Plasma Normetanephrine and Metanephrine for Detecting Pheochromocytoma in von Hippel–Lindau Disease and Multiple Endocrine Neoplasia Type 2
Graeme Eisenhofer, Ph.D., Jacques W.M. Lenders, M.D., Ph.D., W. Marston Linehan, M.D., McClellan M. Walther, M.D., David S. Goldstein, M.D., Ph.D., and Harry R. Keiser, M.D.
Background The detection of pheochromocytomas in patients atrisk for these tumors, such as patients with von Hippel–Lindaudisease or multiple endocrine neoplasia type 2 (MEN-2), is hinderedby the inadequate sensitivity of commonly available biochemicaltests. In this study we evaluated measurements of plasma normetanephrineand metanephrine for detecting pheochromocytomas in patientswith von Hippel–Lindau disease or MEN-2.
Methods We studied 26 patients with von Hippel–Lindaudisease and 9 patients with MEN-2 who had histologically verifiedpheochromocytomas and 50 patients with von Hippel–Lindaudisease or MEN-2 who had no radiologic evidence of pheochromocytoma.Von Hippel–Lindau disease and MEN-2 were diagnosed onthe basis of germ-line mutations of the appropriate genes. Theplasma concentrations of normetanephrine and metanephrine werecompared with the plasma concentrations of catecholamines (norepinephrineand epinephrine) and urinary excretion of catecholamines, metanephrines,and vanillylmandelic acid.
Results The sensitivity of measurements of plasma normetanephrineand metanephrine for the detection of tumors was 97 percent,whereas the other biochemical tests had a sensitivity of only47 to 74 percent. All patients with MEN-2 had high plasma concentrationsof metanephrine, whereas the patients with von Hippel–Lindaudisease had almost exclusively high plasma concentrations ofonly normetanephrine. One patient with von Hippel–Lindaudisease had a normal plasma normetanephrine concentration; thispatient had a very small adrenal tumor (<1 cm). The highsensitivity of measurements of plasma normetanephrine and metanephrinewas accompanied by a high level of specificity (96 percent).
Conclusions Measurements of plasma normetanephrine and metanephrineare useful in screening for pheochromocytomas in patients witha familial predisposition to these tumors.
Von Hippel–Lindau disease and multiple endocrine neoplasiatype 2 (MEN-2) are multisystem neoplastic disorders, inheritedin an autosomal dominant fashion, that account for most currentlyidentified familial pheochromocytomas.1 In patients with vonHippel–Lindau disease, family-specific mutations determinethe varied clinical manifestations, which — in additionto pheochromocytomas — include retinal angiomas, cerebellarhemangioblastomas, and renal, pancreatic, and epididymal tumors.In addition to pheochromocytomas, patients with MEN-2 are predisposedto have medullary thyroid carcinoma and hyperparathyroidismin the A subtype and mucosal neuromas in the B subtype.
The recommended periodic screening for pheochromocytomas inpatients with von Hippel–Lindau disease or MEN-2 is basedon biochemical evidence of excessive catecholamine production.1,2,3,4However, inadequate sensitivity (resulting in false negativetests) is a problem with available assays of plasma and urinarycatecholamines or their metabolites.5,6,7,8,9 This lack of sensitivityis particularly troublesome in patients with von Hippel–Lindaudisease or MEN-2, in whom small suspicious masses may be identifiedby imaging studies but in whom pheochromocytomas may not secretecatecholamines in amounts sufficient to cause an abnormal resulton a biochemical test.1,10,11
A promising new biochemical test for detecting pheochromocytomasinvolves measurements of plasma normetanephrine and metanephrine,the respective O-methylated metabolites of norepinephrine andepinephrine.9 In our study we compared the sensitivity and specificityof measurements of plasma normetanephrine and metanephrine withthose of plasma and urinary catecholamines (norepinephrine andepinephrine), urinary metanephrines (normetanephrine and metanephrinecombined), and urinary vanillylmandelic acid for identifyingthe presence or absence of pheochromocytomas in patients withvon Hippel–Lindau disease or MEN-2.
Methods
Subjects
We studied 73 patients with von Hippel–Lindau diseaseand 12 patients with MEN-2. The patients were initially identifiedon the basis of their medical and family histories, and thediagnosis was confirmed by the identification of germ-line mutationsin the von Hippel–Lindau tumor-suppressor gene or theRET proto-oncogene. All patients were screened prospectivelyfor the presence of pheochromocytoma by computed tomographyand at least two of several biochemical tests. These tests weremeasurements of normetanephrine, metanephrines, and catecholaminesin plasma and of the urinary excretion of catecholamines, metanephrines,and vanillylmandelic acid.
Apart from symptoms, signs, or biochemical evidence of a pheochromocytoma,the decision to perform surgery required radiologic evidenceof a tumor. Confirmation of the presence of a pheochromocytomaand consequent inclusion in the study required a pathologicaldiagnosis of pheochromocytoma. The presence of pheochromocytomaswas confirmed in 26 patients with von Hippel–Lindau diseaseand 9 patients with MEN-2 (8 with MEN-2A and 1 with MEN-2B)(Table 1). Three of the patients with von Hippel–Lindaudisease had pheochromocytomas removed on two separate occasions,one to two years apart. Thirteen patients had bilateral adrenaltumors. Two other patients had previously had bilateral adrenaltumors removed and had recurrent extra-adrenal or adrenal tumors.Four patients had metastases.
Table 1. Demographic Characteristics and Biochemical Values in the Reference Groups, Patients with von Hippel–Lindau Disease or Multiple Endocrine Neoplasia Type 2 without Pheochromocytoma, and Patients with von Hippel–Lindau Disease or Multiple Endocrine Neoplasia Type 2 with Pheochromocytoma.
Nine patients presented with sustained hypertension (systolicblood pressure of >140 mm Hg or diastolic blood pressureof >90 mm Hg). Five other patients — four with MEN-2and one with von Hippel–Lindau disease — had documentedperiods of intermittent hypertension. All patients with hypertensionand an additional four patients with normal blood pressure alsoreported symptoms of pheochromocytoma (e.g., headache, palpitations,or sweatiness).
Forty-seven patients with von Hippel–Lindau disease andthree with MEN-2A had no radiologic evidence of pheochromocytoma;we included them in the study as a comparison group for thepatients with pheochromocytoma (Table 1). A third group of 125normal subjects and 53 patients with hypertension served asa reference population for establishing the 95 percent confidenceintervals for assays of plasma catecholamines, normetanephrine,and metanephrine. The study was approved by the appropriateinstitutional review boards, and all subjects provided writteninformed consent.
Biochemical Assays
Samples of blood were drawn into 10-ml heparinized tubes throughan intravenous cannula in the forearm. The subjects rested ina supine position for 15 minutes after insertion of the cannulabefore the blood sample was collected. They were instructedto avoid acetaminophen, which interferes with the plasma normetanephrineassay,12 for at least five days before blood sampling. Plasmawas stored at –70°C before all assays, which wereusually carried out within one month. Urine specimens were assayedwithin two weeks after collection. Plasma norepinephrine, epinephrine,normetanephrine, and metanephrine were measured by liquid chromatographywith electrochemical detection, as described elsewhere.12,13Twenty-four-hour urinary excretion of norepinephrine, epinephrine,metanephrines (normetanephrine and metanephrine combined), andvanillylmandelic acid was measured at a commercial laboratoryby liquid chromatography with electrochemical detection (forcatecholamines)14 or by spectrofluorometry (for metanephrinesand vanillylmandelic acid).
Analysis of Data
We determined upper reference limits for plasma normetanephrine,metanephrine, norepinephrine, and epinephrine from the 95 percentconfidence intervals in the reference group of 178 subjects(Table 1). The plasma concentrations of normetanephrine, metanephrine,and catecholamines in the 178 subjects were normally distributedafter logarithmic transformation. Thus, upper reference limitswere calculated from the antilogarithm of the mean +2 SD ofthe transformed data. The upper reference limits for urinarycatecholamines, metanephrines, and vanillylmandelic acid wereestablished by the outside laboratory that carried out the tests.
A true positive result for pairs of measurements (plasma normetanephrineand metanephrine, plasma norepinephrine and epinephrine, andurinary norepinephrine and epinephrine) in a patient with pheochromocytoma,or a false positive result in a patient without pheochromocytoma,was defined as a value for either or both measurements thatwas equal to or higher than the respective upper reference limit.A false negative test for pairs of measurements in a patientwith pheochromocytoma, or a true negative test in a patientwithout pheochromocytoma, was defined as values for both measurementsthat were lower than the respective upper reference limits.
The sensitivity of each biochemical test was estimated fromthe percentage of true positive results among the total of thetrue positive and false negative results for patients with pheochromocytoma.The specificity of each biochemical test was estimated fromthe percentage of true negative results among the total of thetrue negative and false positive results for patients withoutpheochromocytoma. The negative predictive value was estimatedfrom the percentage of true negative results among the totalof the true negative and false negative results. The positivepredictive value was estimated from the percentage of true positiveresults among the total of the true positive and false positivetests.
Statistical Analysis
Differences in sensitivity or specificity between measurementsof plasma metanephrines and the other biochemical tests usedfor the diagnosis of pheochromocytoma were assessed with useof McNemar's test.15 Differences in the extent of the increaseabove the upper reference limit among the biochemical testswere compared by analysis of variance with Scheffé'spost hoc test. The relations between tumor mass and biochemical-testresults were examined by simple and multiple linear regressionanalyses. Analysis of variance and linear regression analyseswere carried out on log-transformed data.
Results
Biochemical Studies
Of the 35 patients with pheochromocytoma, all but 2 patients,one with von Hippel–Lindau disease and another with MEN-2,had high plasma concentrations of normetanephrine (Figure 1).The three patients with von Hippel–Lindau disease whohad tumors removed on two separate occasions had high plasmanormetanephrine concentrations on both occasions. Two patientswith von Hippel–Lindau disease and all patients with MEN-2who had pheochromocytoma also had high plasma concentrationsof metanephrine; thus, both plasma normetanephrine and metanephrinewere normal in only 1 of the 38 tests in the 35 patients withfamilial pheochromocytoma.
Figure 1. Plasma Concentrations of Normetanephrine, Norepinephrine, Metanephrine, and Epinephrine (Upper Panels) and Urinary Excretion of Norepinephrine, Epinephrine, Metanephrines, and Vanillylmandelic Acid (Lower Panels).
The values are expressed as percentages of the upper reference limit for each test. Data on individual patients are shown for three groups of patients with von Hippel–Lindau disease and multiple endocrine neoplasia type 2 (MEN-2), as follows: patients with von Hippel–Lindau disease or MEN-2 in whom a pheochromocytoma was ruled out on the basis of normal computed tomography (CT-negative), patients with von Hippel–Lindau disease who had histologically verified pheochromocytomas (VHL), and patients with MEN-2 who had histologically verified pheochromocytomas (MEN-2). The values for patients with pheochromocytoma were determined when the tumors were first identified by computed tomography. The dotted horizontal line represents the upper reference limit for each test. The scales are logarithmic.
In contrast, plasma norepinephrine concentrations were normalin eight patients with von Hippel–Lindau disease and pheochromocytomaand four patients with MEN-2 and pheochromocytoma (Figure 1).Plasma epinephrine concentrations were normal in all exceptone patient with von Hippel–Lindau disease and high inonly six of the nine patients with MEN-2, one of whom had anormal plasma norepinephrine concentration. Ten patients, includingseven with normal plasma concentrations of catecholamines, alsohad normal urinary excretion of both norepinephrine and epinephrine.Urinary excretion of metanephrines was normal in 13 of 37 testsin 34 patients, and the excretion of vanillylmandelic acid wasnormal in 18 of 34 tests in 31 patients.
The sensitivity of measurements of plasma normetanephrine andmetanephrine for the diagnosis of pheochromocytoma was 97 percent,a sensitivity significantly higher than that for plasma norepinephrineand epinephrine (P=0.002), urinary norepinephrine and epinephrine(P=0.004), urinary metanephrines (P<0.001), and urinary vanillylmandelicacid (P< 0.001) (Table 2). The high sensitivity of plasmanormetanephrine and metanephrine was accompanied by high specificity(96 percent).
Table 2. Characteristics of Biochemical Tests for the Detection of Pheochromocytoma in Patients with von Hippel–Lindau Disease or Multiple Endocrine Neoplasia Type 2.
In all patients with MEN-2 or von Hippel–Lindau diseasewho had pheochromocytomas, the plasma concentrations of normetanephrinewere increased by an average of 348 percent above the upperreference limit, a considerably larger relative increase (P<0.001)than those in plasma concentrations of norepinephrine (78 percent)and in urinary excretion of norepinephrine (95 percent), metanephrines(55 percent), and vanillylmandelic acid (8 percent) (Figure 1).In the patients with MEN-2 who had pheochromocytomas, therelative increase in the plasma concentrations of metanephrineabove the upper reference limit (1337 percent) was also muchlarger (P<0.001) than the increases in epinephrine in plasma(82 percent) and urine (258 percent) (Figure 1 and Table 1).
The size of the tumor correlated strongly and positively withthe plasma concentration of normetanephrine (r=0.84, P<0.001)and the urinary excretion of metanephrines (r=0.78, P<0.001)and vanillylmandelic acid (r=0.81, P<0.001); it correlatedmore weakly with the plasma norepinephrine concentration (r=0.52,P=0.001) (Figure 2). There were also weak, but significant,positive relations between tumor size and the plasma concentrationsof epinephrine (r=0.44, P=0.007) and metanephrine (r=0.51, P=0.001)and the urinary excretion of norepinephrine (r=0.51, P=0.001)and epinephrine (r=0.54, P<0.001) (data not shown).
Figure 2. Relations of Tumor Volume to Plasma Concentrations of Normetanephrine and Norepinephrine and Urinary Excretion of Metanephrines and Vanillylmandelic Acid.
The patients with von Hippel–Lindau disease are represented by the solid circles, and the patients with MEN-2 by the open circles. The dotted horizontal line represents the upper reference limit for each test. The scales are logarithmic. To convert values for plasma measurements to picomoles per liter, multiply by 5.46 for normetanephrine and 5.91 for norepinephrine. To convert values for urinary catecholamines and metabolites to nanomoles per day, multiply by 5.26 for metanephrines and 5.05 for vanillylmandelic acid.
Despite similar increases in plasma and urinary norepinephrine,the increases in plasma epinephrine and metanephrine and urinaryepinephrine and metanephrines were considerably larger (P<0.001)in patients with MEN-2 than in patients with von Hippel–Lindaudisease (Figure 1 and Table 1). The patients with pheochromocytomawho had high blood pressure or symptoms had significantly largertumors and higher plasma concentrations of normetanephrine,metanephrine, and catecholamines than the patients who werenormotensive or had no symptoms.
Case Studies
The results of three or more of the several biochemical testswere normal in 10 of the 35 patients with pheochromocytomas(Table 3). Several of these patients are described below.
Table 3. Biochemical Values in Patients with Pheochromocytoma and Negative Results on Three or More of the Five Biochemical Tests.
Patient 9, a 28-year-old woman with normal blood pressure, reportedepisodes of facial flushing during the five years she was monitored.She was otherwise asymptomatic until the year preceding surgery,when she had increasingly frequent headache, lightheadedness,and tachycardia. She had normal plasma catecholamine concentrationsat rest or after the administration of glucagon on four separateoccasions. The results of measurements of the urinary excretionof catecholamines, metanephrines, and vanillylmandelic acidwere normal on most of the seven occasions. In contrast, plasmanormetanephrine concentrations were consistently high and increasedprogressively during the five-year follow-up period. Bilateraladrenal pheochromocytomas (each 3 cm in diameter) were removedabout five years after they were first detected by computedtomography.
Patient 20, a 15-year-old girl without hypertension or symptoms,had normal values for plasma catecholamines and urinary metanephrinesand vanillylmandelic acid. The only initial evidence of a pheochromocytomawas provided by computed tomography, which showed a 2-cm massin one adrenal gland; by the slightly high urinary excretionof norepinephrine (20 percent above the upper reference limit);and by a high plasma normetanephrine concentration (280 percentabove the upper reference limit). One year later, all biochemicaltests were strongly positive. An adrenal pheochromocytoma, 2by 3 cm, was removed.
Patient 21, a 25-year-old woman without hypertension, was followedfor nearly four years. She reported occasional headaches associatedwith anxiety and sweatiness, but her plasma concentrations ofcatecholamines and urinary excretion of catecholamines, metanephrines,and vanillylmandelic acid were normal on three separate occasions.The patient's plasma normetanephrine concentrations, however,were high on all occasions and increased with time. On initialexamination, computed tomography revealed a normal right adrenalgland and some enlargement of the left adrenal gland. Nearlyfour years later, the left adrenal gland remained unchanged,but a small mass was noted in the right adrenal gland. Two smallbilateral pheochromocytomas (1 by 1.5 cm and 2 by 2.5 cm) weresubsequently removed at surgery.
Discussion
In our study, plasma concentrations of normetanephrine or metanephrinewere high on 97 percent of the 38 occasions when pheochromocytomaswere found in 35 patients, a finding that indicates a sensitivityconsiderably superior to that of all other biochemical tests.This high sensitivity agrees with our previous findings in 52patients with mainly sporadic pheochromocytoma, in which nopatients had normal plasma concentrations of both metanephrineand normetanephrine.9 The patient with pheochromocytoma andnormal plasma concentrations of normetanephrine and metanephrine(Patient 26, described in Table 3) represents the only caseof a normal test result in more than 120 patients with pheochromocytomawho have been studied (including unpublished observations inpatients with sporadic pheochromocytomas). The tumor in thisasymptomatic patient was positively identified only after thepatient underwent surgery for a renal carcinoma on the sameside on which computed tomography had revealed a 1-cm adrenalmass.
The large amounts of membrane-bound catechol-O-methyltransferasein chromaffin cells16 are the reason for the high sensitivityof plasma normetanephrine and metanephrine in detecting pheochromocytomas.The membrane-bound enzyme has much higher affinity for catecholaminesthan does the soluble enzyme present in other tissues; thus,the adrenal glands constitute the single largest source of metanephrineand normetanephrine, contributing more than 90 percent of metanephrineand 24 to 40 percent of normetanephrine in plasma.17 In contrast,only 7 percent of plasma norepinephrine is derived from theadrenal glands; the remaining 93 percent is derived from sympatheticnerves.17 To increase plasma norepinephrine concentrations fromnormal (50 percent of the upper reference limit) to the upperreference limit would therefore require a pheochromocytoma tosecrete 14.3 times as much norepinephrine as is normally secretedby the adrenal glands (7 percent of the total norepinephrinein plasma). In contrast, with a 24 percent contribution by theadrenal glands to plasma normetanephrine, only an increase bya factor of 4.2 would be necessary to raise plasma normetanephrineconcentrations to the upper reference limit. These estimatesprovide one explanation for the fact that plasma normetanephrinehas higher sensitivity than does norepinephrine for detectingpheochromocytoma.
This explanation assumes that catecholamines are metabolizedand released by pheochromocytoma cells in a fashion similarto that of normal adrenal chromaffin cells. The available evidenceindicates that metabolism is similar,16 but other evidence suggeststhat catecholamine secretion is not. In particular, despiteconsistently high plasma concentrations of normetanephrine ormetanephrine, some patients with pheochromocytoma have normalplasma concentrations of catecholamines or have high concentrationsonly during paroxysmal attacks.16 The silent or intermittentlysecreting tumors in these patients are therefore continuallymetabolizing catecholamines to metanephrines, without consistentlysecreting the parent amines into the circulation. This processprovides another explanation for the superior sensitivity ofmeasurements of plasma normetanephrine and metanephrine to thoseof plasma and urinary catecholamines.
The low sensitivity of measurements of urinary vanillylmandelicacid for the diagnosis of pheochromocytoma is explained by findingsthat less than 20 percent of the vanillylmandelic acid derivesfrom hepatic metabolism of circulating catecholamines and metanephrinesand more than 80 percent from deaminated catecholamine metabolites.18The latter are derived mainly from norepinephrine in sympatheticneurons.19 Thus, to increase urinary excretion of vanillylmandelicacid above the upper reference limit requires large increasesin plasma catecholamines, normetanephrine, or metanephrine.Consequently, as shown here and in other studies,20,21 urinaryexcretion of vanillylmandelic acid has poor sensitivity foridentifying pheochromocytomas.
We measured urinary metanephrines as the sum of both normetanephrineand metanephrine. Better sensitivity can be obtained by usingfractionated liquid chromatographic measurements of normetanephrineand metanephrine.22,23 Urinary measurements of metanephrinesare, however, routinely determined after the sulfate-conjugatedmetanephrines are hydrolyzed to the free metanephrines. Becausesulfate-conjugated metanephrines constitute more than 95 percentof both free and conjugated metanephrines,24 measurements ofurinary metanephrines reflect different catecholamine metabolitesthan measurements of free metanephrines. The free metanephrinesare produced largely in chromaffin tissue by catechol-O-methyltransferase,16whereas the sulfate-conjugated metanephrines are produced bymonoamine-preferring sulfotransferase, an enzyme concentratedin the gut.25 It is therefore unlikely that fractionated measurementsof urinary metanephrines would have higher sensitivity thanthe measurements of plasma normetanephrine and metanephrinein the free form in the present study.
The consistently high plasma concentrations of metanephrinein patients with MEN-2 and pheochromocytoma and the almost universalelevation of only plasma normetanephrine in patients with vonHippel–Lindau disease and pheochromocytoma indicate anoradrenergic tumor phenotype in von Hippel–Lindau disease,as compared with an adrenergic phenotype in MEN-2. The latterfinding is consistent with the high incidence of epinephrine-producingpheochromocytomas in patients with MEN-226,27,28 and also showsthat a high plasma metanephrine value is more sensitive thana high plasma or urinary epinephrine value for detecting suchtumors.
In summary, the measurement of plasma normetanephrine and metanephrineis a highly sensitive test for detecting pheochromocytoma inpatients with a familial predisposition to these tumors. Asmore patients are identified with familial disorders associatedwith pheochromocytoma, more are being identified as having suchtumors at an earlier age.1 In these and other patients in whomthe tumors are small, standard biochemical tests often yieldfalse negative results.1,10,20 The superior sensitivity of measurementsof plasma normetanephrine and metanephrine should help overcomethis limitation.
We are indebted to Ms. Courtney Holmes and Mr. Jacques J. Willemsenfor their expert technical assistance, to Dr. David J. Venzonfor help with the statistical analysis, and to the staff ofthe National Institutes of Health Clinical Center RadiologyDepartment and the many clinicians who assisted in the study.
Source Information
From the Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke (G.E., D.S.G.), the Urologic Oncology Branch, National Cancer Institute (W.M.L., M.M.W.), and the Hypertension Endocrine Branch, National Heart, Lung, and Blood Institute (H.R.K.) — all at the National Institutes of Health, Bethesda, Md.; and the Department of General Internal Medicine, St. Radboud University Hospital, Nijmegen, the Netherlands (J.W.M.L.).
Address reprint requests to Dr. Eisenhofer at Bldg. 10, Rm. 6N252, National Institutes of Health, 10 Center Dr., MSC-1620, Bethesda, MD 20892-1620, or at ge{at}box-g.nih.gov.
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