How to investigate a young female with primary adrenal insufficiency?

Investigation Protocol for Young Female with Primary Adrenal Insufficiency

The investigation of a young female with primary adrenal insufficiency should begin with measurement of 21-hydroxylase autoantibodies (21OH-Ab) as the first diagnostic test to determine etiology, followed by additional targeted testing based on the results. 1

Initial Etiologic Investigation

• Measure 21OH-Ab as the first diagnostic test, preferably using a validated method such as the commercial kit from FIRS Laboratories (RSR, Cardiff, UK) 1
• If 21OH-Ab is positive, autoimmune adrenal insufficiency is confirmed (accounts for approximately 85% of PAI cases in Western Europe) 1
• Consider Autoimmune Polyendocrine Syndrome type 1 (APS-1) in young patients, especially if other components are present such as hypoparathyroidism, candidiasis, dental enamel dysplasia, keratitis, autoimmune hepatitis, malabsorption, or premature ovarian insufficiency 1

For 21OH-Ab Positive Patients

• If APS-1 is suspected, extend evaluation to include:
  • Measurement of interferon omega or IL-22 autoantibodies 1
  • Mutational analysis of AIRE gene if possible 1
• Screen for other autoimmune conditions commonly associated with PAI:
  • Thyroid function tests and thyroid autoantibodies (autoimmune thyroid disease is common) 1
  • Fasting glucose or HbA1c (for type 1 diabetes) 1
  • Vitamin B12 levels (for autoimmune gastritis) 1

For 21OH-Ab Negative Patients

A more thorough investigation must be undertaken for patients without 21OH-Ab, as this may represent a non-autoimmune form of Addison's disease: 1

• Perform CT scan of adrenal glands to identify:

  • Tumors or masses 1
  • Calcifications typical of tuberculosis 1
  • Evidence of adrenal hemorrhage 1
  • Bilateral adrenal metastasis or lymphoma 1

• Consider infectious causes:

  • Tuberculosis testing (Quantiferon test, PCR) 1
  • HIV testing 1
  • Fungal infection screening 1

• Evaluate for genetic causes (especially important in young patients):

  • Measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy (particularly important even though it's X-linked, as female carriers can develop symptoms) 1
  • Urine steroid profile and sequencing of steroidogenic genes (e.g., CYP21B) to evaluate for congenital adrenal hyperplasia 1
  • Consider sequencing of NR0B1 (DAX1) gene if there are signs of hypogonadotropic hypogonadism 1

• Screen for infiltrative disorders:

  • Evaluate for amyloidosis, hemochromatosis, or xanthogranulomatosis if clinically suspected 1

• Review medication history for adrenal-suppressing drugs:

  • Ketoconazole, etomidate, mitotane, metyrapone 1

Important Considerations

• Remember that previously 21OH-Ab-positive patients may become negative over time, so a negative result does not completely exclude autoimmunity 1
• 21OH-Ab are often absent in children and the elderly, even with autoimmune disease 1
• Consider rare causes such as Kearns-Sayre syndrome (a mitochondrial disorder) which can present with 21OH-Ab positivity 1
• Always tailor further investigations based on history and physical examination findings 1

Management Considerations

• Once etiology is determined, initiate lifelong steroid replacement with both glucocorticoids and mineralocorticoids 1
• Educate the patient about increasing steroid doses during illness or injury 1
• Provide training in intramuscular administration of hydrocortisone during acute adrenal crisis 1
• Recommend wearing a Medic Alert Bracelet and carrying a steroid card 1

Common Pitfalls to Avoid

• Never delay treatment with intravenous hydrocortisone and physiologic saline if acute adrenal crisis is suspected; diagnostic procedures can be completed later 1
• Don't rely solely on 21OH-Ab negativity to rule out autoimmune etiology, especially in young patients 1
• Avoid missing APS-1 in young patients by carefully evaluating for associated conditions 1
• Don't forget to screen for adrenoleukodystrophy in females, as carriers can develop symptoms 1

By following this systematic approach to investigating primary adrenal insufficiency in young females, clinicians can efficiently determine the underlying etiology and establish appropriate management to reduce morbidity and mortality.