Plasma normetanephrine

After the potential confounding influence of medications or other causes of false-positive results have been eliminated, some consideration should be given to the choice of additional biochemical tests and patterns of results necessary for more firmly establishing or refuting the diagnosis of a pheochromocytoma. When initial testing yields elevations in plasma normetanephrine, metanephrine, or both amines, this may be corroborated by a similar pattern of results after additional measurements of urinary normetanephrine and metanephrine. Conversely, when initial testing yields positive results for urinary fractionated metanephrines, additional measurements of plasma free metanephrines are useful. 

Procedure The test is best performed in the morning after an overnight fast. The patient remains recumbent throughout the entire procedure. A forearm venous cannula is placed for baseline and 3-hour blood sampling during the procedure. After at least 20 minutes of supine rest, a baseline blood sample is drawn in a heparinized tube. Clonidine, 4.3 pg/kg of body weight, is then given orally, and a repeat blood sample is drawn 3 hours later. The samples are analyzed for plasma catecholamines, with plasma normetanephrine measurement also recommended. 

Isolated deficiencies of MAO A and B are extremely rare and are associated with distinct clinical and neurochemical phenotypes. Deficiency of MAO A is associated with a behavioral disorder characterized by increased aggressiveness. Plasma and urinary levels of deaminated metabolites of catecholamines are severely decreased, whereas levels of normetanephrine and metanephrine are increased. An increased ratio of plasma normetanephrine to DHPG has therefore been proposed to provide a sensitive marker for the deficiency state. In contrast, deficiency of MAO B is associated with a mild phenotype, the only biochemical alteration is increased urinary excretion of phenylethyiamine. 

Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Reiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 1999 340 1872-9. 

Kobayashi K, DeQuattro V, Kohoch R, Miano L. A radioenzymatic assay for plasma normetanephrine in man and patients with pheochromocytoma. Life Sci 1980 26 567-73,... 

Pheochromocytoma is a tumor of the adrenal medulla or sympathetic ganglion cells. The tumor secretes catecholamines, especially norepinephrine and epinephrine. The patient in the case study at the beginning of the chapter had a left adrenal pheochromocytoma that was identified by imaging. In addition, she had elevated plasma and urinary norepinephrine, epinephrine, and their metabolites, normetanephrine and metanephrine. 

In old rats (26 months old), oral administration of EGb (10 mg/kg and 30 mg/kg, for 7 days) produces elevations of 5-HT in the frontal cortex, hippocampus, striatum and hypothalamus, and of dopamine levels in the hippocampus and hypothalamus compared with controls. On the other hand, EGb decreases the 5-HT level in the pons, and those of norepinephrine in the hippocampus and hypothalamus [157]. In this connection, Racagni et al. [158] showed that the O-methylated amine metabolite of norepinephrine, normetanephrine, was markedly elevated (+500%) in the cerebral cortex by chronic oral administration of EGb (100 mg/kg, for 14 days), suggesting an increase of norepinephrine turnover. In addition, treatment with EGb (50 or 100 mg/kg/day, for 20 days) diminished the increased plasma levels of epinephrine, norepinephrine, and corticosterone induced by acute auditory stress in young and old rats [113]. 

Pagliari, R. Cottet-Emard, J.M. Peyrin, L. Determination of free and conjugated normetanephrine and metanephr-ine in human plasma by high-performance hquid chromatography with electrochemical detection. J. Chromatogr. 

The high diagnostic sensitivity of measurements of plasma free or urinary fractionated normetanephrine and metanephrine makes these tests the most suitable choice for the initial work up of a patient with a suspected pheochromocytoma. Negative results by these tests virtually exclude a pheochromocytoma, whereas negative results by other tests do not. Exceptions include small or microscopic ([Pg.1047]

Increases in plasma or urinary concentrations of L-dopa, dopamine, and methoxytyramine are not sensitive or specific markers of pheochromocytomas. However, when such increases accompany large increases in norepinephrine and normetanephrine, the pattern suggests metastatic disease. Pheochromocytomas that produce exclusively dopamine are extremely rare, but can be found in patients with paragangliomas, particularly where these have metastasized. 

Interpretation For optimum clinical specificity, a positive result highly suggestive of a pheochromocytoma includes an elevation of norepinephrine and normetanephrine at 3 hours and a failure to suppress norepinephrine more than 50% and normetanephrine more than 40 % below the baseline plasma level. 

Additional markers of catecholamine overproduction have been employed to improve the biochemical detection of neuroblastomas. Free dopamine may be abnormal in urine from neuroblastoma patients with VMA and HVA excretion. Combined testing for VMA, HVA, and dopamine may therefore improve tumor detection, and in 1993 an international consensus report on neuroblastoma diagnosis added dopamine to the Hst of acceptable measurements to document the adrenergic nature of the tumor. Plasma measurements of dopamine and L-dopa, the amino acid precursor of dopamine, may also have clinical value and allow the alternate use of plasma. Measurement of methylated metabolites, especially normetanephrine, has also been explored. When urinary normetanephrine, metanephrine, methoxytyra-mine, dopamine, norepinephrine, VMA, and HVA were measured, clinical sensitivity for detection of neuroblastomas was 97% to 100% when results of normetanephrine testing were coupled either with VMA in the infants or with HVA in children greater than age 1. Even with an extended panel of catecholamines and metabolite measurements, a low incidence of nonsecreting tumors continues to be identified and should be considered in the interpretation of a negative test result. 

Interpretation of a biochemical test result as normal or abnormal depends on availability of valid reference intervals (see Chapter 16). For tests of a single analyte, such as VMA, it can be expected that at least 2.5% of patients without pheochromocytomas will have values for the analyte above the upper reference limit and 2.5% below the lower reference limit. Up to a 5% incidence of false-positive results might be expected for tests of pairs of analytes, such as norepinephrine and epinephrine in tests of urinary or plasma catecholamines or normetanephrine and metanephrine in tests of plasma free or urinary fractionated metanephrines. False-positive rates usually, however, tend to be higher than expected this is likely due to reduced control over sampling conditions and sources of interference or differences in clinical characteristics of reference and patient populations. 

Reference intervals for plasma and urinary catecholamines and catecholamine metabolites also differ according to sex and age. Females have lower plasma concentrations of epinephrine and metanephrine than males. Similarly, 24-hour urinary outputs of catecholamines and metanephrines are lower in women than men for epinephrine this difference remains significant when values are normalized for creatinine excretion Plasma levels of norepinephrine and normetanephrine increase with advancing age in adults, whereas plasma levels of epinephrine and metanephrine are little affected. Age-related increases in 24-hour urinary outputs of norepinephrine and normetanephrine have also been reported,but not consistently by all studies. In general, the influences of age... 

The free 0-methylated amine metabolites are present in plasma at picomolar concentrations that have made their accurate measurement technically difficult. Measurements of plasma metanephrines therefore represent relatively recent developments. The.first method enabling accurate measurement of plasma free normetanephrine involved a radioenzymatic assay in which normetanephrine was converted to H-iabeled metanephrine using preparations of the enzyme phenylethanolamine-N-methyltransferase, incubated with H-methyi-labeled S-adenosylmethionine. This method, however, did not allow measurements of metanephrine or methoxytyramine, and therefore had limited clinical utility. 

Kobayashi K, Kolloch R, Dequattro V, Miano L. Increased plasma and urinary normetanephrine in young patients with primary hypertension. Clin Sci (Lond) 1979 57 Suppl 5 173s-6s. 

Determination of 3-Methoxytyramine, Normetanephrine, and Metanephrine in Human Plasma by Gas Chromatography... 

Eisenhofer G, Lenders JW, Timmers H, Maimelli M, Grebe SK, Hofbauer LC, et al. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Qin Chem... 

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