Understanding Plasma Metanephrines: What Your Blood Test Result Means

Plasma metanephrines (plasma free metanephrines) is a blood test that measures metanephrine and normetanephrine, the breakdown products of adrenaline and noradrenaline. It is the recommended first test for pheochromocytoma and paraganglioma, rare tumours that make these stress hormones and can cause high blood pressure, headaches, sweating and a pounding heartbeat. A normal result makes such a tumour unlikely. Elevated plasma metanephrines do not automatically mean a tumour: mild rises are common and are often caused by sitting rather than lying down for the blood draw, certain medicines or physical stress, while a rise of three times the upper limit or more is taken much more seriously.

What the test measures

The adrenal glands, and nerve-like tissue elsewhere in the body, make the hormones adrenaline (epinephrine) and noradrenaline (norepinephrine). Inside the tumour cells these hormones are steadily converted into metanephrine (from adrenaline) and normetanephrine (from noradrenaline). This conversion happens continuously, even when the tumour is not releasing hormone in bursts, which is why metanephrines catch tumours that a single catecholamine measurement could miss. Some laboratories also report 3-methoxytyramine, the breakdown product of dopamine.

A pheochromocytoma grows in the centre of the adrenal gland; a paraganglioma grows outside it, for example near the carotid artery or along nerves in the head and neck. Together they are called PPGL. Either may be benign or cancerous.

Who is tested

Clinicians usually order plasma metanephrines for:

• symptoms that suggest PPGL, especially if they come in episodes;
• symptoms that appear after certain medicines;
• an adrenal mass found by chance on a scan (an "adrenal incidentaloma"), with or without high blood pressure;
• an inherited syndrome or family history that raises the risk;
• a previous PPGL, as follow-up.

Even among people with high blood pressure seen in general clinics, PPGL is found in only about 0.2 to 0.6%.

Reference ranges

There is no single reference range. Each laboratory sets its own, and limits depend on the method, the posture during sampling and your age. As an example from one large study using supine (lying-down) samples:

Normetanephrine normally rises with age, so age-adjusted limits are used to reduce false positives. A hospital laboratory using supine samples applies very similar limits (metanephrine 0.45 nmol/L; normetanephrine from 0.54 nmol/L at ages 5 to 17 to 0.99 nmol/L over 60). Many laboratories, especially in the US, report in pg/mL instead: 1 nmol/L is about 197 pg/mL for metanephrine and about 183 pg/mL for normetanephrine, so the limits above correspond to roughly 89 pg/mL for metanephrine and 86 to 192 pg/mL for normetanephrine. Units and numbers also differ between laboratories, so the figures on your report may look quite different from these. Always compare your result with the range printed on your own report, and check whether it was a seated or supine range.

Why plasma metanephrines can be high

Common causes of a mild rise (often false positives)

• Seated or standing blood draw. Being upright raises metanephrines, especially normetanephrine. Guidelines advise lying down for at least 30 minutes before the sample and using supine reference ranges. Seated sampling increases false positives.
• Medicines, including antidepressants that block noradrenaline reuptake (tricyclics and SNRIs), MAO inhibitors, some blood pressure medicines (labetalol, sotalol, methyldopa) and, with some laboratory methods, paracetamol (acetaminophen). Medicines account for about one in five false-positive results. Do not stop any medicine on your own; your clinician will decide whether a change before retesting is appropriate.
• Physical stress or serious illness, for example in intensive care.
• Cocaine.

Because these tumours are rare, false-positive results considerably outnumber true ones.

The cause the test is looking for (rare)

• Pheochromocytoma or paraganglioma. A rise in both normetanephrine and metanephrine, or a rise in one of them to three times the upper limit or more, is rarely a false positive.

Symptoms

The test result itself causes no symptoms. When a tumour is present, its hormones may cause:

• high blood pressure, sometimes hard to control (the most common sign);
• headaches;
• heavy sweating without an obvious reason;
• a strong, fast or irregular heartbeat;
• shakiness and unusual paleness.

Symptoms often come in episodes and can be triggered by exercise, injury, stress, anaesthesia, surgery or foods high in tyramine. Some tumours cause no symptoms and are found by chance.

What usually happens next

• Borderline result: the usual step is to repeat the test properly, lying down for at least 30 minutes, after reviewing medicines. If they stay raised, a clonidine suppression test may help, or the clinician may simply retest later when suspicion is low.
• Clearly high result: imaging to find the tumour, usually a CT scan of the abdomen and pelvis first; MRI in some situations, and functional scans (such as MIBG or PET) in selected cases.
• 24-hour urine fractionated metanephrines is an accepted alternative or companion test.
• Genetic counselling and testing should be discussed with everyone diagnosed with PPGL, because at least one-third carry an inherited gene change.

A normal result makes PPGL very unlikely, but not impossible: some head and neck paragangliomas, and tumours linked to particular gene changes (SDHx), produce little hormone, and imaging is then the main tool.

Frequently asked questions

What does plasma metanephrines test for?

It screens for pheochromocytoma and paraganglioma by measuring breakdown products of adrenaline and noradrenaline in the blood.

What do elevated plasma metanephrines mean?

Mild elevations are common and often caused by sitting during the blood draw, medicines or physical stress. A rise in both metanephrine and normetanephrine, or a single value three or more times the upper limit, makes a tumour more likely and usually leads to imaging.

What is a normal range for plasma metanephrines?

It depends on the laboratory, your age and whether you were lying down. In one large study, the upper limit for normetanephrine ranged from 0.47 nmol/L in children to 1.05 nmol/L in people over 60, and about 0.45 nmol/L for metanephrine.

Do I need to fast or lie down for the test?

Lying down for at least 30 minutes before the blood draw is recommended. Fasting is generally not needed, but an overnight fast is advised if 3-methoxytyramine is measured as well. Follow your laboratory's instructions.

Can stress or anxiety raise metanephrines?

Physical stress, such as serious illness, can. Being upright during sampling also raises them, which is why the test is done after resting lying down.

Can antidepressants cause high metanephrines?

Yes. Tricyclic antidepressants and SNRIs, which block noradrenaline reuptake, can raise normetanephrine, in one reported case to more than six times the upper limit. SSRIs did not raise these metabolites in the same report. Your clinician will decide how to account for this; do not stop a medicine on your own.

When to see a doctor

If your plasma metanephrines are high, it is worth discussing with your doctor soon, ideally with a list of all your medicines, so the test can be repeated correctly or the next step planned. A mildly raised result is not a reason for alarm. Seek urgent care if you have chest pain, confusion, fainting or signs of a stroke.

Sources

1. Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline — Journal of Clinical Endocrinology & Metabolism
2. Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine — Annals of Clinical Biochemistry (PMC)
3. Pheochromocytoma and Paraganglioma Treatment (PDQ) — Patient Version — National Cancer Institute
4. False-positive results for pheochromocytoma associated with norepinephrine reuptake blockade — Endocrine-Related Cancer (PMC)
5. Metanephrines, free plasma (metanephrine and normetanephrine) — Singapore General Hospital Pathology
6. Metanephrine — PubChem, U.S. National Library of Medicine

Decisions about your health should always be made in consultation with your healthcare provider.