Recent progress in biochemical testing for pheochromocytoma
Background: Since signs and symptoms of pheochromocytomas are unspecific, diagnosis is crucially dependent on biochemical evidence of excessive catecholamine production. Diagnostic workup was previously based on measurement of urinary catecholamines. Subsequently it was shown that pheochromocytomas contain high amounts of catechol-O-methyltransferase (COMT), the enzyme that converts epinephrine to metanephrine and norepinephrine to normetanephrine. This metabolism occurs in a continuous fashion within tumour cells and independently of variations of catecholamine release, providing diagnostic advantages to measuring the metanephrines over the parent catecholamines.
Role of metanephrines: Determination of plasma free metanephrines by liquid chromatographytandem mass spectrometry (LCMS/MS) is now regarded as gold standard. Due to the cost- and time-intensive technique the method is limited to specialized centers. Immunoassays may be an alternative process. The diagnostic value of plasma free and urinary metanephrines measured by either RIA or enzyme immunoassays (EIA) was recently demonstrated by us and others. In our study, urinary fractionated metanephrines demonstrated a slightly lower sensitivity and specificity than their plasma counterparts. Urinary metanephrines largely reflect sulfate-conjugated metabolites, which are formed in gastrointestinal tissue. Thus, they are not related only to pheochromocytoma.
Influence of confounding variables: Non-selective alpha-blockers may be associated with higher levels of norepinephrine and normetanephrine. Beta-blockers, to a much lower extent, may be responsible for elevated levels of metanephrines. We found, that coffee elevated normetanephrine. Furthermore, physical exercise led to relevant changes of metanephrine and normetanephrine and should therefore be avoided prior to sampling. Although effects of age, sex and BMI were small, these variables should be considered when interpreting biochemical results. In contrast, supine rest significantly decreased both metanephrine and normetanephrine when compared to standing rest. Metanephrine and normetanephrine were not significantly influenced by time of day, menstrual cycle or venepuncture. Of note, adjusted thresholds may be required for patients with hereditary syndromes.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.