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Departments of Hormonal Biology (P.B., F.I.) and Endocrine Surgery (A.C., E.S.), Hôpital Saint-Louis; Department of Rheumatology, Hôpital Cochin (C.C.); and Physiology Laboratory, Hôpital Necker-Enfants Malades (J.-C.S.), Assistance Publique-Hôpitaux de Paris, Paris, France
Address all correspondence and requests for reprints to: Dr. Philippe Boudou, Department of Hormonal Biology, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France. E-mail: philippe.boudou{at}sls.aphp.fr.
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Abstract |
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Methods: In the present study we compared two second-generation PTH assays (the total intact PTH assay from Scantibodies Laboratory, Inc., and the intact PTH assay from Nichols Institute Diagnostics) with two third-generation assays (the cyclase-activating PTH assay also from Scantibodies Laboratory and the bio-intact PTH assay from Nichols Institute) in a series of 145 consecutive PHPT patients operated in our endocrine surgery department over a 10-month period. A group of 74 healthy subjects served as controls.
Results: The diagnostic sensitivities for PHPT of the total intact, the intact, the cyclase-activating, and the bio-intact assays were 93.8%, 97.3%, 84.2%, and 89.0%, respectively, with 95% confidence intervals in the control groups of 10–46, 11–60, 8.4–34, and 9–41 ng/liter, respectively.
Conclusion: Our findings demonstrate that the diagnostic sensitivities of second- and third-generation PTH assays are similar. Third-generation PTH assays do not therefore improve the diagnosis of elevated serum PTH levels in PHPT, although there are numerical differences among the values.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Thus, the present study was performed to compare the diagnostic sensitivities of two second-generation assays with the two third-generation PTH assays. This study was carried out in 145 consecutive PHPT patients operated in our endocrine surgery department over a 10-month period.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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One hundred forty-five consecutively operated PHPT patients (28 men and 117 women), aged 61.7 ± 13.2 yr (mean ± SD), were investigated over a 10-month period. These patients, living in Paris and its suburbs, consulted their general practitioners for various complaints or symptoms, such as asthenia, osteoporosis, or urolithiasis. At presentation, hypercalcemia was observed, and additional investigations confirmed the diagnosis of PHPT. These patients were then referred to our unit for surgical intervention. All had normal renal function for their age. A group of 74 healthy subjects (14 men and 60 women) also living in Paris and its suburbs, aged 62.2 ± 4.6 yr (mean ± SD), with serum 25-hydroxyvitamin D (25-OHD) levels above 50 nmol/liter, were used as controls. This investigation was approved by the local ethics committee and was conducted in accordance with the guidelines published in the Declaration of Helsinki. Informed consent was obtained from all patients.
Laboratory methods
Blood samples were collected after an overnight fast, just before the patients entered the surgery room. Serum samples were centrifuged at 4 C, and aliquots were promptly frozen at –80 C. This procedure never exceeded 2 h, because the stability of PTH measured with the third-generation assays has been reported to be shorter than when measured with second-generation assays (4, 7). Calcium, phosphate, albumin, and creatinine were measured by standard chemistry methods. Serum 25-OHD was measured by RIA (DiaSorin, Stillwater, MN). Serum PTH was measured with four different assays, based upon two-site immunometric methods: the Duo PTH immunoradiometric kit from Scantibodies Laboratory, Inc., which includes two different assays, the total intact (T-iPTH) and the CA-PTH assays, and two immunochemiluminometric assays from Nichols Institute Diagnostics, the Nichols Advantage chemiluminescent intact and bio-iPTH assays. The T-iPTH and iPTH assays are referred to as second-generation assays, whereas the CA-PTH and bio-iPTH assays are known as third-generation assays. Both second- and third-generation PTH assays use goat polyclonal purified antibodies. Two types of antibodies were used. The first antibodies, the capture antibodies, were common in both generation of assays and were directed against the 39–84 PTH region, but differed in their interaction with the solid phase (i.e. the antibodies were immobilized onto polystyrene-coated beads for the Scantibodies assays and were biotinylated antibodies reacting with streptavidin-coated particles for the Nichols assays). The second antibodies served as detection antibodies and were specific for each generation assays. They were directed against the 1–34 PTH region in the second-generation assays and against the 1–6 PTH region in the third-generation assays. These antibodies were either iodine or acridinium ester labeled (Scantibodies and Nichols, respectively). In each case, the assays were run according to the manufacturer’s protocol, and analytical characteristics for these PTH assays have been previously reported (4, 5, 7).
Expression of results and statistics
Data are presented using the mean ± SD with the 95% confidence interval (CI) for normal distribution or using the median with the range for nonnormally distributed data. Correlations were calculated using simple regression. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. One hundred thirty-three of the 145 patients had serum 25-OH D concentrations below 50 nmol/liter, although this value has been considered by an expert panel as the minimum level to be maintained in PHPT patients (8). At admission in the endocrine surgery department, total serum calcium levels adjusted for albumin were normal in 22 of 145 patients. Despite the fact that recumbency is known to lower serum total calcium values, these 22 patients were not excluded from the present study because they had persistently elevated serum calcium values before hospitalization and histologically proven PHPT, thus excluding a possible confusion with secondary hyperparathyroidism, especially in the case of the patients with low serum 25-OHD levels (9). One hundred thirty-two patients had single adenomas, one of whom has multiple endocrine neoplasia type 1 (MEN1); eight had multiple adenomas, one of whom had MEN1; four had parathyroid hyperplasia, two of whom had MEN1; and one had parathyroid carcinoma. Median T-iPTH levels were 27% lower than iPTH levels. Similarly, CA-PTH levels were 25% lower than bio-iPTH levels. The percentages of elevated PTH levels when individually measured by T-iPTH, CA-PTH, iPTH, and the bio-iPTH assays were 93.8, 84.2, 97.3, and 89.0%, respectively (Fig. 1). The sensitivities for diagnosis of PHPT as a function of the number of tests applied were: one, 93.8%; two, 95.2%; three, 95.2%; and four, 98.6%.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Silverberg et al. (5) reported above-normal PTH concentrations in 73% and 96% of their patients with PHPT using, respectively, the Allegro and CA-PTH assays, suggesting a better sensitivity with the third-generation assay, whereas the PTH concentrations were reported by Carnevale et al. (6) to be above normal in 77% and 82% of their patients using, respectively, the CA-PTH and the T-iPTH assays, suggesting that the third-generation PTH assay did not improve the diagnostic sensitivity of PHPT. The discrepancies between these two studies and our study could be due to 1) differences in the populations studied, 2) differences in the assays tested, and/or 3) the use of different reference values.
In the two previous studies consisting of 56 men and women (5) or 39 postmenopausal women (6) with PHPT, the sex ratio (5) and the mean age of the patients (5, 6) are very close to those of our population. The biological data in these studies are also consistent with the diagnosis of PHPT despite the fact that only 25% of their patients were operated on. CA-PTH concentrations were less than 200 ng/liter in all patients except for one, two, and 16 patients in Silverberg’s study (5), Carnavale’s study (6), and our study, respectively. The median CA-PTH level in our study was also very similar to the mean values in the other two previous studies. In addition, the Allegro PTH kit tested in Silverberg’s study (5) has been shown (11, 12) to be very closely related to the T-iPTH assay tested in Carnavale’s study (6) and our study. Thus, it is unlikely that the different conclusions of the three studies are related to the two first above-mentioned potential factors (i.e. difference in patient population and differences in the assays tested).
The upper limit of the normal PTH range defined by Carnevale et al. (mean ± 2 SD) (6) in a healthy, gender-matched, control group with a relatively poor 25-OHD status (mean ± SD, 41.2 ± 19.7 nmol/liter) was higher than our own upper limits using the T-iPTH (65 vs. 46 ng/liter) and the CA-PTH (44 vs. 34ng/liter) assays. These different upper normal limits may explain why Carnavale et al. (6) found lower absolute sensitivities than we did using the same assays.
However, the normal values proposed by Silverberg et al. (5) using the Allegro (65 ng/liter) and the CA-PTH (31 ng/liter) assays did not seem to be issued from the same group of healthy subjects. Indeed, the Allegro reference values were initiated in a group of healthy subjects from the Boston area, but without mention of their 25-OHD status (1), whereas the reference values concerning the CA-PTH assay were surprisingly very close to those reported by us (34 ng/liter) in a previous study and in the present study, using either subjects without 25-OHD insufficiency (13) or normal subjects with 25-OHD levels above 50 nmol/liter, respectively.
In view of the similar upper limits of normal levels defined by Silverberg et al. (5) and Carnevale et al. (6) using the second generation assays, we suggest that Silverberg et al. (5) should have found for the CA-PTH assay an upper normal limit closely similar to those found by Carnevale et al. (6) if they had used the same group of control subjects with their two assays. This would have been consistent with similar diagnostic sensitivities between the second and third generations of assays, as shown by Carnevale’s and our study.
In conclusion, the present study demonstrated that third-generation PTH assays manufactured by both companies did not improve the diagnostic sensitivities in a large series of consecutive patients with surgically and histologically proven PHPT. Although both assays manufactured by Nichols Institute Diagnostics produce, for a given assay generation, higher absolute PTH levels than those detected by the Scantibodies assays, this difference in reported values had no effect on clinical effectiveness of the tests when using the same group of healthy control subjects. Finally, absolute PTH values were at or above the midnormal range with the four tests, even in the surgically proven PHPT patients who had PTH levels within the normal range. This is strong evidence against the presence of parathyroid-suppressed hypercalcemia, adding to our observation that these four assays are of similar usefulness for the diagnosis of PHPT.
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Footnotes |
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Abbreviations: bio-iPTH, Bio-intact PTH; CA-PTH, cyclase activating PTH; CI, confidence interval; iPTH, intact PTH; MEN1, multiple endocrine neoplasia type 1; 25-OHD, 25-hydroxyvitamin D; PHPT, primary hyperparathyroidism; T-iPTH, total intact PTH.
Received April 1, 2005.
Accepted September 20, 2005.
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) as a function of our normative data (95% CI; 
). Results are expressed as the log of the PTH concentration.