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ACTH stimulation test

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The ACTH stimulation test (also called the Cortrosyn (aka Cosyntropin) or Synacthen test) is a medical test performed to assess the functioning of the adrenal glands by measuring adrenal response to ACTH.[1][2] ACTH is a hormone produced in the pituitary gland that stimulates the adrenal glands to release cortisol.[2] Specifically, it is used to diagnose or exclude adrenal insufficiency, Addison's disease and related conditions.[2] It involves the injection of synthetic adrenocorticotropic hormone (ACTH) and measures the amount of cortisol, and sometimes aldosterone, the adrenals produce in response.[3] Apart from objectivating adrenal insufficiency, it can distinguish whether the cause is adrenal (low cortisol production) or pituitary (low ACTH production).[1]

In healthy individuals, the cortisol level should double from a value at least in the 20s within 60 minutes. If the cortisol level was a 25 before the stimulation (base level), after the stimulation it should reach at least 50 ug/dl. This test may cause mild side effects in some individuals. These can include nausea, facial flushing or palpitations (a fast or fluttering heart beat) which are normal reactions, but disappear in a few hours.[4]

The ACTH stimulation test is recognized by the medical community as the final say in whether or not an individual has a degree of adrenal insufficiency, although this test is primarily used to determine the presence of Addison's disease and pituitary impairment.[5] If the test does not show Addison's (for example, in true Addison's, the stimulation may start at 3 ug/dl and rise to 4 ug/dl or 6 ug/dl rising to 8 ug/dl), a doctor may see the test as showing the adrenal glands are working and don't recognize any degree of adrenal insufficiency between Addison's (the worst degree of adrenal insufficiency which can cause death) and healthy adrenal function. Secondary adrenal insufficiency if often missed as doctors can see doubling or more from a low base cortisol value with low ACTH being okay or even great, not recognizing this indicates low ACTH production.

Method of preparation and administration

  • Preparation
    Must fast at least 8 hours before the test which should be done before 10 am, but as close to 7 am as possible.[6] This test shouldn't be given if on glucocorticoids, DHEA, pregnenolone or adrenal extract supplement as these will affect test results. Stress and recently administered radioisotope scans can artificially increase levels and may invalidate test results. Spironolactone, contraceptives, licorice, estrogen, androgen and progesterone therapy may also affect both aldosterone and cortisol stimulation test results.[7][8] If aldosterone is to be stimulated, salt and foods significant in sodium must be fasted for 24 hours prior to testing. This allows aldosterone to rise as far as possible. Women must test the first week of their cycle.
  • Administration
    Blood is drawn to get a starting or base cortisol, (plasma ACTH should also be tested) and or aldosterone level, next synthetic ACTH (Synacthen aka Tetracosactide or Cortrosyn aka Cosyntropin) is injected. Approximately 20 mL of heparinized venous blood must be collected at 30 and 60 minutes after the synthetic ACTH injection.[9][10] All blood samples are kept on ice and sent immediately to the laboratory for testing.[6]

Interpretation for cortisol stimulation

Location of the adrenal glands
  • Interpretation for primary adrenal insufficiency and Addison's disease
    The base cortisol level in people with adrenal insufficiency is usually in the mid teens. If the ACTH stimulation test raises cortisol level to 20 ug/dl, that is not doubling and supports the diagnosis of primary adrenal insufficiency. In Addison's, base cortisol is well below 10 ug/dl and rises no more than 25 percent.
  • Interpretation for secondary adrenal insufficiency
    cortisol stimulates to double, triple, quadruple or more from a low base value. Other examples reported include quintupling (5 stimming to 25 ng/dl, 6 stimming to 30), sextupling (4 ug/dl stimming to 24, 4.1 stimming to 26.9, 5 stimming to 30), septupling (0.7 ug/dl stimming to 4.9), decupling (2 ug/dl stimming to 20, 2.7 stimming to 27.6), tridecupling (1.25 ug/dl stimming to 16, a factor of 12.8) and quadecupling (1.7 ug/dl stimming to 24, after 1 1/2 hours reached 27.5 for sexdecupling). These examples illustrate how extreme the ACTH stimulation test result can be in secondary adrenal insufficiency, but most people with secondary only double or triple and usually start with a base cortisol value of at least 10. The base cortisol can be very low because of the bodies lack of natural ACTH. When the synthetic ACTH is given to secondaries, the adrenals go hog wild because they can work, just not getting enough ACTH from the pituitary gland.[6]

    In some instances, a second test performed later can suggest primary adrenal insufficiency (cortisol value less than doubled). The diagnosis may be changed from secondary to primary adrenal insufficiency or to include primary adrenal insufficiency. In secondary adrenal insufficiency, if the adrenal glands lack ACTH for enough time, cortisol production can atrophy[11] and fail to rise to a value at least double the base cortisol value. It is proper to continue with the diagnosis of secondary adrenal insufficiency.
  • Differentiating ACTH impairment from CRH impairment
If secondary adrenal insufficiency is diagnosed, the corticotropin-releasing hormone (CRH) stimulation test can be used to distinguish between a hypothalamic and pituitary cause, but is rarely used in clinical practice. After administration of CRH 100 μg (or 1 μg/kg) IV, the normal response is a rise of plasma ACTH of 30 to 40 pg/mL. Patients with pituitary failure do not respond, whereas those with hypothalamic disease usually do.[12]

Interpretation of ACTH plasma test in conjunction with cortisol stimulation

Location of the pituitary gland
Click to enlarge photo

An ACTH plasma test should always be given at the same time as the ACTH stimulation. This test measures how much ACTH the pituitary is making. A healthy ACTH value should be just into the upper third of the range (assuming a range of 10–60 ng/L). The ACTH plasma and ACTH stimulation test together can give a clearer picture, especially for secondary adrenal insufficiency.[9]

  • Interpretation for primary adrenal insufficiency and Addison's disease
    ACTH will be high[9], either at the top or above range. In Addison's disease, ACTH can be way above range and may reach the hundreds and in rare cases reach the 1000s and 2000s.
  • Interpretation for secondary adrenal insufficiency
    ACTH will be low[9] (usually below 35), but not usually below the range limit. Though uncommon, values for ACTH can reach into the low 40s. 98% of people with secondary fall within range.

Interpretation for aldosterone stimulation

The ACTH stimulation test is occasionally used to stimulate the production of aldosterone at the same time as cortisol to also help in determining if primary (hyperreninemic) or secondary (hyporeninemic) hypoaldosteronism is present.[3] Human ACTH has a slight stimulatory effect on aldosterone[13], but the amount of synthetic ACTH given in the stimulation is equivalent to more than a whole days production of natural ACTH, so the aldosterone response can be easily measured in blood serum.[14] Same as cortisol, aldosterone should double from a respectable base value (around 20 ng/dl, must fast salt 24 hours and sit upright for blood draw) in a healthy individual.

  • Interpretation for primary aldosterone deficiency
    The aldosterone response in the acth stimulation test is blunted or absent in patients with primary adrenal insufficiency.[3] The base value is usually in the mid teens or less and rise to less than double the base value thus indicating primary hypoaldosteronism (potassium and renin enzyme will be high) and an is an indicator of primary adrenal insufficiency or Addison's disease.
  • Interpretation for secondary aldosterone deficiency
    Aldosterone production can go up by several factors from a low base value indicating secondary hypoaldosteronism (potassium and renin enzyme will be low). Usually doubling to quadrupling from a low base aldosterone value is what is seen in secondary adrenal insufficiency. Decupling of aldosterone in the ACTH stimulation test is possible (ie 2 ng/dl stimming to 20).[15] A result of doubling of more of aldosterone may help in tandem with a cortisol stimulation that doubled or more confirm a diagnosis of secondary adrenal insufficiency. In rare cases, an aldosterone stimulation which did not double, but with the presence of low potassium, low renin and low ACTH indicates atrophy of aldosterone production from the lack of renin for an extended period.

    Similar to the cortisol stimulation in ACTH deficiency, a doctor may lack knowledge of how to properly interpret for secondary hypoaldosteronism and think a result of aldosterone doubling or more from a low base value is fantastic.

See also

References

  1. ^ a b Dorin RI, Qualls CR, Crapo LM (2003). "Diagnosis of adrenal insufficiency" (PDF). Ann. Intern. Med. 139 (3): 194–204. PMID 12899587.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b c Elizabeth H. Holt, MD, PhD (2008). "ACTH (cosyntropin) stimulation test". {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b c unknown. "ACTH Stimulation Test" (PDF). APPENDIX – Endocrinology.
  4. ^ unknown. "Synacthen Test" (PDF). {{cite journal}}: Cite has empty unknown parameter: |1= (help); Cite journal requires |journal= (help)
  5. ^ unknown (2006). "ACTH (Cortrosyn) stimulation test". {{cite journal}}: Cite journal requires |journal= (help); Unknown parameter |para= ignored (help); Unknown parameter |sect= ignored (help)
  6. ^ a b c K. Pagana, PhD, RN and T. Pagana, MD, FACS. "Mosby's Diagnostic and Laboratory Test Reference 2nd ed: Adrenocorticotropic hormone stimulation test": 17. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "Mosby's Diagnostic and Laboratory Test Reference 2nd ed." was defined multiple times with different content (see the help page).
  7. ^ K. Pagana, PhD, RN and T. Pagana, MD, FACS. "Mosby's Diagnostic and Lab Test Reference 2nd ed: Aldosterone, Cortisol": 29 and 260. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  8. ^ unknown (2006). "Aldosterone in Blood". {{cite journal}}: Cite journal requires |journal= (help)
  9. ^ a b c d unknown. "ACTH Rapid Stimulation Test (Cortrosyn, Cosyntropin)". {{cite journal}}: Cite journal requires |journal= (help) Cite error: The named reference "ACTHRapidStimulationTest.html" was defined multiple times with different content (see the help page).
  10. ^ NIDDK's Office of Health Research Reports. "Addison's disease". {{cite journal}}: Cite journal requires |journal= (help)
  11. ^ Ashley B. Grossman, MD (2007). "Addison's Disease". Endocrine and Metabolic Disorders. {{cite journal}}: Unknown parameter |para= ignored (help); Unknown parameter |sect= ignored (help)
  12. ^ Ashley B. Grossman, MD (2007). "Secondary Adrenal Insufficiency". Endocrine and Metabolic Disorders sect=Diagnosis. {{cite journal}}: Unknown parameter |para= ignored (help)
  13. ^ unknown. "Role of ACTH in Regulation and Action of Adrenocorticoids": 7 of 52. {{cite journal}}: Cite journal requires |journal= (help)
  14. ^ unknown. "Aldosterone and Renin". {{cite journal}}: Cite journal requires |journal= (help)
  15. ^ L.A. Cunningham and M.A. Holzwarth (1988). "Vasoactive intestinal peptide stimulates adrenal aldosterone and corticosterone secretion". Endocrinology. 122: 2090–2097. PMID 3359977.

Informational resources

http://www.nlm.nih.gov/medlineplus/ency/article/003696.htm
http://www.cc.nih.gov/ccc/patient_education/procdiag/acth.pdf
http://www.labtestsonline.org/understanding/analytes/acth/test.html

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