Can Adrenocorticotropic hormone (ACTH) levels be used to diagnose primary adrenal insufficiency?

From the Guidelines

Yes, ACTH levels can be used to diagnose primary adrenal insufficiency, as they are typically elevated in this condition, whereas they are low in secondary adrenal insufficiency. In primary adrenal insufficiency (Addison's disease), the adrenal glands themselves are damaged and unable to produce sufficient cortisol, which triggers the pituitary gland to release more ACTH in an attempt to stimulate the adrenal glands. This results in significantly elevated ACTH levels, typically greater than 100 pg/mL (22 pmol/L), while cortisol levels remain low. This contrasts with secondary adrenal insufficiency, where the problem originates in the pituitary gland, resulting in low ACTH and low cortisol levels. For proper diagnosis, ACTH measurement should be performed alongside a morning cortisol test, ideally before 8 AM when cortisol levels are naturally highest. If morning cortisol is less than 5 μg/dL (138 nmol/L) with elevated ACTH, this strongly suggests primary adrenal insufficiency, as noted in studies such as 1. However, an ACTH stimulation test (Cosyntropin test) is often needed to confirm the diagnosis, where synthetic ACTH is administered and cortisol response is measured. The combination of high ACTH with poor cortisol response to stimulation definitively establishes the diagnosis of primary adrenal insufficiency.

Key Points for Diagnosis

• Elevated ACTH levels are characteristic of primary adrenal insufficiency.
• Morning cortisol levels less than 5 μg/dL with elevated ACTH suggest primary adrenal insufficiency.
• An ACTH stimulation test can confirm the diagnosis by demonstrating a poor cortisol response to synthetic ACTH, as discussed in 1 and 1.
• The high-dose (250-μg) ACTH stimulation test is considered the most popular diagnostic test for adrenal insufficiency, but the low-dose test may also be used, with studies such as 1 indicating similar diagnostic accuracy between the two tests.

Clinical Considerations

• Patients on corticosteroids for other conditions may have low morning cortisol and ACTH levels due to iatrogenic secondary adrenal insufficiency, making diagnosis challenging, as mentioned in 1.
• Emergent therapy for suspected adrenal insufficiency should be initiated with dexamethasone to allow for subsequent stimulation testing if needed, as recommended in 1 and 1.
• Education on stress dosing and the use of a medical alert bracelet are crucial for patients with adrenal insufficiency, as emphasized in 1.

From the Research

Diagnosis of Primary Adrenal Insufficiency

• Adrenocorticotropic hormone (ACTH) levels can be used as part of the diagnostic process for primary adrenal insufficiency, but they are not the sole indicator 2, 3.
• An ACTH stimulation test is commonly performed to diagnose adrenal insufficiency when basal serum cortisol levels are inconclusive 2.
• The test measures the response of cortisol levels to ACTH stimulation, and a low response can indicate adrenal insufficiency 3, 4.
• Basal cortisol levels can also be used to predict adrenal insufficiency, with levels ≤100 nmol/L having a high positive predictive value and levels ≥450 nmol/L having a high negative predictive value 4.
• Other biochemical tests, such as measurements of dehydroepiandrosterone sulfate (DHEA-S) levels, can also be useful in diagnosing adrenal insufficiency 5.

Interpretation of Test Results

• The interpretation of ACTH stimulation test results should take into account the clinical presentation and likelihood of adrenal insufficiency before testing 2.
• Technical factors, such as the time of day the test is performed and the type of assay used, can affect cortisol values and diagnostic accuracy 2.
• A normal age- and sex-adjusted serum DHEA-S level can practically rule out the diagnosis of adrenal insufficiency, while a low level is not sufficient by itself to establish the diagnosis 5.

Clinical Presentation and Management

• Primary adrenal insufficiency is characterized by inadequate glucocorticoid and mineralocorticoid production, and patients can present with non-specific symptoms such as syncope, nausea, vomiting, weight loss, and hypoglycemia 3, 6.
• Prompt recognition and treatment of adrenal crisis are essential, and maintenance glucocorticoid replacement is usually given as a twice or thrice daily hydrocortisone preparation 6.
• Patients with primary adrenal insufficiency also require mineralocorticoid replacement, and regular monitoring for features of under- and over-replacement is essential during follow-up 6.