Measuring thyroglobulin concentrations in patients with differentiated thyroid carcinoma

J Med Biochem 2010; 29 (4) DOI: 10.2478/v10011-010-0029-4 UDK 577.1 : 61 ISSN 1452-8258 J Med Biochem 29: 245 –253, 2010 Review article Pregledni ~lanak MEASURING THYROGLOBULIN CONCENTRATIONS IN PATIENTS WITH DIFFERENTIATED THYROID CARCINOMA MERENJE KONCENTRACIJE TIREOGLOBULINA KOD PACIJENATA SA DIFERENTOVANIM KARCINOMIMA [TITASTE @LEZDE Svetlana Savin1, Dubravka Cveji}1, Ljiljana Mijatovi}2, Sne`ana @ivan~evi} Simonovi}2 1Institute for the Application of Nuclear Energy – INEP, University of Belgrade, Zemun-Belgrade, Serbia 2Faculty of Medicine, University of Kragujevac, Kragujevac, Serbia Summary: Thyroid carcinomas are the most common malignant endocrine tumors. Thyroglobulin (Tg), a specific thyroid protein, is the most important tumor marker in thyroid oncology. After total thyroidectomy or radioiodine therapy, detectable or increasing serum Tg levels in patients with differentiated thyroid carcinoma indicate persistence of active thyroid tissue or cancer recurrence. Serum Tg concentration primarily reflects three variables: the mass of differentiated thyroid tissue present; the degree of thyrotropin receptor stimulation and the intrinsic ability of the tumor to synthesize and secrete Tg. Measurement of serum Tg by current immunometric (IMA) and radioimmunological (RIA) assays encounters some methodological problems which can diminish its clinical importance. Discrepancy between the results for Tg using different methods may be caused by: different reference materials, specific properties of the primary and secondary antibodies for antigenic determinants on Tg and diverse binding affinities of these epitopes, together with interference by serum factors (usually antibodies to Tg (TgAb)) with the primary and secondary Tg antibodies from the diagnostic set. In the presence of endogenous TgAb, Tg values measured by immunoradiometric assay (IRMA) and similar assays are usually lower than the real concentrations, while in RIA apparently lower or higher results can be obtained. Falsely low values may lead to delay in necessary treatment, while an inappropriately high Tg value can cause patient anxiety and unnecessary scans. Despite current methodological limitations, serum Tg measurement is a useful test for determining worsening disease and monitoring the effects of therapy in patients who have undergone surgery for differentiated thyroid carcinoma. Keywords: antithyroglobulin autoantibodies, differentiated thyroid carcinoma, immunometric assay, thyroglobulin Address for correspondence: Dr Svetlana Savin Institute for the Application of Nuclear Energy – INEP 11080 Zemun – Belgrade, Banatska 31b, Serbia Tel. +381 11 3169058 Fax: +381 11 2618724 e-mail: ssavinªinep.co.rs Kratak sadr`aj: Tiroidni karcinomi su naj~e{}i maligni endokrini tumori. Tireoglobulin (Tg), specifi~ni protein {titaste `lezde, najva`niji je tumorski marker u tireoidnoj onkologiji. Kod pacijenata sa diferentovanim karcinomima tireoideje, nakon operativnog le~enja, koncentracija Tg odre|uje se radi otkrivanja rezidualnog tumorskog tkiva ili postojanja lokalnih, odnosno udaljenih metastaza. Na koncentraciju Tg u serumu uti~u: masa prisutnog tireoidnog tkiva (benignog ili malignog), intenzitet stimulacije receptora za tireostimuli{u}i hormon (TSH) i sposobnost tumorskih }elija da sinteti{u i lu~e Tg. Savremene metode, imunometrijske (IMA) i radioimunolo{ke (RIA), kojima se odre|uje koncentracija Tg u serumu ispitanika, imaju odre|ena ograni~enja koja mogu da umanje klini~ki zna~aj dobijenih rezultata. Usled metodolo{kih razlika, koncentracije Tg u istim uzorcima seruma, izmerene razli~itim testovima, mogu se razlikovati. Faktori koji mogu prouzrokovati razlike u izmerenim koncentracijama Tg su brojni: razli~iti referentni materijali, razlike u specifi~nosti primarnih i sekundarnih antitela za antigenske determinante Tg, razli~it afinitet vezivanja tih antitela za epitope Tg, i interferencija serumskih faktora. Princip testa, kao i eventualno prisustvo TgAt u serumima ispitanika, mo`e uticati na izmerenu koncentraciju Tg. Svako odstupanje izmerenih koncentracija Tg od stvarnih vrednosti mo`e imati ozbiljne posledice: la`no niske vrednosti Tg mogu odlo`iti neophodni tretman pacijenata, dok la`no pove}ane vrednosti Tg mogu prouzrokovati nepotrebni stres, ili ~ak tretman pacijenata. I pored ograni~enih mogu}nosti savremenih metoda, odre|ivanje koncentracije Tg u serumu pacijenata operisanih od diferentovanog tiroidnog karcinoma je koristan test za otkrivanje pogor{anja bolesti i za pra}enje efekata terapije. Klju~ne re~i: diferentovani tireoidni karcinom, imunometrijski test, tireoglobulin, tireoglobulinska antitela 246 Savin et al.: Thyroglobulin measurement in thyroid carcinoma Introduction Thyroid carcinomas are the most common malignant tumors of the endocrine system and their incidence is on the rise (1). Most thyroid carcinomas are differentiated tumors: 88% papillary and 8% follicular (1). Differentiated thyroid carcinoma (DTC) can appear at any time of life with peaks in the third and sixth decade and a median at 44 years (2). Epidemiological data indicating an increase in the number of thyroid carcinomas can partially result from the application of advanced diagnostic methods that can detect micropapillary carcinomas (smaller than 1 cm) or more detailed research of autopsy material which showed a 5–24% incidence of thyroid carcinoma (2). If thyroid carcinoma is diagnosed in a patient, the physician may decide on operative treatment (with or without application of an ablative dose of radioactive iodine – (I131) (3, 4) or clinical follow-up depending on the tumor size and other characteristics (5). Most (90%) thyroid tumors are smaller than 2 cm in diameter and are considered low risk, so less aggressive treatment and monitoring are applied, in accordance with current protocols (3, 4). In disease diagnostics and monitoring of patients with thyroid carcinoma, determining the serum concentration of thyroglobulin (Tg) is very important. Tg is a glycoprotein with a molecular weight of 660 kDa, synthesized exclusively by thyroid follicular cells – thyrocytes. The fact that the thyroid gland is the only organ synthesizing Tg (6) makes this molecule a marker of differentiated thyroid carcinoma relapse or the occurrence of metastasis in the postoperative period, if the thyroid gland tissue was completely removed by a surgical procedure with eventual use of an ablative dose of radioactive iodine (I131). Namely, there is currently no method that can establish whether circulating Tg originates from normal or malignant tissue. However, due to malignant transformation of thyroid follicular cells, the structure of Tg (especially the carbohydrate component) can be changed (7) together with alterations in the secretion mechanism (8). Epitope mapping on the Tg molecule has shown the existence of six different antigenic regions to which different thyroglobulin-specific antibodies (TgAb) can bind (9, 10), most (...truncated)