From the Guidelines
A slightly low ACTH level in the setting of a normal ACTH stimulation test typically indicates secondary adrenal insufficiency that is mild or in early stages, suggesting pituitary dysfunction rather than adrenal gland failure. This condition occurs when the pituitary gland produces insufficient ACTH despite having normal adrenal glands that can respond appropriately when stimulated 1. The normal stimulation test result shows that the adrenal glands themselves can produce cortisol when directly stimulated with synthetic ACTH, confirming that the problem lies with the pituitary rather than the adrenal glands.
Key points to consider in this scenario include:
- The prevalence of adrenal insufficiency, with primary adrenal insufficiency affecting 1 in 8–10,000 children and secondary adrenal insufficiency due to ACTH deficiency affecting approximately 1 in 10,000 children 1.
- The potential for glucocorticoid therapy to cause suppression of the hypothalamo–pituitary–adrenal axis, even at commonly prescribed doses and in a dose-dependent manner 1.
- The importance of evaluating pituitary function through additional hormone testing and possibly pituitary imaging to determine the underlying cause of the slightly low ACTH level.
Management of this condition may involve:
- Further evaluation of pituitary function through additional hormone testing and possibly pituitary imaging.
- Physiologic glucocorticoid replacement, such as hydrocortisone 15-25 mg daily in divided doses, depending on the severity and cause of the condition.
- Addressing any underlying pituitary issues, which may include treatment of underlying conditions such as brain tumors or developmental disorders of the hypothalamus and pituitary.
It is essential to note that all steroid-dependent patients are at risk of adrenal crisis 1, highlighting the need for careful management and monitoring of patients with secondary adrenal insufficiency.
From the Research
Interpretation of Slightly Low ACTH in Normal ACTH Stimulation Test
- A slightly low Adrenocorticotropic hormone (ACTH) level in the context of a normal ACTH stimulation test can be observed in various clinical scenarios, including secondary adrenal insufficiency 2, 3.
- The low-dose ACTH stimulation test is considered a useful tool for evaluating the hypothalamic-pituitary-adrenal (HPA) axis, especially in patients with suspected secondary adrenal insufficiency 2, 4.
- However, the test's sensitivity and specificity can vary depending on the cut-off values used, with some studies suggesting that a cut-off of 401.5 nmol/L may be a better compromise between sensitivity and specificity 4.
- In patients with pituitary disease, the low-dose ACTH stimulation test may not be as sensitive as the overnight metyrapone test for diagnosing secondary hypoadrenalism 3.
- A systematic review and meta-analysis found that both high- and low-dose ACTH stimulation tests have similar diagnostic accuracy for secondary adrenal insufficiency, but may not be adequate to rule out the condition 5.
Clinical Implications
- The presence of a slightly low ACTH level in a normal ACTH stimulation test may require further evaluation to determine the underlying cause, including assessment of the patient's clinical history, physical examination, and other laboratory tests 6, 2.
- The choice of test and interpretation of results should be individualized based on the patient's specific clinical scenario and the expertise of the healthcare provider 4, 3.
- It is essential to consider the limitations and potential biases of the available evidence when interpreting the results of ACTH stimulation tests 5.