Metanephrines, Fractionated, Plasma Free

CPT: 83835
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Synonyms

  • Metanephrine
  • Normetanephrine
  • Plasma Metanephrines
  • Quantitative Metanephrines

Test Includes

Metanephrine; normetanephrine


Special Instructions

For those centers where sampling blood in the fully recumbent, supine position is not possible, testing for 24-hour urine metanephrines (LabCorp test No. 004234) may be preferable.2,15,30


Expected Turnaround Time

3 - 6 days


Related Documents


Specimen Requirements


Specimen

Plasma


Volume

0.6 mL


Minimum Volume

0.4 mL


Container

Lavender-top (EDTA) tube


Collection

Draw blood in chilled lavender-top (EDTA) tube. Invert to mix with preservatives. Centrifuge and transfer the plasma to a labeled plastic transport tube. Refrigerate or freeze separated plasma immediately. Important: The patient should be in a fully recumbent position (lying down) for at least 20 minutes before and during sample collection.


Storage Instructions

Sample must be refrigerated due to limited stability at room temperature. Freeze if unable to maintain refrigerated.


Stability Requirements

Temperature

Period

Room temperature

Unstable

Refrigerated

14 days

Frozen

14 days

Freeze/thaw cycles

Stable x3


Patient Preparation

Patient should be fasting overnight (water and non-caffeinated soft drinks are permissible). Patient should avoid alcohol, coffee, tea, tobacco and strenuous exercise prior to collection. See Limitations section for more information about other potential causes of elevated metanephrines.


Test Details


Use

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


Limitations

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.15,32 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

Inappropriate sampling conditions,15 as well as a number of medications and foods, should be considered as potential causes of borderline elevations of plasma metanephrine and/or normetanephrine.2,5,33,37-38 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.2


Methodology

Liquid chromatography/tandem mass spectrometry (LC/MS-MS)


Reference Interval

Metanephrine, Pl

Age

Male

Female

All ages

0.0–88.0

0.0–88.0

Normetanephrine, Pl

Age

Male

Female

0 to 4 y

Not established

Not established

5 to 11 y

0.0–165.9

0.0–148.0

12 to 19 y

0.0–150.8

0.0–150.8

20 to 40 y

0.0–210.1

0.0–210.1

41 to 50 y

0.0–218.9

0.0–218.9

51 to 60 y

0.0–244.0

0–244.0

61 to 80 y

0.0–285.2

0.0–285.2

>80 y

0.0–297.2

0.0–297.2

Adult reference intervals applied to free metanephrines were originally developed by Eisenhofer and coworkers27 and further validated in subsequent studies.25,26 Recognizing the potential deadly consequences of a missed diagnosis, cutoffs of reference were established to ensure optimum diagnostic sensitivity, with specificity a secondary consideration. Subjects fasted and abstained from caffeinated and decaffeinated beverages overnight. Plasma samples collected after at least 20 minutes of supine rest. For plasma metabolites, optimal performance was obtained using age-specific reference intervals for normetanephrine,25,27 and for metanephrine single cut-offs for males and females that were slightly above 99.5 percentiles contributed to optimized performance.25-26


Additional Information

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 para-sympathetic paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest progenitor cells, including adrenal chromaffin cells and similar cells in extra-adrenal sympathetic and para-sympathetic 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 unusualfor 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 eposodic 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, plasma 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.6-8,15,25-28

To ensure optimal diagnostic accuracy, samples for plasma metanephrine testing should be collected with the patient in a fully recumbent, supine position (for at least 30 minutes before sampling) and reference intervals established in the same position should be used.15 Numerous studies have confirmed that lying supine at rest prior to blood collection prevents false-positive results due to postural-related stimulus of norepinephrine secretion.15,23,24,27,29-31

Applying reference ranges established from samples collected in a supine position, the sensitivity of plasma metanephrines approaches 100%, such that a finding of normal levels has a very high negative predictive value for ruling out catecholamine secreting tumor.15,31 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.15,24,33 In cases of borderline elevation (less than 3-fold the upper limit of the reference interval) repeat testing with sampling in a supine position and/or second-line tests such as the measurement of fractionated 24-hour urinary metanephrines and performance of a clonidine suppression test with measurements of plasma normetanephrine can be performed prior to proceeding to imaging studies.15,34 Chromogranin A levels are elevated in most patients with PPGLs and have been associated with risk of malignancy.34-36 However, the test is not specific and is seen in other disorders such as carcinoid.


Footnotes

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. doi.org/10.1016/j.trac.2016.01.027
2. Eisenhofer G, Peitzsch M. Laboratory evaluation of pheochromocytoma and paraganglioma. Clin Chem. 2014 Dec;60(12):1486-1499.25332315
3. Kolackov K, Tupikowski K, Bednarek-Tupikowska G. Genetic aspects of pheochromocytoma. Adv Clin Exp Med. Nov-Dec 2012;2(6)1:821-829.23457139
4. Martucci VL, Pacak K. Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment. Curr Probl Cancer. 2014 Jan-Feb;38(1):7-41.24636754
5. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005 Aug 20-26;366(9486):665-675.16112304
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):2175-2185.9626157
7. Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev. 2004 Sep;56(3):331-349.15317907
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):297-311.11708294
9. Därr R, Lenders JW, Hofbauer LC, Naumann B, Bornstein SR, Eisenhofer G. Pheochromocytoma - update on disease management. Ther Adv Endocrinol Metab. 2012 Feb;3(1):11-26.23148191
10. Eisenhofer G, Klink B, Richter S, Lenders JW, Robledo M. Metabologenomics of Phaeochromocytoma and Paraganglioma: An Integrated Approach for Personalised Biochemical and Genetic Testing. Clin Biochem Rev. 2017 Apr;38(2):69-100.29332973
11. Franscini LC, Vazquez-Montes M, Buclin T, et al. Pediatric reference intervals for plasma free and total metanephrines established with a parametric approach: relevance to the diagnosis of neuroblastoma. Pediatr Blood Cancer. 2015 Apr;62(4):587-593.25597761
12. Lenders JW. Biochemical diagnosis of pheochromocytoma and paraganglioma. Ann Endocrinol (Paris). 2009 Jun;70(3):161-165.19296926
13. Plouin PF, Amar L, Lepoutre C. Phaeochromocytomas and functional paragangliomas: clinical management. Best Pract Res Clin Endocrinol Metab. 2010 Dec;24(6):933-941.21115162
14. Golden SH, Robinson KA, Saldanha I, Anton B, Landenson PW. Clinical review: Prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab. 2009 Jun;94(6):1853-1878.19494161
15. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Jun;99(6):1915-1942.24893135
16. Melmed S, Polonsky KS, Reed Larsen P, Kronenberg HM. Williams Textbook of Endocrinology. 13th ed. Philadelphia, PA: Elsevier; 2015.
17. Manger WM. The protean manifestations of pheochromocytoma. Horm Metab Res. 2009 Sep;41(9):658-663.19242899
18. Otusanya O, Goraya H, Iyer P, Landi K, Tibb A, Msaouel P. A vicious cycle of acute catecholamine cardiomyopathy and circulatory collapse secondary to pheochromocytoma. Oxf Med Case Reports. 2015 Oct 27;2015(10):343-345.26512333
19. Prejbisz A, Lenders JW, Eisenhofer G, Januszewicz J. Mortality associated with phaeochromocytoma. Horm Metab Res. 2013 Feb;45(2):154-158.23322516
20. Waguespack SG, Rich T, Grubbs E, et al. A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2010 May;95(5):2023-2037.20215394
21. Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug;175(2):G1-G34.27390021
22. Chen H, Sippel RS, O'Dorisio MS, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010 Aug;39(6):775-783.20664475
23. Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med. 1999 Jun 17;340(24):1872-1879.10369850
24. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002 Mar 20;287(11):1427-1434.11903030
25. Eisenhofer G, Peitzsch M, Kaden D, et al. Reference intervals for LC-MS/MS measurements of plasma free, urinary free and urinary acid-hydrolyzed deconjugated normetanephrine, metanephrine and methoxytyramine. Clin Chim Acta. 2019 Mar;490:46-54.30571948
26. Eisenhofer G, Prejbisz A, Peitzsch M et al. Biochemical Diagnosis of Chromaffin Cell Tumors in Patients at High and Low Risk of Disease: Plasma versus Urinary Free or Deconjugated O-Methylated Catecholamine Metabolites. Clin Chem. 2018 Nov;64(11):1646-1656.30097498
27. Eisenhofer G, Lattke P, Herberg M, et al. Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma. Ann Clin Biochem. 2013 Jan;50(Pt 1):62-69.23065528
28. Pamporaki C, Därr R, Bursztyn M, et al. Plasma-free vs deconjugated metanephrines for diagnosis of phaeochromocytoma. Clin Endocrinol (Oxf). 2013 Oct;79(4):476-483.23461656
29. Sussman I, Rothwell T, Wilson A. Supine or sitting? The voice of the patient stakeholders: economics vs clinically and medically sound. Clin Endocrinol (Oxf). 2015 Mar;82(3):464-465.25265273
30. Därr R, Pamporaki C, Peitzsch M, et al. Biochemical diagnosis of phaeochromocytoma using plasma-free normetanephrine, metanephrine and methoxytyramine: importance of supine sampling under fasting conditions. Clin Endocrinol (Oxf). 2014 Apr;80(4):478-486.24102244
31. Lenders JW, Willemsen JJ, Eisenhofer G, et al. Is supine rest necessary before blood sampling for plasma metanephrines? Clin Chem. 2007 Feb;53:352-354.17200132
32. Yu R, Wei M. False positive test results for pheochromocytoma from 2000 to 2008. Exp Clin Endocrinol Diabetes. 2010 Oct;118(9):577-585.19998239
33. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true-from false-positive test results. J Clin Endocrinol Metab. 2003 Jun;88(6):2656-2666.12788870
34. Algeciras-Schimnich A, Preissner CM, Young WF Jr, Singh RJ, Grebe SK. Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma. J Clin Endocrinol Metab. 2008 Jan;93(1):91-95.17940110
35. d'Herbomez M, Forzy G, Bauters C, et al. An analysis of the biochemical diagnosis of 66 pheochromocytomas. Eur J Endocrinol. 2007 May;156(5):569-575.17468193
36. Szalat A, Fraenkel M, Doviner V, Salmon A, Gross DJ. Malignant pheochromocytoma: predictive factors of malignancy and clinical course in 16 patients at a single tertiary medical center. Endocrine. 2011 Apr;39(2):160-166.21069578
37. Neary NM, King KS, Pacak K. Drugs and pheochromocytoma--don't be fooled by every elevated metanephrine. N Engl J Med. 2011 Jun 9;364(23):2268-2270.21651412
38. de Jong WH, Eisenhofer G, Post WJ. Muskiet FAJ, de Vries EGE, Kema IP. Dietary influences on plasma and urinary metanephrines: implications for diagnosis of catecholamine-producing tumors. J Clin Endocrinol Metab. 2009 Aug;94(8):2841-2849.19567530

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
121806 Metanephrines, Frac., Pl. Free 070013 Normetanephrine, Pl pg/mL 2669-0
121806 Metanephrines, Frac., Pl. Free 070023 Metanephrine, Pl pg/mL 38494-1

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