Clonidine Suppression Test for a Reliable Diagnosis of Pheochromocytoma

When To Use

Spyridoula Tsiomidou; Christina Pamporaki; Aikaterini Geroula; Lukas Van Baal; Frank Weber; Henning Dralle; Kurt W. Schmid; Dagmar Führer; Nicole Unger


Clin Endocrinol. 2022;97(5):541-550. 

In This Article

Abstract and Introduction


Objective: In clinical practice, false-positive results in biochemical testing for suspected pheochromocytoma/paraganglioma (PPGL) are not infrequent and may lead to unnecessary examinations. We aimed to evaluate the role of the clonidine suppression test (CST) in the era of analyses of plasma-free metanephrines for the diagnosis or exclusion of PPGL in patients with adrenal tumours and/or arterial hypertension.

Design and Methods: This single-centre, prospective trial investigated the use of CST in 60 patients with suspected PPGL associated with out-patient elevations of plasma normetanephrine (NMN) and/or metanephrine (MN), in most cases accompanied with hypertension or an adrenal mass. Measurements of plasma catecholamines and free metanephrines were performed by liquid chromatography with electrochemical detection and tandem mass spectrometry, respectively.

Results: Forty-six patients entered final analysis (n = 20 with PPGL and n = 26 with a nonfunctional adrenal mass and/or hypertension). CST reliably excluded false-positive baseline NMN results with a specificity of 100%. The sensitivity of CST improved from 85% to 94% when tumours with isolated MN increase (n = 3) were not considered. In patients with elevated baseline NMN (n = 24), CST correctly identified all patients without PPGL. Patients with falsely elevated baseline NMN results (n = 7, 26.9%) exhibited increases of baseline NMN up to 1.7-fold above the upper reference limit.

Conclusion: CST qualifies as a useful diagnostic tool for differential diagnosis of borderline elevated plasma-free NMN in patients with suspected PPGL. In this context, CST helps to correctly identify all false-positive NMN screening results.


Pheochromocytomas and paragangliomas, together referred to as PPGLs, are tumours that arise from chromaffin cells and represent very rare causes of endocrine hypertension (0.2%–0.6% of all hypertensive patients).[1,2] At least 15 PPGL-associated driver genes and 12 different genetic syndromes have been described to date. Germline mutations in subunits of succinate dehydrogenase (SDHx), RET proto-oncogene, von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1), transmembrane protein 127 (TMEM127), and MYC-associated factor X (MAX) genes account for up to 40% of PPGLs.[3] Patients with PPGL suffer from sustained or more often paroxysmal hypertension accompanied in many cases by a combination of hyperhidrosis, palpitations, tremor, nausea, and pallor. Undiagnosed PPGL might lead to a fatal outcome.[4]

Diagnostic tests for the presence of a PPGL are usually initiated on the grounds of signs and symptoms of catecholamine excess, clinical suspicion of secondary hypertension, an adrenal mass, previous history or family history of PPGL, or an established mutation in a tumour susceptibility gene. Several studies have demonstrated high sensitivity and specificity of the measurement of plasma-free metanephrine (MN) and normetanephrine (NMN).[5–7] Alternatively, fractionated metanephrines (in the following referred to MN and NMN together) can be measured in 24 h urine collections, but measurements of plasma-free metanephrines offer better diagnostic performance than the urinary panels, especially when it comes to patients at high risk for disease.[6–9] Liquid chromatography with mass spectrometric detection (LC-MS/MS) has been established as the method of choice for measurements of plasma-free metanephrines.[10–13]

Preanalytical factors that interfere with measurements of plasma-free metanephrines and thus may lead to false-positive results include medication, seasonal temperature variation,[14] activation of the sympathetic nervous system associated with stress (e.g., extreme illness), and acquiring blood samples in the upright position. De Jong et al. demonstrated that plasma NMN and MN levels in blood samples collected in the upright position were 30% and 12% higher than those collected after 30-min rest in the supine position.[15] In other large examined populations, supine, age-adjusted normetanephrine measurements were half as likely to be elevated than those acquired in the seated position.[16,17] Therefore, it is recommended to acquire blood samples after at least 20–30 min rest in a strictly supine position.[15–18] It is well known that the two medications that account for the majority of false-positive elevations of plasma or urinary noradrenaline and normetanephrine (up to 45%) are tricyclic antidepressants and phenoxybenzamine.[19] Other antihypertensive drugs like α1-adrenoceptor blockers, calcium channel blockers, diuretics, and β-adrenoceptor blockers are not significant sources of false-positive results, and their withdrawal before testing is not necessary. Intake of β-adrenoceptor blockers may be associated with false-positive MN results in plasma. As the false-positive rate is not high (ca. 12.5%), routine withdrawal of this medication before testing for PPGL is not recommended, unless an equivocal result has been obtained and repeated testing seems reasonable.[19]

In clinical practice, false-positive results in biochemical testing for a PPGL are not infrequent.[20] In unselected patient populations, false-positive results for plasma-free or urinary fractionated metanephrines might occur in up to 22% of patients;[21] highest false-positive rates were observed for urinary metanephrines, especially urinary NMN.[20,21] In particular, while false positives in both MN and NMN are rare, isolated increases of NMN up to two- to threefold above the upper reference limit (URL) occur more often,[18–20] leading to repeated biochemical testing and imaging examinations until a pheochromocytoma is excluded or confirmed. Traditionally, the clonidine suppression test (CST) involving the measurement of catecholamines before and after oral clonidine administration was used to confirm or exclude the diagnosis of a PPGL. Since the implementation of routine measurement of MN and NMN, CST has become less frequent in clinical practice. In our study, we aimed to evaluate the utility of CST in the diagnostic algorithm for a PPGL, with emphasis on the catecholamine metabolites, and to identify the subpopulation of investigated patients who principally benefit from this test.