What is the workup for elevated Adrenocorticotropic hormone (ACTH) levels?

From the Guidelines

The workup for high ACTH levels should begin with evaluating AM levels of ACTH and cortisol level, as well as basic metabolic panel, renin, and aldosterone, according to the most recent guideline update 1. When approaching a patient with high ACTH, it's crucial to consider the potential for primary adrenal insufficiency (AI) and evaluate for precipitating causes of crisis such as infection.

• Key initial steps include:
  • Evaluating AM levels of ACTH (if > 23 ULN) and cortisol level (if < 3 mg/dL) 1
  • Basic metabolic panel (Na, K, CO2, and glucose) to assess for electrolyte imbalances and glucose abnormalities
  • Renin and aldosterone levels to evaluate for potential mineralocorticoid deficiency
• For indeterminate results, such as AM cortisol between 3 mg/dL and 15 mg/dL, a standard dose ACTH stimulation test should be considered to assess adrenal function 1.
• Imaging studies, such as adrenal CT, may be necessary to evaluate for metastasis or hemorrhage, which are common causes of primary AI 1.
• It's essential to prioritize the evaluation and management of high ACTH levels to prevent morbidity, mortality, and to improve quality of life, particularly in patients with immune-related adverse events or other critical conditions.

From the FDA Drug Label

2. 1 Important Information Before Conducting Metopirone Testing

Assess ability of patient's adrenals to respond to exogenous ACTH before Metopirone is employed as a test

2. 2 Single-Dose Short Test- Recommended Dose and Interpretation Approximately 8 hours after administration of Metopirone, evaluate the values of ACTH and 11-desoxycortisol An intact HPA axis function is generally indicated by an increase in 11‑desoxycortisol to over 70 mcg/L. Because of an overlap between a normal ACTH response and an abnormal ACTH response, the ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency

For a high ACTH workup, the metyrapone test is used to assess the ability of the patient's adrenals to respond to exogenous ACTH.

• The test involves administering a single dose of metyrapone and then evaluating the values of ACTH and 11-desoxycortisol approximately 8 hours later.
• An intact HPA axis function is generally indicated by an increase in 11-desoxycortisol to over 70 mcg/L.
• However, the ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency due to the overlap between normal and abnormal responses 2.

From the Research

High ACTH Workup

• The diagnosis of ACTH-dependent Cushing's syndrome involves several tests, including the low-dose dexamethasone suppression test (LDDST) and the high-dose dexamethasone suppression test (HDDST) 3.
• The LDDST has been shown to have a higher area under the curve (AUC) than the HDDST in differentiating between Cushing's disease and ectopic ACTH syndrome 3.
• However, falsely elevated ACTH levels can occur due to immunoassay interference, highlighting the importance of relying on formal diagnostic criteria rather than misleading laboratory results 4.
• The desmopressin stimulation test and HDDST have been found to be efficient modalities for the diagnosis of Cushing's disease and ectopic ACTH syndrome, with improved accuracy when combined 5, 6.
• The combination of the HDDST and desmopressin stimulation test has been shown to yield a high positive predictive value for Cushing's disease, potentially reducing the need for bilateral inferior petrosal sinus sampling (BIPSS) 6.
• Other diagnostic tests, such as the CRH test and 8 mg DST, have also been found to be effective in diagnosing Cushing's disease 7.

Diagnostic Tests

• LDDST: useful for confirming the diagnosis of Cushing's syndrome and differentiating between Cushing's disease and ectopic ACTH syndrome 3.
• HDDST: useful for differentiating between Cushing's disease and ectopic ACTH syndrome, but may be replaced by LDDST in some cases 3, 5, 6.
• Desmopressin stimulation test: useful for diagnosing Cushing's disease and ectopic ACTH syndrome, especially when combined with HDDST 5, 6.
• CRH test: useful for diagnosing Cushing's disease, especially when combined with 8 mg DST 7.
• BIPSS: considered the gold standard test for differentially diagnosing ACTH-dependent Cushing's syndrome, but is an invasive procedure with limited availability 6.