What is the management approach for a patient with low Adrenocorticotropic hormone (ACTH) and normal cortisol levels?

Management of Low ACTH with Normal Cortisol Levels

A patient with low ACTH and normal cortisol levels should be evaluated for secondary adrenal insufficiency, with immediate endocrinology consultation and further diagnostic testing to determine if this represents early central adrenal insufficiency requiring hormone replacement therapy. 1

Diagnostic Approach

Initial Assessment

• Confirm laboratory findings:
  • Low morning ACTH with normal cortisol levels
  • Check electrolytes (sodium, potassium, CO2, glucose)
  • Consider repeat testing to verify results

Further Diagnostic Testing

• ACTH stimulation test:
  • Standard dose (250 μg) or low-dose (1 μg) ACTH stimulation test
  • Low-dose (1 μg) test may be more sensitive for early or mild secondary adrenal insufficiency 2
  • A peak cortisol response <14-15 μg/dL (with newer specific assays) or <18 μg/dL (with older assays) indicates adrenal insufficiency 3
• Additional hormone evaluation:
  • TSH, free T4 to assess thyroid function
  • LH, FSH, testosterone (males) or estrogen (premenopausal females) if symptoms suggest hypogonadism
  • Consider MRI of brain with pituitary/sellar cuts if multiple hormone deficiencies are present or if headaches/visual changes are reported 1

Clinical Significance

Low ACTH with normal cortisol represents one of three possibilities:

1. Early secondary adrenal insufficiency: The pituitary is failing to produce adequate ACTH, but the adrenal glands are still responding to minimal ACTH stimulation
2. Recent ACTH deprivation: Patients who recently discontinued exogenous glucocorticoids may show this pattern
3. Laboratory error or transient suppression: Requires verification

Management Algorithm

For Asymptomatic Patients

1. Endocrine consultation
2. Monitor for symptoms of adrenal insufficiency (fatigue, weakness, anorexia, nausea, hypoglycemia)
3. Consider watchful waiting with close follow-up if completely asymptomatic
4. Educate patient about symptoms requiring immediate medical attention

For Symptomatic Patients (Mild Symptoms)

1. Endocrine consultation
2. Consider initiating replacement therapy:
   • Hydrocortisone 10-20 mg orally in the morning, 5-10 mg orally in early afternoon 1
   • Alternative: Prednisone 5-10 mg daily
3. Provide patient education:
   • Stress dosing instructions
   • Medical alert bracelet for adrenal insufficiency
   • When to seek medical attention

For Moderate to Severe Symptoms

1. Immediate endocrine consultation
2. Consider holding any immune checkpoint inhibitors if applicable
3. For moderate symptoms:
   • Initiate outpatient treatment at 2-3 times maintenance dose
   • Hydrocortisone 20-30 mg in morning, 10-20 mg in afternoon 1
4. For severe symptoms:
   • Emergency department referral
   • IV hydrocortisone 100 mg or dexamethasone 4 mg
   • Normal saline (at least 2L)
   • Taper to maintenance doses over 7-14 days

Special Considerations

Perioperative Management

• Patients with suspected secondary adrenal insufficiency require stress-dose steroids for procedures:
  • Minor procedures: Double morning dose of hydrocortisone
  • Major procedures: Hydrocortisone 50-100 mg IV at induction, then taper 1

Monitoring and Follow-up

• Regular follow-up with endocrinology
• Monitor for symptoms of under-replacement (fatigue, nausea, hypotension)
• Monitor for symptoms of over-replacement (weight gain, hypertension, hyperglycemia)
• Adjust doses based on clinical response

Common Pitfalls

1. Missing the diagnosis: Low ACTH with normal cortisol can represent early secondary adrenal insufficiency that may progress to overt insufficiency
2. Inadequate stress dosing: Patients need education on increasing doses during illness or stress
3. Starting thyroid replacement before corticosteroids: In patients with multiple pituitary hormone deficiencies, always start corticosteroids first to prevent precipitating adrenal crisis 1
4. Failure to provide emergency instructions: All patients need education on stress dosing and emergency injectable steroids

Remember that patients with secondary adrenal insufficiency (low ACTH) do not typically require mineralocorticoid replacement (fludrocortisone) as aldosterone production remains intact through the renin-angiotensin system 4.