Abstract

Background: Metanephrines (MTN), which include normetanephrine (NMN) and metanephrine (MN), are metabolites of catecholamines formed by o-methylation of norepinephrine and epinephrine respectively, by the enzyme catechol-o-methyl transferase present in its most active form in the chromaffin cell derived tumors, namely pheochromocytoma and paraganglioma (PPGL). The initial biochemical work-up for PPGL aims at measuring MTN in plasma (PMTN) or urine (UMTN), comprising of plasma free metanephrine (PMN), and normetanephrine (PNMN), and/or 24-hour urinary fractionated metanephrine (UMN) and normetanephrine (UNMN). Marked MTN elevations (>3 times the upper limit of normal [ULN]) are highly suggestive of PPGL.1 Rarely, marked MTN elevations have been reported in stress cardiomyopathy, myocardial infarction and with certain medications. Reversible, marked MTN elevations have been reported in two cases of hypertensive emergency (HTNE) in whom imaging did not reveal PPGL.2 This finding questions the validity of measuring MTN in HTNE given the potential of ‘false positive’ MTN elevations, which may subject patients to unnecessary imaging studies, radiation or contrast exposure. Methods: To further investigate the frequency of marked MTN elevations in HTNE, we retrospectively studied the results of PMTN and UMTN measurements in 48 patients (59.7±15.6 years; 48% female; BMI: 31±9.7 kg/m2) hospitalized for HTNE, with end-organ damage manifesting either as encephalopathy (19%), stroke (30%), congestive heart failure (CHF; 54%), myocardial ischemia (MI; 17%), or acute renal injury (AKI; 31%). PMN and PNMN were measured in 47 patients, UMN and UNMN were measured in 16 patients and 15 patients had both PMTN and UMTN measured. Results: Multiple regression analysis did not reveal a significant association between PMTN/UMTN levels and systolic/diastolic blood pressures, type of end-organ damage, or intake of medications known to alter MTN levels. Only 3 (6%) patients had marked MTN elevations, specifically of PNMN (647, 521, and 453 pg/ml; ULN: 148 pg/ml). All 3 patients had CHF and one also had MI and AKI. Imaging in two of the patients did not reveal evidence of PPGL. Imaging for the third patient is in progress. Conclusions: Marked MTN elevations in HTNE are uncommon. When present, they occur mostly due to a non-PPGL condition, where imaging is unlikely to reveal a PPGL. Therefore, we recommend against measuring MTN in the setting of an obvious precipitating cause for HTNE in order to avoid unnecessary testing and imaging. Testing for MTN in HTNE should be pursued only when there is a strong suspicion for PPGL with no clear precipitating cause. However, should testing be performed, marked MTN elevations should not be disregarded as a commonly occurring result of HTNE.

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