How does the Adrenocorticotropic Hormone (ACTH) stimulation test diagnose Addison's disease?

ACTH Stimulation Test for Diagnosing Addison's Disease

The ACTH stimulation test diagnoses Addison's disease by measuring the adrenal glands' ability to respond to exogenous ACTH with cortisol production, with a peak cortisol level below 500 nmol/L (18 μg/dL) after 250 μg ACTH administration confirming primary adrenal insufficiency. 1

Physiological Basis

The ACTH stimulation test works by:

1. Administering synthetic ACTH (cosyntropin/tetracosactide) to directly stimulate the adrenal cortex
2. Measuring the cortisol response at baseline and after stimulation (30 and/or 60 minutes)
3. Evaluating if the adrenal glands can appropriately increase cortisol production

In healthy individuals, ACTH stimulation causes a robust increase in cortisol production. In Addison's disease, the damaged adrenal cortex cannot respond adequately to ACTH stimulation, resulting in an insufficient cortisol response.

Standard Testing Protocol

High-Dose ACTH Test (Preferred Method)

• Administer 250 μg of cosyntropin intravenously or intramuscularly 1
• Measure serum cortisol at baseline and at 30 and/or 60 minutes post-administration
• A peak cortisol level below 500 nmol/L (18 μg/dL) is diagnostic of adrenal insufficiency 1

Low-Dose ACTH Test (Alternative)

• Administer 1 μg of cosyntropin intravenously
• While more sensitive in some cases, the high-dose test is generally preferred due to easier practical modalities and comparable accuracy 1, 2

Interpretation of Results

• Diagnostic criteria for primary adrenal insufficiency:

  • Peak cortisol < 500 nmol/L after ACTH stimulation 1
  • Elevated baseline ACTH levels with low or inappropriately normal cortisol 1

• Additional diagnostic findings:

  • Low aldosterone with elevated plasma renin activity 1
  • Presence of 21-hydroxylase autoantibodies (in autoimmune cases) 1, 3

Clinical Pitfalls and Considerations

1. Pre-test preparations:

   • Stop glucocorticoids and spironolactone on the day of testing 4
   • Discontinue estrogen-containing medications 4-6 weeks before testing (they increase cortisol binding globulin) 4, 5
   • Consider time of day when interpreting results 5

2. Early disease may be missed:

   • In evolving Addison's disease, morning cortisol may initially be normal despite elevated ACTH 6
   • Consider measuring ACTH levels in suspected cases even when cortisol is normal 6
   • Mineralocorticoid deficiency (low aldosterone, high renin) may precede glucocorticoid deficiency 6

3. Assay considerations:

   • Different cortisol assays have different reference ranges 5
   • Consider the clinical presentation when interpreting borderline results 5

4. Special situations:

   • In critical illness, the high-dose (250 μg) ACTH test is recommended over the low-dose test 1
   • Never delay treatment of suspected acute adrenal crisis for diagnostic testing 1

Algorithm for Diagnosis

1. Initial assessment:

   • Measure paired morning serum cortisol and plasma ACTH
   • If cortisol is clearly low (<250 nmol/L) and ACTH is elevated, diagnosis is confirmed 1
   • If cortisol is borderline or normal but clinical suspicion remains high, proceed to ACTH stimulation test

2. ACTH stimulation test:

   • Administer 250 μg cosyntropin IV/IM
   • Measure cortisol at 0,30, and 60 minutes
   • Peak cortisol <500 nmol/L confirms diagnosis 1

3. Determine etiology:

   • Measure 21-hydroxylase autoantibodies (positive in autoimmune Addison's) 1
   • If antibodies are negative, consider adrenal imaging and other causes 1

Remember that in patients with high clinical suspicion and acute presentation, treatment should never be delayed for diagnostic procedures 1. Blood samples for cortisol and ACTH should be secured prior to treatment if possible, but immediate administration of hydrocortisone and saline is the priority.