Comparison of the effectiveness of various methods for determining the level of metanephrines in the diagnosis of pheochromocytomas

BACKGROUND: Pheochromocytoma (PHEO) is a tumor from the chromaffin tissue of the adrenal medulla, capable of hyperproduction of catecholamines. The increased production of hormones by the tumor leads to catecholamine crises, which have a pathological effect on all organs and systems. In the primary diagnosis of pheochromocytomas, it is important to determine the level of the metabolite of catecholamines — metanephrines. Currently, in clinical practice, various methods are used to determine the level of this metabolite: in blood plasma or in urine, total or only free form, fractionated analysis or unfractionated.

AIM: Comparison of the effectiveness of various methods for determining the level of metanephrines for the diagnosis of pheochromocytomas.

MATERIALS AND METHODS: A retrospective single-center cohort study was conducted on a sample of patients who were initially operated on for adrenal neoplasm at the Pirogov St. Petersburg State University High Medical Technology Clinic from November 2007 to December 2022 and who passed analysis to determine the level of blood or urine metanephrins before surgical treatment. The results of tests for metanephrine and tumor size were evaluated.

RESULTS: 1088 patients with adrenal neoplasms who underwent surgical treatment were examined, of which 348 had histologically confirmed the presence of pheochromocytoma. Four types of metanephrine assays were compared: free fractionated plasma metanephrines (232 patients), unfractionated daily urine metanephrines (431 patients), fractionated total daily urine metanephrines (427 patients) and fractionated free daily urine metanephrines (178 patients). The greatest sensitivity was demonstrated by the analysis of free fractionated plasma methanephrines (95.4%). Unlike others, the sensitivity of this analysis did not decrease in the group of patients with small pheochromocytomas (3 cm or less). The greatest specificity was demonstrated by the analysis of unfractionated metanephrines in daily urine (97.8%), with the lowest sensitivity among all tests (67.6%). The study of fractionated total daily urine metanephrins showed good results of sensitivity and specificity, only slightly inferior to the best indicators, and the analysis of free daily urine metanephrins demonstrated unexpectedly low efficiency. There is a positive correlation between the level of metanephrine in the blood and the size of the tumor.

CONCLUSION: Based on the data obtained, the preferred assays for the primary diagnosis of pheochromocytoma can be considered the determination of fractionated free plasma metanephrines and fractionated total daily urine metanephrines, which is consistent with relevant clinical recommendations. It was found that the size of the tumor correlates with the severity of an increase in the level of metanephrins determined by any of the described methods.

1. Lenders JW, Kerstens MN, Amar L, et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. Journal of hypertension. 2020;38(8):1443. doi: 10.1097/HJH.0000000000002438.

2. Pacak K., Tella S. H. Pheochromocytoma and paraganglioma. Endotext [Internet]; 2018. [cited 2023 Feb 8]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK481899/

3. Lloyd RV, Osamura RY, Klöppel G, et al. WHO Classification of Tumours of Endocrine Organs, 4th edn IARC Press. 2017.

4. Lenders JW, Keiser HR, Goldstein DS, et al. Plasma metanephrines in the diagnosis of pheochromocytoma. Annals of internal medicine. 1995;123(2):101-109. doi: 10.7326/0003-4819-123-2-199507150-00004

5. Jain A., Baracco R., Kapur G. Pheochromocytoma and paraganglioma—an update on diagnosis, evaluation, and management. Pediatric Nephrology. 2020;35:581-594.

6. Lenders JW, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma //The Lancet. 2005;366(9486):665-675. doi: 10.1016/S0140-6736(05)67139-5

7. Eisenhofer G, Kopin IJ., Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacological reviews. 2004;56(3):331-349. doi: 10.1124/pr.56.3.1

8. Eisenhofer G, Keiser H, Friberg P, et al. Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. The Journal of Clinical Endocrinology & Metabolism. 1998;83(6):2175-2185. doi: 10.1210/jcem.83.6.4870

9. Eisenhofer G. Free or total metanephrines for diagnosis of pheochromocytoma: what is the difference? Clinical Chemistry. 2001;47(6):988-989. doi: 10.1093/clinchem/47.6.988

10. Eisenhofer G, Huynh, TT, Hiroi M, et al. Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma. Reviews in Endocrine and Metabolic Disorders. 2001(2):297-311. doi: 10.1023/A:1011572617314

11. Melnichenko GA, Troshina EA, Beltsevich DG. Russian Association of Endocrinologist clinical practice guidelines for diagnosis and treatment of pheochromocytoma and paraganglioma. Endocrine Surgery. 2015;9(3):15-33. (In Russ.) doi: 10.14341/serg2015315-33

12. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism. 2014;99(6):1915-1942. doi: 10.1210/jc.2014-1498

13. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? Jama. 2002;287(11): 1427-1434. doi: 10.1001/jama.287.11.1427

14. Grossman A, Pacak K, Sawka A, et al. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Annals of the New York Academy of Sciences. 2006;1073(1):332-347. doi: 10.1196/annals.1353.038

15. Eisenhofer G, Prejbisz A, Peitzsch M, et al. Biochemical diagnosis of chromaffin cell tumors in patients at high and low risk of disease: plasma versus urinary free or deconjugated O-methylated catecholamine metabolites. Clinical chemistry. 2018;64(11):1646-1656. doi: 10.1373/clinchem.2018.291369

16. Sbardella E., Grossman A. B. Pheochromocytoma: an approach to diagnosis. Best Practice & Research Clinical Endocrinology & Metabolism. 2020;34(2):101346. doi: 10.1016/j.beem.2019.101346

17. Molashenko NV, Platonova NM, Beltsevich DG, et all. Diagnosis and differential diagnosis of adrenal incidentalomas. Obesity and metabolism. 2016;13(4):39-44. (In Russ.). doi: 10.14341/OMET20164339-44

18. Lenders JW, Eisenhofer G. Update on modern management of pheochromocytoma and paraganglioma. Endocrinology and Metabolism. 2017;32(2):152-161. doi: 10.3803/EnM.2017.32.2.152

19. Raber W, Raffesberg W, Bischof M, et al. Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma. Archives of Internal Medicine. 2000;160(19):2957-2963. doi: 10.1001/archinte.160.19.2957

20. Guerrero MA, Schreinemakers JM, Vriens MR, et al. Clinical spectrum of pheochromocytoma. Journal of the American College of Surgeons. 2009;209(6):727-732. doi: 10.1016/j.jamcollsurg.2009.09.022