Plasma Metanephrines and Catecholamines

Catecholamines (adrenaline, noradrenaline, dopamine) are made in the adrenal medulla, sympathetic nerves and paraganglia. They are metabolised inside the same cells by catechol-O-methyltransferase to metanephrine, normetanephrine and 3-methoxytyramine (together called metanephrines), which leak continuously into the blood independent of the episodic catecholamine release.

Free plasma metanephrines (or 24-hour urinary fractionated metanephrines) are the first line test for phaeochromocytoma and paraganglioma, because the continuous production makes them more sensitive than catecholamines. They are measured by liquid chromatography with mass spectrometry or electrochemical detection.

The tests diagnose phaeochromocytoma and paraganglioma (together PPGL), a rare, treatable cause of hypertension and a surgical emergency if unrecognised. Catecholamines and vanillylmandelic acid have a role in neuroblastoma.

PPGL occurs in 0.1 to 0.6% of patients with hypertension and in 5% of adrenal incidentalomas. Annual incidence is about 2 to 8 per million. About 40% are linked to germline variants (RET, VHL, NF1, SDHx, MAX, TMEM127), and up to a quarter of those are not suspected clinically. About 10% are malignant, and the risk is higher with extra-adrenal tumours and SDHB variants.

Indications. Paroxysms of headache, sweating and palpitations, resistant or paroxysmal hypertension, hypertension at a young age, adrenal incidentaloma with unenhanced CT density over 10 Hounsfield units, family history or syndrome (MEN2, von Hippel-Lindau, neurofibromatosis type 1, hereditary paraganglioma), hypertensive crisis during anaesthesia or with certain drugs, dilated cardiomyopathy of unclear cause, and surveillance after resection.

Specimen. Plasma free metanephrines: a supine sample after 20 to 30 minutes of rest with an indwelling cannula (a seated sample has a higher false positive rate, and an upper limit adjusted for posture is then used), collected into EDTA or heparin and sent on ice. Fasting overnight and avoiding caffeine are advised. Twenty four hour urine: collected into acid with creatinine measured. Avoid interfering drugs when possible.

Reference limits depend on the method, posture and age. Typical upper limits for supine sampling are metanephrine about 0.3 nmol/L, normetanephrine about 0.6 nmol/L, and methoxytyramine about 0.2 nmol/L. Local ranges take precedence.

Interpretation.

• Normal plasma metanephrines (supine, no interfering drugs) have a negative predictive value over 99% and effectively exclude PPGL, except in some dopamine secreting tumours (add methoxytyramine) and in tumours with episodic secretion.
• Normetanephrine or metanephrine more than 3 to 4 times the upper limit has a positive predictive value close to 100%, and imaging and genetic testing follow.
• Values 1 to 3 times the upper limit are indeterminate and need repeat sampling after medicines are checked, a clonidine suppression test or another test.
• A rise limited to normetanephrine suggests a noradrenergic tumour (extra-adrenal, and the usual pattern in VHL, SDHx and NF1). A rise in metanephrine suggests adrenal origin with adrenaline production (MEN2, NF1). A raised methoxytyramine suggests a dopaminergic or SDHx-related tumour with a higher risk of metastasis.

Plasma catecholamines. Pulsatile and responsive to stress, with a lower sensitivity (about 85%) and specificity than metanephrines. They are used in neuroblastoma (with homovanillic acid and vanillylmandelic acid in urine) and as an extra test in borderline cases. Noradrenaline over 11.8 nmol/L (2000 pg/mL) is nearly always PPGL.

Urinary fractionated metanephrines. Sensitivity about 90 to 95%, and specificity 90 to 95%, which is lower than plasma testing in some series. Used when plasma testing is unavailable or in children.

Clonidine suppression test. Clonidine 0.3 mg given orally and plasma normetanephrine measured at 3 hours. Failure to fall by 40% or more, and a value over the upper limit, supports PPGL, and an appropriate fall suggests a false positive from sympathetic activation.

Causes of false positive results.

• Drugs: tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, monoamine oxidase inhibitors, phenoxybenzamine, sympathomimetics, decongestants (pseudoephedrine), levodopa, amphetamines, cocaine, labetalol (assay specific), buspirone, sulfasalazine (assay specific), and paracetamol (some methods).
• Physiological and clinical: stress, acute illness, sleep apnoea, heart failure, withdrawal from clonidine or alcohol, intracranial pathology, severe pain, seated sampling, caffeine, nicotine, and kidney failure.

Genetic and syndromic associations.

• MEN2: phaeochromocytoma with medullary thyroid carcinoma (calcitonin) and hyperparathyroidism.
• Von Hippel-Lindau: haemangioblastomas, renal cell carcinoma and pancreatic tumours.
• Neurofibromatosis type 1: neurofibromas and café-au-lait spots.
• SDHx: head and neck paraganglioma, abdominal paraganglioma, gastrointestinal stromal tumours and renal cancer.

Critical values and findings needing immediate action.

• Hypertensive crisis, acute heart failure, takotsubo like cardiomyopathy or arrhythmia with markedly raised metanephrines: alpha blockade first (phenoxybenzamine or doxazosin), then beta blockade, volume expansion and surgery with an experienced anaesthetic team.
• Raised metanephrines in a patient scheduled for surgery or biopsy of an adrenal mass.
• Shock or multiorgan failure with suspected catecholamine crisis.
• Pregnancy with severe hypertension, headache and sweating.
• Beta blocker or glucagon given to a patient with unrecognised PPGL, which risks a crisis.

Interferences and pitfalls.

• A seated sample, a missed rest period or a stressful venepuncture causes false positives, and the supine sample with rest is essential.
• Interfering drugs are the commonest cause of false positives. Stopping them (when safe) for 2 weeks before retesting resolves most.
• Mass spectrometry has fewer drug interferences than electrochemical methods.
• Metanephrines are stable in EDTA on ice. Delays and room temperature raise values.
• Normal values can occur in very small tumours, in the first hours after a paroxysm, and in tumours secreting only dopamine.
• A positive test needs imaging (CT or MRI of the abdomen and pelvis, then functional imaging with gallium-68 DOTATATE PET or MIBG), and genetic counselling.
• Chromogranin A is a nonspecific marker, and not a screening test.

Special groups.

• Children: more often hereditary, bilateral and extra-adrenal, and urine testing is used. Neuroblastoma is the commoner catecholamine secreting tumour of childhood.
• Pregnancy: untreated PPGL is dangerous, and diagnosis rests on metanephrines with MRI.
• Older adults: sporadic, unilateral adrenal tumours are typical.
• Patients with an adrenal incidentaloma: only masses with unenhanced density over 10 Hounsfield units need testing.
• Regions: access to genetic testing and functional imaging is limited in many settings.

Follow up tests. Repeat metanephrines off interfering drugs, plasma methoxytyramine, clonidine suppression test, CT or MRI, gallium-68 DOTATATE PET or MIBG, genetic testing (RET, VHL, SDHx, NF1, MAX, TMEM127), calcitonin and calcium, chromogranin A, echocardiography, ECG, glucose, and family screening.