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

Diagnostic Workup for Low ACTH with Normal Cortisol Levels

The diagnostic workup for a patient with low ACTH and normal cortisol levels should focus on secondary adrenal insufficiency with preserved cortisol production, with isolated ACTH deficiency (IAD) being a key consideration. 1, 2

Initial Assessment

• Morning cortisol samples (around 8 AM) are preferred for initial assessment 1
• Confirm the pattern with repeat testing of both ACTH and cortisol levels
• Review medication history for recent glucocorticoid use or medications that could affect the hypothalamic-pituitary-adrenal (HPA) axis
• Assess for symptoms of mild adrenal insufficiency:
  • Fatigue, weakness, anorexia
  • Unintentional weight loss
  • Tendency toward hypoglycemia 2

Diagnostic Testing Algorithm

1. ACTH Stimulation Test (Gold Standard)

   • Standard 250 μg cosyntropin test is preferred 1, 3
   • Low-dose (1 μg) ACTH stimulation test may be more sensitive for secondary adrenal insufficiency but has lower sensitivity compared to other tests 1, 4
   • Normal response: peak cortisol ≥18 μg/dL and/or increment ≥9 μg/dL from baseline 1
   • Patients with isolated ACTH deficiency may have a normal cortisol response despite subnormal ACTH 5

2. Insulin Tolerance Test (ITT)

   • Consider when ACTH stimulation test results are equivocal
   • Gold standard for evaluating the entire HPA axis 5
   • Normal response: peak cortisol >500 nmol/L (>18 μg/dL) and ACTH >17.6 pmol/L 5
   • Contraindicated in patients with seizure disorders, cardiovascular disease, or elderly patients

3. Metyrapone Test

   • More sensitive than low-dose ACTH stimulation test for secondary adrenal insufficiency 4
   • Measures 11-deoxycortisol response (normal >200 nmol/L)
   • Useful when other tests are inconclusive

4. Pituitary Imaging

   • MRI of the pituitary to evaluate for structural abnormalities
   • Particularly important if other pituitary hormones are abnormal

5. Additional Laboratory Testing

   • Complete blood count (may show mild anemia, lymphocytosis, eosinophilia) 2
   • Electrolytes (may show mild hyponatremia with normal potassium) 2
   • Blood glucose (may show hypoglycemia) 2
   • Evaluation of other pituitary hormones (TSH, free T4, LH, FSH, prolactin)
   • Consider autoimmune markers if autoimmune etiology is suspected 1

Differential Diagnosis

1. Isolated ACTH Deficiency (IAD)

   • Rare disorder characterized by secondary adrenal insufficiency with normal secretion of other pituitary hormones 2
   • May be caused by:
     • Traumatic injury
     • Lymphocytic hypophysitis (possibly autoimmune)
     • Genetic factors (especially in neonatal/childhood cases) 2

2. Partial Secondary Adrenal Insufficiency

   • Patients may maintain normal baseline cortisol but have impaired stress response
   • Often have subnormal ACTH responses despite normal cortisol levels 5

3. Recent Exogenous Glucocorticoid Use

   • Can suppress ACTH production while maintaining normal cortisol levels
   • Careful medication history is essential

4. Recovery Phase of Adrenal Insufficiency

   • ACTH may remain suppressed while cortisol production normalizes

Management Considerations

• For patients with confirmed isolated ACTH deficiency:

  • Symptomatic patients require replacement therapy: hydrocortisone 20 mg daily (0.30 mg/kg) or cortisone acetate 25 mg daily (0.35 mg/kg) 2
  • Mild, asymptomatic cases may only require glucocorticoid coverage during stressful events 2
  • Mineralocorticoid replacement is generally not necessary 2

• Patient education regarding:

  • Stress dosing protocols
  • Medical alert identification
  • Emergency steroid administration 1

Pitfalls and Caveats

• Low ACTH with normal cortisol may represent early secondary adrenal insufficiency that could progress to overt insufficiency
• The dose-response relationship between ACTH and cortisol means some patients maintain normal cortisol despite significantly reduced ACTH reserve 5
• Patients with subnormal ACTH but normal cortisol responses may have decreased ACTH secretory reserve but are unlikely to develop adrenal crisis unless pituitary function deteriorates further 5
• Low-dose ACTH stimulation test has limited sensitivity (only 50%) for detecting ACTH deficiency confirmed by metyrapone testing 4
• Timing of tests is important - morning samples are preferred for accurate assessment 1