Upon systematically reviewing the literature, we have determined that fractionated plasma metanehrine measurements are highly sensitive in detecting pheochromocytoma, although specificity of these measurements may be variable, particularly in testing for sporadic disease. A negative fractionated plasma metanephrine measurement is highly effective in ruling out disease. However, a positive test result only moderately increases suspicion of disease, particularly in low risk subjects being tested for sporadic pheochromocytoma.
Pooled likelihood ratios may be applied in estimation of an individual patient's probability of sporadic pheochromocytoma, given a positive biochemical test result. The pre-test probability of sporadic pheochromocytoma (prevalence) is estimated to be 0.5% among screened hypertensive patients [114
], and 5.1% among incidentally discovered adrenal masses >1 cm in diameter in absence of symptoms of adrenal disease [adrenal "incidentalomas"] [3
]. For a patient with positive fractionated plasma metanephrines, the post-test probability of sporadic pheochromocytoma would be 2.8% in the patient with hypertension, and 23.7% in the patient with an adrenal incidentaloma. In other words 97.2% of hypertensive subjects and 76.3% of subjects with incidentaloma would not be expected to have a pheochromocytoma, in spite of a positive test result. Similarly, we may estimate the probability of sporadic pheochromocytoma, given negative fractionated plasma metanephrine measurements, using the pooled negative likelihood ratio value of 0.02. For a patient with normal fractionated plasma metanephrine measurements, the post-test probability of sporadic pheochromocytoma would be estimated to be 0.01% in the patient with hypertension and 0.11% in the patient with an adrenal incidentaloma.
Our findings are limited by the fact that data from the included studies may have been subject to multiple methodologic limitations, possibly resulting in over-estimation of the diagnostic efficacy of fractionated plasma metanephrine measurements. Also, many of the patients studied had known genetic predisposition, previously surgically cured disease, or metastatic pheochromocytoma, thereby limiting the external generalizability of our summary. Furthermore, positivity cut-offs were derived somewhat differently between the studies, possibly accounting for the observed heterogeneity of positive likelihood ratios between studies. The criterion for positivity in the NIH and Vienna studies were based on a NIH laboratory reference range [51
]; whereas a higher criterion was used in the Mayo study, based on a 95% reference range derived by Mayo Medical Laboratories [18
]. The Mayo reference range has been tested in hypertensive patients who were not subject to indwelling intravenous cannulation or prolonged supine rest, possibly accounting for the slightly higher cut-offs. Indeed, a laboratory medicine tradition has to derive normal ranges from "normal" healthy individuals as such individuals reflect the general population and are easily accessible for study. Such ranges are reflective of "non-disease", but their use may be subject to excessively high rates of false positive tests in subjects with conditions mimicking a disease in question who are likely to be tested clinically (such as patients with refractory hypertension in the case of pheochromocytoma testing). Limitations of deriving "non-disease" ranges in subjects with conditions mimicking a disease in question (such as hypertensive patients in this case) may include decreasing sensitivity of testing and the potential for missing a potentially fatal, treatable diagnosis.
It is notable that data on the efficacy of fractionated plasma metanephrine measurements in detection of pheochromocytoma is limited to only three laboratories with patients recruited from 6 clinical centres. This may be a reflection of the labor-intensive, time-consuming nature of the high performance liquid chromatography and electrochemical detection method as well as the nuisance of potential interference with acetaminophen [115
]. A newer method described by Roden et al. may circumvent the acetaminophen interference issue, but is also quite labor-intensive and might not be suitable for widespread clinical laboratory use [104
]. A method of measurement of fractionated plasma metanephrines using liquid chromatography with tandem mass spectrometry shows promise in terms of improved specificity and rapidity of processing of multiple samples [115
]. Further clinical study is indicated to validate such newer assays in clinical patient populations.