Plasma or Urinary Metanephrines for the Diagnosis of Pheochromocytoma? That Is the Question

Several clinical disorders mimic the signs and symptoms of pheochromocytoma; the definitive diagnosis of this condition thus rests primarily on showing excessive and inappropriate production of catecholamine. Because pheochromocytoma is fatal if undiagnosed, biochemical tests used to detect it should have a high sensitivity. In addition, the predictive value of any negative test result should exclude false-negative results as efficiently as possible. A false-positive result is relatively less important because additional testing (using, for example, clonidine suppression, glucagon stimulation, and imaging techniques) can be done to rule out the disease.

In an article recently published in Annals [1], Lenders and colleagues reported that tests for measuring plasma metanephrine levels are more sensitive than tests for measuring plasma catecholamine levels and 24-hour urinary metanephrine levels (sensitivities of 100%, 85%, and 89%, respectively). In this study, the negative predictive value of a normal plasma metanephrine level was 100%. Despite these promising results, the study was limited by the lack of a reference group of patients with panic disorder, β-adrenergic hyperresponsiveness, labile essential hypertension, extra-adrenal tumors, and hereditary endocrine syndromes. In addition, Lenders and colleagues measured urinary metanephrine levels using a colorimetric assay that is inferior to high-performance liquid chromatography. Similarly, high-performance liquid chromatography yields higher plasma catecholamine values than do radioenzymatic techniques. This could explain why Lenders and colleagues found that measurement of plasma catecholamine levels had a lower diagnostic sensitivity for pheochromocytoma.

In this issue, Heron and coworkers [2] compare the clinical utility of measuring the ratio between 24-hour urinary metanephrine and creatinine levels with the utility of measuring 24-hour urinary metanephrine levels alone. In 1013 patients who were referred for hypertension and had biochemical tests for pheochromocytoma, measurement of 24-hour urinary metanephrine levels had a sensitivity of 95% and a negative predictive value of 100%. The metanephrine-to-creatinine ratio had a sensitivity of 100% and a negative predictive value of 100%. However, as the authors noted, the sensitivity improved from 95% to 100% because one patient had a normal urinary metanephrine level but a high metanephrine-to-creatinine ratio.

Heron and colleagues concluded that measuring 24-hour urinary metanephrine levels and correcting them for urinary creatinine excretion “is a simple and sensitive test for pheochromocytoma.” They also suggest that Lenders and coworkers might have underestimated the sensitivity of measurement of urinary metanephrine levels because of the use of the less-sensitive colorimetric assay. High-performance liquid chromatography is admittedly superior to colorimetric assays, but this controversy cannot be resolved without direct comparison of the two assays. It should also be emphasized that Sullivan and Solomon [3] and Kaplan and associates [4] were the first to report the usefulness of the metanephrine-to-creatinine ratio in establishing a biochemical diagnosis of pheochromocytoma. As did the study by Lenders and coworkers, Heron and colleagues' study lacked a reference group of patients with signs and symptoms that mimic pheochromocytoma.

In both of these studies, measurement of the plasma metanephrine level and the 24-hour urinary metanephrine-to-creatinine ratio had the same sensitivities and negative predictive values. However, 24-hour urine collections are difficult to obtain in an outpatient setting; hospitalization may be required to ensure that collection is complete and that proper collection techniques are used. Such specimens are extraordinarily difficult to obtain in young persons. In young persons and in outpatients, a plasma specimen may be preferred because obtaining the specimen is simpler and more rigidly controlled than 24-hour urine collections. In the reports of Lenders and colleagues and Heron and associates, all four tests (measurements of plasma catecholamine level, plasma metanephrine level, 24-hour urinary metanephrine level, and urinary metanephrine-to-creatinine ratio) had excellent specificity when the values were elevated.

Debate about the relative merits of various tests will continue. However, any test will serve as well as another if it is done reliably and in an appropriate clinical setting; if the physician is aware of the limitations and pitfalls of some of the methods of analysis, the pharmacologic and analytical effect of drugs on assay performance, and the expertise and skills of laboratory personnel; and if the physician understands the alterations in catecholamine metabolism that occur with pheochromocytomas. Finally, catecholamine tests developed under rigid quality control in research laboratories may not perform as well in standard clinical settings and commercial reference laboratories.

• Copyright ©2004 by the American College of Physicians