Test Id : META3

Tricyclic antidepressants, labetalol, and sotalol medications may elevate levels of metanephrines producing results that cannot be interpreted. If clinically feasible, it is optimal to discontinue these medications at least 1 week before collection. For advice on assessing the risk of removing patients from these medications and alternatives, consider consultation with a specialist in endocrinology or hypertension.

24-Hour volume (in milliliters) is required.

Supplies: Urine Tubes, 10 mL (T068)

Submission Container/Tube: Plastic urine tube

Specimen Volume: 10 mL

Collection Instructions:

1. Complete 24-hour urine collections are preferred, especially for patients with episodic hypertension; ideally the collection should begin at the onset of a "spell."

2. Collect urine for 24 hours.

3. Add 10 g (pediatric: 3 g) of boric acid or 25 mL (pediatric: 15 mL) of 50% acetic acid as preservative at start of collection.

• Urine Preservatives-Collection and Transportation for 24-Hour Urine Specimens

Note: The addition of preservative or application of temperature controls must occur at the start of the collection.

4 mL

A first- and second-tier screening test for the presumptive diagnosis of catecholamine-secreting pheochromocytomas and paragangliomas

Testing in conjunction with or as an alternative to plasma metanephrine or catecholamine testing

Pheochromocytoma is a rare, though potentially lethal, tumor of chromaffin cells of the adrenal medulla that produces episodes of hypertension with palpitations, severe headaches, and sweating ("spells"). Patients with pheochromocytoma may also be asymptomatic and present with sustained hypertension or an incidentally discovered adrenal mass.

Pheochromocytomas and other tumors derived from neural crest cells (eg, paragangliomas and neuroblastomas) secrete catecholamines (epinephrine, norepinephrine, and dopamine). Dopamine secreting tumors are rarer than norepinephrine and epinephrine secreting tumors.

3-Methoxytyramine (3MT), metanephrine, and normetanephrine are the metabolites of dopamine, epinephrine, and norepinephrine, respectively. These metabolites are further metabolized to vanillylmandelic acid.

Pheochromocytoma cells also have the ability to oxymethylate catecholamines into metanephrines that are secreted into circulation.

In patients that are highly suspect for pheochromocytoma, it may be best to screen by measuring plasma free fractionated metanephrines (a more sensitive assay). This test may be used as the first test for low-suspicion cases and also as a confirmatory study in patients with a less than 2-fold elevation in plasma free fractionated metanephrines or catecholamines. This is highly desirable, as the very low population incidence rate of pheochromocytoma (<1:100,000 population per year) will otherwise result in large numbers of unnecessary, costly, and sometimes risky imaging procedures.

Complete 24-hour urine collections are preferred, especially for patients with episodic hypertension; ideally the collection should begin at the onset of a "spell."

3-Methoxytyramine:

Males: < or =306 mcg/24 hours

Females: < or =242 mcg/24 hours

METANEPHRINE

Males

Normotensives

3-8 years: 29-92 mcg/24 hours

9-12 years: 59-188 mcg/24 hours

13-17 years: 69-221 mcg/24 hours

> or =18 years: 44-261 mcg/24 hours

Reference values have not been established for patients that are <36 months of age.

Hypertensives: <400 mcg/24 hours

Females

Normotensives

3-8 years: 18-144 mcg/24 hours

9-12 years: 43-122 mcg/24 hours

13-17 years: 33-185 mcg/24 hours

> or =18 years: 30-180 mcg/24 hours

Reference values have not been established for patients that are <36 months of age.

Hypertensives: <400 mcg/24 hours

NORMETANEPHRINE

Males

Normotensives

3-8 years: 34-169 mcg/24 hours

9-12 years: 84-422 mcg/24 hours

13-17 years: 91-456 mcg/24 hours

18-29 years: 103-390 mcg/24 hours

30-39 years: 111-419 mcg/24 hours

40-49 years: 119-451 mcg/24 hours

50-59 years: 128-484 mcg/24 hours

60-69 years: 138-521 mcg/24 hours

> or =70 years: 148-560 mcg/24 hours

Reference values have not been established for patients that are <36 months of age.

Hypertensives: <900 mcg/24 hours

Females

Normotensives

3-8 years: 29-145 mcg/24 hours

9-12 years: 55-277 mcg/24 hours

13-17 years: 57-286 mcg/24 hours

18-29 years: 103-390 mcg/24 hours

30-39 years: 111-419 mcg/24 hours

40-49 years: 119-451 mcg/24 hours

50-59 years: 128-484 mcg/24 hours

60-69 years: 138-521 mcg/24 hours

> or =70 years: 148-560 mcg/24 hours

Reference values have not been established for patients that are <36 months of age.

Hypertensives: <900 mcg/24 hours

TOTAL METANEPHRINE

Males

Normotensives

3-8 years: 47-223 mcg/24 hours

9-12 years: 201-528 mcg/24 hours

13-17 years: 120-603 mcg/24 hours

18-29 years: 190-583 mcg/24 hours

30-39 years: 200-614 mcg/24 hours

40-49 years: 211-646 mcg/24 hours

50-59 years: 222-680 mcg/24 hours

60-69 years: 233-716 mcg/24 hours

> or =70 years: 246-753 mcg/24 hours

Reference values have not been established for patients that are <36 months of age.

Hypertensives: <1300 mcg/24 hours

Females

Normotensives

3-8 years: 57-210 mcg/24 hours

9-12 years: 107-394 mcg/24 hours

13-17 years: 113-414 mcg/24 hours

18-29 years: 142-510 mcg/24 hours

30-39 years: 149-535 mcg/24 hours

40-49 years: 156-561 mcg/24 hours

50-59 years: 164-588 mcg/24 hours

60-69 years: 171-616 mcg/24 hours

> or =70 years: 180-646 mcg/24 hours

Reference values have not been established for patients that are <36 months of age.

Hypertensives: <1300 mcg/24 hours

For SI unit Reference Values, see https://www.mayocliniclabs.com/order-tests/si-unit-conversion.html

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

Increased 3-methoxytyramine (3MT) levels are found in patients with pheochromocytoma and dopamine-secreting tumors.

Total urine metanephrine levels of 1300 mcg/24 hours and less, and 3MT levels of 306 mcg/24 hours or less in males and 242 mcg/24 hours or less in females, can be detected in non-pheochromocytoma hypertensive patients

Further clinical investigation (eg, radiographic studies) is warranted in patients whose total urinary metanephrine levels are above 1300 mcg/24 hours (approximately 2 times the upper limit of normal) or whose 3MT levels are elevated and there is a very high clinical index of suspicion.

For patients with total urinary metanephrine levels below 1300 mcg/24 hours, further investigations may also be indicated if either the normetanephrine or the metanephrine fraction of the total metanephrines exceeds their respective upper limit for hypertensive patients.

Finally, repeat testing or further investigations may occasionally be indicated in patients with urinary metanephrine levels below the hypertensive cutoff, or even normal levels, if there is a very high clinical index of suspicion.

Tricyclic antidepressants, levodopa, and significant physical stress (eg, hypertensive stroke) may elevate levels of 3-methoxytyramine (3MT). L-Dopa use will definitely increase results for 3-MT and the results cannot be interpreted. If clinically feasible, these medications should be discontinued at least 1 week before collection.

These tests utilizes a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method and is not affected by the interfering substances that affected older spectrophotometric (Pisano reaction) (ie, diatrizoate, chlorpromazine, hydrazine derivatives, imipramine, monoamine oxidase [MAO] inhibitors, methyldopa, phenacetin, ephedrine, or epinephrine) or high-performance liquid chromatography (HPLC) methods (acetaminophen).

1. van Duinen N, Corssmit EPM, de Jong WHA, et al: 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;169:377-382. doi: 10.1530/EJE-13-0529

2. 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 Jan:95(1):209-214. doi: 10.1210/jc.2009-1632

3. Kantorovich V, Pacak K; Interest of urinary dosage of 3- methoxytyramine in the diagnosis of pheochromocytoma and paraganglioma: report of 28 cases. Ann Clin Biol. 2011;69(5):555-559. doi: 10.168 4 /abc.2011.0612

4. Muskiet FA, Thomasson CG, Gerding AM, et al: Determination of catecholamines and their 3-o-methylated metabolites in urine by mass fragmentography with use of deuterated internal standards. Clin Chem. 1979 Mar;25(3):453-460

5. Hernandez FC, Sanchez M, Alvarez A, et al: A five-year report on experience in the detection of pheochromocytoma. Clin Biochem. 2000;33:649-655

6. Pacak K, Linehan WM, Eisenhofer G, et al: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134:315-329

7. 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

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. Deuterated metanephrine, deuterated normetanephrine, and deuterated 3MT are added prior to the hydrolysis as an internal standard. 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)

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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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