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Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine (W.F.Y.), Mayo Clinic, Rochester, Minnesota 55905; Department of Internal Medicine and Division of Endocrinology (A.M.S.), St. Joseph’s Healthcare, Hamilton, Ontario, Canada L8N 4A6; Department of Internal Medicine and Division of Endocrinology (A.M.S.), McMaster University, Hamilton, Ontario, Canada L8N 3Z5; Centre for Evaluation of Medicines (L.T.), St. Joseph’s Healthcare, Hamilton, Ontario, Canada L8N 1G6; and Department of Clinical Epidemiology and Biostatistics (L.T., A.G.), McMaster University, Hamilton, Ontario, Canada L8N 3Z5
Address all correspondence and requests for reprints to: Dr. William F. Young, Jr., Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
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Abstract |
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In each hypothetical algorithm, imaging would be indicated after positive biochemical testing as follows: algorithm A, fractionated plasma metanephrine measurements above the laboratory reference range; or algorithm B, abnormal measurements of 24-h urinary total metanephrines or catecholamines. In algorithm C, subjects with fractions of plasma metanephrine at or above 0.5 nmol/liter or normetanephrine at or above 1.80 nmol/liter would undergo imaging, whereas those with values between the reference range and these cutoffs would undergo 24-h urinary measurements (total metanephrines and fractionated catecholamines) and be imaged if positive. We determined that, if 100,000 hypertensive patients (including 500 patients with pheochromocytoma) were tested, algorithm A (measurement of fractionated plasma metanephrines alone) would detect 489 pheochromocytoma patients at a cost of 56.6 million dollars, whereas B (24-h urinary measurements) would detect 457 pheochromocytoma patients for 39.5 million dollars, and C (combination of measurements of fractionated plasma metanephrines and urines) would detect 478 patients for 28.6 million dollars. None of the screening strategies for pheochromocytoma described are affordable if implemented on a routine basis in extremely low-risk patients. However, algorithm C may be the least costly, and at a reasonable level of sensitivity, for subjects in whom the suspicion of disease is moderate.
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Introduction |
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Although recent reports have suggested that measurements of fractionated plasma metanephrines may be a convenient biochemical test for pheochromocytoma, an optimal strategy for dealing with mildly elevated (borderline) elevations of these measurements is needed (6, 7, 8, 9, 10). The economic implications of different biochemical testing strategies and subsequent imaging of positive screens have not been explored. Our aim was to explore, using a modeling technique, the economic implications of three proposed biochemical screening strategies (and subsequent imaging) for detection of pheochromocytoma.
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Subjects and Methods |
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We reviewed the medical records of 416 outpatients (including 47 patients with histologically confirmed pheochromocytoma or paraganglioma) who had concurrent measurements of fractionated plasma metanephrines, 24-h urinary total metanephrines, and 24-h urinary catecholamines between January 1, 1999, and November 29, 2001, to estimate the diagnostic efficacy of biochemical tests (updated published series) (Fig. 1
) (11). Indications for testing in patients without pheochromocytoma included hypertension in 148 patients, spells with or without sustained or paroxysmal hypertension in 126, adrenal mass(es) on an imaging study in 57, and high-risk group (including patients with high-risk familial syndromes, pheochromocytomas, or paragangliomas cured surgically previously) in 38 subjects (Fig. 1). Of the 47 pheochromocytoma patients, 30 had an adrenal pheochromocytoma, 17 had at least one extra-adrenal pheochromocytoma, 17 had malignant pheochromocytoma, and 6 had a genetic syndrome predisposing to pheochromocytoma (those with genetic syndrome screened before November 27, 2001) (Fig. 1). After November 27, 2001, subjects with a known genetic predisposition to pheochromocytoma were excluded from the study to prevent excessive representation of subjects with rare familial syndromes who are prone to being seen in quaternary care centers (36 subjects, including 4 subjects with pheochromocytoma excluded). Another 47 subjects were excluded because of an abnormal spectral curve, indicating drug interference in measurement of 24-h urinary total metanephrines.
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Biochemical assays
Liquid chromatography with electrochemical detection was used for measurement of fractionated plasma metanephrines (reported as metanephrine and normetanephrine fractions) and 24-h urinary catecholamines (reported as norepinephrine, epinephrine, and dopamine fractions), whereas urinary total metanephrines were measured by spectrophotometry (12, 13, 14, 15). All biochemical assays were performed at the Mayo Medical Center. In the case of multiple measurements of the same metabolite for the same patient, only the first concurrent measurement of plasma and urinary analytes was included in the study. Fractionated plasma metanephrine measurements were performed via venipuncture in the sitting posture, either fasting or nonfasting.
Interpretation of biochemical tests
For fractionated plasma metanephrines, the upper limits of the 95% reference range established by Mayo Medical Laboratories were 0.5 nmol/liter (98 pg/ml) for the metanephrine fraction and 0.9 nmol/liter (165 pg/ml) for the normetanephrine fraction, and measurements at or above either of these levels were considered positive in algorithm A. A urinary total metanephrine content at or above 6.6 µmol/24 h (
1.3 mg/24 h) was considered positive (15). For urinary catecholamines, values approximately twice that of the upper limit of the 95% reference range were considered positive, specifically the following: 24-h urinary content of norepinephrine at or above 1005 nmol (170 µg), epinephrine at or above 191 nmol (35 µg), or dopamine at or above 4571 nmol (700 µg) (11, 16). A positive 24-h urinary total metanephrine or catecholamine result was defined by positivity of either the urinary total metanephrines or any catecholamine fraction in algorithms B or C. In algorithm C, measurements of plasma metanephrine and normetanephrine within the 95% reference range were considered negative. In contrast, a biochemical test was considered positive in algorithm C, if either the plasma normetanephrine fraction was greater than or equal to twice the upper limit of normal (1.80 nmol/liter; 330 pg/ml) or the plasma metanephrine fraction was above 0.5 nmol/liter (98 pg/ml). In algorithm C, measurements of plasma normetanephrine or metanephrine fractions outside these definitions were considered indeterminate, and urinary testing would be indicated. The cutoffs for positivity for 24-h urinary total metanephrine and fractionated catecholamine measurements were the same for algorithm C as described above for algorithm B. New positivity cutoffs for measurements of fractionated plasma metanephrines in algorithm C have been established (see the supplemental data published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org).
Analyses and assumptions
A modeling technique was used to develop decision trees, incorporating the diagnostic efficacy data of biochemical tests. The horizon (endpoint) of the analyses was diagnosis or exclusion of pheochromocytoma, for hypothetical hypertensive patients subjected to each strategy. The outcome of interest was the number of patients with pheochromocytoma expected to be detected by each strategy. The costs of false-positive biochemical tests were reflected only in the costs of subsequent imaging and not in potential costs of needless surgery or its possible complications.
A decision analysis model of screening of hypertensive patients solely by measurement of fractionated plasma metanephrines was developed, with all positive screens (defined by the metanephrine or normetanephrine fractions being above the reference range), followed by imaging (algorithm A; see Fig. 3A). In algorithm B, only subjects with positive 24-h urinary total metanephrines or catecholamines would undergo further imaging (see Fig. 3B). In algorithm C, those patients with a plasma metanephrine fraction at or above 0.5 nmol/liter (98 pg/ml) or a plasma normetanephrine fraction at or above 1.80 nmol/liter (330 pg/ml) or those with indeterminate plasma measurements but positive urinary testing, would undergo imaging (see Fig. 3C).
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The analysis was performed from a third-party payer perspective, with the term "costs" referring to charges to the third-party payer. All costs were reported in 2002 U.S. dollars. Costs of biochemical testing were obtained from the Mayo Medical Laboratories, and the costs of venipuncture and imaging investigations were obtained from the Mayo Clinic Rochester Business Office (Table 1). The cost of venipuncture was included with plasma measurements. The cost of a 24-h urinary creatinine was included with urinary tests. The cost of urinary diagnostic testing was artificially inflated by 10% to account for the need for repeat urinary measures in those with an incomplete collection or drug interference. Surgical costs were excluded. For the purpose of the decision analysis model, the prevalence of pheochromocytoma in the hypertensive population that would typically be screened was estimated at 0.5% (19).
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Results |
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Based on the data collected from 416 outpatients (including 47 patients with histologically confirmed pheochromocytoma or paraganglioma), who underwent concurrent measurements of fractionated plasma metanephrines, 24-h urinary total metanephrines, and 24-h urinary catecholamines, we estimated the diagnostic efficacy of the three biochemical screening strategies. In algorithm A, measurement of fractionated plasma metanephrines alone (using the upper limit of the 95% reference ranges for the cutoffs for positivity) was estimated to have a sensitivity of 97.9% (46 of 47; 95% CI, 88.9–99.6%) and a specificity of 84.3% (311 of 369; 95% CI, 80.2–87.6%) (Fig. 2). In algorithm B, measurement of 24-h urinary total metanephrines and catecholamines, was estimated to have a sensitivity of 91.5% (43 of 47; 95% CI, 80.1–96.6%) and a specificity of 98.4% (363 of 369; 95% CI, 96.5–99.3%) (Fig. 2). In algorithm C, subjects with positive biochemical testing included subjects with positive fractionated plasma metanephrine measurements (plasma metanephrine fraction of 0.5 nmol/liter or a plasma normetanephrine fraction of 1.80 nmol/liter) as well as those subjects with indeterminate plasma results, but positive 24-h urinary total metanephrines and catecholamines. Thus, using algorithm C, 91.5% (95% CI, 80.1–96.6%) of patients with pheochromocytoma would be expected to have a positive fractionated plasma metanephrine measurement (43 of 47), and 84.3% (95% CI, 80.2–87.6%) of patients without pheochromocytoma would be expected to have a negative measurement (311 of 369) (Fig. 2). Those with indeterminate plasma results who would undergo confirmatory urinary testing, including an estimated 6.4% of patients with pheochromocytoma (3 of 47; 95% CI, 2.2–17.2%) and 11.7% of subjects without pheochromocytoma (43 of 369; 95% CI, 8.8–15.3%). The sensitivity of urinary measures in the pheochromocytoma patients with indeterminate plasma measures would be estimated to be 66.7% (2 of 3; 95% CI, 20.8–93.9%), with a specificity of 100.0% (43 of 43; 95% CI, 91.8–100.0%). The biochemical testing strategy in algorithm C was estimated to have an overall sensitivity of 95.7% (45 of 47; 95% CI, 85.8–98.8%) with a specificity of 95.9% (354 of 369; 95% CI, 93.4–97.5%), when both levels of testing were included (Fig. 2).
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For the purpose of the cost analysis, in all three screening algorithms, a 0.5% prevalence of pheochromocytoma was assumed in a target hypertensive population (19), so 500 patients with pheochromocytoma would be expected to be in a sample of 100,000 hypertensive subjects. In algorithm A, fractionated plasma metanephrine measurements above the reference range would be followed by imaging (Fig. 3A
). If 100,000 subjects with hypertension would be screened using algorithm A, and all those with positive biochemical screens imaged, 489 of 500 subjects with pheochromocytoma (overall sensitivity, 97.8%) would be expected to be detected, and 94,694 of 99,500 of subjects without pheochromocytoma would be reassured with a negative diagnosis (overall specificity, 95.2%). However, 15,621 subjects without pheochromocytoma would undergo CT scanning of the abdomen, and 10,935 of these subjects would undergo [123I]- or [131I]MIBG scanning. The total cost per 100,000 subjects screened would be estimated at 56.6 million dollars (Table 2).
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). Furthermore, 1592 subjects without pheochromocytoma would undergo CT scanning of the abdomen, and 478 of these subjects would undergo [123I]- or [131I]MIBG scanning. The total cost per 100,000 subjects screened would be estimated at 39.5 million dollars (Table 2).
If algorithm C (measurement of fractionated plasma metanephrines in all and 24-h urinary total metanephrines and catecholamines in those with indeterminate plasma values, followed by imaging in all with positive biochemical tests) were followed in 100,000 subjects with hypertension, 478 of 500 subjects with pheochromocytoma would be expected to be detected (95.6%), and 98,245 of 99,500 subjects without pheochromocytoma would be reassured with a negative diagnosis (overall specificity of 98.7%) (Fig. 3C). Furthermore, 4079 subjects without pheochromocytoma would undergo CT scanning, and 1224 of these subjects would undergo [131I]MIBG scintigraphy. The cost of algorithm C for 100,000 subjects screened would be 28.6 million dollars (Table 2).
Sensitivity analyses were performed examining the expense per pheochromocytoma case detected and the expense per patient with true negative test results in whom the diagnosis was ruled out for varying levels of pretest probability of pheochromocytoma (Fig. 4). Using the assumptions of our model, for algorithm A, the cost per pheochromocytoma detected would be expected to range from a high of approximately $115,700 per case detected at a pretest probability of disease of 0.5% to approximately $1,800 per case detected at a pretest probability of disease of 75%. For algorithm B, the cost per pheochromocytoma detected would be expected to range from a high of approximately $86,400 per case detected at a pretest probability of disease of 0.5% to approximately $2,000 per case detected at a pretest probability of disease of 75%. The least expensive algorithm, particularly at the lowest levels of pretest probability of disease, was algorithm C, for which the cost per pheochromocytoma detected would be expected to range from a high of approximately $59,800 per case detected at a pretest probability of disease of 0.5% to approximately $1,800 per case detected at a pretest probability of disease of 75%. Of note, the cost of testing for pheochromocytoma detected of algorithms A and B approached that of C when the pretest level of suspicion of pheochromocytoma was over 5–10% (Fig. 4A). The cost per true negative patient with the diagnosis of pheochromocytoma ruled out by testing was generally lower across all levels of pretest probability of disease in algorithm C, compared with the other algorithms (Fig. 4B).
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We also examined the total cost of imaging 100,000 hypothetical hypertensive patients, including 500 patients with pheochromocytoma, by varying the hypothetical charges for imaging (Table 3). We found that algorithm C was the least expensive of the three algorithms, when the costs of CT and MIBG were 50 or 75% of that charged at Mayo Clinic Rochester. Algorithms A and C were equivalent in total costs, when imaging charges were a quarter of that charged by Mayo Clinic; and algorithm A was slightly less expensive than the others, when imaging charges were 10% (or less) of that charged by Mayo Clinic. Thus, the relative overall cost of each algorithm was variable with imaging charges.
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Discussion |
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In our analysis, we excluded the costs of surgery, because it is unclear how many people with false-positive biochemistry and imaging would undergo needless surgery. However, the rate of surgery for false-positive biochemistry and imaging would be expected to be highest in algorithm A (fractionated plasma metanephrine measurements), lowest in B (24-h urinary measurements), and intermediate in C (combination testing). Thus, had surgical costs been included in a model, we would expect that A (fractionated plasma metanephrines) would appear to be even more costly than the other two strategies. Algorithm B (24-h urinary measurements) would be expected to have the least number of needless surgeries in patients with false-positive biochemical testing and imaging.
Others have suggested that screening exclusively by measurement of fractionated plasma metanephrines (at currently accepted cutoffs) could result in cost savings because of less costs incurred in multiple biochemical tests (21). In contrast, we have found that such a strategy (algorithm A) would be expected to be the most costly because of an excessively high rate of expensive imaging procedures in subjects with mildly elevated levels of plasma normetanephrine. It is important that imaging costs be incorporated in any future analyses of cost effectiveness of biochemical tests for detection of pheochromocytoma.
Our study is limited in external generalizability given that it has been performed in a tertiary care center, the costs to third-party payers may vary among institutions, and the preferences of clinicians and patients for biochemical tests and imaging may be variable. Moreover, spectrophotometric urinary metanephrine measurements have been replaced by HPLC assays in many laboratories, and the sensitivities and specificities of urinary measures in our study may not be generalizable to that of newer assays. Furthermore, our study is limited by the fact that the diagnostic efficacy of MIBG scintigraphy and CT in the quoted settings were extrapolated from the literature and not prospectively determined in patients subject to the presented biochemical testing algorithms. We also studied a relatively small sample size of patients, particularly a limited number of patients with pheochromocytoma with indeterminate fractionated plasma metanephrine measurements. We also studied a limited number of patients with adrenal incidentaloma, and our findings may not be directly generalizable to all such patients, particularly if a mass characteristic of pheochromocytoma is seen on imaging studies.
It is important to consider the broader policy implications of the costs of the algorithms presented for a population-based screening program. It has been previously suggested that the diagnosis of pheochromocytoma should be considered in many Americans with hypertension (6). It is estimated that there are currently 12 million Americans with known uncontrolled hypertension in the United States (22). If all of these patients were screened once using algorithm A (using the Mayo imaging algorithm), the total cost of diagnostic testing would be 6.8 billion dollars, which is more than half the annual direct medical expenditure for hypertension in the United States (10 billion dollars) (23). Even if these 12 million Americans would be screened with the least costly strategy, algorithm C (with the Mayo imaging algorithm), the total cost for diagnostic testing would be estimated at 3.4 billion dollars (approximately one-third of the U.S. yearly hypertension expenditure).
Missing a pheochromocytoma may have devastating consequences for the affected individual, yet the efficacy of a screening program must be balanced with its costs to society. Further research should be directed toward determining characteristics of hypertensive patients who are best served by screening for pheochromocytoma. Other mechanisms of improving cost effectiveness of screening could include improving efficacy of biochemical tests (or combinations of tests), improving specificity of imaging techniques, or lowering costs of biochemical testing and imaging modalities. Furthermore, if less costly biochemical tests, albeit with lower sensitivity, may be available, it is important to consider whether such tests may be preferred for screening of low-risk individuals. Although tremendous progress has been made over the years in detecting pheochromocytoma, widespread screening of hypertensive subjects is not currently affordable, and attention should be focused toward optimal resource use in detecting this rare condition.
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Footnotes |
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Received July 1, 2003.
Accepted February 18, 2004.
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References |
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This article has been cited by other articles:
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  A. A. Malik, A. E. Houni, H. Gulshad, S. Elsiah, and S. Al-Salam An interesting case of paraganglioma BMJ Case Reports, May 25, 2009; 2009(may25_1): bcr1020081150 - bcr1020081150. [Full Text]
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 M. d'Herbomez, G. Forzy, C. Bauters, C. Tierny, P. Pigny, B. Carnaille, F. Pattou, J.-L. Wemeau, and N. Rouaix An analysis of the biochemical diagnosis of 66 pheochromocytomas Eur. J. Endocrinol., May 1, 2007; 156(5): 569 - 575. [Abstract] [Full Text] [PDF]
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