Effect of Selenium on Thyroid Disorders: Scientometric Analysis.

Background
Association of Selenium (Se) deficiency, an essential trace element, has been found with human diseases. Identifying literature trends on the effects of Se on the thyroid may guide in planning future studies.


Methods
A literature search was conducted using the Web of Science database to identify studies on Se and the thyroid published over the 20 years duration (1995-Dec 2014). Scientometric indices were used to draw field maps. The scientific processes, structure, evidence history, and international collaborations were included in the map. The most influential authors, journals, institutions, and countries were also examined.


Results
Our search identified 184 research and review papers. The number of scientific studies on Se and the thyroid has been irregular, but interest in this topic has increased in recent years. The highest number of studies was published in 2014 (16 papers) and overall growth factor of publication was 3.78. Overall, 744 authors from 282 institutions in 43 countries published in this field. The author J. Kohrle (828 citations, 14 publications), and German scientists (1272 citations, 30 publications) were most influential.


Conclusion
This study reveals the interrelationships between different publications on the effects of Se on the thyroid. Leading scientific issues and their extent of impact were successfully determined by examining citations. The results of systematic citations and mapping fields can be used to assist in policy and management contexts.


Introduction
Selenium (Se) is a rare mineral that is essential to the human body. Selenium deficiency has been found to predispose for and lead to numerous diseases, such as cancer, impaired immune function, neurodegenerative age-related disorders, and thyroid hormone axis disturbances. The human thyroid gland has a very high Se content per mass unit, like other endocrine organs and the brain (1)(2)(3)(4). Selenium affects both benign and malignant thyroid diseases. In Hashimoto's thyroiditis, Tcell associated thyroid destruction (TH1-induced) results in hypothyroidism. In Graves' disease, hyperstimulation of the thyroid by autoantibodies (TH2-induced) results in hyperthyroidism. An adequate nutritional supply of Se, iodine, and iron are needed to maintain a healthy thyroid dur-ing childhood, adolescence, adulthood, and old age (5). Humans obtain Se from their diet as selenomethionine (SeMet), selenocysteine, and sulfur amino acid analogs, found in vegetables and animal products. Animal meats and seafood are particularly rich in Se. Populations in numerous areas of the world are susceptible to Se and iron insufficiencies because of low soil content of these minerals, resulted from erosion and glacial washout. An inadequate intake of dietary Se, defined as 3-22 microgram per day (μg/day), is associated with serious endemic diseases, including myxedematous cretinism, osteoarthropathy, and cardiomyopathy. However, the onset of these diseases requires the presence of additional factors, other than Se deficiency, including a diet rich in goitrogenic foods, bacterial or viral infection, and fungal pollutants found in wheat (2). Excess reactive oxygen species and hydrogen peroxide are produced by thyroid follicles during biosynthesis of thyroid hormones. Selenoproteins, including glutathione peroxidase (GPx) and thioredoxin reductase, play a role in protecting the thyroid gland with cellular antioxidative defense systems and redox control. In cases of severe Se deficiency, the lack of GPx activity may contribute to oxidative damage of thyroid cells and result in thyroid damage and fibrosis. Myxedematous cretinism was associated with serious and constant selenium deficiency which leads to impaired thyroid hormone biosynthesis and intensifies follicle destruction and replacement with fibrotic tissue (1). The identification of selenocysteine-containing proteins has discovered the relationships between Se and iodine and the hormone network. Several selenoproteins help protect thyrocytes from hydrogen peroxide produced during thyroid hormone biosynthesis (3). Selenium is important for maintaining thyroid homeostasis and may impact on the natural history of thyroid diseases, including autoimmune thyroiditis (AIT) (2). In fact, current clinical trials demonstrated that selenium treatment was effective against serum concentrations of antithyroid peroxidase in patients with Hashimoto's thyroiditis (6). A number of other trials with dietary supplements included subjects with a variety of pathologies have been per-formed. These demonstrated the positive effects of increasing Se dietary intake. In addition, a current prospective, controlled, blinded study showed promising results of Se-dependent treatments on postpartum thyroiditis and hypothyroidism, a common and serious complication in pregnancy associated with autoimmune thyroid disease (AITD). Epidemiological analyses have shown that a large fraction of goiters are preventable by improving Se intake in endemic areas, provided that an adequate iodine supply is established before Se intervention. Furthermore, Se supplementation was recently shown to be effective in treating two forms of AITD (7). Selenium supplementation seems promising for improving GPx and other selenoprotein activity in many thyroid disorders. The usefulness of Se therapies largely requires the bioavailability of compounds used. Therefore, SeMet may be useful for more long-term Se therapies because of its excellent bioavailability and low toxicity (8). Several different thyroid disorders related to Se deficiency have been evaluated and effects of dietary supplements of Se have been examined (9)(10)(11)(12), but a comprehensive study on scientometric analysis in this field is needed to identify factors that affect outcomes in this field of research, Se treatment advances, and emerging trends. Scientometric analyses can identify gaps in all research fields, allowing us to better understand what types of studies are needed. Careful science policy planning can help eliminate these gaps by focusing studies on specific questions. Furthermore, knowing the trends of scientific study in a specific area and determining the status of current research allows future research studies to be better planned. To the best of our knowledge, few scientometric studies on Se and the thyroid have been reported. Here, we performed such an analysis to better understand what studies on Se and thyroid disorders are needed.

Methods
Scientific publications on Se and the thyroid were searched in the ISI-Web of Science Core Collec-tion. The literature search was restricted to two major indices, the Social Science Citation Index and the Science Citation Index (SCI) Expanded. The search was performed using free keyword searches in the title to retrieve the entire body of literature on thyroid disorders (e.g., thyroiditis, hyperthyroidism, hypothyroidism), and all forms of the Se element (e.g., selenoprotein, selenium, and Se). Keywords were searched only on title of publications in order to ensure that the maximum relationships were remained in between the literature and our research topic. Publications within the past 20 years (1995 Dec 2014) were examined. Both original research and review papers were included in our analyses. Identified scientific publications on the effects of Se on thyroid disorders were analyzed using various different scientometric indices. These included the most active authors and institutions (highest number of publications) and the most influential authors, journals, institutions, and countries (highest number of citations). Publishing and citation trends in different years were examined and the product growth factor was calculated. Trend of science production, clustering of scientific topics and structures, and international collaborations were examined. The analytical and visualization software packages used, included Histcite, Citespace, Vosviewer, and Pajek. The Journal Citation Reports (JCR) database, an ISI information database (Thomson Reuters, New York, NY), was used to obtain the impact factors of journals with the highest number of identified studies and citations.

Total number of published Items
Our results showed that a limited number of papers have been published on Se and the thyroid. Overall, 184 papers met our search criteria and were included in analyses. The number of scientific publications in this area was irregular. A reduction in the number of papers occurred particularly in the late 1990s, but the number of publications has been trending upwards since 2007 ( Fig. 1). The highest number of papers was produced in 2014 (16 papers), and, in sum, the products growth factor was 3.78%. There was a sudden increase in scientific publication in this area in 2006.

Total number of citations
Overall, 184 papers relevant to Se and the thyroid were cited 3815 times that were available in the ISI Web of Science database. Overall, 2975 of the 3815 total citations were self-citations. Whereby, the number of papers cited these publications were 2129 articles. The average number of citations per item was 20.73 and the total H-index was 36. These findings are based on the citations identified from all publications available in the Web of Science database, also known as the Total of Global Citation Score (TGCS) index. However, when only citations identified from the 184 papers to themselves be used, the index is referred to as the total of the local citation score (TLCS) index. The number of citations obtained from the TLCS index was 838. The high TLCS index of a paper reveals its importance in its specialized subject. The highest number of citations obtained with the TGCS (410 citations) and TLCS (97 citations) indices was for papers published in 1996 and in 1995 and 2003, respectively (Fig. 2). The historiography chart of scientific publications in this area (based on the first 100 papers identified using the TGCS) is shown in Fig. 3. Four articles with more than 100 citations are "Selenium, the thyroid, and the endocrine system", "Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations", "The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health" and "Targeted Disruption of the Type 1 Selenodeiodinase gene (Dio1) Results in Marked Changes in Thyroid Hormone Economy in Mice".

Distribution of publications by country and language
The publications identified on Se and the thyroid describe outcomes of studies performed in 43 countries around the world, including Germany (30 papers), the United States (27 papers), England (18 papers), and Poland (12 papers). The highest producers were defined as countries with more than 10 papers, which also included Greece, Italy, and China (11 papers each). The top 3 most influential countries, based on the number of citations identified in the TGCS index, were Germany (1272 citations), the United States (596 citations), and Belgium (401 cita-tions). The vast majority of publications were written in English (180 of 184 papers).

The top journals, institutions, and authors
Totally, 102 journals published scientific articles on how Se affects thyroid disorders during the defined study time period. The most productive (>5 papers) journals included Biological Trace Element Research (23 papers), the European Journal of Endocrinology (7 papers), the Journal of Clinical Endocrinology and Metabolism (7 papers), the Journal of Trace Elements in Medicine and Biology (6 papers), and Thyroid (6 papers). Also, Table 1 summarizes the most influential journals based on the TGCS and TLCS indices.  Table 2 lists the most influential institutes, based on the TLCS and TGCS indices, using the "selenium impact on thyroid disorders" search term. Overall, 744 authors collaborated to produce publications on the effect of Se on thyroid disease. The 10 most influential authors, based on TLCS and TGCS indices listed in Table 3.

Subject trends
The distribution of subject trends was determined based on the ISI-Web of Science "cooccurring subject category indicator" and "page rank." Inter-subject relationships are visually displayed in Fig. 4. Papers on the topic of interest were classified into 50 different ISI-Web of Science subject classes ( Table 4). The highest number of papers were found in endocrinology and metabolism (83 papers), biochemistry and molecular biology (45 papers), and nutrition and dietetics (18 papers). In addition to the subject classification of published papers, analyzing article keywords and subject clustering is shown in Figs. 5 and 6. Subject analysis revealed that 41 scientific subjects had strong citation bursts.

International scientific collaboration
The scientific manuscripts included in this study were the result of international collaborations among 43 countries (Fig. 7). Analyses revealed that scientists and physicians in the following countries had the greatest number of collaborations: England, Germany, France, and the United States.  (14). A scientometric analysis was published on endocrine and diabetes research in SAARC (South Asian Association for Regional Cooperation) Countries which identified trends of related research activity and more influential countries, journals as well as authors in mentioned field (15 Publications were most often categorized into the following subjects: "Endocrinology and Metabolism," "Biochemistry and Molecular Biology," and "Nutrition and Dietetics." Categorization mapping (Fig. 4), showed new aspects of how these subjects were interrelated during the publication years examined. Well-designed studies in special conditions such as necessity of selenium in autoimmuine thyroid disease for instance in pregnant women are needed. These studies may shed light on further research in this field but in special conditions (17)(18)(19).
Using wider databases will formulate valid outcomes (20). Our study was limited since analyses only examined publications indexed in the ISI Web of Science database. The study also had much strength, including the long study period and its thorough investigation of the impact of publications, countries, organizations, and inter-national relationships. Additionally, the inclusion of systematic citation analyses and mapping fields make our findings particularly significant.

Conclusion
This study reveals new aspects of intersubject relationships present in the literature. Leading scientific issues on the effect of Se on thyroid disorders were determined by examining impact extent and study citation sets of published studies. More specifically, the publication impact, organization impact, systematic citation search outcomes, mapping fields, and indicator construction were examined to better understand what policies and management decisions were launched. Our results indicate the need for similar studies to be performed within the next five years to continue our understanding of scientific publication trends in this field.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.