Fact Sheet Plasma /Normetanephrine

Test Name: Metanephrine and Normetanephrine (Plasma)

Specimen:

Sample type: Lithium heparin (no gel) preferred Alternative, EDTA plasma

Minimum volume: Minimum assay volume 1mL (approximately 2mL blood) Smaller volume (500uL plasma) may be acceptable for paediatric patients

Collection requirements: • Supine collection is preferred. The patient should be lying down during and for a minimum of 30 minutes prior to collection because collection in the seated position may result in false positive results. • Consider withdrawing medications known to cause elevation of results (see below). , such as , may also increase release are therefore best avoided before testing. • The sample should be put on ice after collection.

Transport: Separate and freeze plasma within 6 hours of collection. Transport on dry ice.

Stability: Heparinised plasma. Stable for 7 days at 4°C, up to 30 days at -20°C.

Contacts: Send samples to: Department of Clinical Chemistry and Endocrinology Level 4 Campus Centre The Prince of Wales Hospital Barker Street, Randwick, NSW 2031

Enquiries:

Teresa Hewlett Hospital Scientist Department of Clinical Chemistry and Endocrinology Level 4 Campus Centre The Prince of Wales Hospital Barker Street, Randwick, NSW 2031 Tel 02 9382 9082 [email protected]

Phoebe Stanford Clinical Chemistry Registrar Department of Clinical Chemistry and Endocrinology Level 4 Campus Centre The Prince of Wales Hospital

CHEMAI - Plasma Metanephrine Normetanephrine Fact Sheet - 01 Page 1 of 5 Authorised: AR. Horvath Released: 23.01.18 Fact Sheet Plasma Metanephrine/Normetanephrine

Barker Street, Randwick, NSW 2031 Tel 02 9382 1524 Mob 0429537546 [email protected]

Rita Horvath Clinical Director Department of Clinical Chemistry and Endocrinology Level 4 Campus Centre The Prince of Wales Hospital Barker Street, Randwick, NSW 2031 Tel 02 9382 9078 Fax 02 9382 9099 Mob 0404 027 843 [email protected]

Test performance:

Method: LCMS-MS

Testing frequency: Twice weekly

Reference intervals:

Metanephrine 2-115yrs <447 pmol/L (Male and female) Normetanephrine 2-14yrs (male and female) <540 pmol/L 14-20yrs <550 pmol/L 20-23yrs <560 pmol/L 23-26yrs <570 pmol/L 26-28yrs <580 pmol/L 28-30yrs <590 pmol/L 30-32yrs <600 pmol/L 32-34yrs <610 pmol/L 34-35yrs <620 pmol/L 35-36yrs <630 pmol/L 36-37yrs <640 pmol/L 37-39yrs <650 pmol/L 39-40yrs <660 pmol/L 40-41yrs <670 pmol/L 41-42yrs <680 pmol/L 42-43yrs <690 pmol/L 43-44yrs <700 pmol/L 44-45yrs <720 pmol/L 45-46yrs <730 pmol/L

CHEMAI - Plasma Metanephrine Normetanephrine Fact Sheet - 01 Page 2 of 5 Authorised: AR. Horvath Released: 23.01.18 Fact Sheet Plasma Metanephrine/Normetanephrine

46-47yrs <740 pmol/L 47-48yrs <760 pmol/L

48-49yrs <770 pmol/L

49-50yrs <780 pmol/L 50-51yrs <800 pmol/L 51-52yrs <820 pmol/L 52-53yrs <830 pmol/L 53-54yrs <850 pmol/L

54-55yrs <870 pmol/L

55-56yrs <890 pmol/L 56-57yrs <900 pmol/L 57-58yrs <920 pmol/L 58-59yrs <940 pmol/L 59-60yrs <970 pmol/L 60-61yrs <990 pmol/L

61-62yrs <1010 pmol/L 62-63yrs <1030 pmol/L 63-64yrs <1060 pmol/L 64-115yrs <1080 pmol/L

Reference interval for children <2 years of age not available

Source:

Eisenhofer G et al Reference intervals for plasma free with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma Ann Clin Biochem 2013; 50: 62-69.

Interpretation of results

Measurement of plasma metanephrines is recommended as a first line test in the diagnosis of suspected phaeochromocytoma or functional paraganglioma.

The test is designed to have a high sensitivity, such that a negative result essentially excludes this diagnosis. However owing to rarity of these tumours and the generally low pre-test probability the suboptimal specificity means that false positive results are common.

Potential Causes of False positive results: Upright posture, exercise, a cold environment and physiological/mental stress may activate the sympatho-adrenal system resulting in increased release of and production of metanephrines.

Posture: The reference intervals above are based on supine sampling as is recommended for the diagnosis of phaeochromocytoma to maximise diagnostic sensitivity. Upright posture has a stimulating effect on the release of noradrenaline with metabolism to normetanephrine, meaning that reference

CHEMAI - Plasma Metanephrine Normetanephrine Fact Sheet - 01 Page 3 of 5 Authorised: AR. Horvath Released: 23.01.18 Fact Sheet Plasma Metanephrine/Normetanephrine

intervals established in seated patients are higher (up to 2 fold) than supine ranges. Therefore if blood is collected from a seated patient, the chance of a false positive result is increased.

Medications: Medications that block the neuronal uptake of catecholamines, including tricyclics and related drugs used to treat depression, insomnia, neuropathic pain and other medical conditions, are a cause of false positive results which may need to be considered when interpreting results. inhibitors block deamination pathways causing substantial increases in plasma and urinary metanephrines and so these medications should be withdrawn before testing, if possible. Sympathomimetics and stimulants, such as caffeine, that also increase catecholamine release are therefore best avoided before testing.

Table 1. Medications That May Cause Falsely Elevated Results (Adapted from Reference 1)

Medications Normetanephrine Metanephrine Tricyclic antidepressants ++ - (Amitriptyline, imipramine, nortriptyline) Phenoxybenzamine ++ - MAO-inhibitors ++ ++ (, , ) Sympathomimetics + + (, (Sudafed), , albuterol) ++ +

Advice for investigation of elevated results:

The nature and pattern of elevation should be considered when interpreting results. Elevations of both normetanephrine and metanephrine are rare as false-positives and should therefore be treated with a high level of suspicion. Similarly, either normetanephrine or metanephrine increased > 3x the upper reference limit are also rare as false positives and should be followed up in most cases by imaging to locate the tumours. An exception may be in patients under significant stress (e.g. ICU or trauma patients), where high results may be expected. In one study, plasma metanephrine and normetanephrine was elevated up to 7nmol/L in patients with acute severe illness, with normalisation of results upon recovery.

Results that are borderline do not necessarily require imaging for localisation of a tumour. Causes of potential false positive results should be considered in the interpretation of results in these cases. If necessary the test should be repeated at least after 30 minutes in the supine position, and after medications known to cause elevated results have been withdrawn where possible.

Measurements of urinary normetanephrine and metanephrine may be useful to either confirm or refute a diagnosis.

References: 1. Lenders et al. and Paraganglioma: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Meta, 2014; 99: 1915–1942

CHEMAI - Plasma Metanephrine Normetanephrine Fact Sheet - 01 Page 4 of 5 Authorised: AR. Horvath Released: 23.01.18 Fact Sheet Plasma Metanephrine/Normetanephrine

2. Whiting MJ, Doogue MP. Advances in Biochemical Screening for Phaeochromocytoma using Biogenic Amines. Clin Biochem Rev, 2009; 30: 3-17 3. Eisenhofer G et al. Biochemical Diagnosis of Pheochromocytoma: How to Distinguish True- from False- Positive Test ResultsJ Clin Endocrinol Metab, 2003; 88: 2656–26664. 4. Osinga E et al. No influence of antihypertensive agents on plasma free metanephrines. Clinical Biochemistry, 2016; 49:1368–1371 5. Amar L and Eisenhofer G. Diagnosing phaeochromocytoma/paraganglioma in a patient presenting with critical illness: biochemistry versus imaging. Clinical Endocrinology, 2015; 83: 298–302

CHEMAI - Plasma Metanephrine Normetanephrine Fact Sheet - 01 Page 5 of 5 Authorised: AR. Horvath Released: 23.01.18