Clinical Chemistry
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Clinical Chemistry 48: 1731-1738, 2002;
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (23)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bieglmayer, C.
Right arrow Articles by Niederle, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bieglmayer, C.
Right arrow Articles by Niederle, B.
Related Collections
Right arrow Endocrinology and Metabolism
(Clinical Chemistry. 2002;48:1731-1738.)
© 2002 American Association for Clinical Chemistry, Inc.

Kinetic Analyses of Parathyroid Hormone Clearance as Measured by Three Rapid Immunoassays during Parathyroidectomy

Christian Bieglmayer1a, Gerhard Prager1 and Bruno Niederle2

1 Clinical Institute for Medical and Chemical Laboratory Diagnostics and

2 Department of Surgery (Division of General Surgery, Section of Endocrine Surgery), AKH Vienna, A1090 Vienna, Austria.

aAddress correspondence to this author at: Clinical Institute for Medical and Chemical Laboratory Diagnostics, AKH Vienna (University Hospital), Waehringerguertel 18-20, A1090 Vienna, Austria. Fax 43-1-40400-6752; e-mail christian.bieglmayer{at}univie.ac.at.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Rapid intraoperative parathyroid hormone (PTH) measurements are an important prerequisite for minimally invasive parathyroidectomy, serving as a feasible marker for "cure" because of the short half-life of PTH. Because automated analysis may facilitate monitoring, two automated PTH assays were compared with an established manual method.

Methods: We collected 109 plasma samples during minimally invasive surgery on 20 patients with primary hyperparathyroidism and single-gland disease. PTH was analyzed manually with a test from Nichols and by two automated assays from Diagnostic Product Corporation (DPC) and Roche, respectively. PTH half-life and residual concentrations were calculated by two kinetic models.

Results: Despite good overall correlations between methods [DPC = 1.07(Nichols) - 12 ng/L; r = 0.95, Sy|x = 26 ng/L and Roche = 1.16(Nichols) - 2.82 ng/L; r = 0.98; Sy|x = 16 ng/L], marked interindividual differences were observed. The iterative kinetic model failed with a nonuniform PTH decrease, but the interpolative model produced valid results. The mean (SD) half-life of 3.7 ± 1.4 min with DPC differed significantly (P <0.05) from the 4.3 ± 1.6 min with Roche (Nichols, 4.0 ± 1.6 min). DPC produced significantly lower mean residual PTH (15 ng/L) vs Roche (27 ng/L); Nichols results were between them (20 ng/L). However, these differences were clinically irrelevant.

Conclusions: Automated methods are as suitable as the manual test. The preoperative baseline PTH is necessary but is insufficient for kinetic calculations.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Surgical treatment of patients suffering from biochemically confirmed primary hyperparathyroidism (pHPT) 1 is undergoing an evolution. The traditional surgical approach visualizing all four parathyroids and resecting the apparently enlarged gland(s) has been increasingly replaced by minimally invasive (unilateral) surgical procedures aided by preoperative imaging and intraoperative rapid parathyroid hormone (PTH) measurements (1)(2)(3)(4)(5)(6)(7)(8). In most cases, the improved imaging techniques enable exact preoperative localization of the parathyroid adenoma (9). PTH monitoring during the surgical procedure can confirm the removal of all hyperfunctioning parathyroid tissue as the half-life of intact (1–84) PTH is short. An insufficient decrease in PTH indicates persisting pHPT, leading to more extended (bilateral) exploration within the same session. Although PTH monitoring ignores possible changes in the physiologic state of the patient during surgery (e.g., changes of clearing rate) and is deemed invalid if the volume is expanded by intraoperative infusions, it helps to reduce the frequency of repeat surgery.

Measurement of PTH has also undergone evolution. The early generation of PTH RIAs was restricted to N-terminal, midregion, or C-terminal fragments, all of which circulate in high concentrations as they are cleared slowly (10)(11). By use of two monoclonal antibodies specific for the N- and C-terminal regions of the hormone (12), rapid measurement of intact (1–84) PTH became feasible. The sensitivity of tests was further improved by replacement of radiolabels with chemiluminescent groups. Special assay formats allow rapid detection within 15 min, a time-span suitable for intraoperative PTH monitoring (2). To test whether automated analysis by a new generation of assays provides reliable results, we compared two recently developed methods running on immunoassay analyzers with an established manual assay for quick PTH.

Commonly, a 50% decrease versus baseline PTH 5–10 min after resection of the suspected parathyroid adenoma indicates "cure" (1). However, the definition of this "baseline" seems vague, especially as plasma PTH is markedly influenced by surgical manipulations during preparation of the affected gland(s). In addition, the recommendation does not account for interindividual variability of PTH half-life and residual concentration (13). We evaluated these crucial factors by two kinetic models and addressed several questions: (a) Which model fits better to the PTH results and which starting concentration is relevant for kinetic calculations (the preoperative baseline or the PTH concentration just at adenectomy)? (b) Do the assays produce comparable kinetic results and is there an advantage in using automated PTH analyses? (c) Can intraoperative kinetic calculations support the assessment of PTH patterns?


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
patients
To date, minimally invasive parathyroidectomy has been performed at our institution (9) in >170 patients suffering from pHPT. Patients gave informed consent for surgery and blood collection via an extra catheter. All operations were performed by the same surgeon (B.N.). We report here on 20 consecutive patients (18 females and 2 males; mean age, 57.8 ± 12.1 years) with single-gland disease. Renal failure was excluded in all these patients. Adenomas were localized preoperatively by high-resolution ultrasound and by 99mTc-sestamibi scans with single photon emission computed tomography. Blood was collected before skin incision (preoperative baseline concentration), at the time of adenoma resection, and thereafter at intervals of 5 min (0, 5, 10, and 15 min). The surgeon asked for additional blood samples from some patients (e.g., in case of prolonged adenoma preparation or a slow decrease in PTH); the exact time points of these samples were documented. Blood specimens were centrifuged for 1 min in Eppendorf cups and subsequently analyzed.

Success of surgical intervention was judged by an intraoperative PTH decrease (at least 50% within 10 min after adenectomy) related to the preoperative baseline PTH. In case of atypical PTH increase until adenectomy, a later sample was collected for confirmation. Parathyroid tissue was examined histologically. At 1 year after operation, calcium was normal in all patients.

analytical methods and organization
Two chemiluminescence immunoassays [QuiCk-IntraOperativeTM intact PTH (Nichols Laboratories) and Turbo-PTH-intact (Diagnostic Products Corporation; DPC)] and one electrochemiluminescence method (intact-PTH; Roche-Diagnostics) were used for rapid PTH measurements. All assays had been evaluated previously (1)(2)(3)(4)(5)(6)(7)(8)(14)(15)(16) and are approved by the US Food and Drug Administration. The manual assay by Nichols was carried out with the "QuiCk-Pack" system from Nichols Laboratories. If the CV of duplicates exceeded 10%, the sample was reanalyzed. The DPC assay was performed on the Immuno-1 automated analyzer (DPC). The Roche intact-PTH test was performed on an Elecsys-1010 immunoassay analyzer (Roche Diagnostics) with its "Stat-function". Single determinations were sufficient with automated methods, because CVs of duplicates were <4%. Instruments maintenance and test calibration were performed in the main laboratory.

The analytical instruments and other laboratory tools were transported on trolleys to the operating theater, where control samples were reanalyzed. Ten patients were monitored intraoperatively with the Nichols test and another 10 with the Roche test. Direct contact was always possible between surgical and analytical teams because samples were processed in a preparation room adjacent to the operating theater. However, there was too little space for two trolleys; thus, immediate comparative analyses with the other tests were performed in the main laboratory on sample aliquots transported in an ice bath. Although the DPC analyzer could have been transported on a large trolley, for organizational reasons the comparative data on the DPC assay were collected retrospectively from samples stored at -80 °C. Marked influence of one freezing/thawing had been excluded in a pre-experiment.

Assay precision was determined by use of control samples supplied by the respective companies. Day-to- day CVs (n = 12) were 17% (37 ng/L) and 9% (251 ng/L) for the Nichols, 11% (84 ng/L) for the DPC, and 7% (at 54 and 169 ng/L) for the Roche EL1010, respectively. Intraassay CVs (n = 6) were 9% and 7% (Nichols), 6% (DPC), and 4% and 3% (Roche) at the control sample concentrations indicated above.

method comparisons and statistics
Method comparisons (17) were calculated from 109 samples, and individual comparisons for each patient were calculated as well (5–10 samples per patient). Significance of differences (P <0.05) was evaluated by ANOVA and the Tukey–Kramer post-test.

kinetic analyses
Intraoperative PTH half-life and the residual concentrations were calculated by two kinetic models by use of Microsoft Excel on a personal computer. Model A was recently published by Libutti et al. (13) and describes relief of the total suppressed PTH secretion from healthy glands after adenectomy. In this model (Fig. 1 , top), the exponential decay of PTH from the adenoma (concentration ct = c0e-kt, where t is time, c0 is the concentration at t = 0, and k is the rate constant of decay) is superimposed by a time-dependent additive concentration (cm = ct + {Delta}ct, where cm is the measured concentration at time t and {Delta}ct is the additive concentration at time t). This additive concentration stems from the healthy glands, which recover PTH secretion, and is a function of a constant residual PTH concentration R, which is calculated according to Libutti et al. (13) (Eqs. 3 and 4 ) by:

thus:

Because {Delta}ct = cm - c0e-kt, the equation may be expressed as:

(1)
and solved for k:

(2)
For iterative calculations, Libutti et al. (13) used a preoperative baseline PTH concentration (instead of a true c0); c1 and c2 were the concentrations 5 and 10 min after adenectomy. Briefly, k (Eq. 2Up ) was approximated in a first iterative step from c0 and c1 by assuming R = c2. This estimated k value and c2 were used to calculate a new R (Eq. 1Up ), which made calculation of a better fitting k value possible, and so forth. After reaching convergence, the half-life was t1/2 = ln2/k. We performed additional calculations by choosing c0 at the time of adenectomy as well as for c3 at 15 min.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 1. Simulated examples for models A (top) and B (bottom; half-life, 2 min).

Model A, c0 = 130 ng/L; residual PTH (R) = 30 ng/L; cm, measured PTH concentration (sum of ct and {Delta}ct); ct, PTH decay of adenoma; {Delta}ct, relief from PTH suppression of healthy glands ({Delta}ct=0 = 0 and {Delta}ct->{infty} = R). Model B, c0 = 100 ng/L); residual PTH ({rho}) = 30 ng/L; cm, measured PTH concentration (sum of ct and {rho}); ct, PTH decay of adenoma. (Inset), graph of x and y for different {rho} [examples: +0 ({square}); +30 ng/L ({diamondsuit}); +60 ng/L ({triangleup}); +100 ng/L ({circ}); see text for explanation].

We developed a second model, basing it on the assumption that the healthy glands were not totally suppressed and secreted constant concentrations of PTH ({rho}) during surgery, adding to the exponential decay of PTH from the removed adenoma (model B; Fig. 1Up , bottom). Because an exponential decay follows a constant percentage of decrease per identical time intervals (i; e.g., 5 min), the measured concentration cm has to be corrected for {rho}:

(3)
We set up a matrix (Eq. 4 ) for calculating the intercept (b) and the slope (a) of a linear regression line: y = ax + b.

(4)
where cm0 is the PTH concentration at adenectomy.

Combining Eqs. 3Up and 4Up yields {rho} = (ax - y)/(a - 1). Because a = (y - b)/x, the residual concentration {rho} was calculated (Eq. 5 ) from the slope and the intercept of the regression line (Fig. 1Up , inset for model B)

(5)
All measured PTH concentrations were corrected for the residual PTH concentration, followed by an exponential regression analysis: ln(cm - {rho}) = a't + b'. The decay constant was k = -a', and the approximated PTH concentration at adenectomy was c0app = eb'.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The performance and costs of the Nichols, DPC, and Roche tests for rapid PTH differed. The turnaround time from starting the analysis until print-out of results was 16 min for the DPC, 14 min for the Nichols, and 10 min for the Roche assay. Approximately 4 min had to be added to all methods for sample collection, transport to the adjacent room, and centrifugation when the assay was performed at the site of surgery. Although each assay may be performed by a single person, the Nichols manual method was carried out by two technicians because there was a need for exact time-shifted manipulations. All analytical systems were leased. The costs of reagents per test for the DPC and Roche were 12% and 4%, respectively, of the Nichols test costs. Depending on contracts with the companies, costs may be different for other hospitals. Recently, a detailed cost analysis was presented that included working time and auxiliary costs (18).

Correlation analyses for PTH from 109 samples yielded the following equations: DPC = 1.07(Nichols) - 12 ng/L (r = 0.95; Sy|x = 26 ng/L) and Roche = 1.16(Nichols) - 2.8 ng/L (r = 0.98; Sy|x = 16 ng/L). Deviations between the assays became more obvious when comparability was tested for each patient (Fig. 2 ). The slopes of the individual regression lines were between 0.56 and 1.67, and their intercepts were between -98 and 17 ng/L (Nichols vs DPC, r = 0.92–1.0; Sy|x = 1.8–43 ng/L). Comparisons between Nichols and Roche analyses produced individual slopes from 0.60 to 1.32 and intercepts from -59 to 27 ng/L (r = 0.96–1.0; Sy|x = 1.2–20 ng/L).



View larger version (17K):
[in this window]
[in a new window]
  		Figure 2. PTH method comparisons: Nichols vs DPC and Nichols vs Roche.

The individual regression lines from 20 patients were constructed from 5–10 data pairs per patient; all results were within the dynamic range of the assays.

We next investigated how these discrepancies influenced the calculation of PTH elimination kinetics. Table 1 summarizes the kinetic results obtained from models A and B for the three assays. Model A was applied to data from the preoperative baseline and 5 and 10 min, as suggested by Libutti et al. (13). Use of the PTH at adenectomy instead of the preoperative baseline led to lower residual concentrations (significant for DPC and Roche) and significantly longer half-lives with all assays (mean, 1.8 vs 3.7 min). However, model A calculations led to nonsensical results for 11 patients because of unreasonably high negative residual PTH concentrations and prolonged half-lives. Model B (PTH at adenectomy and 5, 10, and 15 min) produced meaningful results for all 20 patients and assays. Lower residual PTH values were produced by the DPC (mean, 15 ng/L; range, 1–46 ng/L) and Nichols (mean, 20 ng/L; range, 0–79 ng/L) assays than by the Roche assay (mean, 27 ng/L; range, 0–89 ng/L). The mean half-life was 3.7 ± 1.4 min (range, 1.8–6.0 min) with the DPC, 4.0 ± 1.6 min (range, 1.8–7.7 min) for the Nichols, and 4.3 ± 1.6 min (range, 2.4–8.1 min) for the Roche assay. Differences in residual PTH and half-lives were significant only between the DPC and Roche assays.


View this table:
[in this window]
[in a new window]
  		Table 1. Residual PTH and PTH half-lives calculated by different kinetic models (n = 9 patients).1

Considering whether these differences in kinetic results are clinically relevant, we first inspected the intraoperative PTH patterns. Shown in Fig. 3 are the results when we used the Nichols PTH assay as an example. The time intervals between starting anesthesia and adenectomy ranged from 20 to 77 min, and the average preparation time of the adenoma was 38 min. In 14 of 20 patients, PTH concentrations decreased until adenectomy (Fig. 3A ), but 6 patients presented with an atypical PTH surge during adenoma preparation (Fig. 3B ).



View larger version (21K):
[in this window]
[in a new window]
  		Figure 3. Time course of PTH before and after adenectomy (t = 0 min).

(A), 14 patients with a decrease in PTH during preparation of the adenoma. (B), atypical PTH surge before adenectomy in 6 patients (arbitrary symbols were used for better identification).

Interestingly, up to one-half of the patients with a decrease in PTH during adenoma preparation (n = 14) already exhibited a PTH <50% of the preoperative baseline value at the time of adenectomy (Table 2 ). Within 10 min, all 14 of these patients fulfilled the criteria for cure (PTH decrease >50% of preoperative baseline value), irrespective of the assay. The results from the six patients with an atypical PTH surge during preparation differed. The DPC PTH assay was the only test that predicted cure at 10 min for all patients. It took 15 min until the Roche PTH was <50% of the preoperative baseline in patients with a transient PTH surge. The Nichols assay failed to predict a cure at 15 min in one case, and samples had to be obtained at later time points to confirm surgical success.


View this table:
[in this window]
[in a new window]
  		Table 2. Number of patients with PTH <50% of preoperative baseline values at indicated time points.1

In contrast to the measured PTH values, the calculated residual PTH was always <50% of the preoperative baseline, apparently serving as a more precise criterion for cure (Fig. 4 ). Furthermore, residual PTH had dropped below the upper reference limit (65 ng/L PTH) for all but two patients with the Nichols assay (74 and 79 ng/L) and in one of them with the Roche test (89 ng/L). Results were available from these two patients at later time points. When these results were added for recalculations, all residual PTH concentrations were within the reference interval (not shown). Cure of all patients was confirmed by their 1-year outcome of normocalcemia.



View larger version (23K):
[in this window]
[in a new window]
  		Figure 4. Percentage of residual PTH ({rho}) related to preoperative baseline PTH.

Approximately three-fourths of the patients presented with a residual PTH <20% of the preoperative baseline value.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Rapid intraoperative PTH monitoring serves as a "biochemically frozen section" (2) and has become an important prerequisite for minimally invasive parathyroidectomy. Major experience has been gathered with the manual Nichols test that was compared with automated assays from DPC and Roche. In principle, the entire analytical system may be transported by trolley to the operating theater, but in this study the DPC analyzer was used only in the main laboratory. We recommend direct contact between surgical and analytical teams; this minimizes the time for transporting blood samples and improves communication.

Methodologic comparison among the three PTH assays produced good overall correlation; however, when we calculated regression lines for each patient, remarkable individual deviations appeared. To investigate the clinical relevance of these differences, we used two approaches: calculation of PTH elimination kinetics and evaluation of criteria to predict cure by intraoperative PTH monitoring.

We retrospectively applied two kinetic models to the data obtained: Model A had already been published by Libutti et al. (13) but did not fit properly. Therefore, we established an alternative procedure (model B). Both models are based on an ideal exponential decay, superimposed by an additive value that is either a function of time ({Delta}ct; model A) or a constant ({rho}; model B). Model A describes fast relief of healthy glands from total PTH suppression after adenectomy because of an unconfirmed assumption that the relief mathematically depends on the same rate constant (k) as the adenomatous PTH decay. Such a "swing-off/swing-on" mechanism seems debatable during the short time frame of surgery. Similarly not verified, model B assumes a constant contribution of PTH from suppressed healthy glands, which may be a more likely condition during surgery. Despite the different suppositions, both models yield identical half-lives and residual concentrations in an ideal setting, but they differ in c0 and the "true" PTH decay curve of the adenoma (Fig. 1Up ).

In model A, the curve function was solved by iterations, assuming three error-free measurements (a minimum of data sets to calculate a curve); because of this rigidity, some calculations yielded nonsensical results. This model could not be used in cases without uniform decreases in PTH, e.g., in most patients with a PTH surge until adenectomy (see footnote a to Table 1Up ). Incongruous results were observed more frequently with the Nichols PTH assay, which exhibited a greater analytical inaccuracy than the other tests. In model B, the disadvantage of requiring an additional (fourth) time point is counterbalanced by its usefulness in allowing interpolation to correct deviating curve data. In addition, the late PTH at 15 min was more reliable for calculating the residual concentration. A less skilled team has a major drawback in that the algorithm used for model B requires equally spaced (in time) blood collections, which can be overcome by calculations with Prism software (GraphPad Software Inc.). This commercial software requires entry of at least four, but arbitrarily spaced, data sets for interpolation. By appropriate program selection ("analyze/non linear regression fit/one phase exponential decay"), the half-life, the constant residual concentration (called the plateau), and c0 (called the span) are calculated together with 95% confidence limits, a correlation coefficient, and a graph. Results from calculations with model B and the software were nearly identical (not shown).

Our main complaint against the method of Libutti et al. (13) concerns the use of a preoperative baseline concentration as a surrogate for c0. During minimally invasive parathyroidectomy, the manipulations by the surgeon influence the PTH concentrations until adenectomy (Fig. 3Up ) obviously to a larger extent than with conventional techniques (19). The preparation of the affected gland within a small unilateral 1.5-cm skin incision may cause squeezing of the glands as a result of mobilization or untimely clamping of small vessels. Extirpation of the adenoma no doubt stopped its PTH efflux into circulation, irrespective of a previous stepwise clamping. The short half-life (1.7 min; range, 0.4–3.8 min) reported by Libutti et al. (13) agrees with the calculations from our data with the preoperative baseline PTH (Table 1Up , model A; baseline, 5, 10); apparently the decrease in PTH until adenectomy causes an underestimation of the half-life. With a two-compartment model, Maier et al. (19) calculated a PTH half-life of 3.4 min based on data from an immunoradiometric Nichols test, yielding results similar to those for model B. However, we do not abandon the procedure of Libutti et al. (13) because when it is applied to later time points, it frequently produces valid results. The calculations with the 0-, 5-, and 15-min data sets more closely matched most results obtained with model B, confirming the necessity to use c0 at adenectomy in kinetic calculations and the benefit gained by use of a late time point. Neither model A nor B is suitable for describing complex elimination kinetics (19) because of the single-compartment assumption when investigating within a short time frame.

Kinetic results from the three PTH assays differed, and the DPC assay produced a significantly shorter half-life and lower residual PTH concentrations than did the Roche assay; results from the Nichols assay were between the two. Presumably the assays are influenced by cross-reactions in a different manner because commercially "intact" PTH assays may detect (1–84) PTH as well as non-(1–84) fragments (20)(21).

A major clinical question that presents itself is the problem as to which PTH concentration, either PTH at adenectomy or preoperative baseline, should be used for reference when calculating the 50% decrease within 10 min. No standard procedure is recommended in the literature. Although for kinetic calculations the PTH at adenectomy was shown to be superior to the concentration at t = 0, it is a different thing to estimate a sufficient PTH decrease. For several reasons, when judging the PTH decrease, the preoperative PTH value should serve as the baseline:

Case 1 (14 patients; Table 2Up ).
The decrease in PTH from the preoperative baseline to adenectomy indicates that the vessels of the affected gland have indeed been clamped before excision. Especially if PTH at adenectomy is <50% and within the reference interval, cure is indicated. PTH at 5 min should serve for confirmation, and additional monitoring may be omitted. If the PTH at excision is >50%, monitoring is required to exclude multiple gland disease. Kinetic calculations are helpful for estimating the residual PTH concentration and the patient’s clearance rate. A slow decrease in PTH may also be caused by a prolonged half-life and not necessarily by additional hyperfunctioning glands. If the residual PTH is within the reference interval, monitoring may be stopped.

Case 2 (6 patients; Fig. 3BUp ).
Increasing PTH from the preoperative baseline to adenectomy originates from squeezing of the glands or the adenoma by surgical manipulations. This causes a rapid and sometimes very high efflux of PTH, which thereafter decreases (our own unpublished observation). Such a manipulation complicates the assessment of monitoring because there is an additional overlay by the PTH decay curve of the previously squeezed gland. Most likely, the rate constants (k) are identical with reference to the PTH decay from the manipulated gland as well as from the resected adenoma. Thus, assuming a constant PTH contribution from the residual bland glands ({rho}), the measured PTH is: cm = (c0 + cS)e-kt + {rho}, where c0 is the PTH from the adenoma at resection and cS is the contribution from the PTH decay of the manipulated gland at the time of adenectomy. The problem is that the ratio between c0 and cS is unknown and c0 + cS is the starting concentration observed when monitoring at adenectomy. In other words, by referring only to the concentration at adenectomy, it is uncertain whether the PTH decrease reflects resection of the adenoma alone (assuming that the PTH of the manipulated gland has already come back to its presqueezed value), both PTH sources (unknown c0/cS ratio), or the manipulated gland alone (assuming that by mistake the adenoma was left in situ and a bland gland was removed).

Thus, for clinical judgement, the preoperative baseline is necessary (a) to be able to distinguish between the effects of surgical preparations such as clamping of vessels or unintentional squeezing of parathyroids, (b) for estimating cure [conceivably PTH at the end of monitoring has to be much lower than before the start the operation, i.e., <50% of baseline (1)], and (c) for estimating the duration of monitoring. Prolonged monitoring may be necessary in cases with an atypical PTH surge until adenectomy (case 2) if the criterion (1) of PTH <50% within 10 min is missed, as shown in Table 2Up . Comparing results of intraoperative monitoring, kinetic calculation of residual PTH may help to reduce the need for expanded monitoring. Although in one case PTH at 15 min was still >50% (Table 2Up ), all assays provided a residual PTH <50% (Fig. 4Up ). Currently we are testing a large group of patients to determine whether calculating the residual PTH from bland glands, which we propose to be normal to below-normal values, may replace the recommended "50% criterion" (1). A more detailed discussion on the pitfalls in PTH monitoring is beyond the scope of this report and will be published elsewhere.

In conclusion, monitoring of the PTH decay appeared to be influenced by surgical manipulations during the more difficult adenoma preparation in minimally invasive parathyroidectomy. Data reduction by kinetic calculations may support assessments by providing additional information on individual half-lives and residual PTH. Kinetic estimations by interpolation of at least four data sets (model B; calculations done either by the algorithm described above or by a commercial software) are a promising alternative to exact calculations on three data sets (model A), which sometimes yield incongruous results because of deviating measurements. Preoperative baseline PTH is inadequate for kinetic calculations and must not be used as a surrogate for the concentration at adenectomy. On the other hand, estimation of cure calls for a relation to the PTH before the treatment starts (preoperative baseline). Understandably, the PTH at the end of monitoring has to be much lower than the preoperative baseline value. In our opinion, it was beneficial to monitor at the site of surgery to keep short distances between sampling as well as analyzing and transporting information. Although interindividual methods of comparing as well as calculating half-life and residual PTH concentrations revealed differences among the three assays, in clinical practice they may be neglected. Because multiple intraoperative measurements are necessary (routinely we do at least five), costs and efficiency may be the main criteria when choosing an automated assay, and it seems advantageous to use the same chemistry as for routine PTH analyses.


   Acknowledgments
 
We greatly appreciate the skillful technical assistance of M. Fritz, S. Gaderer, S. Genner, A. Handler, H. Kieweg, B. Kohler, K. Rettner, C. Röhrer, and I. Samonig. We also thank H. Reichelt, H. Ruis, and W. Rubisch for valuable discussions on interpreting the kinetic models. The study was supported by "Jubiläumsfonds der Österreichischen Nationalbank" Grant 9307.


   Footnotes
 
1 Nonstandard abbreviations: pHPT, primary hyperparathyroidism; PTH, parathyroid hormone; and DPC, Diagnostic Product Corporation.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Irvin GL, III, Dembrow VD, Prudhomme DL. Operative monitoring of parathyroid gland hyperfunction. Am J Surg 1991;162:299-302.[Web of Science][Medline] [Order article via Infotrieve]
  2. Irvin GL, III, Deriso GTI. A new, practical intraoperative parathyroid hormone assay. Am J Surg 1994;168:466-468.[Web of Science][Medline] [Order article via Infotrieve]
  3. Boggs JE, Irvin GL, III, Molinari AS, Deriso GT. Intraoperative parathyroid hormone monitoring as an adjunct to parathyroidectomy. Surgery 1966;120:954-958.
  4. Soffermann RA, Standage J, Tang ME. Minimal-access parathyroid surgery using intraoperative parathyroid hormone assay. Laryngoscope 1998;108:1497-1503.[Web of Science][Medline] [Order article via Infotrieve]
  5. Miccoli P, Bendinelli C, Vignali E, Nazzero S, Ceccini GM, Pinchera A, et al. Endoscopic parathyroidectomy: report of an initial experience. Surgery 1998;124:1077-1079.[Web of Science][Medline] [Order article via Infotrieve]
  6. Bergenfelz A, Isaksson A, Lindenblom P, Westerdahl J, Tibblin S. Measurement of parathyroid hormone in patients with primary hyperparathyroidism undergoing first and reoperative surgery. Br J Surg 1998;85:1129-1132.[Web of Science][Medline] [Order article via Infotrieve]
  7. Patel PC, Pellitteri PK, Patel NM, Fleetwood MK. Use of a rapid intraoperative parathyroid hormone assay in the surgical management of parathyroid disease. Arch Otolaryngol Head Neck Surg 1998;124:559-628.[Abstract/Free Full Text]
  8. Sokoll LJ, Drew H, Udelsman R. Intraoperative parathyroid hormone analysis: a study of 200 consecutive cases. Clin Chem 2000;46:1162-1168.[Abstract/Free Full Text]
  9. Prager G, Cerny C, Kurtaran A, Passler C, Scheuba C, Bieglmayer C, et al. Minimal invasive open parathyreodectomy in an endemic goiter area—a prospective study. Arch Surg 2001;136:810-816.[Abstract/Free Full Text]
  10. Simon M, Cuan J. C-Terminal parathyrin (parathyroid hormone) radioimmunoassays in serum with commercially available reagents. Clin Chem 1980;26:1666-1671.[Abstract/Free Full Text]
  11. Ashby JP, Thakkar H. Diagnostic limitations of region specific parathyroid hormone assays in the investigation of hypercalcemia. Ann Clin Biochem 1988;25:275-279.
  12. Blind E, Schmidt-Gayk H, Scharla S. Two-site assay of intact parathyroid hormone in the investigation of primary hyperparathyroidism and other disorders of calcium metabolism compared with a midregion assay. J Clin Endocrinol Metab 1988;76:353-360.
  13. Libutti SK, Alexander R, Bartlett DL, Sampson ML, Ruddel ME, Skarulis M, et al. Kinetic analysis of the rapid intraoperative parathyroid hormone assay in patients during operation for hyperparathyroidism. Surgery 1999;126:1145-1151.[Web of Science][Medline] [Order article via Infotrieve]
  14. Wenk RE, Efron G, Madamba L. Central laboratory analyses of intact PTH using intraoperative samples. Lab Med 2000;31:158-161.[Abstract/Free Full Text]
  15. Jonson LR, Doherty G, Laimore T, Moley JF, Brunt LM, Koenig J, et al. Evaluation of the performance and clinical impact of a rapid intraoperative parathyroid hormone assay in conjunction with pre-operative imaging and concise parathyroidectomy. Clin Chem 2001;47:919-925.[Abstract/Free Full Text]
  16. Hermsen D, Franzson L, Hoffmann JP, Isaksson A, Kaufmann JM, Leary E, et al. Multicenter evaluation of a new immunoassay for intact PTH measured on the Elecsys® System 2010 and 1010 [Abstract]. Clin Chem 2001;47(Suppl 6):A8.
  17. Martin RF. General Deming regression for estimating systemic bias and its confidence Interval in method-comparison studies. Clin Chem 2000;46:100-104.[Abstract/Free Full Text]
  18. Wians FH, Balko JA, Hsu R, Byrd W, Snyder WH. Intraoperative vs central laboratory PTH testing during parathyroidectomy surgery. Lab Med 2000;31:616-621.[Abstract/Free Full Text]
  19. Maier GW, Kreis ME, Renn W, Pereira PL, Häring HU, Becker HD. Parathyroid hormone after adenectomy for primary hyperparathyroidism. A study of peptide elimination kinetics in humans. J Clin Endocrinol Metab 1998;83:3852-3856.[Abstract/Free Full Text]
  20. Brossard J-H, Cloutier M, Roy L, Lepage R, Gascon-Barré M, D’Amour P. Accumulation of a non-(1–84) molecular form of parathyroid hormone (PTH) detected by intact PTH assay in renal failure; importance in the interpretation of PTH values. J Clin Endocrinol Metab 1996;81:3923-3929.[Abstract/Free Full Text]
  21. Lepage R, Roy L, Brossard J-H, Rousseau L, Dorais C, Lazure C, et al. A non-(1–84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem 1998;44:805-809.[Abstract/Free Full Text]



The following articles in journals at HighWire Press have cited this article:


Home page
 J. Pharmacol. Exp. Ther.Home page
A. K. Abraham, D. E. Mager, X. Gao, M. Li, D. R. Healy, and T. S. Maurer
Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Parathyroid Hormone-Calcium Homeostasis in Rats and Humans
J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 169 - 178.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
I. Titon, A. Cailleux-Bounacer, J. P. Basuyau, H. Lefebvre, A. Savoure, and J. M. Kuhn
Evaluation of a standardized short-time calcium suppression test in healthy subjects: interest for the diagnosis of primary hyperparathyroidism
Eur. J. Endocrinol., September 1, 2007; 157(3): 351 - 357.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
L. M. Henrich, A. D. Rogol, P. D'Amour, M. A. Levine, J. B. Hanks, and D. E. Bruns
Persistent Hypercalcemia After Parathyroidectomy in an Adolescent and Effect of Treatment With Cinacalcet HCl
Clin. Chem., December 1, 2006; 52(12): 2286 - 2293.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
C. Bieglmayer, K. Kaczirek, G. Prager, and B. Niederle
Parathyroid Hormone Monitoring during Total Parathyroidectomy for Renal Hyperparathyroidism: Pilot Study of the Impact of Renal Function and Assay Specificity
Clin. Chem., June 1, 2006; 52(6): 1112 - 1119.
[Abstract] [Full Text] [PDF]

Home page
 Arch SurgHome page
K. Kaczirek, G. Prager, P. Riss, G. Wunderer, R. Asari, C. Scheuba, C. Bieglmayer, and B. Niederle
Novel parathyroid hormone (1-84) assay as basis for parathyroid hormone monitoring in renal hyperparathyroidism.
Arch Surg, February 1, 2006; 141(2): 129 - 134.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (23)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bieglmayer, C.
Right arrow Articles by Niederle, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bieglmayer, C.
Right arrow Articles by Niederle, B.
Related Collections
Right arrow Endocrinology and Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS