Clinical Inquiries

What’s the most practical way to rule out adrenal insufficiency?

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A morning serum cortisol level >13 mcg/dL reliably rules out adrenal insufficiency, and the test is easy and safe to perform. Because of low specificity, patients with a level of ≤13 mcg/dL need further evaluation with the cosyntropin stimulation test (CST) (strength of recommendation [SOR]: A, meta-analysis of diagnostic cohort studies).

The 250 mcg CST requires intravenous (IV) or intramuscular (IM) administration of cosyntropin and multiple blood draws; a normal response reliably rules out primary adrenal insufficiency (SOR: B, meta-analysis of lower-quality diagnostic cohort studies) and moderately decreases the likelihood of secondary adrenal insufficiency (SOR: A, meta-analysis of diagnostic cohort studies). The 1 mcg CST has better diagnostic discrimination, but requires an extra step to dilute the cosyntropin (SOR: A, meta-analysis of diagnostic cohort studies).

Evidence summary

The morning serum cortisol level is the most convenient test for adrenal insufficiency because it requires a single blood draw. The 250 mcg CST involves IV or IM administration of cosyntropin and several blood draws. The 1 mcg CST, introduced to improve detection of partial and secondary adrenal insufficiency, requires dilution of the cosyntropin before administration because the smallest available dose is 250 mcg.

The insulin tolerance test is widely considered the gold standard, but requires close observation, is unpleasant for the patient, and carries some risk. Metyrapone and corticotropin-releasing hormone tests are not widely available.1

Negative CST rules out primary insufficiency

Researchers conducting a meta-analysis of the CST in diagnosing both primary and secondary adrenal insufficiency searched MEDLINE for English-language studies from 1966 to 2002 and used summary receiver-operating characteristic (ROC) curves to combine the sensitivities and specificities from individual studies.2 Four studies of primary adrenal insufficiency showed a negative likelihood ratio of 0.026 for the 250 mcg CST. A negative CST would, therefore, significantly decrease the post-test probability of primary adrenal insufficiency and effectively rule out the condition.

However, primary adrenal insufficiency was already established in the 4 studies, and consecutive testing with an accepted gold standard was not done. Thus, the studies likely overestimate the accuracy of the CST test characteristics.

Using CST results for secondary insufficiency

Twenty studies evaluating the 250 mcg CST for diagnosing secondary adrenal insufficiency were of higher quality. They included patients with and without disease and compared the CST with gold-standard tests, either the insulin tolerance test or metyrapone test. The summary ROC curve indicated a negative likelihood ratio of 0.45, which would decrease only moderately the post-test probability of secondary adrenal insufficiency.


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