Biochemical Diagnosis of Pheochromocytoma: How to Distinguish True- from False-Positive Test Results
Abstract
Measurements of plasma normetanephrine and metanephrine provide a highly sensitive test for diagnosis of pheochromocytoma, but false-positive results remain a problem. We therefore assessed medication-associated false-positive results and use of supplementary tests, including plasma normetanephrine responses to clonidine, to distinguish true- from false-positive results. The study included 208 patients with pheochromocytoma and 648 patients in whom pheochromocytoma was excluded. Clonidine-suppression tests were carried out in 48 patients with and 49 patients without the tumor. Tricyclic antidepressants and phenoxybenzamine accounted for 41% of false-positive elevations of plasma normetanephrine and 44-45% those of plasma and urinary norepinephrine. High plasma normetanephrine to norepinephrine or metanephrine to epinephrine ratios were strongly predictive of pheochromocytoma. Lack of decrease and elevated plasma levels of norepinephrine or normetanephrine after clonidine also confirmed pheochromocytoma with high specificity. However, 16 of 48 patients with pheochromocytoma had normal levels or decreases of norepinephrine after clonidine. In contrast, plasma normetanephrine remained elevated in all but 2 patients, indicating more reliable diagnosis using normetanephrine than norepinephrine responses to clonidine. Thus, in patients with suspected pheochromocytoma and positive biochemical results, false-positive elevations due to medications should first be eliminated. Patterns of biochemical test results and responses of plasma normetanephrine to clonidine can then help distinguish true- from false-positive results.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Clonidine-suppression testing has 100% specificity and 96% sensitivity for failure to reduce plasma metanephrines by 40% in evaluating false-positive elevated catecholamine metabolites.
“If still elevated, they can be further evaluated as false positives by clonidine-suppression testing, with 100% specificity and 96% sensitivity of failure to reduce plasma metanephrines by 40%.322”
From Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association (2018) · cites this paper as [322]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Biochemical Diagnosis of Pheochromocytoma: Which Test Is Best?
Lenders, J. W. M., Pacak, K., Walther, M. M., Linehan, W. M., Mannelli, M., Friberg, P., Keiser, H. R., Goldstein, D. S., & Eisenhofer, G. (2002) · JAMA · doi:10.1001/jama.287.11.1427 · Cited by 1,134 · see citing works
Self-citationSawka, A. M., Jaeschke, R., Singh, R. J., & Young, W. F. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021251 · Cited by 503 · see citing works
Eisenhofer, G., Goldstein, D. S., Stull, R., Keiser, H. R., Sunderland, T., Murphy, D. L., & Kopin, I. J. (1986) · Clinical Chemistry · doi:10.1093/clinchem/32.11.2030 · Cited by 477 · see citing works
Self-citationPheochromocytoma: Diagnosis, Localization and Management
Bravo, E. L., & Gifford, R. W. (1984) · New England Journal of Medicine · doi:10.1056/nejm198411153112007 · Cited by 471 · see citing works
Sympathetic Nervous System Activity in Major Depression
Veith, R. C. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950050071008 · Cited by 457 · see citing works
Evolving Concepts in the Pathophysiology, Diagnosis, and Treatment of Pheochromocytoma
Bravo, E. L. (1994) · Endocrine Reviews · doi:10.1210/edrv-15-3-356 · Cited by 385 · see citing works
Eisenhofer, G., Lenders, J. W. M., Linehan, W. M., Walther, M. M., Goldstein, D. S., & Keiser, H. R. (1999) · New England Journal of Medicine · doi:10.1056/nejm199906173402404 · Cited by 346 · see citing works
Self-citationEisenhofer, G., Keiser, H. R., Friberg, P., Mezey, É., Huynh, T., Hiremagalur, B., Ellingson, T., Duddempudi, S., Eijsbouts, A. M. M., & Lenders, J. W. M. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.6.4870 · Cited by 242 · see citing works
Self-citationSasaki, M., Naomi, S., & Iwaoka, T. (1997) · PubMed · Cited by 229 · see citing works
Determination of metanephrines in plasma by liquid chromatography with electrochemical detection
Lenders, J. W. M., Eisenhofer, G., Armando, I., Keiser, H. R., Goldstein, D. S., & Kopin, I. J. (1993) · Clinical Chemistry · doi:10.1093/clinchem/39.1.97 · Cited by 220 · see citing works
Self-citationMoyer, T. P., Jiang, N. S., Tyce, G. M., & Sheps, S. G. (1979) · Clinical Chemistry · doi:10.1093/clinchem/25.2.256 · Cited by 201 · see citing works
Efficacy and Safety of Doxazosin for Perioperative Management of Patients with Pheochromocytoma
Prys-Roberts, C., & Farndon, J. R. (2002) · World Journal of Surgery · doi:10.1007/s00268-002-6667-z · Cited by 183 · see citing works
Understanding Catecholamine Metabolism as a Guide to the Biochemical Diagnosis of Pheochromocytoma
Eisenhofer, G., Huynh, T., Hiroi, M., & Pacák, K. (2001) · Reviews in Endocrine and Metabolic Disorders · doi:10.1023/a:1011572617314 · Cited by 182 · see citing works
Self-citationRegional release and removal of catecholamines and extraneuronal metabolism to metanephrines.
Eisenhofer, G., Rundquist, B., Åneman, A., Friberg, P., Dakak, N., Kopin, I. J., Jacobs, M. C., & Lenders, J. W. M. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.10.7559889 · Cited by 181 · see citing works
Self-citationDiagnostic Efficacy of Unconjugated Plasma Metanephrines for the Detection of Pheochromocytoma
Raber, W., Raffesberg, W., Bischof, M. G., Scheuba, C., Niederle, B., Gasic, S., Waldhäusl, W. K., & Roden, M. (2000) · Archives of Internal Medicine · doi:10.1001/archinte.160.19.2957 · Cited by 180 · see citing works
SUCCESSFUL OUTCOMES IN PHEOCHROMOCYTOMA SURGERY IN THE MODERN ERA
ULCHAKER, J. C., Goldfarb, D. A., Bravo, E. L., & Novick, A. C. (1999) · The Journal of Urology · doi:10.1016/s0022-5347(01)61762-2 · Cited by 160 · see citing works
Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans
Esler, M. D., Wallin, G., Dorward, P. K., Eisenhofer, G., Westerman, R., Meredith, I., Lambert, G., Cox, H. S., & Jennings, G. (1991) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1991.260.4.r817 · Cited by 124 · see citing works
Self-citationEisenhofer, G., Friberg, P., Pacak, K., Goldstein, D. S., Murphy, D. L., Tsigos, C., Quyyumi, A. A., Brunner, H. G., & Lenders, J. W. M. (1995) · Clinical Science · doi:10.1042/cs0880533 · Cited by 123 · see citing works
Self-citationGlucagon and clonidine testing in the diagnosis of pheochromocytoma.
Grossman, E., Goldstein, D. S., Hoffman, A., et al. (1991) · Hypertension · doi:10.1161/01.hyp.17.6.733 · Cited by 108 · see citing works
Self-citationRegional release and removal of catecholamines and extraneuronal metabolism to metanephrines
Eisenhofer, G. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.80.10.3009 · Cited by 98 · see citing works
Self-citationWenzel, R. R., Allegranza, G., Binggeli, C., Shaw, S., Weidmann, P. U., Lüscher, T. F., & Nolls, G. (1997) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(97)00095-8 · Cited by 85 · see citing works
The Clonidine Suppression Test for Pheochromocytoma
Sjoberg, R. J. (1992) · Archives of Internal Medicine · doi:10.1001/archinte.1992.00400180061009 · Cited by 77 · see citing works
Eisenhofer, G. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.83.6.2175 · Cited by 74 · see citing works
Self-citationHigh blood pressure. A side effect of drugs, poisons, and food
Grossman, E. (1995) · Archives of Internal Medicine · doi:10.1001/archinte.155.5.450 · Cited by 70 · see citing works
Interpreting Hoofbeats: Can Bayes Help Clear the Haze?
Pauker, S. G., & Kopelman, R. I. (1992) · New England Journal of Medicine · doi:10.1056/nejm199210013271407 · Cited by 41 · see citing works
Clonidine Suppression Test for Pheochromocytoma: Examples of Misleading Results*
Taylor, H. C., Mayes, D. M., & Anton, A. H. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-63-1-238 · Cited by 41 · see citing works
Lenz, T., Goßmann, J., Schulte, K.-L., et al. (1988) · New England Journal of Medicine · doi:10.1056/nejm198811243192115 · Cited by 36 · see citing works
Elliott, W. J., & Murphy, M. B. (1988) · The American Journal of Medicine · doi:10.1016/0002-9343(88)90261-6 · Cited by 32 · see citing works
Diagnostic problems in pheochromocytoma
Mannelli, M. (1989) · Journal of Endocrinological Investigation · doi:10.1007/bf03350050 · Cited by 30 · see citing works
Normal Catecholamine Production in a Patient with a Paroxysmally Secreting Phaeochromocytoma
Sinclair, D. A., Shenkin, A., & Lorimer, A. R. (1991) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456329102800420 · Cited by 29 · see citing works
Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma
BRAVO, E. L. (1994) · Endocrine Reviews · doi:10.1210/er.15.3.356 · Cited by 28 · see citing works
Effect of Buspirone on Urinary Catecholamine Assays
Cook, F. J., Chandler, D. W., & Snyder, D. K. (1995) · New England Journal of Medicine · doi:10.1056/nejm199502093320617 · Cited by 27 · see citing works
Pheochromocytoma: issues in diagnosis & treatment.
Young, W. F. (1997) · PubMed · Cited by 26 · see citing works
Clonidine-Suppression Test for Diagnosis of Pheochromocytoma
(1982) · New England Journal of Medicine · doi:10.1056/nejm198201073060115 · Cited by 26 · see citing works
Biochemical diagnosis of phaeochromocytoma: two instructive case reports.
Stewart, M. F., Reed, P., Weinkove, C., et al. (1993) · Journal of Clinical Pathology · doi:10.1136/jcp.46.3.280 · Cited by 25 · see citing works
Diuretic treatment alters clonidine suppression of plasma norepinephrine.
Hui, T., Krakoff, L. R., Felton, K., et al. (1986) · Hypertension · doi:10.1161/01.hyp.8.4.272 · Cited by 23 · see citing works
Clonidine-Suppression Test. A Useful Aid in the Diagnosis of Pheochromocytoma
Bravo, E. L., Tarazi, R. C., Fouad, F. M., et al. (1982) · The Journal of Urology · doi:10.1016/s0022-5347(17)53680-0 · Cited by 21 · see citing works
SUCCESSFUL OUTCOMES IN PHEOCHROMOCYTOMA SURGERY IN THE MODERN ERA
ULCHAKER, J. C., Goldfarb, D. A., Bravo, E. L., et al. (1999) · The Journal of Urology · doi:10.1097/00005392-199903000-00004 · Cited by 20 · see citing works
Clonidine Suppression Test Revisited
LENZ, A. R. T. (1998) · Blood Pressure · doi:10.1080/080370598437367 · Cited by 19 · see citing works
Mannelli, M., Feo, M. L. D., Maggi, M., et al. (1987) · Journal of Endocrinological Investigation · doi:10.1007/bf03348153 · Cited by 17 · see citing works
Pheochromocytoma with elevated metanephrines as the only biochemical finding.
Shawar, L., & Svec, F. A. (1996) · PubMed · Cited by 17 · see citing works
Malignant Phaeochromocytoma with High Circulating DOPA, and Clonidine-Suppressible Noradrenaline
McClean, D. R., Sinclair, L. M. T., Yandle, T. G., et al. (1995) · Blood Pressure · doi:10.3109/08037059509077597 · Cited by 13 · see citing works
The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls
Sjoberg, R. J. (1992) · Archives of Internal Medicine · doi:10.1001/archinte.152.6.1193 · Cited by 12 · see citing works
Raber, W., Raffesberg, W., Kmen, E., et al. (2000) · The Endocrinologist · doi:10.1097/00019616-200010010-00010 · Cited by 10 · see citing works
High blood pressure. A side effect of drugs, poisons, and food
Messerli, F. H. (1979) · Archives of Internal Medicine · doi:10.1001/archinte.139.6.682 · Cited by 8 · see citing works
Evaluation of the clonidine-suppression test in the diagnosis of pheochromocytoma
Plewe, G., Krause, U., Cordes, U., et al. (1988) · Journal of Molecular Medicine · doi:10.1007/bf01726574 · Cited by 7 · see citing works
Clonidine-induced suppression of plasma catecholamines in states of adrenal medulla hyperfunction
Gross, M. D., Shapiro, B., Sisson, J. C., et al. (1987) · Journal of Endocrinological Investigation · doi:10.1007/bf03348148 · Cited by 6 · see citing works
Normal Catecholamine Production in a Patient with a Paroxysmally Secreting Phaeochromocytoma
Popp‐Snijders, C. (1992) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456329202900322 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline
Lenders, J. W. M., Duh, Q.-Y., Eisenhofer, G., Gimenez-Roqueplo, A.-P., Grebe, S. K. G., Murad, M. H., Naruse, M., Pacak, K., & Young, W. F. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1498 · Cited by 2,827 · see citing works
Self-citationCarey, R. M., Calhoun, D. A., Bakris, G. L., Brook, R. D., Daugherty, S. L., Dennison-Himmelfarb, C. R., Egan, B. M., Flack, J. M., Gidding, S. S., Judd, E., et al. (2018) · Hypertension · doi:10.1161/hyp.0000000000000084 · Cited by 1,153 · see citing works
Catecholamine Metabolism: A Contemporary View with Implications for Physiology and Medicine
Eisenhofer, G., Kopin, I. J., & Goldstein, D. S. (2004) · Pharmacological Reviews · doi:10.1124/pr.56.3.1 · Cited by 1,072 · see citing works
Self-citationPheochromocytoma and Paraganglioma
Neumann, H. P. H., Young, W. F., & Eng, C. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1806651 · Cited by 736 · see citing works
Sherlock, M., Scarsbrook, A., Abbas, A., Fraser, S., Limumpornpetch, P., Dineen, R., & Stewart, P. M. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa008 · Cited by 347 · see citing works
“Similarly, false positives can occur with concomitant medications such as sympathomimetic drugs or interfering substances including caffeine; avoiding these for 24 hours before testing is recommended (108,207,208).”
BackgroundClinical guidelines for the management of adrenal incidentaloma
Lee, J.-M., Kim, M. K., Ko, S.-H., Koh, J.-M., Kim, B.-Y., Kim, S. W., Kim, S.-K., Kim, H. J., Ryu, O.-H., Park, J., et al. (2017) · Endocrinology and Metabolism · doi:10.3803/enm.2017.32.2.200 · Cited by 147 · see citing works
Därr, R., Kuhn, M., Bode, C., Bornstein, S. R., Pacak, K., Lenders, J. W. M., & Eisenhofer, G. (2017) · Endocrine · doi:10.1007/s12020-017-1300-y · Cited by 105 · see citing works
Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies
Kamoun, M., Mnif, M. F., Charfi, N., Kacem, F. H., Naceur, B. B., Mnif, F., Dammak, M., Rekik, N., & Abid, M. (2014) · The American Journal of the Medical Sciences · doi:10.1097/maj.0b013e31828aaeee · Cited by 77 · see citing works
Screening for Adrenal-Endocrine Hypertension: Overview of Accuracy and Cost-effectiveness
Schwartz, G. L. (2011) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2011.02.001 · Cited by 36 · see citing works
- Authors
- Eisenhofer, G., Goldstein, D. S., Walther, M. M., Friberg, P., Lenders, J. W. M., Keiser, H. R., & Pacak, K.
- Affiliations
- National Institutes of Health (US)
- National Institute of Neurological Disorders and Stroke (US)
- National Cancer Institute (US)
- Sahlgrenska University Hospital (SE)
- Radboud University Medical Center (NL)
- National Heart, Lung, and Blood Institute (US)
- Corresponding author
- Eisenhofer, Graeme
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2003-06
- Volume
- 88
- Issue
- 6
- Pages
- 2656-2666
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2109611875
- Cited by
- 492
- References
- 48
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 18 · 2023: 20 · 2022: 25 · 2021: 22 · 2020: 24 · 2019: 23 · 2018: 16 · 2017: 29 · 2016: 16 · 2015: 23 · 2014: 33 · 2013: 21 · 2012: 23
- FWCI
- 16.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- pheochromocytoma, false positives, metanephrine, clonidine suppression test, norepinephrine, tricyclic antidepressants, phenoxybenzamine, diagnostic specificity, epinephrine
- MeSH terms
- Adrenal Gland Neoplasms, Adrenergic alpha-Antagonists, Adult, Antidepressive Agents, Tricyclic, Biochemistry, Clonidine, Drug Interactions, False Positive Reactions, Female, Humans, Male, Middle Aged, Norepinephrine, Normetanephrine, Phenoxybenzamine, Pheochromocytoma
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
