Does iodine fortification affect the risk of atrial fibrillation in incident hyperthyroidism? A national register-based cohort.

OBJECTIVE: Iodine fortification (IF) induces an initial increase followed by a decrease in the incidence of hyperthyroidism in the general population. Within the population of hyperthyroid patients, the sex-, age- and subtype distribution changes after IF. The risk of atrial fibrillation (AF) in hyperthyroid patients may be influenced by these factors. Therefore, we aimed to examine how the association between incident hyperthyroidism and AF was affected by IF increasing the population iodine intake from moderate-mild iodine deficiency to low adequacy. DESIGN, PATIENTS AND MEASUREMENTS: Incident hyperthyroid patients were included at the date of first inpatient or outpatient diagnosis, and AF diagnoses within 3 months before to 6 months after the index date were identified in Danish nationwide registers, 1997-2018. The relative risk (RR) of AF each calendar year (reference: 1997; IF introduced: 2000) was analyzed in Poisson regression models adjusted for age, sex, educational level, geographic region, and comorbidities. RESULTS: Overall, in 62,201 patients with incident hyperthyroidism 7.9% were diagnosed with AF. There was a minor nonsignificantly increased risk of AF during the first years after IF followed by a gradual decrease to RR 0.76 (0.62-0.94) in 2017. There were no statistically significant differences in the development in the risk of AF by sex, age group, or geographic region. CONCLUSIONS: Results indicate that IF may reduce the risk of concomitant AF in hyperthyroid patients. If these results are confirmed, IF may not only reduce the population incidence of hyperthyroidism but also reduce the burden of morbidity in the remaining hyperthyroid patients.

Influence of educational level on test and treatment for incident hypothyroidism.

OBJECTIVE: The incidence of hypothyroidism is not expected to differ by socioeconomic factors. However, the decision to test and initiate treatment may differ. We aimed to examine whether educational level influences the probability of thyroid stimulation hormone (TSH)-measurement and initiation of levothyroxine treatment. DESIGN: Citizens in the greater Copenhagen Area during 2001-2015 were included. Individual-level data on educational level, diagnoses, GP-contact, TSH-measurement and medication were derived from administrative and healthcare registers. The relative risks (RR) between educational levels of annual TSH-measurement and treatment initiation following a TSH-measurement were analysed in Poisson regression models with generalized estimation equations. RESULTS: A TSH-measurement was performed in 19% of 9,390,052 person years. The probability of TSH-measurement was higher with short (RR 1.16 [95% CI 1.15-1.16]) and medium (RR 1.11 [95% CI 1.06-1.12]) compared with long education. Treatment was initiated after 0.8% of 2,049,888 TSH-measurements. For TSH < 5 mIU/L, RR for treatment initiation ranged between 0.47 (95%CI 0.39-0.57) and 0.78 (95%CI 0.67-0.91) for short and medium compared with long education. For TSH 5-10 mIU/L, there was no statistically significant difference. For TSH > 10 mIU/L, RR was 1.07 (95% CI 1.02-1.12) for short and 1.08 (95% CI 1.03-1.13) for medium compared with long education. CONCLUSION: The probability of TSH-measurement was higher with shorter education, and the probability of treatment initiation with TSH > 10 mIU/L was marginally higher with short-medium education compared with long education. However, the probability of treatment initiation with TSH < 5 mIU/L, that is treatment incongruous with guidelines, was substantially higher in persons with long education.

Changes in subtypes of overt thyrotoxicosis and hypothyroidism following iodine fortification.

OBJECTIVE: To investigate the impact of mandatory iodine fortification (IF) on the incidence of nosological subtypes of overt thyrotoxicosis and hypothyroidism. DESIGN: We identified and scrutinized all possible new cases of overt thyrotoxicosis and hypothyroidism in an open cohort in Northern Jutland (n = 309 434; 1 January 1997) during the years 2014-2016. Individual medical history was evaluated to verify and detail the incidence of overt thyroid dysfunction and for classification into nosological subtypes. A number of cases were excluded during final verification due to spontaneous normalization of thyroid function, as they had no medical history suggesting a known condition, which could transiently affect thyroid function (subacute/silent thyroiditis, PPTD and iatrogenic thyroid dysfunction). An identical survey was conducted in 1997-2000 prior to mandatory IF of salt (13 µg/g) that was in effect from year 2001. RESULTS: The standardized incidence rate (SIR) of verified overt thyrotoxicosis decreased markedly from 97.5/100 000/year in 1997-2000 to 48.8 in 2014-2016 (SIRR: 0.50 [95% CI: 0.45-0.56]). This was due to a distinct decrease in the SIR of multinodular toxic goitre (SIRR: 0.18 [0.15-0.23]), solitary toxic adenoma (SIRR: 0.26 [0.16-0.43]) and to a lesser degree Graves' disease (SIRR: 0.67 [0.56-0.79]). SIR for overt hypothyroidism was unaltered by 2014-2016 (SIRR: 1.03 [0.87-1.22]). However, age distribution shifted with more young and fewer elderly cases of verified overt hypothyroidism. CONCLUSION: Mandatory IF caused a substantial reduction in SIR of verified overt thyrotoxicosis (especially of nodular origin) while avoiding an increase in SIR of verified overt hypothyroidism.

Thyrotoxicosis after iodine fortification. A 21-year Danish population-based study.

OBJECTIVE: Monitoring the influence of cautious iodine fortification (IF) on the incidence rate of overt thyrotoxicosis in Denmark with formerly frequent multinodular toxic goitre. DESIGN: A 21-year (1997-2017) prospective population-based study identified all new cases of overt biochemical thyrotoxicosis in two open cohorts: a Western cohort with moderate iodine deficiency (ID) and an Eastern cohort with mild ID (total n = 533 969 by 1 January 1997). A diagnostic algorithm was applied to all thyroid function tests performed within the study areas. Mandatory IF of salt was initiated in mid-2000 (13 ppm). This study is a part of DanThyr. RESULTS: The standardized incidence rate (SIR) of thyrotoxicosis at baseline (1997-1998) was 128.5/100.000/year in the cohort with moderate ID and 80.1 in the cohort with mild ID. SIR increased markedly in both cohorts during the initial years of IF (moderate/mild ID: +39/+52% in 2000-2001/2004-2005) and subsequently decreased to baseline level (mild ID) or below (moderate ID) by 2008. The decline was due to a marked decrease in the incidence rate among elderly subjects and a moderate decrease among the middle aged. The follow-up period for the mildly iodine deficient cohort was restricted to 2008. A continuous decline in SIR was observed for the remainder of the study period in the area with moderate ID (33% below baseline in 2016-2017). CONCLUSION: The rise in thyrotoxicosis incidence with cautious mandatory IF returned to baseline level after 7-8 years and levelled out at 33% below baseline in the population with previously moderate ID after 16-17 years.

Serum thyroglobulin as a biomarker of iodine deficiency in adult populations.

OBJECTIVE: To clarify which factors may influence the serum Tg level in an adult population and how this may affect Tg as a biomarker of iodine deficiency (ID). DESIGN AND METHODS: Two identical cross-sectional studies were performed before (C1a: 1997-98, n = 4649) and after (C2: 2004-05, n = 3570) the Danish mandatory iodine fortification (IF) of salt (2000). Additionally, a follow-up study of C1a was performed after IF (C1b: 2008-10, n = 2465). The studies took place in two regions with mild (Copenhagen) and moderate (Aalborg) ID before IF. Serum Tg was measured by immunoradiometric method and investigated as outcome variable in multivariate models. RESULTS: Multiple factors were associated with serum Tg. Some were directly related to iodine intake (cohort, urinary iodine concentration (UIC) level and region), and some were likely mediators of iodine intake effects on Tg (thyroid nodularity, thyroid size and autonomy with low TSH). Others were caused by Tg assay interference (Tg-Ab positivity), aggravation of ID (childbirths and smoking) or TSH stimulation of the thyroid. Estimated 24-h urinary iodine excretion was a more sensitive predictor of Tg than UIC. Iodine supplement users had low median Tg values compared with nonusers both before and after IF. CONCLUSIONS: Multiple factors should be taken into consideration when evaluating Tg as a marker of ID in adult populations, and the Tg results may depend on the assay used. Still, Tg is a sensitive marker of ID. We suggest including a reference population with known sufficient iodine intake when Tg is used to evaluate ID.

Gender differences in symptoms of hypothyroidism: a population-based DanThyr study.

OBJECTIVES: We examined the gender-specific symptom prevalences in hypothyroidism and in healthy controls and explored the extent to which symptoms indicative of thyroid status may be different in women and men. DESIGN AND METHODS: Patients newly diagnosed with overt autoimmune hypothyroidism (n = 140) and controls free of thyroid disease (n = 560) recruited from the same population participated in a population-based study of The Danish Investigation of Iodine Intake and Thyroid Diseases (DanThyr). Participants underwent a comprehensive programme including blood tests and completion of questionnaires. The gender-specific distribution of 13 hypothyroidism-associated symptoms and a simple combined score (0-13) was explored in conditional uni- and multivariate models taking into account a broad spectrum of possible confounders. Diagnostic odds ratios (DORs) were calculated as measures for the association between participant status (case vs control) and presence of symptoms (yes vs no). RESULTS: In overt autoimmune hypothyroidism, 94·9% of women and 91·3% of men (P = 0·62) reported at least one of the hypothyroidism-associated symptoms, with tiredness as the most common symptom followed by dry skin and shortness of breath. In contrast, women free of thyroid disease self-reported at least one hypothyroidism-associated symptom considerably more often than men (73·7% vs 51·1%, P < 0·001). DORs (±SEM) for 0-1/2-3/4-13 symptoms were 0·07 (0·04-0·10)/2·15 (1·57-2·94)/7·99 (6·15-10·4) in men and 0·21 (0·16-0·28)/0·62 (0·58-0·66)/1·99 (1·90-2·09) in women. CONCLUSION: The presence of symptoms is more indicative for overt autoimmune hypothyroidism in men than in women, and presumably persistent symptoms after therapy of hypothyroidism will be more common in women.

The Danish investigation on iodine intake and thyroid disease (DanThyr): history and implications.

Due to mild-to-moderate iodine deficiency in Denmark, health authorities initiated a voluntary iodine fortification (IF) program in 1998, which became mandatory in 2000. In line with recommendations from the World Health Organization, the Danish investigation on iodine intake and thyroid disease (DanThyr) was established to monitor the effect on thyroid health and disease. The program involved different study designs and followed two Danish sub-populations in the years before IF and up till 20 years after. Results showed that the IF was successfully implemented and increased the level of iodine intake from mild-moderate iodine deficiency to low adequacy. The level of thyroglobulin and thyroid volume decreased following IF, and there was an indication of fewer thyroid nodules. The incidence of hyperthyroidism increased transiently following IF but subsequently decreased below the pre-fortification level. Conversely, thyroid-stimulating hormone levels and the prevalence of thyroid autoimmunity increased along with an increase in the incidence of hypothyroidism. These trends were mirrored in the trends in treatments for thyroid disease. Most differences in thyroid health and disease between regions with different iodine intake levels before IF attenuated. This review illustrates the importance of a monitoring program to detect both beneficial and adverse effects and exemplifies how a monitoring program can be conducted when a nationwide health promotion program - as IF - is initiated.

Selenium supplementation and placebo are equally effective in improving quality of life in patients with hypothyroidism.

PURPOSE: We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479). METHODS: We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 µg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after six weeks, three, six, 12, and 18 months. RESULTS: In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 [95%CI:24.5-33.6] and 28.0 [24.5-33.1], respectively; P=0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 [95%CI:1512-2512] vs. 2344 kIU/L [1862-2951]; P=0.016) but did not influence LT4 dosage or free triiodothyronine/free thyroxin ratio. CONCLUSION: In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 µg selenium or placebo for 12 months improved QoL to the same extent.

Serum selenium is low in newly diagnosed Graves' disease: a population-based study.

CONTEXT: Selenium deficiency may play an important role in the initiation and progression of autoimmune thyroid disease. OBJECTIVE: To compare serum selenium (s-Se) values in patients with newly diagnosed autoimmune thyroid disease and controls from the Danish population. DESIGN AND SETTINGS: S-Se was measured in triplicate by a fluorimetric method. PARTICIPANTS: Patients with newly diagnosed Graves' disease (GD) (n = 97) or autoimmune overt hypothyroidism (AIH) (n = 96), euthyroid subjects with high serum levels of thyroid peroxidase antibody (TPO-Ab) (TPO-Ab > 1500 U/ml, n = 92) and random controls (n = 830). MAIN OUTCOME MEASURE: Differences in s-Se values. RESULTS: S-Se was lower in patients with GD than in controls (mean (SD), GD: 89·9 µg/l (18·4); controls: 98·8 µg/l (19·7), P < 0·01). This was confirmed in a multivariate logistic regression model adjusting for age, sex, mineral supplements, smoking, geographical region and time of sampling (P < 0·01). In a linear model, s-Se was similar in patients with AIH (mean (SD): 98·4 µg/l (24·9)) and in controls (P = 0·86). In the multivariate model however, s-Se was marginally lower in patients with AIH compared to controls (P = 0·04). There was no significant difference in s-Se between euthyroid participants with high TPO-Ab and random controls (linear: P = 0·97; multivariate: P = 0·27). CONCLUSION: Patients with newly diagnosed GD and AIH had significantly lower s-Se compared with random controls. Our observation supports the postulated link between inadequate selenium supply and overt autoimmune thyroid disease, especially GD.

Graves' hyperthyroidism and moderate alcohol consumption: evidence for disease prevention.

BACKGROUND: We recently demonstrated that moderate alcohol consumption is associated with a considerable reduction in the risk of autoimmune hypothyroidism, similar to findings in other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. We aimed to study a possible association between alcohol intake and autoimmune Graves' hyperthyroidism. DESIGN: This is a population-based, case-control study. METHODS: In a well-defined Danish population (2,027,208 person-years of observation), we prospectively identified patients with new overt thyroid dysfunction and studied 272 patients with Graves' hyperthyroidism. For each patient, we recruited four age-gender-region-matched controls with normal thyroid function (n = 1088). MEASUREMENTS: Participants gave detailed information on current and previous alcohol intake as well as other factors to be used for analyses. The association between alcohol intake and development of hyperthyroidism was analysed in conditional multivariate Cox regression models. RESULTS: Graves' patients had a lower reported alcohol consumption than controls (median units of alcohol (12 g) per week: 2 vs 4, P < 0·001). In a multivariate regression model, alcohol consumption was associated with a dose-dependent reduction in risk for development of overt Graves' hyperthyroidism. Odds ratios (95% confidence interval) compared with the reference group with a recent (last year) consumption of 1-2 units of alcohol per week were as follows: 0 units/week 1·73 (1·17-2·56), 3-10 units/week 0·56 (0·39-0·79), 11-20 units/week 0·37 (0·21-0·65), ≥21 units/week 0·22 (0·08-0·60). Similar results were found for maximum previous alcohol consumption during a calendar year. No interaction was found with the type of alcohol consumed (wine vs beer), smoking habit, age, gender or region of inhabitancy. CONCLUSIONS: Moderate alcohol consumption is associated with a considerable reduction in the risk of Graves' disease with hyperthyroidism--irrespective of age and gender. Autoimmune thyroid disease seems to be much more dependent on environmental factors than hitherto anticipated.

Smoking cessation is followed by a sharp but transient rise in the incidence of overt autoimmune hypothyroidism - a population-based, case-control study.

BACKGROUND: Current smoking is associated with a low prevalence of thyroid autoantibodies. On the other hand, smoking withdrawal enhances thyroid autoantibody level and may be a risk factor for the development of hypothyroidism. The aim of this study was to assess the association between smoking habits (smoking cessation in particular) and development of autoimmune hypothyroidism. DESIGN: Population-based, case-control study. PARTICIPANTS: Cases (n = 140) newly diagnosed with primary autoimmune overt hypothyroidism were identified prospectively by population monitoring (2,027,208 person-years of observation) of all thyroid function tests performed in the two well-defined geographical areas. Individually, age-, sex- and region-matched euthyroid controls (n = 560) were simultaneously included from the same population. MEASUREMENTS: Participants gave details on smoking habits including smoking withdrawal and other lifestyle factors. Smoking habits were verified by measuring urinary cotinine (a nicotine metabolite). RESULTS: Incident hypothyroidism was very common in people who had recently stopped smoking: OR vs never smokers (95%-CI); quit smoking <1 years, 7·36 (2·27-23·9); 1-2 years, 6·34 (2·59-15·3); 3-10 years, 0·75 (0·30-1·87); >10 years, 0·76 (0·38-1·51). Results were consistent in both sexes and irrespective of age. Within two years after smoking cessation, the percentage of hypothyroid cases attributable to cessation of smoking was 85%. The current smoking was not associated with altered risk of developing overt hypothyroidism [OR, 0·92 (0·57-1·48)]. CONCLUSIONS: The risk of having overt autoimmune hypothyroidism diagnosed is more than 6-fold increased the first 2 years after cessation of smoking. Clearly, smoking cessation is vital to prevent death and severe disease. However, awareness of hypothyroidism should be high in people who have recently quit smoking, and virtually any complaint should lead to thyroid function testing.

A cautious iodization programme bringing iodine intake to a low recommended level is associated with an increase in the prevalence of thyroid autoantibodies in the population.

UNLABELLED: Autoantibodies against the thyroid gland with thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) as the most common can often be demonstrated in serum. The effect of public iodization programmes on antibody prevalence is uncertain. AIM: To measure the concentrations of thyroid autoantibodies in the Danish population before and after mandatory iodization of salt. METHODS: Two identical cross-sectional population studies were performed before (Cohort 1 (C1), year 1997-1998, n = 4649, median urinary iodine 61 µg/l) and 4-5 years after (Cohort 2 (C2), year 2004-2005, n = 3570, median urinary iodine 101 µg/l) mandatory iodine fortification of salt was implemented in Denmark. Blood tests were analysed for TPO-Ab and Tg-Ab using sensitive assays. RESULTS: Antibodies were more frequent in C2 than in C1: TPO-Ab > 30 U/ml, C1 vs C2: 14·3 vs 23·8% (P < 0·001) and Tg-Ab > 20 U/ml, C1 vs C2: 13·7 vs 19·9% (P < 0·001). The C2 vs C1 effect was confirmed in multivariate regression models (C1 reference): TPO-Ab: OR (95% CI): 1·80 (1·59-2·04) and Tg-Ab: 1·49 (1·31-1·69). The increase in the frequency of thyroid antibodies was most pronounced in young women and especially observed at low concentrations of antibodies. CONCLUSION: The prevalence of both TPO-Ab and Tg-Ab was higher 4-5 years after a cautious iodine fortification of salt was introduced in Denmark. The increase was most pronounced in young women and in the low concentrations of antibody. Further studies are needed to evaluate the long-term effects of increased iodine intake on thyroid autoimmunity in the population.

Doubling in the use of thyroid hormone replacement therapy in Denmark: association to iodization of salt?

Iodization of salt is an effective strategy to prevent iodine deficiency disorders. Recent studies, however, indicate that increasing the iodine intake in a population may give rise to an increased incidence of hypothyroidism, but the association has not been fully clarified. In Denmark, iodization of salt was initiated in 1998 because of mild-to-moderate iodine deficiency. The aim of this study was to evaluate the effect of the raised iodine intake on the nationwide incident use of thyroid hormone replacement therapy (levothyroxine) to treat hypothyroidism. Data on all use of levothyroxine was extracted from the Register of Medicinal Product Statistics during the period 1995-2009 and linked to other nationwide registers by use of the Danish identification number. Persons with previous thyroid surgery were excluded. In the studied period 71,565 incident users were identified. The incidence rate increased 75% in the moderately iodine deficient region (72.2 incident users/100,000 person-years in 1997 to 126.6 in 2008) and 87% in the mildly deficient region (86.9-162.9). When stratified by sex and age-group (00-39, 40-64, 65+) the largest relative increase was seen among women in the youngest age-group, where more than a doubling was seen. The mechanisms behind the increase may be a result of iodine-induced hypothyroidism, although a higher diagnostic activity with regard to thyroid dysfunction and intensified treatment of subclinical hypothyroidism may also play a role. Our findings stress the need for caution when initiating iodine fortification programs to keep the intake within the optimal range, and the need for continuous monitoring.

Stagnation in body mass index in Denmark from 1997/1998 to 2004/2005, but with geographical diversity.

INTRODUCTION: We analyzed the trend in body mass index (BMI) as well as in the prevalence of overweight and obesity among Danish adults, mainly women, from 1997/1998 to 2004/2005 and evaluated any regional differences. MATERIAL AND METHODS: Data were drawn from two cross-sectional population-based studies conducted in parallel in Aalborg and Copenhagen from 1997/1998 and 2004/2005. Height and weight were measured in a total of 7,487 participants in the two cohorts. RESULTS: In the total cohort, we found no significant difference in BMI from 1997/1998 to 2004/2005 (p = 0.828). There was an increase in BMI in Aalborg of 0.32 (p = 0.030), while in Copenhagen we observed a statistically significant decrease in BMI of 0.30 (p = 0.017). The difference in change over time in BMI between the two regions was significant (p = 0.002). Also the difference in the trend in prevalence of overweight and obesity was statistically significant between the two cities (p = 0.010). CONCLUSION: Our results indicate that the obesity epidemic is leveling off - at least among women - and that it may even be receding in Copenhagen. Nevertheless, the absolute average BMI values and the prevalence of overweight and obesity in both cities are high which underlines the need for further initiatives to prevent obesity-related health risks in the future. FUNDING: The DanThyr studies were supported by funding from the Tømmerhandler Vilhelm Bang Foundation, the Copenhagen Corporation Research Foundation, the 1991 Pharmacy Foundation, the Danish Medical Foundation, the Health Insurance Foundation, the Agnes and Knut Mørk Foundation, the Wedel Wedelsborg Foundation, the Ortho-Clinical Foundation and BRAHMS Diagnostica. TRIAL REGISTRATION: not relevant.

Does Subclinical Hypothyroidism Add Any Symptoms? Evidence from a Danish Population-Based Study.

BACKGROUND: Few studies have scrutinized the spectrum of symptoms in subclinical hypothyroidism. METHODS: From 3 Danish Investigation on Iodine Intake and Thyroid Diseases (DanThyr) cross-sectional surveys performed in the period 1997 to 2005, a total of 8903 subjects participated in a comprehensive investigation including blood samples and questionnaires on previous diseases, smoking habits, alcohol intake, and education. From the 3 surveys we included patients with subclinical hypothyroidism (n = 376) and euthyroid controls (n = 7619). We explored to what extent patients with subclinical hypothyroidism reported 13 previously identified hypothyroidism-associated symptoms (tiredness, dry skin, mood lability, constipation, palpitations, restlessness, shortness of breath, wheezing, globus sensation, difficulty swallowing, hair loss, dizziness/vertigo, and anterior neck pain). In various uni- and multivariate regression models we searched for circumstances predicting why some patients have more complaints than others. RESULTS: Subclinically hypothyroid patients did not report higher hypothyroidism score [(median, interquartile range), 2 (0-4) vs 2 (0-4), P = .25] compared with euthyroid controls. Within the group of subclinical hypothyroid patients, comorbidity had the highest impact on symptoms (tiredness, shortness of breath, wheezing; all P < .001); TSH level had no impact on symptom score; and younger age was accompanied by higher mental burden (tiredness, P < .001; mood lability, P < .001; restlessness, P = .012), whereas shortness of breath was associated with high body mass index (P < .001) and smoking (P = .007). CONCLUSION: Patients with a thyroid function test suggesting subclinical hypothyroidism do not experience thyroid disease-related symptoms more often than euthyroid subjects. In subclinical hypothyroidism, clinicians should focus on concomitant diseases rather than expecting symptomatic relief following levothyroxine substitution.

The association of thyroid stimulation hormone levels with incident ischemic heart disease, incident stroke, and all-cause mortality.

PURPOSE: Thyroid dysfunction may affect the risk of cardiovascular disease and mortality through effects on myocardial and vascular tissue and metabolism. Levels of thyroid stimulating hormone (TSH) indicates thyroid function. We aimed to assess the association between TSH-levels and incident ischemic heart disease (IHD), incident stroke, and all-cause mortality. METHODS: We included 13,865 participants (18-71 years, 51.6% women) from five cohort studies conducted during 1974-2008 were included. TSH was measured at the baseline examination and classified as <0.4; 0.4-2.5 (ref.); 2.5-5.0; 5.0-10, or >10 mU/l. Incident IHD, incident stroke, and all-cause mortality were identified in registries until ultimo 2013. Data were analysed by multivariate Cox regression with age as underlying time axis. Results from the individual cohorts were pooled by random-effects meta-analysis. RESULTS: The crude incidence rate was for IHD 7.8 cases/1000 person years (PY); stroke 5.4 cases/1000 PY; and all-cause mortality 11.3 deaths/1000 PY (mean follow-up: 14 years). Analyses showed no statistically significant associations between TSH-levels and incident IHD or incident stroke in the partly or fully adjusted models. There was a statistically significant association between TSH of 2.5-5 mU/l and all-cause mortality (hazard ratio 1.145 (95% CI 1.004-1.306) compared with TSH of 0.4-2.5 mU/l in the fully adjusted model. CONCLUSION: The results do not provide evidence of a harmful effect of decreased or increased TSH on IHD or stroke in the general population. However, there is some indication of an elevated risk for all-cause mortality with TSH 2.5-5 mU/l compared with 0.4-2.5 mU/l.

Lower prevalence of mild hyperthyroidism related to a higher iodine intake in the population: prospective study of a mandatory iodization programme.

OBJECTIVE: Marked differences in pattern of thyroid dysfunction are seen in populations with different iodine intakes. We evaluated the influence of a higher iodine intake on thyroid hormone levels and the prevalence of thyroid dysfunction in the Danish population. DESIGN: Two cross-sectional studies matched on a group level according to sex and age. PARTICIPANTS: In all, 8219 individuals were examined before (n = 4649) or after (n = 3570) the introduction of a mandatory iodization programme in 2000 in two regions with established mild and moderate iodine deficiency. Serum TSH, fT(4) and fT(3 )were measured. An ultrasonography of the thyroid was performed. RESULTS: We found a higher median serum TSH after the introduction of mandatory iodization of salt: 1.51 mU/l (10-90th percentiles: 0.72-3.00) vs. 1.30 mU/l (10-90th percentiles: 0.59-2.66) before iodization. The difference was found in both regions and across age groups. There was a lower prevalence of mild hyperthyroidism and a tendency towards a lower prevalence of overt hyperthyroidism. The prevalence of mild hypothyroidism increased, most pronounced among young women after iodization. Conversely, there was a lower prevalence of undiagnosed overt hypothyroidism. However, when currently treated participants were included, the prevalence of hypothyroidism increased after iodization in the area with formerly mild iodine deficiency. CONCLUSION: A change in pattern of thyroid dysfunction was seen in relation to mandatory iodization of salt. There was no rise in the prevalence of hyperthyroidism and the prevalence of mild hyperthyroidism was halved. Conversely, prevalence of hypothyroidism increased.

Previous Live Births and Induced Abortions May Precede Later Development of Graves' Hyperthyroidism.

OBJECTIVE: To investigate the association between reproductive history and later development of various nosological subtypes of overt hyperthyroidism. STUDY DESIGN: From the Danish population, we included incident hyperthyroid women, and for each case we recruited 4 euthyroid age-sex-region-matched controls from the same sub-population. Hyperthyroid cases/controls were: Graves' disease (GD, n = 232/928), multinodular toxic goitre (MNTG, n = 91/364), solitary toxic adenoma (STA, n = 21/84). Patients diagnosed with hyperthyroidism within 1 year after delivery including post-partum GD were excluded. In multivariate conditional regression models (reference: no reproductive events), we analysed the association between development of GD/MNTG/STA and reproductive factors such as age at menarche/menopause, reproductive span, number of pregnancies/childbirths/abortions, investigations for infertility, and years on oral contraceptives. We adjusted for possible confounders such as alcohol intake, smoking, co-morbidity, and education. Age was studied as a potential effect measure modifier. RESULTS: GD patients diagnosed before the age of 40 years had given births more often than control subjects (OR [95% CI] for 1/2/3+ births [ref.: nulliparous] were 1.57 [0.80-3.11]/2.06 [1.001-4.22]/3.07 [1.50-6.26]), and they had induced abortions performed more often (OR for 1/2+ induced abortions [ref.: no: events] were 0.99 [0.54-1.84]/2.24 [1.12-4.45]). No associations were observed between any reproductive factor and the development of MNTG or STA. CONCLUSIONS: Childbirths and induced abortions may be followed by development of Graves' hyperthyroidism after the post-partum period. This was not the case for the non-autoimmune subtypes of hyperthyroidism.

Increased Incidence Rate of Hypothyroidism After Iodine Fortification in Denmark: A 20-Year Prospective Population-Based Study.

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.

Iodine intake before and after mandatory iodization in Denmark: results from the Danish Investigation of Iodine Intake and Thyroid Diseases (DanThyr) study.

Iodine deficiency is still common in some European countries. In Denmark an iodine fortification programme was introduced in 1998 and a monitoring programme was established prior to iodization. This study reports the change in urinary iodine excretion caused by fortification and investigates determinants of iodine intake after fortification. Iodine excretion in casual urine samples was assessed in 4649 subjects in 1997-8 and in 3570 comparable subjects in 2004-5 in women 18-22, 25-30, 40-45 and 60-65 years of age and in men 60-65 years of age living in Aalborg (western part of Denmark) or Copenhagen (eastern part of Denmark). These areas had moderate and mild iodine deficiency, respectively, before iodine fortification. All subjects filled in a FFQ and a questionnaire regarding lifestyle factors. Iodine excretion, expressed as the estimated 24 h urinary iodine excretion and as urinary iodine concentration, increased significantly in all age and sex groups. However, the iodine intake was still below the recommended in the youngest age groups in both cities and in women 40-45 years of age living in Aalborg. Intake of milk and salt had strong significant direct associations with iodine excretion (P < 0.001). It is concluded that although the median iodine intake in the whole study population is at the recommended level, some groups still have an intake below the recommended. It is important to have a moderate milk intake to obtain a sufficient iodine intake in Denmark.