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Diagnostic Efficacy of Unconjugated Plasma Metanephrines for the Detection of Pheochromocytoma

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Diagnostic Efficacy of Unconjugated Plasma Metanephrines for the Detection of Pheochromocytoma ORIGINAL INVESTIGATION Diagnostic Efficacy of Unconjugated Plasma Metanephrines for the Detection of Pheochromocytoma Wolfgang Raber, MD; Wolfgang Raffesberg; Martin Bischof, MD; Christian Scheuba, MD; Bruno Niederle, MD; Slobodan Gasic, MD; Werner Waldha¨usl, MD; Michael Roden, MD Background: Recently, measurement of plasma meta- months after surgery. Patients with pheochromocytoma nephrines was suggested to improve the detection of (n=17) and with histologically proved other adrenal pheochromocytoma compared with the other common tumors (n=14) were studied before, during, and after biochemical tests. surgery. Objective: To examine the diagnostic precision of mea- Results: Measurement of plasma metanephrines and surements of plasma metanephrines, plasma catechol- plasma and urinary catecholamines provided 100% and amines, and urinary catecholamines and to assess their 82% sensitivity, respectively, for the detection of pheo- variability. chromocytoma (P,.001). Levels of plasma catechol- amines but not metanephrines increased in response to Methods: Plasma metanephrine as well as plasma and change of posture (norepinephrine, P=.03; epineph- urinary catecholamine concentrations were measured rine, P=.07) and intraoperative stress (norepinephrine, by high-performance liquid chromatography with elec- P=.002; epinephrine, P=.009). trochemical detection. Before surgery, responses of plasma metanephrines and catecholamines to change of Conclusions: Plasma metanephrines offer improved posture were determined. Intraoperatively, metaneph- efficacy for the diagnosis of pheochromocytoma. Less vari- rines and catecholamines were measured before skin ability in response to external factors may favor plasma incision, during maximal mechanical tumor manipula- metanephrines in the screening for this disease. tion, and repetitively after the tumor was separated from the circulation. Patients were reexamined 1 and 3 Arch Intern Med. 2000;160:2957-2963 IAGNOSIS OF pheochromo- nal metabolites of catecholamines, by high- cytoma still poses consid- performance liquid chromatography with erable problems, as al- electrochemical detection.6 Recently, an most half of patients extended report by Eisenhofer et al7 fa- initially have no or only vored plasma metanephrines in particu- paroxysmal hypertension or may even be lar for oligosymptomatic, and even asymp- D1 asymptomatic. Even the classic symptom tomatic subjects at high risk for pheo- triad of bilateral diffuse headache, sweat- chromocytoma, such as patients with von ing, and palpitations provides diagnostic ac- Hippel–Lindau disease or family members curacy of only 6%.2 Autopsy studies show of patients with multiple endocrine neopla- that the disease is not recognized in 20% to sia type 2 (MEN 2).7 However, the supe- 75% of patients during life but represents riority of plasma metanephrines has not yet the cause of death in half of them.3,4 Proper been supported by others. diagnosis of pheochromocytoma by highly The aims of this study were (1) to com- sensitive biochemical tests therefore re- pare the diagnostic efficacy of plasma cat- mains of paramount importance. echolamines and metanephrines, (2) to in- From the Division of Simple biochemical screening, largely vestigate the suggested independence8 of Endocrinology and Metabolism, independent of external influences such plasma metanephrines of large increases in Department of Medicine III as posture or stress, in general should im- plasma catecholamine concentrations in pa- (Drs Raber, Bischof, Gasic, prove the diagnostic sensitivity. Im- tients with pheochromocytoma compared Waldha¨usl, and Roden and proved accuracy in the diagnosis of pheo- with those with histologically proved other Mr Raffesberg), and the 5 Department of Surgery chromocytoma has been suggested with adrenal tumors, and (3) to observe the in- (Drs Scheuba and Niederle), the use of determination of plasma meta- traoperative time course of metanephrine University of Vienna, nephrines (metanephrine and normeta- and catecholamine levels in patients with Vienna, Austria. nephrine), the O-methylated extraneuro- pheochromocytoma. (REPRINTED) ARCH INTERN MED/ VOL 160, OCT 23, 2000 WWW.ARCHINTERNMED.COM 2957 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 PATIENTS AND METHODS (Colouchem II; ESA, Chelmsford, Mass) was used for chro- matography. This allowed detection of plasma concentra- tions of normetanephrine as low as 55 pmol/L and of meta- PATIENTS nephrine as low as 82 pmol/L. Recovery was estimated to range from 90% to 105% of the internal standard. The in- We studied 17 patients with pheochromocytoma and 14 pa- terassay coefficients of variation were 5% (normetaneph- tients with histologically verified other adrenal tumors rine) and 8% (metanephrine) at physiologic plasma hor- (Table 1). In 3 patients the diagnosis of MEN 2A was proved mone concentrations ±1 SD (normetanephrine, 430±30 by identification of germline mutations of the RET proto- pmol/L; metanephrine, 150±10 pmol/L). Upper limits of oncogene. Fourteen patients with pheochromocytoma (all but the normal range were adapted from Lenders et al5 to 1 with sporadic disease) had sustained hypertension (sys- allow comparison of results (normetanephrine, 660 pmol/L; tolic blood pressure of .140 mm Hg or diastolic blood pres- metanephrine, 300 pmol/L; norepinephrine, 3000 pmol/L; sure of .90 mm Hg). Two other patients (1 with sporadic and epinephrine, 540 pmol/L). pheochromocytoma and 1 with MEN 2A) had documented Plasma catecholamines were analyzed by reverse- periods of intermittent hypertension. All patients with hy- phase high-performance liquid chromatography9 with pertension and an additional patient with normal blood pres- the use of plasma catecholamine extraction tubes (ESA) sure (with the familial disease) also reported symptoms of for the isolation procedure. Interassay and intra-assay pheochromocytoma (eg, headache, palpitations, or exces- coefficients of variance were less than 5% for both com- sive sweating). Patients with histologically confirmed other pounds. adrenal diseases served as a reference group (Table 1). Urine samples were collected in plastic flasks contain- ing 10 mL of 25% hydrochloric acid. After extraction by ion- BIOCHEMICAL ASSAYS exchange columns and separation by high-performance liq- uid chromatography, catecholamines were measured by Three 24-hour urine samples (of which the highest con- electrochemical detection (Pharmacia KB, Uppsala, Swe- centrations are given) for the determination of norepineph- den) by means of kits (Chromsystem, Munich, Germany). rine and epinephrine were obtained before surgery, and one 24-hour urine collection was obtained at 1 and at 3 months DATA ANALYSIS after surgery. Blood samples for the determination of nor- metanephrine, metanephrine, norepinephrine, and epi- The 3 tests involved the determination of 2 compounds nephrine in plasma were drawn into 10-mL heparinized (plasma normetanephrine and metanephrine, plasma nor- tubes through an intravenous cannula in the forearm. Pa- epinephrine and epinephrine, and urinary norepineph- tients rested in the supine position for 20 minutes before rine and epinephrine). A positive or negative result was de- blood sampling. Additional blood samples were subse- fined as normal or elevated values, respectively, for both quently collected after 10 minutes in the upright position substances in the pair. Preoperative values were obtained in all patients. Blood pressure and heart rate were mea- before the institution of a-blockade in 16 patients. Two pa- sured repeatedly. None of the patients was taking acetami- tients (1 with life-threatening paroxysms of hypertension nophen, which can interfere with the plasma normeta- and 1 with sustained hypertension .250/140 mm Hg) had nephrine assay.6 Intraoperatively, blood was obtained at been taking this medication for 3 and 10 days before the baseline (after intubation, before skin incision) and during first blood sample was drawn. Diagnostic procedures were maximal mechanical tumor manipulation in 15 patients. evaluated by sensitivity, specificity, and positive and nega- Blood samples were also drawn from a central venous can- tive predictive values.10 nula immediately before and repeatedly after clipping of the adrenal vein to follow the time course of plasma meta- STATISTICAL ANALYSIS nephrine and catecholamine levels in 6 patients. All blood samples were transferred into prechilled heparinized Comparisons of sensitivity or specificity between plasma tubes, immediately placed on ice, and centrifuged (4°C, metanephrines and other biochemical tests were per- 2000 rpm) within 15 minutes to separate the plasma. formed with the use of the McNemar test.11 Median in- Plasma was stored at −80°C before assay. The study was creases of plasma metanephrine and catecholamine con- approved by the appropriate institutional review boards, centrations during the upright position test and the and all patients gave their informed consent to participate. maximum intraoperative stress, respectively, were ana- The high-performance liquid chromatography method lyzed by the Wilcoxon rank sum test. The differences in for the determination of plasma metanephrines6 was opti- the extent of increase above the upper reference limit of mized by modifications in the extraction and chromato- normal among the biochemical tests (both preoperatively graphic procedures. Briefly, extraction was performed on and during surgery) were compared by
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