Subclinical thyrotoxicosis is a condition affecting up to 10% of the population in some studies. We have reviewed literature and identified studies describing prevalences, causes and outcomes of this condition. Treatment should be considered in all subjects if this biochemical abnormality is persistent, especially in case of symptoms of thyrotoxicosis or in the presence of any complication. In particular, treatment should be offered in those subclinically thyrotoxic patients with a sustained serum TSH below 0.1 U/L. However it is important to recognise that there are no large controlled intervention studies in the field and thus there is no high quality evidence to guide treatment recommendations. In particular, there is no evidence for therapy and there is weak evidence of harm from thyrotoxicosis if serum TSH is in the 0.1–0.4 IU/L range. In this review, we describe the different causes of subclinical thyrotoxicosis, and how treatment should be tailored to the specific cause. We advocate radioactive iodine treatment to be the first-line treatment in majority of patients suffering from subclinical thyrotoxicosis due to multinodular toxic goitre and solitary toxic adenoma, but we do generally not recommend it as the first-line treatment in patients suffering from subclinical Graves’ hyperthyroidism. Such patients may benefit mostly from antithyroid drug therapy. Subclinical thyrotoxicosis in early pregnancy should in general be observed, not treated. Moreover, we advocate a general restriction of therapy in cases where no specific cause for the presumed thyroid hyperactivity has been proven.
Allan Carlé, Stine Linding Andersen, Kristien Boelaert, and Peter Laurberg
Allan Carlé, Nils Knudsen, Inge Bülow Pedersen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, and Peter Laurberg
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).
Population-based study of thyrotoxicosis at disease onset.
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.
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.
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.
Stine Linding Andersen, Allan Carlé, Jesper Karmisholt, Inge Bülow Pedersen, and Stig Andersen
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.
Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, and Peter Laurberg
Few population-based studies have described the epidemiology of subtypes of hyperthyroidism.
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).
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.
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).
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.
Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, and Peter Laurberg
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.
To study the array of symptoms as they are reported in newly diagnosed overt autoimmune hypothyroidism using a population-based case–control design.
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.
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).
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.
Anne Krejbjerg, Lena Bjergved, Inge Bülow Pedersen, Allan Carlé, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, and Peter Laurberg
Our objective was to investigate individual serum thyroglobulin (Tg) changes in relation to iodine fortification (IF) and to clarify possible predictors of these changes.
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.
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.
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.
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.
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.
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.
Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, Torben Jørgensen, and Peter Laurberg
Alcohol consumption is an important protective risk factor for many autoimmune diseases. We wished to study the association between alcohol consumption and autoimmune hypothyroidism.
Population-based, case–control study, 1997–2001, Denmark.
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.
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.
Alcohol consumption seems to confer considerable protection against development of overt autoimmune hypothyroidism irrespective of sex and type of alcohol consumed.
Pernille Vejbjerg, Nils Knudsen, Hans Perrild, Peter Laurberg, Allan Carlé, Inge Bülow Pedersen, Lone B Rasmussen, Lars Ovesen, and Torben Jørgensen
The iodine status of a population is traditionally evaluated by either urinary iodine (UI) excretion or by some measure of thyroid volume and the prevalence of goitre. In this prospective study of a mandatory iodization programme, we aimed to evaluate serum thyroglobulin (Tg) as a marker of iodine status in the population.
Two identical cross-sectional studies were performed before (1997–1998, n=4649) and after (2004–2005, n=3570) the initiation of the Danish iodization programme in two areas with mild and moderate iodine deficiency. Serum Tg was measured from blood samples. Thyroid volume was measured by ultrasonography.
Before iodization, the median serum Tg was considerably higher in moderate than in mild iodine deficiency. Iodization led to a lower serum Tg in all examined age groups. The marked pre-iodization difference in Tg level between the regions was eliminated. The prevalence of Tg above the suggested reference limit (40 μg/l) decreased from 11.3 to 3.7% (P<0.0001). Using bootstrapping, we demonstrated a higher efficacy of Tg than of thyroid volume to show a difference between pre- and post-iodization values.
We found serum Tg to be a suitable marker of iodine nutrition status in the population. The results may suggest that the Danish iodization programme has led to a sufficient iodine intake, even if the median UI excretion is still marginally low according to WHO criteria.