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Коморбідний ендокринологічний пацієнт

Международный эндокринологический журнал Том 16, №6, 2020

Prognostic significance of risk factors for thyrotoxicosis development in radioiodine therapy

Авторы: Ubaydullaeva N.B., Allayarova G.I., Almuradov F.F.
Republican Specialized Scientific and Practical Medical Center of Endocrinology named after academician Yo.Kh. Turakulov Ministry of Health of the Republic of Uzbekistan, Tashkent, Republic of Uzbekistan

Рубрики: Эндокринология

Разделы: Клинические исследования

Актуальність. Хвороба Грейвса — системне автоімунне захворювання, яке розвивається внаслідок вироблення антитіл до рецептора тиреотропного гормона, що клінічно проявляється дифузними структурними змінами щитоподібної залози з розвитком синдрому тиреотоксикозу, а також поєднується з екстратиреоїдними проявами. Метою дослідження було виявлення факторів ризику рецидиву хвороби Грейвса в жінок, які отримували терапію радіоактивним йодом. Матеріали та методи. Під спостереженням перебували 93 жінки репродуктивного віку, які отримували радіойодотерапію (РЙТ). Ми проаналізували результати анкетування, оцінили фактори ризику рецидиву тиреотоксикозу і провели ретроспективний і проспективний аналіз клінічних показників і даних анамнезу. Середній вік пацієнтів становив 36,9 ± 7,1 року. Контрольну групу становили 35 здорових жінок віком 33,5 ± 7,6 року. Рівні тиреотропного гормона, вільного трийодотироніну, вільного тироксину й антитіл до тиреоїдної пероксидази визначали імунохемілюмінесцентним методом. Результати. Щоб оцінити якість прогностичної моделі рецидиву тиреотоксикозу, ми розрахували всі параметри факторів ризику AUC. Найбільш значущими факторами ризику розвитку рецидиву тиреотоксикозу після РЙТ із високим відносним ризиком були вік понад 30 років (ВР = 7,59; EF = 8,82 %), обсяг щитоподібної залози ≥ 30 см3 (ВР = 6,84; EF = 85,38 %), тривалість лікування ≥ 2 років (ВР = 6,37; EF = 84,30 %), комплаєнтність пацієнта (ВР = 6,19; EF = 83,84 %), кількість процедур РЙТ (ВР = 5,74; EF = 82,58%) і доза РЙТ 300 МБк (ВР = 5,41; EF = 81,52 %). Висновки. Установлено, що вік понад 30 років (AUC — 0,88), обсяг щитоподібної залози ≥ 30 см3 (AUC — 0,86), тривалість лікування ≥ 2 років (AUC — 0,86), комплаєнтність пацієнта (AUC — 0,85), число процедур РЙТ (AUC — 0,85) і доза I131 (AUC — 0,82) мають першорядне значення.

Актуальность. Болезнь Грейвса — системное аутоиммунное заболевание, развивающееся в результате выработки антител к рецептору тиреотропного гормона, что клинически проявляется диффузными структурными изменениями щитовидной железы с развитием синдрома тиреотоксикоза, а также сочетается с экстратиреоидными проявлениями. Целью исследования было выявление факторов риска рецидива болезни Грейвса у женщин, получавших терапию радиоактивным йодом. Материалы и методы. Под наблюдением находились 93 женщины репродуктивного возраста, получавшие радиойодотерапию (РЙТ). Мы проанализировали результаты анкетирования, оценили факторы риска рецидива тиреотоксикоза и провели ретроспективный и проспективный анализ клинических показателей и данных анамнеза. Средний возраст пациентов составил 36,9 ± 7,1 года. Контрольную группу составили 35 здоровых женщин в возрасте 33,5 ± 7,6 года. Уровни тиреотропного гормона, свободного трийодотиронина, свободного тироксина и антител к тиреоидной пероксидазе определяли иммунохемилюминесцентным методом. Результаты. Чтобы оценить качество прогностической модели рецидива тиреотоксикоза, мы рассчитали все параметры факторов риска AUC. Наиболее значимыми факторами риска развития рецидива тиреотоксикоза после РЙТ с высоким относительным риском были возраст старше 30 лет (ОР = 7,59; EF = 8,82 %), объем щитовидной железы ≥ 30 см3 (ОР = 6,84; EF = 85,38 %), продолжительность лечения ≥ 2 лет (ОР = 6,37; EF = 84,30 %), комплайентность пациента (ОР = 6,19; EF = 83,84 %), количество процедур РЙТ (ОР = 5,74; EF = 82,58 %) и доза РЙТ 300 МБк (ОР = 5,41; EF = 81,52 %). Выводы. Установлено, что возраст старше 30 лет (AUC — 0,88), объем щитовидной железы ≥ 30 см3 (AUC — 0,86), продолжительность лечения ≥ 2 лет (AUC — 0,86), комплайентность пациента (AUC — 0,85), число процедур РЙТ (AUC — 0,85) и доза I131 (AUC — 0,82) имеют первостепенное значение.

Background. Graves’ disease (GD) is a systemic autoimmune disease that develops as a result of the production of antibodies to the thyroid-stimulating hormone receptor, which is clinically manifested by diffuse structural changes in the thyroid gland with the development of thyrotoxicosis syndrome, and also combined with extrathyroid manifestations. The purpose of the study was to identify Graves’ disease recurrence risk factors in women received radioiodine therapy. Materials and methods. 93 women of reproductive age who received radioiodine therapy (RIT) were under obsewrvation. We analyzed the results of the questionnaire and assessed the thyrotoxicosis recurrence risk factors with performed retrospective and prospective analysis of clinical and medical history indicators. Patient’s average age was 36.9 ± 7.1 years. The control group included 35 healthy women aged 33.5 ± 7.6 years. Thyroid stimulating hormone (TSH), free triiodothyonine (fT3) and free thyroxine (fT4) and thyroperoxidase antibodies (TPOAb) levels determined by the immunochemiluminescent method. Results. In order to evaluate the quality of a prognostic model of the thyrotoxicosis recurrence we calculated all risk factors parameters of the AUC. The most significant risk factors for the development of thyrotoxicosis recurrence after RTI with a high relative risk and etiological fraction were age over 30 years (RR = 7.59; EF = 8.82 %), thyroid volume ≥ 30 cm3 (RR = 6.84; EF = 85.38 %), treatment duration ≥ 2 years (RR = 6.37; EF = 84.30 %), patient compliance (RR = 6.19; EF = 83.84 %), RIT multiplicity (RR = 5.74; EF = 82.58 %) and a dose of RIT 300 MBq (RR = 5.41; EF = 81.52 %). Conclusions. It was revealed that the age is older than 30 years (AUC — 0.88), thyroid volume ≥ 30 cm3 (AUC — 0.86), treatment duration ≥ 2 years (AUC – 0.86), patient compliance (AUC — 0.85), RIT multiplicity (AUC — 0.85) and the dose of RIT (AUC — 0.82) have excellent predictive power.

Ключевые слова

хвороба Грейвса; радіойодотерапія; фактори ризику

болезнь Грейвса; радиойодотерапия; факторы риска

Graves’ disease; radioiodine therapy; risk factors

doi: http://dx.doi.org/https://doi.org/10.22141/2224-0721.16.6.2020.215390

Introduction

Graves’ disease (GD) is a systemic autoimmune disease that develops as a result of the production of antibodies to the thyroid-stimulating hormone receptor, which is clinically manifested by diffuse structural changes in the thyroid gland with the development of thyrotoxicosis syndrome, and also combined with extrathyroid manifestations [1–3].

Radioiodine therapy (RIT) for thyrotoxicosis treatment used for over 60 years. In recent decades, this method has proven to be effective and safe, and in many countries, RIT used even as the first line of GD therapy without prior conservative treatment. According to many foreign studies, RIT effectiveness criterion is the achievement of a persistent decrease of thyroid function, or hypothyroidism [4, 5].

The results of different studies indicate that, despite the high effectiveness of RIT, in 17–20 % of cases after treatment, develops thyrotoxicosis recurrence [6, 7]. There are no specific recommendations for the GD recurrence after RIT prevention; also, there are no unified criteria for prescribing therapeutic activity of radioactive iodine. The applied activities of I131 in the treatment of GD vary significantly, ranging from 200 to 1000 MBq.

Radioiodine therapy is an alternative method of radical treatment of GD. RIT advantages: non-invasiveness, absence of surgical and anesthetic risks, possibility of conducting therapy during incomplete compensation of thyrotoxicosis, which is dangerous during surgical treatment, relative cheapness. The need for re-treatment after radioiodine therapy varies from 10 to 48 % [8–10].

The relevance of this study lies in the fact that the recently observed significant increase of GD in Uzbekistan is one of the main reasons for the disability increase, and the decrease in the quality of life of patients in this category. The implementation of this grant will contribute to improving GD diagnostics with the use of high-tech methods and pathogenetically sound comprehensive treatment of GD, which will lead to life expectancy increase, disability reduction, and quality of life improvement.

The purpose of the study: to identify Graves’ disease recurrence risk factors in women received radioiodine therapy.

Materials and methods

93 women of reproductive age who received RIT were under obsewrvation. We analyzed the results of the questionnaire and assessed the thyrotoxicosis recurrence risk factors with performed retrospective and prospective analysis of clinical and medical history indicators.

Patient’s average age was 36.9 ± 7.1 years. The control group included 35 healthy women aged 33.5 ± 7.6 years. Each woman filled out a pre-designed questionnaire beforehand. Thyroid stimulating hormone (TSH), free triiodothyonine (fT3) and free thyroxine (fT4) and thyroperoxidase antibodies (TPOAb) levels determined by the immunochemiluminescent method in the Republican Specialized Scientific and Practical Medical Center of Endocrinology of the Ministry of Health of the Republic of Uzbekistan.

Predictive efficacy (AUC classifier) was determined with the use of standard formula: AUC = (Se + Sp)/2; where Se (sensitivity) and Sp (specificity).

Ethical review. The study was approved by the Republican Specialized Scientific and Practical Center of Endocrinology of the Ministry of Health of the Republic of Uzbekistan (protocol number 6/5, May 19, 2020) with written informed consent obtained from each participant. Each patient received detailed information about the study and gave written informed consent to participate.

To determine the most diagnostically significant risk factors, was carried out an integral assessment of the risk factors of thyrotoxicosis using the method of normalizing intensive indicators of E.N. Shigan, based on the Bayesian probabilistic method.

Statistical analysis of the obtained data: statistical processing of the results carried out using the computer program Microsoft Excel using the methods of variation statistics and using Student’s t-test. Differences between groups were considered statistically significant at P < 0.05.

Results

In accordance with the objectives, on the complex and comprehensive prospective basis and retrospective study of patients with GD, were determined prognostic factors for the outcome of the disease and evaluated their role in the thyrotoxicosis recurrence development.

Data analysis showed that the risk range for the thyrotoxicosis recurrence development is in the range of 58.36–270.26.

This range accepted as 100 %. After dividing the scale into three equal intervals and named intervals as following: weak — 58.36–128.99 — f avorable forecast, risk values within 30%; moderate — 128.99–199.63 — required careful monitoring, risk values within 30–59 %; high — 199.63–270,26 — unfavorable prognosis, the probability of thyrotoxicosis relapse developing from 60% to 100%.

Subsequently, taking into account the data of the prognostic table by the value of the relative risk (ОР — RR) (Table 1), we determined the ranking position of each factor and calculated its etiological fraction (EF).

An analysis of the data found that the most significant risk factors for the thyrotoxicosis recurrence development with a high relative risk and etiological fraction were (almost complete conditionality) age over 30 years (RR = 7.59; EF = 86.82 %), thyroid volume ≥ 30 cm3 (RR = 6.84; EF = 85.38 %), treatment duration ≥ 2 years (RR = 6.37; EF = 84.30 %), patient compliance (RR = 6.19; EF = 83.84 %), multiplicity of RIT (RR = 5.74; EF = 82.58 %) and dose of RIT 300 MBq (RR = 5.41; EF = 81.52 %).

In the very high disease conditionality category entered: disease debut ≥ 2 years (RR = 4.68; EF = 78.63 %) and TSH level < 0.17 mIU/l (RR = 3.31; EF = 69.79 %).

The average high gradation of the thyrotoxicosis recurrence development conditionality was: fТ3 level > 5.8 pmol/l (RR = 2.96; EF = 66.22 %), fТ4 level > 23 pmol/lL (RR = 2.73; EF = 63.37 %), TPO level ≥ 12 IU/ml (RR = 2.44; EF = 59.02 %) and GD heredity (RR = 2.38; EF = 57.98 %).

The average degree gradation of the thyrotoxicosis recurrence development conditionality was: stress (RR = 1.98; EF = 49.49 %), childbirth ≥ 5 (RR = 1.75; EF = 42.86 %) and endocrine ophthalmopathy (RR = 1.54; EF = 35.06 %).

By multifactorial analysis we assessed the prognostic probability of each factor in the thyrotoxicosis recurrence development.

In order to evaluate the quality of a prognostic model of the thyrotoxicosis recurrence we calculated all risk factors parameters of the AUC (Table 2).

Moreover, the aggregate prognostic value of risk factors is defined as “good” (AUC — 0.89).

Then we evaluated the diagnostic efficacy of each factor. As a result of the analysis, it is established that the age 30 years (AUC — 0.88), thyroid volume ≥ 30 cm3 (AUC — 0.86), treatment duration ≥ 2 years (AUC — 0.86), patient compliance (AUC — 0.85), RIT multiplicity (AUC — 0.85) and RIT dose (AUC — 0.82) have excellent prognostic power. The “good” prognostic significance category includes such factors as: disease debut ≥ 2 years (AUC — 0.76), TSH level < 0.17 mIU/l (AUC — 0.79), fT3 level > 5.8 pmol/l (AUC — 0.74), fT4 level > 23 pmol/l (AUC — 0.73), TPO Ab level (AUC — 0.71), GD heredity (AUC — 0.72) and stress (AUC is 0.70).

Discussion

Publications aimed at highlighting the reduction of thyrotoxicosis recurrence developmen, as well as the personalization of the approach when prescribing the therapeutic activities of radioactive iodine, are few in number.

There are various approaches to the radionuclide treatment of GD, in particular the use of the dosimetric planning of RIT method, or the use of fixed dose of I131. Liu M. et al. showed that within a year after RIT with the usage of dosimetric planning method, as a result of which the calculated activities ranged from 370 to 555 MBq, 49.7 % of patients achieved euthyroidism, 38.3 % — hypothyroidism, and in 12.0 % developed thyrotoxicosis recurrence. During the analyzing the causes of RIT inefficiency, the only criterion was the level of 2-hour absorption of thyroid gland radioactive iodine was more than 58.5 % [11].

K. Manohar et al. showed that within a year after RIT, 16.6 % of patients developed thyrotoxicosis recurrence. The applied activities of I131 ranged from 259 to 370 MBq. Multiple regression analyses showed that there was no statistically significant relationship between the results of RIT and gender, age, thyroid hormone levels, thyroid volume, and administered therapeutic activity of radioactive iodine. The only criterion for the in-efficiency of RIT in this study was the index of radiopharmaceutical capture during scintigraphy of the thyroid gland with 99mTc-Pertechnetate. So, in patients with radiopharmaceutical absorption at the 20 minute of the study more than 17.75%, the risk of development of thyrotoxicosis recurrence was 3 times higher (OR 3.14; p = 0.014) [7]. A high level of thyroid uptake can reflect on the rapid turnover of iodide in thyrocytes, which reduces the time spent in them by therapeutic I131, which in turn leads to treatment failure.

Conclusions

Thus, were determined the most statistically significant factors of development of thyrotoxicosis recurrence in women with GD received RIT. Among the factors associated with the development of thyrotoxicosis recurrence, the most prognostically significant were age over 30 years, thyroid volume ≥ 30 cm3, treatment duration ≥ 2 years, patient compliance, RIT multiplicity, a dose of RIT, and also the disease debut ≥ 2 years, TSH level < 0.17 mIU/l, fT3 > 5.8 pmol/l, fT4 > 23 pmol/l and GD heredity.

Conflict of interest. The authors declare that there are no conflicts of interest and financial interest regarding the publication of this paper.

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