What are the serum investigations for diagnosing pheochromocytoma (adrenal gland tumor)?

From the Guidelines

Serum investigation for pheochromocytoma should begin with measuring plasma free metanephrines (metanephrine and normetanephrine), which is the most sensitive and specific initial test. This test should be performed after the patient has been resting supine for at least 30 minutes, and ideally in the morning after fasting overnight. If plasma metanephrines are unavailable, 24-hour urinary fractionated metanephrines and catecholamines can be used as an alternative, as recommended by the American Heart Association 1. Patients should avoid medications that may interfere with results, including tricyclic antidepressants, levodopa, sympathomimetics, and acetaminophen, for at least 2 weeks before testing if possible. They should also avoid caffeine, alcohol, and nicotine for 24 hours before the test. If initial results are borderline or equivocal, the test should be repeated. Positive biochemical findings should be followed by anatomical imaging studies such as CT or MRI to localize the tumor. Pheochromocytomas produce excess catecholamines (epinephrine, norepinephrine, dopamine), which are metabolized to metanephrines. Measuring these metabolites is more reliable than measuring the catecholamines themselves because metanephrines are produced continuously by the tumor, whereas catecholamine secretion can be episodic, potentially leading to false-negative results. The recent guideline from the European Society of Hypertension also supports the use of plasma free metanephrines as the initial test for diagnosing pheochromocytoma 1. Additionally, the 2023 guideline from the Canadian Urological Association recommends screening for pheochromocytoma with plasma or 24-hour urinary metanephrines in patients with adrenal incidentalomas that display ≥ 10 HU on non-contrast CT or who have signs/symptoms of catecholamine excess 1.

Some key points to consider when interpreting the results include:

• The sensitivity and specificity of plasma free metanephrines, which are 96%−100% and 89%−98%, respectively, as reported by the American Heart Association 1.
• The importance of avoiding medications that may interfere with results, as emphasized by the European Society of Hypertension 1.
• The need to repeat the test if initial results are borderline or equivocal, as recommended by the Canadian Urological Association 1.
• The use of anatomical imaging studies such as CT or MRI to localize the tumor after positive biochemical findings, as suggested by the American Heart Association 1 and the European Society of Hypertension 1.

It is also worth noting that other studies, such as those published in 2008 1 and 2020 1, provide similar recommendations for the diagnosis of pheochromocytoma, but the most recent and highest quality study should be prioritized when making a definitive recommendation. Therefore, the 2018 study from the American Heart Association 1 and the 2023 guideline from the Canadian Urological Association 1 should be considered the most authoritative sources for guiding clinical practice.

From the Research

Serum Investigations for Diagnosing Pheochromocytoma

The diagnosis of pheochromocytoma, a tumor of the adrenal gland, relies heavily on biochemical evidence of catecholamine production by the tumor. Several serum investigations can be used for this purpose, including:

• Measurements of plasma free metanephrines (normetanephrine and metanephrine) 2, 3, 4, 5
• Plasma catecholamines (epinephrine and norepinephrine) 3, 4, 5
• Urinary fractionated metanephrines 3, 6, 4, 5
• Urinary total metanephrines 6, 5
• Urinary vanillylmandelic acid (VMA) 6, 5

Comparison of Diagnostic Tests

Studies have compared the effectiveness of these tests in diagnosing pheochromocytoma:

• Plasma free metanephrines have been shown to have high sensitivity (95.4-99%) and specificity (89-92%) 2, 3, 4, 5
• Urinary fractionated metanephrines have high sensitivity (97%) but lower specificity (69%) 5
• Plasma catecholamines have lower sensitivity (84%) and specificity (81%) compared to plasma free metanephrines 5
• Urinary VMA has low sensitivity (64%) but high specificity (95%) 5

Clinical Recommendations

Based on the available evidence, the following tests are recommended for the diagnosis of pheochromocytoma:

• Plasma free metanephrines as the first-line test 3, 4, 5
• Urinary fractionated metanephrines as an alternative or additional test 3, 6, 4, 5
• Other tests, such as plasma catecholamines and urinary VMA, may be used in specific clinical contexts or when the above tests are not available 6, 5