Plasma Metanephrines in the Diagnosis of Pheochromocytoma

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Background

Pheochromocytoma is a tumor of chromaffin cells most commonly arizing from the adrenal medulla and usually presenting as hypertension. The tumor is a rare cause of hypertension, but never-the-less must be excluded in a significant number of the 400,000 Americans diagnosed with high blood pressure each year.

The clinician is usually alerted to the presence of the tumor if the patient does not respond to antihypertensive therapy or complains of symptoms such as headaches, sweatiness, palpitations or attacks of anxiety. These symptoms can reflect the effects of high circulating levels of catecholamines (norepinephrine and epinephrine) secreted by a tumor.

Measurements of catecholamines in urine or plasma or catecholamine metabolites in urine typically provide the standard initial test in the diagnosis of the tumor. However, catecholamines are not specific for the tumor, they are secreted by sympathetic nerves and the adrenal medulla and may be increased by other clinical conditions and in response to many stimuli including emotional distress. Moreover, some tumors appear to secrete catecholamines episodically and not all catecholamine metabolites are elevated in patients with pheochromocytoma.

Normetanephrine and metanephrine are O-methylated metabolites of norepinephrine and epinephrine. This report focuses on the use of plasma concentrations of these metabolites for diagnosis of pheochromocytoma.

Findings


The higher percentage of patients with elevated plasma normetanephrine concentrations than elevated norepinephrine concentrations (97% versus 68% for adrenal tumors) shows how the former measurement provides a more sensitive test for the presence of a tumor than the latter (Figure 1). The one patient with normal plasma normetanephrine concentrations (i.e below the upper reference limits) had elevated plasma metanephrine concentrations. Thus, normal plasma concentrations of normetanephrine and metanephrine exclude the presence of a pheochromocytoma, whereas normal plasma catecholamines do not.

Plasma concentrations of epinephrine and its metabolite, metanephrine, are less consistently elevated than norepinephrine and normetanephrine (Figure 2). However, a much higher proportion of patients have elevations in plasma metanephrine than epinephrine. The less consistent elevations in epinephrine and metanephrine than normetanephrine and norepinephrine reflects the predominantly noradrenergic nature of most pheochromocytomas. This is particularly true of extra-adrenal tumors. In contrast, a much higher proportion of adrenal tumors secrete epinephrine or metabolize the catecholamine to metanephrine.

Interestingly, all patients with MEN-2 that we have examined to date show increases in plasma free metanephrine, indicating an adrenergic phenotype (epinephrine producers) in these patients. In contrast, patients with Von Hippel-Lindau disease show a noradrenergic phenotype (norepinephrine producers) with increases in only normetanephrine.


Out of all control subjects assayed to date, none have had plasma concentrations of metanephrine above 1.0 pmol/ml. Thus, a plasma concentration of metanephrine above this value almost certainly indicates the presence of a pheochromocytoma. Moreover a high plasma metanephrine combined with a ratio of plasma metanephrine to normetanephrine of more than 0.2 is highly indicative of an adrenal location of the tumor (Figure 3).

Conclusions/Implications

Measurements of plasma concentrations of metanephrines (normetanephrine and metanephrine) provides a test that can reliably exclude the presence of a pheochromocytoma. Other currently available tests (e.g. plasma catecholamines, urinary metanephrines, urinary VMA) can result in false-negative results in some patients with the tumor (i.e. these tests do not reliably exclude a tumor). Thus, exclusion of pheochromocytoma typically requires multiple and repeated tests carried out with considerable expense. A missed diagnosis can have disastrous consequences for the patient. The advantage of plasma free metanephrines over other tests is that these measurements appear to reliably exclude a pheochromocytoma in suspected cases so that no further tests are necessary. Apart from avoiding a missed diagnosis, there are obvious cost-benefits of this for any health-care system.

Some of this work is presented in more detail in a number of papers published since 1995.

Reprint requests should be directed to Graeme Eisenhofer at ge@box-g.nih.gov

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