The 1 mcg CST: More discriminating than 250 mcg
Using a ROC curve generated from 22 studies, the authors found the test characteristics of the 250 mcg CST and the 1 mcg CST to be similar. Only 7 of these studies included paired data for the standard- and low-dose CST in the same patients, however. In the 7 studies with paired data, the 1 mcg CST had better diagnostic discrimination, based on a larger area under the ROC, than the 250 mcg CST.
13 mcg/dL is the rule-out threshold for morning serum cortisol
A subsequent meta-analysis, based on a PubMed search of English-language studies from 1966 to 2006, compared the performance of morning serum cortisol, the 1 mcg CST, and the 250 mcg CST for diagnosing secondary adrenal insufficiency. This analysis used patient-level data obtained from the original investigators instead of reported study-level results.3 Data from patients described as normal, healthy control subjects were excluded.
Studies included in the meta-analysis used an accepted gold-standard test, such as the insulin tolerance test or metyrapone test. Studies that were performed in a critical care setting or used older, less reliable cortisol assays were excluded, as were studies for which patient-level data couldn’t be obtained. Three new studies were included, and 12 of the previously used studies were excluded.
Instead of using the reported cortisol cutoff levels, the authors defined a negative test as the mean cortisol level (the “rule-out threshold”) above which the negative likelihood ratio of adrenal insufficiency is <0.15. The rule-out thresholds for morning serum cortisol, 1 mcg CST, and 250 mcg CST were 13, 22, and 30 mcg/dL, respectively.
An optimal testing strategy for secondary insufficiency
The authors proposed an optimal testing strategy for secondary adrenal insufficiency (assuming a low or moderate pretest probability) that starts with a morning serum cortisol measurement:
- A serum cortisol level >13 mcg/dL can effectively rule out adrenal insufficiency.
- If the morning serum cortisol is <13 mcg/dL, a 1 mcg CST >22 mcg/dL can rule out adrenal insufficiency.
- Patients would need an insulin tolerance test or metyrapone test only if the low-dose CST is <22 mcg/dL.
Recommendations
Williams Textbook of Endocrinology states that a basal cortisol level higher than 14.5 mcg/dL invariably indicates an intact hypothalamic-pituitary-adrenal axis. However, to confirm the diagnosis of adrenal insufficiency, all patients, except those with a recent pituitary insult, should undergo a CST. An insulin tolerance test should be done only if the patient has a subnormal response to cosyntropin (to rule out a false-positive CST) or has had a recent pituitary insult.4