From the Guidelines
Investigations for low cortisol should begin with morning serum cortisol levels, followed by a high-dose (250-μg) ACTH stimulation test to confirm adrenal insufficiency, as recommended by the Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 guidelines 1.
Initial Evaluation
The short synacthen test involves measuring baseline cortisol, administering 250 mcg of synthetic ACTH (synacthen/cosyntropin) intravenously or intramuscularly, then measuring cortisol levels at 30 and 60 minutes post-administration.
- A peak cortisol response below 500-550 nmol/L (18-20 μg/dL) suggests adrenal insufficiency.
- The high-dose ACTH test is preferred over the low-dose test due to its easier practical modalities and comparable accuracy, as stated in the guidelines 1.
Differentiating Primary and Secondary Causes
Once adrenal insufficiency is confirmed, measuring ACTH levels helps differentiate between primary (high ACTH, low cortisol) and secondary/tertiary causes (low/normal ACTH, low cortisol) 1.
- For primary adrenal insufficiency, additional tests include adrenal antibodies to identify autoimmune adrenalitis, and adrenal imaging (CT/MRI) to detect structural abnormalities.
- For secondary/tertiary causes, pituitary MRI is recommended to identify pituitary lesions, while measuring other pituitary hormones can detect hypopituitarism.
Further Evaluation and Management
In certain cases, insulin tolerance testing or glucagon stimulation testing may be needed to assess the entire hypothalamic-pituitary-adrenal axis 1.
- These investigations are crucial for determining the underlying cause of cortisol deficiency, which guides appropriate treatment strategies including hormone replacement therapy.
- It is essential to start corticosteroids first when planning hormone replacement therapy for multiple deficiencies, as other hormones can accelerate the clearance of cortisol and precipitate adrenal crisis 1.
From the FDA Drug Label
2.5 Administration Information • Obtain blood sample for baseline serum cortisol. Obtain blood samples again for assessment of cortisol levels exactly 30 minutes and 60 minutes after administration of cosyntropin for injection.
2.6 Interpretation of Plasma Cortisol Levels after Cosyntropin for Injection • Stimulated plasma cortisol levels of less than 18 mcg/dL at 30- or 60-minutes post cosyntropin for injection are suggestive of adrenocortical insufficiency.
Investigations for low cortisol involve administering cosyntropin for injection and measuring plasma cortisol levels at baseline, 30 minutes, and 60 minutes after administration.
- Baseline measurement: Obtain a blood sample for baseline serum cortisol.
- Post-administration measurements: Obtain blood samples again for assessment of cortisol levels exactly 30 minutes and 60 minutes after administration of cosyntropin for injection.
- Interpretation: Stimulated plasma cortisol levels of less than 18 mcg/dL at 30- or 60-minutes post cosyntropin for injection are suggestive of adrenocortical insufficiency 2.
From the Research
Investigations for Low Cortisol
Investigations for low cortisol involve various tests to diagnose adrenal insufficiency. The following are some of the key points to consider:
- The cosyntropin stimulation test is commonly used to diagnose adrenal insufficiency, but its interpretation can be challenging due to technical aspects such as time of day, type of assay, and sample source used for cortisol measurement 3.
- Morning serum cortisol level can be used as a predictor of adrenal insufficiency, with a level of > or = 300 nmol/L excluding the possibility of adrenal insufficiency, and a level of < 110 nmol/L suggesting adrenal insufficiency 4.
- The relationship between morning serum cortisol and the short ACTH test has been studied, with a mean basal morning cortisol level of > or = 234 nmol/L predicting a normal cortisol response in the ACTH test with optimal sensitivity and specificity 4.
- A morning serum cortisol level of ≤323.3 nmol/L can predict central adrenal insufficiency diagnosed by insulin tolerance test with a sensitivity of 87.7% and specificity of 46.1% 5.
- New diagnostic cutoffs for adrenal insufficiency after cosyntropin stimulation using the Abbott Architect cortisol immunoassay have been established, with a threshold of 14.6 μg/dL at 60 minutes after stimulation recommended 6.
- Baseline morning cortisol level can be used to predict pituitary-adrenal reserve, with assay-specific cutoffs proposed for three commonly used modern cortisol immunoassays: Advia Centaur, Architect, and Roche Modular System 7.
Key Findings
Some of the key findings from the studies include:
- The importance of considering clinical presentation and technical factors when interpreting the results of the ACTH stimulation test 3.
- The use of morning serum cortisol level as a cost-effective screening test to predict the results of the ACTH test 4.
- The establishment of new diagnostic cutoffs for adrenal insufficiency after cosyntropin stimulation using the Abbott Architect cortisol immunoassay 6.
- The proposal of assay-specific morning cortisol levels to predict the integrity of the hypothalamo-pituitary-adrenal axis 7.
Diagnostic Thresholds
The following diagnostic thresholds have been proposed:
- A morning serum cortisol level of > or = 300 nmol/L to exclude adrenal insufficiency 4.
- A morning serum cortisol level of < 110 nmol/L to suggest adrenal insufficiency 4.
- A threshold of 14.6 μg/dL at 60 minutes after cosyntropin stimulation using the Abbott Architect cortisol immunoassay 6.
- Assay-specific cutoffs for predicting pituitary-adrenal reserve: 358 nmol/l for Siemens, 336 nmol/l for Abbott, and 506 nmol/l for Roche 7.