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Symptom-dependent cut-offs of urine metanephrines improve diagnostic accuracy for detecting pheochromocytomas in two separate cohorts, compared to symptom-independent cut-offs

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Abstract

The development of advanced imaging techniques has increased the detection of subclinical pheochromocytomas. Because of the substantial proportions of subclinical pheochromocytomas, measurement of urine metanephrine concentrations is crucial due to detect or exclude pheochromocytoma. Although urine metanephrines are elevated in symptomatic subjects, diagnostic cut-offs according to the presence of adrenergic symptoms have not been studied. Pheochromocytomas patients who underwent adrenalectomy at Samsung Medical Center and a control group were compared to determine cut-off concentrations of urine metanephrines. An independent population was analyzed for urine metanephrines with different kits to validate the improvement in diagnostic accuracy using adjusted cut-offs. Symptom-dependent cut-offs of urine metanephrines were higher for symptomatic patients (307 μg/day in males, 235 μg/day in females for urine metanephrine, and 1,045 μg/day in males and 457 μg/day in females for urine normetanephrine) than for asymptomatic patients (206 μg/day in males, 199 μg/day in females for urine metanephrine, and 489 μg/day in males and 442 μg/day in females for urine normetanephrine). Symptom-dependent cut-offs of urine metanephrines improved a specificity from 92.7 % to 96.3 % and a high sensitivity of 97.8 % was maintained. Using the Symptom-dependent cut-offs raised diagnostic accuracy by 5.5 % (p <0.001). Similar trend was also observed in an independent population using different hormone kits. Using symptom-dependent cut-offs of urine metanephrines in symptomatic patients for pheochromocytomas resulted in a significant improvement in diagnostic accuracy in two separate cohorts.

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References

  1. J.W. Lenders, G. Eisenhofer, M. Mannelli, K. Pacak, Phaeochromocytoma. Lancet 366, 665–675 (2005). doi:10.1016/s0140-6736(05)67139-5

    Article  PubMed  Google Scholar 

  2. A.R. McNeil, B.H. Blok, T.D. Koelmeyer, M.P. Burke, J.M. Hilton, Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust. N Z J. Med. 30, 648–652 (2000)

    Article  CAS  PubMed  Google Scholar 

  3. M. Mannelli, L. Ianni, A. Cilotti, A. Conti, Pheochromocytoma in Italy: a multicentric retrospective study. Eur. J. Endocrinol. 141, 619–624 (1999)

    Article  CAS  PubMed  Google Scholar 

  4. R. Kopetschke, M. Slisko, A. Kilisli, U. Tuschy, H. Wallaschofski, M. Fassnacht, M. Ventz, F. Beuschlein, M. Reincke, N. Reisch, M. Quinkler, Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma. Eur. J. Endocrinol. 161, 355–361 (2009). doi:10.1530/eje-09-0384

    Article  CAS  PubMed  Google Scholar 

  5. H. Wachtel, I. Cerullo, E.K. Bartlett, R.E. Roses, D.L. Cohen, R.R. Kelz, G.C. Karakousis, D.L. Fraker, Clinicopathologic characteristics of incidentally identified pheochromocytoma. Ann. Surg. Oncol. 22, 132–138 (2015). doi:10.1245/s10434-014-3933-x

    Article  PubMed  Google Scholar 

  6. A.R. Oshmyansky, A. Mahammedi, A. Dackiw, D.W. Ball, R.D. Schulick, M.A. Zeiger, S.S. Siegelman, Serendipity in the diagnosis of pheochromocytoma. J. Comput. Assist. Tomogr. 37, 820–823 (2013). doi:10.1097/RCT.0b013e31829cbecf

    Article  PubMed  Google Scholar 

  7. T. Noshiro, K. Shimizu, T. Watanabe, H. Akama, S. Shibukawa, W. Miura, S. Ito, Y. Miura, Changes in clinical features and long-term prognosis in patients with pheochromocytoma. Am. J. Hypertens. 13, 35–43 (2000)

    Article  CAS  PubMed  Google Scholar 

  8. L. Amar, A. Servais, A.P. Gimenez-Roqueplo, F. Zinzindohoue, G. Chatellier, P.F. Plouin, Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J. Clin. Endocrinol. Metab. 90, 2110–2116 (2005). doi:10.1210/jc.2004-1398

    Article  CAS  PubMed  Google Scholar 

  9. J.W. Lenders, Q.Y. Duh, G. Eisenhofer, A.P. Gimenez-Roqueplo, S.K. Grebe, M.H. Murad, M. Naruse, K. Pacak, W.F. Young Jr., Endocrine, S.: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 1915–1942 (2014). doi:10.1210/jc.2014-1498

    Article  CAS  PubMed  Google Scholar 

  10. N. Unger, C. Pitt, I.L. Schmidt, M.K. Walz, K.W. Schmid, T. Philipp, K. Mann, S. Petersenn, Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass. Eur. J. Endocrinol. 154, 409–417 (2006). doi:10.1530/eje.1.02097

    Article  CAS  PubMed  Google Scholar 

  11. E. Pussard, A. Chaouch, T. Said, Radioimmunoassay of free plasma metanephrines for the diagnosis of catecholamine-producing tumors. Clin. Chem. Lab. Med. 52, 437–444 (2014). doi:10.1515/cclm-2013-0406

    Article  CAS  PubMed  Google Scholar 

  12. M. Haissaguerre, M. Courel, P. Caron, S. Denost, C. Dubessy, P. Gosse, V. Appavoupoulle, G. Belleannee, M.L. Jullie, M. Montero-Hadjadje, L. Yon, J.B. Corcuff, C. Fagour, C. Mazerolles, T. Wagner, M.L. Nunes, Y. Anouar, A. Tabarin, Normotensive incidentally discovered pheochromocytomas display specific biochemical, cellular, and molecular characteristics. J. Clin. Endocrinol. Metab. 98, 4346–4354 (2013). doi:10.1210/jc.2013-1844

    Article  CAS  PubMed  Google Scholar 

  13. K. Kobayashi, R. Kolloch, V. Dequattro, L. Miano, Increased plasma and urinary normetanephrine in young patients with primary hypertension. Clin. Sci. (Lond) 57 Suppl 5, 173s–176s (1979)

    Article  CAS  Google Scholar 

  14. S.Y. Sohn, H.D. Park, S.Y. Lee, J.H. Kim, B.C. Jung, H.J. Kim, H.W. Jang, K.W. Kim, M.K. Lee, Y.K. Min, J.H. Kim, Different diagnostic cut-off values of urinary fractionated metanephrines according to sex for the diagnosis of pheochromocytoma in Korean subjects. Endocr. J. 59, 831–838 (2012)

    Article  CAS  PubMed  Google Scholar 

  15. M.N. Starkman, O.G. Cameron, R.M. Nesse, T. Zelnik, Peripheral catecholamine levels and the symptoms of anxiety: studies in patients with and without pheochromocytoma. Psychosom. Med. 52, 129–142 (1990)

    Article  CAS  PubMed  Google Scholar 

  16. S.Y. Shin, Y.R. Park, Y. Shin, H.J. Choi, J. Park, Y. Lyu, M.S. Lee, C.M. Choi, W.S. Kim, J.H. Lee, A de-identification method for bilingual clinical texts of various note types. J. Korean Med. Sci. 30, 7–15 (2015). doi:10.3346/jkms.2015.30.1.7

    Article  PubMed  Google Scholar 

  17. M.J. Pencina, R.B. D’Agostino Sr., R.B. D’Agostino Jr., R.S. Vasan, Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat. Med. 27, 157–172 (2008). doi:10.1002/sim.2929 discussion 207-112

    Article  PubMed  Google Scholar 

  18. S.H. Lee, S.W. Lee, S.H. Ahn, T. Kim, K.H. Lim, B.J. Kim, E.H. Cho, S.W. Kim, T.H. Kim, G.S. Kim, S.Y. Kim, J.M. Koh, C. Kang, Multiple gene polymorphisms can improve prediction of nonvertebral fracture in postmenopausal women. J. Bone Miner. Res. 28, 2156–2164 (2013). doi:10.1002/jbmr.1955

    Article  CAS  PubMed  Google Scholar 

  19. S.H. Lee, M.I. Kang, S.H. Ahn, K.H. Lim, G.E. Lee, E.S. Shin, J.E. Lee, B.J. Kim, E.H. Cho, S.W. Kim, T.H. Kim, H.J. Kim, K.H. Yoon, W.C. Lee, G.S. Kim, J.M. Koh, S.Y. Kim, Common and rare variants in the exons and regulatory regions of osteoporosis-related genes improve osteoporotic fracture risk prediction. J. Clin. Endocrinol. Metab. 99, E2400–2411 (2014). doi:10.1210/jc.2014-1584

    Article  CAS  PubMed  Google Scholar 

  20. S.F. Rimoldi, U. Scherrer, F.H. Messerli, Secondary arterial hypertension: when, who, and how to screen?. Eur. Heart J. 35, 1245–1254 (2014). doi:10.1093/eurheartj/eht534

    Article  PubMed  Google Scholar 

  21. M. Mannelli, J.W. Lenders, K. Pacak, G. Parenti, G. Eisenhofer, Subclinical phaeochromocytoma. Best Pract. Res. Clin. Endocrinol. Metab. 26, 507–515 (2012). doi:10.1016/j.beem.2011.10.008

    Article  PubMed  PubMed Central  Google Scholar 

  22. G. Eisenhofer, D.S. Goldstein, I.J. Kopin, J.R. Crout, Pheochromocytoma: rediscovery as a catecholamine-metabolizing tumor. Endocr. Pathol. 14, 193–212 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. S. Kannan, A. Purysko, C. Faiman, E.M. Remer, L. Shah, J. Bena, A. Siperstein, E. Berber, A. Fergany, E. Bravo, A.H. Hamrahian, Biochemical and radiological relationships in patients with pheochromocytoma: lessons from a case control study. Clin. Endocrinol. (Oxf) 80, 790–796 (2014). doi:10.1111/cen.12420

    Article  CAS  Google Scholar 

  24. J.W. Lenders, K. Pacak, M.M. Walther, W.M. Linehan, M. Mannelli, P. Friberg, H.R. Keiser, D.S. Goldstein, G. Eisenhofer, Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287, 1427–1434 (2002)

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by a grant from Dong-A ST (Seoul, Republic of Korea, project No. 2011-04-090) and from the Asan Institute for Life Sciences (Seoul, Republic of Korea, project No. 2014-1215). The funding source had no role in the oversight or design of the study, in the analysis or interpretation of the data, or in the decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Yoon Young Cho, Young Nam Kim & Jae Hyeon Kim

  2. Division of Endocrinology and Metabolism, Department of Medicine, Gyeongsang National University School of Medicine, Jinju, Korea

    Yoon Young Cho

  3. Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea

    Yoon Young Cho

  4. Division of Endocrinology and Metabolism, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea

    Kee-Ho Song & Sooyoun Park

  5. Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

    Seong Hee Ahn, Hyeonmok Kim, Beom-Jun Kim, Jung-Min Koh & Seung Hun Lee

  6. Department of Endocrinology, Inha University School of Medicine, Incheon, Korea

    Seong Hee Ahn

  7. Division of Endocrinology and Metabolism, Department of Internal Medicine, Dong-A University Medical Center, Dong-A University College of Medicine, Busan, Korea

    Sunghwan Suh

  8. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Soo-Youn Lee

  9. Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

    Sail Chun

  10. Samsung Biomedical Research Institute, Seoul, Korea

    Jae Hyeon Kim

  11. Department of Health Sciences & Technology, SAIHST, Sungkyunkwan University, Seoul, Korea

    Jae Hyeon Kim

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  1. Yoon Young Cho
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  11. Jung-Min Koh
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  12. Seung Hun Lee
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  13. Jae Hyeon Kim
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Correspondence to Seung Hun Lee or Jae Hyeon Kim.

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Yoon Young Cho and Kee-Ho Song are the joint first authors.

Seung Hun Lee and Jae Hyeon Kim are the joint senior authors.

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Cho, Y.Y., Song, KH., Kim, Y.N. et al. Symptom-dependent cut-offs of urine metanephrines improve diagnostic accuracy for detecting pheochromocytomas in two separate cohorts, compared to symptom-independent cut-offs. Endocrine 54, 206–216 (2016). https://doi.org/10.1007/s12020-016-1049-8

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