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.

Symptoms and biomarkers associated with undiagnosed celiac seropositivity.

BACKGROUND: Studies have indicated that underdiagnosis and diagnostic delay are common in celiac disease. Therefore, it is important to increase our knowledge of what symptoms and biomarkers could identify undiagnosed cases of celiac disease. METHODS: We screened for celiac disease antibodies in stored blood samples from 16,776 participants in eight population-based studies examined during 1976-2012. Undiagnosed celiac seropositivity was defined as celiac disease antibody positivity (IgG-deamidated gliadin peptide above 10.0 U/mL and/or IgA-tissue transglutaminase (TTG) or IgG-TTG above 7.0 U/mL) without a known diagnosis of celiac disease in the National Patient Register. In all studies general health symptoms were recorded by participant-completed questionnaire, including self-perceived health, tiredness, headache and gastrointestinal symptoms. Furthermore, blood samples were drawn for analyses of biomarkers e.g. hemoglobin, blood glucose, cholesterol, liver parameters and vitamins. The participants with undiagnosed celiac seropositivity were matched by sex, age and study with four controls among the celiac disease antibody negative participants. RESULTS: We excluded, five participants with known celiac disease, resulting in a population of 16,771 participants. In this population 1% (169/16,771) had undiagnosed celiac seropositivity. There were no statistically significant differences in symptoms between cases and controls. Undiagnosed celiac seropositivity was associated with low blood cholesterol (< 5 mmol/L) and low hemoglobin (< 7.3 mmol/L for women and < 8.3 mmol/L for men). CONCLUSION: In this general population study, undiagnosed cases of celiac seropositivity did not have more symptoms than controls, confirming the diagnostic difficulties of celiac disease and the low prognostic value of symptoms for a diagnosis of celiac disease. Furthermore, decreased levels of cholesterol and/or hemoglobin in the blood were associated with undiagnosed celiac seropositivity.

Long-term Consequences of Undiagnosed Celiac Seropositivity.

INTRODUCTION: Diagnosed celiac disease (CD) is associated with lymphoproliferative malignancy and gastrointestinal cancer, but little is known about the long-term consequences of undiagnosed CD. We aimed to investigate long-term consequences of undiagnosed CD for mortality and incidence of cancer and other chronic diseases. METHODS: We screened biobank serum samples for immunoglobulin (Ig) A and IgG tissue transglutaminase (TTG) and IgG deamidated gliadin peptide in a study of 8 population-based cohort studies comprising 16,776 participants examined during 1976-2012 and followed with >99% complete follow-up in Danish nationwide registries until December 31, 2017, regarding vital status and incidence of diseases. Undiagnosed CD was defined as antibody positivity (IgA-TTG or IgG-TTG ≥ 7 U/mL and/or IgG deamidated gliadin peptide ≥ 10 U/mL) in individuals without a diagnosis of CD recorded in the National Patient Register. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox regression analyses with age as the underlying time scale. RESULTS: The prevalence of undiagnosed CD was 1.0% with no statistically significant increase over time. Undiagnosed CD was associated with increased risk of cancer overall (HR, 1.57; 95% CI, 1.16-2.11), gastrointestinal cancer (HR, 2.33; 95% CI, 1.35-4.04), cancer of the uterus (HR, 3.95; 95% CI, 1.46-10.69), breast cancer (HR, 1.98; 95% CI, 1.02-3.82), head and neck cancer (HR, 3.12; 95% CI, 1.15-8.43), and cardiovascular disease (HR, 1.37; 95% CI, 1.01-1.85). We found no statistically significant association between undiagnosed CD and mortality (HR, 1.19; 95% CI, 0.87-1.61). DISCUSSION: Undiagnosed CD was associated with increased risk of cardiovascular disease and cancer suggesting that untreated CD has serious long-term health consequences not only affecting the gastrointestinal tract (see Visual Abstract, Supplementary Digital Content, http://links.lww.com/AJG/B566).

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.

Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone.

BACKGROUND: Levels of serum thyroid-stimulating hormone (TSH) indicate thyroid function, because thyroid hormone negatively controls TSH release. Genetic variants in the vascular endothelial growth factor A (VEGFA) gene are associated with TSH levels. The aim of this study was to characterise the association of VEGFA variants with TSH in a Danish cohort and to identify and characterise functional variants. METHODS: We performed an association study of the VEGFA locus for circulating TSH levels in 8445 Danish individuals. Lead variants were tested for allele-specific effects in vitro using luciferase reporter and gel-shift assays. RESULTS: Four SNPs in VEGFA were associated with circulating TSH (rs9472138, rs881858, rs943080 and rs4711751). For rs881858, the presence of each G-allele was associated with a corresponding decrease in TSH levels of 2.3% (p=8.4×10-9) and an increase in circulating free T4 levels (p=0.0014). The SNP rs881858 is located in a binding site for CHOP (C/EBP homology protein) and c/EBPß (ccaat enhancer binding protein ß). Reporter-gene analysis showed increased basal enhancer activity of the rs881858 A-allele versus the G-allele (34.5±9.9% (average±SEM), p=0.0012), while co-expression of CHOP effectively suppressed the rs881858 A-allele activity. The A-allele showed stronger binding to CHOP in gel-shift assays. CONCLUSIONS: VEGF is an important angiogenic signal required for tissue expansion. We show that VEGFA variation giving allele-specific response to transcription factors with overlapping binding sites associate closely with circulating TSH levels. Because CHOP is induced by several types of intracellular stress, this indicates that cellular stress could be involved in the normal or pathophysiological response of the thyroid to TSH. TRIAL REGISTRATION NUMBER: NCT00289237, NCT00316667; Results.

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.

Interaction between filaggrin null mutations and tobacco smoking in relation to asthma.

BACKGROUND: The mechanisms underlying the association between filaggrin (FLG) deficiency and asthma are not known. It has been hypothesized that FLG deficiency leads to enhanced percutaneous exposure to environmental substances that might trigger immune responses. We hypothesized that interactions between FLG deficiency and environmental exposures play a role in asthma development. OBJECTIVE: We sought to investigate possible interactions between FLG null mutations and tobacco smoking in relation to asthma. METHODS: A total of 3471 adults from a general population sample participated in a health examination. Lung function and serum specific IgE levels to inhalant allergens were measured, and information on asthma and smoking was obtained by means of questionnaire. Participants were genotyped for the 2 most common FLG null mutations in white subjects: R501X and 2282del4. Another Danish population was used for replication. RESULTS: The FLG null mutation genotype was significantly associated with a higher prevalence of asthma and decreased FEV(1)/forced vital capacity ratio. In logistic regression analyses with asthma as the outcome, a significant interaction was found between FLG null mutations and smoking status (P = .02). This interaction was confirmed, although it was not statistically significant, in another Danish population study. Interactions between FLG genotype and cumulated smoking exposure were found in relation to asthma (P = .03) and decreased FEV(1)/forced vital capacity ratio (P = .03). A 3-way interaction was found among FLG genotype, smoking, and asthma, suggesting that the FLG-smoking interaction mainly played a role in nonatopic subjects. CONCLUSION: FLG null mutations modified the effects of smoking on the risk of asthma. This finding might have implications for risk stratification of the population.

Vitamin D status and changes in cardiovascular risk factors: a prospective study of a general population.

OBJECTIVES: A low vitamin D level has been associated with increased cardiovascular disease risk but possible mechanisms remain unclear. We investigated the association between vitamin D levels and 5-year changes in blood pressure, lipid profile and incidence of the metabolic syndrome, hypertension and hypercholesterolemia. METHODS: A random sample of 6,784 individuals aged 30-60 years from a general population was investigated in the Inter99 study in 1999-2001. Vitamin D (serum 25-hydroxyvitamin D) was measured at baseline by high-performance liquid chromatography, and 4,330 individuals participated at the 5-year follow-up and were included in the present study. RESULTS: The median baseline vitamin D concentration was 48.0 nmol/l. In multivariable linear regression analyses, a 10 nmol/l higher baseline level of vitamin D was associated with a decrease in triglycerides and very low density lipoprotein cholesterol by 0.52 (p = 0.03) and 0.66% (p = 0.005), respectively. In multivariable logistic regression analyses, the odds ratios per 10 nmol/l higher baseline vitamin D level were 0.95 (p < 0.05) and 0.94 (p = 0.01) for the development of the metabolic syndrome and hypercholesterolemia, respectively. There was no association between vitamin D and blood pressure. CONCLUSIONS: An optimal vitamin D status may influence cardiovascular health by changing the lipid profile in a favorable direction and decreasing the incidence of the metabolic syndrome.

Register-based information on thyroid diseases in Europe: lessons and results from the EUthyroid collaboration.

Objective: Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. Design: Register-based cross-sectional study. Methods: National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated. Results: Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. Conclusions: The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.

Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP).

PURPOSE: Bone turnover markers (BTM) are gaining ground in clinical practice but to fully use their potential there is a need for establishing valid reference intervals (RI). Consequently, the purpose of the study was to establish general RI as well as suggested clinical RI for carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP) in children and adolescents. METHOD: BTM were measured on Danish children and adolescents participating in the CHAMPS-study DK. A total of 762 participants were included (8-18 years, 50.4% girls) contributing a total of 1410 study visits. The RI was calculated based on 2-years age spans. Participants with biochemical signs of metabolic bone disease were excluded. RESULTS: The differences in RI between age groups clearly reflect changes in growth with an initial increase in BTM, greatest in boys, and a subsequent decrease most pronounced in girls. ß-CTX and PINP are markers most affected by these changes, compared to OC and bone ALP. The suggested clinical 95% RI included participants with vitamin D insufficiency but no biochemical signs of metabolic bone disease which did not markedly alter the RI. CONCLUSION: RI for ß-CTX, PINP, OC and bone ALP varies with age and sex. ß-CTX and PINP which reflect bone resorption and formation processes are mostly affected by these changes. We suggest a set of clinically applicable 95% RI for the four BTM to heighten the usefulness and generalizability of the RI.

The economic impact of prevention, monitoring and treatment strategies for iodine deficiency disorders in Germany.

OBJECTIVE: More than 30% of the German population suffers from mild to moderate iodine deficiency causing goiter and other iodine deficiency disorders (IDDs). The economic burden of iodine deficiency is still unclear. We aimed to assess costs for prevention, monitoring and treatment of IDDs in Germany. DESIGN: We performed a comprehensive cost analysis. METHODS: We assessed direct medical costs and direct non-medical costs for inpatient and outpatient care of IDDs and costs for productivity loss due to the absence of work in 2018. Additionally, we calculated total costs for an IDD prevention program comprising universal salt iodization (USI). We performed threshold analyses projecting how many cases of IDDs or related treatments would need to be avoided for USI to be cost-saving. RESULTS: Annual average costs per case in the year of diagnosis were € 211 for goiter/thyroid nodules; € 308 for hyperthyroidism; and € 274 for hypothyroidism. Average one-time costs for thyroidectomy were € 4184 and € 3118 for radioiodine therapy. Average costs for one case of spontaneous abortion were € 916. Annual costs of intellectual disability were € 14,202. In the German population, total annual costs for USI would amount to 8 million Euro. To be cost-saving, USI would need to prevent, for example, 37,900 cases of goiter/thyroid nodules. CONCLUSION: USI potentially saves costs, if a minimum amount of IDDs per year could be avoided. In order to recommend the implementation of USI, a full health-economic evaluation including a comprehensive benefit-harm assessment is needed.

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.

Effects of age and sex on osteocalcin and bone-specific alkaline phosphatase-reference intervals and confounders for two bone formation markers.

Bone formation markers bone-specific alkaline phosphatase and osteocalcin are used in many clinical situations. Therefore, we calculated reference intervals for the two markers and investigated how they are influenced by several factors including sex and age. Furthermore, we established clinically relevant reference intervals for the two markers. OBJECTIVE: The bone turnover markers (BTMs), bone-specific alkaline phosphatase (bone ALP), and osteocalcin (OC), are frequently measured formation markers. The purpose of this study was to establish reference intervals (RIs) for the two BTMs in a general adult Danish population. METHODS: Bone ALP and OC were measured on the iSYS (IDS Plc) automatic analyzer in samples from the Danish Health2006 5-year follow-up study on serum from 2308 participants (54% women, age range 24-76). Participants with self-reported diagnosis of osteoporosis or receiving hormonal replacement were excluded from analyses while participants on hormonal contraceptives were included. RESULTS: The geometric mean and 95%RI for bone ALP were 13.9 µg/L (7.6-25.6) for men and 13.8 µg/L (7.0-27.4) for women, while for OC 16.0 µg/L (7.5-34.4) for men and 18.6 µg/L (8.1-42.9) for women. Levels of bone ALP increased with increasing age (ß 1.004, p < 0.001), while female sex had no effect. OC levels decreased with increasing age (ß 0.998, p = 0.009) and increased with female sex (ß 1.104, p < 0.001). Based on our findings, we propose for bone ALP and OC three clinical RIs for men based on age and three clinical RI for women based on age and menopausal status. CONCLUSION: The RI for bone ALP and OC varies with age and sex and the BTMs are influenced differently by the two factors. Consequently, the need for establishing valid RIs is of great importance before the full potential of BTM can be used in clinical practice.

The association of celiac disease and allergic disease in a general adult population.

Background: The relationship between allergy and celiac disease (CD) is not clear. Objective: The objective of this article is to investigate the association of CD and CD antibody positivity with hay fever, asthma and immunoglobulin (Ig)E sensitization in a general adult population. Methods: A total of 2297 individuals were screened for CD antibodies and underwent allergy testing. CD antibody-positive participants were invited to undergo clinical evaluation including biopsies. Additionally, biobank blood samples from four population-based studies (6423, 973, 1718 and 1101 participants) with data on IgE sensitization to inhalant allergens were screened for CD antibodies. CD antibody-positive participants were screened for serum IgE against food allergens in three biobank studies. CD-antibody positivity was defined as IgA or IgG tissue transglutaminase ≥7 U/ml and/or IgG deamidated gliadin peptide ≥10 U/ml. Results: The nine participants (0.4%) diagnosed with CD had significantly higher prevalence of IgE sensitization to wheat and dust mites. The prevalence of CD antibody positivity was 0.8% (18/2297), and these participants had a significantly higher prevalence of IgE sensitization to food allergens (Fx5), egg, dust mites and mugwort. In the biobank studies, the prevalence of CD antibody positivity was 0.8% to 1.2%. One study showed a positive association between CD antibody positivity and IgE sensitization for dog, horse and food allergens. Conclusion: We found a possible association of CD and IgE sensitization to some food and inhalant allergens in the Health2006 study. In further studies, however, we could not consistently replicate these associations.

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.

Trends in treatments of thyroid disease following iodine fortification in Denmark: a nationwide register-based study.

BACKGROUND: Long-term iodine exposure may influence the frequency of thyroid disease treatments through fluctuations in thyroid diseases. Yet, the long-term fluctuations in thyroid disease treatments upon iodine fortification (IF) are not fully known. We aimed to examine the development in thyroid disease treatments in Denmark before and following the implementation of IF in 2000. METHODS: Nationwide data on antithyroid medication, thyroid hormone therapy, thyroid surgery, and radioiodine treatment were obtained from Danish registries. Negative binominal regression was applied to analyze annual changes in treatment rates adjusted for region of residence, sex, and age. RESULTS: Incidence of antithyroid medication transiently increased but fell and reached steady state from 2010 at an incidence rate ratio (RR) of 0.72 (95% confidence interval [CI] 0.67-0.77) compared to year 2000. Thyroid hormone therapy increased and reached steady state in 2010 at an incidence RR of 1.75 (95% CI 1.62-1.89) compared to year 2000. Thyroid surgery was constant except for higher rates in 2014-2015, and radioiodine treatment fluctuated with no apparent pattern. CONCLUSION: Ten years after IF, a steady state was observed for incident antithyroid medication below the level at IF, and thyroid hormone therapy above the level at IF. Only small changes were observed in thyroid surgery and radioiodine treatment. In the same period, changes in diagnostic and treatment practices and lifestyle factors are likely to have occurred and should be considered when evaluating the effects of IF on treatment of thyroid diseases.

Trends in Costs of Thyroid Disease Treatment in Denmark during 1995-2015.

BACKGROUND: Iodine fortification (IF) may contribute to changes in costs of thyroid disease treatment through changes in disease patterns. From a health economic perspective, assessment of the development in costs of thyroid disease treatment in the population is pertinent. OBJECTIVES: To assess the trends in annual medicine and hospital costs of thyroid disease treatment during 1995-2015 in Denmark, i.e., before and after the introduction of mandatory IF in 2000. METHODS: Information on treatments for thyroid disease (antithyroid medication, thyroid hormone therapy, thyroid surgery, and radioiodine treatment) was obtained from nationwide registers. Costs were valued at 2015 prices using sales prices for medicines and the Danish Diagnosis-Related Group (DRG) and Danish Ambulatory Grouping System (DAGS) tariffs of surgeries/radioiodine treatments. Results were adjusted for changes in population size and age and sex distribution. RESULTS: The total direct medicine and hospital costs of thyroid disease treatment increased from EUR ∼190,000 per 100,000 persons in 1995 to EUR ∼270,000 per 100,000 persons in 2015. This was mainly due to linearly increased costs of thyroid hormone therapy and increased costs of thyroid surgery since 2008. Costs of antithyroid medication increased slightly and transiently after IF, while costs of radioiodine treatment remained constant. Costs of thyroid hormone therapy and thyroid surgery did not follow the development in the prevalence of hypothyroidism and structural thyroid diseases observed in concurrent studies. CONCLUSION: The costs of total direct medicine and hospital costs for thyroid disease treatment in Denmark increased from 1995 to 2015. This is possibly due to several factors, e.g., changes in treatment practices, and the direct effect of IF alone remains to be estimated.

IgE sensitization to inhalant allergens and the risk of airway infection and disease: A population-based study.

BACKGROUND: Immunoglobulin E (IgE) sensitization, which is the propensity to develop IgE antibodies against common environmental allergens, is associated with a lymphocyte T-helper type 2 (Th2) skewed immune response and a high risk of allergic respiratory disease. Little is known about whether IgE sensitization confers an increased risk of respiratory infections in adults. We investigated the association between IgE sensitization and the incidence of acute airway infections, other infections and chronic lower airway disease events as recorded in nation-wide registries. METHODS: We included 14,849 persons from five population-based studies with measurements of serum specific IgE positivity against inhalant allergens. Participants were followed by linkage to Danish national registries (median follow-up time 11.3 years). The study-specific relative risks were estimated by Cox regression analysis, meta-analysed, and expressed as hazard ratios, HRs (95% confidence intervals, CIs). RESULTS: The relative risks for IgE sensitized vs. non-sensitized were: for pneumonia (HR = 1.20, 95% CI: 1.01, 1.41), other acute airway infection (HR = 0.86, 95% CI: 0.60, 1.22), infection (HR = 1.06, 95% CI: 0.90, 1.24), asthma (HR = 2.26, 95% CI: 1.79, 2.86), and other chronic lower airway disease (HR = 1.31, 95% CI: 1.08, 1.58). In never smokers, the higher risk of pneumonia (HR = 1.73, 95% CI: 1.23, 2.44) and asthma (HR = 3.17, 95% CI: 2.10, 4.76) among IgE sensitized was more pronounced. CONCLUSIONS: IgE sensitization was associated with a higher risk of asthma, other chronic lower airway diseases, and pneumonia. However, the association between IgE sensitization and pneumonia may be explained by undiagnosed asthma causing the pneumonia. Further studies are needed for confirmation.

Longitudinal associations between lifestyle and vitamin D: A general population study with repeated vitamin D measurements.

Several lifestyle factors have been found to be associated with vitamin D status in cross-sectional studies, but it is not clear whether a change in these factors can actually affect the vitamin D level. We investigated the association between repeated measurements of physical activity, body mass index (BMI), diet, alcohol consumption, and smoking habits, and corresponding levels of vitamin D during 5 years of follow-up of a large general population sample. We included 4185 persons who participated and had vitamin D (serum-25-hydroxyvitamin D, 25-OH-D) measurements in the Inter99 study at baseline (1999-2001) and 5-year follow-up. In a subsample, 25-OH-D was also measured at 1- and 3-year follow-ups. We used mixed models to examine the association between repeated measurements of lifestyle factors and 25-OH-D levels. In multivariable analyses of repeated measurements, the difference in 25-OH-D was -0.32 ng/ml (95 % CI -0.37, -0.28) per 1 kg/m(2) increase in BMI; 4.50 ng/ml (95 % CI 3.84, 5.15) for persons moderately/vigorously physically active versus sedentary; 1.82 ng/ml (95 % CI 1.09, 2.56) for persons with healthy versus unhealthy dietary habits; 0.05 ng/ml (95 % CI 0.03, 0.07) per 1 standard drink/weak increase in alcohol consumption; and 0.86 ng/ml (95 % CI 0.36, 1.35) for never smokers versus daily smokers. Our study shows that lower BMI, a higher level of physical activity, a healthier diet and possibly a higher alcohol intake, and not smoking, are associated with higher 25-OH-D levels.