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.

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.

Comparison of three competitive immunoassays for measurement of TSH receptor antibodies in patients with Graves' disease.

Thyrotropin (TSH) receptor antibodies (TRAb) mediate the hyperthyroidism of Graves' disease (GD). The aim of the study was to compare the diagnostic performance and assay agreement between three immunoassays for the measurement of TRAb in patients with newly diagnosed GD. TRAb was measured with three different assays [H-TRAb (BRAHMS Diagnostica), M22-Man (RSR Limited) and M22-Aut (Roche Diagnostics)] in 387 participants who were recruited from two Danish population-based studies and diagnosed with GD (n = 101), multinodular toxic goitre (n = 88), primary autoimmune hypothyroidism (n = 100) or included as controls (n = 98). Coefficient of variation for duplicate measurements with each of the three assays were H-TRAb: 3.6%, M22-Man: 9.4%, M22-Aut: 7.7%. Frequency of TRAb positivity in patients with GD were H-TRAb: 95%, M22-Man: 94%, M22-Aut: 96%. Receiver operating characteristic analysis revealed a high sensitivity (H-TRAb: 95%, M22-Man: 93%, M22-Aut: 95%) and specificity (H-TRAb: 99%, M22-Man: 99%, M22-Aut: 97%) for the diagnosis of GD with all assays. Comparison of TRAb levels showed inter-assay variability and values were considerably lower with the M22-Man assay. All TRAb assays showed a high diagnostic performance for GD, but a high inter-assay variability was observed limiting the use of different assays in clinical monitoring of patients with GD.

Can Elastography Predict Growth of Incidental Thyroid Nodules? A Pilot Two-Year Follow-Up Study.

The objective of this study was to examine the ultrasonography (US) and ultrasound elastography (USE) features of thyroid incidentalomas in a population exposed to iodine deficiency and to investigate whether baseline elasticity scores (ES) predicted changes in thyroid nodule US characteristics. We conducted a two-year follow-up pilot study of thyroid incidentalomas by US and USE. One sonographer performed the US and USE examination on the same apparatus at baseline and at follow-up. We evaluated 83 incidental thyroid nodules detected in a population study. The follow-up period saw no change in median thyroid nodule diameter (p = 0.18) or in the prevalence of thyroid nodule US characteristics (hypoechoic: p = 0.05; solid nodule: p = 1.00; microcalcifications: p = 0.55). Individual changes in thyroid nodule diameter (>20%) were seen in 23% (11% had decreased, and 12% had increased in diameter). Changes in ES were frequently observed; 37% changed from ES A + B to ES C + D, and 27% changed from ES C + D to ES A + B. In a multivariate logistic regression model, we found no association between baseline ES and individual changes in nodule size. In an area with mild iodine deficiency and a high prevalence of thyroid nodules, thyroid USE performed on thyroid incidentalomas did not predict individual changes in thyroid nodule size.

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

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

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.

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.

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

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

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.

An increased incidence of overt hypothyroidism after iodine fortification of salt in Denmark: a prospective population study.

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

Effect of a mandatory iodization program on thyroid gland volume based on individuals' age, gender, and preceding severity of dietary iodine deficiency: a prospective, population-based study.

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

MECHANISMS IN ENDOCRINOLOGY: Neurodevelopmental disorders in children born to mothers with thyroid dysfunction: evidence of fetal programming?

Fetal programming is a long-standing, but still evolving, concept that links exposures during pregnancy to the later development of disease in the offspring. A fetal programming effect has been considered within different endocrine axes and in relation to different maternal endocrine diseases. In this critical review, we describe and discuss the hypothesis of fetal programming by maternal thyroid dysfunction in the context of fetal brain development and neurodevelopmental disorders in the offspring. Thyroid hormones are important regulators of early brain development, and evidence from experimental and observational human studies have demonstrated structural and functional abnormalities in the brain caused by the lack or excess of thyroid hormone during fetal brain development. The hypothesis that such abnormalities introduced during early fetal brain development increase susceptibility for the later onset of neurodevelopmental disorders in the offspring is biologically plausible. However, epidemiological studies on the association between maternal thyroid dysfunction and long-term child outcomes are observational in design, and are challenged by important methodological aspects.

Epidemiology of subtypes of hypothyroidism in Denmark.

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

The association between hypoechogenicity or irregular echo pattern at thyroid ultrasonography and thyroid function in the general population.

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

The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives.

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

Thyroid peroxidase and thyroglobulin auto-antibodies in patients with newly diagnosed overt hypothyroidism.

OBJECTIVES: Thyroid autoimmunity is a major cause for hypothyroidism. We describe thyroid auto-antibodies in patients with various nosological subtypes of hypothyroidism identified in a population study. DESIGN: Population-based follow-up study identifying all new cases of hypothyroidism in an open cohort. METHODS: We established a monitoring system, and identified all new cases with primary overt hypothyroidism (n = 685) in a 4 year period in a well-defined population cohort (2,027,208 person-years of observation). Patients were sub-classified into: spontaneous hypothyroidism, presumably of autoimmune origin (n = 578); non-spontaneous hypothyroidism (associated with medication, delivery, neck-irradiation or subacute thyroiditis, n = 97); and congenital hypothyroidism (n = 10). A total of 186 adult patients (61% of those invited) underwent thyroid ultrasonography and measurements of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb). RESULTS: In spontaneously hypothyroid patients: >99% were antibody-positive (TPOAb or TgAb), TPOAb were more often measurable than TgAb (95.9 vs. 80.7%, p < 0.001). A statistically significant but modest correlation was observed between the two antibodies (Pearson's r2 = 0.11, p < 0.001). In a multivariate regression model both TPOAb and TgAb were positively associated with thyroid enlargement (p < 0.001), whereas no association was found with sex, age, iodine deficiency level or serum TSH level. We found no differences in patient characteristics between those who mainly developed TPOAb vs. those who preferentially harboured TgAb. CONCLUSIONS: Autoimmunity played a dominant role in practically all patients classified as spontaneously hypothyroid. Thyroid enlargement was associated with high levels of TPOAb and TgAb. We found no clue to why some spontaneously hypothyroid patients predominantly developed TPOAb whereas others mainly generated TgAb.

Hypothyroid Symptoms Fail to Predict Thyroid Insufficiency in Old People: A Population-Based Case-Control Study.

BACKGROUND: Clinic-based studies have indicated that older hypothyroid patients may present only few symptoms. METHODS: In this population-based study of hypothyroidism, we investigated how the power of symptom presence predicts overt hypothyroidism in both young and older subjects. We identified patients newly diagnosed with overt autoimmune hypothyroidism in a population (n = 140, median thyroid-stimulating hormone, 54.5; 95% confidence interval [CI], 28.3-94.8; median total T4, 37; 95% CI, 18-52) and individually matched each patient with 4 controls free of thyroid disease (n = 560). Participants filled out questionnaires concerning the presence and duration of symptoms. We compared the usefulness of hypothyroidism-associated symptoms in predicting overt hypothyroidism in different age groups (young: <50 years, middle age: 50-59 years, old: ≥60 years) also taking various confounders into account. RESULTS: In young hypothyroid patients, all 13 hypothyroidism-associated symptoms studied were more prevalent than in their matched controls, whereas only 3 of those (tiredness, shortness of breath, and wheezing) were more prevalent in old patients. The mean numbers of symptoms presented at disease onset were 6.2, 5.0, and 3.6 at the ages of 0 to 49 years, 50 to 59 years, and 60+ years, respectively. In young versus old people with 0 to 1 symptoms, the odds ratio for being hypothyroid was 0.04 (95% CI, 0.007-0.18) versus 0.34 (95% CI, 0.15-0.78) (reference all other groups). In young versus old subjects reporting ≥4 symptoms, the odds ratio for being hypothyroid was 16.4 (95% CI, 6.96-40.0) versus 2.22 (95% CI, 1.001-4.90). Receiver operating characteristic analyses revealed that the symptom score was an excellent tool for predicting hypothyroidism in young men (area under the receiver operating characteristic curve, 0.91; 95% CI, 0.82-0.998), whereas it was poor in evaluating older women (area under the receiver operating characteristic curve, 0.64; 95% CI, 0.54-0.75). CONCLUSION: Hypothyroid symptom score is a good discriminating tool to identify hypothyroidism in young patients but fails to identify hypothyroidism in the elderly. Thus, thyroid function should be tested on wide indications in old age.

Double vision is a major manifestation in moderate to severe graves' orbitopathy, but it correlates negatively with inflammatory signs and proptosis.

CONTEXT: Double vision (diplopia) is a major determinant of work disability in patients with Graves' orbitopathy (GO), but is not part of the classification NOSPECS classification of GO. OBJECTIVE: The objectives of the study were to quantitate diplopia in patients with moderate to severe GO and to study associations with other disease and patient variables. DESIGN: This was a single-center prospective study of consecutive patients at the time of referral. SETTING: The study was conducted at the University Hospital Thyroid-Eye Clinic. PATIENTS: Patients included 216 patients diagnosed with moderate to severe and active GO. MAIN OUTCOME MEASURES: Binocular diplopia in field of gaze and monocular fields of motility were prospectively recorded on diagrams and measured by planimetry. Fields of diplopia were correlated to other disease and patient variables. RESULTS: Six patients had only one functional eye and were excluded. Among the remaining 210 patients, diplopia was present in 75.2%. In patients with diplopia, this ranged from 5% to 100% (observed in 11.4% of patients) of binocular field of gaze. The field of diplopia correlated positively with eye motility restriction and with asymmetrical affection of orbits but negatively with signs of inflammation and proptosis that often are the main outcome measures in clinical studies of GO therapy. CONCLUSION: Diplopia is very common in moderate to severe GO and a major cause for active therapy. In moderate to severe GO, the field of diplopia correlates negatively with some other indicators of disease activity, which may be explained by the physiological properties of binocular fusion.

Serum thyroglobulin before and after iodization of salt: an 11-year DanThyr follow-up study.

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