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.

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).

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.

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.

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.

Lifestyle-Related Factors and Atopy in Seven Danish Population-Based Studies from Different Time Periods.

BACKGROUND: The prevalence of allergic respiratory disease tends to increase in populations that adopt the so-called Westernized lifestyle. We investigated the association between atopy and several possible lifestyle-related factors in seven Danish population-based studies. METHODS: A total of 20048 persons participated in the seven studies. We used logistic regression to analyse the associations between possible determinants and atopy defined as serum specific IgE or skin prick test positivity against inhalant allergens. Associations were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). In addition, individual participant data meta-analyses were performed. RESULTS: Atopy was significantly associated with younger age (OR per 1 year increase in age: 0.97; 95% CI: 0.97, 0.98); male sex (OR for males versus females: 1.34; 95% CI: 1.24, 1.45), heavy drinking (OR for heavy drinkers versus light drinkers: 1.15; 95% CI: 1.04, 1.27), never smoking (OR for current versus never smokers: 0.73; 95% CI: 0.67, 0.80), and higher educational level (OR for educated versus uneducated: 1.27; 95% CI: 1.15, 1.41). Atopy was not associated with blood pressure, serum total cholesterol, physical activity or body mass except in women only, where we found a positive association (OR for obese vs. normal weight: 1.18; 95% CI: 1.00, 1.39) with ptrend = 0.032. CONCLUSIONS: Of interest for preventive purposes, we found that atopy was associated with some of the reversible lifestyle-related factors that characterize a Westernized lifestyle.

The association of atopy with incidence of ischemic heart disease, stroke, and diabetes.

Allergy is a systemic inflammatory disease that could theoretically affect the risk of cardiovascular disease (CVD) and diabetes through inflammatory pathways or mast cell-induced coronary spasm. Whether allergy is associated with an increased risk of CVD and diabetes is largely unknown. We investigated the association between atopy as assessed by IgE sensitization, a well-accepted biomarker of allergy, and incidence of ischemic heart disease, stroke, and diabetes in five Danish population-based cohorts. A total of 14,849 participants were included in the study. Atopy was defined as serum-specific IgE positivity to inhalant allergens. The Danish National Diabetes Register enabled identification of incident diabetes. Likewise, the Danish Registry of Causes of Death and the Danish National Patient Register provided information on fatal and non-fatal ischemic heart disease and stroke. Data were analyzed by Cox regression analyses with age as underlying time axis and adjusted for study cohort, gender, education, body mass index, alcohol intake, smoking habits, physical activity during leisure time, serum lipids, and blood pressure. The prevalence of atopy was 26.9 % (n = 3,994). There were 1,170, 817, and 1,063 incident cases of ischemic heart disease, stroke, and diabetes, respectively (median follow-up 11.2 years). The hazard ratios, HRs (95 % confidence intervals, CIs) for atopics versus non-atopics: for ischemic heart disease (HR 1.00, 95 % CI 0.86, 1.16), stroke (HR 1.18, 95 % CI 0.99, 1.41), and diabetes (HR 1.06, 95 % CI 0.91, 1.23). Our results did not support the hypothesis that atopy is associated with higher risk of ischemic heart disease, stroke, or diabetes. However, a small-moderately increased risk cannot be excluded from our data.

Atopy and development of cancer: a population-based prospective study.

BACKGROUND: Atopy is the familial or personal propensity to develop IgE antibodies against environmental allergens. Atopy, theoretically, could both prevent and promote the development of cancer. However, evidence from epidemiologic studies has been inconclusive. OBJECTIVE: We investigated the longitudinal association between atopy and the incidence of total and specific types of cancers of 5 Danish population-based studies. METHODS: Atopy was defined as serum specific IgE positivity against inhalant allergens. A total of 14,849 persons were followed up prospectively by linkage to the Danish Cancer Registry. We used Cox regression analysis, and risk was expressed as hazard ratios (HR) (95% CIs) for persons with atopy versus those without atopy. RESULTS: There were 1919 incident cancers (median follow-up, 11.8 years). There were no statistically significant associations between atopy and risk of any cancer (HR 1.00 [95% CI, 0.89-1.12]), any cancer excluding nonmelanoma skin cancer (HR 0.93 [95% CI, 0.82-1.07]), head and neck cancer (HR 1.74 [95% CI, 0.98-3.09]), colorectal cancer (HR 0.92 [95% CI, 0.64-1.32]), cancer of the bronchus and lung (HR 0.78 [95% CI, 0.54-1.13]), breast cancer (HR 1.00 [95% CI, 0.73-1.37]), cancer of the uterus (HR 0.90 [95% CI, 0.43- 1.88]), prostate cancer (HR 0.79 [95% CI, 0.53-1.18]), urinary cancer (HR 1.08 [95% CI, 0.60-1.96]), malignant melanoma (HR 0.95 [95% CI, 0.54-1.66]), and nonmelanoma skin cancer (HR 1.20 [95% CI, 0.98-1.47]). CONCLUSION: Our data did not support the hypothesis that atopy is associated with an altered risk of total cancer development, although effects of atopy on specific types of cancer cannot be excluded.

Prospective population-based study of the association between serum 25-hydroxyvitamin-D levels and the incidence of specific types of cancer.

BACKGROUND: Observational studies have suggested an inverse association between vitamin D status and cancer. We investigated the prospective associations between vitamin D status and the total and specific type of cancer in three cohorts from the general Danish population. METHODS: A total of 12,204 individuals 18 to 71 years old were included. The level of 25-hydroxyvitamin D was measured at baseline, and information about cancer was obtained from the Danish Cancer Registry. RESULTS: During the 11.3-year median follow-up time, there were 1,248 incident cancers. HRs [95% confidence intervals (CI)] per 10 nmol/L higher baseline vitamin D level were: for all cancers (HR = 1.02; 95% CI, 0.99-1.04), all cancers excluding non-melanoma skin cancer, NMSC (HR = 1.00; 95% CI, 0.97-1.03), head and neck cancer (HR = 0.97; 95% CI, 0.84-1.12), colorectal cancer (HR = 0.95; 95% CI, 0.88-1.02), cancer of bronchus and lung (HR = 0.98; 95% CI, 0.91-1.05), breast cancer (HR = 1.02; 95% CI, 0.96-1.09), cancer of the uterus (HR = 1.10; 95% CI, 0.95-1.27), prostate cancer (HR = 1.00; 95% CI, 0.93-1.08), cancer of the urinary organs (HR = 1.01; 95% CI, 0.90-1.14), NMSC (HR = 1.06; 95% CI, 1.02-1.10), and malignant melanoma (HR = 1.06; 95% CI, 0.95-1.17). CONCLUSIONS: Apart from a significantly higher risk for NMSC with higher vitamin D status, we found no statistically significant associations between vitamin D status and total or specific cancers. IMPACT: Our results do not indicate that there is an impact of vitamin D on total cancer incidence.

Vitamin D status, liver enzymes, and incident liver disease and mortality: a general population study.

Vitamin D deficiency is common among patients with liver diseases. Both cholestatic and non-cholestatic liver diseases can cause vitamin D deficiency. Whether vitamin D status can also affect liver function is poorly understood. To investigate the association between vitamin D status, liver enzymes, and incident liver disease, we included a total of 2,649 individuals from the Monica10 study conducted in 1993-1994. Vitamin D status as assessed by serum 25-hydroxyvitamin, serum alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transferase (GGT) were measured at baseline. Information on fatal and non-fatal liver disease was obtained from the Danish National Patient Register and The Danish Registry of Causes of Death, respectively. Median follow-up time was 16.5 years, and there were 62 incident cases of fatal and non-fatal liver disease. Multivariable Cox regression analyses with age as underlying time axis and delayed entry showed a statistically significant inverse association between vitamin D status and incident liver disease with a hazard ratio = 0.88 (95 % confidence interval 0.79-0.99) per 10 nmol/l higher vitamin D status at baseline (adjusted for gender, season, alcohol consumption, smoking, physical activity, dietary habits, education, body mass index, and ALT). The risk of having a high level of ALT, AST, or GGT tended to be higher for lower vitamin D levels, although not statistically significant. In this general population study, vitamin D status was inversely associated with incident liver disease. Further studies are needed to determine whether patients in risk of developing impaired liver function should be screened for vitamin D deficiency for preventive purposes.

Vitamin D status and cause-specific mortality: a general population study.

BACKGROUND: Vitamin D deficiency is associated with an increased risk of all-cause mortality in observational studies. The specific causes of death underlying this association lack clarity. We investigated the association between vitamin D status and cause-specific mortality. METHODS: We included a total of 9,146 individuals from the two population-based studies, Monica10 and Inter99, conducted in 1993-94 and 1999-2001, respectively. Vitamin D status was assessed as serum 25-hydroxyvitamin D. Information on causes of death was obtained from The Danish Register of Causes of Death until 31 December 2009. There were a total of 832 deaths (median follow-up 10.3 years). RESULTS: Multivariable Cox regression analyses with age as underlying time axis and vitamin D quartiles showed significant associations between vitamin D status and death caused by diseases of the respiratory system, the digestive system, and endocrine, nutritional and metabolic diseases with hazard ratios (HRs) 0.26 (p(trend) = 0.0042), 0.28 (p(trend) = 0.0040), and 0.21 (p(trend) = 0.035), respectively, for the fourth vitamin D quartile compared to the first. We found non-significantly lower HRs for death caused by mental and behavioural diseases and diseases of the nervous system, but no association between vitamin D status and death caused by neoplasms or diseases of the circulatory system. CONCLUSION: The associations of vitamin D status and cause-specific mortality suggest that we also look elsewhere (than to cardiovascular disease and cancer) to explain the inverse association between vitamin D status and mortality.

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.