How do you diagnose adrenal insufficiency?

How to Rule Out Adrenal Insufficiency

A morning serum cortisol >500 nmol/L (>18 μg/dL) with a paired ACTH measurement effectively rules out adrenal insufficiency, while levels <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness are diagnostic of primary adrenal insufficiency. 1, 2

Initial Diagnostic Approach

First-Line Testing (Morning 8 AM)

• Obtain paired measurements of serum cortisol and plasma ACTH as the initial diagnostic test—this is the recommended first step per consensus guidelines 1, 2
• Add a basic metabolic panel (sodium, potassium, CO2, glucose) to assess for electrolyte abnormalities commonly seen in adrenal insufficiency 2
• Measure DHEAS levels to help distinguish primary from secondary adrenal insufficiency 3

Interpreting Morning Cortisol Results

For patients in acute illness or with high clinical suspicion:

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency—no further testing needed 1, 2
• Cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion of primary adrenal insufficiency 1, 2
• Cortisol >500 nmol/L (>18 μg/dL) effectively rules out adrenal insufficiency 1, 4

For stable outpatients:

• Cortisol >13 μg/dL (358 nmol/L) reliably rules out adrenal insufficiency 5
• Cortisol 5-10 μg/dL (140-275 nmol/L) with low or inappropriately normal ACTH suggests secondary adrenal insufficiency 6, 3

Critical pitfall: Approximately 10% of patients with primary adrenal insufficiency may present with normal cortisol concentrations but clearly elevated ACTH (>300 pg/mL)—this represents early Addison's disease and should not be dismissed 7

Cosyntropin Stimulation Test (When Needed)

Indications for Testing

Proceed to cosyntropin stimulation testing when:

• Morning cortisol is indeterminate (between 5-18 μg/dL or 140-500 nmol/L) 3, 5
• Clinical suspicion remains high despite borderline morning cortisol 6
• Evaluating for secondary adrenal insufficiency 8
• Ruling out adrenal insufficiency in hypo-osmolar hyponatremia (as it can mimic SIADH) 6

Test Protocol

Standard high-dose protocol (preferred):

• Administer 0.25 mg (250 μg) cosyntropin IV or IM 1, 4
• Obtain baseline cortisol, then measure at 30 and 60 minutes post-administration 4
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 4
• Peak cortisol >550 nmol/L (>18-20 μg/dL) rules out adrenal insufficiency 6, 2

Important technical considerations:

• Perform testing in the morning whenever possible—afternoon testing significantly increases false-positive rates (odds ratio 6.98) 9
• Use minimal IV tubing as ACTH can be lost through tubing, reducing the effective dose from 1 μg to 0.5-0.8 μg 9
• The high-dose test is preferred over low-dose (1 μg) testing due to easier administration, FDA approval, and comparable diagnostic accuracy 6

Medications That Interfere with Testing

Stop these medications before testing:

• Glucocorticoids and spironolactone on the day of testing—they falsely elevate cortisol levels 1, 4
• Estrogen-containing drugs 4-6 weeks before testing—they increase cortisol-binding globulin, artificially elevating total cortisol 1, 4
• Long-acting glucocorticoids may need longer washout periods 4

Exception: If you must treat suspected adrenal crisis but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone—it doesn't interfere with cortisol assays 6

Clinical Context Matters

High-Risk Scenarios Requiring Immediate Consideration

• Any patient on ≥20 mg/day prednisone (or equivalent) for ≥3 weeks with unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 6
• Vasopressor-resistant hypotension despite multiple agents 6
• Unexplained collapse, hypotension, vomiting, or diarrhea 1, 2

Key Clinical Features

• Hyponatremia is present in 90% of newly diagnosed cases, but don't rely on electrolytes alone 1, 6
• Hyperkalemia occurs in only ~50% of cases—its absence does not rule out adrenal insufficiency 1, 6
• Hyperpigmentation, hypoglycemia, and acidosis increase clinical suspicion 1, 2

Critical Safety Principle

Never delay treatment of suspected acute adrenal insufficiency for diagnostic testing—if the patient is clinically unstable with suspected adrenal crisis, immediately give:

• IV hydrocortisone 100 mg bolus 6, 2
• 0.9% saline infusion at 1 L/hour 6, 2
• Draw blood for cortisol and ACTH before treatment if possible, but don't delay therapy 2

The diagnosis can always be established after treatment has been initiated—mortality is high if adrenal crisis goes untreated 1, 6

Determining the Underlying Cause

Once adrenal insufficiency is confirmed:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first—autoimmunity accounts for ~85% of primary adrenal insufficiency in Western populations 6, 2
• If antibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1, 2
• In male patients with negative antibodies, measure very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 2