In a patient with multiple sclerosis who presents with new‑onset weight gain and moon‑face, what laboratory tests should be ordered to evaluate for glucocorticoid‑induced Cushing syndrome?

Laboratory Workup for Glucocorticoid-Induced Cushing Syndrome in MS Patients

Order at least two of the following three first-line screening tests: late-night salivary cortisol, 24-hour urinary free cortisol (UFC), and 1-mg overnight dexamethasone suppression test (DST). 1

Initial Screening Tests

Primary Screening Panel (Choose at Least Two)

• Late-night salivary cortisol is the most accurate single screening test with 95% sensitivity and 100% specificity 1
• 24-hour urinary free cortisol (UFC) with diagnostic threshold >193 nmol/24h (collect 2-3 samples to account for day-to-day variability) demonstrates 89% sensitivity and 100% specificity 1
• 1-mg overnight dexamethasone suppression test with morning serum cortisol >50 nmol/L (>1.8 µg/dL) indicating failed suppression has only 1.9% false-negative rate 1, 2

Critical First Step: Exclude Exogenous Glucocorticoids

• Obtain detailed medication history including all formulations: oral, topical, inhaled, ocular drops, and injected steroids, as any route can cause iatrogenic Cushing syndrome 3, 4
• Screen for factitious use if the patient has access to glucocorticoids, as hidden self-administration can mimic endogenous disease 3
• Check for drug interactions with CYP3A4 inducers (phenytoin, rifampin) or oral estrogens that alter cortisol metabolism and binding 1

Confirmatory Testing After Positive Screening

If Two Screening Tests Are Abnormal

• Morning plasma ACTH (08:00-09:00h) to distinguish ACTH-dependent (>5 ng/L or >1.1 pmol/L) from ACTH-independent (<5 ng/L) disease 1, 2
• Midnight serum cortisol to document loss of normal circadian rhythm, which supports autonomous hypercortisolism 1

Additional Metabolic Assessment

• Serum potassium and bicarbonate as hypokalemia with metabolic alkalosis is especially prominent in ectopic ACTH secretion 1
• Fasting glucose or HbA1c since hyperglycemia or impaired glucose tolerance occurs in the majority of Cushing syndrome cases 1
• Blood pressure measurement as hypertension is present in 70-90% of patients 1, 2

Key Clinical Discriminators to Document

• Central obesity pattern with fat redistribution to face ("moon face"), supraclavicular fossae, and dorsocervical region ("buffalo hump") distinguishes true Cushing syndrome from simple obesity 5, 1
• Wide violaceous striae ≥1 cm on abdomen, thighs, or arms are highly specific physical findings 5, 1
• Proximal muscle weakness affecting hip flexors and shoulder girdle (difficulty rising from chair) 1
• Thin, fragile skin with easy bruising after minor trauma 1

Common Pitfalls to Avoid

• Do not rely on a single screening test as false-positives are common in severe obesity, uncontrolled diabetes, major depression, and chronic alcoholism (pseudo-Cushing states) 1
• Measure serum dexamethasone levels if DST results are equivocal to rule out malabsorption or rapid metabolism 1
• Consider cyclic Cushing syndrome if initial tests are normal but clinical suspicion remains high; repeat testing during symptomatic periods 6
• Verify medication compliance for MS disease-modifying therapies that may interact with cortisol metabolism 1

Algorithmic Approach

1. First, exclude exogenous glucocorticoids from all sources (oral, topical, inhaled, ocular) 3, 4
2. Perform two different screening tests from the triad: late-night salivary cortisol, 24-hour UFC, or 1-mg DST 1, 6
3. If both abnormal, measure morning ACTH to determine ACTH-dependent vs. independent disease 1, 2
4. If discordant results, perform a third screening test or Dex-CRH test (cortisol rise >38 nmol/L at 15 minutes indicates true Cushing syndrome) 1
5. Add metabolic panel (potassium, glucose) and blood pressure to assess comorbidities 1, 2

The average diagnostic delay is 3 years from symptom onset, resulting in increased cardiovascular mortality, making timely laboratory evaluation critical 1.