[ovaries]] and the [[Adrenal gland|adrenals]] are the main source of [[androgens]] in women.
*The adrenals produce dehydroepiandrosterone (DHEA) and its sulfate, which are converted peripherally to androstenedione and testosterone.
*[[Dehydroepiandrosterone|The adrenals produce dehydroepiandrosterone (DHEA) and its sulfate, which are converted peripherally to androstenedione and testosterone.]]
*Women with complaints of decreased libido or sexual well-being may be treated with DHEA replacement.
*Women with complaints of decreased libido or sexual well-being may be treated with [[Dehydroepiandrosterone|DHEA]] replacement.
*DHEA should be discontinued periodically to assess these symptoms.
*[[Dehydroepiandrosterone|DHEA]] should be discontinued periodically to assess these symptoms.
:*Preferred regimen (1): DHEA 50 mg orally once daily
:*Preferred regimen (1): [[Dehydroepiandrosterone|DHEA]] 50 mg orally once daily


==References==
==References==

Latest revision as of 17:33, 18 September 2017

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

Overview

The mainstay of treatment for Addison disease is corticosteroid replacement, if there is persistent mineralocorticoid deficiency, it should be combined with fludrocortisone.

Medical therapy

The mainstay of treatment for Addison's disease is pharmacotherapy which is replacement of deficient hormones. Medical management of Addison's disease can be discussed under two categories:[1][2][3][4][5][6][7]

  • Acute management ( Addison's crisis)
  • Chronic management

Acute management

The main stay of treatment includes glucocorticosteroids and supportive therapy.

Goals

Supportive therapy

Pharmacotherapy

Adult

  • Preferred regimen (1): Dexamethasone IV 2-8 mg/dose q12h followed by an oral 0.5 mg maintenance dose.
  • Preferred regimen (1): Hydrocortisone 100 mg bolus immediately; followed by either 100 mg q8h (or) 300 mg q24 by continuous infusion for 2 to 3 days; then 100 to 150 mg q24h and taper to 75 mg/d before switching to oral maintenance dose
    • Note: Maintenance dose 10 mg in the morning, 5 mg around noon, and 5 mg in the afternoon (or) 10 to 15 mg in the morning and 5 to 10 mg in the afternoon.

Pediatric

  • Preferred regimen (1): Hydrocortisone 1 to 2 mg/kg/dose bolus immediately; followed by 25 to 150 mg/d, given in divided doses every 6 to 8 hours (in infants and young children)or150 to 250 mg/d given in divided doses every 6 to 8 hours (in older children).

Management of Hyperkalemia

Chronic management

The main stay of treatment includes glucocorticosteroids and mineralocorticoids.

Goals

  • Adequate daily supplementation of glucocorticoid and mineralocorticoid to mimic normal physiology. This should aim to maintain normal blood pressure, blood glucose, and fluid volume, and instill a sense of well-being in the patient
  • Advise patients on medication for minor illness (febrile illness or emesis) to double or triple their usual dose of glucocorticoid. In case of severe illness, they should inject themselves with a large dose of glucocorticoid and seek immediate medical attention
  • If patients are monitored to normalize ACTH level, they are almost invariably overtreated with glucocorticoid resulting in iatrogenic Cushing syndrome. Treatment monitoring is primarily based on clinical features.
  • Ensure that patients are aware that they must be vigilant in maintaining their therapeutic regimen.

Precautions

  • All patients with known Addison disease should have an emergency plan in place for corticosteroid supplementation (oral or intramuscular), to be implemented if significant illness occurs.
  • Immediate action is needed for the signs of Addisonian crisis in a known Addison disease patient
  • If the patient has pre filled syringes (emergency kit) and presents with Addisonian crisis while far from a hospital, an intramuscular injection should be given and the patient transferred to the nearest emergency room for intravenous normal saline and intravenous hydrocortisone.
  • In an undiagnosed patient who requires immediate corticosteroid treatment, dexamethasone may be given as it does not interfere with ACTH stimulation testing.

Pharmacotherapy

Glucocorticosteroid

  • Preferred regimen (1): Cortisone 10 to 37.5 mg q12h orally given in 2 divided doses with two-thirds of the total dose given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.)
  • Preferred regimen (2): Hydrocortisone : 15-30 mg/day orally given in 2 divided doses with two-thirds of the total dose given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.)
  • Preferred regimen (3): Dexamethasone : 0.25 to 0.75 mg orally once daily
  • Preferred regimen (4): Prednisone : 2.5 to 5 mg orally once daily

Mineralocorticosteroid'

mild-to-moderate stress:

  • Alternative regimen (1): Cortisone 50-100 mg/day orally given in 2 divided doses with two-thirds of the total dose given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.) for 3 days
  • Alternative regimen (2): Hydrocortisone 30-90 mg/day orally given in 2 divided doses with two-thirds of the total dose given in the morning (around 8 a.m.) and one third in the afternoon (noon to 4 p.m.) for 3 days
  • Alternative regimen (3): Dexamethasone 0.50 to 2.25 mg orally once daily for 3 days
  • Alternative regimen (4): Prednisone 5-15 mg orally once daily for 3 days

Severe stress

Women with decreased libido

Androgen replacement

  • Preferred regimen (1): DHEA 50 mg orally once daily

References

  1. ↑ Gan EH, Pearce SH (2017). "MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addison's disease". Eur. J. Endocrinol. 176 (3): R123–R135. doi:10.1530/EJE-16-0581. PMID 27810905.
  2. ↑ Inder WJ, Meyer C, Hunt PJ (2015). "Management of hypertension and heart failure in patients with Addison's disease". Clin. Endocrinol. (Oxf). 82 (6): 789–92. doi:10.1111/cen.12592. PMID 25138826.
  3. ↑ Tucci V, Sokari T (2014). "The clinical manifestations, diagnosis, and treatment of adrenal emergencies". Emerg. Med. Clin. North Am. 32 (2): 465–84. doi:10.1016/j.emc.2014.01.006. PMID 24766944.
  4. ↑ Napier C, Pearce SH (2014). "Current and emerging therapies for Addison's disease". Curr Opin Endocrinol Diabetes Obes. 21 (3): 147–53. doi:10.1097/MED.0000000000000067. PMID 24755997.
  5. ↑ Grossman A, Johannsson G, Quinkler M, Zelissen P (2013). "Therapy of endocrine disease: Perspectives on the management of adrenal insufficiency: clinical insights from across Europe". Eur. J. Endocrinol. 169 (6): R165–75. doi:10.1530/EJE-13-0450. PMC 3805018. PMID 24031090.
  6. ↑ Napier C, Pearce SH (2012). "Autoimmune Addison's disease". Presse Med. 41 (12 P 2): e626–35. doi:10.1016/j.lpm.2012.09.010. PMID 23177474.
  7. ↑ Quinkler M (2012). "[Addison's disease]". Med Klin Intensivmed Notfmed (in German). 107 (6): 454–9. doi:10.1007/s00063-012-0112-3. PMID 22907517.

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