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Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California (C.A.S., L.M.B., M.K., J.S.L.), Los Angeles, California 90033; and Southern California Permanente Medical Group (S.F.), Panorama City, California 91402
Address all correspondence and requests for reprints to: Dr. C. A. Spencer, University of Southern California Endocrine Services Laboratory, Edmondson Room 111, 1840 North Soto Street, Los Angeles, California 90032. E-mail: cspencer{at}usc.edu.
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Abstract |
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Objective: This study compared Tg measurements made in TgAb-negative and TgAb-positive sera using four RIA and 10 immunometric assay (IMA) methods.
Design: TgAb detection using a panel of 12 direct methods was contrasted with four Tg recovery tests. Sera from 110 normal euthyroid subjects (68 TgAb negative/42 TgAb positive) and 131 TgAb-negative DTC patients had Tg and/or TgAb analyses made by 10 laboratories in four countries. Euthyroid controls were used to compare Tg and TgAb ranges, sensitivities, and TgAb interference, whereas DTC patients were used to study Tg assay specificities, hook effects, and the influence of high Tg levels on TgAb measurements.
Results: Tg methods had high between-method variability [47 ± 3% (±SEM)] that was only marginally reduced by CRM-457 standardization (37 ± 3%). All methods had suboptimal sensitivity, and some failed to detect Tg in some normal euthyroid controls. Although direct TgAb measurements were more reliable than exogenous recovery tests, TgAb status was only concordant in 65% of sera. Only four of 42 (9.5%) sera containing TgAb had antibody detected by all direct methods. All IMA methods reported paradoxically undetectable Tg for many TgAb-positive euthyroid controls, suggesting TgAb interference, whereas RIA methods reported appropriate normal range values for these same subjects. Some sera displaying interference had TgAb detected by only a minority of methods.
Conclusions: Specificity differences, suboptimal sensitivity, hook effects, and an inability to reliably detect interfering TgAb compromise the clinical utility of current Tg and TgAb methods. All of the IMA methods were prone to underestimate serum Tg in the presence of TgAb, whereas the RIA methods appeared resistant to TgAb interference.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Suboptimal Tg assay functional sensitivity compromises the detection of recurrent DTC in the absence of recombinant human TSH (rhTSH) stimulation (10). This problem is exacerbated by the wide methodological biases that preclude a comparison of assay sensitivities in absolute terms [nanograms per milliliter (micrograms per liter)] as is customary for analytes such as TSH (4, 11). It follows that the methods with the highest sensitivity for detecting recurrent DTC would be those displaying the greatest discrimination between their functional sensitivity and the lower reference limit for euthyroid subjects with intact thyroid glands (11, 12). At the upper end of the measurement range, Tg methods can suffer from hook problems, by which the very high antigen concentrations sometimes seen in patients with metastatic disease exceed the binding capacity of the capture antibody and cause inappropriately low values (3, 13).
Assay interferences are particularly problematic. Heterophilic antibody or Tg autoantibody (TgAb) interferences can cause over- or underestimation of serum Tg concentrations (14, 15). Although manufacturers have reduced the risk of heterophilic antibody interference by adding blockers to assay reagents, TgAb interference is more difficult to detect and overcome (15, 16). The prevalence of TgAb in DTC patients (
20%) is approximately twice that of the general population (17, 18, 19, 20). There has been growing recognition that serial TgAb measurements per se provide a clinically valuable surrogate tumor marker, because TgAb concentrations respond to changes in Tg antigen (17, 20, 21, 22). However, TgAb methods are highly variable and cannot be used interchangeably, and the use of exogenous Tg recovery tests to detect interfering TgAb is widely considered unreliable (4, 17, 23, 24, 25, 26). Circulating TgAb interferes with serum Tg measurements in a qualitative, quantitative, and method-dependent manner (17, 24, 27). IMA methods are prone to underestimate serum Tg in the presence of TgAb, whereas RIA methods have the potential to either under- or overestimate Tg depending on the affinity and specificity of the antibody reagents (3, 6, 17, 24, 27, 28, 29, 30, 31).
The technical issues that currently compromise the reliability of Tg measurements have prompted the American and European Thyroid Associations to sanction a need to assess the impact of Tg and TgAb method differences on the management of patients with DTC. The current study compares 16 different methods for detecting TgAb (12 direct assays and four recovery tests) and 14 different Tg methods (four RIA and 10 IMA). A panel of 110 sera obtained from euthyroid control subjects was used to compare Tg reference ranges and relative assay sensitivities and to study the influence of TgAb on serum Tg measurements. In addition, 131 sera from patients with DTC were used to study Tg assay specificities, hook effects, and the influence of excess Tg antigen on TgAb measurements.
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Subjects and Methods |
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Two cohorts of serum specimens were studied. Euthyroid controls (n = 110) were used to compare Tg reference ranges (±2 SD of log-transformed values), calculate relative assay biases and assess the presence of TgAb interference. All control subjects were recruited through a University of Southern California institutional review board-approved protocol after obtaining appropriate informed consent. These subjects (70 females and 40 males) were between 22 and 60 yr of age and had serum TSH in the 0.4–3.0 mIU/liter range (and no palpable thyroid abnormalities). Sera from 128 thyroidectomized, TgAb-negative DTC patients (93 females and 38 males; median age, 49 yr; range, 14–85 yr) with postoperative serum Tg in the 1–100 ng/ml (µg/liter) range were retrieved from a frozen archive to study differences in Tg method specificities. Three additional sera from DTC patients (two females and one male) with widespread metastatic disease and very elevated serum Tg concentrations [47,500, 116,000, and 227,000 ng/ml (µg/liter)] were used to check for hook effects on Tg measurements and evaluate the influence of excess Tg antigen concentrations on TgAb measurements. All specimens were aliquoted and sent to the participating laboratories for analysis by 14 different Tg (four RIA and 10 IMA) and 12 different TgAb methods. Standard manufacturers’ protocols were employed, and the laboratories were blinded to the origin and TgAb status of the specimens.
TgAb methods
Table 1A
lists the methodological principles of the 12 direct TgAb methods together with the participating laboratories. The table contrasts the manufacturers’ limits with the experimentally determined limits established from a cohort of 68 unequivocally TgAb and thyroid peroxidase antibodies negative euthyroid control subjects. Methods were: 1) ACC, Access (Beckman Coulter, Fullerton, CA); 2) DYN, DYNOTest (Brahms Diagnostica, Berlin, Germany); 3) KRY, Kryptor (Brahms Diagnostica); 4) IMM, Immulite (Diagnostic Products Corp., Los Angeles, CA); 5) ESO (Esoterix, Calabasas, CA); 6) FLY (Fleury Laboratory, Sao Paulo, Brazil) (32); 7) FUJ, Fujirebo (Serodia, Tokyo, Japan); 8, KRO (Kronus, Boise, ID); 9, ADV, Advantage (Nichols Institute Diagnostics, San Juan Capistrano, CA); 10) NIB, bead assay (Nichols Institute Diagnostics); 11) ELE, Elecsys 2010 (Roche, Indianapolis, IN); and 12) TOS, Tosoh A1S-600II (Tosoh Corp., San Francisco, CA).
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Table 1B
lists the methodological principles of the 14 Tg methods together with their sensitivity estimates. Methods 1–4 used RIA methodology, and methods 5–14 used IMA methodology. Methods were: 1) USC (University of Southern California, Los Angeles, CA) (17, 33); 2) DSL (Diagnostic Systems Laboratories, Webster, TX); 3) ESO (Esoterix) (34); 4) UCH (University of Chicago, Chicago, IL); 5) ADV, Advantage (Nichols Institute Diagnostics); 6) NIB, bead assay (Nichols Institute Diagnostics); 7) KRO (Kronus); 8) CIS (CIS U.S., Inc., Bedford, MA); 9) ACC, Access (Beckman Coulter); 10) ESO (Esoterix) (34); 11) IMM, Immulite (Diagnostic Products Corp.); 12) DEL, Delphia (PerkinElmer, Norton, OH); 13) KRY, Kryptor (Brahms Diagnostica); and 14) DYN, DYNOTest Tg Plus (Brahms Diagnostica). Different polyclonal antibodies were used by each of the four RIA methods. Different capture and signal monoclonal antibodies were employed for each IMA method. The sensitivities of methods 1, 3, 6, 10, 11, and 12 were established according to the National Academy of Clinical Biochemistry guideline that defines Tg assay functional sensitivity as the lowest Tg value that can be measured in TgAb-negative human serum with a 20% CV over a 6- to 12-month period employing two different lots of reagents (4). When functional sensitivities were not available (methods 2, 4, 5, 7, 8, 9, 13, and 14), the clinical reporting limit of the participating laboratory was used as the sensitivity estimate.
Tg recovery procedures
Four Tg IMA methods (CIS, DEL, DYN, and KRY) incorporated a Tg recovery procedure to detect interfering TgAb. The amount of exogenous Tg added differed between procedures, with the CIS and KRY procedures both using 40 µg Tg, and the DEL and DYN methods using 25 and 50 µg Tg, respectively. All recoveries were performed according to the manufacturer’s protocols.
Methods for determining TgAb interference
Physiological benchmark. Sera from euthyroid subjects with an intact thyroid gland are expected to contain a normal amount of Tg protein as a consequence of thyroid hormone biosynthesis regardless of the presence of TgAb. It follows that sera from euthyroid subjects with circulating TgAb should have serum Tg within the reference range for TgAb-negative euthyroid controls.
Methodological benchmark. Current guidelines state that TgAb interference is characterized by discordance between the Tg values reported by different classes of method (RIA vs. IMA) (4). Because between-method biases can result from standardization or specificity differences, RIA vs. IMA discordances are not indicative of interference unless Tg values are first bias-corrected for differences seen in the absence of TgAb. Such biases were eliminated in this study by correcting each Tg value to the all-method mean for that specimen, so that any remaining discordance could be attributed to interference. The procedure for assessing interference was as follows: 1) each method had the Tg values of each specimen bias-corrected to the all-method mean; 2) using bias-corrected values, the mean RIA value (of methods 1–4) of each specimen was calculated; 3) for each specimen, the percentage CV of the RIA method mean and the bias-corrected test value were calculated; 4) the mean ± 2 SD cutoff of these CVs for the TgAb-negative specimen cohort (n = 68) was used to define the expected relationship between the test method and RIA in the absence of TgAb; and 5) when the percentage CV between the RIA method mean and the bias-corrected value of the test method exceeded the method-specific limit, interference was judged to be present.
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Results |
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A cohort of 68 serum specimens was identified in which TgAb appeared unequivocally absent by all methods using manufacturer’s limits (TgAb-negative cohort). The experimentally determined limits (mean ± 2 SD) for this cohort are shown in Table 1A.
Forty-two euthyroid controls had TgAb detected by one or more TgAb methods using the experimentally determined cutoffs (TgAb-positive cohort). Fourteen of these 42 (33%) specimens had TgAb detected by a single method. When possible, these isolated TgAb-positive results were confirmed by repeat analysis. Eight (19%) specimens had TgAb detected by two methods, five (12%) specimens by three methods, one (2%) specimen by four methods, two (5%) specimens by six methods, two (5%) specimens by eight methods, three (7%) specimens by nine methods, one (2%) specimen by 10 methods, and two (5%) specimens by 11 methods. Only four (10%) specimens had TgAb detected by all 12 direct TgAb methods. Overall, there was poor concordance between the methods (positive vs. negative), but a weak association was apparent between absolute TgAb values and the number of methods reporting a positive test for that specimen (Fig. 1A). Not shown in Fig. 1 were the discordant TgAb results seen for the three specimens with Tg in excess of 40,000 ng/ml (µg/liter). Nine direct methods detected no TgAb in these specimens, whereas three methods (KRY, DYN, and ELE) reported markedly elevated (>1000 IU/ml) TgAb values.
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). Although the pattern of failed DEL recoveries was similar to the direct methods, DEL recovery failed to detect interfering TgAb in 12 specimens (no. 2, 3, 6, 7, 9, 10, 20, 21, 24, 35, 39, and 40) that exhibited both physiological and methodological benchmarks for TgAb interference. TgAb-negative specimens
Figure 2 shows serum Tg concentrations for the TgAb-negative cohort relative to the sensitivities and reference ranges for each method. Most methods (DSL, UCH, KRO, CIS, ESO, IMM, DEL, KRY, and DYN) reported paradoxically undetectable Tg values for one or more sera. The lower limit of the reference range was either below (DYN) or coincident with the sensitivity estimates (UCH and DEL). The mean method values ranged from 14.1 ng/ml (µg/liter) for assay 5 (ADV) down to 3.1 ng/ml (µg/liter) for assay 14 (DYN). A 2-fold difference remained [14.1 vs. 6.2 ng/ml (µg/liter), respectively] after correcting DYN to CRM-457 standardization with the manufacturer’s factor. The percentage CV for all methods vs. only CRM-457-standardized methods was 47 ± 3% (±SEM) vs. 37 ± 3%, respectively. Variability across the RIA methods was less than that for IMA methods (28.9 ± 4% vs. 44.4 ± 1% CV; P < 0.001, respectively). After correcting each data point to the all-method mean for that specimen to remove bias, the bias-corrected mean values fell within a tighter range [8.7–9.8 ng/ml (µg/liter); Fig. 3]. However, the percentage CV of the bias-corrected values remained more than 2-fold higher than the reported within-person variability of circulating Tg (14%) regardless of CRM-457 standardization (32 ± 3% vs. 31 ± 3%, non-CRM-457 vs. CRM-457 standardized methods, respectively) (5). This suggested that the bias between methods reflected differences in assay specificity for circulating Tg isoforms rather than standardization differences.
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shows the relationship between ADV and NIB values for the TgAb-negative cohort (mean of two runs), and Fig. 4B shows the same relationship for the cohort of 128 TgAb-negative DTC patients. Although ADV values were significantly higher than NIB values for both groups, the percentage ADV/NIB ratio was 4-fold higher when measuring tumor-derived Tg (DTC sera) vs. nonneoplastic Tg protein of normal controls [149 ± 37% (±SD) vs. 111 ± 15%, respectively; P < 0.01]. Serial measurements of archived sera from four DTC patients showed that the relationship between the methods was patient specific and remained constant during long-term monitoring despite 30-fold changes in Tg concentrations (Fig. 4, inset).
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TgAb-positive specimens
Figure 5 displays the pattern of methodological discordances seen for the individual specimens of the TgAb-positive cohort shown in Fig. 1. Discordance was judged relative to the method-specific percentage CV limit established for the TgAb-negative cohort. The RIA mean (of methods 1–4) was used as a reference. Specimens with discordant RIA measurements had a percentage CV that exceeded the ±2 SD limit of the TgAb-negative cohort (55%). For most specimens, methodological discordance was weakly related to the number of TgAb methods reporting positive tests. However, 16 specimens with TgAb detected by only a minority of methods displayed discordances by one or more IMA methods. In contrast, specimens 29 and 33 with TgAb detected by the majority of methods displayed discordance only with a minority of IMA methods. Figure 6 shows the serum Tg measurements for the TgAb-positive cohort, grouped according to the presence of methodological discordance. The majority of RIA values fell within the reference ranges established for the TgAb-negative cohort. In contrast, all IMA methods reported paradoxically undetectable serum Tg for many specimens displaying methodological discordance. In contrast, the IMA values of specimens without methodological discordance fell within the reference ranges for the TgAb-negative cohort. In general, there was good concordance between the methodological and physiological benchmarks for TgAb interference. It should be noted that six specimens (no. 2, 3, 6, 7, 9, and 10), with TgAb detected by only one method, displayed interference, evidenced by the presence of both methodological and physiological benchmarks.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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14%) and was only modestly reduced (37%) by CRM-457-standardization (3, 5, 7, 9). It should be acknowledged that this study was not designed to evaluate whether some degree of between-method variability resulted from differences in assay matrices. The minimal bias among the four RIA methods contrasted with the wide biases seen among the 10 IMA methods. This probably reflected specificity differences in the capture and/or signal monoclonal antibody reagents used for IMA methodology, vs. the broader epitope specificity inherent with using polyclonal antibodies for RIA (8, 35). A comparison of two IMA methods (ADV and NIB) detected differences in assay specificities for tumor-derived Tg isoforms (in DTC patients) that appeared to be patient specific (Fig. 4). This probably reflected heterogeneity in iodination, glycosylation, molecular conformation, and/or epitope presentation of the Tg isoforms secreted by neoplasms (8, 36, 37). It follows that when changing Tg methods, assay specificity differences preclude the use of a bias correction factor derived from measuring nonneoplastic Tg in normal subjects. Instead, it is necessary to rebaseline the Tg of individual patients (4).
IMA methodology offers practical advantages and is preferred by most laboratories. Unfortunately, the sensitivity improvements seen after replacing TSH RIA with IMA methodology was not apparent in this study of Tg IMA methods, as judged from paradoxically undetectable Tg reported for some euthyroid control subjects without evidence of TgAb. Wide methodological biases preclude comparing Tg assay sensitivities in absolute terms [nanograms per milliliter (micrograms per liter)] (11). Instead, the degree of discrimination between the assay functional sensitivity and the lower limit of the reference range provides a clinically relevant gauge of relative assay sensitivity (11). An optimal target for functional sensitivity would be a Tg value approximately 100-fold below the lower reference limit (4, 11). This target is much lower than would be expected for Tg arising from postoperative thyroid remnants [1=2 ng/ml (µg/liter) when TSH is not elevated] (4). The methods evaluated in this study displayed less than a 10-fold difference between their sensitivity and lower reference limits, and many reported paradoxically undetectable Tg for some TgAb-negative controls. This suggests that current Tg methods have suboptimal sensitivity for managing patients with DTC. When more sensitive Tg methods become more widely available, the diagnostic accuracy of Tg measurements made without rhTSH stimulation will dramatically improve and probably obviate the need for rhTSH (10, 12).
Tumor marker IMA methods are prone to hook effects, whereby the excessively high antigen concentrations characteristic of patients with metastatic disease can exceed the binding capacity of the antibody reagents and cause an inappropriately low result (3, 13, 38). Seven of the 10 IMA methods reported appropriately high Tg values for the three sera with Tg in excess of 40,000 ng/ml (µg/liter). In contrast, the ACC, KRO, and KRY methods failed to report an appropriately elevated Tg for the specimen with the highest concentration [227,000 ng/ml (µg/liter)], suggesting that some IMA methods are still susceptible to hook problems. The guidelines recommend that physicians request their laboratories to perform log dilutions when patients with metastatic disease have a paradoxically nonelevated serum Tg reported (4).
All sera sent for Tg measurement require adjunctive TgAb testing to assess the risk of interference, because TgAb status can change over time (4, 17, 19). There is growing awareness that serum TgAb concentrations per se can be used as a surrogate antigen (Tg) marker (17, 20, 21, 22). However, serial TgAb monitoring necessitates the use of the same TgAb method, because assays vary in sensitivity, specificity, and absolute values despite claiming standardization against the International Reference Preparation MRC 65/93 (4, 17, 22, 23, 39). These TgAb methodological differences probably result from differences in assay specificity for the conformational epitopes characteristic of endogenous Tg antibodies (4, 17, 22, 23, 39). TgAb heterogeneity appears to be patient specific, because the ratios between TgAb measurements made with different assays remain constant during the serial monitoring of individual patients (17). Competitive TgAb assay formats may report false-positive TgAb in the presence of high antigen (Tg) concentrations (40, 41, 42). This problem was seen with the ELE, DYN, and KRY methods when measuring the specimens with Tg in excess of 40,000 ng/ml (µg/liter). The comparison of the 12 direct TgAb methods and four exogenous Tg recovery tests employed sera from euthyroid control subjects. Such subjects provided a realistic challenge for two reasons. First, euthyroid controls have TgAb concentrations that are relatively low and characteristic of the majority of TgAb-positive patients with DTC (75%; USC Endocrine Laboratory). Second, TgAb-positive normal controls are reported to display epitope specificities similar to the diverse antigenic determinant pattern characteristic of TgAb-positive patients with DTC (22, 26, 43). In accord with other reports, this study found that the propensity for TgAb interference was only weakly related to the TgAb concentration and that direct TgAb measurement was more reliable than the Tg recovery approach for detecting interfering TgAb (3, 4, 7, 13, 17, 24, 25, 29). Also, interfering TgAb was not always detected by either direct TgAb measurement or a recovery test (4, 17, 19, 20, 26, 29, 44, 45).
TgAb interference remains a major problem that compromises the clinical utility of Tg testing for the approximately 20% of DTC patients that have circulating TgAb (17, 18, 19, 20). The cohort of TgAb-positive euthyroid controls provided a physiological benchmark for assessing the presence of TgAb interference. Specifically, euthyroid subjects with intact thyroid glands are expected to produce a normal amount of Tg protein as a natural consequence of thyroid hormone biosynthesis regardless of the presence of TgAb. It follows that sera from such subjects should have Tg concentrations within the reference range for TgAb-negative controls. Discordance between Tg measured by the different classes of assay (RIA vs. IMA) was adopted as an additional methodological benchmark for detecting TgAb interference (4, 17, 26, 46). The physiological and methodological benchmarks were usually concordant, i.e. many TgAb-positive controls had paradoxically low or undetectable Tg reported by all IMA methods. In contrast, the RIA values for these same sera fell appropriately within the reference limits, suggesting that RIA was the more reliable class of assay to use in the presence of TgAb. It is well known that IMA methods are prone to underestimate Tg in TgAb-positive sera, presumably because Tg-TgAb complexes are unable to participate in the two-site immunometric reaction (24, 29, 42). Although TgAb interference with IMA methodology is always unidirectional (underestimation), the influence of TgAb on RIA measurements is variable and assay dependent (27). Early studies reported that TgAb caused overestimation of Tg measured by RIA, presumably when endogenous TgAb sequestered [125I]Tg tracer (27). In contrast, more recent studies have suggested that TgAb causes underestimation of Tg measured by RIA, presumably when the second antibody reagent precipitates endogenous TgAb-[125I]Tg complexes (6, 30, 31, 41). RIA methods that employ high affinity polyclonal antibodies coupled with species-specific second antibodies are claimed to be resistant to TgAb interference (17, 47, 48). There was no evidence of overestimation with the RIA methods tested in this study. One specimen (no. 34) with RIA values above the reference range also had high IMA values. This study suggested that RIA methodology was relatively unaffected by low concentrations of TgAb, as judged by the physiologically appropriate Tg values reported for all TgAb-positive euthyroid control subjects. In contrast, all IMA methods reported paradoxically low or undetectable Tg for many of these same subjects. It should be noted that it was not possible to use the physiological benchmark to assess whether very high TgAb concentrations would have interfered with RIA measurements.
This study of 14 Tg methods (four RIA and 10 IMA) reports that current Tg assays have suboptimal sensitivity and display different specificities, especially when measuring tumor-derived Tg. The study is the first to use a combination of physiological and methodological benchmarks to assess the effects of TgAb on a wide range of Tg methods. Inappropriately undetectable Tg resulting from TgAb interference was seen with all of the IMA methods, underscoring current guidelines that recommend that laboratories not report an undetectable Tg IMA when TgAb is present (4). Some sera containing TgAb had detectable, but subnormal, Tg IMA values, suggesting that some degree of interference was probably present. Thus, even detectable IMA measurements may be unreliable in the presence of TgAb, because changes in a Tg IMA value over time might reflect changes in the TgAb concentration and not changes in tumor burden. This study suggested that Tg RIA measurements were resistant to interference by the low TgAb concentrations typically seen in TgAb-positive patients with DTC. Because such low TgAb concentrations were not always detected by current TgAb assays, RIA methodology appeared to be the more reliable class of assay. However, because few Tg RIA methods remain available, serial TgAb concentrations, measured by the same method, may serve as a surrogate antigen (Tg) marker for monitoring DTC patients with circulating TgAb (4, 21).
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Acknowledgments |
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Footnotes |
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First Published Online June 28, 2005
Abbreviations: CV, Coefficient of variation; DTC, differentiated thyroid carcinoma; IMA, immunometric assay; rhTSH, recombinant human TSH; Tg, thyroglobulin; TgAb, Tg antibody.
Received March 28, 2005.
Accepted June 21, 2005.
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), as are those showing no discordance (
). The shaded bars denote the reference range calculated from the TgAb-negative controls, as shown in Fig. 2