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Objective: To monitor the impact of a cautious iodine fortification (IF) on the incidence of overt hypothyroidism in two subpopulations with different levels of preexisting iodine deficiency (ID)., Design: A 20-year (1997 to 2016) prospective population-based study identified all new cases of diagnosed overt biochemical hypothyroidism in two open cohorts: a western cohort with moderate ID (n = 309,434; 1 January 1997) and an eastern cohort with mild ID (n = 224,535; 1 January 1997). A diagnostic algorithm was applied to all thyroid function tests performed within the study areas, and possible new cases were verified individually. Mandatory IF of salt was initiated in mid-2000 (13 ppm). The current study is a part of the DanThyr study., Results: At baseline, standardized incidence rates (SIRs) of hypothyroidism were 32.9 and 47.3/100.000/y in the cohorts with moderate and mild ID, respectively. The SIR of hypothyroidism increased significantly in both cohorts after implementing mandatory IF, with peak values of 150% in 2014 to 2016 for the moderate ID cohort and 130% in 2004 to 2005 for the mild ID cohort. Significant increases in SIR were seen among the young and middle-aged participants of both cohorts, whereas no changes were seen among the elderly participants (≥60 years). The follow-up period for the mildly iodine-deficient cohort was restricted up to and including 2008., Conclusion: The cautious initiation of the IF program in Denmark caused a sustained increase in hypothyroidism incidence among subjects residing in areas of moderate and mild ID but only among the young and middle-aged participants., (Copyright © 2019 Endocrine Society.)

Objective: Our objective was to investigate individual serum thyroglobulin (Tg) changes in relation to iodine fortification (IF) and to clarify possible predictors of these changes., Design: We performed a longitudinal population-based study (DanThyr) in two regions with different iodine intake at baseline: Aalborg (moderate iodine deficiency (ID)) and Copenhagen (mild ID). Participants were examined at baseline (1997) before the mandatory IF of salt (2000) and again at follow-up (2008) after IF., Methods: We examined 2465 adults and a total of 1417 participants with no previous thyroid disease and without Tg-autoantibodies were included in the analyses. Serum Tg was measured by immunoradiometric method. We registered participants with a daily intake of iodine from supplements in addition to IF., Results: Overall, the follow-up period saw no change in median Tg in Copenhagen (9.1/9.1 μg/l, P=0.67) while Tg decreased significantly in Aalborg (11.4/9.0 μg/l, P<0.001). Regional differences were evident before IF (Copenhagen/Aalborg, 9.1/11.4 μg/l, P<0.001), whereas no differences existed after IF (9.1/9.0 μg/l, P=1.00). Living in Aalborg (P<0.001) and not using iodine supplements at baseline (P=0.001) predicted a decrease in Tg whereas baseline thyroid enlargement (P=0.02) and multinodularity (P=0.01) were associated with an individual increase in Tg during follow-up., Conclusions: After IF we observed a decrease in median Tg in Aalborg and the previously observed regional differences between Aalborg and Copenhagen had levelled out. Likewise, living in Aalborg was a strong predictor of an individual decrease in serum Tg. Thus, even small differences in iodine intake at baseline were very important for the individual response to IF., (© 2015 European Society of Endocrinology.)

Context: Limited longitudinal data are available on changes in the thyroid gland structure in a population and how this is influenced by iodine fortification (IF)., Objective: Our objective was to clarify how IF influenced thyroid gland structure in 2 regions with different iodine intake at baseline (Copenhagen, mild iodine deficiency [ID]; Aalborg, moderate ID)., Design and Setting: We conducted a longitudinal population-based study (DanThyr) where participants were examined before (1997) and after (2008) the Danish mandatory IF of salt (2000)., Participants: We examined 2465 adults, and ultrasonography was performed by the same sonographers using the same equipment, after controlling performances., Main Outcome Measure: Change in thyroid gland structure was evaluated., Results: The follow-up period saw an increased prevalence of multinodularity (9.8%-13.8 %, P < .001), especially in the previously moderate ID region of Aalborg (9.1%-15.4%, P < .001), whereas no change in prevalence was seen for solitary nodules (5.6%-5.1%, P = .34). In individual participants, changes in thyroid structure and disappearance of thyroid nodules during the 11 years was common with an overall normalization rate of 21.2 (95% confidence interval [CI] = 17.9-24.9) per 1000 person-years. Solitary nodules had a significantly higher normalization rate than multiple nodules (normalization rate ratio 0.47 [95% CI = 0.32-0.67]). A regional difference (Aalborg vs Copenhagen) was seen between normalization rates of multiple nodules (normalization rate ratio 0.29 [95% CI = 0.12-0.64]), but not for solitary nodules (normalization rate ratio 0.81 [95% CI = 0.53-1.21])., Conclusions: Changes in the thyroid gland structure with both appearance and disappearance of thyroid nodules are common after an iodization program.

Background: It is generally accepted that patients suffering from hypothyroidism may express few symptoms, but this has not been studied in a population-based study design., Objectives: To study the array of symptoms as they are reported in newly diagnosed overt autoimmune hypothyroidism using a population-based case-control design., Methods: Patients with new overt autoimmune hypothyroidism (n=140) and their individually matched thyroid disease-free controls (n=560) recruited from the same population underwent a comprehensive program and self-reported a number of symptoms. We identified the symptoms associated with overt hypothyroidism and calculated positive (LR+) and negative (LR-) likelihood ratios as well as diagnostic odds ratios (DORs) as measures for the association between disease state and symptoms., Results: Among 34 symptoms investigated, 13 symptoms were statistically overrepresented in hypothyroidism. Hypothyroid patients suffered mostly from tiredness (81%), dry skin (63%), and shortness of breath (51%). Highest DORs (95% CI) were reported for tiredness (5.94 (3.70-9.60)), hair loss (4.58 (2.80-7.51)), and dry skin (4.09 (2.73-6.16)). A hypothyroidism-component-score was defined as the number of hypothyroidism-associated symptoms (range: 0-13). LR+ for participants with a hypothyroidism-component-score of 0 was 0.21 (0.09-0.39), meaning that the post-test probability was lowered to 21% of what it was before asking for symptoms. LR+ for scores of 1-2/3/4-6/7-9/10-13 were: 0.47 (0.30-0.72)/1.16 (0.70-1.87)/1.90 (1.29-2.45)/3.52 (2.30-5.36)/6.29 (2.30-17.7)., Conclusions: None of the individual symptoms of hypothyroidism had high LRs or DORs. Thus, neither the presence nor absence of any individual hypothyroidism symptom was reliable in the decision making of who should have their thyroid function tested. Therefore, even minor suspicion should lead to a blood test., (© 2014 European Society of Endocrinology.)

Context: The 1-year postpartum period is often accompanied by increased risk for thyroid disease., Objective: The objective of the study was to investigate the role of reproductive risk factors in the development of autoimmune overt hypothyroidism in the years after the 1-year postpartum period., Design, Setting, and Subjects: In a population study, we included Danish women with new autoimmune overt hypothyroidism not diagnosed within the first year after a pregnancy (n = 117; median age 53.0 y) and age- and region-matched euthyroid controls from the same population (n = 468)., Main Outcome Measures: In conditional multivariate logistic regression models, we analyzed the associations between the development of autoimmune hypothyroidism and age at menarche/menopause, years of menstruations, pregnancies, spontaneous and induced abortions, live births, and years on oral contraceptives and postmenopausal hormone replacement therapy, also taking various possible confounders into account., Results: In multivariate regression models with no event as reference, the odds ratios (ORs) for hypothyroidism [95% confidence interval (CI)] after one/two/three or more live births were 1.72 (0.56-5.32)/3.12 (1.14-8.48)/4.51 (1.65-12.3) and 1.02 (0.57-1.81)/2.70 (1.27-5.75) after one/two or more induced abortions. Findings were valid only for women having hypothyroidism diagnosed before the age of 55 years. We found no association between disease development and other reproductive risk factors investigated., Conclusions: Previous live births and induced abortions were major risk factors for the development of autoimmune overt hypothyroidism in women aged up to 55 years. The increased risk for hypothyroidism after giving birth extends longer than just to the 1-year postpartum period, and numbers of previous pregnancies should be taken into account when evaluating the risk of hypothyroidism in a young women.

Objective: To assess the individuals' thyroid volume changes after the mandatory nationwide iodine fortification (IF) program in two Danish areas with different iodine intake at baseline (Copenhagen, mild iodine deficiency (ID) and Aalborg, moderate ID)., Design: A longitudinal population-based study (DanThyr)., Methods: We examined 2465 adults before (1997) and after (2008) the Danish IF of salt (2000). Ultrasonography was carried out by the same sonographers using the same equipment, after controlling performances. Participants treated for thyroid disease were excluded from analyses., Results: Overall, median thyroid volume had increased in Copenhagen (11.8-12.2 ml, P=0.001) and decreased in Aalborg, although not significantly (13.3-13.1 ml, P=0.07) during the 11 years of follow-up. In both regions, there was an age-related trend in individual changes in thyroid volume from baseline to follow-up; thyroid volume increased in women <40 years of age and decreased in women >40 years of age. IN A MULTIVARIATE REGRESSION MODEL, HIGHER AGE AT ENTRY WAS A PREDICTOR (P0.05) FOR THYROID VOLUME DECREASE 20% DURING THE FOLLOW-UP PERIOD (WOMEN AGED 4045 YEARS: odds ratio (OR) 4.3 (95% CI, 2.2-8.2); women aged 60-65 years: 5.8 (2.9-11.6)) and individuals of higher age were also less likely to have an increase in thyroid volume (women aged 40-45 years: OR 0.2 (0.1-0.3); women aged 60-65: OR 0.3 (0.2-0.4))., Conclusions: Age-dependent differences in thyroid volume and enlargement had leveled out after the Danish iodization program. Thus, the previously observed increase in thyroid volume with age may have been caused by ID.

Objective: To characterize thyroid hormone levels at the time of diagnosis in the nosological types of thyrotoxicosis diagnosed in the population and to analyze determinants for serum thyroxine (T4) and tri-iodothyronine (T3)., Design: Population-based study of thyrotoxicosis at disease onset., Methods: In the period 1997-2000, we prospectively identified all patients diagnosed with incident primary overt thyrotoxicosis in a Danish population cohort and classified patients into ten well-defined nosological types of disease (n=1082). Untreated levels of serum T3, T4, and T3:T4 ratio were compared and related to sex, age, level of iodine deficiency, smoking status, alcohol intake, iodine supplement use, co-morbidity, and TSH receptor antibodies (TRAbs) in multivariate models., Results: Graves' disease (GD) patients had much higher levels of T3 and higher T3:T4 ratio at diagnosis compared with other thyrotoxic patients, but with a profound negative association between hormone levels and age. In GD, patients diagnosed in the area with more severe iodine deficiency had lower levels of T3 and T4. TRAb-negative GD patients had biochemically mild thyrotoxicosis. Higher age was also associated with lower degree of biochemical thyrotoxicosis in nodular toxic goiter. We found no association between serum T3 and T4 and sex, smoking habits, iodine supplements, alcohol intake, or co-morbidity in any type of thyrotoxicosis., Conclusions: The study gives new insight into the hormonal presentation of thyrotoxicosis and showed that young age, positive TRAb levels, but also residency in the area with higher iodine intake was positively associated with biochemical disruption in GD.

Context: Few data are available on the effect of iodine fortification on thyroid function development in a population., Objective: Our objective was to evaluate changes in thyroid function after iodine fortification in a population and to identify predictors for changes in serum TSH., Design and Setting: A longitudinal population-based study of the DanThyr C1 cohort examined at baseline (1997-1998) and reexamined 11 yr later (2008-2010). The mandatory program for iodization of salt was initiated in 2000., Participants: A total of 2203 individuals, with no previous thyroid disease, living in two areas with different levels of iodine intake, with measurement of TSH and participation in follow-up examination were included in the analysis., Main Outcome Measure: Change in serum TSH was evaluated., Results: During the 11-yr follow-up, mean TSH increased significantly from 1.27 mU/liter [95% confidence interval (CI) = 1.23-1.30] to 1.38 mU/liter (CI = 1.34-1.43) (P < 0.001). The most pronounced increase was observed in the area with the highest iodine intake [1.30 mU/liter (CI = 1.25-1.35) to 1.49 mU/liter (CI = 1.43-1.55), P < 0.001], whereas the increase was not significant in the low-iodine-intake area [1.24 (CI = 1.19-1.29) to 1.28 (CI = 1.23-1.34), P = 0.06)]. Change in TSH was positively associated with the presence of thyroid peroxidase antibody at baseline (P < 0.001) and negatively associated with baseline thyroid enlargement (P < 0.001) and multiple nodules (P < 0.001)., Conclusions: Even small differences in the level of iodine intake between otherwise comparable populations are associated with considerable differences in TSH change at the 11-yr follow-up. Multinodular goiter predicted a less pronounced TSH increase during follow-up, which may be explained by iodine-dependent activity of autonomous nodules.

Objective: Alcohol consumption is an important protective risk factor for many autoimmune diseases. We wished to study the association between alcohol consumption and autoimmune hypothyroidism., Design: Population-based, case-control study, 1997-2001, Denmark., Methods: Patients with newly diagnosed autoimmune overt hypothyroidism (n=140) were prospectively identified in a population (2 027 208 person-years of observation), and their matched controls with normal thyroid function (n=560) were recruited simultaneously from the same population. Participants gave information on alcohol intake, smoking, previous diseases, education, and family history of hypothyroidism. The association between alcohol intake and development of hypothyroidism was analyzed in conditional regression models., Results: Hypothyroid cases had reported a lower alcohol consumption than controls (median units of alcohol (12 g) per week: 3 vs 5, P=0.002). In a multivariate regression model, alcohol consumption was associated with a reduction in risk for development of overt autoimmune hypothyroidism. Odds ratios (95% confidence interval) compared with the reference group with a recent (last year) consumption of 1-10 units of alcohol per week were as follows: 0 units/week, 1.98 (1.21-3.33); 11-20 units/week, 0.41 (0.20-0.83); and ≥21 units/week, 0.90 (0.41-2.00). Similar results were found for maximum previous alcohol consumption during a calendar year. No interaction was found with type of alcohol consumed (wine vs beer), sex, or region of inhabitancy., Conclusions: Alcohol consumption seems to confer considerable protection against development of overt autoimmune hypothyroidism irrespective of sex and type of alcohol consumed.

Objective: Few population-based studies have described the epidemiology of subtypes of hyperthyroidism., Design: A prospective population-based study, monitoring two well-defined Danish cohorts in Aalborg with moderate iodine deficiency (n=311 102) and Copenhagen with only mild iodine deficiency (n=227 632)., Methods: A laboratory monitoring system identified subjects with thyroid function tests suggesting overt hyperthyroidism (low s-TSH combined with high s-thyroxine or s-triiodothyronine). For all subjects, we collected information on medical history, thyroid scintigraphy and thyroid hormone receptor antibody (TRAb) measurement. Information was used to disprove or verify primary overt hyperthyroidism and to subclassify hyperthyroidism into nosological disorders., Results: From 1997 to 2000 (2 027 208 person-years of observation), we verified 1682 new cases of overt hyperthyroidism. The overall standardized incidence rate (SIR) per 100 000 person-years was 81.6, and was higher in Aalborg compared with Copenhagen (96.7 vs 60.0, P<0.001), giving an SIR ratio (SIRR (95% confidence interval (CI))) between moderate versus mild iodine-deficient areas of 1.6 (1.4-1.8). Nosological types of hyperthyroidism (percentage/SIRR (95% CI)): multinodular toxic goitre (MNTG) 44.1%/1.9 (1.6-2.2), Graves' disease (GD) 37.6%/1.2 (0.99-1.4), solitary toxic adenoma (STA) 5.7%/2.4 (1.3-3.5), 'mixed type' hyperthyroidism (TRAb-positive, scintigraphicly multinodular) 5.4%/6.0 (3.0-12), subacute thyroiditis 2.3%/0.9 (0.4-1.4), postpartum thyroid dysfunction 2.2%/1.6 (0.8-3.0), amiodarone-associated hyperthyroidism 0.8%/7.1 (1.1-65), hyperthyroidism after thyroid radiation 0.7%/12.3 (0.8-50), lithium-associated hyperthyroidism 0.7%/0.97 (0.4-4.8) and hyperthyroidism caused by various other factors 0.7%. Lifetime risk for overt hyperthyroidism was 10.5%/6.5%/2.4% (females/all/males)., Conclusion: Hyperthyroidism was common in Denmark with MNTG and GD as dominating entities. The higher incidence of hyperthyroidism in the most iodine-deficient region was caused by higher frequency of MNTG, 'mixed-type', STA and amiodarone-associated hyperthyroidism.

Objective: Iodization of salt was introduced in Denmark in 1998 because of mild-to-moderate iodine deficiency (ID). The aim of this study was to analyze the utilization rate of surgery and radioiodine therapy for benign thyroid disorders before and after the introduction of iodization, and to study a possible association between the changes and the raised iodine intake., Design: A nationwide register study., Methods: Information on operations and radioiodine treatments for benign thyroid disorders was extracted from nationwide registers in the years 1990 to 2007. Treatment rates are presented for surgery and for radioiodine separately, and as a combined rate, both nationwide and split by the regions of prior mild and moderate ID., Results: A total of 65 605 treatments were identified: 26 456 operations and 39 149 radioiodine treatments. In the first years of iodization (1998-2000; rate ratio 2000/1997), the combined treatment rate increased with 2.5% (95% confidence interval (CI): -1.8-7.1). Split by prior ID level, the increase was seen in the region of moderate ID, but a decrease was seen in the region of mild ID. After 2000, the combined rate decreased, and ended up being 11.1% (95% CI: 7.1-15.0) lower in 2007 than before iodization (rate ratio 2007/1997). The changes were primarily due to changes in the use of radioiodine therapy as the surgery rates remained almost constant., Conclusions: Iodization seemed to be associated with a temporary increase in the utilization rate of surgery and radioiodine therapy in the region of prior moderate ID, probably as a result of treatment of iodine-induced hyperthyroidism, but the rates ended up being lower than before iodization.

Objective: The iodine status of a population is traditionally evaluated by either urinary iodine (UI) excretion or by some measure of thyroid volume and the prevalence of goitre. In this prospective study of a mandatory iodization programme, we aimed to evaluate serum thyroglobulin (Tg) as a marker of iodine status in the population., Methods: Two identical cross-sectional studies were performed before (1997-1998, n=4649) and after (2004-2005, n=3570) the initiation of the Danish iodization programme in two areas with mild and moderate iodine deficiency. Serum Tg was measured from blood samples. Thyroid volume was measured by ultrasonography., Results: Before iodization, the median serum Tg was considerably higher in moderate than in mild iodine deficiency. Iodization led to a lower serum Tg in all examined age groups. The marked pre-iodization difference in Tg level between the regions was eliminated. The prevalence of Tg above the suggested reference limit (40 microg/l) decreased from 11.3 to 3.7% (P<0.0001). Using bootstrapping, we demonstrated a higher efficacy of Tg than of thyroid volume to show a difference between pre- and post-iodization values., Conclusion: We found serum Tg to be a suitable marker of iodine nutrition status in the population. The results may suggest that the Danish iodization programme has led to a sufficient iodine intake, even if the median UI excretion is still marginally low according to WHO criteria.

Context: Iodine-induced hyperthyroidism has been reported in the early phases of almost all iodine fortification programs, depending on prior iodine intake in the population, the amount of fortification, and the rate of change., Objective: The aim of the study was to monitor the effect of the Danish iodine fortification program on incidence of hyperthyroidism as measured by the incident use of antithyroid medication., Design: We conducted a register study. Using the unique identification number of all Danes, we linked data from the Register of Medicinal Product Statistics and the Civil Registration register on an individual level. All dispensing of antithyroid medication from 1995 to 2007 was studied. The place of residency was used to divide patients into mildly and moderately iodine-deficient groups., Main Outcome Measure: We measured the incident use of antithyroid medication., Results: In the region with moderate iodine deficiency, the number of incident users of antithyroid medication increased 46% in the first 4 yr of iodine fortification. The use increased the most among the youngest age group (younger than 40 yr) and the oldest age group (older than 75 yr). In the mildly iodine-deficient region, the number of incident users increased only 18%, and only in the youngest age groups (below 40 and 40-59 yr). After 4 yr of fortification, the incidence rates started to fall and reached baseline, for most groups, 6 yr after onset of fortification., Conclusions: This study shows that iodine fortification induced a temporary, modest increase in the incidence of hyperthyroidism as measured by use of antithyroid medication. A new steady state has not yet evolved.

Context: Primary overt autoimmune hypothyroidism is often divided into primary idiopathic hypothyroidism with thyroid atrophy (Ord's disease) and hypothyroidism with goitre (Hashimoto's disease)., Objective: The aim of the present study was to characterize the two subtypes of disease., Design and Setting: This was a population-based study identifying patients newly diagnosed with overt autoimmune hypothyroidism., Patients: We prospectively identified all patients with incident overt autoimmune hypothyroidism in a Danish population cohort, and 247 patients were invited to join a comprehensive program including thyroid ultrasonography and measurements of thyroid autoantibodies. Of the 144 patients investigated (58% of all invited), 139 were compared with 556 sex-, age-, and region-matched controls from the cohort., Results: Patients had lower median (11.6 ml vs. 13.5 ml, P = 0.001) and a more dispersed distribution of thyroid volumes compared with controls (P < 0.001). Log thyroid volume showed a Gaussian distribution in both males and females with no bimodal pattern. Nearly all patients had measurable thyroid autoantibodies, but with increasing thyroid volume (quartile I, II, III, and IV), levels of circulating antibodies were higher (median thyroid peroxidase autoantibody 1540, 3122, 4686, and 7058 kU/liter; median thyroglobulin autoantibody 72, 143, 119, and 1195 kU/liter), and thyroid volume correlated negatively with echogenicity (r = -0.21, P = 0.011). Patients with the smallest volumes were biochemically more hypothyroid at diagnosis (median serum T(4) 21.0, 45.5, 45.0, and 36.7 nmol/liter; median serum TSH 81.0, 40.9, 45.4, and 55.6 mU/liter). No difference between groups was observed in prevalence of TSH receptor autoantibody (14.7, 5.6, 14.7, and 8.3%) or duration of symptoms before hypothyroidism was diagnosed., Conclusions: In primary autoimmune hypothyroidism, thyroid volume follows a normal distribution. Cases with thyroid atrophy and goiter are only extremes within this distribution and do not represent separate disorders. However, patients with low vs. high thyroid volume differ with respects to several characteristics.

Background: Autoimmune thyroid diseases are common and the prevalence of circulating thyroid antibodies (thyroid peroxidase antibody, TPO-Ab and thyroglobulin antibody, Tg-Ab) is high in the population. The knowledge of a possible association between lifestyle factors and circulating thyroid antibodies is limited., Aim: To evaluate the correlation between smoking habits and the presence of circulating TPO-Ab and Tg-Ab., Material and Methods: In a cross-sectional comparative population study performed in two areas of Denmark with moderate and mild iodine deficiency, 4649 randomly selected subjects from the population in some predefined age groups between 18 and 65 years were examined. Blood tests were analysed for TPO-Ab and Tg-Ab using assays based on the RIA technique. The participants answered questionnaires, were clinically examined and blood and urine samples collected., Results: Data were analysed in multivariate logistic regression models. There was a negative association between smoking and the presence of thyroid autoantibodies in serum. This association was observed for the presence of TPO-Ab and/or Tg-Ab, TPO-Ab (without respect to Tg-Ab status), Tg-Ab (without respect to TPO-Ab status) and both antibodies together. The association between smoking and thyroid autoantibodies was stronger for Tg-Ab than for TPO-Ab. There was no association between smoking and TPO-Ab measured alone or between smoking and TPO-Ab when Tg-Ab was included in the model as an explanatory variable., Conclusion: Smoking was negatively associated with the presence of thyroid autoantibodies with the strongest association between smoking and Tg-Ab. The study design precludes any conclusions as to the cause of the negative association between smoking thyroid autoantibodies.

Context: Iodine fortification (IF) of salt was introduced in Denmark in 1998. Little is known about the effect of a minor increase in iodine intake on the incidence of hypothyroidism. We prospectively identified all new cases of overt hypothyroidism in two areas of Denmark before and for the first 7 yr after IF had been introduced., Methods: A computer-based register was used to identify continuously all new cases of overt hypothyroidism in two subcohorts with previous moderate and mild iodine deficiency (ID), respectively (Aalborg, n = 310,124, urinary iodine = 45 microg/liter; and Copenhagen, n = 225,707, urinary iodine = 61 microg/liter). Data were obtained 1) before IF (1997-1998), 2) during voluntary IF (1999-2000), 3) during early (2001-2002) and 4) during late (2003-2005) period with mandatory IF., Results: The overall incidence rate of hypothyroidism increased during the study period: baseline, 38.3/100,000.yr; voluntary IF, 43.7 (not significant vs. baseline); early mandatory IF, 48.7 [vs. baseline, rate ratio (RR) = 1.27; 95% confidence interval (CI) = 1.10-1.47]; and late mandatory IF, 47.2 (vs. baseline, RR = 1.23; 95% CI = 1.07-1.42). There was a geographic difference because hypothyroidism increased only in the area with previous moderate ID: Aalborg, late mandatory IF vs. baseline, 40.3/29.7 (RR = 1.11; 95% CI = 1.11-1.66); Copenhagen, 56.7/51.6 (RR = 1.10; 95% CI = 0.90-1.34). The increase occurred in young and middle-aged adults., Conclusion: Even a cautious iodization of salt was accompanied by a moderate increase in the incidence rate of overt hypothyroidism. This occurred primarily in young and middle-aged subjects with previous moderate ID.

Objective: We aimed to evaluate prospectively the effect of 4 yr of mandatory iodization of salt (13 ppm iodine) on thyroid volume in two regional areas with respectively mild and moderate iodine deficiency., Methods: Two separate cross-sectional studies were performed before (n=4649) and after (n=3570) the iodization in year 2000 in two areas with mild and moderate iodine deficiency. Women aged 18-22, 25-30, 40-45, and 60-65 yr and men aged 60-65 yr were examined. Thyroid ultrasonography was performed., Results: A lower median thyroid volume was seen in all age groups after iodization. The largest relative decline was found among the younger females from the area with previous, moderate iodine deficiency. Only a minor decrease was seen among the youngest participants in the area with previous, mild iodine deficiency. After iodization, there were no regional differences in median thyroid volume in the age groups younger than 45 yr. When adjusted for confounders, a lower mean volume was seen among those with multiple nodules in both areas and in the group with diffuse structure in the area with moderate iodine deficiency. Before the iodization, 17.6% of the total cross-section had thyroid enlargement; after the iodization, 10.9% of the cross-section had thyroid enlargement., Conclusion: In this prospective study, we demonstrated a lower thyroid volume in all age groups after iodization of salt. The decline was largest in the area with former, moderate iodine deficiency. The equal volumes in the regions among the younger age groups indicate approximation to an optimal iodine intake.

Objective: Patients with overt hypothyroidism show decreased echogenicity of the thyroid at ultrasonography (US). The aim of this study was to investigate the association between echogenicity of the thyroid/irregular echo pattern, and thyroid function in the general population, i.e. subjects without overt thyroid disease., Design: A cross-sectional investigation of 4649 randomly selected adult subjects., Methods: Blood samples were analysed for serum TSH, thyroid hormones and thyroid autoantibodies. US of the thyroid was performed., Results: Participants with decreased echogenicity (n=379) had a higher mean TSH (1.65 mU/l) compared with subjects with normal echogenicity (1.21 mU/l, P<0.0001). The association was stronger in subjects with markedly decreased echogenicity (4.20 mU/l, P<0.0001). A similar association was seen when the subjects were divided into subgroups according to the level of TSH; more subjects with high levels of TSH had decreased echogenicity (P<0.0001). Likewise, more subjects with high levels of TSH had an irregular echo pattern (P<0.0001). Subjects with decreased echogenicity had a higher risk of having thyroid autoantibodies than subjects without decreased echogenicity (P<0.0001). This association was stronger when echogenicity was markedly decreased., Conclusions: We demonstrated an association between hypoechogenicity at thyroid US and higher levels of serum TSH even in subjects without overt thyroid disease, suggesting decreased echogenicity as an early sign of thyroid dysfunction. Irregular echo pattern, whether accompanied by hypoechogenicity or not, was another possible marker of thyroid failure. This indicates a possible use of thyroid US in detecting early and subclinical thyroid dysfunction.

Context: To prevent goiter and nodular hyperthyroidism, iodine fortification (IF) of salt was introduced in Denmark in 1998. We prospectively registered all new cases of overt hyperthyroidism in two areas of Denmark before and for the first 6 yr after iodine fortification., Methods: We used a computer-based register of all new cases of hyperthyroidism in two population subcohorts with moderate iodine deficiency (Aalborg, n = 310,124) and mild iodine deficiency (Copenhagen, n = 225,707), respectively. Data were obtained 1) before IF (1997-1998); 2) during voluntary IF (1999-2000); 3) during the early (2001-2002) period of mandatory IF; and 4) during the late (2003-2004) period with mandatory IF., Results: The overall incidence rate of hyperthyroidism increased [baseline, 102.8/100,000/year; voluntary IF, 122.8; early mandatory IF, 140.7; late mandatory IF, 138.7 (P for trend <0.001)]. Hyperthyroidism increased in both sexes (P < 0.001) and in all age groups: 0-19, 20-39, 40-59, and 60+ yr (P for trend <0.001). The increase was relatively highest in young adults aged 20-39 yr: late mandatory IF (percent increase from baseline), age 20-39, 160%, P < 0.001; age 40-59, 29%, P < 0.01; age 60+ yr, 13%, P = not significant., Conclusion: Even a cautious iodization of salt results in an increase in the incidence rate of hyperthyroidism. Contrary to current concepts, many of the new cases were observed in young subjects, and are presumably of autoimmune origin. Furthermore, monitoring is expected to show a decrease in the number of elderly subjects suffering from nodular hyperthyroidism.

Objective: Denmark was an area of iodine deficiency, and mandatory iodine fortification of table salt and salt in bread (13 p.p.m. iodine) was initiated in 2000/2001. The Danish investigation on iodine intake and thyroid disease (DanThyr) is the monitoring of the iodine fortification program., Design and Methods: DanThyr consists of three main parts: a study of population cohorts initialized before (n=4649) and after (n=3570) iodization of salt, a prospective identification of incident cases of overt hyper- and hypothyroidism in a population of around 550,000 people since 1997, and compilation of data from the national registers on the use of thyroid medication, thyroid surgery, and radioiodine therapy. Studies were carried-out in parallel in subcohorts living in areas with differences in iodine content of ground water., Results: The study showed profound effects of even small differences in iodine intake level on the prevalence of goiter, nodules, and thyroid dysfunction. Mild and moderate iodine deficiency was associated with a decrease in serum TSH with age. Other environmental factors were also important for goiter development (increase in risk, smoking and pregnancy; decrease in risk, oral contraception and alcohol consumption), and the individual risk depended on the genetic background. Environmental factors had only a minor influence on the prevalence of thyroid autoantibodies in the population. There were more cases of overt hypothyroidism in mild than in moderate iodine deficiency caused by a 53% higher incidence of spontaneous (presumably autoimmune) hypothyroidism. On the other hand, there were 49% more cases of overt hyperthyroidism in the area with moderate iodine deficiency. The cautious iodine fortification program, aiming at an average increase in iodine intake of 50 mug/day has been associated with a 50% increase in incidence of hyperthyroidism in the area with the most severe iodine deficiency. The incidence is expected to decrease in the future, but there may be more cases of Graves' hyperthyroidism in young people., Conclusion: A number of environmental factors influence the epidemiology of thyroid disorders, and even relatively small abnormalities and differences in the level of iodine intake of a population have profound effects on the occurrence of thyroid abnormalities. Monitoring and adjustment of iodine intake in the population is an important part of preventive medicine.

Objective: Studies of hypothyroidism are often based on referred patients, and limited information is available on the incidence rates of subtypes of hypothyroidism in the general population. We therefore studied incidences of subtypes of primary, overt hypothyroidism in a Danish population cohort and compared incidences in two subcohorts with different levels of iodine intake., Design: A prospective population-based study, monitoring a well-defined cohort representative of the Danish population., Methods: The Danish Investigation of Iodine Intake and Thyroid Diseases registry of hyper- and hypothyroidism was established as part of the monitoring of the iodine fortification of salt in Denmark. A computer-based system linked to laboratory databases identified all patients diagnosed with new, biochemically overt hypothyroidism in populations living in Aalborg (moderate iodine deficiency, n = 311,102) and Copenhagen (mild iodine deficiency, n = 227,632). We subsequently evaluated all identified patients to verify incident thyroid disease, and subclassified hypothyroidism into nosological types., Results: During a 4-year period (2,027,208 person-years) 685 new cases of overt hypothyroidism were diagnosed in the cohort; the incidence rate was 32.8 per 100,000 person-years (standardised to the Danish population). Nosological types of hypothyroidism were: spontaneous (presumably autoimmune) 84.4%, post-partum 4.7%, amiodarone-associated 4.0%, subacute thyroiditis 1.8%, previous radiation or surgery 1.8%, congenital 1.6% and lithium-associated 1.6%. Crude incidence rates were 29.0 around Aalborg and 40.6 in an area of Copenhagen. The higher incidence rate of hypothyroidism in the area with higher iodine intake was caused solely by more cases of spontaneous (presumably autoimmune) hypothyroidism, whereas the incidence of non-spontaneous hypothyroidism (all types combined) was significantly lower in the area with higher iodine intake., Conclusion: In a population-based study we observed a higher incidence of hypothyroidism with higher iodine intake. This was due solely to the entity of spontaneous hypothyroidism. The occurrence of overt hypothyroidism was relatively low in Denmark.

Background: Thyroid autoimmunity is more common in females than in males. One possible explanation for this female preponderance may be the effect of oestrogens on the immune system. It has also been suggested that foetal microchimerism involving transfer of foetal cells into maternal tissue during pregnancy may play an important role., Objective: We investigated the association between the presence of circulating thyroid autoantibodies and previous pregnancy, parity and the use of oral contraceptives (OCs) and hormone replacement therapy (HRT) in a population cohort., Methods: We examined 3712 women randomly selected from the general population. Serum was analysed for thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) using assays based on an RIA technique (DYNO test). Data were analysed in logistic regression models to adjust for possible confounders. Women previously treated for thyroid disease or with pregnancy within 1 year prior to the study were excluded from the analyses., Results: In both univariate and multivariate models and whether the presence of TPO-Ab and Tg-Ab was investigated alone or in combination, findings were negative with respect to an association between circulating thyroid antibodies and previous pregnancy, number of pregnancies, parity and previous abortion. There was no association between thyroid autoantibodies and use of OCs. Women aged 60-65 years receiving HRT now or previously had a lower prevalence of Tg-Ab (univariate, P = 0.01; multivariate, P = 0.02). No such association was observed between HRT and TPO-Ab., Conclusion: In this population study there was no association between previous pregnancy, parity and thyroid antibodies, which argues against the role of microchimerism as a trigger of thyroid autoimmunity. Exogenous oestrogens may reduce aspects of autoimmunity.

Context: Increasing prevalence of overweight in the population is a major concern globally; and in the United States, nearly one third of adults were classified as obese at the end of the 20th century. Few data have been presented regarding an association between variations in thyroid function seen in the general population and body weight., Objective: The aim of this study was to investigate the association between thyroid function and body mass index (BMI) or obesity in a normal population., Design: A cross-sectional population study (The DanThyr Study) was conducted., Participants: In all, 4649 participants were investigated, and 4082 were eligible for these analyses after exclusion of subjects with previous or present overt thyroid dysfunction., Main Outcome Measures: The study examined the association between category of serum TSH or serum thyroid hormones and BMI or obesity in multivariate models, adjusting for possible confounding., Results: We found a positive association between BMI and category of serum TSH (P < 0.001) and a negative association between BMI and category of serum free T(4) (P < 0.001). No association was found between BMI and serum free T(3) levels. The difference in BMI between the groups with the highest and lowest serum TSH levels was 1.9 kg/m(2), corresponding to a difference in body weight of 5.5 kg among women. Similarly, the category of serum TSH correlated positively with weight gain during 5 yr (P = 0.04), but no statistically significant association was found with weight gain during 6 months (P = 0.17). There was an association between obesity (BMI > 30 kg/m(2)) and serum TSH levels (P = 0.001)., Conclusions: Our results suggest that thyroid function (also within the normal range) could be one of several factors acting in concert to determine body weight in a population. Even slightly elevated serum TSH levels are associated with an increase in the occurrence of obesity.

Around 3-4 billion people in the world are covered by iodine supplementation programs to prevent developmental brain damage and other iodine deficiency (ID) disorders. Mild ID is associated with more hyperthyroidism and less hypothyroidism in the population than a high iodine intake. Knowledge of the iodine intake levels where the shifts in incidences occur is important for planning of iodine supplementation programs. A computer-based register linked to thyroid diagnostic laboratories was used to continuously identify all new cases of overt hyper- and hypothyroidism in two population cohorts with moderate and mild ID, respectively (Aalborg, n = 310,124; urinary iodine, 45 micro g/liter; and Copenhagen, n = 225,707; urinary iodine, 61 micro g/liter). The investigation was initiated before iodization of salt in Denmark and was part of the monitoring program. In 1997-1998, the incidence rate of overt hyperthyroidism was high in the area with the lowest iodine intake (92.9/100,000 per year) compared with the area with only mild ID (65.4/100,000 per year). Standardized rate ratio was 1.49, and 95% confidence interval was 1.22-1.81. The opposite relationship was present for overt hypothyroidism (moderate ID, 26.5/100,000 per year; mild ID, 40.1/100,000 per year; standardized rate ratio, 0.73; 95% confidence interval, 0.55-0.97). The different incidence rates were confirmed during each of the two following years. The results of this prospective investigation of the incidence of overt hyper- and hypothyroidism suggest that iodine supplementation of a population may increase the incidence of overt hypothyroidism, even if the population is moderately iodine-deficient. In such a population, the increase in risk of hypothyroidism should be weighed against the risk of ID disorders such as hyperthyroidism due to multinodular toxic goiter. The optimal level of iodine intake to prevent thyroid disease may be a relatively narrow range around the recommended daily iodine intake of 150 micro g.

Objective: Pregnancy has been suggested as part of the explanation of the gender difference in the prevalence of goitre, but opposing results have been reported on the association between pregnancy and goitre. We investigated the association between parity and thyroid volume and a possible impact of iodine deficiency and tobacco smoking on this association., Design: A comparative, cross-sectional study of 3712 women randomly sampled from the general population in two geographical areas with moderate and mild iodine deficiency., Methods: The participants answered questionnaires with an obstetric anamnesis, and ultrasonography of the thyroid was performed. Data were analysed in linear models and logistic regression analysis to adjust for age, iodine status, use of oral contraceptives and smoking habits. Women with present or recent pregnancies were excluded from the analyses., Results: A higher thyroid volume was found among parous than among nulliparous women (P=0.007). The association between parity and thyroid volume was strongest in the youngest age groups, in the region with the most severe iodine deficiency, and among smokers. No association was found between parity and the prevalence of solitary or multiple thyroid nodules. Number of births, age at menarche or menopause, the number of fertile years, and age at first childbirth were not associated with thyroid volume., Conclusion: Pregnancy increases thyroid volume, particularly when combined with tobacco smoking and iodine deficiency. The effect is probably reversible seen over a spectrum of several years.

Serum Tg is widely used in the control of thyroid cancer but also in the diagnosis of certain other thyroid diseases. Serum Tg may be useful in the characterization of the iodine status of a population, but little is known about determinants of serum Tg levels. We examined a random selection of 4,649 subjects from 2 regions in Denmark with different iodine status. Thyroid volume and structure were determined with ultrasonography, and thyroid function tests and Tg analysis were performed. The factor with the closest association with serum Tg levels was thyroid volume at ultrasonography (P < 0.001). Also thyroid nodularity (P < 0.001) and iodine excretion (P < 0.001) had close associations to serum Tg, even after adjusting for the influence of the other parameters. Thyroid dysfunction had a less pronounced but still highly significant association with serum Tg (P < 0.001), but no relation was found to serum TSH in general. The association with age seemed to rely on differences in the prevalence of thyroid abnormalities, and men had lower Tg levels than women of the same age. There was a marked difference in serum Tg between the two regions with slightly different iodine excretion also after adjusting for the other factors. In conclusion, serum Tg reflects thyroid abnormalities and thyroid function and is a sensitive marker of iodine deficiency in a population.

Objective: The pattern of thyroid dysfunction seems to depend on the iodine status of the population. Prevalence of thyroid dysfunction could be a parameter to consider when evaluating iodine deficiency disorders in a population., Design: Comparative cross-sectional investigation in two regions in Denmark with marginally different iodine excretion., Methods: A random selection of 4649 participants from the Civil Registration System in Denmark in age groups between 18 and 65 years were examined. Thyroid dysfunction was evaluated from blood samples and questionnaires, and compared with results from ultrasonography., Results: Median iodine excretion was 53 microg/l in Aalborg and 68 microg/l in Copenhagen. Previously diagnosed thyroid dysfunction was found with the same prevalence in the regions. Serum TSH was lower in Aalborg than in Copenhagen (P=0. 003) and declined with age in Aalborg, but not in Copenhagen. Not previously diagnosed hyperthyroidism was found with the same overall prevalence in the regions, but in age >40 years hyperthyroidism was more prevalent in Aalborg (1.3 vs 0.5%, P=0.017). Not previously diagnosed hypothyroidism was found more frequently in Aalborg (0.6 vs 0.2%, P=0.03). Hyperthyroidism was more often associated with macronodular thyroid structure at ultrasound in Aalborg and hypothyroidism was more often associated with patchy thyroid structure in Copenhagen., Conclusions: Significant differences in thyroid dysfunction were found between the regions with a minor difference in iodine excretion. The findings are in agreement with a higher prevalence of thyroid autonomy among the elderly in the most iodine-deficient region.

Objective: Multinodular goitre has been found with a high prevalence in iodine-deficient areas, but less frequently in iodine-replete areas; the iodine intake sufficient to prevent goitre has not been established, however., Methods: We report data from an ultrasonic investigation of the thyroid glands of 2656 randomly selected subjects aged 41 to 71 years in an area with borderline iodine deficiency., Results: Median iodine concentration in spot urine samples was 70microg/l. Multinodular thyroid structure was found in 23% of the population, increasing in women from 20 to 46% with increasing age, and in men from 7 to 23%. Solitary, scintigraphically cold, thyroid nodules >10mm were found in 2.4% of the population with the same prevalence in the different age and sex groups. Two years of follow-up of these cold nodules revealed no signs of malignancies. Median thyroid volume was 11.0ml. Thyroid enlargement (>18ml for women and >25ml for men) was found among 13. 1% of the women and 6.2% of the men, and the prevalence increased with age. The presence of thyroid nodules was related to positive anti-thyroperoxidase antibody (TPO Ab) titres, whereas thyroid enlargement was associated with iodine excretion <50microg/day., Conclusions: Thyroid enlargement was associated with low iodine excretion and median thyroid volume was slightly increased compared with iodine-replete areas. Multinodular thyroid structure was found with a high prevalence and was associated with TPO Ab >200kU/l. Cold thyroid nodules were moderately prevalent, with no cases of detected malignancies during 2 years of follow-up.