Metanephrines for Pheochromocytoma

Pheochromocytoma is a tumor arising from chromaffin cells of the adrenal medulla. Pheochromocytoma and other tumors derived from neural crest cells, such as paragangliomas and neuroblastomas, secrete the catecholamines, epinephrine and norepinephrine. The ratio of epinephrine to norepinephrine is normally 0.2. Norepinephrine is synthesized from tyrosine via dopa and dopamine in the brain, chromaffin tissue, and sympathetic nerve endings. Epinephrine is formed from norepinephrine in adrenal chromaffin cells. Both compounds are inactivated by catechol-O-methyl transferase to form normetanephrine and metanephrine. Plasma metanephrines exist as free ( < 7%) and conjugated (93%) forms. Some normetanephrine and metanephrine is converted to vanillylmandelic acid (VMA). Urine contains small amounts of catecholamines and much larger amounts of metanephrine, normetanephrine, and VMA.

Pheochromocytomas occur in about one of every 1000 hypertensive patients; about half of those affected have paroxysmal hypertension. They occur equally in men and women, primarily during the third through fifth decades of life. Symptoms are dependent on the quantity of catecholamine secreted and whether the release is sustained or intermittent. Most tumors usually secrete more norepinephrine than epinephrine. Patients typically present with dramatic paroxysms of hypertension accompanied by severe headache, pallor, drenching perspiration, and palpitations. Paroxysms may occur anywhere from once a year to several times a day and usually persist for 10 to 60 minute's duration.

The biochemical diagnosis of pheochromocytoma depends on the demonstration of excessive production of these hormones. Measurement of metanephrines is more sensitive than measurement of catecholamines because they are more stable. The most reliable screening tests for diagnosis of pheochromocytoma is measurement of plasma-free fractionated metanephrines and urinary fractionated metanephrines, in which normetanephrine and metanephrine are quantitated separately. In patients that are highly suspect for pheochromocytoma the best strategy is to initially test for plasma free fractionated metanephrines because it is the most sensitive assay. The 24-hour urinary fractionated metanephrines, which is a more specific assay, should be used as the first test for low suspicion cases and also as a confirmatory study in patients with < 2-fold elevation in plasma free fractionated metanephrines.

Test	Sensitivity (%)	Specificity (%)
Plasma free metanephrines	99	89
Urinary fractionated metanephrines	97	69
Urinary catecholamines	86	88
Plasma catecholamines	84	81
Urinary total metanephrines	77	93
Vanillylmandelic acid (VMA)	64	95

The high sensitivity of plasma free or urinary fractionated metanephrines means that normal test results almost always exclude the presence of pheochromocytoma. Exceptions include asymptomatic small tumors that produce and metabolize negligible amounts of norepinephrine or epinephrine. Also, patients being treated with metyrosine may have artifactually decreased plasma metanephrine levels.

Elevated metanephrine levels do not always indicate pheochromocytoma. Elevated results may be caused by physical stress or medications. Many of the patients being tested for pheochromocytoma have underlying clinical conditions that are associated with increased sympathetic activity such as hypertension, heart failure, stroke, baroreflex failure and cardiogenic shock.

Substances that increase endogenous catecholamine levels can result in borderline elevations of plasma metanephrines. Examples include:

Monoamine oxidase inhibitors
Catecholamine reuptake inhibitors including cocaine & local anesthetics
Some anesthetic gases, particularly halothane
Withdrawal from medical or recreational sedatives such as alcohol, benzodiazepines, opioids and central acting anti-hypertensive drugs

Tricyclic antidepressants, levodopa and beta blockers such as labetalol and sotalol may significantly elevate urinary metanephrine levels. Usually these conditions can be distinguished from pheochromocytoma by the magnitude of the metanephrine increase above the reference range. Hypertensive patients without pheochromocytoma may have total urinary metanephrine levels up to 1300 ug per 24 hours, while patients with pheochromocytoma usually have higher levels. Further clinical investigation and radiographic studies are warranted for patients with total metanephrine values >1300 ug/24 hours. Pheochromocytoma is likely if the plasma free normetanephrine level is >1.40 nmol/L (reference range is < 0.9) and if the plasma free metanephrine level is >0.5 (reference range < 0.5 nmol/L).

For a patient with episodic hypertension, specimen collection should ideally begin with the onset of a spell. If possible, medications associated with elevated catecholamines should be discontinued at least one week prior to specimen collection. Specimen requirement for plasma fractionated free metanephrines is one lavender top (EDTA) tube of blood. Specimen requirement for urinary fractionated metanephrines is 10 mL of urine from a 24-hour urine specimen collected in a container with 10 g of boric acid or 25mL of 50% acetic acid. Urine specimen should be kept cold during collection.




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