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.

A Case of Sleep Apnea Syndrome Manifesting Severe Hypertension with High Plasma Norepinephrine Levels

“…The diagnosis is made by the measurement of urinary catecholamines and the identification of tumor by CT scanning, magnetic resonance imaging, or radionucleotide scanning with MIBG or octreotide [18]. Since 90% of the cases are derived from the adrenal medulla, the measurement of the levels of urinary metanephrine, a metabolite of E, is thought to be a sensitive biochemical screening test [19][20][21][22]. In the present case, we found an elevation of urinary normetanephrine, but not metanephrine levels and failed to locate the suspected adrenal tumor on either side.…”

Diagnosis and Localization of Pheochromocytoma

“…Because of the entirely normal plasma norepinephrine levels, the plasma normetanephrine/norepinephrine ratio (0.69) was also increased above the range previously established for patients with false-positive increases in plasma normetanephrine (0.09 to 0.52). 4 The concentration of metanephrine was within normal limits. The elevated plasma normetanephrine concentration and increased plasma normetanephrine/norepinephrine ratio were the first and only biochemical findings supporting a diagnosis of pheochromocytoma in this case.…”

Evaluation of the clonidine suppression test in the diagnosis of phaeochromocytoma

“…Antidepressants alter the alpha-2-imidazole autoreceptor sensitivity, eliminating the clonidine suppressive effects, 7 whereas beta-blockers can inhibit the metabolism of free noradrenaline and, therefore, cause false-positive results. 15 Eisenhofer et al 6 found that tricyclic antidepressants and phenoxybenzamine accounted for 44-45% of false-positive elevation in plasma and urinary noradrenaline.…”

“…[17][18][19][20] There is, however, still the possibility of false-positive results in which levels of metabolites are above the upper limit of normal, but not high enough to definitely diagnose phaeochromocytoma. Eisenhofer et al 6 have shown that, in such cases, clonidine suppression testing combined with measurement of plasma metanephrines can distinguish true-from false-positive results. In a series of 48 patients with phaeochromocytoma who underwent clonidine testing, 16 had normal levels or decreases in noradrenaline after clonidine.…”

“…As with all biochemical tests, false positives must be expected and, therefore, high levels of catecholamines and their metabolites do not necessarily reflect the presence of a tumour. 6 Patients with essential hypertension may have suggestive symptoms and borderline increases in catecholamines or, alternatively, drugs can interfere with the laboratory assays thus creating diagnostic uncertainty. 7 Such drugs, which will be discussed later, should be withheld for 1-2 weeks before testing.…”