Shift of the TSH reference range with improved iodine supply in Northeast Germany Till Ittermann 1 , Rehman M Khattak 1 , Matthias Nauck 2 , Caio M M Cordova 4 and Henry Vo ¨ lzke 1,3 1 Institute for Community Medicine, Ernst Moritz Arndt University, University of Greifswald, Walther-Rathenau Straße 48, D-17475 Greifswald, Germany, 2 Institute of Clinical Chemistry and Laboratory Medicine, University of Greifswald, Greifswald, Germany, 3 DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, University of Greifswald, Greifswald, Germany and 4 Departamento de Cie ˆ ncias Farmace ˆ uticas, Universidade Regional de Blumenau, Blumenau, Brazil Correspondence should be addressed to T Ittermann Email till.ittermann@ uni-greifswald.de Abstract Objective: Germany was iodine deficient until the mid-1990s when a nationwide iodine fortification program became effective. It is expected that after a longer period of sufficient iodine supply, median TSH values in the general population will shift to the right. Hence, the previous TSH reference range does not reflect the current TSH distribution in the general population of Germany. Thus, we aimed to establish a new reference range for serum TSH levels. Design and methods: We used data from the Study of Health in Pomerania TREND, a population-based study including 4420 individuals. The reference population consisted of 1596 individuals without diagnosed thyroid diseases or thyroid-related findings in ultrasound and serum analysis. Serum TSH levels were measured by an immunochemiluminescent procedure on a Siemens Dimension Vista. Results: The overall reference range for TSH was 0.49 mIU/l (95% CIZ0.44; 0.53)–3.29 mIU/l (95% CIZ3.08; 3.50). The lower reference limit differed significantly by sex, whereas the upper reference limit showed no significant difference between males and females. Age was significantly associated with the 2.5th TSH percentile in males but not in females, whereas age was significantly associated in males and females for the 97.5th TSH percentile. Conclusions: We demonstrate a shift toward the right of the TSH reference range in comparison with data from the same study region 10 years earlier, which is likely due to the improved iodine supply of the study region. Our study indicates that TSH reference limits are dependent on past and current iodine supply of populations. European Journal of Endocrinology (2015) 172, 261–267 Introduction There is an ongoing debate on which reference range for serum thyroid-stimulating hormone (TSH) levels is appro- priate, particularly to define hypothyroidism (1, 2, 3, 4, 5). That debate is related to the heterogeneity in TSH reference ranges established in previous studies (6, 7, 8, 9, 10, 11, 12, 13) with differences of the upper TSH limit between 2.12 mIU/l (12) and 5.30 mIU/l (13). These discrepancies can be explained by different study popu- lations, age ranges (4), laboratory methods (14), and iodine supplies of populations (15, 16). In regions with iodine deficiency, reference intervals for serum TSH levels tend to be lower than that in regions with sufficient iodine supply, leading to higher reference intervals in North America (6) and East Asia (8, 10, 13) than that in large parts of Europe (7, 9, 12), where most countries are inherently iodine deficient (17). Besides the current supply, the history of iodine supply also influences regional TSH reference ranges. In Germany iodine deficiency persisted until the mid 1990s. In 1993 an improved legislation was established, followed by an increased use of iodized salt in households and food industries. Consequently, median iodine European Journal of Endocrinology Clinical Study T Ittermann and others TSH reference range shift with improved iodine supply 172 :3 261–267 www.eje-online.org Ñ 2015 European Society of Endocrinology DOI: 10.1530/EJE-14-0898 Printed in Great Britain Published by Bioscientifica Ltd.