Metanephrines for Pheochromocytoma

Pheochromocytoma is a rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla that occurs in about one of every 1000 hypertensive patients. This tumor occurs equally in men and women, primarily during the third through fifth decades of life. Prevalence is higher in patients with the following clinical situations:

  • Hyperadrenergic spells
  • Hypertension onset at young age (<20 years)
  • Hypertension resistant to treatment
  • Positive family history
  • Predisposing syndrome such as MEN 2 or neurofibromatosis 1
  • History of GIST or pulmonary chondromas
  • Incidentally discovered adrenal mass
  • Idiopathic dilated cardiomyopathy
  • Pressor response to anesthesia, surgery or angiography

Symptoms are dependent on the quantity of catecholamine secreted and whether the release is sustained or intermittent. Approximately half of those affected exhibit paroxysmal hypertension. 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 minutes.

Pheochromocytoma produces the catecholamines, epinephrine and norepinephrine. Within the tumor cells, these catecholamines are converted into metanephrine and normetanephrine. Both metanephrines and catecholamines are secreted into the circulation, where metanephrine and normetanephrine are further metabolized to conjugated metanephrines and vanillylmandelic acid.

The biochemical diagnosis of pheochromocytoma depends on the demonstration of excessive production of these hormones. Measurement of metanephrines is more sensitive than catecholamines because they are more stable and reach higher, sustained levels in the circulation. Measurement of plasma free metanephrines is the best initial test for excluding pheochromocytoma. A plasma test is much simpler to collect than a 24 hour urine specimen and is more suitable in children and in patients with renal insufficiency.

Pheochromocytoma is likely if the plasma free normetanephrine level is at least 1.5 x the upper limit of the reference range and if the plasma free metanephrine level is above the reference range. Sensitivity of plasma metaneprhines is 99-100%, making it extremely unlikely that individuals with normal levels have a pheochromocytoma.

Specificity of plasma metaneprhines is 85-89%.The lower specificity means that many patients with hypertension and mildly elevated plasma metanephrines probably do not have pheochromocytoma. Elevated results may be caused by physical stress or medications. Most false positive results for plasma metanephrines simply reflect inadequate preparation of patients before phlebotomy. Blood collection should be performed after at least 30 minutes of supine rest, with the patient as comfortable and stress-free as possible. If possible, medications associated with elevated metanephrines should be discontinued at least one week prior to specimen collection.

Drugs that increase endogenous catecholamine levels can produce 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

Due to the low prevalence of pheochromocytoma , mildly elevated plasma free metanephrine levels should be confirmed with measurement of fractionated urinary metanephrines in a 24 hour urine collection. For a patient with episodic hypertension, specimen collection should ideally begin with the onset of a spell.

Further clinical and radiologic investigation is warranted in patients whose total urinary metanephrine levels are approximately 2 times the upper limit of normal. Further investigation may also be indicated for those patients with lower levels of total urinary metanephrine if either the normetanephrine or the metanephrine fraction of the total metanephrines exceed their respective upper limit for hypertensive patients.

Specimen requirement for plasma fractionated free metanephrines is one lavender top (EDTA) tube of blood. Specimen requirement for urinary fractionated metanephrines is a 24-hour urine specimen collected in a container with the appropriate preservative. Urine specimen should be kept refrigerated during collection.


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