What is the appropriate procedure for ordering an adrenocorticotropic hormone (ACTH) and cortisol test for a 53-year-old patient with new onset wheezing and suspected adrenal dysfunction due to potential underlying conditions such as lung cancer?

How to Order ACTH and Cortisol Testing

Before ordering any biochemical tests, first exclude iatrogenic Cushing syndrome by confirming the patient is not taking exogenous glucocorticoids, as failure to do so leads to unnecessary testing without patient benefit. 1

Step 1: Medication Review and Preparation

Stop the following medications before testing:

• Glucocorticoids and spironolactone: Discontinue on the day of testing, as these falsely elevate cortisol levels 2
• Long-acting glucocorticoids: May require longer discontinuation period before testing 2
• Estrogen-containing drugs: Stop 4-6 weeks before testing, as they increase cortisol-binding globulin (CBG) levels and falsely elevate plasma total cortisol 2

Alternative approach if estrogens cannot be stopped: Measure CBG levels concomitantly; if CBG is elevated, plasma total cortisol levels are inaccurate 2

Step 2: Initial Screening Tests for Cushing Syndrome

The Endocrine Society recommends one of the following three initial tests (perform more than one measurement of each): 1

• 24-hour urinary free cortisol test (more than one measurement)
• Late-night salivary cortisol test (more than one measurement)
• Dexamethasone suppression test: Either 1 mg overnight OR 2 mg/day for 2 days

These tests screen for hypercortisolism, not adrenal insufficiency. If you suspect adrenal insufficiency instead, proceed to Step 3.

Step 3: Testing for Adrenal Insufficiency (ACTH Stimulation Test)

For suspected adrenal insufficiency, order the cosyntropin (ACTH) stimulation test as follows: 2, 3, 4

Dosing:

• Adults: 0.25 mg cosyntropin IV or IM 2
• Pediatric patients (birth to <2 years): 0.125 mg (0.5 mL of reconstituted solution) 2
• Pediatric patients (2-17 years): 0.25 mg (1 mL of reconstituted solution) 2

Timing of Blood Draws:

1. Baseline: Obtain serum cortisol before cosyntropin administration 2
2. 30 minutes post-injection: Obtain serum cortisol exactly 30 minutes after cosyntropin 2
3. 60 minutes post-injection: Obtain serum cortisol exactly 60 minutes after cosyntropin 2

Interpretation:

• Stimulated plasma cortisol <18 mcg/dL at 30 or 60 minutes is suggestive of adrenocortical insufficiency 2
• Baseline cortisol <100 nmol/L (<3.6 mcg/dL) alongside raised ACTH can diagnose primary adrenal insufficiency without further testing 3

Step 4: Simultaneous ACTH Measurement

When ordering baseline cortisol, simultaneously order plasma ACTH to differentiate primary from secondary adrenal insufficiency: 3, 4

• Primary adrenal insufficiency: Low cortisol + elevated ACTH 3
• Secondary adrenal insufficiency: Low cortisol + low or inappropriately normal ACTH 3
• Ectopic ACTH syndrome (paraneoplastic Cushing): Elevated cortisol + elevated ACTH 5, 6, 7

Step 5: Additional Laboratory Tests in Suspected Ectopic ACTH Syndrome

In patients with suspected lung cancer and Cushing features, order the following alongside cortisol and ACTH: 5, 7

• Serum potassium: Hypokalemia is characteristic of ectopic ACTH 1, 5
• Serum bicarbonate: Metabolic alkalosis commonly present 1, 5
• Serum glucose: Hyperglycemia frequently occurs 5
• Serum sodium: Check for concurrent SIADH, which must be excluded before diagnosing adrenal insufficiency 5

Critical Timing Considerations

For patients with suspected ectopic ACTH syndrome from small cell lung cancer (SCLC):

• Diagnose hypercortisolism during initial evaluation before starting chemotherapy, as untreated hypercortisolism increases mortality from opportunistic infections and venous thromboembolism 1
• 30-50% of SCLC patients have biochemical evidence of ectopic ACTH production, though most are asymptomatic 5
• After initiating cancer treatment, patients may develop acute adrenal insufficiency due to rapid tumor response, requiring close monitoring 6

Special Circumstances

If you cannot perform the ACTH stimulation test immediately and need to treat empirically:

• Use dexamethasone instead of hydrocortisone for empiric treatment, as dexamethasone does not interfere with subsequent cortisol testing 8
• Hydrocortisone will falsely elevate cortisol levels and invalidate testing 8

Conditions affecting cortisol-binding globulin that require special consideration: 2, 4

• Low CBG: Cirrhosis, nephrotic syndrome (falsely lowers total cortisol)
• High CBG: Pregnancy, estrogen therapy (falsely elevates total cortisol)
• Consider salivary cortisol testing in these conditions as an alternative 4

Common Pitfalls to Avoid

• Do not order testing while patient is on glucocorticoids or spironolactone 2
• Do not fail to measure ACTH simultaneously with cortisol, as this is essential for determining the etiology 3, 4
• Do not use hydrocortisone for empiric treatment if you plan to perform diagnostic testing, as it interferes with cortisol assays 8
• Do not delay diagnosis in suspected ectopic ACTH syndrome from lung cancer, as early recognition before chemotherapy reduces treatment-related mortality 1