Graeme Eisenhofer Ph.D. and Karel Pacak M.D. Ph.D.
National Institutes of Health, Bethesda, Maryland
Diagnosis of pheochromocytoma typically requires confirmation by several tests, perhaps the most important being biochemical evidence of excessive catecholamine production by the tumor. This is usually achieved from measurements of catecholamines and certain catecholamine metabolites in urine or plasma (Table 1). However, the catecholamines, norepinephrine and epinephrine, are also produced by sympathetic nerves and the adrenal medulla and are thus not specific to pheochromocytomas. Therefore, high levels of catecholamines and their metabolites may be produced by a variety of conditions or disease states involving increased release of catecholamines from sympathetic nerves or the adrenal medulla (1). Sometimes pheochromocytomas may be "silent"; that is they may not produce catecholamines in amounts sufficient to produce a positive biochemical test result or the associated typical clinical signs and symptoms. Also, many pheochromocytomas secrete catecholamines episodically; between episodes, plasma concentrations or urinary excretion of catecholamines may be normal. Thus, tests of plasma or urinary catecholamines and urinary metabolites of catecholamines do not always reliably exclude or confirm the presence of a tumor (2-6). A more recently developed biochemical test involving measurements of plasma free normetanephrine and metanephrine, respective metabolites of norepinephrine and epinephrine, offers advantages over other tests for diagnosis of pheochromocytoma (5).
_____________________________________________________________ TABLE 2. BIOCHEMICAL TESTS FOR DIAGNOSIS OF PHEOCHROMOCYTOMA _____________________________________________________________ Biochemical Test and Normal Reference Range (lower and upper reference limits of normal)* _____________________________________________________________ 1. Urine Catecholamines (measured by HPLC) Norepinephrine (15-80 micrograms/day) Epinephrine (0-20 micrograms/day) 2. Urine Deconjugated Fractionated Metanephrines (measured by HPLC) Normetanephrine-sulfate (44-540 micrograms/day) Metanephrine-sulfate (26-230 micrograms/day) 3. Urine Deconjugated Total Metanephrines (measured by Spectrofluorimetry) (0-1.2 milligrams/day) (Sum of free plus sulfate conjugated metanephrine & normetanephrine) 4. Urine VMA (measured by Spectrofluorimetry) (0-7.9 milligrams/day) 5. Plasma Catecholamines (measured by HPLC) Norepinephrine (80-498 picograms/milliliter) Epinephrine (4-83 picograms/milliliter) 6. Plasma Free Metanephrines (measured by HPLC) Normetanephrine (18-112 picograms/milliliter) Metanephrine (12-61 picograms/milliliter) 7. Plasma Deconjugated Metanephrines (measured by HPLC) Normetanephrine-sulfate (610-3170 picograms/milliliter) Metanephrine-sulfate (316-1706 picograms/milliliter) _____________________________________________________________ * Reference ranges indicate lower and upper reference limits of a normal population commonly estimated from the 95% confidence intervals. Reference ranges may vary from laboratory to laboratory. A milligram is 1/1000 th (10 to the -3) of a gram; A microgram is 1/1,000,0000 th (10 to the -6) of a gram. A picogram is 1/1,000,000,000,000 (10 to the -12) of a gram.
The first step in catecholamine metabolism involves the actions either one of two enzymes:  monoamine oxidase, an enzyme that removes the amine part of the catecholamine; and  catechol-O-methyltransferase, an enzyme that adds a methyl group to form normetanephrine from norepinephrine and metanephrine from epinephrine (Figure 1). The actions of monoamine oxidase on norepinephrine and epinephrine results in formation of a single metabolite called 3,4-dihydroxyphenylglycol, or as it is commonly abbreviated, DHPG. Removal of the amine to form the metabolite, 3,4-dihydroxymandelic acid (DHMA), is not a favored pathway (7-9). DHPG is further metabolized by catechol-O-methyltransferase to form 3-methoxy-4-hydroxyphenylglycol (MHPG). This metabolite is also produced to a limited extent by the actions of monoamine oxidase on both normetanephrine and metanephrine (10,11).
In humans, 3-methoxy-4-hydroxymandelic acid - more commonly known as vanillylmandelic acid (VMA) - is the principal end-product of norepinephrine and epinephrine metabolism, produced largely from MHPG and to a lesser extent from normetanephrine and metanephrine (12-14) (Figure 1). VMA is present in urine and plasma at very high concentrations (Table 1), which like the conjugated metanephrines, makes measurement of VMA relatively simple. It is this that has made measurements of urinary VMA a time honored, though not necessarily sensitive, biochemical test for diagnosis of pheochromocytoma.
With the exception of VMA, all the catecholamines and their metabolites are metabolized by a further enzyme that adds a sulfate group to the molecules. These sulfate conjugates, as they are called, represent other major end-products of catecholamine metabolism that are typically present in plasma and urine at higher concentrations than the free compounds. In particular, the sulfate conjugates of the normetanephrine and metanephrine are present in plasma and urine in concentrations more than 25-fold higher than those of the free compounds. Assays of urine metanephrines, typically used for diagnosis of pheochromocytoma, employ a deconjugation step so that sulfate-conjugated metanephrines comprise the bulk of these measurements. Thus, these assays are largely measurements of different metabolites (i.e., sulfate- conjugated derivatives) from those of the free metanephrines. The latter are present in plasma and urine at much lower and harder to detect concentrations than their sulfate-conjugated derivatives.
Pheochromocytomas, differ from the adrenal medulla in that the tumors mainly secrete norepinephrine, whereas the predominant catecholamine secreted by the adrenal medulla is epinephrine. It is norepinephrine that is therefore more consistently elevated in patients with pheochromocytoma, although a significant but much smaller proportion may also show elevations in plasma or urinary epinephrine (19). Pheochromocytomas causing elevations in only epinephrine are generally rather uncommon. Increases in epinephrine either occuring alone or in combination with norepinephrine are, however, quite common in pheochromocytomas associated with multiple endocrine neoplasia type 2 (20,21).
Since norepinephrine is the predominant catecholamine secreted by pheochromocytomas, an understanding of its metabolism after release and production within sympathetic nerves, as compared with after release directly into the bloodstream by a pheochromocytoma, is particularly important. Because monoamine oxidase is the only catecholamine-metabolizing enzyme present in noradrenergic or sympathetic nerves, the norepinephrine metabolized within these nerves is all converted to DHPG (22-24) (Figure 2). As a consequence, the DHPG appearing in plasma is almost exclusively produced in sympathetic nerves, whereas the additional presence of catechol-O-methyltransferase in extraneuronal cells means that normetanephrine is exclusively produced from norepinephrine in extraneuronal cells, such as smooth muscle cells or liver cells (17,23). Much of the DHPG formed in nerves is metabolized further to 3-methoxy-4-hydroxyphenylglcol (MHPG) by catechol-O-methyltransferase in extraneuronal cells (10,23). Thus, in contrast to DHPG and normetanephrine, MHPG reflects both neuronal metabolism of norepinephrine to DHPG and extraneuronal metabolism of DHPG and normetanephrine, but is mainly derived from the DHPG produced initially in nerves (10).
Comparison of removal and metabolism of catecholamines by neuronal and extraneuronal cells has indicated that the former cells are far more important than the latter for inactivation of neuronally released norepinephrine (11,17,25). This means that most of the norepinephrine produced and released by nerves is metabolized within the nerves themselves (Figure 2). Most of this is from metabolism of norepinephrine that leaks from stores of the transmitter into the neuronal cytoplasm where the enzyme monoamine oxidase is located.
The above considerations combined with the series nature of neuronal and extraneuronal removal and metabolism (25) explain why very little of the DHPG in plasma (<1%) is derived from neuronal metabolism of norepinephrine released directly into the bloodstream (Figure 2). Thus, release of norepinephrine from a pheochromocytoma directly into the bloodstream causes only small increases in DHPG compared with release of norepinephrine from nerves (24,26). Hence, patients with pheochromocytoma and high norepinephrine levels often have normal or only slightly elevated plasma concentrations of DHPG (26,27). Therefore, findings of a high norepinephrine combined with a normal DHPG provide supportive evidence that an increased plasma concentration of norepinephrine is not due to excessive release from sympathetic nerves and might rather reflect a tumor (26,28,29). While it cannot be ignored that both an increased norepinephrine and DHPG could reflect an unusual tumor that also produces DHPG, this pattern is more typical of a state of increased release of norepinephrine by sympathetic nerves.
In contrast to the greater importance of neuronal over extraneuronal pathways for metabolism of neuronally released norepinephrine, the reverse is the situation for metabolism of circulating norepinephrine (Figure 2). In humans only 20-30% of the norepinephrine in the bloodstream is removed by and metabolized in nerves, whereas this proportion is 90% and more for that produced and released by nerves (11,30,31). This in part reflects the series nature of neuronal and extraneuronal removal and metabolizing mechanisms operating between sites of neuronal release within tissues and the bloodstream, but is also influenced by organs such as the liver that play an important role in the removal of circulating catecholamines by uptake into and metabolism by extraneuronal cells (14,32). As a result, about 20% of circulating levels of the extraneuronal metabolite, normetanephrine, are produced from circulating norepinephrine (32,33), a relatively high amount compared to the less than 1% for the neuronal metabolite, DHPG. Since pheochromocytomas secrete catecholamines directly into the bloodstream, extraneuronal production of normetanephrine and metanephrine from circulating catecholamines provides one reason why the metanephrines are better markers for a tumor than other metabolites that are largely derived from neuronal metabolism.
VMA, the major end-product of norepinephrine and epinephrine metabolism, is produced almost exclusively from the removal and metabolism by the liver of catecholamines and their metabolites that circulate in the bloodstream (14) (Figure 2). This is because the enzyme responsible for formation of VMA from MHPG, alcohol dehydrogenase, is localized to the liver (34,35). The substantial production of VMA from circulating DHPG and MHPG, most of which is derived from neuronal norepinephrine metabolism, explains why VMA is a relatively insensitive marker for pheochromocytoma compared with the precursors norepinephrine, epinephrine, normetanephrine and metanephrine (36-40).
A problem with use of plasma or urinary catecholamines for diagnosis of pheochromocytoma is that some tumors are quiescent and may not secrete large amounts of catecholamines while other tumors appear to secrete catecholamines episodically. Thus, plasma levels and urinary outputs of catecholamines are normal in some patients with pheochromocytoma and the presence of a pheochromocytoma cannot be reliably excluded using measurements of plasma or urinary catecholamine concentrations (2-6,37,43-45). In contrast, the metanephrines (either normetanephrine or metanephrine or both) are constantly produced by the actions of catechol-O-methyltransferase on catecholamines leaking from stores within tumor cells and therefore show much more consistent increases above normal in patients with pheochromocytoma than plasma catecholamines (5,41). This means that measurements of plasma normetanephrine and metanephrine reliably excludes the presence of all but the smallest of pheochromocytomas. Where excluded, no other tests are necessary. This means that measurements of plasma metanephrines avoid a missed diagnosis and minimize the need to run multiple diagnostic tests to exclude the presence of a tumor. It also means that a person with normal plasma concentrations of normetanephrine and metanephrine can be fairly confident of not having a pheochromocytoma.
Since, the free metanephrines are formed extraneuronally, and to a large extent within chromaffin tissues (e.g., adrenal medulla and pheochromocytomas), these metabolites are also more sensitive markers for a pheochromocytoma than the other catecholamine metabolites that are derived mainly from neuronal sources.
Urinary metanephrines are commonly measured after acid hydrolysis and thus largely represent sulfate-conjugated normetanephrine and metanephrine. A substantial amount of the normetanephrine-sulfate is derived from sulfate conjugation of normetanephrine produced in parts of the body other than the adrenal medulla or pheochromocytoma tumor chromaffin tissue. Therefore the sulfate-conjugated normetanephrine, as commonly measured in urine, is a less sensitive marker of pheochromocytoma than the free normetanephrine measured in plasma. Nevertheless, measurements of urinary deconjugated normetanephrine and metanephrine, performed by modern HPLC methods, do provide a reasonably sensitive biochemical test for diagnosis of pheochromocytoma; these measurements may be more sensitive than measurements of catecholamines (6,46).
Measurements of the combined sum of urinary outputs of normetanephrine and metanephrine in sulfate-conjugated plus free form (commonly known as urinary total metanephrines), as measured by out-dated spectrofluorometric methods, are not sensitive tests of a pheochromocytoma and have limited value in the initial work-up of a patient suspected of having a pheochromocytoma. The low sensitivity of urinary VMA also makes this test less than satisfactory for the initial biochemical diagnosis of a pheochromocytoma.
Since upper reference limits of normal of most diagnostic tests are typically established from the 95% confidence intervals (with 2.5% below and 2.5% above) of a range of values determined in a reference population (see Table 1 for normal reference limits), it can be expected that all tests will give at least a 2.5% incidence of false-positive results (i.e., 2.5% of all tests results will show an elevated value that might suggest the presence of a tumor when none is really present). This means that no biochemical test can be expected to have 100% specificity and the best that might be expected would be 97.5%. In practice, however, the specificity of biochemical tests are often lower than 97.5%. This is particularly problematic for the biochemical tests used to detect pheochromocytoma.
Since the catecholamines and their metabolites are normally produced by sympathetic nerves and the adrenal medulla, none of these compounds are highly specific for the presence of a pheochromocytoma. In particular, plasma and urinary catecholamines may be elevated by a variety of physiological, pharmacological and pathological conditions (1). As yet, none of the various biochemical markers of pheochromocytoma have been shown by any rigorous study to be any more specific than the others for diagnosis of a tumor. Nevertheless, the combination of measurements of catecholamines and of certain metabolites can be useful in helping to distinguish elevated catecholamines due to a tumor from elevated catecholamines secondary to increased release from sympathetic nerves or the adrenal gland.
Increased release of catecholamines from sympathetic nerves or the adrenal gland secondary to exercise, mental stress, low blood pressure, low blood volume, low blood glucose or certain drugs are all conditions that may elevate plasma and urinary catecholamines and cause false positive test results. During blood sampling and 24 hr urine collections these influences must be avoided. Upright posture is another important determinant of catecholamine release, increasing plasma norepinephrine by as much as 3-fold above values in the lying position. Therefore, collection of blood samples should be performed with the patient resting quietly in the lying position for at least 20 minutes before sampling with an indwelling intravenous catheter previously inserted to avoid any possible acute stress associated with insertion of the needle.
A wide variety of pathological conditions may be associated with elevated plasma and urinary catecholamines. Congestive heart failure, renovascular hypertension, hypernoradrenergic hypertension, shock, sepsis, dumping syndrome, sleep apnea, anxiety neurosis and panic disorder are some of the syndromes that may be associated with elevated plasma or urinary catecholamines and clinical symptoms suggestive of a pheochromocytoma.
The above physiological and pathological conditions can also lead to elevated production of metanephrines and VMA, with attendant false-positive test results for these metabolites. However, because production of these metabolites is somewhat independent of catecholamine release from the sympathetic nerves or the adrenal medulla, their proportional increases are typically less than those in catecholamines. The metanephrines, in particular, are relatively poor markers of increased release of catecholamines from sympathetic nerves or the adrenal gland (33,41). Theoretically, this should make the metanephrines less prone to false-positive results in physiological and pathological states associated with sympatho-adrenalmedullary activation. However, there are other factors to consider that may additionally contribute to false positive test results for these tests. Deficiencies or pharmacological inhibition of MAO increases both urinary deconjugated and plasma free metanephrines due impaired breakdown of the metabolite by MAO and increased shunting of metabolism through O-methylation pathways (47,48). Severe renal failure can be particularly problematic in patients suspected of having a pheochromocytoma, making urine test results unreliable or urine collection impossible (49). In these patients biochemical diagnosis typically requires assays of plasma catecholamines and metanephrines. However, the sympathetic nerves can be activated in these patients resulting in elevated plasma norepinephrine concentrations. Also, end-products of catecholamine metabolism, that depend on elimination by the kidneys - such as the sulfate-conjugated metanephrines - tend to build up in plasma to very high levels (50). Reduced renal perfusion in states such as congestive heart failure and hypertension with impaired renal function can also reduce the circulatory clearance of metabolic end-products leading to increased plasma concentrations independent of any effect of sympathetic activation.
During interpretation of biochemical test results it is important to keep in mind that these are numerical values and should not be simply considered as simply either negative (within the normal range) or positive (above the normal range). Rather, the magnitude of an increase above normal values should also be considered. For example, a patient presenting with suggestive symptoms and a plasma norepinephrine concentration of over 2500 pg/mL (14.8 pmol/mL), approximately 5 times above the upper reference limit of normal, is far more likely to have a pheochromocytoma than a patient with the same symptoms and a plasma norepinephrine concentration just above the upper reference limits. The few conditions where plasma norepinephrine can reach such high levels (e.g., hypernoradrenergic hypertension, end stage congestive heart failure, circulatory shock) are easily excluded. In patients with pheochromocytoma, plasma concentrations of normetanephrine and metanephrine typically show much larger relative increases above the upper reference limits than observed for tests of catecholamines, urinary metanephrines and VMA. This indicates that at the higher limits more specific for a tumor, measurements of plasma normetanephrine and metanephrine provide better proof (i.e., are more specific) of a pheochromocytoma than other available tests.
Because of the high sensitivity of the test, our recommendation is to use HPLC measurements of plasma free normetanephrine and metanephrine as the initial biochemical test of choice. This test should preferably be combined with HPLC measurements of plasma catecholamines collected under appropriately controlled circumstances for further interpretation of any elevations in plasma free metanephrines. To circumvent false-positive test results, appropriate consideration should always be given to interference with assay results by any drugs that the patient may be taking. In centers where measurements of plasma free metanephrines are not available, we recommend that initial biochemical tests for exclusion of a pheochromocytoma should include either HPLC measurements of plasma or 24 hr urine deconjugated (free + sulfate-conjugated) normetanephrine and metanephrine combined with measurements of plasma or urinary catecholamines. Because of a lower sensitivity, a finding of a normal 24 hr urinary output of VMA is of little practical use in initial exclusion of a pheochromocytoma.
If plasma free metanephrines have been run, and they are well within the normal range, then it is highly unlikely that the patient has anything but a very small tumor (< 1 cm) and there should be little need to run further tests at this stage. On the other hand, normal results for each of the other biochemical tests, even when performed in combination, are still possible in a small percentage of patients with a pheochromocytoma. Thus, if plasma free metanephrines have not been run, but the other above test results are all normal, then it is still possible that the patient has a pheochromocytoma. If suggestive signs or symptoms persist, repeat biochemical testing may be appropriate.
Other indicators of sympatho-adrenalmedullary activation rather than a pheochromocytoma are the distict patterns of biochemical test results that accompany sympathetic activation as opposed to a tumor. Patterns of biochemical test results that are more suggestive of increased release from sympathetic nerves or the adrenal gland than from a tumor (such as occurs in hypernoradrenergic hypertension, renovascular hypertension, congestive heart failure, panic disorder, dumping syndrome, and other conditions), include proportionally larger elevations above the upper reference limits of normal of plasma norepinephrine or epinephrine than of plasma normetanephrine or metanephrine. In sympathetic activation, increases in plasma DHPG that parallel the increases in norepinephrine typically reflect a source of the elevated norepinephrine from sympathetic nerves rather than from a pheochromocytoma. This pattern of biochemical test results combined with a negative clonidine suppression test result (i.e., a substantial decrease in plasma norepinephrine after clonidine) is highly suggestive of sympathetic activation rather than a tumor, and, unless imaging studies suggest otherwise, a pheochromocytoma can be excluded and no further tests should be necessary.
In most cases of positive initial biochemical test results, where clinical suspicion of a pheochromocytoma remains reasonable, a CT or MRI scan of the entire abdomen may be immediately appropriate. A finding of an adrenal or abdominal mass together with suggestive clinical signs and symptoms and highly elevated catecholamines and their metabolites and an appropriate pattern of changes in metabolites and catecholamine precursors (i.e., larger relative increases in plasma free metanephrines than catecholamines and/or normal plasma DHPG levels) might be all that is needed at this stage to justify surgery. However, in more ambiguous cases it might also be appropriate to follow up with MIBG scintigraphy, preferably using the 123- iodine labeled compound rather than the 131-iodine labeled compound.
In rare cases, where imaging studies are all negative, but where suspicion of a pheochromocytoma remains high, it may be appropriate to consider a vena caval sampling procedure to establish the source of the high circulating levels of catecholamines or free metanephrines. In this procedure a catheter is threaded up the vena cava (normally from the major vein in the upper leg) allowing sampling of blood from various organs and tissues. A high concentration at one sampling site compared with others helps to localize the site responsible (i.e., the site of the tumor) for the elevated plasma concentrations of normetanephrine, metanephrine, norepinephrine and or epinephrine.
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This article has been adapted from other work by the authors and written for the express purpose of dissemination of relevant information to members of the Pheochromocytoma Support Site and all who visit the site. Pheochromocytoma is a rare tumor that is often misdiagnosed. It is therefore important that people with the tumor or suspected of harboring the tumor should be well informed with the most up-to-date information about available and most appropriate methods for diagnosis of the tumor.