Tests
1st tests to order
serum comprehensive chemistry panel
Test
Incidental laboratory findings such as hypo- or hyperglycemia, hypokalemia, hypomagnesemia, and a contraction alkalosis may raise suspicion of glucocorticoid use.
Electrolyte abnormalities consistent with mineralocorticoid deficiency such as hyperkalemia are absent because the renin-angiotensin-aldosterone system remains intact.
Result
possible hypo- or hyperglycemia, hypokalemia, hypomagnesemia, contraction alkalosis
serum a.m. cortisol
Test
Patients at risk for adrenal insufficiency during tapering (e.g., those with comorbidities), or who have symptoms of adrenal insufficiency, are candidates for a morning (taken between 9 and 10 a.m.) serum cortisol test. The test should be conducted only after reaching the range of a physiologic equivalent daily dose.
Results: >10 micrograms/dL (300 nmol/L): predicts normal serum cortisol response to insulin-induced hypoglycemia or short ACTH test; 5 to 10 micrograms/dL (150 to 300 nmol/L): indeterminate, consider stimulation test; <5 micrograms/dL (150 nmol/L): likely adrenal insufficiency.[37]
Serum cortisol cutoffs serve as a guide. While higher serum cortisol values indicate recovery of the hypothalamic-pituitary-adrenal (HPA) axis, guidelines note that the value of morning serum cortisol should be viewed as a continuum.[37]
Random serum cortisol levels are not recommended as reliable indicators of adrenal status.
Usually, values fall in the range where adrenal status is unclear. Further confirmation with a stimulation test is suggested if there is any doubt that an exogenous corticosteroid regimen can be discontinued.
Salivary cortisol is of limited value in the diagnosis of adrenal insufficiency and is not routinely recommended.[42] It may be considered in patients in whom phlebotomy is impractical or difficult; or those with hepatic disease with hypoalbuminemia and cirrhosis, where salivary cortisol levels correlate better with adrenal function and plasma free cortisol than does total plasma cortisol.[43][44]
Result
<5 micrograms/dL (150 nmol/L): likely adrenal insufficiency
adrenocorticotropic hormone (ACTH) stimulation test
Test
A stimulation test may be considered in a patient with an indeterminate serum cortisol value.[37][38] Routine ACTH stimulation testing is not, however, recommended to assess hypothalamic-pituitary-adrenal (HPA) axis recovery in patients tapering or discontinuing corticosteroid therapy.[37]
A synthetic derivative of ACTH (250 micrograms of cosyntropin) is injected intravenously or intramuscularly.[45] Cortisol levels are drawn at 0, 30, and 60 minutes after the administration.
The ACTH stimulation test may be unreliable in patients with recent onset of HPA axis suppression, where the adrenal glands have not had sufficient time to atrophy. If patients are taking hydrocortisone or prednisone, it is recommended to withhold the treatment for 24 hours before the test, to avoid false positives. Other corticosteroid preparations, such as dexamethasone, do not cross-react with the cortisol assay used for the ACTH stimulation test.[45]
Result
rise of cortisol to an absolute level >10 micrograms/dL (300 nmol/L) indicates that adrenal insufficiency is highly unlikely
CBC
Tests to consider
insulin tolerance test (ITT)
Test
Labor intensive. Evaluates the entire hypothalamic-pituitary-adrenal axis and is capable of assessing partial adrenal suppression.[45]
The ITT can be used if there is a need to determine if the patient has concomitant growth hormone deficiency. It can also be used to evaluate whether the patient has secondary adrenal insufficiency due to a recent pituitary insult (e.g., pituitary surgery). In this situation, the adrenal glands can still mount a normal response to the adrenocorticotropic hormone stimulation test up to 2 to 3 weeks after the pituitary insult because of adrenal reserve. However, the ITT may uncover that the pituitary gland is not capable of responding to stress.
Short-acting insulin is given intravenously. Plasma cortisol and glucose levels are taken at 0, 30, and 60 minutes. The test is stopped when the patient has symptomatic hypoglycemia with a glucose level <40 mg/dL.[45]
Normal is a rise of serum cortisol to greater than or equal to 18 micrograms/dL. Abnormal is cortisol <18 micrograms/dL.
Requires vigilance because hypoglycemia is an endpoint. Contraindicated in older adults, and in people with cardiovascular disease or seizure disorder.
Result
serum cortisol <18 micrograms/dL with symptomatic hypoglycemia and glucose <40 mg/dL
overnight metyrapone test
Test
Labor intensive. Evaluates the entire hypothalamic-pituitary-adrenal axis and is capable of assessing partial adrenal suppression.[45]
It can be used to evaluate whether the patient has secondary adrenal insufficiency due to a recent pituitary insult (e.g., pituitary surgery).
Metyrapone is given, with a maximum of 3 g given orally at 12 midnight. Serum cortisol and 11-deoxycortisol levels are taken at 8 a.m. the following day.
Normal if 11-deoxycortisol >7 micrograms/dL regardless of cortisol level. Abnormal when 11-deoxycortisol <7 micrograms/dL regardless of cortisol.
This test assesses the entire hypothalamic-pituitary-adrenal axis. There is a risk of precipitating adrenal insufficiency because metyrapone blocks a step in cortisol synthesis. Phenytoin and phenobarbital may lead to false negative results.
Result
abnormal when 11-deoxycortisol <7 micrograms/dL regardless of cortisol
urine synthetic glucocorticoids
Test
Performed if there is doubt that the patient received exogenous glucocorticoids that could have caused adrenal suppression. An example would be a patient who had intra-articular injections for pain a few months ago, presents with fatigue, and has an abnormal adrenocorticotropic hormone stimulation test.[29]
Not well studied, but may be useful as a marker of absorption. A negative test is not helpful.
Result
may be positive
Emerging tests
home waking salivary cortisone
Test
Results from a prospective diagnostic accuracy study indicate that noninvasive waking salivary cortisone testing for the diagnosis of adrenal insufficiency is similarly accurate to that of standard ACTH stimulation testing.[46] Patients preferred home waking salivary cortisone testing to the standard ACTH stimulation test, which requires both a clinic visit and venesection.[46][47] A real-world service evaluation identified reporting to clinicians as a barrier to implementation.[47]
Result
may be adrenal insufficiency
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