What is the diagnostic workup for Addison's disease and autoimmune hypopituitarism?

Diagnostic Workup for Addison's Disease and Autoimmune Hypopituitarism

The diagnostic workup for Addison's disease requires measurement of morning cortisol and ACTH levels, followed by ACTH stimulation testing, while autoimmune hypopituitarism evaluation should include pituitary hormone panel and MRI with pituitary cuts.

Addison's Disease (Primary Adrenal Insufficiency) Workup

Initial Evaluation

• Morning cortisol and ACTH levels: Low cortisol with elevated ACTH indicates primary adrenal insufficiency 1
• Electrolytes: Look for hyponatremia (present in 84% of cases) and hyperkalemia (present in only one-third of cases) 2
• ACTH stimulation test: Gold standard diagnostic test
  • Administration of 0.25 mg cosyntropin (synthetic ACTH) IV or IM
  • Measure serum cortisol at 30 and/or 60 minutes
  • Normal response: cortisol should exceed 550 nmol/L (approximately 20 μg/dL) 1

Etiological Diagnosis

1. 21-hydroxylase antibodies (21OH-Ab): First test to establish autoimmune etiology (accounts for 85% of PAI cases) 1
2. Adrenal CT scan: To identify structural causes like tuberculosis (calcifications), hemorrhage, tumors, or metastases 1
3. Very long-chain fatty acids (VLCFA): In males to screen for adrenoleukodystrophy 1
4. Additional testing based on clinical suspicion:
   • Interferon-omega or IL-22 autoantibodies if APS-1 (Autoimmune Polyendocrine Syndrome type 1) is suspected 1
   • NR0B1 (DAX1) gene sequencing if associated with hypogonadotropic hypogonadism 1

Autoimmune Hypopituitarism Workup

Initial Evaluation

• Pituitary hormone panel:
  • Low ACTH with low cortisol (central adrenal insufficiency)
  • Low/normal TSH with low free T4 (central hypothyroidism)
  • Low LH/FSH with low testosterone (males) or estradiol (females) 1
  • Evaluate for diabetes insipidus (hypernatremia, polyuria) 1

Imaging and Additional Testing

• MRI brain with pituitary/sellar cuts: Essential for patients with multiple endocrine abnormalities, new severe headaches, or visual changes 1
• ACTH stimulation testing: For indeterminate results (morning cortisol between 3-15 μg/dL) 1

Distinguishing Primary from Secondary Adrenal Insufficiency

• Primary adrenal insufficiency: Low cortisol with high ACTH
• Secondary adrenal insufficiency: Low cortisol with low or inappropriately normal ACTH 1

Important Clinical Considerations

Critical Caution

• Do not delay treatment if adrenal crisis is suspected:
  • Immediate IV hydrocortisone (100 mg) and isotonic saline infusion
  • Blood samples for cortisol and ACTH should be secured before treatment if possible
  • Diagnosis can be established later 1

Monitoring High-Risk Individuals

• Patients with positive 21OH-Ab without overt disease should be monitored for development of adrenal insufficiency 1, 3
• Patients on immune checkpoint inhibitors require regular monitoring of adrenal function 1

Common Pitfalls to Avoid

1. Waiting for all classic symptoms: Only a minority of patients present with marked hyperkalemia 2
2. Missing subtle presentations: Unexplained hyponatremia and/or elevated TSH should prompt consideration of undiagnosed Addison's disease 2
3. Delaying diagnosis by expecting additional abnormalities in routine blood tests 2
4. Failing to distinguish between primary and secondary adrenal insufficiency: The relationship between ACTH and cortisol is crucial for proper diagnosis and management 1

By following this systematic approach to diagnosis, clinicians can identify both Addison's disease and autoimmune hypopituitarism early, preventing potentially life-threatening adrenal crises and initiating appropriate hormone replacement therapy.