What is the workup for a patient with low Adrenocorticotropic hormone (ACTH)?

Workup of Low ACTH

The definitive workup for a patient with low ACTH should include a cosyntropin (ACTH) stimulation test to differentiate between primary and secondary adrenal insufficiency, with secondary adrenal insufficiency characterized by low ACTH and low cortisol levels. 1

Initial Assessment

• Morning cortisol sample (around 8 AM) is preferred for initial assessment
• Random plasma cortisol level >18 μg/dL in a stressed patient makes adrenal insufficiency unlikely
• If morning cortisol is <3 μg/dL, this is virtually diagnostic for adrenal insufficiency
• For cortisol values between 5-18 μg/dL, further testing is required

Diagnostic Testing Algorithm

1. ACTH Stimulation Test (Gold Standard)

   • Standard test: 250 μg cosyntropin IV
   • Low-dose test: 1 μg cosyntropin IV (more sensitive for secondary adrenal insufficiency)
   • Normal response: peak cortisol ≥18 μg/dL and/or increment ≥9 μg/dL from baseline
   • The low-dose test can reveal mild adrenal insufficiency not detected by the standard high-dose test 2

2. Plasma ACTH Measurement

   • Low ACTH with low cortisol indicates secondary adrenal insufficiency
   • High ACTH with low cortisol indicates primary adrenal insufficiency

3. Insulin Tolerance Test (ITT)

   • Used when ACTH stimulation test is contraindicated or results are equivocal
   • Considered the gold standard for assessing hypothalamic-pituitary-adrenal axis function 3

4. Extended ACTH Test

   • Useful for differentiating primary from secondary adrenal insufficiency
   • In secondary adrenal insufficiency, aldosterone response to ACTH is normal while cortisol response is subnormal 4

Differential Diagnosis for Low ACTH

• Isolated ACTH deficiency (IAD)
• Pituitary tumor or other hypothalamic-pituitary diseases
• Steroid-induced adrenal suppression
• Lymphocytic hypophysitis (possibly autoimmune)
• Traumatic brain injury affecting pituitary function
• Genetic causes (especially in neonates and children)

Additional Workup

• Check for electrolyte abnormalities (typically normal Na and K in secondary adrenal insufficiency)
• Complete blood count may reveal mild anemia, lymphocytosis, and eosinophilia
• Screen for associated autoimmune conditions (thyroid function, blood glucose, HbA1c)
• In autoantibody-negative individuals, consider imaging of the pituitary gland (MRI)
• For patients on inhaled corticosteroids, check 24-hour urinary free cortisol excretion 2

Management Considerations

• For symptomatic patients, replacement therapy with hydrocortisone 15-25 mg daily in divided doses is usually sufficient 5
• For mild, near-asymptomatic disease, glucocorticoid replacement may only be needed during stressful events 6
• Mineralocorticoid replacement (fludrocortisone) is generally not necessary in secondary adrenal insufficiency as aldosterone production is maintained 6
• Patients require education on stress dosing and should be equipped with a steroid card and emergency glucocorticoid preparation 5

Common Pitfalls to Avoid

• Failing to recognize adrenal insufficiency in acutely ill patients
• Not considering adrenal insufficiency in pregnant women with unexplained persistent nausea, fatigue, and hypotension
• Abrupt withdrawal of corticosteroid therapy can precipitate adrenal crisis 7, 8
• Standard high-dose ACTH test may miss mild cases of secondary adrenal insufficiency; consider low-dose test when clinical suspicion is high 2, 3
• Not starting corticosteroids first when treating multiple endocrine deficiencies, which could precipitate adrenal crisis 1