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.

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.

A nationwide registry-based observational study of thyroid disease incidence in the Faroe Islands.

OBJECTIVE: The occurrence of thyroid disease varies among populations. While the iodine nutrition level of the Faroese seems to have been decreasing over the past decades, there is no systematic evaluation of the thyroid disease pattern in the Faroe Islands. Such knowledge of thyroid disease occurrence in the North Atlantic region may support healthcare planning and prevention. To investigate incidence rates, including subtypes of thyroid diseases, and demographic characteristics of thyroid disease patients in the Faroe Islands, to improve understanding of the patterns and trends of these disorders. DESIGN AND METHOD: A registry-based observational study was conducted over 10 years, encompassing all adult Faroese individuals. PATIENTS AND MEASUREMENTS: Health records from general practitioners and hospitals were used to identify incident cases of thyroid diseases. Validation was performed using multiple data sources. The incidence rates were standardised using population data from the middle of the study period 2006-2018. RESULTS: Among the 1152 individuals diagnosed with thyroid disease, the standardised incidence rates per 100,000 person-years were 55 for hyperthyroidism and 112 for hypothyroidism, and around four times higher in women than in men. Hashimoto's thyroiditis was the dominant cause of hypothyroidism, while Graves' disease was the leading cause of hyperthyroidism. The incidence of hypothyroidism increases with age. A decreasing trend was observed over time for both hypothyroidism and hyperthyroidism. CONCLUSION: Considering the decrease in iodine nutrition levels over the past decades, we were surprised by the high incidence of autoimmune thyroid disease. The findings highlight the need for continuous monitoring of thyroid disease occurrence in coastal areas of the North Atlantic Ocean.

Hyperthyroidism in Danish Pregnant Women During a 20-Year Period.

CONTEXT: Hyperthyroidism in pregnancy is a clinical concern, and surveillance of any change in the occurrence of hyperthyroidism in pregnancy is important, especially when a mandatory iodine fortification (IF) program is implemented such as in Denmark in the year 2000. OBJECTIVE: To investigate any change in the occurrence of hyperthyroidism and the use of antithyroid drugs (ATDs) in Danish pregnant women during a 20-year period before and after the implementation of IF. METHODS: A nationwide register-based cohort (1997-2016) and 2 birth cohorts with biochemical data (the Danish National Birth Cohort, 1997-2003, and the North Denmark Region Pregnancy Cohort, 2011-2015) were used to study maternal use of ATDs in pregnancy and frequency of early pregnancy biochemical hyperthyroidism during a 20-year period prior to and after the implementation of mandatory IF. RESULTS: In the nationwide cohort, the adjusted odds ratio (aOR) for treatment with ATDs was 1.51 (95% CI, 1.30-1.74) after mandatory IF (2001-2004) compared with baseline (1997-1999). The increase was more pronounced in the previously moderately iodine-deficient West Denmark (aOR 1.67; 95% CI, 1.36-2.04) than the mildly deficient East Denmark (aOR 1.30; 95% CI, 1.06-1.60) and returned to baseline levels at the end of follow-up in both regions. No time-related difference in early pregnancy biochemical hyperthyroidism was observed. CONCLUSION: The use of ATDs in Danish pregnant women increased following the implementation of IF and then leveled out. Results comply with observations in the general Danish population and suggest that IF influences the occurrence of autoimmune hyperthyroidism in younger individuals.

Hyperthyroidism in pregnancy: design and methodology of a Danish multicenter study.

BACKGROUND: Graves' disease (GD) is the main cause of hyperthyroidism in women of the fertile age. In pregnant women, the disease should be carefully managed and controlled to prevent maternal and fetal complications. Observational studies provide evidence of the adverse effects of untreated hyperthyroidism in pregnancy and have in more recent years substantiated a risk of teratogenic side effects with the use of antithyroid drugs (ATDs). These findings have challenged the clinical recommendations regarding the choice of treatment when patients become pregnant. To extend observational findings and support future clinical practice, a systematic collection of detailed clinical data in and around pregnancy is needed. METHODS: With the aim of collecting clinical and biochemical data, a Danish multicenter study entitled 'Pregnancy Investigations on Thyroid Disease' (PRETHYR) was initiated in 2021. We here describe the design and methodology of the first study part of PRETHYR. This part focuses on maternal hyperthyroidism and recruits female patients in Denmark with a past or present diagnosis of GD, who become pregnant, as well as women who are treated with ATDs in the pregnancy, irrespective of the underlying etiology. The women are included during clinical management from endocrine hospital departments in Denmark, and study participation includes patient questionnaires in pregnancy and postpartum as well as review of medical records from the mother and the child. RESULTS: Data collection was initiated on November 1, 2021 and covered all five Danish Regions from March 1, 2022. Consecutive study inclusion will continue, and we here report the first status of inclusion. As of November 1, 2022, a total of 62 women have been included in median pregnancy week 19 (interquartile range (IQR): 10-27) with a median maternal age of 31.4 years (IQR: 28.5-35.1). At inclusion, 26 women (41.9%) reported current use of thyroid medication; ATDs (n = 14), Levothyroxine (n = 12). CONCLUSION: This report describes a newly established systematic and nationwide collection of detailed clinical data on pregnant women with hyperthyroidism and their offspring. Considering the course and relatively low prevalence of GD in pregnant women, such nationwide design is essential to establish a sufficiently large cohort.

Giant Parathyroid Tumor: Parathyroid Adenoma versus Parathyroid Carcinoma.

Parathyroid adenoma is the most common cause of primary hyperparathyroidism (PHPT). We present the preoperative detection of a giant parathyroid adenoma (GPA) using (99mTc)-sestamibi parathyroid scintigraphy in a patient presenting with severely elevated parathyroid hormone, hypercalcemia, hypophosphatemia, and vitamin D insufficiency. The patient complained of cerebral symptoms and intermittent abdominal discomfort without constipation. After surgical removal of the hyperactive parathyroid gland and D vitamin supplementation, all blood tests were normalized. The clinical and paraclinical characteristics of GPA may raise the suspicion of parathyroid carcinoma, but not absolutely in this case.

Cut-offs for thyroid peroxidase and thyroglobulin antibodies in early pregnancy.

Objective: Thyroid disease in women of reproductive age is mainly of autoimmune origin, and thyroid peroxidase antibodies (TPO-Ab) as well as thyroglobulin antibodies (Tg-Ab) are key markers. Adding to this, much focus in pregnancy is on euthyroid women who are thyroid antibody positive. Evidence to substantiate the cut-offs for the definition of thyroid autoantibody positivity in early pregnant women is warranted. Methods: Stored serum samples from 14,030 Danish pregnant women were used for the measurement of TPO-Ab, Tg-Ab, TSH, and free thyroxine (ADVIA Centaur XPT, Siemens Healthineers). Among all women, a reference cohort of 10,905 individuals was identified for the establishment of antibody cut-offs. Percentile cut-offs for TPO-Ab and Tg-Ab were determined using regression on order statistics (the reference cohort). The established cut-offs were then applied (the full cohort), and frequencies of early pregnancy as well as later diagnosis of hypothyroidism were evaluated. Results: The highest established cut-offs (95th, 97.5th, and 99th percentiles) were 59, 68, and 81 U/mL for TPO-Ab and 33, 41, and 52 U/mL for Tg-Ab. When the cut-offs were applied in the full cohort, 11.0, 10.2, and 9.7% were TPO-Ab positive, whereas 13.3, 12.3, and 11.2% were Tg-Ab positive. Antibody-positive women (TPO-Ab and/or Tg-Ab) had higher median TSH and were more likely to have hypothyroidism in early pregnancy and to be diagnosed with hypothyroidism during follow-up. Conclusions: This large study established and evaluated pregnancy-specific cut-offs for TPO-Ab and Tg-Ab. The findings are important regarding the classification of exposure in pregnancy and assessment of thyroid autoimmunity per se.

Prolonged APTT and autoimmune overt hypothyroidism identified postpartum: a case report.

Introduction: Thyroid disorders have been linked to abnormalities in the coagulation system, and a hypocoagulant state has been proposed in hypothyroidism. The assessment of thyroid function is, however, not routinely recommended as part of the assessment for coagulation disorders. Case presentation: We present a 32-year-old woman who had no history of thyroid disease and who recently gave birth preterm because of severe preeclampsia and intrauterine growth restriction. Due to severe placental dysfunction, she underwent a routine biochemical assessment of the coagulation system 6 months postpartum, and a prolonged activated partial thromboplastin time (APTT) (43 s) was identified along with a low level of coagulation factor VIII (0.44 IU/mL), and a low level of von Willebrand factor (vWF) antigen (0.35 IU/mL), vWF activity (0.38 IU/mL) as well as reduced generation of thrombin. The assessment of thyroid function in the patient identified autoimmune, overt hypothyroidism with a thyroid-stimulating hormone (TSH) concentration of 139 mIU/L, low levels of the peripheral thyroid hormones (total thyroxine: 43 nmol/L, total triiodothyronine: 0.9 nmol/L), and high levels of thyroid peroxidase antibodies (296 U/mL) as well as thyroglobulin antibodies (927 U/mL). Conclusion: In this case, prolonged APTT provided a diagnostic clue for the assessment of thyroid function in a young woman with a recent history of severe placental dysfunction. The identification of autoimmune, overt hypothyroidism emphasizes that measurement of TSH may be of clinical importance in cases of unexplained prolonged APTT or other biochemical signs of abnormalities in the coagulation system. Established facts: Hypothyroidism has been associated with alterations of the coagulation system suggesting a hypocoagulant state. At present, measurement of thyroid-stimulating hormone is not routinely recommended as part of the assessment for coagulation disorders. Novel insights: In this case, biochemical assessment of the coagulation system was routinely performed following a pregnancy complicated by severe placental dysfunction. Overt hypothyroidism of autoimmune origin was identified secondary to prolonged activated partial thromboplastin time (APTT) postpartum along with low levels of coagulation factor VIII, von Willebrand factor, and thrombin generation. Measurement of thyroid-stimulating hormone may be considered in cases of unexplained prolonged APTT.

Prevalence and predictors of adequate treatment of overt hypothyroidism - a population-based study.

The aim of this study is to evaluate the adequacy of treatment, and to identify factors influencing treatment of hypothyroidism. Patients newly diagnosed with overt hypothyroidism (n=345) were identified via a register linked to a laboratory database. In selected periods with staff available, 165 patients were invited, and 113 (68.5 %) accepted participating in a comprehensive program including blood tests and completion of questionnaires. We performed a longitudinal follow-up on thyroid function tests 10 years after the diagnosis. Time to reach a serum TSH level of 0.2-10 mU/L (termed as clinically acceptable) and biochemical normalization (TSH: 0.2-5.0 mU/L), respectively, were analyzed using Kaplan Meier survival analysis. Predictors for longer duration to reach the normal TSH range were identified using cox proportional hazards regression. Only 67.7 % of the patients were in the euthyroid range on the long term after diagnosis of overt hypothyroidism (2 years: 59.4 %; 10 years: 67.7 %). Median time to the first normal TSH was 8.9 months (95 % CI: 7.6-10.2 months). The factors associated with longer duration until normalization of TSH after multivariate analysis were age (HR 0.79 per 10 years; 95 % CI: 0.66-0.94; P = <0.01), smoking (HR 0.47; 95 % CI: 0.26-0.83; P = <0.01), serum TSH at diagnosis (HR 0.96 per 10 mU/L; 95 % CI: 0.93-0.99; P = 0.02) and BMI (HR 0.96 per kg/m2; 95 % CI: 0.91-0.99; P = 0.03). A considerable number of hypothyroid patients remained inadequately treated. When treating hypothyroid patients, special attention should be addressed to those patients who never or lately obtain euthyroid status.

Raised mortality in old adults with a history of hyperthyroidism following iodine fortification.

OBJECTIVE: A transient rise in the occurrence of hyperthyroidism ensued the introduction of iodine fortification (IF) of salt in Denmark. Older adults are at risk of complications to hyperthyroidism that could prove fatal to vulnerable individuals. We evaluated the association between thyroid function and mortality in older adults before and after nationwide implementation of IF. DESIGN: Retrospective cohort study. PATIENTS: All 68-year-olds from the general population in the city of Randers were invited to participate in a clinical study in 1988 and followed until death, emigration or end of study (31 December 2017) using Danish registries. MEASUREMENTS: Baseline measures comprised of a questionnaire, physical examination and blood and urine samples. Kaplan-Meier survival curves and Cox regression were used to determine the association between thyroid function and death before and after IF. Time-stratification of results before and after IF was employed due to violation of proportional hazards assumptions in Cox regression. RESULTS: Median urinary iodine concentration was 42 µg/L at baseline consistent with moderate iodine deficiency. Hyperthyroidism (thyrotropin < 0.4 mIU/L) occurred in 37 (9.1%) participants. Kaplan-Meier survival curves showed an increase in mortality among participants with hyperthyroidism after IF. There was no significant association between hyperthyroidism and mortality before IF compared to euthyroid participants, but after IF hyperthyroid subjects had an increased mortality (adjusted hazard ratio: 2.22, 95% confidence interval: 1.44-3.44). CONCLUSIONS: IF was associated with raised mortality among older adults with a history of hyperthyroidism and moderate iodine deficiency. Our results highlight the need for cautious iodine supplementation and for monitoring of IF.

Body Weight Changes in Hyperthyroidism: Timing and Possible Explanations during a One Year Repeated Measurement Study.

BACKGROUND: Weight gain during treatment of hyperthyroidism is a frequent and for many patients unwanted outcome. With this repeated measurement study, we explored the timing of weight changes during the first year of antithyroid drug (ATD) treatment and assessed the correlation between body weight changes and changes in thyroid hormones, resting energy expenditure (REE), physical activity level, and energy efficiency. METHODS: Patients with new onset hyperthyroidism were investigated every second month during the first year of ATD treatment. At each investigation, the following were measured: body weight, thyroid hormone concentrations, physical activity level, and daily number of steps, REE, and exercise performance. RESULTS: Two men and eleven women, all sedentary, mean age 49(SD: 9.3) years were included. Significant changes after 1 year occurred for body weight (68.9-74.1 kg), thyroid hormones (free T3 [fT3] 17.5 to 4.42 pmol/L), REE (1,630-1,484 kcal/24 h), and energy efficiency at lower (50 W) workloads (16.0-17.6%). In individual patients, only REE and fT3 correlated to changes in body weight. Physical activity level did not change during treatment. CONCLUSION: In this study, treatment of hyperthyroidism was associated with marked increase in body weight in the patients. This increase correlated to a decrease in REE and only to a negligible extent to changes in energy efficiency and not at all to changes in physical activity level of daily living.

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.

Long-term iodine nutrition is associated with longevity in older adults: a 20 years' follow-up of the Randers-Skagen study.

Iodine intake affects the occurrence of thyroid disorders. However, the association of iodine intake with longevity remains to be described. This led us to perform a 20 years' follow-up on participants from the Randers-Skagen (RaSk) study. Residents in Randers born in 1920 (n 210) and Skagen born in 1918-1923 (n 218) were included in a clinical study in 1997-1998. Mean iodine content in drinking water was 2 µg/l in Randers and 139 µg/l in Skagen. We collected baseline data through questionnaires, performed physical examinations and measured iodine concentrations in spot urine samples. Income data were retrieved from Danish registries. We performed follow-up on mortality until 31 December 2017 using Danish registries. Complete follow-up data were available on 428 out of 430 of participants (99·5 %). At baseline, the median urinary iodine concentration was 55 µg/l in Randers and 160 µg/l in Skagen residents. Participants were long-term residents with 72·8 and 92·7 % residing for more than 25 years in Randers and Skagen, respectively. Cox regression showed that living in Skagen compared with Randers was associated with a lower hazard ratio (HR) of death in both age- and sex-adjusted analyses (HR 0·60, 95 % CI 0·41, 0·87, P = 0·006), but also after adjustment for age, sex, number of drugs, Charlson co-morbidity index, smoking, alcohol and income (HR 0·60, 95 % CI 0·41, 0·87, P = 0·008). Residing in iodine-replete Skagen was associated with increased longevity. This indicates that long-term residency in an iodine-replete environment may be associated with increased longevity compared with residency in an iodine-deficient environment.

Levothyroxine Formulations: Pharmacological and Clinical Implications of Generic Substitution.

Oral levothyroxine (LT4) is the standard therapy for patients with hypothyroidism. Oral LT4 is available in several formulations, including tablets, soft gel capsules and oral solution. Multiple brand-name and generic LT4 tablets are available. In the US, the Food and Drug Administration (FDA) has developed a protocol for establishing bioequivalence of LT4 formulations based on serum thyroxine (T4) levels after a single oral dose administered to healthy volunteers. This protocol has been criticized by professional endocrinology associations for using healthy individuals and ignoring serum thyroid-stimulating hormone (TSH) levels. In addition, the protocol did not initially correct for baseline T4 levels, although this was changed in a later version. There are concerns that the FDA's protocol could allow products with clinically significant differences in bioavailability to be declared therapeutically equivalent and interchangeable. Once a generic LT4 has been shown to be bioequivalent to a brand-name LT4, it may be substituted for that brand-name LT4 with no need for dose adjustment or follow-up therapeutic monitoring. Often, the substitution is made by the pharmacy without the physician's knowledge. Even small differences between LT4 formulations can cause significant changes in TSH levels. This may be a particular concern in vulnerable populations, including elderly, pregnant, and pediatric patients. Problems that can be encountered when switching between formulations or when original products are reformulated are discussed in this review. These problems include altered efficacy and adverse events, some of which can be caused by excipients. Patients should be maintained on the same LT4 preparation if possible. If the LT4 preparation is changed, TSH levels should be evaluated and, if necessary, the dose of LT4 adjusted.Funding: Merck.Plain Language Summary: Plain language summary available for this article.

Hypothyroidism in Context: Where We've Been and Where We're Going.

Hypothyroidism affects up to 5% of the general population, with a further estimated 5% being undiagnosed. Over 99% of affected patients suffer from primary hypothyroidism. Worldwide, environmental iodine deficiency is the most common cause of all thyroid disorders, including hypothyroidism, but in areas of iodine sufficiency, Hashimoto's disease (chronic autoimmune thyroiditis) is the most common cause of thyroid failure. Hypothyroidism is diagnosed biochemically, being overt primary hypothyroidism defined as serum thyroid-stimulating hormone (TSH) concentrations above and thyroxine concentrations below the normal reference range. Symptoms of hypothyroidism are non-specific and include mild to moderate weight gain, fatigue, poor concentration, depression, and menstrual irregularities, while the consequences of untreated or under-treated hypothyroidism include cardiovascular disease and increased mortality. Levothyroxine has long been the main tool for treating hypothyroidism and is one of the world's most widely prescribed medicines. In adults with overt hypothyroidism, levothyroxine is usually prescribed at a starting dose of 1.6 µg/kg/day, which is then titrated to achieve optimal TSH levels (0.4-4.0 mIU/L), according to the therapeutic target. We here summarise the history of levothyroxine and discuss future issues regarding the optimal treatment of hypothyroidism. Because nearly one-third of patients with treated hypothyroidism still exhibit symptoms, it is important that levothyroxine is used more appropriately to achieve maximum benefit for patients. In order to ensure this, further research should include more accurate assessments of the true prevalence of hypothyroidism in the community, optimisation of the levothyroxine substitution dose, proper duration of treatment, and identification of patients who may benefit from combination therapy with levothyroxine plus levotriiodothyronine.Funding: Merck.Plain Language Summary: Plain language summary available for this article.

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.

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.

Pregnancy Week-Specific Reference Ranges for Thyrotropin and Free Thyroxine in the North Denmark Region Pregnancy Cohort.

BACKGROUND: Physiological changes in maternal thyroid function during pregnancy necessitate the use of pregnancy-specific reference ranges. Dynamic changes in thyrotropin (TSH) within the first trimester of pregnancy have been reported, but more evidence is needed to substantiate the findings. The objective of this study was to estimate pregnancy week-specific reference ranges for maternal TSH and free thyroxine (fT4) in early pregnancy. METHODS: The study consecutively recruited serum residues from blood samples collected as part of the prenatal screening in the North Denmark Region, 2011-2015. TSH, fT4, thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were measured using an ADVIA Centaur XPT immunoassay. The reference cohort included 10,337 pregnant women who had no thyroid disease or other autoimmune diseases and were TPOAb- and TgAb negative. The main outcome measures were lower and upper reference limits (2.5th and 97.5th percentiles) for TSH and fT4 stratified by week of pregnancy. RESULTS: Blood samples were drawn in pregnancy weeks 4-20 (median week 10), and 92% of the pregnancies ended with a live birth. TSH varied considerably in the first trimester of pregnancy, and the levels were highest in early pregnancy (weeks 4-6: 0.6-3.7 mIU/L) followed by a gradual decline to lower levels in weeks 9-11 (0.1-2.8 mIU/L) and 12-14 (0.03-2.8 mIU/L). Maternal fT4 showed less variation (weeks 4-6: 12-20 pmol/L; weeks 9-11: 13-21 pmol/L; weeks 12-14: 13-20 pmol/L). CONCLUSIONS: The results corroborate dynamic week-specific changes in maternal TSH in early pregnancy. The use of uniform lower and upper reference limits for TSH in early pregnancy may be too simple.

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.

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.