Metanephrines, Fractionated, Quantitative, 24-Hour Urine

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CPT Code:


Test Type: 10 mL aliquot Urine (24-hour)
Stability Time:



Room temperature

14 days


14 days


14 days

Reference Range:

Normetanephrine, U, 24 Hr




0 to 8 y



9 to 12 y



13 to 20 y



21 to 30 y



>30 y



Metanephrine, U, 24 hr




0 to 8 y



9 to 12 y



13 to 17 y



>17 y




Evaluation of catecholamine-secreting tumors of the adrenal medulla (pheochromocytomas) and extra-adrenal sympathetic and parasympathetic paragangliomas.

The low prevalence of PPGL combined with the limited diagnostic specificity of the metanephrine test means that false-positive results far outnumber true-positive results.15,27 As outlined in the Endocrine Society Guidelines,15 all patients with positive test results should receive appropriate follow-up according to the extent of increased values and clinical presentation of the patient. The nature of this follow-up is a matter of clinical judgment based on the pretest probability of tumor and the extent and pattern of increases in test results.15

A number of medications and foods should be considered as potential causes of borderline elevations of plasma metanephrine and/or normetanephrine.2,5,27,28,32,33 These include:

- selective serotonin and norepinephrine reuptake inhibitors (SSNRIs)

- tricyclic antidepressants

- alpha blockers

- beta blockers

- monoamine oxidase inhibitors

- caffeine

- cigarette smoking

- strenuous exercise

Confirmatory testing after exclusion of these and other sources of false-positive results is often useful for ruling out disease.15

This test was developed and its performance characteristics determined by LabCorp. It has not been cleared or approved by the Food and Drug Administration.

Metanephrine and normetanephrine (together referred to as metanephrines) are the 3-methoxy metabolites of the catecholamines, epinephrine and norepinephrine, respectively. The methylation of catecholamines is accomplished by catecholamine O-methyltransferase, a membrane-bound enzyme of chromaffin cells.1-8 Levels of these metabolites can be increased in both plasma and urine in patients with catecholamine-producing tumors such as pheochromocytomas, paragangliomas and neuroblastomas. Pheochromocytomas, intra-adrenal paraganglioma, and extra-adrenal sympathetic and parasympathetic paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest progenitor cells including adrenal chromaffin cells and similar cells in extra-adrenal sympathetic and parasympathetic paraganglia. Approximately 10% of pheochromocytomas and 35% of paragangliomas are malignant. About a third of these tumors are associated with three specific syndromes; von Hippel-Lindau syndrome, multiple endocrine neoplasia type 2 (MEN 2), and neurofibromatosis type 1. A number of germline mutations responsible for PPGLs have been identified.9,10 Neuroblastomas are derived from immature embryonic neuroblast cells that also form tumors at adrenal and extra-adrenal locations, but present almost exclusively in childhood.11

Patients with PPGLs can present with episodic hypertension related to excessive catecholamine synthesis and variety of other symptoms that can include tachycardia, headache, palpitations, profuse diaphoresis, and pallor.5,12 Less frequently, these tumors can manifest as nausea, vomiting, flushing, and weight loss. In young patients with normal body weight, hypertension with diabetes mellitus may suggest PPGL.13 Many patients present with an unidentified mass lesion and no specific clinical symptoms associated with PPGL. Given the relative non-specificity of symptoms and the low prevalence of the condition (less than 1 per 100,000 individuals in the general population),14 it is not unusual for the diagnosis of PPGL to be delayed. The critical first step for diagnosis is to recognize the possibility of the tumor.15-17 The consequences of delayed detection can be severe as excessive catecholamine secretion can precipitate life-threatening hypertension, intracerebral hemorrhage, and cardiac arrhythmias.18,19 When detected early, these tumors are potentially curable.20

Diagnosis of pheochromocytoma and paraganglioma relies on biochemical evidence of catecholamine production by the tumor. Guidelines suggest that measurement of plasma free metanephrines or urinary fractionated metanephrines should be performed in symptomatic patients,15,22 patients with an adrenal incidentaloma,21 and in individuals who have a hereditary risk for developing a pheochromocytoma or paraganglioma.10 Metanephrines are produced continuously by the normal adrenal and by tumors via a process that is independent of catecholamine release, which for some tumors occurs at low rates or is episodic in nature.6-8,15 While non-chromaffin cells of the sympathetic nervous system are the major sites of norepinephrine metabolism, they do not convert catecholamines to metanephrines because they lack the catecholamine O-methyltransferase enzyme. Consequently, levels of free metanephrines reflect functional chromaffin cell quantity and become elevated in patients with catecholamine producing chromaffin tumors.1,6 Since many PPGLs produce and metabolize catecholamines but do not secrete the amines continuously or in amounts sufficient to produce a diagnostic signal, the metanephrines are superior to the parent catecholamines as diagnostic biomarkers.23,24 The high diagnostic accuracy of measurements of urine fractionated metanephrines and plasma free metanephrines has been confirmed by a large number of studies.6-8,15,25-26,34

Normetanephrine or metanephrine elevated 3-fold or more above upper cutoffs are rarely false positives and should be followed up in most cases by imaging to locate the tumor.15,24,28 In cases of borderline elevation (less than 3-fold the upper limit of the reference interval), repeat testing and/or second-line tests such clonidine suppression test with measurements of plasma normetanephrine can be performed prior to proceeding to imaging studies.15,29 Chromogranin A levels are elevated in most patients with PPGLs and have been associated with risk of malignancy.34-35 However, the test is not specific and is seen in other disorders such as carcinoid.

1. Eisenhofer G, Peitzsch M, McWhinney BC. Impact of LC-MS/MS on the laboratory diagnosis of catecholamine-producing tumors. Trends in Analytical Chemistry. 2016 Nov;84:106-116.

2. Eisenhofer G, Peitzsch M. Laboratory evaluation of pheochromocytoma and paraganglioma. Clin Chem. 2014 Dec;60(12):1486-1499. PubMed 25332315

3. Kolackov K, Tupikowski K, Bednarek-Tupikowska G. Genetic aspects of pheochromocytoma. Adv Clin Exp Med. Nov-Dec 2012;2(6)1:821-829. PubMed 23457139

4. Martucci VL, Pacak K. Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment. Curr Probl Cancer. 2014 Jan-Feb;38(1):7-41. PubMed 24636754

5. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005 Aug 20-26;366(9486):665-675. PubMed 16112304

6. Eisenhofer G, Keiser H, Friberg P, et al. Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. J Clin Endocrinol Metab. 1998 Jun;83(6):2175-2185. PubMed 9626157

7. Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev. 2004 Sep;56(3):331-349. PubMed 15317907

8. Eisenhofer G, Huynh TT, Hiroi M, Pacak K. Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma. Rev Endocr Metab Disord. 2001 Aug;2(3):297-311. PubMed 11708294

9. Därr R, Lenders JW, Hofbauer LC, N

Collection Details:

Patient Preparation:

No caffeine before or during collection. Monamine oxidase inhibitors should be discontinued at least one week prior to beginning collection.

Collection Instructions:

Record total 24-hour urine volume on the request form.

Plastic urine container with no preservative or 6N HCl.

Instruct the patient to void at 8 AM and discard the specimen. Then collect all urine including the final specimen voided at the end of the 24-hour collection period (ie, 8 AM the next morning). Screw the lid on securely. Label container with patient's name, date and time collection started, and date and time collection finished. Measure and record total 24-hour volume. Mix well; send aliquot. (HCl is an acceptable preservative if required for a concurrently collected assay. PeopleSoft item number for this container is No. 21584.)

Room temperature.