How do I diagnose and manage a patient with suspected cortisol imbalance?

Diagnostic Approach to Suspected Cortisol Imbalance

Start with early morning (8 AM) serum cortisol and plasma ACTH measurements to determine whether the patient has excess cortisol (Cushing's syndrome), deficient cortisol (adrenal insufficiency), or neither. 1

Initial Clinical Assessment

Look specifically for these features to guide your testing strategy:

For suspected hypercortisolism (Cushing's syndrome):

• Central obesity with thin extremities, facial plethora, wide purple striae (>1 cm), proximal muscle weakness, easy bruising, and hypertension 2
• Diabetes, osteoporosis, or psychiatric symptoms in younger patients without other clear causes 2

For suspected adrenal insufficiency:

• Unexplained hypotension, collapse, nausea/vomiting, weight loss, or lethargy 1
• Hyponatremia (present in 90% of new diagnoses), though hyperkalemia occurs in only ~50% of cases 1
• History of chronic steroid use (≥20 mg/day prednisone equivalent for ≥3 weeks) 1

Step 1: Morning Cortisol and ACTH

Obtain paired measurements at 8 AM:

Interpretation for adrenal insufficiency:

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH = primary adrenal insufficiency 1
• Cortisol <400 nmol/L (<14.5 μg/dL) with low/normal ACTH = secondary adrenal insufficiency 1
• Cortisol >500 nmol/L (>18 μg/dL) effectively rules out adrenal insufficiency 1

Critical pitfall: If the patient is clinically unstable with suspected adrenal crisis, never delay treatment for diagnostic testing—give IV hydrocortisone 100 mg immediately plus 0.9% saline at 1 L/hour 1

Step 2: Screening Tests for Cushing's Syndrome

If hypercortisolism is suspected based on clinical features, proceed with any or all of these first-line tests (no single test is preferred): 2

Option A: Dexamethasone Suppression Test (DST)

• Give 1 mg dexamethasone orally at midnight 2
• Measure serum cortisol at 8 AM 2
• Normal: cortisol suppresses to <50 nmol/L (<1.8 μg/dL) 3
• Preferred for shift workers or those with disrupted sleep schedules 2
• Not reliable in women on oral estrogen 2
• Consider measuring dexamethasone level if false-positive suspected 2

Option B: 24-Hour Urine Free Cortisol (UFC)

• Collect 2-3 separate 24-hour collections to assess variability 2
• Elevated UFC indicates hypercortisolism 2
• More specific than DST in patients with depression or stress (pseudo-Cushing's) 3

Option C: Late-Night Salivary Cortisol (LNSC)

• Collect 2-3 samples at 11 PM (nadir time) 2
• May be easier for patients to complete than UFC 2
• Sensitivity 92% for Cushing's syndrome 4
• If adrenal tumor suspected, only use if cortisone levels can also be reported 2

Important caveat: In mild or episodic Cushing's syndrome, 92% of patients have at least one normal test result 5. Therefore, if clinical suspicion remains high despite initial normal results, repeat testing on multiple occasions, especially when the patient is symptomatic 5

Step 3: Confirmatory Testing Based on Initial Results

If Adrenal Insufficiency Suspected but Morning Cortisol Indeterminate (140-400 nmol/L):

Perform ACTH stimulation test (cosyntropin test): 1

• Administer 0.25 mg (250 mcg) cosyntropin IM or IV 1
• Measure serum cortisol at baseline and 30 minutes post-administration 1
• Peak cortisol >550 nmol/L (>18-20 μg/dL) = normal adrenal function 1
• Peak cortisol <500 nmol/L (<18 μg/dL) = diagnostic of adrenal insufficiency 1

Critical consideration: If you need to treat suspected adrenal crisis but still want diagnostic testing capability, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone doesn't interfere with cortisol assays 1

If Cushing's Syndrome Confirmed, Determine Etiology:

Measure plasma ACTH: 3

• High ACTH = pituitary (70%) or ectopic ACTH (10%) 3
• Low/suppressed ACTH = adrenal source (20%) 3

Obtain pituitary MRI if ACTH-dependent Cushing's suspected, though ~33% of scans remain negative even with confirmed disease 2

Step 4: Ruling Out Pseudo-Cushing's

If tests suggest mild hypercortisolism but clinical picture is atypical:

• Consider underlying depression, alcoholism, or severe obesity as causes of false-positive results 2
• Monitor for 3-6 months with repeat testing to see if symptoms resolve 2
• Treatment of underlying condition (e.g., depression) can restore normal cortisol levels 2
• Dex-CRH test or desmopressin test can help distinguish, but should be done at expert centers 2

Step 5: Etiologic Workup for Confirmed Adrenal Insufficiency

For primary adrenal insufficiency (high ACTH, low cortisol):

• Measure 21-hydroxylase autoantibodies (positive in ~85% of autoimmune cases) 1
• If antibodies negative, obtain adrenal CT to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1
• In males with negative antibodies, measure very long-chain fatty acids to screen for adrenoleukodystrophy 2

For secondary adrenal insufficiency (low ACTH, low cortisol):

• Evaluate other pituitary hormones (TSH, free T4, LH, FSH, testosterone/estradiol) 2
• Consider pituitary MRI with sellar cuts if multiple hormone deficiencies present 2

Critical Management Points

All patients diagnosed with adrenal insufficiency require: 2, 1

• Lifelong glucocorticoid replacement (hydrocortisone 15-25 mg daily in divided doses, or equivalent) 2
• Mineralocorticoid replacement with fludrocortisone 50-200 mcg daily if primary adrenal insufficiency 1
• Medical alert bracelet 2, 1
• Education on stress-dose doubling during illness 2, 1
• Injectable hydrocortisone for emergency self-administration 2

When treating both adrenal insufficiency and hypothyroidism: Always start corticosteroids several days before thyroid hormone replacement to prevent precipitating adrenal crisis 2, 1

Common pitfall: Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and cause iatrogenic secondary adrenal insufficiency, confounding diagnostic testing 2, 1. Stop these medications at least 5 half-lives before testing if clinically safe 6