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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Hypothyroid symptoms and the likelihood of overt thyroid failure: a population-based case-control study.

BACKGROUND: It is generally accepted that patients suffering from hypothyroidism may express few symptoms, but this has not been studied in a population-based study design. OBJECTIVES: To study the array of symptoms as they are reported in newly diagnosed overt autoimmune hypothyroidism using a population-based case-control design. METHODS: Patients with new overt autoimmune hypothyroidism (n=140) and their individually matched thyroid disease-free controls (n=560) recruited from the same population underwent a comprehensive program and self-reported a number of symptoms. We identified the symptoms associated with overt hypothyroidism and calculated positive (LR+) and negative (LR-) likelihood ratios as well as diagnostic odds ratios (DORs) as measures for the association between disease state and symptoms. RESULTS: Among 34 symptoms investigated, 13 symptoms were statistically overrepresented in hypothyroidism. Hypothyroid patients suffered mostly from tiredness (81%), dry skin (63%), and shortness of breath (51%). Highest DORs (95% CI) were reported for tiredness (5.94 (3.70-9.60)), hair loss (4.58 (2.80-7.51)), and dry skin (4.09 (2.73-6.16)). A hypothyroidism-component-score was defined as the number of hypothyroidism-associated symptoms (range: 0-13). LR+ for participants with a hypothyroidism-component-score of 0 was 0.21 (0.09-0.39), meaning that the post-test probability was lowered to 21% of what it was before asking for symptoms. LR+ for scores of 1-2/3/4-6/7-9/10-13 were: 0.47 (0.30-0.72)/1.16 (0.70-1.87)/1.90 (1.29-2.45)/3.52 (2.30-5.36)/6.29 (2.30-17.7). CONCLUSIONS: None of the individual symptoms of hypothyroidism had high LRs or DORs. Thus, neither the presence nor absence of any individual hypothyroidism symptom was reliable in the decision making of who should have their thyroid function tested. Therefore, even minor suspicion should lead to a blood test.

Thyroid nodules in an 11-year DanThyr follow-up study.

CONTEXT: Limited longitudinal data are available on changes in the thyroid gland structure in a population and how this is influenced by iodine fortification (IF). OBJECTIVE: Our objective was to clarify how IF influenced thyroid gland structure in 2 regions with different iodine intake at baseline (Copenhagen, mild iodine deficiency [ID]; Aalborg, moderate ID). DESIGN AND SETTING: We conducted a longitudinal population-based study (DanThyr) where participants were examined before (1997) and after (2008) the Danish mandatory IF of salt (2000). PARTICIPANTS: We examined 2465 adults, and ultrasonography was performed by the same sonographers using the same equipment, after controlling performances. MAIN OUTCOME MEASURE: Change in thyroid gland structure was evaluated. RESULTS: The follow-up period saw an increased prevalence of multinodularity (9.8%-13.8 %, P < .001), especially in the previously moderate ID region of Aalborg (9.1%-15.4%, P < .001), whereas no change in prevalence was seen for solitary nodules (5.6%-5.1%, P = .34). In individual participants, changes in thyroid structure and disappearance of thyroid nodules during the 11 years was common with an overall normalization rate of 21.2 (95% confidence interval [CI] = 17.9-24.9) per 1000 person-years. Solitary nodules had a significantly higher normalization rate than multiple nodules (normalization rate ratio 0.47 [95% CI = 0.32-0.67]). A regional difference (Aalborg vs Copenhagen) was seen between normalization rates of multiple nodules (normalization rate ratio 0.29 [95% CI = 0.12-0.64]), but not for solitary nodules (normalization rate ratio 0.81 [95% CI = 0.53-1.21]). CONCLUSIONS: Changes in the thyroid gland structure with both appearance and disappearance of thyroid nodules are common after an iodization program.

Association between TSH-Receptor Autoimmunity, Hyperthyroidism, Goitre, and Orbitopathy in 208 Patients Included in the Remission Induction and Sustenance in Graves' Disease Study.

Background. Graves' disease may have a number of clinical manifestations with varying degrees of activity that may not always run in parallel. Objectives. To study associations between serum levels of TSH-receptor autoantibodies and the three main manifestations of Graves' disease (hyperthyroidism, goiter, and presence of orbitopathy) at the time of diagnosis of hyperthyroidism. Methods. We describe a cohort of 208 patients with newly diagnosed Graves' hyperthyroidism. Patients were enrolled in a multiphase study of antithyroid drug therapy of Graves' hyperthyroidism, entitled "Remission Induction and Sustenance in Graves' Disease (RISG)." Patients were systematically tested for degree of biochemical hyperthyroidism, enlarged thyroid volume by ultrasonography, and the presence of orbitopathy. Results. Positive correlations were found between the levels of TSH-receptor autoantibodies in serum and the three manifestations of Graves' disease: severeness of hyperthyroidism, presence of enlarged thyroid, and presence of orbitopathy, as well as between the different types of manifestations. Only around half of patients had enlarged thyroid gland at the time of diagnosis of hyperthyroidism, whereas 25-30% had orbitopathy. Conclusions. A positive but rather weak correlation was found between TSH-receptor antibodies in serum and the major clinical manifestation of Graves' disease. Only half of the patients had an enlarged thyroid gland at the time of diagnosis.

Development of autoimmune overt hypothyroidism is highly associated with live births and induced abortions but only in premenopausal women.

CONTEXT: The 1-year postpartum period is often accompanied by increased risk for thyroid disease. OBJECTIVE: The objective of the study was to investigate the role of reproductive risk factors in the development of autoimmune overt hypothyroidism in the years after the 1-year postpartum period. DESIGN, SETTING, AND SUBJECTS: In a population study, we included Danish women with new autoimmune overt hypothyroidism not diagnosed within the first year after a pregnancy (n = 117; median age 53.0 y) and age- and region-matched euthyroid controls from the same population (n = 468). MAIN OUTCOME MEASURES: In conditional multivariate logistic regression models, we analyzed the associations between the development of autoimmune hypothyroidism and age at menarche/menopause, years of menstruations, pregnancies, spontaneous and induced abortions, live births, and years on oral contraceptives and postmenopausal hormone replacement therapy, also taking various possible confounders into account. RESULTS: In multivariate regression models with no event as reference, the odds ratios (ORs) for hypothyroidism [95% confidence interval (CI)] after one/two/three or more live births were 1.72 (0.56-5.32)/3.12 (1.14-8.48)/4.51 (1.65-12.3) and 1.02 (0.57-1.81)/2.70 (1.27-5.75) after one/two or more induced abortions. Findings were valid only for women having hypothyroidism diagnosed before the age of 55 years. We found no association between disease development and other reproductive risk factors investigated. CONCLUSIONS: Previous live births and induced abortions were major risk factors for the development of autoimmune overt hypothyroidism in women aged up to 55 years. The increased risk for hypothyroidism after giving birth extends longer than just to the 1-year postpartum period, and numbers of previous pregnancies should be taken into account when evaluating the risk of hypothyroidism in a young women.

Iodine fortification may influence the age-related change in thyroid volume: a longitudinal population-based study (DanThyr).

OBJECTIVE: To assess the individuals' thyroid volume changes after the mandatory nationwide iodine fortification (IF) program in two Danish areas with different iodine intake at baseline (Copenhagen, mild iodine deficiency (ID) and Aalborg, moderate ID). DESIGN: A longitudinal population-based study (DanThyr). METHODS: We examined 2465 adults before (1997) and after (2008) the Danish IF of salt (2000). Ultrasonography was carried out by the same sonographers using the same equipment, after controlling performances. Participants treated for thyroid disease were excluded from analyses. RESULTS: Overall, median thyroid volume had increased in Copenhagen (11.8-12.2 ml, P=0.001) and decreased in Aalborg, although not significantly (13.3-13.1 ml, P=0.07) during the 11 years of follow-up. In both regions, there was an age-related trend in individual changes in thyroid volume from baseline to follow-up; thyroid volume increased in women <40 years of age and decreased in women >40 years of age. IN A MULTIVARIATE REGRESSION MODEL, HIGHER AGE AT ENTRY WAS A PREDICTOR (P0.05) FOR THYROID VOLUME DECREASE 20% DURING THE FOLLOW-UP PERIOD (WOMEN AGED 4045 YEARS: odds ratio (OR) 4.3 (95% CI, 2.2-8.2); women aged 60-65 years: 5.8 (2.9-11.6)) and individuals of higher age were also less likely to have an increase in thyroid volume (women aged 40-45 years: OR 0.2 (0.1-0.3); women aged 60-65: OR 0.3 (0.2-0.4)). CONCLUSIONS: Age-dependent differences in thyroid volume and enlargement had leveled out after the Danish iodization program. Thus, the previously observed increase in thyroid volume with age may have been caused by ID.

Determinants of serum T4 and T3 at the time of diagnosis in nosological types of thyrotoxicosis: a population-based study.

OBJECTIVE: To characterize thyroid hormone levels at the time of diagnosis in the nosological types of thyrotoxicosis diagnosed in the population and to analyze determinants for serum thyroxine (T4) and tri-iodothyronine (T3). DESIGN: Population-based study of thyrotoxicosis at disease onset. METHODS: In the period 1997-2000, we prospectively identified all patients diagnosed with incident primary overt thyrotoxicosis in a Danish population cohort and classified patients into ten well-defined nosological types of disease (n=1082). Untreated levels of serum T3, T4, and T3:T4 ratio were compared and related to sex, age, level of iodine deficiency, smoking status, alcohol intake, iodine supplement use, co-morbidity, and TSH receptor antibodies (TRAbs) in multivariate models. RESULTS: Graves' disease (GD) patients had much higher levels of T3 and higher T3:T4 ratio at diagnosis compared with other thyrotoxic patients, but with a profound negative association between hormone levels and age. In GD, patients diagnosed in the area with more severe iodine deficiency had lower levels of T3 and T4. TRAb-negative GD patients had biochemically mild thyrotoxicosis. Higher age was also associated with lower degree of biochemical thyrotoxicosis in nodular toxic goiter. We found no association between serum T3 and T4 and sex, smoking habits, iodine supplements, alcohol intake, or co-morbidity in any type of thyrotoxicosis. CONCLUSIONS: The study gives new insight into the hormonal presentation of thyrotoxicosis and showed that young age, positive TRAb levels, but also residency in the area with higher iodine intake was positively associated with biochemical disruption in GD.

High age predicts low referral of hyperthyroid patients to specialized hospital departments: evidence for referral bias.

BACKGROUND: Hospital-based studies may be hampered by referral bias. We investigated how the phenomenon may influence studies of hyperthyroid patients. METHODS: By means of a computer-based linkage to the laboratory database and subsequent detailed evaluation of subjects with abnormal test results, we prospectively identified all 1148 patients diagnosed with overt hyperthyroidism in a four-year period in and around Aalborg City, Denmark. Each patient was classified according to nosological type of hyperthyroidism. We studied the referral pattern of patients to local hospital units, and analyzed how referral depended on subtype of disease, sex, age, and degree of biochemical hyperthyroidism. RESULTS: In a 4-year period, 1032 hyperthyroid patients were diagnosed at primary care offices, and 435 of these (42.2%) were referred to specialized units, 92 patients had hyperthyroidism diagnosed in other hospital departments (referral: 43, 46.7%), and 24 patients had hyperthyroidism diagnosed at the specialized unit after referral for other diseases. Patients suffering from Graves' disease (GD; n=474, median age=65.8 years) were referred more often (odds ratio=1.7 [95% confidence interval 1.3-2.2]) than those diagnosed with multinodular toxic goiter (MNTG; n=525, median age=74.6 years). Higher age was associated with less referral of patients suffering from MNTG (referred vs. nonreferred patients, 64.0 vs. 77.4 years, p<0.001) and GD (43.9 vs. 56.4 years, p<0.001), whereas GD patients referred to a hospital had more severe biochemical hyperthyroidism (serum total triiodothyronine, 4.86 vs. 3.79 nmol/L; serum total thyroxine, 204 vs. 180 nmol/L; both p<0.001). Findings were confirmed in multivariate models reporting age as a significant predictor for referral in both GD and MNTG patients (both p<0.001). Among referred hyperthyroid patients (all combined), those aged up to 40 years (referral rate, 66.8%) were represented 11.6 (6.6-20.6) times more often than those aged 80 years and above (referral rate, 14.8%). CONCLUSIONS: Hyperthyroid patients referred to a specialized hospital unit were younger (GD+MNTG) and had more severe biochemical hyperthyroidism (GD) compared to nonreferred patients. Thus, referral bias may influence hospital-based studies of hyperthyroid patients, and may hamper external generalization of such studies. Whether the referral bias of hyperthyroid patients in Denmark can be generalized to other countries or cultures remains unknown.