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International Journal of Endocrinology
OpuriHOAbHi AOCAigweHHq
/Original Researches/
UDC 616.441-008.61 DOI: https://doi.Org/10.22141/2224-0721.16.6.2020.215390
Ubaydullaeva N.B. G, Allayarova G.I. C, Almuradov F.F. E> 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
Prognostic significance of risk factors for thyrotoxicosis development in radioiodine therapy
For citation: Miznarodnij endokrinobgicnij zurnal. 2020;16(6):502-506. doi: 10.22141/2224-0721.16.6.2020.215390
Abstract. 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 (.fT33) 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.
Keywords: Graves' disease; radioiodine therapy; risk factors
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 hy-pothyroidism [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 ap-
© 2020. The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, CC BY, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.
For correspondence: Ubaydullaeva N.B., MD, PhD, Senior Researcher, Republic Specialized Scientific and Practice Medical Center of Endocrinology, Mirzo Ulugbek st., 56, Tashkent, 100125, Republic of Uzbekistan; e-mail: redact@i.ua
Full list of author information is available at the end of the article.
OpurrnoAbHi AOCAigweHHfl /Original Researches/
plied 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 radio-iodine 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 thyro-peroxidase 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.
Table 1. The distribution of risk factors by degree of significance for the thyrotoxicosis recurrence development and the degree of condition of the disease in women, depending on the relative risk, etiological fraction and the corresponding risk factors
Risk factors RR EF, % Rank Conditionality degree RR EF, %
Age over 30 7.59 86.82 1 Almost complete 5.0 81-100
Thyroid volume > 30 cm3 6.84 85.38 2
Duration of treatment > 2 years 6.37 84.30 3
Patient Compliance 6.19 83.84 4
RIT multiplicity (n = 1) 5.74 82.58 5
RIT dose 300 MBq 5.41 81.52 6
Disease debut > 2 years 4.68 78.63 7 Very high 3.2 67-80
TSH < 0.17 mlU/l 3.31 69.79 8
fT3 > 5.8 pmol/l 2.96 66.22 9 High 2 51-66
fT4 > 23 pmol/l 2.73 63.37 10
TPO Ab > 12 IU/ml 2.44 59.02 11
GD heredity 2.38 57.98 12
Stress 1.98 49.49 13 Avarage 1.5 33-50
Childbirth > 5 1.75 42.86 14
Endocrine ophthalmopathy 1.54 35.06 15
OpMNHOAbHi AOCAÎA^eHHA /Original Researches/
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 (OP — 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 %).
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: fT3 level > 5.8 pmol/l (RR = 2.96; EF = 66.22 %), fT4 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).
_iEI
Discussion
Publications aimed at highlighting the reduction of thy-rotoxicosis 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.
Table 2. Risk factors associated with the development of recurrent thyrotoxicosis and their prognostic significance
Prognostic factor AUC
Age over 30 0.88
Thyroid volume > 30 cm3 0.86
Duration of treatment > 2 years 0.86
Patient compliance 0.85
RIT multiplicity (n = 1) 0.85
Dose RIT 300 MBq 0.82
Disease debut > 2 years 0.76
TSH < 0.17 mIU/l 0.79
fT3 > 5.8 pmol/l 0.74
fT4 > 23 pmol/l 0.73
GD heredity 0.72
Stress 0.70
TPO Ab > 12 IU/ml 0.71
Childbirth > 5 0.68
Endocrine ophthalmopathy 0.63
Total indicator 0.89
i El
Орипнальш досл^ження /Original Researches/
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.
References
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Received 21.07.2020 Revised 14.09.2020 Accepted 29.09.2020 ■
Information about authors
Ubaydullaeva N.B., MD, PhD, Senior Researcher, 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; ORCID iD: https://orcid.org/0000-0002-5950-0523
Allayarova G.I., PhD, Senior Researcher, 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; ORCID iD: https://orcid.org/0000-0002-7469-4928
Almuradov F.F., MD, Researcher, 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; ORCID iD: https://orcid.org/0000-0002-8480-1790
Убайдуллаева Н.Б., Аллаярова Г.1., Алмурадов Ф.Ф.
Республканський спе^а^зований науково-практичний медичний центр ендокринологП МОЗ Республки Узбекистан, м. Ташкент, Республка Узбекистан
Прогностичне значення фактор1в ризику розвитку рецидиву тиреотоксикозу
при радюйодотерапп
Резюме. Актуальшсть. Хвороба Грейвса — системне авто-iмунне захворювання, яке розвиваеться внаслщок вироб-лення антитш до рецептора тиреотропного гормона, що клшчно проявляеться дифузними структурними змшами щитоподiбноl залози з розвитком синдрому тиреотоксикозу, а також поеднуеться з екстратирео1дними проявами. Метою до^дження було виявлення факторiв ризику рецидиву хвороби Грейвса в жшок, яш отримували тератю радюак-тивним йодом. Матерiалu та методи. Пд спостереженням перебували 93 жшки репродуктивного вшу, яю отримували радюйодотерапш (РЙТ). Ми проаналiзували результати анкетування, оцшили фактори ризику рецидиву тиреотоксикозу i провели ретроспективний i проспективний аналiз
клшчних показниюв i даних анамнезу. Середнш вгк пащен-пв становив 36,9 ± 7,1 року. Контрольну групу становили 35 здорових жшок вшом 33,5 ± 7,6 року. Рiвнi тиреотропного гормона, вшьного трийодотироншу, вшьного тироксину й антитш до тиреовдно! пероксидази визначали iмунохемiлю-мшесцентним методом. Результати. Щоб оцшити яшсть прогностично'1 моделi рецидиву тиреотоксикозу, ми роз-рахували вш параметри факторiв ризику АиС. Найбшьш значущими факторами ризику розвитку рецидиву тиреотоксикозу тсля РЙТ iз високим вщносним ризиком були вш понад 30 рошв (ВР = 7,59; ЕБ = 8,82 %), обсяг щитоподiбноl залози > 30 см3 (ВР = 6,84; ЕБ = 85,38 %), тривалють лшу-вання > 2 роив (ВР = 6,37; ЕБ = 84,30 %), комплаентшсть
Орипнальш дослiдження /Original Researches/
iEI
пащента (ВР = 6,19; ЕБ = 83,84 %), юльшсть процедур РЙТ (ВР = 5,74; ЕБ = 82,58%) i доза РЙТ 300 МБк (ВР = 5,41; ЕБ = 81,52 %). Висновки. Установлено, що вш понад 30 рошв (АиС — 0,88), обсяг щитоподiбноl залози > 30 см3 (АиС — 0,86), тривалiсть лiкування > 2 роив (АиС — 0,86), комп-
лаентнiсть пацiента (АиС — 0,85), число процедур РЙТ (АиС — 0,85) i доза I131 (АиС — 0,82) мають першорядне значення.
Ключовi слова: хвороба Грейвса; радюйодотерапш; фактори ризику
Убайдуллаева Н.Б., Аллаярова Г.И., Алмурадов Ф.Ф.
Республиканский специализированный научно-практический медицинский центр эндокринологии МЗ Республики Узбекистан, г. Ташкент, Республика Узбекистан
Прогностическое значение факторов риска развития рецидива тиреотоксикоза
при радиойодотерапии
Резюме. 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 экстратиреоидны-ми 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 трийодоти-ронина, свободного тироксина и антител к тиреоидной
пероксидазе определяли иммунохемилюминесцентным методом. Результаты. Чтобы оценить качество прогностической модели рецидива тиреотоксикоза, мы рассчитали все параметры факторов риска АиС. Наиболее значимыми факторами риска развития рецидива тиреотоксикоза после РЙТ с высоким относительным риском были возраст старше 30 лет (ОР = 7,59; ЕБ = 8,82 %), объем щитовидной железы > 30 см3 (ОР = 6,84; ЕБ = 85,38 %), продолжительность лечения > 2 лет (ОР = 6,37; ЕБ = 84,30 %), комп-лайентность пациента (ОР = 6,19; ЕБ = 83,84 %), количество процедур РЙТ (ОР = 5,74; ЕБ = 82,58 %) и доза РЙТ 300 МБк (ОР = 5,41; ЕБ = 81,52 %). Выводы. Установлено, что возраст старше 30 лет (АиС — 0,88), объем щитовидной железы > 30 см3 (АиС — 0,86), продолжительность лечения > 2 лет (АиС — 0,86), комплайентность пациента (АиС — 0,85), число процедур РЙТ (АиС — 0,85) и доза I131 (АиС — 0,82) имеют первостепенное значение. Ключевые слова: болезнь Грейвса; радиойодотерапия; факторы риска
