Clinical Presentation and Initial Workup of Cushing's Syndrome in Primary Care
Recognizing Cushing's Syndrome: Key Clinical Features
Primary care physicians should specifically look for the highly discriminatory signs that distinguish Cushing's syndrome from simple obesity or metabolic syndrome: facial plethora, proximal myopathy (difficulty rising from a chair or climbing stairs), wide (>1 cm) reddish-purple striae, and easy bruising without significant trauma. 1
Additional features to assess during physical examination include: 2
- Central obesity with weight gain despite stable or decreased height (particularly important in children) 3
- Skin changes: thin skin, poor wound healing, acne 1
- Musculoskeletal findings: osteoporosis, vertebral compression fractures 1
- Metabolic abnormalities: new-onset or worsening diabetes, hypertension, hypokalemia 1
- Psychiatric symptoms: depression, anxiety, cognitive impairment 1
- Reproductive issues: menstrual irregularities, decreased libido, hirsutism 1
First-Line Screening Tests: The PCP's Diagnostic Algorithm
Once clinical suspicion is raised, rule out exogenous glucocorticoid use first (including inhaled, topical, and injected steroids), then perform 2-3 of the following first-line screening tests to confirm hypercortisolism. 3, 4
Recommended Initial Tests (Choose 2-3):
1. Late-Night Salivary Cortisol (LNSC) - Most practical for primary care 3
- Collect at least 2-3 samples on consecutive days between 11 PM and midnight 3
- Sensitivity: 95%, Specificity: 100% 3
- Easiest for patient compliance compared to 24-hour urine collection 3
- Patient can collect at home without clinic visit 1
2. 24-Hour Urinary Free Cortisol (UFC) - Highest combined accuracy 3, 5
- Collect at least 2-3 samples to account for day-to-day variability 3
- Sensitivity: 89-97%, Specificity: 91-100% 3, 5
- Measures overall cortisol production 3
- UFC measured by LC-MS/MS achieves the best diagnostic accuracy among all first-line tests 5
3. Overnight 1-mg Dexamethasone Suppression Test (DST) 3
- Give 1 mg dexamethasone at 11 PM, measure serum cortisol at 8 AM 3
- Normal response: cortisol <1.8 μg/dL (50 nmol/L) 3
- Caution: Less useful in women taking estrogen-containing oral contraceptives 3
- Consider measuring dexamethasone levels alongside cortisol to rule out malabsorption 3, 4
Interpretation Strategy:
If any test is abnormal, repeat 1-2 screening tests to confirm before referral. 3, 4 This reduces false positives from physiological stress or pseudo-Cushing's states.
If all tests are normal, Cushing's syndrome is unlikely. 3
For high clinical suspicion (multiple discriminatory signs), perform all three tests simultaneously. 3
For low clinical suspicion, start with LNSC alone due to ease of collection. 4
Critical Pitfalls: Pseudo-Cushing's States
The following conditions cause false-positive screening results and must be considered before pursuing further workup: 3, 4
- Severe obesity 3, 4
- Uncontrolled diabetes mellitus 3, 4
- Major depression 3, 4
- Chronic alcoholism 3, 4
- Pregnancy (increased corticosteroid-binding globulin) 6
- Medications: CYP3A4 inducers (phenytoin, rifampin), estrogens 6
When to Refer to Endocrinology
Refer patients with confirmed abnormal screening tests (2+ positive results) to endocrinology for: 4
Plasma ACTH measurement (morning, 8-9 AM) to differentiate ACTH-dependent from ACTH-independent causes 3, 7
Special Consideration: Cyclic Cushing's Syndrome
If screening results are inconsistent or clinical suspicion remains high despite normal tests, consider cyclic Cushing's syndrome. 3 This requires periodic re-evaluation with repeated screening tests during symptomatic periods. 3
Pediatric Considerations
In children, screen only if weight gain is combined with either decreased height standard deviation score or decreased height velocity - this distinguishes Cushing's from simple obesity. 3 Refer pediatric cases to specialized centers with pediatric endocrinology expertise. 4