Metanephrines (plasma)

Metanephrines are the 3-O-methylated metabolites of catecholamines. They are formed in chromaffin cells by the action of catechol-O-methyl transferase which produces metanephrine from adrenaline; normetanephrine from noradrenaline; and 3-methoxytyramine from dopamine.

Measurement of metanephrines is used to demonstrate elevated production of catecholamines and is recommended as a first line investigation for the diagnosis of phaeochromocytoma and paraganglioma (PPGL) ¹

PPGL are rare neuroendocrine tumours arising from adrenal chromaffin cells (phaeochromocytoma) and extra-adrenal chromaffin cells of the sympathetic paravertebral ganglia (paraganglioma). Rarely these tumours are biochemically silent but commonly they produce excessive levels of one or more catecholamines. The presence of membrane-bound catechol-O-methyl transferase in tumour cells results in the metabolism of secreted catecholamines to their respective metanephrines. This occurs in a continuous manner, independent of catecholamine release, thus providing a diagnostic advantage of metanephrines measurement over catecholamines.

Plasma metanephrine measurement may be considered when signs and symptoms of catecholamine excess are present, particularly if paroxysmal. These include:

- Hypertension
- Sweating
- Anxiety
- Palpitations
- Headache

Other clinical settings where plasma metanephrine testing is indicated include:

- PPGL symptoms provoked by use of medications associated with adverse effects*
- Adrenal incidentaloma, with or without hypertension
- Hereditary predisposition or syndromic features suggesting hereditary PPGL

(MEN-2, Von Hippel-Lindau syndrome, Neurofibromatosis type-1)
- Previous history of PPGL

*dopamine D2 receptor antagonists, βadrenergic receptor blockers, sympathomimetics, opioid analgesics, norepinephrine reuptake inhibitors (including tricyclic antidepressants), serotonin reuptake inhibitors, monoamine oxidase inhibitors, corticosteroids, peptides (ACTH, glucagon), neuromuscular blocking agents.

These reference ranges are based on a seated population. If users wish to use supine sampling (after 30 min supine rest) we recommend using appropriate reference intervals. Please refer to the Imperial Endocrine Bible (http://www.imperialendo.com/for-doctors/endocrine-bible) for further information.

Samples must be transported on ice and arrive in the laboratory within 2 hours.
If not collected on ice samples must arrive within 30 minutes.
Samples that do not fulfil the collection criteria will not be suitable for analysis

Patient preparation

• Dietary restrictions
• Patients should ideally fast overnight prior to the test in order to avoid false-positive test results.
• Ingestion of catecholamine-rich foodstuffs (e.g. pineapple, kiwi, walnuts, bananas, tomatoes) has been shown to significantly increase plasma free 3-methoxytyramine concentrations. Plasma free metanephrine and normetanephrine were not shown to be affected by diet².

Medications

A number of medications and drugs have been demonstrated to pharmacodynamically interfere with plasma metanephrine concentrations.

Please refer to the Imperial Endocrine Bible (http://www.imperialendo.com/for-doctors/endocrine-bible) for a list of major drugs and medications that may cause false-elevations in plasma metanephrines.

Medications that interfere with catecholamine secretion, metabolism and reuptake should be discontinued prior to sampling. If this is not practical an alternative approach is to re-test if initial results are found to be elevated.

References 

1. Lenders JWM et al. Pheochromocytoma and paraganglioma: An Endocrine Society Clinical Practice Guideline. JCEM 2014; 99: 1915-42.
2. de Jong WHA et al. Dietary influences on plasma and urinary metanephrines: Implications for diagnosis of catecholamine-producing tumors. JCEM 2009; 94: 2841-49.