Plasma Free Metanephrines for Detecting Pheochromocytomas in von Hippel-Lindau Disease and Multiple Endocrine Neoplasia II
Background
Von Hippel-Lindau (VHL) disease and multiple endocrine neoplasia type 2 (MEN-2) are inherited conditions associated with a predisposition to develop certain tumors. Individuals with MEN-2 are predisposed to tumors of the thyroid and the parathyroid glands, and sometimes tumors of the mucous membranes, while those with von Hippel-Lindau disease are predisposed to tumors or cysts of the brain and spinal cord, eyes, pancreas and kidneys. Both familial conditions are also associated with a predisposition to pheochromocytomas.
The genetic mutations responsible for VHL disease and MEN-2 are now known. Therefore, it is possible using modern genetic techniques to identify individuals with these familial conditions. Once identified, it is important that individuals with the genetic mutations receive periodic medical check-ups to screen for the presence of tumors associated with their familial condition. This periodic surveillance allows early detection and treatment of tumors that might otherwise prove fatal.
A problem with most currently available biochemical tests for diagnosis of pheochromocytoma is their lack of sensitivity. That is, a test result can be normal in some patients with the tumor, so that the tumor escapes detection. This is particularly troublesome in individuals with VHL disease and MEN-2 where periodic surveillance could potentially pick up the tumors at an early stage, before many of the typical signs and symptoms of excess catecholamine secretion by the tumor become apparent to the patient or physician.
A new biochemical test for detection of pheochromocytomas involves measurements of plasma concentrations of the metanephrines, normetanephrine and metanephrine, metabolites of the catecholamines, norepinephrine and epinephrine. These metabolites are produced within pheochromocytoma tumor tissue independently of any secretion of the catecholamines into the bloodstream. This report summarizes the usefulness of measurements of plasma concentrations of free normetanephrine and metanephrine for detecting pheochromocytomas in individuals with VHL disease and MEN-2.
The findings for plasma metanephrines and catecholamines in the patients with pheochromocytoma are shown in the bar graphs in the 4 panels of the figure below, where each bar represents a specific patient the height of which indicates the plasma concentration for that patient. Plasma metanephrines are shown on the left, catecholamines on the right, normetanephrine and its precursor catecholamine, norepinephrine, on the top, and metanephrine and its precursor catecholamine, epinephrine, on the bottom. Within each panel, patients with MEN-2 are shown by the gray bars on the right and those with VHL disease by the blue bars on the left. The lower green dotted horizontal line for each panel depicts the upper reference limit of normal for that specific test, so that positive test results suggesting a pheochromocytoma lie above the green dashed line and negative results or normal values below the line. The upper red dashed line indicates a concentration of over 5 times the upper reference limit; any patient with a concentration above this line almost certainly has a tumor.
The first point to note from the figure is that 13 patients, 33% of the total, had plasma concentrations of norepinephrine within the normal range whereas only two patients, about 5%, had normal plasma concentrations of normetanephrine; one of these patients, however, had an elevated plasmametanephrine leaving only one patient with a negative test or normal value for both plasma normetanephrine and metanephrine. The second point to note is that there are also more patients with elevated plasma concentrations of metanephrine than of epinephrine, particularly in the patients with MEN-2 where every patient had an elevated metanephrine,but where only 60% of patients had an elevated epinephrine. Interestingly, the pattern of consistent increases in plasma metanephrine in the patients with MEN-2 indicates a distinctly adrenergic tumor phenotype in these patients, with the relative lack of increases of plasma free metanephrinein patients with VHL disease indicating a noradrenergic phenotype in these patients. A third point to note is that patients with pheochromocytoma show much more severe elevations in plasma metanephrines than catecholamines; here in this series of patients close to 50% had concentrations of normetanephrine or metanephrine over 5-fold above the upper reference limits compared to only10% for norepinephrine and epinephrine. This difference is particularly pronounced for metanephrine and epinephrine in patients with MEN-2, over 90% of whom could be definitely diagnosed with pheochromocytoma based on an elevated plasma metanephrine alone - that is there was no question from the extent of increases in metanephrine that these MEN-2 patients must have had a pheochromocytoma. In contrast, epinephrine was increased to the same extent in only one patient. This serves to emphasize that in addition to considering overall sensitivity (ie percent of positive results) it is also important to consider the extent of increase above normal - this represents additional information that can be used to make a definitive diagnosis. What about the other biochemical tests used for diagnosis of pheochromocytoma, such as urinary outputs of metanephrines, VMA and catecholamines? A summary of the usefulness of these tests compared with plasma free metanephrines is shown in the table below.
Out of the 39 separately diagnosed incidents of pheochromocytoma there was only one patient with a negative test result for both plasmanormetanephrine and metanephrine - this was in a patient with a very small tumor of less than 1 cm diameter that was only diagnosed after the patient was operated for a renal carcinoma on the same side that a CT scan picked up a small adrenal mass. As shown in the table above, the sensitivity of plasma free metanephrines was therefore less than perfect at 97%, but considerably and significantly superior than that of all other biochemical tests that had sensitivities of only 46 to 72%. What do the numbers in the table mean in practical terms for patients with VHL disease or MEN-2 who undergo periodic screening for the presence of pheochromocytomas? The sensitivity of 46% for VMA means that use of this test to screen for pheochromocytomas will reveal the presence of the tumor in only 46% of patients who actually harbor the tumor. This means that over 50% pheochromocytomas will be missed by this test compared with 35% missed by testing urinary metanephrines, 28% missed by testing urinary catecholamines, 31% missed by testing plasma catecholamines and only 3%missed by testing plasma free metanephrines. The specificity of 96% for plasma metanephrines means that 96% of patients who don't harbor a pheochromocytoma will have a normal test result for both plasma normetanephrine and metanephrine. In the remaining four percent the test may suggest a pheochromocytoma even though there isn't one; in these patients the tumor would need to be ruled out by further testing.
Conclusions
The results show that measurements of plasma free metanephrines offer a considerably superior biochemical test for diagnosis of pheochromocytoma than provided by other biochemical tests. This superiority is particularly evident in patients with familial pheochromocytoma where tumors are more likely to be found by periodic screening studies at an early stage when they are small and do not secrete catecholamines in amounts sufficient enough to cause signs or symptoms or positive results for other biochemical tests. Patients with VHL disease or MEN-2 should undergo periodic surveillance for the presence of pheochromocytomas using measurements of plasma free normetanephrine and metanephrine as the primary biochemical screening test.
A summary of findings presented at the 81st Annual Meeting of the Endocrine Society, San Diego, California, June 15, 1999, and published in the New England Journal of Medicine, June 17, 1999 as an article authored by G. Eisenhofer, J.W.M. Lenders, W.M. Linehan, M.M. Walther, D.S. Goldstein and H.R. Keiser.