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How thyroglobulin recovery test really adds to anti-thyroglobulin antibodies quantitative assay whe
TgR testing has complementary value to quantitative TgAb measurement in selected cases.
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Luca Giovanella, MD Ente Ospedaliero Cantonale, 6500 Bellinzona (Switzerland), Luca Ceriani, Franco Keller
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luca.giovanella{at}eoc.ch Luca Giovanella, et al.
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How thyroglobulin recovery test really adds to anti-thyroglobulin antibodies quantitative assay when serum thyroglobulin is employed to manage differentiated thyroid carcinoma? Serum thyrogobulin (Tg) is the yard-stick in the follow-up and management of differentiated thyroid cancer (DTC) [1,2]. However, some problems as thyroglobulin antibodies (TgAb) and heterofile antibodies (HAb) interferences and assays standardization remain overt and substantially complicate daily clinical practice in thyroid oncology [3]. Since in the last years serum Tg assay supplemented and eclipsed other diagnostic procedures and Tg increase alone can be used to guide radioiodine treatment, it is mandatory for the clinical laboratory to optimize its Tg detection method as well as interferences screening procedures. For these reasons we read the recent paper by Adrienne C.M. Persoon and co-workers [4] with great interest. The authors collected sera from 127 patients having DTC and performed immunochemiluminometric assay (ICMA) of thyroglobulin on Nichols Advantage platform. Tg-Ab measurements was done either by chemiluminescence immunoassay (Tg-Ab ICMA on Advantage Nichols) or by microparticle enzyme immunoassay (Tg-Ab MEIA on AxSYM, Abbot Diagnostics). The recovery test (Tg-R) was performed by a newly developed recovery assay on Nichols Advantage platform. Finally, a reference Tg-RIA was used as benchmarking in some patients to confirm interferences on Tg assay. We analyzed the results and discussion and focused on three major points requiring, in our opinion, further elucidations. a. Tg-recovery in patients with negative TgAb titer: Only one patient among 97 (ICMA) and 99 (MEIA) showed slightly disturbed Tg-R test (67.5%, reference range 70-120%). Interference was supported by different results of ICMA and RIA Tg assays. However, TgAb may falsely increase serum Tg concentration when competitive assays are used. Even if authors employed a RIA test declared to be minimally interfered by TgAb, we observed an inverse relationship between Tg-RIA levels and Tg-R results in their patients series. Additionally, because ICMA Tg was undetectable, the correction (ICMA=1.8xRIA plus intra- assays CV) cannot be properly calculated. Finally, by considering a 0.2 ng/mL variability at 1.0 ng/mL (functional sensitivity), the concentration of RIA-Tg ranged from undetectable [0.8 ng/mL] to borderline detectable [1.2 ng/mL]. Consequently, false-positive and/or intra-assay variability of RIA test should be also considered especially by considering that undetectable Tg was clinically expected in these NED patient. In conclusion, no overt nor clinically significant interferences were found in TgAb-negative patients and the role of Tg-R in this group appears to be negligible. b. Tg-recovery in patients with positive TgAb titer: Seventeen of 127 patients had positive TgAb assay. The Tg-recovery test cannot be performed due to very high Tg concentration in one patient with advanced DTC. Ten patients showed a disturbed Tg-recovery test according to TgAb elevation. However, six patients showed normal recovery test. In one of these, having a relapsing disease, the Tg was detectable even with positive TgAb assays: consequently, Tg-recovery test added no relevant information. Four out of remaining 5 patients, all with complete remissionof the disease after 2-11 years, showed a slight elevation of TgAb by ICMA(3) or MEIA (1) while one patient showed a 10-fold elevated ICMA TgAb and slightly elevated TgA by MEIA. By plotting TgAb levels against Tg-R results we observed that low serum TgAb levels are related to normal recovery in these patienst series. As TgAb disapparence or significant decrease characterizes disease-free patients, the kinetic trend of TgAb levels should be also considered to understand the significance of low TgAb titer properly [5]. Consequently, Tg-R seems to add no relevant informations if TgAb reduction is observed during the follow-up. However a normal Tg-R should confirm the absence of interference in patients with low TgAb levels especially if observed during the follow-up as in some patients described by Peerson and co-workers. c. Tg-recovery and HAb interference: One patient showed a detectable (8.6 mcg/L) ICMA-Tg with undetectable Tg by both RIA and IRMA assays. The Tg-R showed a slight over-recovery (126%)and specific HAb screening by dedicated tube assay confirmed HAb interference. This interference is present in 1.5-3% of automated Tg assays and should be suspected if Tg results do not fit the clinical picture as in this case [6]. Consequently, over-recovery adds no clinically relevant information in this case. In conclusion, the Tg-R was not clinically useful in most cases in this series. However, a possible role should be considered in patients with low TgAb titers if isapparence curve was not evaluated or is doubt. On this basis we think that the recovery-test should be used only in selected cases rather than on routine basis. A case-discussion between clinicians and clinical chemists in order to tailor the best diagnostic strategy in these ases is advisable.
References [1] Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L e al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003; 88: 1433-41. [2] Giovanella L, Ceriani L, Ghelfo A, Keller F, Sacchi A, Maffioli M et al. Thyroglobulin assay during thyroxine treatment in low-risk differentiated thyroid cancer management: comparison with recombinant human thyrotropin-stimulated assay and imaging procedures. Clin Chem Lab Med 2006; 44:248-52 [3] Despres N, Grant AM. Antibody interference in thyroid assays: a potential for clinical misinformation. Clin Chem 1998; 44: 440-54. [4] Persoon ACM, Links TP, Wilde J, Sluiter WJ, Wolffenbuttel BHR, van den Ouweland JMW. Thyroglobulin (Tg) recovery testing with quantitative Tg antibody measurement for determining interference in serum Tg assays in differentiated thyroid carcinoma. Clin Chem 2006; 52: 1196-9. [5] Spencer CA, Takeuchi M, Kazarosyan M, Wang CC, Guttler RB, Singer PA et al. Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998; 83: 1121-7. [6] Preissner CM, O’Kane DJ, Singh RJ, Morris JC, Grebe SK. Phantoms in the assay tube: eterophile antibody interferences in serum thyroglobulin assays. J Clin Endocrinol Metab 2003; 88: 3069-74. |
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Adrienne C. M. Persoon University Medical Centre Groningen, Thera. P. Links, Johannes. M.W. van den Ouweland
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adriennepersoon{at}hotmail.com Adrienne C. M. Persoon, et al.
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We thank dr. Giovanella for his response (1) on our paper in which we showed that testing for thyroglobulin (Tg) recovery by the Nichols Advantage Tg Recovery assay (TgR) has value complementary to that of quantitative Tg antibody (TgAb) measurement in the detection of interference in Tg measurements, in particular in sera with low TgAb titers (2). We would like to comment on the three points mentioned in his electronic letter. a. Tg-recovery in patients with negative TgAb titer: We agree with Giovanella that from the inverse relationship between the Tg radioimmunoassay (TgRIA) and the TgR assay it might be concluded that the TgRIA is more susceptible to interference by TgAb than previously claimed (3). Nevertheless, the eventually falsely elevated TgRIA as well as the compromised TgR (67,5%) in one TgAb negative patient both are suggestive of interference either by autoantibodies not recognized by the TgAb assays or from substances other than TgAb. Giovanella also remarks the borderline positive TgRIA result in this patient. On inquiry at the UCLA laboratory we have been informed that the TgRIA’s functional sensitivity (20% inter-CV) is even better (0,5 ìg/L) than the 1 ìg/L reported in our paper (personal communication), which makes us to conclude that intra-assay variability is unlikely to be responsible for the positive TgRIA result in this patient. We agree with Giovanella that at present we cannot conclude that the interference observed in this patient is of clinical significance. However, when a falsely negative Tg result is suspected in a TgAb negative patient, it might be worthwhile to repeat testing either by TgR or by another TgAb assay. b. Tg-recovery in patients with positive TgAb titer: In patients with low TgAb titers, no interference could be found by TgR testing or TgRIA/ Tg immunochemiluminometric assay (TgICMA) comparison. Since the detection of TgAb in general is considered alarming (4), it is important to distinguish signal noise in the TgAb assay from true circulating TgAb in these cases. Furthermore, the presence of low TgAb titers does not indicate Tg interference per se. A normal TgR might be helpful in these cases in making a well-considered decision on the necessity of further clinical investigations. This might prevent unnecessary imaging and patient concern, at the moment of detection of TgAb. We agree with Giovanella that follow-up studies are needed to prove the absence of disease activity in patients with normal TgR and undetectable Tg in which low Tgab levels persist. c. Tg-recovery and HAB interference: Heterophilic antibody (HAB) interference is an underestimated assay problem in Tg measurement, leading to false positive Tg results. This can result in unwarranted therapy. In our study, we suspected over-recovery in one sample with a TgR of 126%. Tg was unexpectedly detectable by TgICMA (8.6 ìg/L) in this patient with no clinical evidence of disease, whereas Tg was undetectable by RIA and immunoradiometric assay (IRMA). As stated by Preissner et al. (5), HAB interference should be suspected if Tg results do not fit the clinical picture. There is no gold standard for the identification of HAB interference. Used methods as blocking tubes, repeating Tg measurement with a different assay and dilution series all have limitations and often combinations of methods are needed to confirm HAB interference. In this study, we showed that TgR can be an additional method in the sometimes difficult identification of HAB interference. Concluding, we agree with Giovanella that TgR should not be used on a routine basis. As we stated in the conclusion of our commented study, TgR testing may have complementary value to quantitative TgAb measurement, in particular in sera with low TgAb titers and in the detection of HAB interference. Unfortunately, discontinuation of Nichols Institute Diagnostics impedes further research to confirm the potential added value of this TgR assay. Adrienne C.M. Persoon Thera. P. Links Johannes M.W van den Ouweland References: 1. Giovaenlla L. How thyroglobulin recovery test really adds to anti- thyrogloblin antibodies quantitative assay when serum thyroglobulin is employed to manage differentiated thyroid carcinoma? Clin Chem 2006; 7 november (electronic letter). 2. Persoon ACM, Links TP, Wilde J, Sluiter WJ, Wolffenbuttel BHR, van den Ouweland JMW. Thyroglobulin (Tg) recovery testing with quantitative Tg antibody measurement for determining interference in serum Tg assays in differentiated thyroid carcinoma. Clin Chem 2006; 52: 1196-99. 3. Spencer CA, Bergoglio LM, Kazarosyan M, Fatemi S. and LoPresti JS. Clinical Impact of thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas. J Clin Endocrinol Metab 2005; 90; 5566-75. 4. Chung JK, Park YJ, Kim TY, So Y, Kim SK, Park DJ et al. Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiatedthyroid cancer after thyroid ablation. Clin Endocrinol 2002; 57: 215–21. 5. Preissner CM, O’Kane DJ, Singh RJ, Morris JC, Grebe SKG. Phantoms in the assay tube: heterophile antibody interferences in serum thyroglobulin assays. J Clin Endocrinol Metab 2003; 88: 3069-74. |
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