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Inge Bülow Pedersen, Peter Laurberg, Nils Knudsen, Torben Jørgensen, Hans Perrild, Lars Ovesen and Lone Banke Rasmussen

Background: Thyroid autoimmunity is more common in females than in males. One possible explanation for this female preponderance may be the effect of oestrogens on the immune system. It has also been suggested that foetal microchimerism involving transfer of foetal cells into maternal tissue during pregnancy may play an important role.

Objective: We investigated the association between the presence of circulating thyroid autoantibodies and previous pregnancy, parity and the use of oral contraceptives (OCs) and hormone replacement therapy (HRT) in a population cohort.

Methods: We examined 3712 women randomly selected from the general population. Serum was analysed for thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) using assays based on an RIA technique (DYNO test). Data were analysed in logistic regression models to adjust for possible confounders. Women previously treated for thyroid disease or with pregnancy within 1 year prior to the study were excluded from the analyses.

Results: In both univariate and multivariate models and whether the presence of TPO-Ab and Tg-Ab was investigated alone or in combination, findings were negative with respect to an association between circulating thyroid antibodies and previous pregnancy, number of pregnancies, parity and previous abortion. There was no association between thyroid autoantibodies and use of OCs. Women aged 60–65 years receiving HRT now or previously had a lower prevalence of Tg-Ab (univariate, P = 0.01; multivariate, P = 0.02). No such association was observed between HRT and TPO-Ab.

Conclusion: In this population study there was no association between previous pregnancy, parity and thyroid antibodies, which argues against the role of microchimerism as a trigger of thyroid autoimmunity. Exogenous oestrogens may reduce aspects of autoimmunity.

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Allan Carlé, Nils Knudsen, Inge Bülow Pedersen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen and Peter Laurberg

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.

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Inge Bülow Pedersen, Peter Laurberg, Nils Knudsen, Torben Jørgensen, Hans Perrild, Lars Ovesen and Lone Banke Rasmussen

Background

Autoimmune thyroid diseases are common and the prevalence of circulating thyroid antibodies (thyroid peroxidase antibody, TPO-Ab and thyroglobulin antibody, Tg-Ab) is high in the population. The knowledge of a possible association between lifestyle factors and circulating thyroid antibodies is limited.

Aim

To evaluate the correlation between smoking habits and the presence of circulating TPO-Ab and Tg-Ab.

Material and methods

In a cross-sectional comparative population study performed in two areas of Denmark with moderate and mild iodine deficiency, 4649 randomly selected subjects from the population in some predefined age groups between 18 and 65 years were examined. Blood tests were analysed for TPO-Ab and Tg-Ab using assays based on the RIA technique. The participants answered questionnaires, were clinically examined and blood and urine samples collected.

Results

Data were analysed in multivariate logistic regression models. There was a negative association between smoking and the presence of thyroid autoantibodies in serum. This association was observed for the presence of TPO-Ab and/or Tg-Ab, TPO-Ab (without respect to Tg-Ab status), Tg-Ab (without respect to TPO-Ab status) and both antibodies together. The association between smoking and thyroid autoantibodies was stronger for Tg-Ab than for TPO-Ab. There was no association between smoking and TPO-Ab measured alone or between smoking and TPO-Ab when Tg-Ab was included in the model as an explanatory variable.

Conclusion

Smoking was negatively associated with the presence of thyroid autoantibodies with the strongest association between smoking and Tg-Ab. The study design precludes any conclusions as to the cause of the negative association between smoking thyroid autoantibodies.

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Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen and Peter Laurberg

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.

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Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen and Peter Laurberg

Objective

Few population-based studies have described the epidemiology of subtypes of hyperthyroidism.

Design

A prospective population-based study, monitoring two well-defined Danish cohorts in Aalborg with moderate iodine deficiency (n=311 102) and Copenhagen with only mild iodine deficiency (n=227 632).

Methods

A laboratory monitoring system identified subjects with thyroid function tests suggesting overt hyperthyroidism (low s-TSH combined with high s-thyroxine or s-triiodothyronine). For all subjects, we collected information on medical history, thyroid scintigraphy and thyroid hormone receptor antibody (TRAb) measurement. Information was used to disprove or verify primary overt hyperthyroidism and to subclassify hyperthyroidism into nosological disorders.

Results

From 1997 to 2000 (2 027 208 person-years of observation), we verified 1682 new cases of overt hyperthyroidism. The overall standardized incidence rate (SIR) per 100 000 person-years was 81.6, and was higher in Aalborg compared with Copenhagen (96.7 vs 60.0, P<0.001), giving an SIR ratio (SIRR (95% confidence interval (CI))) between moderate versus mild iodine-deficient areas of 1.6 (1.4–1.8). Nosological types of hyperthyroidism (percentage/SIRR (95% CI)): multinodular toxic goitre (MNTG) 44.1%/1.9 (1.6–2.2), Graves' disease (GD) 37.6%/1.2 (0.99–1.4), solitary toxic adenoma (STA) 5.7%/2.4 (1.3–3.5), ‘mixed type’ hyperthyroidism (TRAb-positive, scintigraphicly multinodular) 5.4%/6.0 (3.0–12), subacute thyroiditis 2.3%/0.9 (0.4–1.4), postpartum thyroid dysfunction 2.2%/1.6 (0.8–3.0), amiodarone-associated hyperthyroidism 0.8%/7.1 (1.1–65), hyperthyroidism after thyroid radiation 0.7%/12.3 (0.8–50), lithium-associated hyperthyroidism 0.7%/0.97 (0.4–4.8) and hyperthyroidism caused by various other factors 0.7%. Lifetime risk for overt hyperthyroidism was 10.5%/6.5%/2.4% (females/all/males).

Conclusion

Hyperthyroidism was common in Denmark with MNTG and GD as dominating entities. The higher incidence of hyperthyroidism in the most iodine-deficient region was caused by higher frequency of MNTG, ‘mixed-type’, STA and amiodarone-associated hyperthyroidism.

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Charlotte Cerqueira, Nils Knudsen, Lars Ovesen, Peter Laurberg, Hans Perrild, Lone B Rasmussen and Torben Jørgensen

Objective

Iodization of salt was introduced in Denmark in 1998 because of mild-to-moderate iodine deficiency (ID). The aim of this study was to analyze the utilization rate of surgery and radioiodine therapy for benign thyroid disorders before and after the introduction of iodization, and to study a possible association between the changes and the raised iodine intake.

Design

A nationwide register study.

Methods

Information on operations and radioiodine treatments for benign thyroid disorders was extracted from nationwide registers in the years 1990 to 2007. Treatment rates are presented for surgery and for radioiodine separately, and as a combined rate, both nationwide and split by the regions of prior mild and moderate ID.

Results

A total of 65 605 treatments were identified: 26 456 operations and 39 149 radioiodine treatments. In the first years of iodization (1998–2000; rate ratio 2000/1997), the combined treatment rate increased with 2.5% (95% confidence interval (CI): −1.8–7.1). Split by prior ID level, the increase was seen in the region of moderate ID, but a decrease was seen in the region of mild ID. After 2000, the combined rate decreased, and ended up being 11.1% (95% CI: 7.1–15.0) lower in 2007 than before iodization (rate ratio 2007/1997). The changes were primarily due to changes in the use of radioiodine therapy as the surgery rates remained almost constant.

Conclusions

Iodization seemed to be associated with a temporary increase in the utilization rate of surgery and radioiodine therapy in the region of prior moderate ID, probably as a result of treatment of iodine-induced hyperthyroidism, but the rates ended up being lower than before iodization.

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Pernille Vejbjerg, Nils Knudsen, Hans Perrild, Peter Laurberg, Inge Bülow Pedersen, Lone B Rasmussen, Lars Ovesen and Torben Jørgensen

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.

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Peter Laurberg, Torben Jørgensen, Hans Perrild, Lars Ovesen, Nils Knudsen, Inge Bülow Pedersen, Lone B Rasmussen, Allan Carlé and Pernille Vejbjerg

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 μg/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.

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Allan Carlé, Peter Laurberg, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen and Torben Jorgensen

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.

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Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, Torben Jørgensen and Peter Laurberg

Objective

Alcohol consumption is an important protective risk factor for many autoimmune diseases. We wished to study the association between alcohol consumption and autoimmune hypothyroidism.

Design

Population-based, case–control study, 1997–2001, Denmark.

Methods

Patients with newly diagnosed autoimmune overt hypothyroidism (n=140) were prospectively identified in a population (2 027 208 person-years of observation), and their matched controls with normal thyroid function (n=560) were recruited simultaneously from the same population. Participants gave information on alcohol intake, smoking, previous diseases, education, and family history of hypothyroidism. The association between alcohol intake and development of hypothyroidism was analyzed in conditional regression models.

Results

Hypothyroid cases had reported a lower alcohol consumption than controls (median units of alcohol (12 g) per week: 3 vs 5, P=0.002). In a multivariate regression model, alcohol consumption was associated with a reduction in risk for development of overt autoimmune hypothyroidism. Odds ratios (95% confidence interval) compared with the reference group with a recent (last year) consumption of 1–10 units of alcohol per week were as follows: 0 units/week, 1.98 (1.21–3.33); 11–20 units/week, 0.41 (0.20–0.83); and ≥21 units/week, 0.90 (0.41–2.00). Similar results were found for maximum previous alcohol consumption during a calendar year. No interaction was found with type of alcohol consumed (wine vs beer), sex, or region of inhabitancy.

Conclusions

Alcohol consumption seems to confer considerable protection against development of overt autoimmune hypothyroidism irrespective of sex and type of alcohol consumed.