L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 RESEARCH Register-based information on thyroid diseases in Europe: lessons and results from the EUthyroid collaboration Line Tang Møllehave 1, Marie Holm Eliasen1, Ieva Strēle2, Allan Linneberg1,3, Rodrigo Moreno-Reyes4,5, Ludmila B Ivanova6, Zvonko Kusić7,8, Iris Erlund9, Till Ittermann 10, Endre V Nagy11, Ingibjorg Gunnarsdottir12,13, Jonathan Eli Arbelle14,15, Aaron Milton Troen16, Valdis Pīrāgs17, Lisbeth Dahl18, Alicja Hubalewska-Dydejczyk19, Malgorzata Trofimiuk-Müldner19, João Jacome de Castro20, Mafalda Marcelino20, Simona Gaberšček21,22, Katja Zaltel21,22, Manuel Puig-Domingo23,24, Lluis Vila25, Sofia Manousou26,27, Helena Filipsson Nyström28,29,30, Michael Bruce Zimmermann31, Karen R Mullan32, Jayne Valerie Woodside33, Henry Völzke10 and Betina Heinsbæk Thuesen1 1 Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark 2 The Institute of Occupational Safety and Environmental Health, Riga Stradiņš University, Riga, Latvia 3 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 4 Nuclear Medicine Department, Erasme Hospital, Brussels, Belgium 5 Université Libre de Bruxelles, Bruxelles, Belgium 6 Faculty of Medicine, Sofia University St. Kl. Ohridski, Sofia, Bulgaria 7 Croatian Academy of Sciences and Arts, Zagreb, Croatia 8 School of Medicine, Zagreb, Croatia 9 Department of Government Services, Finnish Institute for Health and Welfare, Helsinki, Finland 10 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany 11 Division of Endocrinology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary 12 Faculty of Food Science and Nutrition, University of Iceland, Reykjavik, Iceland 13 Department of Clinical Nutrition, Landspitali-National University Hospital, Reykjavik, Iceland 14 Division of Medicine, Maccabi Healthcare Services, Tel Aviv, Israel 15 Goldman School of Medicine, Ben Gurion University of the Negev, Beer Sheva, Israel 16 The Institute of Biochemistry Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel 17 Internal Medicine, University of Latvia, Riga, Latvia 18 Seafood, Nutrition and Environmental State, Institute of Marine Research (IMR), Bergen, Norway 19 Chair and Department of Endocrinology, Jagiellonian University, Medical College, Cracow, Poland 20 Endocrine Department, Armed Forces Hospital, Lisbon, Portugal 21 Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia 22 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 23 Department of Endocrinology and Nutrition, Germans Trias Research Institute and Hospital, Badalona, Spain 24 Universitat Autònoma de Barcelona, Barcelona, Spain 25 Endocrinology and Nutrition Service, Hospital Moisés Broggi, Sant Juan Despi, Barcelona, Spain 26 Sahlgrenska Academy, Institute of Medicine, Gothenburg, Sweden 27 Frölunda Specialist Hospital, Västra Frölunda, Sweden 28 Department of Endocrinology, Specialist Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden 29 Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 30 Wallenberg Centre of Molecular and Translational Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden 31 Health Sciences and Technology, ETH Zurich, Zurich, Switzerland 32 Regional Centre for Endocrinology and Diabetes, Belfast Health and Social Care Trust, Belfast, UK 33 Centre for Public Health, Queen’s University Belfast, Belfast, UK Correspondence should be addressed to L T Møllehave: line.tang.moellehave@regionh.dk Abstract Objective: Registers of diagnoses and treatments exist in different forms in the European Key Words countries and are potential sources to answer important research questions. Prevalence ff Europe and incidence of thyroid diseases are highly dependent on iodine intake and, thus, ff registries iodine deficiency disease prevention programs. We aimed to collect European register ff iodine ff thyroid diseases https://ec.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-21-0525 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. Design: Register-based cross-sectional study. Methods: National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates Results: Register data on ≥1 thyroid diagnoses or treatments were available from were calculated. 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. Conclusions: The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes Endocrine Connections across Europe. (2022) 11, e210525 Introduction Register-based data on treatments and diagnoses of Iodine intake in a population is a main factor behind thyroid disease can be used as proxies for thyroid disease thyroid disease epidemiology. Iodine deficiency is frequency in a population. This has, for example, been associated with adverse outcomes ranging from severe successfully utilized in Denmark (1). In many European mental retardation and stunting to goiter/thyroid countries, treatments for thyroid disease and/or nodules and hyperthyroidism (8). However, the window diagnoses of thyroid disorders are documented in of adequate iodine intake is narrow, hence, iodine excess nationwide or regional registers. This encompasses may increase the risk of hypothyroidism and autoimmune registers of diseases, medications and other treatments, thyroid disorders in a population (9). hospital admissions, and ambulatory care, as well as Most regions of Europe will be iodine deficient without registries related to health insurance. Ideally, for use programs to prevent iodine deficiency disorders (IDD). in research projects, a register should cover the entire However, the implementation and type of IDD prevention country/region or a large, well-defined sub-population programs depend on stakeholder barriers, political whereby it is representative, and the data should be of prioritization (10), and cultural differences. The IDD acceptable validity (2). prevention programs range from general recommendations European registers have previously been collated for for intake of iodine-rich foods, over recommendations research projects in, for example, melanoma (3), asthma for iodine supplementation especially for pregnant and (4), and cerebral palsy (5) and several initiatives to promote lactating women, to voluntary or mandatory iodine and improve the collaboration and utilization of registers fortification (IF), most commonly addition of iodine to in Europe are established (6, 7). However, the availability table salt and salt in bread (11). An overview of IF programs and applicability of register data for assessment of thyroid and iodine intake across 23 European countries/regions outcomes from the European countries have not yet been are presented in Table 1. The optimal level of iodine intake examined. After a thorough assessment of the quality and and the most effective IDD prevention program remains to comparability of data across countries, European registers be established. can potentially represent valuable and efficient data In many countries, the assessment of median urinary sources for evaluating differences in thyroid outcomes iodine concentration in representative population across the countries/regions. samples is used to classify the iodine status and to steer IDD https://ec.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-21-0525 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 Table 1 IDD prevention and iodine intake in the European countries. Iodine fortification strategy Iodine intake, Median UIC, μg/L Country Country code (13, 14, 15, 16, 17, 18) (population, year) (18, 19, 20, 21, 22, 23) Belgium BE Voluntary fortification of salt, 10–15 ppm since 2009 Insufficient, 80 (SAC, 1998) Adequate, 113 (SAC, 2010–2011) Bulgaria BG Mandatory fortification of salt, 28–55 ppm since Adequate, 111 (SAC, 1996) 1994/1996 Adequate, 182 (SAC, 2008) Adequate, 176 (SAC, 2012) Croatia HR Mandatory fortification of salt, 19 ppm since 2011 Adequate, 140 (SAC, 2002) Adequate, 248 (SAC, 2009) Czech Republic CZ Voluntary fortification of salt, 27 ppm since 2016 Adequate, 119 (SAC, 2000) Adequate 163 (SAC, 2010) Denmark DK Mandatory fortification of salt, 13 ppm since 2000 Insufficient, 61 (A, 1997–1998) Adequate, 101 (A, 2004–2005) Adequate, 145 (SAC, 2015) Finland FI Voluntary fortification of salt, 25 ppm since Adequate, 164 (A, 1997) approx. 1946 Insufficient, 83 (A, 2013) Germany DE Voluntary fortification of salt, 20 ppm since 1993 Adequate, 148 (SAC, 1999) Adequate, 122 (SAC, 2003–2006) Insufficient, 89 (SAC+A, 2014–2017) United Kingdom UK Northern Ireland None Adequate, 111 (SAC, 2014–2015) Scotland None N/A Greece GR Voluntary fortification of salt, 30 ppm since 1987 Adequate, 202 (2001) Adequate, 132 (A, 2017–2018) Hungary HU Mandatory fortification of salt, 19 ppm since 2013 Insufficient, 80 (SAC, 1994–1997) Adequate, 228 (SAC, 2005) Iceland IS None Adequate, 150 (A, 1998) Adequate, 200 (A, 2007–2008) Ireland IE None Insufficient, 82 (A, 1999) Adequate, 111 (SAC, 2014–2015) Israel IL None Insufficient, 83 (SAC, 2016) Latvia LV Voluntary fortification of salt, 20–50 (40–100) ppm Insufficient, 59 (SAC, 2000) since 2005 Adequate, 110 (SAC, 2010–2011) North Macedonia MK Mandatory fortification of salt, 25 ppm since 1999 Adequate, 241 (2007) Adequate, 216 (2016) Norway NO Voluntary fortification of salt, 5 ppm since 1938 Adequate, 104 (1999–2001) Insufficient, 75 (A, 2017–2018) Poland PL Mandatory fortification of salt, 23 ppm since 1997 Insufficient, 84 (SAC, 1999) Adequate, 112 (SAC, 2009–2011) Adequate, 120 (SAC, 2017) Portugal PT None Adequate, 106 (SAC, 2010) Slovenia SI Mandatory fortification of salt, 19 ppm since 1999 Adequate, 140 (A, 2003–2005) Spain ES Voluntary fortification of salt, 60 ppm since 1983 Adequate, 109 (SAC, 1995, 2000–2002) Adequate, 117 (2009–2010) Adequate, 173 (SAC, 2011–2012) Sweden SE Voluntary fortification of salt, 10 ppm since 1936, Adequate, 125 (SAC, 2006–2007) 50 ppm since 1966 Switzerland CH Voluntary fortification of salt, 25 ppm since 2014 Adequate, 115 (SAC, 1999) Adequate, 120 (2009) Adequate, 137 (SAC, 2015) A, adults; N/A, not available; SAC, school-aged children; UIC, urinary iodine concentration. prevention programs. While this approach is relatively programs ensuring sufficient iodine intake are robustly simple, it is not sufficient to evaluate the aim of such associated with a low burden of thyroid-related diseases prevention programs, which is to reduce the prevalence in populations. and incidence of thyroid diseases and related treatments The EUthyroid project was an ambitious collaborative and to save expenditures in healthcare systems (12). project with participation and representatives from most This can potentially be achieved by analyses of register EU countries funded by the European Union’s Horizon data. We hypothesized that efficient IDD prevention 2020 research and innovation program under grant https://ec.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-21-0525 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 agreement no. 634453. The overall aim of the EUthyroid intervals) were derived from Eurostat (http://ec.europa. project was to ‘evaluate iodine deficiency prevention and eu/eurostat) or provided from the national EUthyroid monitoring programs in European countries, to initiate representatives for regional or sub-national populations. capacity building for harmonized European ID prevention Ethical and/or data handling approvals were obtained and monitoring programs’. in each country according to national regulations to In this paper, we report lessons and results from work obtain aggregated register data. Only aggregated data package 1 of the EUthyroid project. Firstly, we evaluate the were collected and, thus, no patient-level data (personal availability, applicability, and comparability of the register data) were handled thereby protecting the privacy of the data on thyroid outcomes in the European countries, individuals. and second, we report country-specific rates of thyroid outcomes and seek to identify patterns in the relationship with iodine supply across Europe. Critical assessment and selection of data and variables The national representatives were also requested to provide a description of the data sources and health care Materials and methods organization factors relevant to assess the completeness Register data and validity of the data provided. The applicability of the provided data from each Representatives from each country participating in the country was critically assessed. For inclusion in the EUthyroid project were requested to deliver national database and calculation of raw rates the provided data had register data on diagnoses, medical treatments, and to fulfill the criteria for the requested data. For comparison procedures for thyroid disorders. All data were requested between countries and calculation of standardized rates, for the calendar years 2011–2014 and stratified by sex and the data and variables had to be stratified by sex and age, age in 5-year intervals. If this was not available, we allowed collected from comparable data sources, and registered for the available data that best approximated these criteria, by comparable methods. The critical assessment was for example, data from 2015, data from a well-defined conducted by the senior author, BHT. sub-population, or data in 10-year age intervals. Specific diagnoses and treatments requested were: Diagnoses: Annual number of persons diagnosed with Iodine intake thyroid cancer (ICD-10: C73), congenital iodine- Populations’ iodine intakes were derived from published deficiency syndrome (ICD-10: E00), iodine-deficiency- reports of urinary iodine concentrations in school-aged related thyroid disorders and allied conditions children or adults and summarized in Table 1. Iodine intake (ICD-10: E01), subclinical iodine-deficiency (ICD- was classified as insufficient, adequate, or excess according 10: E02), other hypothyroidism (ICD-10: E03), to current WHO epidemiological recommendations (24). other nontoxic goiter (ICD-10: E04), thyrotoxicosis/ Early and recent iodine intake were classified as iodine hyperthyroidism (ICD-10: E05), thyroiditis (ICD-10: intake approximately 15–20 years before and after 2001, E06), other thyroid disorders (ICD-10: E07), and one respectively. or more thyroid related diagnoses (ICD-10: E00-E07). Treatments: Annual number of persons with at least one dispensed dose and total number of defined daily Statistical methods doses of antithyroid medication and thyroid hormone Rates of medications were calculated as 1-year period therapy. Annual number of persons with at least one prevalence per 10,000 persons. Rates of diagnoses were procedure and the total number procedures for all calculated per year per 10,000 persons. Raw rates were thyroid surgeries, thyroid surgeries with benign calculated with the treatments and diagnoses as the indication, all radioiodine treatments, radioiodine numerator and the demographic data of the population treatments with benign indication, and fine needle as the denominator in the provided sex and/or age strata biopsies. where possible. The demographic data of the total populations (total Standardized rates were calculated to remove the effect number of individuals and stratified by sex and 5-year age of the differences in sex and age distributions between https://ec.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-21-0525 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 the European countries. This was done by calculating the unsuitable to be included in the database. See an overview proportion of each sex and age-specific strata in the total of data and assessments in the Supplementary Tables 1 and European Standard Population (25) and multiplying this 2 (see section on supplementary materials given at the end by the raw rate in the corresponding strata for each country of this article). Raw rates for data included in the database before summarizing the overall standardized rate in each are presented in the Supplementary Tables 3, 4, and 5. country. When data were provided for more than one The outcome variables were grouped into six calendar year, the rates were calculated as the average of the categories: thyroid medication, thyroid surgery, calendar years available. radioiodine treatment, fine needle biopsies, diagnoses Comparisons between countries were done using of thyroid diseases, and diagnoses of incident thyroid standardized rates. No formal statistical tests were applied cancer. Sex- and age-stratified data from all categories were in the comparison of rates between countries. available from four countries, whereas data from only one outcome variable were available from four countries. The critical assessment of the data included in the database Results found that data on the use of thyroid medication, number of thyroid surgeries, and incidence of thyroid cancer were Data availability and data assessment of acceptable quality and thus appropriate for calculation Table 2 provides an overview of the data sources and of standardized rates and comparison between countries. Fig. 1 provides an overview of the flow of the data In contrast, data on diagnoses of thyroid diseases acquisition, critical assessments, and calculations. except for thyroid cancer were not considered suitable Register data for at least one thyroid outcome was for comparisons across countries. In some countries, available and provided from 22 out of 23 participating registrations included patients treated in primary care countries/regions. However, the critical assessment whereas only patients attending hospitals were included concluded that data from three countries were considered in other countries, and it was not possible to distinguish Table 2 Data requested and provided with stratification level and area. Thyroid Thyroid Fine needle Diagnoses of Diagnoses of Country Country code medication surgery Radio-iodine biopsies thyroid disease thyroid cancer Belgium BE Sex/age Sex/age Sex/age Sex/age N/A Sex/age Bulgaria BG Sex Sex Total Sex Sex Sex/age Croatia HR N/A N/A N/A N/A N/A Sex Czech Republic CZ Sex/age Sex/age Sex/age Sex/age Sex/age Sex Denmark DK Sex/age Sex/age Sex/age Sex/age Sex/age Sex/age Finland FI Sex/age Sex/age Sex/age Sex/age Sex/age Sex/age Germany DE Sex/agea N/A N/A N/A Sex/agea N/A United Kingdom UK Northern Ireland N/A N/A N/A N/A N/A Sex/age Scotland N/A N/A N/A N/A N/A Sex/age Greece GR Totala N/A Totala N/A Totala Totala Hungary HU Sex/age Sex/age Sex/age N/A Age Age Iceland IS Sex N/A N/A N/A N/A Sex Ireland IE N/A N/A N/A N/A N/A Sex/age Israel IL Sex/age N/A N/A N/A Sex/age Sex/age Latvia LV Sex/age Sex/age Sex/age Sex/age Sex/age Sex/age North Macedonia MK Totala N/A N/A N/A N/A N/A Norway NO Sex/age Sex/age N/A N/A Sex/age Sex/age Poland PL Totala Total N/A N/A Total Sex/age Portugal PT Totala Sex/age Sex/agea N/A Sex/age Sex/Age Slovenia SI Total Sex/age Sex/age Sex/age Sex/age Sex/age Spain ES Sex/age Sex/age Sex/age Sex/age Sex/age Sex/age Sweden SE Sex/age Sex/age Total N/A Sex/age Sex/age Switzerland CH N/A N/A N/A N/A N/A N/A Bold indicates National data; Italics indicate regional data or data from less defined sub-populations. a Data not suitable for inclusion in the database and calculation of raw rates. N/A, not available. https://ec.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-21-0525 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 ICD-10 caused some misclassification. Data on radioiodine and fine-needle biopsies were only available from a few countries and were generally considered unreliable. Thyroid medication Data from nine countries were found to be appropriate for comparison of standardized rates of thyroid medication between countries. Hereby we found that the use of antithyroid medication was lowest for Sweden, Finland, Norway, and Spain (8.6–13.7 users/10,000 persons) and highest for Denmark, Latvia, and Hungary (34.8–43.2 users/10,000 persons). Conversely, the use of thyroid hormone therapy was lowest for Latvia, Denmark, and Hungary (192.4–253.1 users/10,000 persons) and highest for the Czech Republic, Belgium, Finland, Sweden, and Norway (424.8–612.8 users/10,000 persons) (Table 3). There was a clear indication of higher use of antithyroid medication relative to thyroid hormone therapy for countries with early iodine insufficiency. However, there was no apparent pattern in the association between recent iodine intake and use of thyroid medications. Thyroid surgeries For thyroid surgeries, data from 10 countries were found to be appropriate for comparison between countries. We found that the standardized rates of thyroid surgeries for benign indications were lowest for the Czech Republic, Slovenia, Norway, Sweden, and Spain (1.4–2.0 Figure 1 patients/10,000 persons), all with early iodine adequacy, Overview of data availability, critical assessments, and calculation of rates. and highest for Belgium, Latvia, and Hungary (4.3–5.1 between incidence and prevalence data. Furthermore, patients/10,000 persons), all with early iodine insufficiency in some countries registration of diagnoses was based on (Table 4). However, no clear pattern was indicated for the ICD-9 system whereas the ICD-10 system was used in thyroid surgeries for all indications or when compared other countries and the conversion of data from ICD-9 to with recent iodine intake. Table 3 Thyroid medication use per 10,000 persons, sex- and age-standardized. Thyroid medication Thyroid hormone Thyroid hormone Country Country code Antithyroid medication, users Antithyroid medication, DDD therapy, users therapy, DDD Belgium BE 19.28 481.46 Czech Republic CZ 26.60 612.83 Denmark DK 43.19 8825 241.76 58,356 Finland FI 9.94 513.95 Hungary HU 34.78 4386 253.09 39,040 Latvia LV 41.51 5372 192.36 30,901 Norway NO 13.12 424.78 Spain ES 13.71 1672 308.24 55,989 Sweden SE 8.59 3235 432.84 91,269 DDD, defined daily dose. https://ec.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-21-0525 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 Table 4 Thyroid surgeries per 10,000 persons, sex- and age-standardized. Thyroid surgery All indications, number All indications, number Benign indications, number Benign indications, number Country Country code of persons of procedures of persons of procedures Belgium BE 5.67 5.05 Czech Republic CZ 5.94 6.11 1.42 1.55 Denmark DK 3.77 4.10 3.37 3.51 Finland FI 4.12 4.38 3.68 3.79 Hungary HU 4.57 5.27 4.29 4.83 Latvia LV 5.20 5.31 4.73 4.76 Norway NO 3.20 3.28 1.99 2.00 Slovenia SI 1.57 1.57 Spain ES 2.77 2.27 Sweden SE 5.35 5.53 2.20 2.22 Thyroid cancer thyroid hormone therapy in countries with early iodine insufficiency. There was no apparent pattern in the Data on standardized rates of thyroid cancer diagnoses association between thyroid cancer and iodine intake. were assessed to be appropriate for comparison between 13 countries/regions. The lowest rates were found in Bulgaria, Northern Ireland, and Scotland (0.4–0.5 patients/10,000 Registers, data availability, and data quality persons) and the highest rates in Denmark, Latvia, and All but one of the 23 participating countries had data on Hungary (0.9–1.4 patients/10,000 persons) (Table 5), with at least one thyroid outcome. However, the data sources, no clear pattern in the association between early or recent the number of variables. and the quality of register data iodine intake and cancer rates. varied widely due to differences in the organization of the healthcare systems, digitization, history/culture, and Discussion political decisions. This is also recognized in previous papers acknowledging the vast potential of the European In this first collation of register data on thyroid outcomes registers but also addressing the challenges (6, 7, 26). from European countries, we found a high degree of Nationwide health registries were established in heterogeneity in the availability and quality of register data the Scandinavian countries, Latvia, Hungary, and in between countries. Data for thyroid medication, thyroid the Region of Catalonia in Spain. In contrast, Croatia, surgery, and thyroid cancer were suitable for comparison Germany, Greece, Great Britain, North Macedonia, and between 9, 10, and 13 countries, respectively. These data Switzerland provided no data from registers fulfilling the indicated higher rates of antithyroid medication and requested criteria. Register data from the Czech Republic, thyroid surgery for benign disease and lower rates of Belgium, and Bulgaria were derived from health insurance companies covering the majority of the population or a Table 5 Incident thyroid cancer per 10,000 persons, sex- and well-defined sub-population. These encompass both public age-standardized. and private health insurance companies. Information on Country Country code Diagnoses of thyroid cancer thyroid cancer was available from most countries. Belgium BE 0.87 For all data sources, the representativity and validity Bulgaria BG 0.40 were assessed. There was little concern regarding the Denmark DK 1.38 representativity in the Nordic registers (27), but some health Finland FI 0.90 Great Britain UK insurance registers may carry a risk of social stratification Northern Ireland 0.46 hampering the representativity. European cancer registries Scotland 0.49 have a long history and the coverage is generally high (6). Hungary HU 0.91 The validity of registers could be compromised by over-, Ireland IE 0.65 Latvia LV 1.12 under-, or misreporting. Thyroid medications require Norway NO 0.73 prescriptions in most European countries and are rarely Slovenia SI 0.72 prescribed in hospitals. This increases the probability of Spain ES 0.89 correct reporting as most registers are based on redeemed Sweden SE 0.62 prescriptions (26). However, for example, in the Latvian https://ec.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-21-0525 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 National Health Service register, only reimbursed previous research both when comparing the Scandinavian prescriptions were registered. Some patients may have countries who have rather similar registers, healthcare private insurance or choose to pay fully out-of-pocket and systems, and health behaviors, but also when including are thus not registered. The validity of thyroid surgeries was data from quite different countries. also assessed to be appropriate for the included countries. Thus, the findings of the highest rates of treatments In cancer registries, the data are generally reliable but most frequently applied for hyperthyroidism and/ comparability is still somewhat influenced by diverse or structural thyroid diseases in countries with early methods between countries (6). In contrast, diagnoses iodine insufficiency and, conversely, the highest rates other than cancer were considered to be unreliable. of treatment for hypothyroidism in countries with early Registration of thyroid diagnoses varies both between iodine adequacy correspond with previous studies within countries and can also vary within countries between countries comparing areas with high and low iodine intake health care providers and specialists; for example, the rates (37, 38, 39) and over time when iodine adequacy was of congenital iodine-deficiency syndrome were far higher achieved after introduction of IDD prevention programs in some countries than what national experts regard as (40, 41, 42, 43). However, it is a limitation that the specific plausible. Validation studies are rarely available for any of indication for treatment is not known. the registers (26). We also found that rates of thyroid cancer did not In addition, between-country differences in other correlate with early or recent iodine intake, for which risk factors for thyroid outcomes (e.g. alcohol (28, 29), previous results are not fully consistent (44). Previous smoking (30), and other micronutrient deficiencies (31)) studies have indicated that increased iodine intake is and between-country differences in diagnostic activity associated with an increase in the ratio between papillary and treatment practices may also influence the rates and follicular thyroid cancer (45), which was not measured of thyroid outcomes independently of iodine intake. in our study. Nevertheless, whether the overall incidence Especially differences in ultrasound utilization can of thyroid cancer is influenced by the population level impact the detection and thus diagnoses and treatment iodine intake is still not clear (44). for thyroid nodules and cancer. Despite clinical practice We chose to only examine overall patterns in the guidelines developed by recognized professional relationship between iodine intake and rates of thyroid associations, surveys among clinicians find some outcomes because the available data on iodine intake variability and divergence from guidelines in the clinical were collected by different methods, timepoints, and management of Grave’s disease, hypothyroidism, and populations across the European countries and thus not thyroid nodules (32, 33, 34). Furthermore, during 2001– sufficiently comparable. If valid data on early and recent 2009/2015 a fall in threshold for treatment initiation of iodine intake in Europe are harmonized it will be possible to thyroid hormone therapy was observed in both Great perform more advanced statistical analyses of associations Britain and in Denmark leading to more prescriptions between the burden of thyroid diseases and iodine intake of thyroid hormone therapy, but the fall in treatment (46, 47). threshold was markedly steeper in Denmark (35, 36). Of note, our results indicate a higher correlation It is a limitation that we were unable to adjust for these between early iodine intake and thyroid outcomes than between-country differences. recent iodine intake. Many of the included countries Overall, collection and comparisons of register-based have introduced IDD prevention programs and achieved data from European countries are time-consuming and iodine sufficiency during the past two decades, and complicated. When it comes to the burden of thyroid thus the adult population may still be affected by the diseases, the potential consequences of differences in exposure to decades of iodine insufficiency. Biologically iodine intake status and IDD prevention programs may be it is plausible that thyroid function and thereby thyroid overshadowed by within- and between-country sources of disease are influenced by the lifetime iodine intake level bias and confounding. (48). Furthermore, the introduction of IF can cause a temporary rise in incident hyperthyroidism in countries with previous ID (8) or may induce thyroid dysfunction Differences in thyroid medication, surgery, due to excessive iodine intake (49). This could affect and cancer rates the rates of treatment in several included countries. Despite the potential biases in comparisons, we still found In Denmark, steady states were achieved for rates of fairly consistent rates of thyroid outcomes in line with thyrotoxicosis but not for hypothyroidism approximately https://ec.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-21-0525 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. L T Møllehave et al. Thyroid diseases in Europe 11:3 e210525 10 years after the implementation of mandatory IF (42, the valuable registry information. The current increase 43). Our study indicates that it may take even longer before in digitization and awareness of the possibilities within the difference between former iodine adequacy and iodine register research may lead to more valid register data sources insufficiency is negated between countries. Despite overall on thyroid diagnoses and treatment with easy access and iodine adequacy, iodine deficiency can still be present in utilization in the European countries in the future. This vulnerable groups, for example, pregnant women, which is will be of great value to thyroid research. observed in several countries (46). The results show no differences between countries characterized by different IDD prevention strategies. Thus, a Conclusion and perspectives best-practice model of IDD prevention cannot be identified The availability and quality of register data on thyroid through this study. This may be explained, firstly, by the diagnoses and treatments are highly heterogeneous difference in coverage and impact of especially voluntary between Europeans countries. Thus, comparison of rates IF. Second, IDD prevention programs are optimally of thyroid outcomes is currently only possible between a designed to compensate for the level of iodine deficiency limited number of countries. The available data indicate in the target population, thus, similar iodine intakes may lower rates of antithyroid medication and thyroid surgery be achieved from different IDD prevention strategies. for benign disease and higher rates of thyroid hormone therapy in countries with early iodine intake adequacy, Strengths and limitations and no difference for thyroid cancer or according to recent iodine intake. The main strengths of this study are, firstly, the strong As stated in the Krakow Declaration, evaluation of collaboration between representatives from thyroid primary thyroid outcomes is essential in the control of IDD research and clinical environments from the European prevention programs (50). Registers may be an effective countries. The national EUthyroid representatives tool for this evaluation. Thus, the present project serves as had or obtained knowledge of the availability and initial exploration of the availability and quality of register documentation of data that would not be possible for data of thyroid outcomes across Europe, while more one researcher from one country. Second, the acquisition in-depth examination of the validity and comparability of of several thyroid outcomes enabled us to evaluate registers is still needed to fully utilize the potential of the different aspects of thyroid disease and the relationship registers. with iodine intake. Third, the critical assessment of data secured that only data of appropriate quality was included. However, the critical assessment was based Supplementary materials on evaluations of the available documentation, and This is linked to the online version of the paper at https://doi.org/10.1530/ EC-21-0525. thorough validation of most of the variables was not possible. Raw rates were calculated for all provided data included in the database, however, it is important to note Declaration of interest that these should be interpreted with caution because The authors have no conflicts of interest to declare. The author Alicja Hubalewska-Dydejczyk is an editor of the journal. the validity of some data is uncertain and comparison of the raw rates will be confounded by differences in sex- and age distributions. Only few variables met the criteria Funding for comparison between countries and these variables This work was supported by the European Union’s Horizon 2020 research were only available for few countries, which is a major and innovation program under grant agreement no. 634453. Data analyses were further supported by the project SUPERTHYREOSE, funded limitation. This in combination with the heterogeneity by the German G-BA (VSF2_2019-167). 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