Discussion: Hormonal Workup - Metanephrines
When Is Testing Necessary?
The vast majority of published guidelines recommend biochemical testing for pheochromocytoma in all patients with adrenal lesions in >1cm in accordance with the majority of published guidelines. 1–3
Guidelines published by the American Association of Endocrine Surgeons in 2022 and the Canadian Urological Association in 2023, allow for the omission of catecholamine testing in patients with no clinical signs of catecholamine excess and a lesion density of <10 HU on non-contrast CT imaging due to a very low prevalence of pheochromocytoma in this population. 4,5 The Canadian guidelines cite one study in which all 376 pheochromocytomas identified had HU >=10 (with two having HU of exactly 10). However, rare counter examples have been reported,6 the consequences of a missed diagnosis can be severe, and testing is relatively in-expensive.
What Tests Should be Performed?
Broad consensus exists that measurement of either free plasma metanephrines or 24-hour urinary fractionated metanephrines is appropriate with similar diagnostic performance for biochemical testing for catecholamine excess.1–3,6,7
Plasma catecholamines (epinephrine, norepinephrine, dopamine) can be drawn, but must be drawn after an indwelling IV catheter is placed and the patient rests for at least 30 minutes supine. Therefore, this is rarely required as a screening test.
How Accurate Are the Tests?
The Table 5 from the 2014 Endocrine Society guidelines for management on pheochromocytoma and paraganglionoma summarizes the available data nicely from 5 studies that compared plasma vs urine tests.7 In general, for plasma metanephrines sensitivity was >95% and specificity was 80-90%. For urine metanephrines, sensitivity was 90-95% and specificity ranged widely from 70-90%. The authors stress that no high quality direct comparisons can be made between the two types of tests
How Should The Tests Be Performed?
To our knowledge, the only guidelines to address this issue in detail were published by the Endocrine Society in 2014,7 so our recommendations reflect those guidelines. Sections 1.3, 1.4 and Table 7 are of particular relevance. Support for statements here can be found in those guidelines unless otherwise cited.
Strong evidence shows the superiority of liquid chromatography with mass spectrographic or electrochemical detection of metanephrines (urine or plasma) compared to immunoassays.
Plasma metanephrines should be measured with the patient in the supine position using reference ranges for supine patients, as multiple studies have shown significant reduction in diagnostic accuracy (e.g 2.8 fold increase in false positive rate) with other methods.
The conceptual underpinning of this is that it is well established that metanephrines increase with seated posture relative to supine in normal patients, but one study showed no such increase in patients with pheochromocytoma; thus the separation of distributions of metanephrine levels between the normal and pheochromocytoma population is less when both groups are seated.
Numerous medications are thought to potentially interfere with testing either by directly interfering with the accuracy of metanephrine measurements by the assays or by altering patient physiology. (See Lenders et al Table 7).
The guidelines cite case reports wherein mesalamine, sulfasalazine, and venlafaxine seemed to be the cause of falsely elevated metanephrine levels and stronger data supporting phenoxybenzamine and tricyclic antidepressants causing similar false positives8. They also cite the initial description of detection of metanephrines with liquid chromatography with electrochemical detection to support the possible interference of acetaminophen in the assay. However in many cases the interference is only theoretical, and in most cases the effect size is poorly described.
How Should the Tests be Interpreted?
There is no universally accepted algorithm for interpretation of urine and plasma metanephrine results.
The guidelines note that elevation of BOTH metanephrine and normetanephrine above the reference range is very specific for pheochromocytoma or paraganglioma
The guidelines similarly note that elevation of EITHER of these greater than 3x the upper limit of normal for a particular test is also very specific.
In the majority of cases of pheochromocytoma, laboratory testing is unequivocal.
Most ambiguous cases can be adjudicated by repeat testing with close attention to stopping medications that might interfere with testing and to ensuring the test is done with the patient in the supine position using appropriate reference values.
1. Zeiger MA, Thompson GB, Duh QY, et al. American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas. Endocr Pract. 2009;15(1):1-20. doi:10.4158/EP.15.S1.1
2. Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016;175(2):G1-G34. doi:10.1530/EJE-16-0467
3. Lee JM, Kim MK, Ko SH, et al. Clinical Guidelines for the Management of Adrenal Incidentaloma. Endocrinol Metab Seoul Korea. 2017;32(2):200-218. doi:10.3803/ENM.2017.32.2.200
4. Rowe NE, Kumar RM, Schieda N, et al. Canadian Urological Association guideline: Diagnosis, management, and followup of the incidentally discovered adrenal mass. Can Urol Assoc J. 2023;17(2):12-24. doi:10.5489/cuaj.8248
5. Yip L, Duh QY, Wachtel H, et al. American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary. JAMA Surg. 2022;157(10):870-877. doi:10.1001/jamasurg.2022.3544
6. Corwin MT, Caoili EM, Elsayes KM, et al. Performance of CT With Adrenal-Washout Protocol in Heterogeneous Adrenal Nodules: A Multiinstitutional Study. Am J Roentgenol. Published online February 28, 2024. doi:10.2214/AJR.23.30769
7. Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942. doi:10.1210/JC.2014-1498
8.Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical Diagnosis of Pheochromocytoma: How to Distinguish True- from False-Positive Test Results. J Clin Endocrinol Metab. 2003;88(6):2656-2666. doi:10.1210/jc.2002-030005
Image credit: https://commons.wikimedia.org/wiki/File:Catecholamine_and_trace_amine_biosynthesis.svg
Last updated by Marshall Strother and Julie Hallanger-Johnson on April 1, 2024
