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 (PϽ.001). Levels of plasma catecholamines 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.

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 PATIENTS AND METHODS (Colouchem II; ESA, Chelmsford, Mass) was used for chromatography. This allowed detection of plasma concentrations 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 Ͼ140 mm Hg or diastolic blood pres- metanephrine, 300 pmol/L; norepinephrine, 3000 pmol/L; sure of Ͼ90 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 liquid 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 normetanephrine, 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 ␣-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 Ͼ250/140 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 analysis of vari- solid-phase extraction columns (Isolute SCX; Interna- ance with Scheffe´ post hoc test. The correlation between tional Sorbent Technology, Hengoed, South Wales), and tumor mass and biochemical test results was described by an electrochemical detector with microdialysis cells the Spearman rank correlation.

RESULTS of plasma normetanephrine level (Figure 1). Plasma metanephrine testing was falsely negative in 5 of the 17 DIAGNOSTIC EFFICACY patients with pheochromocytoma. However, these 5 patients (4 with adrenal tumors and 1 with an extra- All patients with pheochromcytoma were separated from adrenal sporadic tumor) had elevated normetanephrine all patients with other adrenal tumors by determination concentrations. Thus, measurement of plasma normeta-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Demographic and Clinical Characteristics of Patients With Pheochromocytoma and With Histologically Verified Other Adrenal Tumors*

Pheochromocytoma Other Adrenal (n = 17) Tumors (n = 14) Sex, No. F:M 14:3 10:4 Diagnosis Sporadic pheochromocytoma (n = 14) Hormonally inactive (n = 6) MEN 2A (n = 3) Conn syndrome (n = 5) Cushing disease (n = 2) Cushing adrenal adenoma (n = 1) Age, mean (SD), y 46 (5) 44 (3) Hypertension, No./Total No. (%) 14/17 (82) 7/13 (54) Diameter on CT, mean (SD), cm 5.5 (2.5) 5.0 (3.0) MIBG scan abnormal 15/17 ND Surgery, No. Endoscopic 10 9 Open 7 0

*MEN indicates multiple endocrine neoplasia; CT, computed tomography; MIBG, iodine 131[131I] meta-iodobenzyl guanidine; and ND, not done.

10 000 Plasma Normetanephrine Plasma Norepinephrine Urinary Norepinephrine A B C

1000

100

≤10

10 000 Plasma Metanephrine Plasma Epinephrine Urinary Epinephrine D E F

1000

100 % of Upper Reference Limit % of Upper Reference Limit

≤10

PHEO OAT PHEO OAT PHEO OAT

Figure 1. Preoperative concentrations, expressed as percentages of the upper reference limit (dashed line), for plasma metanephrines, plasma catecholamines, and urinary excretion of catecholamines. Data are presented for individual patients with pheochromocytoma (PHEO) and histologically verified other adrenal tumors (OAT).

nephrine with or without metanephrine was positive in (2 with familial adrenal tumors, 6 with sporadic adrenal all patients with pheochromocytoma. tumors, and 1 with a sporadic extra-adrenal tumor). Three In contrast, plasma norepinephrine level was normal of these patients had elevated plasma norepinephrine con- in 4 patients with pheochromocytoma (2 with sporadic and centrations. Both plasma norepinephrine and epineph- 2 with familial adrenal tumors). Plasma epinephrine level rine levels were therefore normal in 3 of 17 patients with was normal in 9 of 17 patients with pheochromocytoma pheochromocytoma (Figure 1).

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Diagnostic Efficacy of Biochemical Tests for the Detection of Pheochromocytoma

No./ Total No. (%)

Biochemical Test Sensitivity Specificity Negative Predictive Value Positive Predictive Value Plasma normetanephrine and metanephrine 17/17 (100) 14/14 (100) 14/14 (100) 17/17 (100) Plasma norepinephrine and epinephrine 14/17 (82) 14/14 (100) 14/17 (82) 14/17 (82) Urinary norepinephrine and epinephrine 14/17 (82) 13/14 (94) 16/17 (94) 14/17 (82)

P = .03 P = .07 PHEO OAT P = .02 P = .09

A B C D

10 000 10 000 1000 1000

1000 100 100

1000 Plasma Epinephrine, pg/mL Plasma Metanephrine, pg/mL Plasma Norepinephrine, pg/mL Plasma Normetanephrine, pg/mL 100 10 10

10 100 1 1 Recumbent Upright Recumbent Upright Recumbent Upright Recumbent Upright

Figure 2. Plasma metanephrines and catecholamines in the recumbent and upright positions in patients with pheochromocytoma (PHEO) and those with other adrenal tumors (OAT). Individual absolute concentrations are given. Median values are represented by full horizontal lines. Blood samples were drawn after 20 minutes in the recumbent position and subsequently after 10 minutes in the upright position from an indwelling forearm catheter. To convert values for plasma measurements to picomoles per liter, multiply by 5.46 for normetanephrine, 5.91 for norepinephrine, 5.08 for metanephrine, and 5.46 for epinephrine.

Similarly, urinary norepinephrine concentration was In patients with pheochromocytoma, plasma nor- normal in 5 patients with pheochromocytoma (3 with metanephrine concentrations were increased up to ap- sporadic and 2 with familial adrenal tumors). One of these proximately 1000% above the upper reference limit (Fig- patients (with sporadic adrenal disease) had elevated ure 1), which was not larger (P=.77) than the increase urinary epinephrine concentration. Seven patients with in plasma norepinephrine level but considerably higher pheochromocytoma (1 with a familial tumor, 5 with spo- (PϽ.001) than that in plasma metanephrine (600%) and radic adrenal tumors, and 1 with a sporadic extra- epinephrine (400%) concentrations, and in the urinary adrenal tumor) had urinary epinephrine concentrations excretion of norepinephrine (600%) and epinephrine within the normal range. Four of them, however, had el- (550%). evated urinary norepinephrine excretion. Overall, urinary norepinephrine and epinephrine levels were within POSTURE DEPENDENCE the normal range in 3 of 17 patients with pheochromocytoma (Figure 1). Mean plasma norepinephrine concentration increased The sensitivity of plasma metanephrines (normeta- (P=.03) in all patients with pheochromocytoma by 300% nephrine and metanephrine) for the diagnosis of pheo- in response to change to the upright position (Figure 2). chromocytoma was 100% and thus 17% higher than that The median increase was 19858 pmol/L (range, 1478- of plasma (82%; PϽ.001) and urinary (82%; PϽ.001) nor- 35460 pmol/L), whereas plasma normetanephrine con- epinephrine and epinephrine concentrations (Table 2). centrations did not change significantly. Plasma epineph-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 P = .002 P = .009 A PHEO B C D OAT P = .05 P<.001

10 000 1 000 000 10 000 100 000

100 000 10 000

1000 1000

10 000

1000 Plasma Epinephrine, pg/mL Plasma Metanephrine, pg/mL

Plasma Norepinephrine, pg/mL 1000 Plasma Normetanephrine, pg/mL 100 100

100 100

10 10 10 10 Baseline Maximum Baseline Maximum Baseline Maximum Baseline Maximum Manipulation Manipulation Manipulation Manipulation

Figure 3. Intraoperative plasma concentrations of metanephrines and catecholamines at the beginning of surgery and during maximal mechanical tumor manipulation in patients with pheochromocytoma (PHEO) and those with other adrenal tumors (OAT). Individual absolute concentrations are given. Median values are represented by full horizontal lines. Blood samples were drawn from an indwelling central venous catheter. To convert values for plasma measurements to picomoles per liter, multiply by 5.46 for normetanephrine, 5.91 for norepinephrine, 5.08 for metanephrine, and 5.46 for epinephrine.

rine displayed a trend (P=.07) to rise (median increase, The size of the tumor in patients with pheochro- 546 pmol/L; range, 27-8190 pmol/L) in 14 patients. Four mocytoma but not in those with other adrenal tumors patients (who had adrenal pheochromocytoma with nor- correlated positively with the preoperative plasma con- mal plasma epinephrine levels) had identical or lower centrations of normetanephrine (r=0.70; PϽ.001) and plasma epinephrine concentrations in the upright com- metanephrine (r=0.62; PϽ.001) but not with plasma nor- pared with the supine position. Plasma metanephrine con- epinephrine (r=0.18; P=.86) or epinephrine (r=0.28; centrations were not significantly different. P=.68). Similarly, plasma norepinephrine level was increased (P=.02) in the upright posture, while plasma con- INTRAOPERATIVE TIME COURSE OF PLASMA centrations of epinephrine (P=.09), normetanephrine, and METANEPHRINES AND CATECHOLAMINES metanephrine were not significantly higher in patients with other adrenal tumors (Figure 2). Plasma concentrations of catecholamines and metanephrines were studied in 6 patients during unilateral lapa- INTRAOPERATIVE STRESS DEPENDENCE roscopic adrenal surgery for sporadic (n=5) and familial (n=1) pheochromocytoma (Figure 4). A transient Plasma norepinephrine concentrations rose (P=.002) increase in catecholamine level and, to a lesser extent, markedly during surgery (Figure 3) in all patients with in metanephrine level was seen after clipping of the ad- pheochromocytoma (median increase, 164000 pmol/L; renal vein and before a fall in the respective plasma con- range, 6800-2240000 pmol/L) when measured during centrations. maximal mechanical tumor manipulation and compared with that before skin incision. Plasma normeta- POSTOPERATIVE EVALUATION nephrine level did not change significantly (median increase, 7370 pmol/L; range, 300-22600 pmol/L). Plasma Fourteen (88%) of 16 patients displayed normal bio- epinephrine level increased (P=.009) markedly in all pa- chemical results in all tests at 3 months after surgery (me- tients (median increase, 24730 pmol/L; range, 440- dian values, 290 pmol/L for normetanephrine, 76 pmol/L 371280 pmol/L), while plasma metanephrine level did for metanephrine, 1890 pmol/L for norepinephrine, and not. Again, the extent of increase above the upper refer- 87 pmol/L for epinephrine). One patient with MEN 2A ence limit of normal in response to intraoperative me- displayed continuously increasing plasma metaneph- chanical stress was higher (PϽ.001) for plasma cat- rine concentrations at 1 month (290 pmol/L), 3 months echolamines than for plasma metanephrines. Similar (533 pmol/L), and 6 months (645 pmol/L) after unilat- results were obtained in patients with other adrenal tu- eral adrenal surgery despite a negative postoperative io- mors (Figure 3). dine 131 [131I] meta-iodobenzyl guanidine (MIBG) scan.

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 A B

1000 100 000

10 000

100

1000 Plasma Norepinephrine, pg/mL Plasma Normetanephrine, pg/mL

10 100

C D

10 000 100 000

1000 10 000

100 1000

10 100 Plasma Epinephrine, pg/mL Plasma Metanephrine, pg/mL

1 10 –200 20 40 6080 100 120 140160 180 200 –200 20 40 6080 100 120 140160 180 200 Minutes Minutes

Figure 4. Intraoperative time course of plasma concentrations of metanephrines and catecholamines after clipping of the adrenal vein (zero time). Absolute plasma concentrations are given from 20 minutes before until 175 minutes after separation of the tumor from blood circulation in patients with sporadic (n=5) and familial (n=1) pheochromocytoma who underwent endoscopic adrenal surgery. To convert values for plasma measurements to picomoles per liter, multiply by 5.46 for normetanephrine, 5.08 for metanephrine, 5.91 for norepinephrine, and 5.46 for epinephrine.

Another patient with the familial disease had increased rine result reported so far in histologically confirmed plasma metanephrine level (498 pmol/L), borderline pheochromocytoma. plasma normetanephrine level (628 pmol/L), and el- The present study also found that plasma metaneph- evated urinary epinephrine excretion (41 µg/24 h). This rine concentrations are largely unsusceptible to exter- patient remained asymptomatic and refused further di- nal influences such as change of posture (Figure 2) or agnostic and therapeutic procedures. the mechanical stress imposed by either endoscopic or open surgery (Figure 3). In contrast, large increases in COMMENT plasma catecholamine levels were observed in response to these procedures, findings that were observed equally Plasma concentrations of unconjugated normetaneph- in patients with pheochromocytoma and those with his- rine and metanephrine showed superior sensitivity tologically documented other adrenal tumors. This is in (PϽ.01) for the diagnosis of pheochromocytoma com- keeping with results obtained by others in humans (by pared with plasma and urinary catecholamines. While means of glucagon stimulation or insulin hypoglycemia plasma and urinary catecholamines were increased in tests) that show plasma metanephrine levels to be insen- only 83% of patients, plasma metanephrines were sitive to short-term increase of plasma catecholamine lev- elevated in all patients. This is in keeping with previous els.8 This independence of external influences indicates findings in sporadic pheochromocytoma6 and, more that determination of plasma metanephrine levels will not recently, MEN 2 and von Hippel–Lindau disease.5 In require time-consuming standardization of blood sam- particular, all patients with pheochromocytoma in our pling necessary for correct determination of plasma cat- study could be identified by determination of plasma echolamine levels and will be therefore more suitable as normetanephrine alone. Thus, one patient with a small a screening test. pheochromocytoma and normal plasma normetaneph- Tumor volume was highly correlated with plasma rine concentrations described by Eisenhofer et al7 con- metanephrine concentrations but not with plasma cat- tinues to represent the only false-negative normetaneph- echolamine levels, supporting evidence that metaneph-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 rines are produced by catechol-O-methyltransferase within (metanephrines) reported in clearance studies of these tumors.8 This is in keeping with previous findings in spo- compounds.13,18 radic pheochromocytoma.5 In conclusion, determination of plasma metaneph- While the adrenal gland constitutes the single larg- rine and, in particular, normetanephrine levels offers im- est source of metanephrine and normetanephrine, con- proved efficacy for the detection of pheochromocy- tributing more than 90% of metanephrine and up to 40% toma. Less variability in response to external factors may of normetanephrine in plasma, only approximately 7% favor determination of metanephrine levels in screen- of plasma norepinephrine is derived from the adrenal ing for and postoperative control of the disease. glands, with the remainder being derived from sympathetic nerves.12 About 3.5 times more norepinephrine than Accepted for publication April 28, 2000. normetanephrine that is normally secreted by the adre- Reprints: Michael Roden, MD, Division of Endocrinol- nal glands would therefore have to be produced by an ogy and Metabolism, Department of Medicine III, Univer- adrenal pheochromocytoma to increase the respective sity of Vienna, Wa¨hringer Gu¨rtel 18-20, A-1090 Wien, Aus- plasma concentrations to above the upper limit of nor- tria (e-mail: [email protected]). mal, which has been suggested to explain the higher sensitivity of plasma normetanephrine for detection of pheo- REFERENCES chromocytoma.7 Plasma norepinephrine concentrations, on the other 1. 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