Plasma Metanephrines Interpreter
Plasma Metanephrines Interpreter
Plasma free metanephrines are close to 99% sensitive for phaeochromocytoma and paraganglioma, and that sensitivity is bought with specificity: in unselected testing the false-positive rate is around 20 to 25%. This page takes a raised result, the posture it was drawn in, the drugs the patient was on and how ill they were, and says whether it is likely to be real. The single most useful rule is that an elevation of three times the upper reference limit or more is rarely a false positive, and a marginal one usually is. For the arithmetic, see the plasma metanephrine unit converter and the plasma normetanephrine unit converter.
Is this metanephrine real?
Result + confounders → true or false positiveA 54-year-old on amitriptyline for neuropathic pain, screened after an adrenal nodule was seen incidentally. Supine sample, read against a supine interval, patient well. Normetanephrine 1,370 pmol/L against an upper reference limit of 610 pmol/L; metanephrine within range.
The three numbers that decide whether an elevation is real
About one and a half to three times — equivocal. Repeat supine and off interfering drugs; clonidine suppression if it persists.
Just above the limit — most of these are not tumours. Overall false-positive rate in unselected testing is around 20 to 25%.
Posture — seated sample against a supine interval took false positives from 1.1% to 24.6% in 183 patients, with sensitivity unchanged (Casey 2017).
- why multiples and not concentrations
- because the upper reference limit is the part that varies. Casey’s laboratory used 610 pmol/L for supine normetanephrine and 1,180 pmol/L for seated — the same analyte, the same platform, a two-fold difference. Method, age and posture all move it. A page that printed one number as the upper limit would be making the error it is trying to prevent, so this one asks for yours
- three-fold
- the Endocrine Society guideline’s own wording is that solitary increases elevated three-fold or more above upper cutoffs are rare as false positives and should be followed up in most cases by imaging. Three, not four. It is a statement about the rarity of large false positives, not a diagnostic cut-off, and it does not mean that anything below three-fold is normal
- normetanephrine against metanephrine
- normetanephrine comes from noradrenaline and is made by adrenal and extra-adrenal tumours alike; metanephrine comes from adrenaline, which needs the adrenal enzyme phenylethanolamine N-methyltransferase, so a raised metanephrine points to an adrenal tumour. An isolated normetanephrine rise is both the commonest true pattern for a paraganglioma and the commonest false positive, which is why this page asks which one is raised
- 3-methoxytyramine
- the metabolite of dopamine, and the one that is not on every panel. A purely dopamine-secreting paraganglioma can present with normal metanephrine and normetanephrine, and these tumours are more often extra-adrenal, more often SDHB-related and more often malignant. If the clinical or genetic suspicion is high and the standard panel is normal, ask whether 3-methoxytyramine was measured
- LC-MS/MS, not immunoassay
- recommendation 1.2 of the guideline asks for liquid chromatography with mass spectrometric or electrochemical detection rather than other methods, because immunoassays substantially underestimate plasma concentrations and have lower diagnostic sensitivity. If your laboratory uses an immunoassay, a normal result is less reassuring than the 99% figure suggests
- clonidine suppression
- 300 µg per 70 kg orally, baseline after 20 minutes supine, second sample at three hours. Positive for a tumour when plasma normetanephrine is still elevated at three hours and has fallen by less than 40% from baseline; the guideline quotes a purported specificity of 100% and a sensitivity of 97%. It needs supervision, because clonidine lowers blood pressure
Worked example
A 54-year-old on amitriptyline for neuropathic pain, screened after an adrenal nodule was seen incidentally. Supine sample, read against a supine interval, patient well. Normetanephrine 1,370 pmol/L against an upper reference limit of 610 pmol/L; metanephrine within range.
1,370 ÷ 610 = 2.25 times the upper reference limit — above the limit, and below the three-fold line at which a false positive becomes rare
Posture and interval match, and the patient was well, so two of the three big confounders are excluded
The third is present: amitriptyline is a tricyclic antidepressant, on Table 7 of the Endocrine Society guideline for both normetanephrine and metanephrine
Isolated normetanephrine is also the pattern tricyclics produce, and tricyclics with phenoxybenzamine account for 41 to 45% of raised normetanephrine in patients without a tumour
So the likeliest explanation is the drug. Discuss withdrawal with the prescriber, allow about two weeks, and repeat supine
Had the same patient's normetanephrine been 1,900 pmol/L — 3.1 times the limit — the answer would have changed: three-fold or more is rarely a false positive even with a drug on board, and the next step would have been imaging rather than a repeat
Drugs that falsely raise plasma metanephrines
| Drug | Raises | How much it matters |
|---|---|---|
| Tricyclic antidepressants | Normetanephrine and metanephrine | Most. With phenoxybenzamine, 41–45% of raised normetanephrine in patients without a tumour |
| Phenoxybenzamine | Normetanephrine and metanephrine | Most, and awkward — it is often being given because a phaeochromocytoma is suspected |
| SNRIs (venlafaxine, duloxetine) | Normetanephrine | Documented above 4 times the upper reference limit — high enough to mimic a tumour |
| Monoamine oxidase inhibitors | Normetanephrine and metanephrine | Substantial |
| Paracetamol | Normetanephrine and metanephrine | Analytical, not pharmacological — depends on your laboratory’s method. Ask |
| Labetalol, sotalol, methyldopa | Normetanephrine and metanephrine | Listed in the guideline’s Table 7 |
| Sulfasalazine | Metanephrine | Listed in the guideline’s Table 7 |
| Buspirone | Normetanephrine | Listed in the guideline’s Table 7 |
| Cocaine and sympathomimetics | Normetanephrine | Listed in the guideline’s Table 7 |
| Levodopa | 3-methoxytyramine | Matters only if the dopamine metabolite was measured |
| SSRIs | Nothing | Not on the list — no increase in plasma metanephrines |
What posture does to the same 183 patients
| Reference interval used | Sensitivity | Specificity | False positives |
|---|---|---|---|
| Seated interval on seated samples | 100% | 98.9% | 2 of 183 (1.1%) |
| Supine interval on the same seated samples | 100% | 74.7% | 45 of 183 (24.6%) |
Why this test is over-called, and what actually separates signal from noise
Plasma free metanephrines are the most sensitive biochemical test available for phaeochromocytoma and paraganglioma, at close to 99%. That is a real achievement and it rests on a mechanism rather than on assay refinement: a catecholamine-secreting tumour metabolises catecholamines continuously inside its own cells, producing a steady output of metanephrine and normetanephrine, whereas the secretion of adrenaline and noradrenaline themselves is episodic and can be entirely normal between surges. Measuring the metabolites therefore catches the tumour on a day when the patient has no symptoms.
The price is specificity, and it is paid by a much larger group of people. Phaeochromocytoma is rare; the test is sent often. Fagundes and Almeida put the false-positive rate for plasma free or urinary fractionated metanephrines in unselected populations at around 20 to 25%, and attribute roughly a fifth of those to drugs. Because the tumour is rare and the false positives are not, the positive predictive value of a marginal elevation in an unselected patient is low — which is a statement about arithmetic rather than about the assay.
Three things cause nearly all of it, and all three are askable. The first is posture. Standing or sitting activates the sympathetic nervous system and raises normetanephrine, so a seated sample read against a supine reference interval is being compared with the wrong number. Casey and colleagues measured what that costs: applying supine intervals to 183 seated samples took the false-positive rate from 1.1% to 24.6% while sensitivity stayed at 100%. The second is medication, and it is concentrated in a small number of drugs — tricyclic antidepressants and phenoxybenzamine between them account for 41 to 45% of raised normetanephrine in patients without a tumour, and venlafaxine has been documented above four times the upper limit. The third is acute illness, which raises the metabolites genuinely rather than artefactually, which is why no correction exists for it.
Against all of that, the most useful single discriminator is magnitude. The Endocrine Society guideline states that solitary increases elevated three-fold or more above upper cutoffs are rare as false positives and should be followed up in most cases by imaging. Below that, and particularly below about twice the upper limit, a confounder is more often the answer than a tumour, and the correct next step is usually a properly drawn repeat rather than a scan. Where a repeat stays equivocal, the guideline offers the clonidine suppression test. For the unit arithmetic, use the plasma metanephrine unit converter and the plasma normetanephrine unit converter; for the adrenal lesion that often prompts the test in the first place, the adrenal incidentaloma interpreter.
Frequently asked questions
How high does a metanephrine have to be to mean something?
Three times the upper reference limit is the number the Endocrine Society guideline gives: "Findings of solitary increases in either normetanephrine or metanephrine elevated 3-fold or more above upper cutoffs are also rare as false-positives and should be followed up in most cases by imaging." That is a statement about how rarely large false positives occur, not a diagnostic cut-off, and it cuts one way only — a result below three-fold is not normal, it is equivocal. In practice a marginal elevation in a well patient with no confounder is most often repeated rather than scanned, and an elevation of three-fold or more on a clean sample goes to imaging.
Does it matter whether the blood was taken sitting or lying down?
Enough to change the answer. The guideline suggests drawing blood supine and using reference intervals established in the same position, and quantifies the mismatch in both directions: seated sampling produces a 2.8-fold increase in false positives, and using seated intervals on supine samples produces a 3-fold increase in false negatives. Casey and colleagues measured the practical cost in 183 patients — applying supine intervals to seated samples took false positives from 2 patients to 45, specificity from 98.9% to 74.7%, with sensitivity unchanged at 100%. Either protocol is defensible on its own. What is not defensible is a seated sample read against a supine interval, and that combination is common because the laboratory usually does not know how the sample was taken.
Which drugs have to be stopped before testing for phaeochromocytoma?
The plasma interference list in the guideline’s Table 7 is paracetamol, labetalol, sotalol, alpha-methyldopa, tricyclic antidepressants, buspirone, phenoxybenzamine, monoamine oxidase inhibitors, sympathomimetics and cocaine, with sulfasalazine for metanephrine and levodopa for 3-methoxytyramine. Note that the guideline does not actually recommend routine withdrawal — it says these drugs can produce mildly to markedly raised values and should be considered when interpreting the result. In practice, tricyclics and phenoxybenzamine matter most, SNRIs can produce large elevations, and paracetamol interferes with some chromatographic methods analytically rather than pharmacologically so it depends on your laboratory. SSRIs are not on the list and do not need to be stopped. Where a drug is withdrawn, about two weeks is the usual interval and the prescriber should be involved.
Can an acute illness cause a raised metanephrine?
Yes, and genuinely rather than artefactually. Severe acute and chronic illness is accompanied by sympathoadrenal activation, which raises plasma and urinary metanephrines, especially normetanephrine. The guideline names physiological stress associated with extreme illness, as in intensive care settings, among the things to consider when interpreting marked elevations. Because the analyte really does rise, there is no correction factor and no threshold that separates the two causes in that setting. If the question is urgent in an unwell patient, image rather than repeating the blood test — imaging is not confounded by illness or by any of the interfering drugs.
What is a clonidine suppression test and when is it used?
It is the guideline’s suggested way of resolving a borderline elevation that persists after a properly drawn repeat. Clonidine 300 µg per 70 kg is given orally, a baseline sample is taken after 20 minutes supine, and a second sample at three hours. Clonidine suppresses normal sympathetic noradrenaline release but not autonomous secretion by a tumour, so a result that remains elevated at three hours and has fallen by less than 40% from baseline is positive. The guideline quotes a purported diagnostic specificity of 100% with a sensitivity of 97%. It requires supervision because clonidine lowers blood pressure, and it is not universally available; the guideline’s alternatives are combining chromogranin A with urinary fractionated metanephrines, or waiting six months or more and retesting.
Related calculators
References
- Lenders JWM, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SKG, Murad MH, Naruse M, Pacak K, Young WF. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–1942. doi:10.1210/jc.2014-1498. R.1.2: liquid chromatography with mass spectrometric or electrochemical detection rather than other methods. R.1.3: "we suggest drawing blood with the patient in the supine position and use of reference intervals established in the same position". Magnitude: "Findings of solitary increases in either normetanephrine or metanephrine elevated 3-fold or more above upper cutoffs are also rare as false-positives and should be followed up in most cases by imaging." Table 6, clonidine suppression; Table 7, interfering drugs.
- Casey R, Griffin TP, Wall D, Dennedy MC, Bell M, O’Shea PM. Screening for phaeochromocytoma and paraganglioma: impact of using supine reference intervals for plasma metanephrines with samples collected from fasted/seated patients. Ann Clin Biochem. 2017;54(1):170–173. doi:10.1177/0004563216646395. 183 patients, 5 (2.7%) with confirmed phaeochromocytoma. Seated intervals on seated samples: sensitivity 100%, specificity 98.9%, 2 false positives (1.1%). Supine intervals on the same samples: sensitivity 100%, specificity 74.7%, 45 false positives (24.6%). Upper limits, pmol/L: normetanephrine 610 supine, 1,180 seated; metanephrine 310 supine, 510 seated.
- Fagundes GFC, Almeida MQ. Pitfalls in the diagnostic evaluation of pheochromocytomas. J Endocr Soc. 2024;8(6):bvae078. doi:10.1210/jendso/bvae078. False-positive rate "around 20% to 25%" in unselected populations; drugs about 20% of false positives; tricyclics and phenoxybenzamine 41–45% of raised normetanephrine in patients without PPGL; venlafaxine documented above 4 times the upper reference limit; SSRIs showed no increase; seated sampling in earlier series gave specificity of about 76–85% with sensitivity 93–97%.
- Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev. 2004;56(3):331–349. doi:10.1124/pr.56.3.1. The mechanistic basis for measuring metabolites rather than catecholamines: continuous intratumoural metabolism against episodic secretion.
Medical Disclaimer: The tools and content provided here are for educational and reference purposes only. They are not intended to substitute for professional medical advice, diagnosis, or treatment. Clinical decisions should always be based on the comprehensive assessment of a qualified healthcare professional.