Plasma Metanephrines Are Markers of Pheochromocytoma Produced by Catechol-O-Methyltransferase Within Tumors

Abstract

This study examined whether the high sensitivity of plasma free metanephrines for diagnosis of pheochromocytoma may result from production of free metanephrines within tumors. Presence in pheochromocytomas of catechol-O-methyltransferase (COMT), the enzyme responsible for conversion of catecholamines to metanephrines, was confirmed by Western blot analysis, enzyme assay, and immunohistochemistry. Western blot analysis and enzyme assay indicated that membrane-bound and not soluble COMT was the predominant form of the enzyme in pheochromocytoma. Immunohistochemistry revealed colocalization of COMT in the same chromaffin cells where catecholamines are translocated into storage vesicles by the vesicular monoamine transporter. Levels of free metanephrines in pheochromocytoma over 10,000 times higher than plasma concentrations in the same patients before removal of tumors indicated production of metanephrines within tumors. Comparisons of the production of metanephrines in patients with pheochromocytoma with production from catecholamines released or infused into the circulation indicated that more than 93% of the consistently elevated levels of circulating free metanephrines in patients with pheochromocytoma are derived from metabolism before and not after release of catecholamines into the circulation. The data indicate that the elevated plasma levels of free metanephrines in patients with pheochromocytoma are derived from catecholamines produced and metabolized within tumors. Some tumors do not secrete catecholamines, but all appear to metabolize catecholamines to free metanephrines, thus explaining the better sensitivity of plasma free metanephrines over other tests for diagnosis of pheochromocytoma.

Review of Pediatric Pheochromocytoma and Paraganglioma

“…Metabolic processes unrelated to the tumor produce VMA, decreasing its sensitivity for diagnosis. Conversely, the production of plasma free metanephrines is constant and independent of the release of catecholamines, which is episodically secreted (47), making these the gold standard for diagnosis (46, 48). The degree of elevation of catecholamine metabolites (49) ought to be assessed when evaluating for catecholamine-secreting tumors, as shown in Figure 2.…”

Subtype Diagnosis of Primary Aldosteronism: Is Adrenal Vein Sampling Always Necessary?

“…The main advantage of a metanephrine measurement is that it avoids cortisol fluctuation (metanephrine is produced continuously from epinephrine leaking from storage vesicles within adrenal medullary cells), it is not influenced by ACTH (1,24) stimulation, and the gradient between the adrenal and peripheral sample is significantly higher [77]. In fact, metanephrine is produced almost exclusively in the adrenals [78] and is rapidly cleared from the circulation, allowing a greater adrenal/peripheral ratio compared to the cortisol ratio. Furthermore, a metanephrine assay may be particularly useful in some specific situations in which a cortisol assay could give misleading information (e.g., the co-existence of subclinical hypercortisolism) [79].…”

THERAPY OF ENDOCRINE DISEASE: Treatment of malignant pheochromocytoma and paraganglioma

“…The most robust studies of the characterization of MPP patients at the time of the diagnosis have suggested that metastatic adrenal and extra-adrenal tumors occur at equal rates and that the survival rates of metastatic adrenal and extraadrenal tumors overlap (2); w60% of MPP patients have tumor burden-and hormone-related manifestations (e.g., pain, hypertension, and constipation) (3); most MPPs produce noradrenaline and normetanephrine and/or dopamine and methoxytyramine, which partly reflects the higher risk of malignancy associated with SDHB mutations and extra-adrenal locations (4,5,6,7,8); most MPP patients have apparently sporadic tumors or tumors associated with germline or somatic mutations of the succinate dehydrogenase subunit B (SHDB) gene (2,9,10). The high prevalence of SDHB mutations (30-50% of patients) supports the screening of all patients with MPPs for such mutations.…”