What are the diagnostic steps and treatment options for adrenal insufficiency?

Diagnosis of Adrenal Insufficiency

The gold standard for diagnosing adrenal insufficiency is the cosyntropin stimulation test, with a normal response defined as cortisol exceeding 550 nmol/L (>18-20 μg/dL) after administration of 0.25 mg cosyntropin. 1

Initial Diagnostic Steps

1. Morning serum cortisol and ACTH measurements:

   • Low cortisol (<140 nmol/L or <5 μg/dL) with elevated ACTH (>300 pg/mL) suggests primary adrenal insufficiency 1
   • Low cortisol with low/normal ACTH suggests secondary adrenal insufficiency 1, 2

2. Cosyntropin (Synacthen) stimulation test:

   • Administer 0.25 mg cosyntropin intravenously or intramuscularly
   • Measure serum cortisol at baseline, 30 and/or 60 minutes
   • Normal response: cortisol exceeding 550 nmol/L at any timepoint 3, 1
   • Note: If clinical suspicion of adrenal crisis exists, give hydrocortisone immediately before testing 3

3. Electrolyte and renin-aldosterone assessment:

   • Measure plasma renin activity and aldosterone levels
   • Primary adrenal insufficiency: elevated renin, low aldosterone 1
   • Check for hyponatremia and hyperkalemia (common in primary adrenal insufficiency) 1, 2

Determining Etiology

1. Primary Adrenal Insufficiency:

   • Test for 21-hydroxylase autoantibodies (21OH-Ab) - positive in ~85% of cases indicates autoimmune etiology 3, 1
   • Adrenal imaging (CT scan) to identify calcifications, hemorrhage, infiltrative disorders, or metastases 1
   • Consider additional testing based on clinical suspicion:
     • Very long-chain fatty acids (VLCFA) for adrenoleukodystrophy
     • Tuberculosis screening (Quantiferon test, PCR)
     • Genetic testing for rare causes 3, 1

2. Secondary Adrenal Insufficiency:

   • Pituitary imaging (MRI) to identify tumors, hemorrhage, or other abnormalities
   • Evaluate other pituitary hormones (TSH, LH, FSH, GH) 2

3. Glucocorticoid-induced Adrenal Insufficiency:

   • Review medication history for recent glucocorticoid use or tapering 4
   • Often underdiagnosed - ~50% of patients on oral glucocorticoids have adrenal insufficiency 4

Diagnostic Criteria Summary

Type	ACTH Level	Cortisol Level	Electrolytes	Hyperpigmentation
Primary	High	Low	↓Na, ↑K	Present
Secondary	Low	Low	Usually normal	Absent

Common Pitfalls and Caveats

1. Never delay treatment if adrenal crisis is suspected - give intravenous hydrocortisone immediately and start physiologic saline infusion before completing diagnostic workup 3

2. False negative results in secondary adrenal insufficiency with the standard cosyntropin test - consider insulin hypoglycemia test or metyrapone test if high clinical suspicion exists 5

3. Medications affecting test results:

   • Estrogens and anticonvulsants can affect cortisol measurements
   • CYP3A4 inducers may interfere with glucocorticoid absorption 1

4. Special populations:

   • In children under 2 years: hypoglycemia, dehydration, and convulsions are common presentations
   • Circadian rhythm of cortisol isn't established until after 4 months of age 5
   • In pregnancy or with oral contraceptives: use urinary free cortisol (UFC) rather than serum cortisol 1

5. Renal dysfunction: UFC is unreliable in patients with CrCl <60mL/min 1

By following this diagnostic algorithm and being aware of potential pitfalls, clinicians can accurately diagnose adrenal insufficiency and initiate appropriate treatment to reduce morbidity and mortality associated with this condition.