Test Id : METRN

Patient Preparation:

1. For at least 48 hours prior to test, patient should avoid use of cold medicines, nose drops, and nasal sprays.

2. Patients taking tricyclic antidepressants and labetalol and sotalol (beta blockers) may have falsely elevated levels of metanephrines. If medically feasible, for at least 1 week before specimen collection, the patient should not take these medications.

Supplies: Urine Tubes, 10 mL (T068)

Collection Container/Tube: Clean, plastic urine collection container

Submission Container/Tube: Plastic, 10 mL urine tube

Specimen Volume: 10 mL

Collection Instructions:

1. Collect a random urine specimen.

2. No preservative.

If not ordering electronically, complete, print, and send a Oncology Test Request (T729) with the specimen.

3 mL

A second-order screening test for the presumptive diagnosis of pheochromocytoma in patients with non-episodic hypertension

Confirming positive plasma metanephrine results in patients with non-episodic hypertension

Pheochromocytoma is a rare, potentially lethal, tumor of chromaffin cells of the adrenal medulla that produces episodes of hypertension with palpitations, severe headaches, and sweating ("spells").

Pheochromocytomas and other tumors derived from neural crest cells (eg, paragangliomas and neuroblastomas) secrete catecholamines (epinephrine and norepinephrine).

Metanephrine and normetanephrine are the 3-methoxy metabolites of epinephrine and norepinephrine, respectively. Both are further metabolized to vanillylmandelic acid.

Pheochromocytoma cells are also able to oxymethylate catecholamines into metanephrines that are secreted into circulation.

METANEPHRINE/CREATININE

Normotensives

0-2 years: 82-418 mcg/g creatinine

3-8 years: 65-332 mcg/g creatinine

9-12 years: 41-209 mcg/g creatinine

13-17 years: 30-154 mcg/g creatinine

> or =18 years: 29-158 mcg/g creatinine

NORMETANEPHRINE/CREATININE

Males

Normotensives

0-2 years: 121-946 mcg/g creatinine

3-8 years: 92-718 mcg/g creatinine

9-12 years: 53-413 mcg/g creatinine

13-17 years: 37-286 mcg/g creatinine

18-29 years: 53-190 mcg/g creatinine

30-39 years: 60-216 mcg/g creatinine

40-49 years: 69-247 mcg/g creatinine

50-59 years: 78-282 mcg/g creatinine

60-69 years: 89-322 mcg/g creatinine

> or =70 years: 102-367 mcg/g creatinine

Females

Normotensives

0-2 years: 121-946 mcg/g creatinine

3-8 years: 92-718 mcg/g creatinine

9-12 years: 53-413 mcg/g creatinine

13-17 years: 37-286 mcg/g creatinine

18-29 years: 81-330 mcg/g creatinine

30-39 years: 93-379 mcg/g creatinine

40-49 years: 107-436 mcg/g creatinine

50-59 years: 122-500 mcg/g creatinine

60-69 years: 141-574 mcg/g creatinine

> or =70 years: 161-659 mcg/g creatinine

TOTAL METANEPHRINE/CREATININE

Males

Normotensives

0-2 years: 241-1,272 mcg/g creatinine

3-8 years: 186-980 mcg/g creatinine

9-12 years: 110-582 mcg/g creatinine

13-17 years: 78-412 mcg/g creatinine

18-29 years: 96-286 mcg/g creatinine

30-39 years: 106-316 mcg/g creatinine

40-49 years: 117-349 mcg/g creatinine

50-59 years: 130-386 mcg/g creatinine

60-69 years: 143-427 mcg/g creatinine

> or =70 years: 159-472 mcg/g creatinine

Females

Normotensives

0-2 years: 241-1,272 mcg/g creatinine

3-8 years: 186-980 mcg/g creatinine

9-12 years: 110-582 mcg/g creatinine

13-17 years: 78-412 mcg/g creatinine

18-29 years: 131-467 mcg/g creatinine

30-39 years: 147-523 mcg/g creatinine

40-49 years: 164-585 mcg/g creatinine

50-59 years: 184-655 mcg/g creatinine

60-69 years: 206-733 mcg/g creatinine

> or =70 years: 230-821 mcg/g creatinine

Increased metanephrine and normetanephrine levels are found in patients with pheochromocytoma and tumors derived from neural crest cells.

Increased urine metanephrines can be detected in non-pheochromocytoma hypertensive patients; quantification may help distinguish these patients from those with tumor-induced symptoms.

While screening for pheochromocytoma is best accomplished by measuring free fractionated metanephrines in plasma (a more sensitive assay), follow-up testing with urinary fractionated metanephrines (a more specific assay) may identify false-positive results. Twenty-four-hour urine collections are preferred, especially for patients with episodic hypertension; ideally the collection should begin at the onset of a "spell."

This test utilizes a liquid chromatography tandem mass spectrometry method and is not affected by the interfering substances that affected the previously utilized spectrophotometric (Pisano reaction) method (ie, diatrizoate, chlorpromazine, hydrazine derivatives, imipramine, monoamine oxidase inhibitors [MAOI], methyldopa, phenacetin, ephedrine, or epinephrine).

This method is also not subject to the known interference of acetaminophen, which is seen with the plasma metanephrine test using high-performance liquid chromatography with electrochemical detection.

When N-acetylcysteine is administered at levels sufficient to act as an antidote for the treatment of acetaminophen overdose, it may lead to falsely decreased creatinine results.

1. van Duinen N, Corssmit EPM, de Jong WHA, Brookman D, Kema P, Romijn JA. Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites. Eur J Endocrinol. 2013;169(3):377-382 doi:10.1530/EJE-13-0529

2. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134(4):315-329

3. Sawka AM, Singh RJ, Young WF Jr. False positive biochemical testing for pheochromocytoma caused by surreptitious catecholamine addition to urine. Endocrinologist. 2001;11:421-423

4. Eisenhofer G, Grebe S, Cheung NKV. Monoamine-producing tumors. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:1421

5. Shen Y, Cheng L. Biochemical diagnosis of pheochromocytoma and paraganglioma. In: Mariani-Costantini R, ed. Paraganglioma: A Multidisciplinary Approach. Codon Publications; 2019. Accessed May 2, 2024. Available at www.ncbi.nlm.nih.gov/books/NBK543224/

6. Hernandez FC, Sanchez M, Alvarez A, et al. A five-year report on experience in the detection of pheochromocytoma. Clin Biochem. 2000;33(8):649-55. doi:10.1016/s0009-9120(00)00172-7

7. van Duinen N, Steenvoorden D, Kema IP, et al. Increased urinary excretion of 3-methoxytyramine in patients with head and neck paragangliomas. J Clin Endocrinol Metab. 2010;95(1):209-14. doi:10.1210/jc.2009-1632

8. Le Jacques A, Abalain JH, Le Saos F, Carre JL. Significance of 3-methoxytyramine urine measurement in the diagnosis of pheochromocytomas and paragangliomas: about 28 patients. Ann Biol Clin (Paris). 2011;69(5):555-9. French. doi:10.1684/abc.2011.0612

9. Muskiet FA, Thomasson CG, Gerding AM, Fremouw-Ottevangers DC, Nagel GT, Wolthers BG. Determination of catecholamines and their 3-O-methylated metabolites in urine by mass fragmentography with use of deuterated internal standards. Clin Chem. 1979;25(3):453-60

10. Hirsch D, Grossman A, Nadler V, Alboim S, Tsvetov G. Pheochromocytoma: Positive predictive values of mildly elevated urinary fractionated metanephrines in a large cohort of community-dwelling patients. J Clin Hypertens (Greenwich). 2019;21(10):1527-1533. doi:10.1111/jch.13657

Urinary metanephrines are determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Urinary metanephrines occur largely in conjugated form. After urine samples are acidified and hydrolyzed in a heat block, metanephrine and normetanephrine are extracted from the specimens utilizing extraction cartridges. The metanephrine, normetanephrine, and 3-methoxytyramine (3MT) are eluted from the cartridge and analyzed by LC/MS/MS using multiple reaction monitoring in positive mode. Deuterated metanephrine (d3-metanephrine), deuterated normetanephrine (d3-normetanephrine), and deuterated 3MT (d4-3MT) are added prior to the hydrolysis as internal standards. The metanephrine, normetanephrine, and 3-MT concentrations are quantified using ratios of the peak areas to deuterium labeled internal standards by LC-MS/MS.(Unpublished Mayo method)

Creatinine:

The enzymatic method is based on the determination of sarcosine from creatinine with the aid of creatininase, creatinase, and sarcosine oxidase. The liberated hydrogen peroxide is measured via a modified Trinder reaction using a colorimetric indicator. Optimization of the buffer system and the colorimetric indicator enables the creatinine concentration to be quantified both precisely and specifically.(Package insert: Creatinine plus ver 2. Roche Diagnostics; V15.0, 03/2019)

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This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

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