Metanephrines for Pheochromocytoma

Neuroendocrine tumors are responsible for approximately 0.3% of cases of hypertension. 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

There are two types of neuroendocrine tumors: pheochromocytomas and paragangliomas. Pheochromocytoma is a rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla. Pheochromocytoma occurs equally in men and women, primarily during the third through fifth decades of life.

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.

Paragangliomas arise from chromaffin cells outside of the adrenal glands such as the sympathetic and parasympathetic ganglia. Paragangliomas originating in sympathetic paravertebral ganglia are located in the thorax, abdomen and pelvis. They produce norepinephrine and dopamine. Paragangliomas arising from parasympathetic ganglia occur in the head and neck and usually do not produce catecholamines.

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. 

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 fractionated plasma metanephrines is the best initial test for excluding pheochromocytoma. Fractionated means that metanephrine and normetanephrine are measured separately. 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.

A positive test is interpreted as an elevation of either metanephrine or normetanephrine. Pheochromocytoma or paraganglioma is likely if the plasma free normetanephrine level is 3-fold higher than the upper limit of the reference range.  Sensitivity of plasma metaneprhines is 99-100%, making it extremely unlikely that individuals with normal levels have a pheochromocytoma or paraganglioma.

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 or paraganglioma. Most false positive results for plasma metanephrines simply reflect inadequate preparation of patients before phlebotomy. Blood collection should be performed after an overnight fast and 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.

Stress, illness strenuous physical activity,  or withdrawal from opioids, benzodiazepines, alcohol or smoking may markedly increase metanephrines. Drugs that increase endogenous catecholamine levels can produce elevations of plasma metanephrines. Examples include:

Drug Metanephrine Normetanephrine
Acetaminophen Not affected Increased
Alpha Methyldopa Not affected Increased
Tricyclic antidepressants Not affected Increased
Mesalamine/salfasalazine Not affected Increased
Phenoxybenzamine Not affected Increased
Monoamine oxidase inhibitors Increased Increased
Sympathomimetics Increased Increased
Cocaine Not affected Increased
Levodopa Increased Increased

 

Due to the low prevalence of pheochromocytoma and paraganglioma, 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.

Metanephrine and normetanephrine are extracted from plasma and analyzed using liquid chromatography-tandem mass spectrometry. 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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