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{{Addison's disease}}
{{Addison's disease}}


{{CMG}}
{{CMG}} ; {{AE}} {{ADG}}
 
==Overview==
==Overview==
 
Diagnosis of Addison's disease is made by routine blood tests and specific tests. [[ACTH]] stimulation test is a specific test employed to determine the function of adrenal glands and to diagnose Addison's disease. The prominent finding of a rapid ACTH stimulation test includes failure of [[cortisol]] to rise in response to [[ACTH]] injection. Other routine [[laboratory]] tests employed include plasma [[cortisol]] level, serum [[ACTH]] level, [[plasma renin activity]], [[aldosterone]] levels and serum biochemistry.


==Laboratory Findings==
==Laboratory Findings==
[[Image:Cortisol-2D-skeletal.png|thumb|[[Cortisol]]]][[Image:Aldosterone-2D-skeletal.png|thumb|[[Aldosterone]]]]
Diagnosis of Addison's disease is made by routine blood tests and specific tests. The aim of these tests is to determine the levels of [[cortisol]] and then to establish the cause of deficiency.<ref name="pmid20399314">{{cite journal |vauthors=Chakera AJ, Vaidya B |title=Addison disease in adults: diagnosis and management |journal=Am. J. Med. |volume=123 |issue=5 |pages=409–13 |year=2010 |pmid=20399314 |doi=10.1016/j.amjmed.2009.12.017 |url=}}</ref><ref name="pmid24330030">{{cite journal |vauthors=Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C, Falorni A, Gan EH, Hulting AL, Kasperlik-Zaluska A, Kämpe O, Løvås K, Meyer G, Pearce SH |title=Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency |journal=J. Intern. Med. |volume=275 |issue=2 |pages=104–15 |year=2014 |pmid=24330030 |doi=10.1111/joim.12162 |url=}}</ref><ref name="pmid23893277">{{cite journal |vauthors=Puttanna A, Cunningham AR, Dainty P |title=Addison's disease and its associations |journal=BMJ Case Rep |volume=2013 |issue= |pages= |year=2013 |pmid=23893277 |pmc=3736622 |doi=10.1136/bcr-2013-010473 |url=}}</ref>
A diagnosis of Addison's disease is made by laboratory tests. The aim of these tests is first to determine whether levels of cortisol are insufficient and then to establish the cause. In its early stages, adrenal insufficiency can be difficult to diagnose. A review of a patient's medical history based on the symptoms, especially the dark tanning of the skin, will lead a doctor to suspect Addison's disease.
*Specific tests to determine the function of [[adrenal glands]] include:
 
**[[ACTH]] stimulation test
===Tetracosactide Test===
**[[CRH]] stimulation test
*Routine blood tests
**Plasma [[cortisol level]]
**Serum [[ACTH]] level
**[[Plasma renin activity]] and [[aldosterone]] levels
**[[Serum biochemistry]]
===Diagnostic decision===
{| class="wikitable"
!Clinical setting
!Best initial test
|-
|Non-acute
|
* 8AM [[cortisol]]
|-
|Acute illness
|
* Random plasma [[cortisol]] and [[ACTH]] levels


In suspected cases of Addison's disease, one needs to demonstrate that adrenal hormone levels are low even after appropriate stimulation with synthetic pituitary hormone [[tetracosactide]]. Two tests are performed, the short and the long test.
* Followed by [[cortisol]] levels 30 and 60 minutes after [[cosyntropin]] administration.
|}


The short test compares blood cortisol levels before and after 250 micrograms of tetracosactide (IM/IV) is given. If, one hour later, [[plasma]] cortisol exceeds 170 nmol/L and has risen by at least 330 nmol/L to at least 690 nmol/L, adrenal failure is excluded. If the short test is abnormal, the long test is used to differentiate between primary adrenal failure and secondary adrenocortical failure.
==Specific tests to determine adrenal gland function==


The long test uses 1 mg tetracosactide (IM). Blood is taken 1, 4, 8, and 24 hours later. Normal plasma cortisol level should reach 1000 nmol/L by 4 hours. In primary Addison's disease, the cortisol level is reduced at all stages whereas in secondary corticoadrenal insufficiency, a delayed but normal response is seen.
===ACTH Stimulation Test (Rapid ACTH Stimulation Test)===
*This is the most specific test for diagnosing Addison's disease.  
*In this test, blood [[cortisol]], urine [[cortisol]], or both are measured before and after a synthetic form of [[ACTH]] is given by injection.  
*It is called short, or rapid [[ACTH]] test because measurement of [[cortisol]] in blood is repeated 30 to 60 minutes after an intravenous [[ACTH]] injection.
*250 µg synthetic [[ACTH]] ([[cosyntropin]]) is administered [[intravenously]] or [[intramuscularly]].
*The normal response after an injection of [[ACTH]] is a rise in blood and urine [[cortisol]] levels.
* Those with primary adrenal insufficiency fail to increase [[cortisol]] levels above 18 µg/dL; those with secondary or tertiary adrenal insufficiency also fail to achieve [[cortisol]] levels above 18 µg/dL as long as their condition has been present long enough to allow [[adrenal atrophy]] (about 2-4 weeks).
* If a subnormal [[cortisol]] response occurs, [[ACTH]] measurement and other tests should distinguish between primary and secondary and tertiary causes
* Patients with either form of adrenal insufficiency respond poorly or do not respond at all.


===ACTH Stimulation Test===
{{familytree/start}}
{{familytree | | | | | | | | | A01 | | | | | |A01=8 am cortisol}}
{{familytree | | | | | | | | | |!| | | | | | | | }}
{{familytree | | |,|-|-|-|-|-|-|+|-|-|-|-|-|-|.| }}
{{familytree | | B01 | | | | | B02 | | | | | B03 |B01=>15Ug/dL|B02=3-15Ug/dL|B03=<3Ug/dL}}
{{familytree | | |!| | | | | | |!| | | | | | |!| }}
{{familytree | | I01 | | | | | |!| | | | | | I02 | I01=Adrenal insufficiency is <br>ruled out|I02=Measure ACTH}}
{{familytree | | | | | | | | | C01 | | | | | | |C01= 30 min cortisol during<br>
cosyntropin stimulation test }}
{{familytree | | | | | | | | | |!| | | | | | | | }}
{{familytree | | | | | |,|-|-|-|^|-|-|-|-|.| | | }}
{{familytree | | | | | D01 | | | | | | | D02 | | |D01=>18Ug/dL|D02=<18Ug/dL}}
{{familytree | | | | | |!| | | | | | | | |!| | | }}
{{familytree | | | | | J01 | | | | | | | |!| | |J01=Adrenal insufficiency is ruled out }}
{{familytree | | | | | | | | | | | | | | E01 | | |E01=Adrenal insufficiency confirmed}}
{{familytree | | | | | | | | | | | | | | |!| | | }}
{{familytree | | | | | | | | | | | | | | F01 | | |F01=Measure ACTH}}
{{familytree | | | | | | | | | |,|-|-|-|-|^|-|-|-|-|.|}}
{{familytree | | | | | | | | | G01 | | | | | | | | | G02 |G01=Low/normal|G02=Elevated}}
{{familytree | | | | | | | | | |!| | | | | | | | | |!|}}
{{familytree | | | | | | | | | H01 | | | | | | | | | H02 |H01=Secondary<br> Adrenal insufficiency|H02=Primary<br> Adrenal insufficiency}}


This is the most specific test for diagnosing Addison's disease. In this test, blood cortisol, urine cortisol, or both are measured before and after a synthetic form of ACTH is given by injection. In the so-called short, or rapid, ACTH test, measurement of cortisol in blood is repeated 30 to 60 minutes after an intravenous ACTH injection. The normal response after an injection of ACTH is a rise in blood and urine cortisol levels. Patients with either form of adrenal insufficiency respond poorly or do not respond at all.
{{familytree/end}}


===CRH Stimulation Test===
===CRH Stimulation Test===
* When the response to the short [[ACTH]] test is abnormal, a "long" [[CRH]] stimulation test is required to determine the cause of adrenal insufficiency.
* In this test, 1 μg synthetic [[CRH]] is injected intravenously and blood [[cortisol]] is measured before and 30, 60, 90, and 120 minutes after the injection.
* There is some evidence that the low-dose [[ACTH]] test is more sensitive than the standard 250 μg test in identifying partial or mild cases of secondary or tertiary adrenal insufficiency
* Patients with primary adrenal insufficiency have high [[ACTH|ACTHs]] but do not produce [[cortisol]].
* Patients with secondary adrenal insufficiency have deficient cortisol responses but absent or delayed ACTH responses.
* Absent [[ACTH]] response points to the [[pituitary]] as the cause; a delayed [[ACTH]] response points to the [[hypothalamus]] as the cause.


When the response to the short ACTH test is abnormal, a "long" CRH stimulation test is required to determine the cause of adrenal insufficiency. In this test, synthetic CRH is injected intravenously and blood cortisol is measured before and 30, 60, 90, and 120 minutes after the injection. Patients with primary adrenal insufficiency have high ACTHs but do not produce [[cortisol]]. Patients with secondary adrenal insufficiency have deficient cortisol responses but absent or delayed ACTH responses. Absent ACTH response points to the pituitary as the cause; a delayed ACTH response points to the [[hypothalamus]] as the cause.
== Routine investigations ==
Routine investigations include
*Plasma [[cortisol level]]
*Serum [[ACTH]] level
*[[Plasma renin activity]] and [[aldosterone]] levels
*Serum biochemistry
{| class="wikitable"
!Test
!Advantage
!Normal values
!Laboratory Finding
|-
|Plasma [[cortisol]]
|
* Screening test for adrenal insufficiency
|
* Plasma [[cortisol]]: >18 µg/dL at 8<small>AM</small>
|
* <3 µg/dL: suggests evidence of adrenal insufficiency
* 3-18 µg/dL: non-diagnostic, although levels <10 µg/dL raise suspicion of adrenal insufficiency
* >18 µg/dL precludes the diagnosis of adrenal insufficiency
|-
|Serum ACTH level
|
* Helps to distinguish primary from secondary/tertiary adrenal insufficiency
|
* ACTH: 5-30 ng/mL
|
* In Addison disease: [[ACTH]] elevated (usually >60 ng/mL) in the face of a low or low-normal cortisol
* In secondary/tertiary adrenal insufficiency: [[ACTH]] is low (usually <5 ng/mL) in the face of low cortisol
|-
|[[Plasma renin activity]] and [[aldosterone]] levels
|
* A compensatory increase in PRA is the earliest response to mild [[aldosterone]] deficiency.
|
* Normal PA (ng/dL) to PR (ng/mL/h) is less than 20 with plasma [[aldosterone]] levels less than 15 ng/dL.
|
* Patients with Addison disease have increased [[aldosterone]] levels
* [[Plasma renin activity]] exhibits a compensatory rise
|-
|Serum biochemistry
|
* Simple, widely available test
|
* [[Sodium]]: 135-145 mEq/L
* [[Potassium]]: 3.8-5.5 mEq/L
* [[Chloride]]: 95-105 mEq/L
* [[BUN]]: 8-18 mg/dL
* [[Creatinine]]: 0.6-1.2 mg/dL
|In Addison disease:
* [[Sodium]] and [[chloride]] levels may be decreased
* [[Potassium]] levels may be increased
* [[BUN]]-to-[[creatinine]] ratio may be increased (prerenal azotemia)
* Mild non–anion-gap [[metabolic acidosis]]
|}


In patients suspected of having an addisonian crisis, the doctor must begin treatment with injections of salt, fluids, and glucocorticoid hormones immediately. Although a reliable diagnosis is not possible while the patient is being treated for the crisis, measurement of blood ACTH and cortisol during the crisis, and before glucocorticoids are given, is enough to make the diagnosis. Once the crisis is controlled and medication has been stopped, the doctor will delay further testing for up to 1 month to obtain an accurate diagnosis.
==References==
{{Reflist|2}}


=== Suggestive features===
[[Category:Endocrinology]]
 
[[Category:Disease]]
Routine investigations may show:
[[Category:Medical emergencies]]
* [[Complete blood count]] and differential count - [[Eosinophilia]] and [[lymphocytosis]] (increased number of [[eosinophil]]s or [[lymphocyte]]s, two types of [[white blood cell]]s).  [[Normocytic anemia]] may be present.
[[Category:Emergency medicine]]
* [[Hypoglycemia]] (worse in children)
[[Category:Intensive care medicine]]
* [[Serum electrolytes]]:
[[Category:Needs overview]]
** [[Hyponatraemia]] (low blood sodium levels)
** [[Hyperkalemia]] (raised blood [[potassium]] levels), due to loss of production of the hormone [[aldosterone]]
** Mild [[hypercalcemia]] - in 20% patients
** Mild non–anion-gap [[metabolic acidosis]]
* Serum [[cortisol]] - decreased (<25mcg/dL)
* Urine and sweat [[sodium]] - elevated
* Elevated [[BUN]] and [[creatinine]] - when [[hypovolemia]] is the cause.
* [[Prolactin]] - mild elevation may be present.
 
==References==
{{reflist|2}}


{{WH}}
{{WH}}
{{WS}}
{{WS}}

Latest revision as of 13:14, 12 October 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

Diagnosis of Addison's disease is made by routine blood tests and specific tests. ACTH stimulation test is a specific test employed to determine the function of adrenal glands and to diagnose Addison's disease. The prominent finding of a rapid ACTH stimulation test includes failure of cortisol to rise in response to ACTH injection. Other routine laboratory tests employed include plasma cortisol level, serum ACTH level, plasma renin activity, aldosterone levels and serum biochemistry.

Laboratory Findings

Diagnosis of Addison's disease is made by routine blood tests and specific tests. The aim of these tests is to determine the levels of cortisol and then to establish the cause of deficiency.[1][2][3]

Diagnostic decision

Clinical setting Best initial test
Non-acute
Acute illness

Specific tests to determine adrenal gland function

ACTH Stimulation Test (Rapid ACTH Stimulation Test)

  • This is the most specific test for diagnosing Addison's disease.
  • In this test, blood cortisol, urine cortisol, or both are measured before and after a synthetic form of ACTH is given by injection.
  • It is called short, or rapid ACTH test because measurement of cortisol in blood is repeated 30 to 60 minutes after an intravenous ACTH injection.
  • 250 µg synthetic ACTH (cosyntropin) is administered intravenously or intramuscularly.
  • The normal response after an injection of ACTH is a rise in blood and urine cortisol levels.
  • Those with primary adrenal insufficiency fail to increase cortisol levels above 18 µg/dL; those with secondary or tertiary adrenal insufficiency also fail to achieve cortisol levels above 18 µg/dL as long as their condition has been present long enough to allow adrenal atrophy (about 2-4 weeks).
  • If a subnormal cortisol response occurs, ACTH measurement and other tests should distinguish between primary and secondary and tertiary causes
  • Patients with either form of adrenal insufficiency respond poorly or do not respond at all.
 
 
 
 
 
 
 
 
8 am cortisol
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>15Ug/dL
 
 
 
 
3-15Ug/dL
 
 
 
 
<3Ug/dL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adrenal insufficiency is
ruled out
 
 
 
 
 
 
 
 
 
 
 
 
Measure ACTH
 
 
 
 
 
 
 
 
30 min cortisol during
cosyntropin stimulation test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>18Ug/dL
 
 
 
 
 
 
<18Ug/dL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adrenal insufficiency is ruled out
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adrenal insufficiency confirmed
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measure ACTH
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low/normal
 
 
 
 
 
 
 
 
Elevated
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary
Adrenal insufficiency
 
 
 
 
 
 
 
 
Primary
Adrenal insufficiency

CRH Stimulation Test

  • When the response to the short ACTH test is abnormal, a "long" CRH stimulation test is required to determine the cause of adrenal insufficiency.
  • In this test, 1 μg synthetic CRH is injected intravenously and blood cortisol is measured before and 30, 60, 90, and 120 minutes after the injection.
  • There is some evidence that the low-dose ACTH test is more sensitive than the standard 250 μg test in identifying partial or mild cases of secondary or tertiary adrenal insufficiency
  • Patients with primary adrenal insufficiency have high ACTHs but do not produce cortisol.
  • Patients with secondary adrenal insufficiency have deficient cortisol responses but absent or delayed ACTH responses.
  • Absent ACTH response points to the pituitary as the cause; a delayed ACTH response points to the hypothalamus as the cause.

Routine investigations

Routine investigations include

Test Advantage Normal values Laboratory Finding
Plasma cortisol
  • Screening test for adrenal insufficiency
  • <3 µg/dL: suggests evidence of adrenal insufficiency
  • 3-18 µg/dL: non-diagnostic, although levels <10 µg/dL raise suspicion of adrenal insufficiency
  • >18 µg/dL precludes the diagnosis of adrenal insufficiency
Serum ACTH level
  • Helps to distinguish primary from secondary/tertiary adrenal insufficiency
  • ACTH: 5-30 ng/mL
  • In Addison disease: ACTH elevated (usually >60 ng/mL) in the face of a low or low-normal cortisol
  • In secondary/tertiary adrenal insufficiency: ACTH is low (usually <5 ng/mL) in the face of low cortisol
Plasma renin activity and aldosterone levels
  • A compensatory increase in PRA is the earliest response to mild aldosterone deficiency.
  • Normal PA (ng/dL) to PR (ng/mL/h) is less than 20 with plasma aldosterone levels less than 15 ng/dL.
Serum biochemistry
  • Simple, widely available test
 In Addison disease:

References

  1. ↑ Chakera AJ, Vaidya B (2010). "Addison disease in adults: diagnosis and management". Am. J. Med. 123 (5): 409–13. doi:10.1016/j.amjmed.2009.12.017. PMID 20399314.
  2. ↑ Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C, Falorni A, Gan EH, Hulting AL, Kasperlik-Zaluska A, Kämpe O, Løvås K, Meyer G, Pearce SH (2014). "Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency". J. Intern. Med. 275 (2): 104–15. doi:10.1111/joim.12162. PMID 24330030.
  3. ↑ Puttanna A, Cunningham AR, Dainty P (2013). "Addison's disease and its associations". BMJ Case Rep. 2013. doi:10.1136/bcr-2013-010473. PMC 3736622. PMID 23893277.

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