Investigations
1st investigations to order
serum comprehensive chemistry panel
Test
Although not diagnostic, incidental laboratory findings such as hypo- or hyperglycaemia, hypokalaemia, hypomagnesaemia, and a contraction alkalosis may raise suspicion of glucocorticoid use.
Electrolyte abnormalities consistent with mineralocorticoid deficiency such as hyperkalaemia are absent because the renin-angiotensin-aldosterone system remains intact.
Result
possible hypo- or hyperglycaemia, hypokalaemia, hypomagnesaemia, contraction alkalosis
serum a.m. cortisol
Test
The morning serum cortisol has been used as a screening test, but it is not reliable in predicting adrenal reserve. Because adrenocorticotropic hormone (ACTH) has been suppressed by the exogenous corticosteroid, serum cortisol is expected to be low.
Results: ≥497 nanomol/L (18 micrograms/dL): predicts normal serum cortisol response to insulin-induced hypoglycaemia or short ACTH test; 110 to 469 nanomol/L (4-17 micrograms/dL): unclear, best to proceed to a stimulation test; <110 nanomol/L (4 micrograms/dL): likely adrenal insufficiency.[35]
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.
Result
<110 nanomol/L (4 micrograms/dL): likely adrenal insufficiency
salivary a.m. cortisol
Test
Like the morning serum cortisol, the morning salivary cortisol can be used as a screening test but it is not reliable in predicting adrenal reserve.[36][37] Salivary cortisol is expected to be low as a consequence of adrenocorticotropic hormone suppression by exogenous corticosteroid.
Results: ≥1849 nanomol/L (≥0.67 micrograms/dL): predicts normal serum cortisol response to insulin-induced hypoglycaemia; 414 to 1849 nanomol/L (0.15-0.67 micrograms/dL): unclear, best to proceed to a stimulation test; <414 nanomol/L (<0.15 micrograms/dL): likely adrenal insufficiency.
Values usually fall within the equivocal range. Further confirmation with a stimulation test is suggested if there is any doubt.
Result
<414 nanomol/L (<0.15 micrograms/dL): likely adrenal insufficiency
adrenocorticotropic hormone (ACTH) stimulation test
Test
Relatively easy to do and reliable.
A synthetic derivative of ACTH is injected intravenously or intramuscularly in a dose of 250 micrograms.[44] This dose is the most commonly used in practice and can be prepared even in the office setting.[44] Cortisol levels are drawn at 0, 30, and 60 minutes after the administration of cosyntropin. Normal is a rise to >497 nanomol/L (18 micrograms/dL) at any time during the test.
Using 1 or 10 micrograms of ACTH, compared with 250 micrograms, has been suggested as more sensitive in identifying adrenal hypofunction. However, these preparations require dilutions and intravenous infusions rather than the simpler intramuscular and intravenous injections by which the 250 microgram dose is administered.[45][46][47][48][49] A meta-analysis comparing the 1 mcg ACTH stimulation test versus the 250 mcg dose showed low sensitivity and high specificity of each for diagnosing secondary adrenal insufficiency, with similar diagnostic accuracy of the two doses.[52]
The ACTH stimulation test may be unreliable in patients with recent onset of hypothalamic-pituitary-adrenal axis suppression, where the adrenal glands have not had sufficient time to atrophy. If patients are taking hydrocortisone or prednisolone, it is recommended to withhold the treatment for 24 hours before the test in order to avoid false positives. Other corticosteroid preparations, such as dexamethasone, do not cross-react with the cortisol assay used for the ACTH stimulation test.
Result
rise of cortisol to an absolute level >497 nanomol/L (18 micrograms/dL) excludes adrenal insufficiency
FBC
Investigations to consider
insulin tolerance test (ITT)
Test
Although somewhat cumbersome, the ITT evaluates the entire hypothalamic-pituitary-adrenal axis and is capable of assessing partial adrenal suppression.[44]
ITT can be used if there is concomitant need to determine whether the patient also has growth hormone deficiency, for which the ITT is also a diagnostic test. 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 at a dose of 0.1 to 0.15 units/kg 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 hypoglycaemia with a glucose level <2.2 mmol/L (40 mg/dL).[44]
Normal is a rise of serum cortisol to greater than or equal to 497 nanomol/L (18 micrograms/dL). Abnormal is cortisol <497 nanomol/L (18 micrograms/dL).
Requires vigilance because hypoglycaemia is an endpoint. Contraindicated in older adults and in people with cardiovascular disease or seizure disorder.
Result
serum cortisol <497 nanomol/L (18 micrograms/dL) with symptomatic hypoglycaemia and glucose <2.2 mmol/L (40 mg/dL)
overnight metyrapone test
Test
Although somewhat cumbersome, it evaluates the entire hypothalamic-pituitary-adrenal axis and is capable of assessing partial adrenal suppression.[44]
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 at a dose of 30 mg/kg, with a maximum of 3 g given orally at midnight. Serum cortisol and 11-deoxycortisol levels are taken at 8 a.m. the following day.
Normal if 11-deoxycortisol >200 nanomol/L (7 micrograms/dL) regardless of cortisol level. Abnormal when 11-deoxycortisol <200 nanomol/L (7 micrograms/dL) regardless of cortisol level.
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 <200 nanomol/L (7 micrograms/dL) regardless of cortisol level
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.[28]
Not well studied but may be useful as a marker of absorption. A negative test is not helpful.
Result
may be positive
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