What is the appropriate workup and management for a patient presenting with symptoms suggestive of either Cushing's syndrome or adrenal insufficiency?

Workup and Management of Cushing's Syndrome versus Adrenal Insufficiency

Begin by determining whether the patient has cortisol excess (Cushing's syndrome) or cortisol deficiency (adrenal insufficiency) through focused history, physical examination, and first-line biochemical testing—these are opposite ends of the cortisol spectrum requiring fundamentally different diagnostic pathways.

Initial Clinical Assessment

Key Historical Features to Distinguish the Two Conditions

For Cushing's Syndrome:

• Progressive weight gain with continued growth arrest in children 1
• New-onset or worsening hypertension, diabetes, or osteoporosis 1
• Exogenous corticosteroid use (most common cause) 1

For Adrenal Insufficiency:

• Unexplained weight loss, anorexia, and profound fatigue (50-95% of cases) 2
• Nausea, vomiting (20-62%), particularly morning symptoms 3, 2
• History of chronic corticosteroid use ≥20 mg/day prednisone for ≥3 weeks 3
• Unexplained collapse, hypotension, or gastrointestinal symptoms 3

Physical Examination Findings

Cushing's Syndrome:

• Abnormal fat distribution in supraclavicular and temporal fossae 4
• Wide purple striae (>1 cm) 4
• Proximal muscle weakness 4

Adrenal Insufficiency:

• Postural hypotension (hallmark feature) 2
• Hyperpigmentation, salt craving (suggests primary adrenal insufficiency) 3, 2
• Normal skin color (suggests secondary adrenal insufficiency due to low ACTH) 3

Diagnostic Algorithm

Step 1: Exclude Exogenous Corticosteroid Use

• Document all corticosteroid exposure including oral, inhaled (fluticasone), topical, and injectable forms 3, 1
• Exogenous steroids are the most common cause of Cushing's syndrome and can cause iatrogenic secondary adrenal insufficiency 3, 1

Step 2: First-Line Screening Tests

If Cushing's Syndrome is Suspected:

Perform any two of the following three first-line tests 1:

• 1-mg overnight dexamethasone suppression test (excellent screening with only 1.9% false-negative rate) 5
• 24-hour urinary free cortisol excretion 1, 5
• Late-night salivary cortisol measurement 1

If Adrenal Insufficiency is Suspected:

• Morning (8 AM) serum cortisol AND plasma ACTH measured simultaneously 3

  • Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH = primary adrenal insufficiency 3
  • Cortisol <400 nmol/L with elevated ACTH = strong suspicion of primary adrenal insufficiency 3
  • Low cortisol with low/inappropriately normal ACTH = secondary adrenal insufficiency 3
  • Cortisol 140-275 nmol/L (5-10 μg/dL) with low ACTH = secondary adrenal insufficiency 3

• Basic metabolic panel to assess for hyponatremia (present in 90% of cases) and hyperkalemia (only 50% of cases) 3, 2

Step 3: Confirmatory Testing

For Cushing's Syndrome:

Once screening is positive:

• Measure plasma ACTH to differentiate ACTH-dependent (80-85%) from ACTH-independent (15-20%) causes 1
• 8-mg high-dose dexamethasone suppression test combined with ACTH levels for differential diagnosis 5
• Bilateral inferior petrosal sinus sampling with ACTH-releasing hormone to distinguish pituitary from ectopic ACTH secretion 4

For Adrenal Insufficiency:

• Cosyntropin (ACTH) stimulation test is the gold standard when initial results are indeterminate 3
  • Administer 0.25 mg (250 mcg) cosyntropin IV or IM 3
  • Measure serum cortisol at baseline, 30 minutes, and 60 minutes 3
  • Peak cortisol <500 nmol/L (<18 μg/dL) = diagnostic of adrenal insufficiency 3
  • Peak cortisol >550 nmol/L (>18-20 μg/dL) = normal, excludes adrenal insufficiency 3

Step 4: Etiologic Workup

For Primary Adrenal Insufficiency:

• Measure 21-hydroxylase autoantibodies (autoimmunity accounts for ~85% of cases in Western populations) 3
• If autoantibodies negative, obtain adrenal CT imaging to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 3
• In males with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 3

For Cushing's Syndrome:

• Imaging with pituitary MRI for ACTH-dependent disease 4
• Adrenal CT for ACTH-independent disease 4

Critical Management Principles

Emergency Treatment of Adrenal Crisis

Never delay treatment for diagnostic procedures if adrenal crisis is suspected 3, 2:

• Immediate IV hydrocortisone 100 mg bolus 3
• 0.9% saline infusion at 1 L/hour (at least 2L total) 3
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 3

Maintenance Treatment of Adrenal Insufficiency

Glucocorticoid Replacement:

• Hydrocortisone 15-25 mg daily in divided doses (e.g., 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM) 3
• Alternative: Prednisone 4-5 mg daily or cortisone acetate 25-37.5 mg daily 3

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only):

• Fludrocortisone 50-200 µg daily 3
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity 3

Patient Education (Mandatory):

• Double or triple dose during illness, fever, or physical stress 3
• Prescribe hydrocortisone 100 mg IM injection kit with self-injection training 3
• Medical alert bracelet indicating adrenal insufficiency 3
• Endocrine consultation for stress-dose planning before surgery 3

Treatment of Cushing's Syndrome

• Surgical resection of tumor is optimal treatment for all forms 4
• Ketoconazole is the medical treatment of choice for inoperable or recurrent cases 4
• Bilateral adrenalectomy or radiotherapy for refractory cases 4

Common Pitfalls and Caveats

Testing Pitfalls

• Do not attempt cortisol testing in patients actively taking corticosteroids—the assay measures both endogenous and exogenous steroids, yielding uninterpretable results 3
• Absence of hyperkalemia does not rule out adrenal insufficiency—it occurs in only ~50% of cases 3, 2
• Hyponatremia can mimic SIADH—always perform cosyntropin stimulation test to rule out adrenal insufficiency in hypo-osmolar hyponatremia before diagnosing SIADH 3
• Exogenous steroids including inhaled fluticasone can affect test results 3

Treatment Pitfalls

• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis 3
• In patients on chronic steroids, wait for adequate washout time (hydrocortisone 24 hours, prednisone longer) before performing definitive HPA axis testing 3
• If diagnostic uncertainty exists with ongoing steroid use, opt for empiric glucocorticoid replacement and test for ongoing need at 3 months rather than attempting testing while on steroids 3

Special Considerations

• Dexamethasone 4 mg IV can be used instead of hydrocortisone if you need to treat suspected adrenal crisis but still want to perform diagnostic testing later, as dexamethasone does not interfere with cortisol assays 3, 6
• Multidisciplinary review by endocrinologists, surgeons, and radiologists should occur when imaging is not consistent with a benign lesion or hormone hypersecretion is evident 7