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Коморбідний ендокринологічний пацієнт
Коморбідний ендокринологічний пацієнт

Международный эндокринологический журнал Том 18, №7, 2022

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Використання тесту на антитіла до рецептора тиреотропного гормона в амбулаторній практиці для диференційної діагностики гіпертиреозу

Використання тесту на антитіла до рецептора тиреотропного гормона в амбулаторній практиці для диференційної діагностики гіпертиреозу

Авторы: I.V. Pankiv
Bukovinian State Medical University, Chernivtsi, Ukraine

Рубрики: Эндокринология

Разделы: Справочник специалиста

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Резюме

Мета. Антитіла (AТ) до рецептора тиреотропного гормона (ТТГ) (рТТГ) відіграють важливу роль у патогенезі автоімунних захворювань щитоподібної залози. В огляді наводиться термінологія для опису антитіл до рТТГ (АТ-рТТГ), обговорюються методика і показання до використання тесту на АТ-рТТГ в амбулаторній практиці. Методи. Огляд літератури та обговорення. Результати. АТ-рТТГ можуть імітувати або блокувати дію ТТГ чи бути функціонально нейтральними. Стимулюючі АТ-рТТГ є специфічними біомаркерами хвороби Грейвса (ХГ) і відповідають за її клінічні прояви. АТ-рТТГ також можуть бути виявлені у пацієнтів з тиреоїдитом Хашимото, у яких вони можуть сприяти виникненню в подальшому гіпотиреозу. Визначення АТ-рТТГ можна проводити за допомогою імунологічних аналізів, які виявляють специфічне зв’язування АТ з рТТГ, або аналізів, які також надають інформацію про їх функціональну активність і ефективність. Застосування методів молекулярного клонування призвело до значного прогресу в методології, що дозволило розробити клінічно корисні біологічні аналізи. Рецептори до ТТГ вна­слідок взаємодії з тиреостимулювальними антитілами при ХГ або з надлишком ТТГ при первинному гіпотиреозі відіграють роль автоантигена, ініціюючи автоімунний процес. Існують свідчення, які вказують на пряму кореляцію рівнів АТ-рТТГ із клінічною активністю автоімунного процесу, що визначає тяжкість та прогноз захворювання. Рецептор ТТГ містить домен і для стимулюючих, і для блокуючих антитіл. При ХГ стимулюючі імуноглобуліни, зв’язуючись із рТТГ, імітують стимуляцію щитоподібної залози за допомогою ТТГ, що призводить до гіпертиреоїдизму. Частка стимулюючих антитіл становить близько 60–80 %, проте при сумарному визначенні антитіл поєднання ефекту стимулюючих та блокуючих антитіл може призводити до розбіжностей клініко-лабораторних даних у пацієнта. Висновок. Вимірювання АТ-рТТГ (особливо стимулюючих) рекомендується для швидкої діагностики, диференційної діагностики та лікування пацієнтів із ХГ, ендокринною орбітопатією.

Objective. Antibodies (Abs) to the thyroid stimulating hormone receptor (TSHR) play an important role in the pathogenesis of autoimmune thyroid disease (AITD). We define the complex terminology that has arisen to describe TSHR-Abs, and discuss significant advances that have been made in the development of clinically useful TSHR-Abs assays. Methods. Literature review and discussion. Results. TSHR-Abs may mimic or block the action of TSH or be functionally neutral. Stimulating TSHR-Abs are specific biomarkers for Graves’ disease and responsible for many of its clinical manifestations. TSHR-Abs may also be found in patients with Hashimoto thyroiditis in whom they may contribute to the hypothyroidism. Measurement of TSHR-Abs in general, and functional Abs in particular is recommended for the rapid diagnosis of Graves’ disease, differential diagnosis and management of patients with AITD, especially during pregnancy, and in AITD patients with extrathyroidal manifestations such as orbitopathy. Measurement of TSHR-Abs can be done with either immunoassays that detect specific binding of Abs to the TSHR or cell-based bioassays, which also provide information on their functional activity and potency. Application of molecular cloning techniques has led to significant advances in methodology that have enabled the development of clinically useful bioassays. When ordering TSHR-Abs, clinicians should be aware of the different tests available and how to interpret results based on which assay is performed. The availability of an international standard and continued improvement in bioassays will help promote their routine performance by clinical laboratories and provide the most clinically useful TSHR-Abs results. Conclusion. Measurement of TSHR-Abs in general, and functional (especially stimulating) Abs in particular is recommended for the rapid diagnosis, differential diagnosis, and management of patients with Graves hyperthyroidism, related thyroid eye disease, during pregnancy, as well as in Hashimoto thyroiditis patients with extrathyroidal manifestations and/or thyroid-binding inhibiting immunoglobulin positivity.


Ключевые слова

хвороба Грейвса; гіпертиреоз; антитіла до рецептора тиреотропного гормона

Graves’ disease; hyperthyroidism; thyroid stimulating hormone receptor antibody

doi: http://dx.doi.org/10.22141/2224-0721.18.7.2022.1216
Graves’ disease (GD) is the most common cause of hyperthyroidism [1]. It is important to distinguish GD from other causes of hyperthyroidism for optimal management. Thyroid stimulating hormone receptor antibody (TSHR-Ab) test is a commonly used test for this purpose. However, the sensitivity for this test in routine clinical practice may be affected by various factors leading to fallacies in diagnosis.
Autoimmune thyroid disease is commonly associated with the presence of autoantibodies (Abs) to a number of thyroid antigens, such as thyroid peroxidase (TPO), thyroglobulin (Tg), and the TSH receptor (TSHR) [1]. TSHR-Ab are unique in that they are functionally significant, such that they can act as either agonists that stimulate thyroid growth or antagonists that block the activity of TSH [2].
GDis caused by TSHR-Ab, which stimulate the TSHR on the surface of thyroid follicular cells. Unlike other autoimmune diseases where autoantibodies may be epiphenomena (e.g., Hashimoto’s thyroiditis, type 1 diabetes mellitus), TSHRAb plays an important role in the pathogenesis of the disease [2]. 
It is expected that the presence of TSHR-Ab is diagnostic of GD. Other causes of hyperthyroidism in clinical practice include various forms of thyroiditis, autonomously functioning thyroid nodule (AFTN), toxic multi‑nodular goiter, gestational thyrotoxicosis, and exogenous intake of levothyroxine. In iodine‑sufficient areas, the most common cause of hyperthyroidism is GD, followed by nodular thyroid disease and thyroiditis. However, according to the age and iodine sufficiency, a higher proportion of subjects may have toxic nodular goiter or silent thyroiditis [4].
The distinction between various causes of hyperthyroidism is important because the treatment differs with the etiology. The differential diagnosis of hyperthyroidism is performed with a combination of history, clinical examination, biochemical investigations, thyroid scintigraphy, TSHR-Ab test, ultrasound thyroid with Doppler, and follow‑up of the patient through the natural history of the disease [5].
Unlike ultrasound and thyroid scintigraphy, which require specialized equipment, the TSHR-Ab test can be performed with automated hormone analyzer platforms with short turnaround times. This has made the TSHR-Ab test apreferred method to diagnose GD. A meta‑analysis showed that the overall pooled sensitivity and specificity of the second‑ and third‑generation TSHR-Ab assays are above 97 % [6].
The incorporation and early utilization of TSHR-Ab into current diagnostic algorithms conferred a 46 % shortened time to diagnosis of GD and a cost saving of 47 % [7]. The American Thyroid Association and the European Thyroid Association recommend the use of TSR-Ab for the diagnosis of GD [8, 9].
However, there are various limitations in the interpretation of TSHR-Ab. This includes the types of assays used, bioactivity of TSHR-Ab, and the presence of TSHR-Ab in people with other autoimmune diseases, thyroid diseases, and even non-autoimmune diseases. Further, the cut‑offs of TSHR-Ab for optimum diagnosis vary according to the type of the assay and manufacturer, leading to variable sensitivity and specificity of the assays. 
In subjects with suppressed TSH, diagnosing GD will make a difference in management.
M. John et al. [10] assessed the utility of TSHR-Ab to differentiate GD from non GD in subjects with suppressed TSH. The TSHR-Ab test performed with an electrochemiluminescence immunoassay using the cut‑off recommended by the manufacturer (1.75 IU/l) had a high sensitivity for diagnosis of GD. However, at this cut‑off, the specificity of the assay was 62.9 %. Using an ROC curve analysis, authors derived an optimal cut‑off of 3.37 IU/L, which gave an optimum sensitivity and specificity of 91.2 % and 90.12 %, respectively. 
Although GD is the most common cause of hyperthyroidism, there are several other conditions causing the hyperthyroid state, such as toxic multi‑nodular goiter, AFTN, and various forms of thyroiditis (silent, postpartum, autoimmune, etc.). In the absence of extra‑thyroidal manifestations of GD or extra‑thyroidal autoimmunity, this differential diagnosis is performed using radioactive iodine uptake, technetium pertechnate scan, TSHR-Ab test, or Doppler ultrasound. Because other modalities require specialized equipment or radiation safety procedures, the TSHR-Ab test remains an attractive method for differential diagnosis. 
Commercial TSHR-Ab assays are cost‑effective and have a rapid turnover time [11]. TSHR-Ab can be measured using competition‑based assays, such as thyroid binding inhibiting immunoglobulin (TBII) assays, or assays that detect cyclic adenosine monophosphate production [thyroid stimulating immunoglobulin (TSI) assays]. TBII assays have been refined gradually, and currently available third‑generation assays are automated with a lower cost and a faster turnaround time. However, the heterogenicity of human TSHR-Ab has significant effects on the clinical performance of different assay methods [11]. 
The sensitivity of TSHR-Ab for the overall group of subjects (146 subjects with GD) was 95.89, whereas it was 98.4 for those with newly diagnosed GD (n = 125). However, the specificity was 62.96 for both groups. Although the overall numbers were small, TSHR-Ab was less likely to be positive beyond the initial period of diagnosis. It is well known that the serum levels of TRAb reduce in subjects with prolongedillness because of GD on autoimmune thyroid diseases. This has been suggested to be because of waning autoimmunity [11]. The cut‑offs recommended by the manufacturer are usually used for various tests. In six subjects with GD (4.1 %), the TSHR-Ab levels were less than 1.75 U/l. 
Although the sensitivity of TSHR-Ab for diagnosis of GD has improved with the use of third‑generation assays, GD subjects with negative TSHR-Ab are documented in various studies. In a study involving 440 subjects with various forms of thyrotoxicosis, 18 % of the subjects with GD were found to be negative for TSHR-Ab. Subjects negative for TSHR-Ab had lower levels of free T3 and free T4, a lower probability of smoking, higher antithyroid peroxidase, and a higher risk of orbitopathy [12].
In another study using multi‑modality imaging for the diagnosis of GD, the sensitivity and specificity of TSHR-Ab were 93 % and 91 %, respectively [13]. Studies have also shown that there is a reduced risk of relapse of GD after stopping therapy in people who were TSHR-Ab‑negative at diagnosis and throughout treatment in comparison with TSHR-Ab‑positive GD [14]. Histological studies have shown that there is a distinct histological pattern in TSHR-Ab‑negative GD characterized by less severe papillate hyperplastic epithelia and enlarged colloids and more lymphocytic infiltration [15].
In general, TSHR-Ab‑negative GD seems to be a less severe form of GD in comparison to TSHR-Ab‑positive GD [15]. Diffuse technetium uptake in scintigraphy with thyrotoxicosis with absent TSHR-Ab may be seen in germline mutation of the TSH receptor or in a sub‑set of subjects with toxic multi‑nodular goiter. In a series of 89 subjects with TSHR-Ab‑negative thyrotoxicosis and diffuse goiter, 4.5 % had germline mutations in the TSH receptor. In this study, 10 % of TSHR-Ab‑negative patients without mutations subsequently became TSHR-Ab‑positive [16].
TSHR-Ab may mimic or block the action of TSH or be functionally neutral. Stimulating TSHR-Ab are specific biomarkers for GD and responsible for many of its clinical manifestations. 

Conclusion

The TSHR-Ab test is a sensitive test to differentiate between subjects with GD and non GD presenting with hyperthyroidism. In subjects with discordance between clinical features and TSHR-Ab, thyroid scintigraphy should be considered.
 
Received 25.08.2022
Revised 04.10.2022
Accepted 14.10.2022

Список литературы

  1. Ehlers M., Schott M., Allelein S. Graves’ disease in clinical perspective. Front Biosci. (Landmark Ed). 2019 Jan 1. 24(1). 35-47. doi: 10.2741/4708. PMID: 30468646.
  2. Diana T., Kahaly G.J. Thyroid Stimulating Hormone Receptor Antibodies in Thyroid Eye Disease-Methodology and Clinical Applications. Ophthalmic Plast. Reconstr. Surg. 2018 Jul/Aug. 34(4S Suppl 1). S13-S19. doi: 10.1097/IOP.0000000000001053. PMID: 29771755.
  3. Alvin Mathew A., Papaly R., Maliakal A., Chandra L., Antony M.A. Elevated Graves’ Disease-Specific Thyroid-Stimulating Immunoglobulin and Thyroid Stimulating Hormone Receptor Antibody in a Patient with Subacute Thyroiditis. Cureus. 2021 Nov 10. 13(11). e19448. doi: 10.7759/cureus.19448. PMID: 34912598; PMCID: PMC8664564.
  4. Sharma A., Stan M.N. Thyrotoxicosis: Diagnosis and Management. Mayo Clin. Proc. 2019 Jun. 94(6). 1048-1064. doi: 10.1016/j.mayocp.2018.10.011. Epub 2019 Mar 25. PMID: 30922695.
  5. Vaidya B., Pearce S.H. Diagnosis and management of thyrotoxicosis. BMJ. 2014 Aug 21. 349. g5128. doi: 10.1136/bmj.g5128. PMID: 25146390.
  6. Tozzoli R. The increasing clinical relevance of thyroid‑stimulating hormone receptor autoantibodies and the concurrent evolution of assay methods in autoimmune hyperthyroidism. J. Lab. Precis Med. 2018. 3. 27. doi: 10.21037/jlpm.2018.03.05.
  7. McKee A., Peyerl F. TSI assay utilization: impact on costs of Graves’ hyperthyroidism diagnosis. Am. J. Manag. Care. 2012 Jan 1. 18(1). e1-14. PMID: 22435785.
  8. Ross D.S., Burch H.B., Cooper D.S., Greenlee M.C., Laurberg P., Maia A.L., Rivkees S.A., et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct. 26(10). 1343-1421. doi: 10.1089/thy.2016.0229. 
  9. Kahaly G.J., Bartalena L., Hegedüs L., Leenhardt L., Poppe K., Pearce S.H. 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur. Thyroid J. 2018 Aug. 7(4). 167-186. doi: 10.1159/000490384. 
  10. John M., Jagesh R., Unnikrishnan H., Jalaja M.M.N., Oommen T., Gopinath D. Utility of TSH Receptor Antibodies in the Differential Diagnosis of Hyperthyroidism in Clinical Practice. Indian J. Endocrinol. Metab. 2022 Jan-Feb. 26(1). 32-37. doi: 10.4103/ijem.ijem_388_21. Epub 2022 Apr 27. PMID: 35662753; PMCID: PMC9162259.
  11. Barbesino G., Tomer Y. Clinical review: Clinical utility of TSH receptor antibodies. J. Clin. Endocrinol. Metab. 2013 Jun. 98(6). 2247-55. doi: 10.1210/jc.2012-4309. PMID: 23539719; PMCID: PMC3667257.
  12. Zuhur S.S., Bilen O., Aggul H., Topcu B., Celikkol A., Elbuken G. The association of TSH-receptor antibody with the clinical and laboratory parameters in patients with newly diagnosed Graves’ hyperthyroidism: experience from a tertiary referral center including a large number of patients with TSH-receptor antibody-negative patients with Graves’ hyperthyroidism. Endokrynol. Pol. 2021. 72(1). 14-21. doi: 10.5603/EP.a2020.0062. PMID: 32944926.
  13. Zuhur S.S., Ozel A., Kuzu I., Erol R.S., Ozcan N.D., Basat O., Yenici F.U., Altuntas Y. The Diagnostic Utility of Color Doppler Ultrasonography, Tc-99m Pertechnetate Uptake, and TSH-Receptor Antibody for Differential Diagnosis of Graves’ Disease and Silent Thyroiditis: A Comparative Study. Endocr. Pract. 2014 Apr. 20(4). 310-9. doi: 10.4158/EP13300.OR. PMID: 24246346.
  14. Kawai K., Tamai H., Matsubayashi S., Mukuta T., Morita T., Kubo C., Kuma K. A study of untreated Graves' patients with undetectable TSH binding inhibitor immunoglobulins and the effect of anti-thyroid drugs. Clin. Endocrinol. (Oxf). 1995 Nov. 43(5). 551-6. doi: 10.1111/j.1365-2265.1995.tb02919.x. PMID: 8548939.
  15. Kawai K., Tamai H., Mori T., Morita T., Matsubayashi S., Katayama S., Kuma K., Kumagai L.F. Thyroid histology of hyperthyroid Graves’ disease with undetectable thyrotropin receptor antibodies. J. Clin. Endocrinol. Metab. 1993 Sep. 77(3). 716-9. doi: 10.1210/jcem.77.3.7690362. PMID: 7690362.
  16. Nishihara E., Fukata S., Hishinuma A., Amino N., Miyauchi A. Prevalence of thyrotropin receptor germline mutations and clinical courses in 89 hyperthyroid patients with diffuse goiter and negative anti-thyrotropin receptor antibodies. Thyroid. 2014 May. 24(5). 789-95. doi: 10.1089/thy.2013.0431. Epub 2014 Jan 24. PMID: 24279482.

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