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1 Maturitas 71 (12) Contents lists available at SciVerse ScienceDirect Maturitas j ourna l h o me page: Iodine deficiency influences thyroid autoimmunity in old age A comparative population-based study Stig Andersen a,, Finn Iversen b, Steen Terpling b, Klaus M. Pedersen a, Peter Gustenhoff a, Peter Laurberg a a Department of Endocrinology and Medicine, Aalborg University Hospital, Denmark b Skagen Hospital, Vensyssel Hospital, Skagen, Denmark a r t i c l e i n f o Article history: Received 1 September 11 Received in revised form 26 September 11 Accepted 1 October 11 Keywords: Natural iodine intake Thyroid antibodies Residence time Old age Tap water iodine a b s t r a c t Objective: To assess thyroid autoimmunity among elderly people living in an area with low iodine intake compared to the sustained recommended iodine intake from a natural source, and to estimate the importance of migration. Design and setting: Iodine content of drinking water is highly different in the Danish towns Randers and Skagen. We collected blood and spot urine samples from 4 long-term Randers and Skagen dwellers aged 75 8 years, who filled in a questionnaire. We measured thyroid peroxidase antibody () and thyroglobulin antibody () in serum and iodine and creatinine in urine. Results: Participation rate was 47% (n = 212 (men/women 82/1) in Randers; 218 (84/134) in Skagen). Iodine deficiency prevailed in Randers while Skagen dwellers were iodine replete (median urinary iodine 74 g/24 h vs. 184 g/24 h, p <.1). Thyroid antibodies were more frequent in Randers than in Skagen residents (42% vs. 32%; p =.6) and more likely with iodine excretion <5 g/24 h (OR, 95%CI: 1.9, ). Differences between towns increased with longer duration of residence as trends in the occurrence of and were opposite (p <.1; p =.7). Conclusions: Thyroid autoantibodies were common in old age, influenced by the iodine intake level, and the lowest frequency was found at the recommended iodine intake level. 11 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Aging of the immune system is complex [1] and changes seem to reflect dysregulation of the immune responses rather than impaired function [2]. On the one hand the innate immune system is activated in the elderly [3] and age is a major risk factor in many chronic inflammatory diseases [4 6]. On the other hand the adaptive immune response is lower in old age and the response to peptide antigens is impaired [7]. Still, organ specific autoantibodies are a common finding in healthy elderly [8,9]. Autoimmune thyroid disease is the most common organspecific autoimmune disorder and a hallmark is the presence of thyroid autoantibodies directed against, i.e. thyroglobulin or thyroid peroxidase [1]. The prevalence of thyroid antibodies varies between populations under the influence of genetic [11] and environmental factors [12,13]. An important environmental factor in upholding normal thyroid function is iodine [14]. While the role of the iodine intake level in the etiology of non-autoimmune thyroid disorders is well established, the association between population iodine intake level and thyroid autoimmunity is more devious. In particular, data on iodine intake and thyroid autoimmunity in old age are scarce. Iodine fortification programmes raise the iodine intake level in many populations. Yet, the occurrence of thyroid antibodies in old people with a stable iodine intake at the level recommended by the WHO [15] needs to be detailed. This led us to compare the impact of long-standing recommended iodine intake vs. long-standing mild to moderate iodine deficiency on thyroid autoimmunity in old age in residents of two areas with distinctly different iodine intakes [16,17] that influenced the occurrence of thyroid disorders [18]. In addition, we assessed the impact of duration of the iodine intake levels on the occurrence of thyroid autoantibodies. 2. Methods Corresponding author at: Arctic Health Research Centre, Department of Endocrinology and Medicine, Aalborg University Hospital, Hobrovej 18-22, 9 Aalborg, Denmark. Tel.: ; fax: address: stiga@dadlnet.dk (S. Andersen). The investigation was carried out in the two towns Randers and Skagen on the peninsula Jutland in Denmark. Though situated relatively close they differed by aquifer source rock, and both tap /$ see front matter 11 Elsevier Ireland Ltd. All rights reserved. doi:1.116/j.maturitas

2 S. Andersen et al. / Maturitas 71 (12) Table 1 Descriptives of the participants from the two towns Randers and Skagen in Jutland, Denmark. Randers Skagen p * n % n % Residence time.4 >25 years % 1 92% > years 15 71% % >55 years 86 41% 9 41% Gender.98 Men 82 39% 84 38% Women 1 61% % Age (years) a 78 (77 78) 76 (75 8) <.1 Smoker b.44 Present 54 26% 46 21% Past 81 39% 95 44% Never 74 35% 75 35% Alcohol use c.4 Daily 32 16% 34 16% Occasionally % % Never 23 11% 43 % Use of supplements 94 45% 79 36%.7 with iodine d Urinary iodine <.1 excretion ( g/24 h) e All 74 (45; 118) 184 (144; 246) No supplement use 5 (37; 83) 177 (137; 219) Tap water iodine content ( g/l) 2. 1 a Median (25; 75 percentiles). b e Data missing on 5 in b, 12 in c, 2 in d and 2 in e. e Corrected for age and gender specific creatinine excretions (men.95 g/l; women.7 g/l). * Chi-squared test for comparing proportions, Mann Whitney for comparing medians. water iodine and urinary iodine excretion levels differed markedly (Table 1) [16,17] Populations and procedures The populations have been described in detail previously [18]. In brief, we invited all men and women born 19 living in the city of Randers with a total population of 55,897 (n = 483), and all men and women born 1918 through 1923 living in Skagen with a total population of 1,78 (n = 432). Names and addresses were obtained from the national civil registration system in which every individual living in Denmark is recorded. A questionnaire regarding treatment for thyroid disease, use of iodine containing vitamin and mineral preparations, duration of residence, smoking habits and use of alcohol was filled in. Nonattenders did not differ from participants in gender, number of years in town, smoking habits, frequency of disease or present treatment for thyroid disease as evaluated from telephone interviews in 1% of non-attenders. The investigation took place at the local hospital or, at request, as home visits. Data were collected prior to the initiation of the Danish iodine fortification program [19]. The study was approved by the regional ethics committee for Nordjylland and Viborg county Sample collection and assays A venous blood sample was drawn using minimal tourniquet and a non-fasting spot urine sample was collected in iodine free polyethylene containers from all participants. Serum was separated and samples were stored at C until analysis. Thyroid peroxidase antibodies () were measured using Dynotest RIA (BRAHMS Diagnostica, Berlin, Germany) with a functional sensitivity of ku/l [13]. Thyroglobulin antibodies () were measured with an RIA (DYNOtest, BRAHMS Diagnostica, Berlin, Germany) with a functional sensitivity of ku/l [13]. Iodine content of urine was determined by the Sandell Kolthoff reaction modified after Wilson and van Zyl [] as described in detail previously [21,22]. Urinary creatinine was determined by a kinetic Jaffé method [23] and used to estimate age and gender specific 24 h iodine/creatinine ratio (men,.95 g/24 h; women,.7 g/24 h) as recommended [24]. In all assays, samples were mixed from the two towns and analysed in random order Statistical analysis Frequencies among populations were compared using 2 - test, and medians compared using Mann Whitney U-test. Jonckheere Terpstra test was used to test for trends with time. Dependent variables entered in logistic regression models were serum above ku/l, above ku/l, and either above these levels. Explanatory variables entered were gender, smoking habits, alcohol use and either town of residence or iodine excretion. Data were processed using the statistical package for the social sciences (SPSS) version 13.. A p-value of less than.5 was considered significant. 3. Results Table 1 shows the characteristics of the 4 participants. The participation rate was 47%. More women than men participated in accordance with the demographic characteristics of the age group with no difference between towns. Inclusion of a wider age-range in the smaller town of Skagen caused a difference in mean age (Randers/Skagen, 77.5/76.4 years, p <.1) without influence on thyroid antibody prevalence (, p =.79;, p =.71). The majority of participants were long-time dwellers with 75% living in town for more than years. Still, there was some difference between towns in duration of residence and in the number of alcohol abstainers while smoking frequencies were similar (Table 1). Urinary iodine excretion was in the recommended range in Skagen dwellers while Randers residents were mild to moderately iodine deficient (Table 1) Iodine intake level Overall, hosting a thyroid antibody was more common in the old iodine deficient compared to the iodine replete olds in the crude comparison (Table 2). This was also found in multivariate logistic regression models (p =.3, OR, 95%-CI: 2., ) adjusting for gender, smoking and alcohol use. Moderate iodine deficiency, as defined by having a urinary iodine excretion below 5 /24 h, increased the risk of hosting a thyroid antibody (p =.18; OR, 95%- CI: 1.9, , reference: urinary iodine excretion >5 g/24 h) Migration The distribution of thyroid autoantibodies differed between residents of the two towns and varied with the duration of residence as shown in Fig. 1. Living more than 25 years in Randers associated with markedly higher frequency of (p =.3), and occurred in 7.5% more long-time residents compared to newcomers. Trends with duration of residence were opposite in the iodine deficient and the iodine replete towns for both (p <.1) and (p =.7), and and occurred 9.% and 7.3% less frequently among long-time residents compared to newcomers in Skagen (Fig. 1). The differences between towns in the number of olds that hosted a thyroid autoantibody increased with number of

3 S. Andersen et al. / Maturitas 71 (12) Table 2 Prevalence of thyroid peroxidase antibodies () and thyroglobulin antibodies () in serum from old Randers and Skagen dwellers with long-standing natural low and recommended iodine intake respectively. a b TPO- a or b n c % p d n c % p b % p d Town Randers % %.31 42%.6 Skagen 8 22% 18 29% 32% Residence time Randers >55y 86 23% %.3 49%.1 <25y 38 16% 38 1% 21% Skagen >55y 84 21% %.77 28%.48 <25y 16 29% 14 36% 43% Gender Randers Women % %.28 44%.36 Men 82 11% 82 29% 38% Skagen Women % < %.1 43% <.1 Men 79 6% 74 16% 16% Smoker Randers Yes 53 19% %.61 45%.48 No % % % Skagen Yes 46 % %.35 43%.11 No % % 29% Alcohol daily Randers Yes 32 19% %.6 28%.1 No % % 43% Skagen Yes 32 12% %.29 24%.38 No % 151 % 34% a s- above g/l. b s- above g/l. c Number of samples measured. d Chi-squared test. years living in the iodine deficient and iodine replete areas respectively (<25 years/25 55 years/>55 years: p =.12/.4/.2) Sustained iodine intake level Fig. 2 illustrates the occurrence of thyroid autoantibody among those who had lived more than 55 years in iodine deficient Randers or in iodine replete Skagen. Differences between towns are distinct with more Randers than Skagen dwellers hosting a thyroid autoantibody, one thyroid autoantibody without the other, alone, alone, and. 4. Discussion Thyroid autoantibodies were common in 75 thru 8 years old men and women with both deficient and recommended iodine intake. Thyroid autoimmunity differed between residents of the two towns. More iodine deficient than iodine replete old people harboured a thyroid autoantibody and differences increased with duration of residence. The aging process affects the immune system that becomes less responsive to antigenic challenges and the incidence and morbidity of infections increase with age. The innate immune system is activated in the elderly with increased concentration of inflammatory cytokines causing a pro-inflammatory environment [3] that accelerates and complicates degenerative diseases [1] and causes an increased incidence of autoimmune disorders [4 6]. Also, the adaptive immune system is influenced by age through thymic involution with decreasing production of naive T-cells, and signalling defects in elderly T-cells and B-cells have been suggested [6,25]. Thus, autoantibodies are common in old age [8,9], but whether this is due to immune aging or related to prolonged environmental challenges is not known. Age influences the prevalence of and. Both autoantibodies increased with age from 7 and 9% in the young to 22 and % for and respectively in the 6 thru 65 year old women in a Danish population based study that used the same assays as our study [13]. We found even higher prevalence rates of both and of 37 and 28% in women irrespective of iodine intake level. This is consistent with the suggested influence of age on thyroid autoimmunity [8]. The frequencies found in our study were markedly higher than the 1% and 11% previously reported in centenarians [9]. Differences in analytical methods may be of importance, but the results suggest a peak in thyroid autoimmunity between the age of 65 or 1 years. A decrease after the age of 8 years could relate to a natural wastage of those who harbour thyroid autoantibodies. Iodine is a key environmental factor that affects the thyroid [14,18,19]. Excessive iodine intake aggravates thyroid autoimmune reactions [26] and when long-standing it associated with autoimmune thyroid disease [27 29]. Still, most studies of thyroid autoantibodies among the old lack data on iodine excretion in the subjects studied [9,,31]. Iodine intake did not influence the occurrence of thyroid autoantibody in those under the age of 45 years in a large population based survey [13] in keeping with findings in other areas [32]. However, the prevalence of thyroid autoantibodies increased with age, and in the oldest age group (6 thru 65 years) thyroid autoantibodies were more common in the moderately iodine deficient than in the mildly iodine deficient subjects [13]. Our participants were 15 years older and the difference in iodine intake levels were more pronounced. Our finding that thyroid autoantibodies occurred more frequently with iodine deficiency was dominated by a difference in. Iodine deficiency associated with a rise in frequency especially among men who rose almost to the level of women. This suggests that iodine deficiency may increase the pro-inflammatory environment in men in old age as thyroglobulin levels were elevated with iodine deficiency in both women and men [18]. The effect of iodine deficiency on immune aging was supported by the influence of migration and residence time. It may seem paradoxical that are more common in iodine deficiency while overt autoimmune hypothyroidism is less

4 42 S. Andersen et al. / Maturitas 71 (12) <25 years <25 years y Years living in Randers y Years living in Skagen 55y + 55y + Fig. 1. The occurrence of and split by number of years living in town. Upper panel is residents of Randers and lower panel is residents of Skagen. Trends differed markedly ( p <.1; p =.7). common with mild to moderate iodine deficiency [14,33]. This finding supports that is generated as a response to TG release from the iodine deficient thyroid and suggests that this is only little pathogen. Other environmental differences may be at play. Tap water iodine coexisted with humic substances [16]. However, there are no indications that these influence the immune system. Gender and smoking influence thyroid autoimmunity and was thus included in the multivariate analysis. More than 55 years of residence in aloneal ns.4 aloneal Randers ns BothB <.1 Onene Ab Skagen.1 Any Any Ab Fig. 2. The occurrence of and among 75 thru 8 years old men and women who had lived more than 55 years in either Skagen with long-standing recommended iodine intake from a natural source or in Randers with moderate iodine deficiency. Frequencies were compared using chi-squared test and p-values less than.5 are given for each pair while ns designates p >.5. The Skagen population had the recommended iodine intake [17]. Duration of residence in Skagen likely reflected duration of a daily iodine intake at the recommended level because tap water is an important component of the diet that supplied this iodine intake [17,34] and the iodine content of tap water in Skagen was unaltered with time [16]. Also, sustained iodine deficiency has been confirmed in Randers [18,35] and low migration rates were found in both towns. Furthermore, the present study was carried out prior to the initiation of the Danish iodine fortification program [19]. Thus, the two towns were suitable for comparing an influence of sustained different iodine intake levels. This approach has been used in other areas with different iodine intake levels [13,27,29]. The iodine intake among those who had moved to Randers or Skagen is not known for the preceding period. However, investigations on the iodine content of tap water in Denmark suggest previous iodine intake levels somewhere between the two levels found in the areas included here [16,34]. In conclusion, the prevalence of circulating thyroid autoantibodies differed with both residence and migration to/from an area of iodine deficiency and an area with sustained recommended iodine intake of natural origin. Hence, the impact of aging on the immune system is modified by this dietary environmental factor. Also, data suggest a peak in thyroid autoimmunity between the age of 65 and 1 years. Contributors SA: Conception of idea, study design, raising of funds, data collection, analysis and interpretation of data, and writing of the FI: Raising of funds, data collection and reviewing of the ST: Raising of funds, data collection and reviewing of the KMP: Conception of idea, data collection and reviewing of the PG: Data collection and reviewing of the PL: Conception of idea, design of the study, raising of funds, data collection, analysis of data, interpretation of data, and writing of the Competing interests SA, FI, ST, KMP, PG, PL: No conflicts of interest. Funding source The study was supported by Karen Elise Jensen Foundation. Practical support was provided by Vensyssel Hospital and the municipality of Skagen. These were not involved in the study design, analysis or interpretation of data, writing of the manuscript or decision to submit the paper for publication. No financial profit was possible. Ethical approval Informed consent was obtained from each participant as required by the ethics committee for Viborg and Nordjylland County. References [1] Grubeck-Loebenstein B, Wick G. The aging of the immune system. Adv Immunol 2;8: [2] Shaw CA, Joshi S, Greenwood H, Panda A, Lor d JM. Aging of the innate immune system. Curr Opin Immunol 1;22:57 13.

5 S. Andersen et al. / Maturitas 71 (12) [3] Gameiro CM, Romão F, Castelo-Branco C. Menopause and aging: changes in the immune system a review. Maturitas 1;67:316. [4] Larbi A, Fulop T, Pawelec G. Immune receptor signaling, aging and autoimmunity. Adv Exp Med Biol 8;6: [5] Weyand CM, Goronzy JJ. Giant-cell arteritis and polymyalgia rheumatica. Ann Intern Med 3;139: [6] Goronzy JJ, Shao L, Weyand CM. Immune aging and rheumatoid arthritis. Rheum Dis Clin North Am 1;36: [7] Jefferson T, Rivetti D, Rivetti A, et al. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet 5;366(9492): [8] Moulias R, Proust J, Wang A, et al. Age-related increase in autoantibodies. Lancet 1984;1(8386): [9] Andersen-Ranberg K, Høier-Madsen M, Wiik A, Jeune B, Hegedüs L. High prevalence of autoantibodies among Danish centenarians. Clin Exp Immunol 4;138: Marcocci C, Chiovato L. Thyroid-directed antibodies. In: Braverman LE, Utiger RD, editors. Werner and Ingbar s The Thyroid. 8th ed.. p [11] Brix TH, Hansen PS, Kyvik KO, Hegedüs L. Aggregation of thyroid autoantibodies in first-degree relatives of patients with autoimmune thyroid disease is mainly due to genes: a twin study. Clin Endocrinol 4;6: [12] Prummel MF, Strieder T, Wiersinga WM. The environment and autoimmune thyroid diseases. Eur J Endocrinol 4;15: [13] Pedersen IB, Knudsen N, Jørgensen T, Perrild H, Ovesen L, Laurberg P. Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clin Endocrinol 3;58: [14] Laurberg P, Cerqueira C, Ovesen L, Rasmussen LB, Perrild H, Andersen S, Pedersen IB, Carlé A. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res Clin Endocrinol Metab 1;24: [15] Assessment of Iodine Deficiency Disorders and Monitoring their Elimination: A Guide for Programme Managers. 3rd ed. Geneva: World Health Organization; 7. [16] Andersen S, Petersen SB, Laurberg P. Iodine in drinking water in Denmark is bound in humic substances. Eur J Endocrinol 2;147: [17] Andersen S, Pedersen KM, Iversen F, Terpling S, Gustenhoff P, Petersen SB, Laurberg P. Naturally occurring iodine in humic substances in drinking water is bioavailable and determines population iodine intake. Br J Nutr 8;99: [18] Andersen S, Iversen F, Terpling S, Pedersen KM, Gustenhoff P, Laurberg P. More hypothyroidism and less hyperthyroidism with sufficient iodine nutrition compared to mild iodine deficiency a comparative population-based study of older people. Maturitas 9;64: [19] Laurberg P, Jørgensen T, Perrild H, Ovesen L, Knudsen N, Pedersen IB, Rasmussen LB, Carlé A, Vejbjerg P. The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives. Eur J Endocrinol 6;155: [] Wilson B, van Zyl A. The estimation of iodine in thyroidal amino acids by alkaline ashing. S Afr J Med Sci 1967;32:7 82. [21] Laurberg P. Thyroxine and 3,5,3 -triiodothyronine content of thyroglobulin in thyroid needle aspirates in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab 1987;64: [22] Andersen S, Hvingel B, Kleinschmidt K, Jørgensen T, Laurberg P. Changes in iodine excretion in 5 69-y-old denizens of an Arctic society in transition and iodine excretion as a biomarker of the frequency of consumption of traditional Inuit foods. Am J Clin Nutr 5;81: [23] Bartels H, Bohmer M, Heierli C. Serum creatinine determination without protein precipitation. Clin Chim Acta 1972;37: [24] Vejbjerg P, Knudsen N, Perrild H, Laurberg P, Andersen S, Rasmussen LB, Ovesen L, Jørgensen T. Estimation of iodine intake from various urinary iodine measurements in population studies. Thyroid 9;19: [25] Leng J, Goldstein DR. Impact of aging on viral infections. Microbes Infect 1;12:11 4. [26] Papanastasiou L, Vatalas IA, Koutras DA, Mastorakos G. Thyroid autoimmunity in the current iodine environment. Thyroid 7;17: [27] Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G. High incidence of multinodular toxic goiter in the elderly population in a low iodine intake area vs high incidence of Graves disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. J Intern Med 1991;229:415. [28] Konno N, Makita H, Yuri K, Iizuka N, Kawasaki K. Association between dietary iodine intake and prevalence of subclinical hypothyroidism in the coastal regions of Japan. J Clin Endocrinol Metab 1994;78: [29] Teng X, Shan Z, Chen Y, Lai Y, Yu J, Shan L, Xue B, Li Y, Li N, Li Z, Wang S, Xing Q, Xue H, Zhu L, Hou X, Fan C, Teng W. More than adequate iodine intake may increase subclinical hypothyroidism and autoimmune thyroiditis: a crosssectional study based on two Chinese communities with different iodine intake levels. Eur J Endocrinol 11;164: [] Magri F, Muzzoni B, Cravello L, Fioravanti M, Busconi L, Camozzi D, Vignati G, Ferrari E. Thyroid function in physiological aging and in centenarians: possible relationships with some nutritional markers. Metabolism 2;51(1):15 9. [31] Roti E, Gardini E, Minelli R, Bianconi L, Braverman LE. Prevalence of anti-thyroid peroxidase antibodies in serum in the elderly: comparison with other tests for anti-thyroid antibodies. Clin Chem 1992;38(1): [32] Li Y, Teng D, Shan Z, et al. Antithyroperoxidase and antithyroglobulin antibodies in a five-year follow-up survey of populations with different iodine intakes. J Clin Endocrinol Metab 8;93: [33] Carlé A, Laurberg P, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Rasmussen LB, Jørgensen T. Epidemiology of subtypes of hypothyroidism in Denmark. Eur J Endocrinol 6;154:21 8. [34] Pedersen KM, Laurberg P, Nøhr S, Jørgensen A, Andersen S. Iodine in drinking water varies by more than 1-fold in Denmark. Importance for iodine content of infant formulas. Eur J Endocrinol 1999;1: 3. [35] Pedersen KM, Laurberg P. Urinary iodine excretion and individual iodine supplementation among elderly subjects: a cross-sectional investigation in the commune of Randers, Denmark. Eur J Endocrinol 1995;132:171 4.