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      Serum thyroglobulin evaluation on LC-MS/MS and immunoassay in TgAb-positive patients with papillary thyroid carcinoma

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          Abstract

          Objective

          This study aimed to elucidate disproportionately low serum thyroglobulin (Tg) values in Tg antibody (TgAb)-positive patients with structural recurrence of papillary thyroid carcinoma (PTC) using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

          Design

          A retrospective study was performed on 176 patients in whom Tg and TgAb levels were measured between 2016 and 2021. Several comprehensive analyses of Tg-LC-MS/MS with an electrochemiluminescence immunoassay for Tg (Tg-ECLIA) were conducted using serum samples.

          Methods

          TgAb-positive patients who underwent total thyroidectomy with multiple lung metastases due to PTC were evaluated using Tg-LC-MS/MS and Tg-ECLIA. Tg expression in lymph node metastases and metastatic lesions was evaluated by immunohistochemistry and Tg levels of aspiration washouts were also evaluated. Two in vitro assays were performed to elucidate TgAb interference.

          Results

          Tg concentrations of negative TgAb in both assays were similar (R 2= 0.99; n  = 52). Patients with structural recurrence showed higher Tg values with Tg-LC-MS/MS than with Tg-ECLIA. The undetectable proportion was significantly lower with Tg-LC-MS/MS (31.6%, 6/19) than with Tg-ECLIA (68.4%, 13/19; P  = 0.023). The spike-recovery rate and Tg concentrations determined by the serum mixture text ( n  = 29) were significantly reduced to 75.0% (118.3–88.7%) and 81.3% (107.0–87.0%), respectively, with TgAb using Tg-ECLIA (both P  < 0.001) confirming assay interference but not using Tg-LC-MS/MS (91.8–92.3%, P  = 0.77 and 98.4–100.8%, P  = 0.18, respectively).

          Conclusions

          TgAb had no effect on the Tg-LC-MS/MS assay but yielded 19–25% lower values in Tg-ECLIA. Tg-LC-MS/MS is preferable for monitoring serum Tg levels in TgAb-positive patients, although those with structural recurrence often had disproportionally low Tg values.

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          Most cited references16

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          Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma.

          C A Spencer, M Takeuchi, M Kazarosyan … (1998)
          The prevalence of circulating thyroid autoantibodies (TgAb or antithyroid peroxidase) was increased nearly 3-fold in patients with differentiated thyroid cancers (DTC) compared with the general population (40% vs. 14%, respectively). Serum TgAb (with or without antithyroid peroxidase) was present in 25% of DTC patients and 10% of the general population. Serial postsurgical serum TgAb and serum Tg patterns correlated with the presence or absence of disease. Measurements of serum Tg were made in 87 TgAb-positive sera by a RIA and two immunometric assay (IMA) methods to study TgAb interference. TgAb interference, defined as a significant intermethod discordance (>41.7% coefficient of variation) between the Tg RIA and Tg IMA values relative to TgAb-negative sera, was found in 69% of the TgAb-positive sera. TgAb interference was characterized by higher Tg RIA vs. IMA values and was, in general, more frequent and severe in sera containing high TgAb concentrations. However, some sera displayed marked interference when serum TgAb was low (1-2 IU/mL), whereas other sera with very high TgAb values (>1000 IU/mL) displayed no interference. An agglutination method was found to be too insensitive to detect low TgAb concentrations (1-10 IU/mL) causing interference. Exogenous Tg recovery tests were an unreliable means for detecting TgAb interference. Specifically, the exogenous Tg recovered varied with the type and amount of Tg added and the duration of incubation employed. Further, recoveries of more than 80% were found for some sera displaying gross serum RIA/IMA discordances. The measurement of serum Tg in DTC patients with circulating TgAb is currently problematic. It is important to use a Tg method that provides measurements that are concordant with tumor status. IMA methods are prone to underestimate serum when TgAb is present, increasing the risk that persistent or metastatic DTC will be missed. The RIA method used in this study provided more clinically appropriate serum Tg values in the group of TgAb-positive patients with metastatic DTC. Furthermore, as serial serum TgAb measurements paralleled serial serum Tg RIA measurements, TgAb concentrations may be an additional clinically useful tumor marker parameter for following TgAb-positive patients. Disparities between serial serum Tg and TgAb measurements might alert the physician to the possibility of TgAb interference with the serum Tg measurement and prompt a more cautious use of such data for clinical decision-making.
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            Quantification of thyroglobulin, a low-abundance serum protein, by immunoaffinity peptide enrichment and tandem mass spectrometry.

            Andrew N Hoofnagle, Jessica O Becker, Mark H Wener … (2008)
            Quantification of serum tumor markers plays an important role in determining whether patients treated for cancer require further therapy. Whereas large-scale proteomic efforts aim to identify novel tumor markers to facilitate early detection, optimization of methods for quantifying known tumor markers offers another approach to improving management of malignancies. For example, immunoassays used in clinical practice to measure established tumor markers suffer from potential interference from endogenous immunoglobulins and imperfect concordance across platforms-problems that also plague many other immunoassays. To address these important limitations, this study used peptide immunoaffinity enrichment in concert with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify thyroglobulin, a well-characterized tumor marker. We identified 3 peptides in tryptic digests of thyroglobulin that were detected at low concentrations by tandem mass spectrometry, raised polyclonal antibodies to those peptides, and used the antibodies to extract the 3 corresponding peptides from tryptic digests of human serum. We quantified each endogenous peptide using LC-MS/MS and multiple reaction monitoring with external calibrators. The detection limit for endogenous thyroglobulin in serum was 2.6 microg/L (4 pmol/L). Direct comparison with immunoassay revealed good correlation (r(2) = 0.81). Immunoaffinity peptide enrichment-tandem mass spectrometry can detect tryptic peptides of thyroglobulin at picomolar concentrations while also digesting the endogenous immunoglobulins that can potentially interfere with traditional immunoassays. Our observations suggest a general analytical strategy for using immunoaffinity isolation together with tandem mass spectrometry to quantify tumor antigens and other low-abundance proteins in human serum.
            Article 0 comments Cited 67 times – based on 0 reviews     Review now
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              Thyroglobulin (Tg) Testing Revisited: Tg Assays, TgAb Assays, and Correlation of Results With Clinical Outcomes.

              Brian C Netzel, Stefan Grebe, B Gisella Carranza Leon … (2015)
              Measurement of thyroglobulin (Tg) by mass spectrometry (Tg-MS) is emerging as a tool for accurate Tg quantification in patients with anti-Tg autoantibodies (TgAbs).
              Article 0 comments Cited 57 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Eur Thyroid J
                Journal ID (iso-abbrev): Eur Thyroid J
                Journal ID (publisher-id): ETJ
                Title: European Thyroid Journal
                Publisher: Bioscientifica Ltd (Bristol )
                ISSN (Print): 2235-0640
                ISSN (Electronic): 2235-0802
                Publication date (Electronic): 07 December 2021
                Publication date Collection: 01 February 2022
                Volume: 11
                Issue: 1
                Electronic Location Identifier: e210041
                Affiliations
                [1 ]Kuma Hospital , Center for Excellence in Thyroid Care, Kobe, Japan
                [2 ]ASKA Pharmamedical Co. , Ltd. Fujisawa, Japan
                Author notes
                Correspondence should be addressed to E Nishihara: nishihara@ 123456kuma-h.or.jp
                Article
                Publisher ID: ETJ-21-0041
                DOI: 10.1530/ETJ-21-0041
                PMC ID: 9142804
                PubMed ID: 34981756
                SO-VID: 08740137-cdeb-4bd9-9638-3a26f6266e2e
                Copyright © © The authors
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                Date received : 22 November 2021
                Date accepted : 07 December 2021
                Categories
                Subject: Research

                Keywords: serum thyroglobulin,interference with tgab,lc-ms/ms,structural recurrence
                Data availability:
                Keywords: serum thyroglobulin, interference with tgab, lc-ms/ms, structural recurrence

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