24-Hour Urine Metanephrines Testing Protocol
When to Order the Test
Screen for pheochromocytoma/paraganglioma using 24-hour urine fractionated metanephrines in patients with adrenal incidentalomas displaying >10 HU on non-contrast CT, or in those with signs/symptoms of catecholamine excess (headache, palpitations, sweating, paroxysmal hypertension). 1, 2
Specific Clinical Indications
- Early-onset hypertension (<30 years of age) 2
- Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) 2
- Paroxysmal hypertension with classic triad symptoms (headache, palpitations, sweating—which has 93.8% specificity and 90.9% sensitivity) 2
- Significant blood pressure variability or episodic symptoms despite treatment 2
- Family history of pheochromocytoma or hereditary syndromes 2
- Adrenal incidentaloma with >10 HU on unenhanced CT 1
When NOT to Screen
- Do not screen patients with unequivocal adrenocortical adenomas confirmed on unenhanced CT (HU <10) and no signs or symptoms of adrenergic excess 1
Test Characteristics
24-hour urine fractionated metanephrines have sensitivity of 86-97% and specificity of 86-95%, making them an acceptable alternative to plasma testing, particularly for low-risk patients or pediatric patients who are continent of urine. 2, 3
- Urinary free metanephrines demonstrated 100% sensitivity in one comparative study, superior to urinary catecholamines (84%), urinary VMA (72%), and plasma catecholamines (76%) 3
- The test measures normetanephrine, metanephrine, and 3-methoxytyramine 4
Pre-Test Preparation: Critical Medication and Food Interferences
Before testing, confirm that interfering agents were avoided, as several medications and foods can cause false positive results. 1, 2
Medications That Interfere with Results
- β-blockers: increase urinary normetanephrine 4
- Calcium channel blockers: increase urinary normetanephrine 4
- Loop diuretics: increase urinary normetanephrine 4
- α-blockers: increase both urinary normetanephrine AND metanephrine 4
- Non-metformin antidiabetic drugs: increase urinary normetanephrine but decrease metanephrine 4
- Neuroleptics: increase urinary normetanephrine 4
- Antidepressants (especially tricyclics): decrease urinary metanephrine and can cause false elevations in catecholamine metabolites 2, 4
- Glucocorticosteroids: decrease urinary metanephrine 4
Important Caveat About Alpha-Blockers
- Doxazosin and other alpha-1 selective blockers used in preoperative management of pheochromocytoma do NOT need to be discontinued for testing 2
Collection Pitfall to Avoid
- Verify the laboratory correctly inputs the 24-hour urine volume—incorrect volume entry (e.g., 9750 mL instead of 975 mL) can lead to false positive results and incorrect diagnosis. 5
Interpretation Algorithm
Step 1: Confirm Pre-Analytical Factors
- Verify interfering medications were avoided 1, 2
- Confirm correct urine volume was entered by laboratory 5
- Check that patient is continent of urine (otherwise use plasma testing) 1, 2
Step 2: Interpret Based on Degree of Elevation
≥4 times upper limit of normal:
- Results are consistent with pheochromocytoma/paraganglioma 1, 2
- Proceed immediately to imaging to localize the lesion 1, 2
- Do NOT perform fine needle biopsy—this is contraindicated due to risk of hypertensive crisis 2, 6
2-4 times upper limit of normal:
- Repeat testing in 2 months 1, 2
- Consider genetic testing for hereditary syndromes, especially in younger patients 1, 2
- Assess for hyperadrenergic symptoms (sustained or intermittent palpitations, tachycardia, diaphoresis, tremors, new-onset hypertension) 2
Marginally elevated (1-2 times upper limit):
- Repeat testing in 6 months 1, 2
- Consider clonidine suppression test to exclude false positivity (100% specificity, 96% sensitivity) 1, 2
- False positive elevations are usually <4 times upper limit of normal and may be related to obesity, obstructive sleep apnea, or medications 2
Step 3: Additional Biomarkers for Risk Stratification
- Measure plasma methoxytyramine when available—elevated levels indicate higher malignancy risk 2
- Consider serum chromogranin A as optional marker 1
Imaging After Positive Biochemical Confirmation
Only proceed to imaging after biochemical confirmation—never perform imaging or biopsy before excluding pheochromocytoma, as unrecognized tumors can cause life-threatening hypertensive crises. 2
- Whole-body MRI (skull base to pelvis) is preferred over CT due to risk of hypertensive crisis with IV contrast 1, 2
- For hereditary syndromes, begin whole-body MRI surveillance biennially starting at age 6-8 years 1
- If initial imaging is negative but biochemical evidence is positive, extend imaging to include chest and neck 2
- Consider functional imaging (FDG-PET or SSTR PET/CT) for high-risk features: tumor ≥5 cm, extra-adrenal location, SDHB mutation, or plasma methoxytyramine >3-fold above upper limit 1, 2
Post-Surgical Follow-Up Protocol
Measure plasma or urine metanephrines 2-8 weeks post-operatively to confirm complete resection. 1, 2
- Repeat imaging at 3-6 months post-operatively 1
- All patients require lifelong surveillance due to risk of recurrence, metastasis, or new tumors 1, 2
- Follow-up every 3-4 months for 2-3 years, then every 6 months 2
- Annual blood pressure measurements and biochemical testing at minimum 1
High-Risk Patients Requiring Intensive Surveillance
- SDHB mutations (higher risk of malignancy and metastasis) 1, 2
- Extra-adrenal tumors 2
- Tumors >5 cm 2
- PASS score ≥4 2
Pediatric Considerations
For pediatric patients with hereditary paraganglioma/pheochromocytoma syndromes, begin annual surveillance at age 6-8 years with 24-hour urine fractionated metanephrines once continent of urine. 1
- Use plasma metanephrines before continence is achieved 1
- Reference pediatric-specific intervals for interpretation 1
- For von Hippel-Lindau syndrome, begin surveillance at age 2 years 2