What lab tests are recommended for a patient suspected of having adrenal failure, considering their medical history and potential electrolyte imbalances?

Laboratory Testing for Suspected Adrenal Failure

The initial diagnostic workup for suspected adrenal insufficiency requires paired measurement of early morning (8 AM) serum cortisol and plasma ACTH, followed by a cosyntropin stimulation test if baseline results are indeterminate. 1, 2, 3

Initial Diagnostic Laboratory Panel

First-Line Tests (Morning, 8 AM)

• Serum cortisol: A level <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 2. Levels between 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH suggest secondary adrenal insufficiency 2, 3
• Plasma ACTH: Elevated ACTH with low cortisol indicates primary adrenal insufficiency, while low or inappropriately normal ACTH with low cortisol indicates secondary adrenal insufficiency 1, 2, 3
• Dehydroepiandrosterone sulfate (DHEAS): Low levels support the diagnosis of adrenal insufficiency 1, 3

Basic Metabolic Panel

• Sodium: Hyponatremia is present in 90% of newly diagnosed cases, though levels may be only marginally reduced 1, 2
• Potassium: Hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases—its absence does NOT rule out the diagnosis 1, 2
• Glucose: Check for hypoglycemia, particularly in children 1
• Calcium: Between 10-20% of patients have mild or moderate hypercalcemia at presentation 1

Critical pitfall: Do not rely on electrolyte abnormalities alone to make or exclude the diagnosis—the classic combination of hyponatremia and hyperkalemia is unreliable because sodium is often only marginally reduced and potassium is elevated in only half of cases 1. Additionally, severe vomiting can cause hypokalaemia and alkalosis instead 1.

Confirmatory Testing When Initial Results Are Indeterminate

Cosyntropin (Synacthen) Stimulation Test

This is the gold standard confirmatory test when baseline cortisol levels are neither clearly normal nor clearly diagnostic 2, 4, 5.

Test Protocol

• Administer 0.25 mg cosyntropin (tetracosactide) intramuscularly or intravenously 1, 2
• Measure serum cortisol at baseline and at 30 and/or 60 minutes post-administration 1, 2
• The test can be performed at any time of day, though morning is preferred 1

Interpretation

• Peak cortisol >550 nmol/L (>18-20 μg/dL): Normal response, rules out adrenal insufficiency 2, 4, 3
• Peak cortisol <500 nmol/L (<18 μg/dL): Diagnostic of adrenal insufficiency 1, 2, 4

Important consideration: The high-dose (250 mcg) test is recommended over the low-dose (1 mcg) test due to easier practical administration, comparable diagnostic accuracy, and FDA approval 2.

Etiologic Workup After Confirming Adrenal Insufficiency

For Primary Adrenal Insufficiency

1. 21-hydroxylase (anti-adrenal) autoantibodies: First-line test to identify autoimmune etiology, which accounts for ~85% of cases in Western populations 2, 4
2. Adrenal CT imaging: If autoantibodies are negative, obtain CT to evaluate for hemorrhage, metastatic disease, tuberculosis, fungal infections, or other structural abnormalities 2, 4
3. Very long-chain fatty acids (VLCFA): In male patients with negative antibodies, check for adrenoleukodystrophy 2
4. Plasma renin activity (PRA) and aldosterone: Elevated PRA with low aldosterone confirms mineralocorticoid deficiency in primary adrenal insufficiency 1, 2

For Secondary Adrenal Insufficiency

• Evaluate for pituitary disease with MRI of the pituitary gland 6
• Assess other pituitary hormone deficiencies (TSH, LH, FSH, prolactin, IGF-1) 2
• Review medication history for opioids, exogenous steroids, or other HPA axis suppressants 2, 3

Critical Pitfalls and Special Considerations

Never Delay Treatment for Testing

Treatment of suspected acute adrenal crisis should NEVER be delayed for diagnostic procedures 1, 2, 4. If the patient is clinically unstable with hypotension, collapse, or severe symptoms, immediately administer:

• IV hydrocortisone 100 mg bolus 2
• 0.9% saline infusion at 1 L/hour (at least 2L total) 2
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay treatment 2

Confounding Factors That Invalidate Testing

• Exogenous steroids: Oral prednisolone, dexamethasone, and inhaled fluticasone suppress the HPA axis and confound cortisol interpretation 1, 2. Hydrocortisone must be held for 24 hours before testing; other steroids require longer washout periods 2
• Patients on chronic corticosteroids: Wait until the patient has been weaned off corticosteroids before performing definitive HPA axis testing, or test for HPA axis recovery after 3 months of maintenance therapy 2
• Exception for emergency treatment: If you need to treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 2

Additional Laboratory Findings to Note

• TSH: May be mildly elevated (4-10 IU/L) at presentation due to lack of cortisol's inhibitory effect on TSH production 1
• Anemia, eosinophilia, lymphocytosis: May be present 1
• Elevated liver transaminases: Can occur 1

Ongoing Monitoring for Patients on Replacement Therapy

Once diagnosed and treated, patients require regular laboratory monitoring 4:

• Serum electrolytes (sodium, potassium): Monitor regularly to assess mineralocorticoid replacement adequacy in primary adrenal insufficiency 4
• Morning cortisol levels: Measure periodically to assess if replacement dosing is appropriate, though interpretation is complex in patients on exogenous steroids 4
• Annual screening: For associated autoimmune conditions including thyroid function, diabetes, pernicious anemia, and celiac disease 2