What is the appropriate workup for adrenal insufficiency?

Workup of Adrenal Insufficiency

Initial Laboratory Testing

Begin with early morning (8 AM) serum cortisol and plasma ACTH measurements as your first-line diagnostic tests. 1, 2 These should be drawn between 7:30-8:00 AM when cortisol levels are naturally at their peak. 3

Interpreting Initial Results

Primary adrenal insufficiency:

• Morning cortisol <250 nmol/L (<9 μg/dL or <5 μg/dL) with elevated ACTH is diagnostic in the setting of acute illness 1, 2
• Often accompanied by hyponatremia (present in 90% of cases) and hyperkalemia (though hyperkalemia occurs in only ~50% of cases) 1, 4
• Low DHEAS levels support the diagnosis 2

Secondary adrenal insufficiency:

• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH 1, 2, 5
• Low or low-normal DHEAS levels 2
• May have additional pituitary hormone deficiencies 1

Obtain a basic metabolic panel (sodium, potassium, CO2, glucose) simultaneously to assess for characteristic electrolyte abnormalities. 1

Confirmatory Testing: Cosyntropin Stimulation Test

When morning cortisol is intermediate (140-400 nmol/L or 5-14 μg/dL) or clinical suspicion remains high despite initial results, perform the cosyntropin (Synacthen) stimulation test. 4, 1, 2

Test Protocol

• Administer 0.25 mg cosyntropin (tetracosactide) intramuscularly or intravenously 4, 1
• Obtain baseline serum cortisol and ACTH before administration 4
• Measure serum cortisol at 30 and/or 60 minutes post-administration 4, 1
• A peak cortisol value >550 nmol/L (>18-20 μg/dL) is normal; <500-550 nmol/L is diagnostic of adrenal insufficiency 4, 1, 2

Important Caveats

The cosyntropin test can give false-normal results in secondary adrenal insufficiency, particularly in early or partial cases. 6 If secondary adrenal insufficiency is strongly suspected despite a normal cosyntropin test, consider insulin tolerance testing (the gold standard for secondary AI) or metyrapone testing. 7, 6

Etiologic Workup for Primary Adrenal Insufficiency

Once primary adrenal insufficiency is confirmed biochemically, determine the underlying cause using the following algorithm: 4

1. Measure 21-hydroxylase (anti-adrenal) autoantibodies first - autoimmunity accounts for ~85% of primary AI cases in Western populations 4, 1

2. If autoantibodies are positive: Diagnosis is autoimmune Addison's disease 4

3. If autoantibodies are negative: Obtain CT imaging of the adrenals to evaluate for:

   • Hemorrhage
   • Tumors
   • Tuberculosis or fungal infections
   • Other structural abnormalities 4, 1

4. In male patients with negative antibodies: Assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 4

5. In children and young adults with PAI plus hypoparathyroidism and/or candidiasis: Consider autoimmune polyglandular syndrome type 1 (APS-1), confirmed by anti-interferon omega antibodies or AIRE gene mutation analysis 4

Etiologic Workup for Secondary Adrenal Insufficiency

Evaluate for pituitary or hypothalamic pathology: 4, 1

• Measure additional pituitary hormones: TSH, free T4, LH, FSH, testosterone (males) or estradiol (premenopausal females) 4
• Obtain MRI of the brain with pituitary/sellar cuts if multiple endocrine abnormalities are present or if patient has new severe headaches or vision changes 4
• Review medication history for glucocorticoids, opioids, or immune checkpoint inhibitors 2, 5

Critical Pitfalls to Avoid

Never delay treatment in suspected adrenal crisis to perform diagnostic testing. 1, 7 If adrenal crisis is suspected clinically (hypotension, shock, altered mental status), immediately:

• Administer IV hydrocortisone 100 mg bolus 4, 1
• Infuse 0.9% saline at 1 L/hour 4, 1
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 4, 7

Do not rely on the absence of hyperkalemia to rule out primary adrenal insufficiency - it is present in only 50% of cases. 1

Cannot interpret AM cortisol in patients currently taking exogenous corticosteroids (prednisolone, dexamethasone, inhaled fluticasone) - these interfere with cortisol assays. 4, 3 Hold hydrocortisone for 24 hours and other steroids for longer periods before assessing endogenous adrenal function. 3

When treating patients with both adrenal insufficiency and hypothyroidism, always start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 4, 1

Special Consideration: Hyponatremia

In patients presenting with hypo-osmolar hyponatremia, adrenal insufficiency must be excluded before diagnosing SIADH, as both conditions present identically with euvolemic hypo-osmolar hyponatremia and inappropriately elevated urine osmolality. 1 The cosyntropin stimulation test is medically necessary in this clinical scenario to differentiate the two conditions. 1