Epidemiology of subtypes of hyperthyroidism in Denmark: a population-based study

in European Journal of Endocrinology

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.

Abstract

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.

Keywords:

Introduction

Primary overt hyperthyroidism is a common disease worldwide. The incidence rate of hyperthyroidism is influenced by a number of factors, of which the iodine intake in the population may be important. In areas with high iodine intake level, hypothyroidism is more common than hyperthyroidism (1, 2), whereas hyperthyroidism dominates in areas with mild and moderate iodine deficiency (3, 4). Hyperthyroidism may be divided into a number of nosological subtypes with different aetiology, clinical presentation, prognosis and outcome of therapy. The incidence of individual subtypes may also be dependent on the iodine intake level (3, 5, 6). However, the information on the epidemiology of subtypes of hyperthyroidism and the effect of environmental factors including iodine intake is limited.

Often, it is difficult to compare studies, as the criteria of inclusion, exclusion and for classification into subtypes may be different. Many studies not only included patients with biochemical overt hyperthyroidism, but also patients with subclinical hyperthyroidism (7), or may have identified patients by means of biochemical screening (2). Other studies only evaluated certain age groups (8). Most studies were based on patients referred to hospital departments (6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18), potentially leading to referral bias (19).

The iodine fortification programme in Denmark was introduced rather late compared with many other countries. From year 2001, all household salt produced in Denmark and salt for industrial production of bread have been iodine-enriched, abiding by the law (20). We have previously published data on the incidence of primary overt hyperthyroidism in two Danish areas with different iodine intake in the period 1997–1998 (21). This study did not allow evaluation of how the various subtypes of disease contributed to the overall incidences. Now, we have expanded the study period to also include patients diagnosed with hyperthyroidism in the period 1999–2000, and to include detailed data on individual patients. This allowed us to estimate incidence rates of the nosological subtypes of hyperthyroidism and to compare various subtypes of the disease in two areas slightly different in iodine intake level.

Subjects and methods

The present study is part of The Danish Investigation on Iodine Intake and Thyroid Diseases (DanThyr), which is an ongoing monitoring of the Danish iodine fortification programme (20). This study deals with the period 1997–2000 just before iodine fortification of salt became effective in Denmark.

Population cohort

We have previously published data on the iodine status of people living in the two areas under study (22), an area of mild iodine deficiency in Copenhagen in East-Denmark (227 632 inhabitants, study period May 1997 to December 2000, median urinary iodine excretion (UIE) was 61 μg/l) and an area of moderate iodine deficiency around Aalborg in West-Denmark (311 102 inhabitants, March 1997 to December 2000, median UIE was 45 μg/l (22)). The total person-years of observation were 2 027 208. Information on population size, age and sex distribution was obtained from Statistics Denmark (23). For the calculations, we used population data per January 1, 1999. The combined cohort (n=538 734) was representative of the Danish population (24).

Identification of ‘possible new cases’ with hyperthyroidism

Patients were prospectively identified using a monitoring system of diagnostic laboratories covering all hospital and primary care institutions in the two regions studied. Thus, no intervention or active screening was performed. The use of this system for identification of ‘possible new cases’ have been described previously in detail (25, 26). In brief, results of all thyroid function tests in the two cohort areas were on a daily basis imported from laboratory databases into a register database. Four different laboratories (I: Aalborg Hospital, II: Bispebjerg Hospital, III: Frederiksberg Hospital, IV: Laboratory of General Practitioners in Copenhagen; II–IV all in Copenhagen) participated in the identification process. The register database identified ‘possible new cases’ (thus automatically excluding previously diagnosed cases) with blood tests fulfilling the criteria of overt, biochemical hyperthyroidism, i.e. with low serum TSH and either high serum thyroxine (T4) (total T4, or free T4, fT4) or high serum triiodothyronine (T3) (total T3). For the four laboratories, we used clinical cut-off values as suggested by the manufacturers: TSH <0.2 mU/l (all four laboratories: I–IV); total T4>140/140/160/140 nmol/l (I/II/III/IV); fT4>23.8/22.0 pmol/l (II/IV, laboratory I and III did not use fT4); total T3>2.7/2.1/2.5/2.5 nmol/l (I/II/III/IV). A detailed assay description including comparison between the four diagnostic laboratories has been given previously (26, 27).

A careful method evaluation (25) showed that about 98% of the population investigated was registered with and had consulted a general practitioner, who practiced within the study area, and submitted blood samples to the involved laboratories for analyses. During a 60 days test period, a manual search of abnormal thyroid function test revealed a 100% sensitivity of the automated identification system, as described in detail previously (25).

Data collection on ‘possible new cases’

In order to verify and subclassify hyperthyroidism, we collected all available data from hospital medical records, laboratory files, blood samples from subjects and thyroid scintigraphy from departments of nuclear medicine. Furthermore, we asked the general practitioners for additional medical information. In selected periods, where staff were available for a comprehensive investigative programme, a subgroup of patients (n=887) were contacted shortly after they had been diagnosed with incident hyperthyroidism. Those who accepted an invitation (n=554) joined a comprehensive investigation programme, including questioning of medical history, thyroid gland ultrasound investigation and measurement of TSH receptor antibody (TRAb) in serum. Non-participants were asked to answer a simple questionnaire (response, n=206). We collected the following information in order to verify and subclassify patients with hyperthyroidism: i) thyroid function tests performed after the initial test, which suggested hyperthyroidism; ii) information on treatment with l-T4, thyrostatic drugs, amiodarone, lithium, cytokines, estrogens, radioiodine and thyroid surgery; iii) thyroid scintigraphy (performed on 1051=62.5% of all patients); iv) TRAb measurements (performed in 577=34.3% of all patients) using DYNOtest TRAK human by BRAHMS (TRAb level >1.0 IU/l was regarded as antibody-positive (TRAb+)) (28); v) supplemental information on delivery, neck pain, available erythrocyte sedimentation rate measurements and other types of neck surgery.

Verification of incident cases

All ‘possible new cases’ (n=2362) identified with biochemical hyperthyroidism with no previous thyroid dysfunction already known by the general practitioner were individually evaluated. This led to exclusion of a substantial number of patients (n=680). Most of the subjects were excluded because a subsequent thyroid function test performed within 3 weeks revealed biochemical normalization without treatment, and with no medical history suggesting a transient hyperthyroid state (n=277). Other subjects had previously suffered from hyperthyroidism (n=76). Patients receiving amiodarone treatment were only verified as overtly hyperthyroid if they had elevated serum T3, as the combination of low TSH+high T4+normal T3 was considered to be a normal response to medication (29) in patients being subclinically hyperthyroid (n=72). Some patients were excluded as they had high total T4 caused by a high thyroid hormone-binding capacity due to pregnancy or use of contraceptives (n=71), a few others were excluded because neither a confirmative thyroid function test nor therapy could be verified (n=73), or they had iatrogenic hyperthyroidism caused by l-T4 treatment of hypothyroidism, euthyroid goitre or psychiatric disease (n=55), or the biochemical abnormality was caused by laboratory errors (n=30). Two out of four participating laboratories used fT4 and total T4 in combination. To avoid epidemiological bias between the four laboratories and thus the two regions under study, the few subjects with high fT4 but normal total T4 were excluded from the study (n=26). The rest of the patients were excluded due to a number of other reasons (n=47).

As depicted in Fig. 1, patients were verified as suffering from overt hyperthyroidism, if none of the above listed criteria for exclusion were fulfilled, and they also fulfilled at least one of these criteria: i) sustained biochemical signs of overt hyperthyroidism after 3 weeks (n=909); ii) treatment for hyperthyroidism instituted within 3 weeks after initial thyroid function test (n=708); iii) normal thyroid function tests after 3 weeks without treatment but with signs or history suggesting transient hyperthyroidism (postpartum thyroiditis, lithium-/amiodarone-/cytokine-therapy, subacute thyroiditis (SAT), or surgical manipulation of the thyroid; total, n=44). The remainder of patients included with biochemical signs of overt hyperthyroidism (n=21) had no confirmative thyroid function test and had no history of thyroiditis. The primary care physicians had required thyroid function tests to evaluate possible thyroid dysfunction, but the patients died shortly (within 2 months) after the thyroid function test had been performed. They were considered to be true hyperthyroid cases without further proof.

Figure 1
Figure 1

Number of patients with hyperthyroidism fulfilling the criteria used for verification (n=1682) in the DanThyr study in the period 1997–2000. A total of 909 patients had sustained hyperthyroidism after 3 weeks, 1313 patients had received treatment within 3 weeks and 138 had a history suggesting transient hyperthyroidism.

Citation: European Journal of Endocrinology 164, 5; 10.1530/EJE-10-1155

Classification of incident cases into nosological subtypes of hyperthyroidism

For each patient, hyperthyroidism was nosologically classified into one of the following conditions based on medical history, thyroid scintigraphy and TRAb measurements:

  • Graves' disease (GD): positive TRAb measurement (TRAb+, TRAb>1.0 IU/l) or a non-suppressed homogeneous uptake in the entire thyroid gland on scintigraphy.
  • Multinodular toxic goitre (MNTG): thyroid scintigraphy showed a heterogeneous uptake with at least two nodules of enhanced accumulation combined with absent or diminished uptake in the rest of the gland. If TRAb was negative or not measured, MNTG was the diagnosis.
  • ‘Mixed type’ hyperthyroidism: patients with thyroid scintigraphy, suggesting MNTG, but with positive TRAb, suggesting GD.
  • Solitary toxic adenoma (STA): one nodule of enhanced uptake combined with absent or low accumulation in rest of the thyroid gland.
  • SAT (de Quervain thyroiditis): transient hyperthyroidism, with no history of excessive iodine intake (amiodarone or contrast media), no medication which could explain the transient thyrotoxic period (amiodarone, lithium and cytokines) and with at least two of three SAT criteria fulfilled (absent or low uptake with no visible thyroid nodules on scintigraphic picture; elevated erythrocyte sedimentation rate; or neck pain).
  • Postpartum thyroid dysfunction (PPTD): overt hyperthyroidism diagnosed within 1 year after delivery. If TRAb was negative or not measured, PPTD was the diagnosis. If TRAb was positive, the patient was classified as GD.
  • Amiodarone-associated hyperthyroidism: overt hyperthyroidism diagnosed during or within 12 months after amiodarone treatment.
  • Radioiodine-associated hyperthyroidism: transient overt hyperthyroidism developed within a month after radioiodine treatment of euthyroid goitre was performed.
  • Lithium-associated hyperthyroidism: overt hyperthyroidism in patients previously (<12 months) or currently treated with lithium.
  • ‘Manipulation thyroiditis’ with hyperthyroidism: transient hyperthyroidism developed shortly after thyroid manipulation during surgery on thyroid or parathyroid gland.
  • Hyperthyroidism associated with previous (<12 months) or current cytokine therapy: we carefully scrutinized all available information, but found no patients with this disorder. Neither did we identify any history of prior contrast media or other types of excessive iodine exposure as the course for hyperthyroidism.

By means of the above-mentioned criteria, we were able to classify hyperthyroidism for most of the patients (n=1147). However, no TRAb measurements or thyroid scintigraphy were available on a large fraction of the patients (n=535), but a complete medical history indicated that they could not suffer from subtype e to k. In other words, they suffered from MNTG, GD, ‘mixed type’, or STA (a to d). In order to classify these patients, we employed hot-deck imputation of missing values using the principle of ‘nearest neighbour imputation’ (30). This was done after stratification according to region and sex, and subsequent sorting according to age.

Statistical analysis

Age-standardized incidence rates (SIRs) and SIR ratios (SIRRs) were calculated according to standard procedures (31, 32). For SIR and SIRR, we calculated 95% confidence intervals (CIs) or z values for the t-test assuming approximation from Poisson to Gaussian distribution (32), or calculated s.e.m. in case of few patients in part studies.

Lifetime risk, defined as the probability of an inhabitant to have diagnosed overt hyperthyroidism during an average lifetime, was estimated using the calculated incidence rates applied to the Danish demographic population (23). For the calculations, we assumed that SIRs were identical in different generations, i.e. no cohort effect being present, and that the combined study population was representative of the entire Danish population.

Ethical approval

This study was approved by Regional Ethics Committees in Aalborg and Copenhagen. Registry permission was obtained from the Danish Data Protection Agency. No conflicts of interest were present.

Results

Total incidence of hyperthyroidism

In the combined cohort, we identified and verified 1682 new cases of overt hyperthyroidism. Thus, the incidence rate of hyperthyroidism in the combined Danish cohort was 81.6 per 100 000 person-years. Hyperthyroidism was more frequent in the area of moderate versus mild iodine deficiency (Aalborg versus Copenhagen; 96.7 vs 60.0 per 100 000 person-years; SIRR=1.6 (95% CI: 1.4–1.8)).

Subtypes of hyperthyroidism

In all the 1682 patients newly diagnosed with overt hyperthyroidism, we were able to classify subtype of disease directly in 1147 patients suffering from MNTG (n=405), GD (n=484), ‘mixed type’ (n=65), STA (n=71), SAT (n=38), PPTD (n=37), amiodarone thyrotoxicosis (n=14), radioiodine thyrotoxicosis (n=12), lithium thyrotoxicosis (n=11) and due to other causes (n=10; nine patients had no uptake on the thyroid scintigram and no history suggesting specific type of disease; one patient had thyrotoxicosis shortly after removal of parathyroid hormone excreting adenoma). Hot-deck imputation was performed on the remaining 535 patients with no definite subtype of hyperthyroidism and gave subtype classification into MNTG (n=336), GD (n=149), ‘mixed type’ (n=25) and STA (n=25).

Data on nosological type of disease, age and sex of the 1682 patients newly diagnosed with hyperthyroidism are depicted in Table 1, which also includes the age and sex composition of the background population.

Table 1

Number of hyperthyroid patients according to nosological subtype of disease, sex and age.

Age intervals (years)a
Type of diseaseSex0–910–1920–2930–3940–4950–5960–6970–7980–9090+All ages
HyperthyroidismbFemale05110169177204224277195271388
Male02153132515477302294
Multinodular toxic goitreFemale00011318611020617027641
Male00114141839212100
Graves' diseaseFemale0582122102706956120518
Male0112202125171900115
‘Mixed type’ hyperthyroidismcFemale005513272115077
Male001314130013
Solitary toxic adenomaFemale00145112096056
Male00113511118040
PostpartumdFemale00172000000037
Subacute thyroiditiseFemale0017175010031
Male00031120007
Amiodarone-associatedfFemale00000201003
Male010212230011
Lithium-associatedgFemale00202212009
Male00000011002
Post-radiationhFemale000050311010
Male00000020002
Various subtypesiFemale00202100106
Male00011001104
Study populationjFemale31 04324 16247 90141 50633 09232 42023 35523 50615 2573134275 376
Male32 75925 32547 72645 65534 66432 61520 70616 0147113781263 358

Age intervals 0–9.99, 10–19.99 etc.

All nosological types of hyperthyroidism.

Multinodular Tc-99 uptake pattern on thyroid scintigraphy with positive TRAb measured.

Postpartum thyroid dysfunction (PPTD) presenting with hyperthyroidism within 1 year after delivery.

Subacute thyroiditis (SAT) presenting with hyperthyroidism.

Hyperthyroidism in patients treated with amiodarone (within 12 months).

Hyperthyroidism in patients treated with lithium (within 12 months).

Hyperthyroidism developed after thyroid radioiodine treatment (within 1 month).

Hyperthyroidism associated with a mixture of disorders (see text). One patient had ‘manipulation thyroiditis’ with hyperthyroidism developed 2 days after surgery for parathyroid adenoma.

Study population on January 1, 1999 in the combined cohort (Copenhagen and Aalborg).

The SIRs of the nosological subtypes of hyperthyroidism are shown in Table 2. MNTG and GD were the dominating types of hyperthyroidism, accounting for more than 80% of all cases. STA and SAT were also common types of hyperthyroidism.

Table 2

SIRs of nosological types of hyperthyroidism in Denmark.

SIRa (CIb)%cMedian agedF/M-ratioe
Multinodular toxic goitre35.0 (30.1–40.0)44.175.26.4
Graves' disease31.2 (26.4–35.9)37.646.04.5
Solitary toxic adenoma4.8 (2.9–6.7)5.766.51.4
‘Mixed type’f4.7 (2.8–6.6)5.456.35.9
Subacute thyroiditis2.0 (0.8–3.2)2.344.54.4
Postpartum thyroid dysfunctiong1.6 (0.6–2.6)2.230.7
Amiodarone-associated0.72 (0–1.5)0.856.10.27
Radiation-induced0.63 (0–1.3)0.764.05.0
Lithium-associated0.54 (0–1.2)0.756.64.5
Various typesh0.47 (0–1.0)0.646.41.5
All types combined81.6 (73.9–89.2)10061.84.7

SIR per 100 000 person-years (age-adjusted to the Danish population, January 1, 1999).

95% CI of SIRs.

Number of patients/1682 (in percentage).

Median age at diagnosis for all 1682 hyperthyroid patients, including those who were classified by means of ‘hot-deck imputation’.

SIRR between SIR for females and males.

TRAb+ (suggesting GD) and with a heterogeneous uptake pattern on thyroid scintigraphy (suggesting MNTG).

SIR was 3.3 per 100 000 female-years, and IR was 11.0 per 100 000 female years in the ages 20–40 years.

Mixture of not proven painless thyroiditis (n=9), and thyroid gland manipulation during neck surgery (n=1).

The median age of patients classified with various subtypes of hyperthyroidism is shown in Table 2. Patients were on average 61.8 years old with a span from 30.7 years among women diagnosed with PPTD to 75.2 years in patients suffering from MNTG.

The age-specific incidence rates of the three most common nosological subtypes of hyperthyroidism (GD, MNTG and STA) are depicted in Fig. 2. The age-specific incidence rate of GD was quite constant in subjects aged 30–80 years, whereas an almost exponential rise with age was observed for MNTG. GD was the dominating type of hyperthyroidism in patients up to 45 years of age. Because of the age composition of the population, the highest number of patients with GD was observed within the age interval 30–39 years (Table 1). With advancing age above 45 years, MNTG increasingly outnumbered GD. The incidence rate for STA also rose with age and peaked in the sixth decade, but without the profound rise with advancing age as observed for MNTG.

Figure 2
Figure 2

Age-specific incidence rates (IR) of the three most common nosological types of hyperthyroidism in Denmark (Graves' disease, multinodular toxic goitre and solitary toxic adenoma).

Citation: European Journal of Endocrinology 164, 5; 10.1530/EJE-10-1155

Regional difference in incidence of hyperthyroidism

The age-specific incidence rates of hyperthyroidism (all types combined) in four groups stratified according to region and gender are depicted in Fig. 3. The overall incidence of overt hyperthyroidism rose almost linearly with age, and female sex was a strong risk factor throughout the entire span of ages. In both gender and at all ages above 20 years, a higher incidence was observed in Aalborg (moderate ID) compared with Copenhagen (mild ID).

Figure 3
Figure 3

Incidence rates (±s.e.m.) of hyperthyroidism according to age group, gender and region of inhabitancy.

Citation: European Journal of Endocrinology 164, 5; 10.1530/EJE-10-1155

The regional difference in incidence of overt hyperthyroidism was further studied for the various subtypes. The higher incidence of hyperthyroidism in Aalborg compared with Copenhagen was caused by more cases with MNTG (SIRR (95% CI)=1.9 (1.6–2.2)), STA (SIRR=2.4 (1.3–3.5)), ‘mixed type’ hyperthyroidism (SIRR=6.0 (3.0–12)) and amiodarone-associated hyperthyroidism (SIRR=7.1 (1.1–65)). No statistical significant regional difference was observed with regards to GD (SIRR=1.2 (0.99–1.4)), SAT (SIRR=0.9 (0.4–1.4)), PPTD (SIRR=1.6 (0.8–30)), post-radiation thyrotoxicosis (SIRR=12.3 (0.8–50)), or Li-thyrotoxicosis (SIRR=0.97 (0.4–4.8)).

Sex distribution among subtypes of hyperthyroidism

In the combined cohort, the lifetime risk for development of overt hyperthyroidism was calculated to be 6.5% (Table 3), with more than four times predominance in women (10.5 vs 2.4% in men). The pronounced female preponderance was present for all subtypes (ratio between 4.4 and 6.4) except for STA (ratio was 1.4) and amiodarone-associated hyperthyroidism (ratio was 0.27).

Table 3

Life time risk (in percentage) for having diagnosed overt hyperthyroidism in Denmark.

AllWomenMen
Multinodular toxic goitre3.05.00.9
Graves' disease2.33.80.9
Solitary toxic adenoma0.50.60.4
All types combined6.510.52.4

Discussion

We provide data on the incidence rates of subtypes of overt, primary hyperthyroidism in two Danish subcohorts with mild and moderate iodine deficiency.

Total incidence of hyperthyroidism

Hyperthyroidism was common in Denmark with an SIR of 81.6 per 100 000 person-years. The sensitive design used in the present study may be responsible for the high incidence compared with previous Danish studies reporting incidence rates (per 100 000 person-years) of 22.0 (17), 27.6 (33), 38.7 (4), 44.0 (11) and 60.5 (34). Interestingly, during World War II, the incidence rate in Denmark increased from 24.6 to 81.5 (35) – the reason for this still remains unknown. The total incidence rate of hyperthyroidism was quite high in Denmark compared with other countries reporting figures of 22.7 in UK (36), 23.6 in Iceland (37), 25.8 in New Zealand (38), 25.8 rising to 43.0 in a Swedish region before and after salt iodization (14, 39), 32.0 in Spain (7), 32.7 in another Swedish region studying adults only (8), 34.7 also in Sweden (40), 36.9 in China after iodine fortification of salt (41), 46.0 in Scotland (42), around 50 in two Austrian studies (6, 43) and above 100 after excessive iodine exposure in Tasmania (44). A comparison between these studies and the present study is difficult, as they differ with regards to the design. In our study, all subjects with biochemical hyperthyroidism diagnosed in the population were individually scrutinized. No active screening was performed, and the patients who were not referred to hospital were included as well as referred patients. However, the most likely cause for the higher incidence of hyperthyroidism in our study is the magnitude of iodine deficiency. In Denmark, the incidence of hyperthyroidism was more than twice the incidence of hypothyroidism, 81.6 vs 32.8 per 100 000 person-years of observation (27). Even comparing the two regions (Aalborg versus Copenhagen) only slightly differing in iodine deficiency, the ratio of hyperthyroidism to hypothyroidism was highest in the region of moderate versus mild iodine deficiency (3.3 vs 1.6).

Subtypes of hyperthyroidism

The incidence of MNTG in Denmark (34.6 per 100 000 person-years) is higher than in most other countries studied, where the calculated SIRs spanned from 3.3 to 30.5 per 100 000 person-years (6, 8). All these studies were performed in regions with a higher iodine intake in the population compared with Denmark. This supports that MNTG is an important complication to long-standing low iodine intake. Thus, constitutively activating TSH receptor mutations have been demonstrated in hot microscopic areas of euthyroid iodine-deficient goitres (45).

The incidence of GD was quite high in Denmark, but this may be due to the sensitive design of our study. In order to compare the relative frequency of GD versus MNTG, we calculated a ratio between SIRs of GD and MNTG of 0.9 (31.2/35.0), which was comparable to the ratio of 0.8 in another Danish study (3). Other iodine-deficient countries have also reported low incidence rate ratios of GD/MNTG (6, 46). However, from other studies reporting GD to be more frequent than MNTG, we have calculated ratios of 1.4 in a Swedish study (39), 1.9 in a Danish study of patients referred to hospital (47), 2.1 in Spain (7), 2.3 in New Zealand (38), 3.3 from another Swedish study (14), 7.4 in a Swedish study from 2008 (8), 13.5 in Iceland (37) and 16 in a South African study on the Black population (15).

The three most common types of hyperthyroidism had very different age distribution, with GD dominating in young people, and MNTG dominating in the old. This is similar to a previous finding in an iodine-deficient Denmark population (3). STA was also more prominent in patients being >50 years of age. However, the peak incidence of this subtype of disease was seen around 60 years of age, whereas the MNTG incidence continued to increase with age. We previously found a similar difference (48), but have no good explanation for this difference in age association.

Regional difference in incidence of hyperthyroidism

In both genders and at all ages, we found a higher incidence of hyperthyroidism in Aalborg (moderate ID) compared with Copenhagen (mild ID). The small difference in iodine intake, mostly caused by differences in ground water iodine content (49), had a large impact on the incidence of subtypes of hyperthyroidism. While the incidence of GD was similar, MNTG was 87% more frequent in the most iodine-deficient region.

There was a higher incidence of amiodarone-associated hyperthyroidism in the area with the highest degree of iodine deficiency. It is well established that amiodarone-induced hyperthyroidism is common in iodine-deficient populations (50). We further studied the amiodarone intake in the two study regions. The use of amiodarone in Denmark is registered by Danish Medicines Agency (www.laegemiddelstyrelsen.dk) as defined daily doses (DDD). In the years 1997–2000, the average DDD in Aalborg was 0.90 (span from 0.67 to 1.17), which was more than twice the DDD in Copenhagen reported to be 0.44 (span from 0.37 to 0.48). Thus, the high incidence of amiodarone-associated hyperthyroidism in Aalborg was at least partly caused by a more frequent prescription of amiodarone.

Study strengths and limitations

We identified patients with overt hyperthyroidism as they are diagnosed in the population, in hospitals and in primary care institutions. Inclusion in the present study would require that a physician took initiative to diagnose thyroid dysfunction by requesting thyroid function tests.

Patients were subclassified according to the scintigraphic picture, but a proportion of the hyperthyroid patients had no scintiscan performed. Age differed between those who had scintiscan performed and those who had not (median age 56.8 vs 74.0 years). In a logistic multivariate regression model, we tested if sex, age, region of inhabitancy and degree of hyperthyroidism could predict whether a scintiscan was performed or not. Only age (P<0.001) and region (P<0.001) were significant predictors. To avoid bias from the age-/region-dependent ability to subclassify hyperthyroidism, we used hot-deck imputation. This was done to minimize selection bias to a minimum. However, this mathematical procedure would make CIs around incidence rates to widen, and therefore less reliable. As 31.8% of all patients newly diagnosed with hyperthyroidism were classified by means of imputation, we reanalyzed data after down-regulation of person-years of observation by the same fraction to obtain broader CIs and higher z values for the t-test. This conservative handling of data did not alter any of our conclusions: we still found a statistically significant difference in incidence ratio between Aalborg and Copenhagen with regards to MNTG (P<0.001), ‘mixed-type’ (P<0.001), STA (P=0.003), and no regional difference in occurrence of GD (P=0.10).

We previously reported that up to 15–20% of hyperthyroid patients with a multinodular scintigraphic pattern are TRAb positive (28). Even higher frequencies of TRAb positivity have been reported in clinic-based studies from Germany (51). The difference may be caused by differences in iodine intake and study design. Most likely, this is GD on top of a nodular goitre (28). We have labelled this entity ‘mixed type’ hyperthyroidism, as the scintigraphic picture suggested MNTG, whereas the measurable TRAb indicated GD.

Conclusion

Hyperthyroidism was very common in Denmark with a lifetime risk of 10.5% in women. This was due to a high frequency of MNTG probably caused by iodine deficiency. Even a slight difference in iodine deficient state between two study areas resulted in a large difference in the incidence of MNTG. The study highlights the need for an increase in iodine intake in Denmark (20).

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was part of The Danish Investigation of Iodine Intake and Thyroid Diseases (DanThyr), which is supported by grants from the Danish Medical Foundation, the 1991 Pharmacy Foundation, North Jutland County Research Foundation, Tømmerhandler Wilhelm Bangs Foundation and Copenhagen Hospital Corporation Research Foundation. We are indebted to the general practitioners in Copenhagen and Northern Jutland for their collaboration.

Acknowledgements

Deep thanks should also be addressed to the laboratories involved. Finally, we thank staff of the hospital record offices in Aalborg, Bispebjerg and Frederiksberg for their collaborative support.

References

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    CanarisGJManowitzNRMayorGRidgwayEC. The Colorado thyroid disease prevalence study. Archives of Internal Medicine2000160526534doi:10.1001/archinte.160.4.526.

    • Search Google Scholar
    • Export Citation
  • 2

    VanderpumpMPTunbridgeWMFrenchJMAppletonDBatesDClarkFGrimleyEJHasanDMRodgersHTunbridgeF. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clinical Endocrinology1995435568doi:10.1111/j.1365-2265.1995.tb01894.x.

    • Search Google Scholar
    • Export Citation
  • 3

    LaurbergPPedersenKMVestergaardHSigurdssonG. High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. Journal of Internal Medicine1991229415420doi:10.1111/j.1365-2796.1991.tb00368.x.

    • Search Google Scholar
    • Export Citation
  • 4

    LaurbergPBulowPIPedersenKMVestergaardH. Low incidence rate of overt hypothyroidism compared with hyperthyroidism in an area with moderately low iodine intake. Thyroid199993338doi:10.1089/thy.1999.9.33.

    • Search Google Scholar
    • Export Citation
  • 5

    BaltisbergerBLMinderCEBurgiH. Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency. European Journal of Endocrinology1995132546549doi:10.1530/eje.0.1320546.

    • Search Google Scholar
    • Export Citation
  • 6

    MostbeckAGalvanGBauerPEberOAtefieKDamKFeichtingerHFritzscheHHaydlHKohnHKonigBKoriskaKKroissALindPMarktBMaschekWPeslHRamschak-SchwarzerSRiccabonaGStockhammerMZechmannW. The incidence of hyperthyroidism in Austria from 1987 to 1995 before and after an increase in salt iodization in 1990. European Journal of Nuclear Medicine199825367374doi:10.1007/s002590050234.

    • Search Google Scholar
    • Export Citation
  • 7

    GalofreJCGarcia-MayorRVFluitersEFernandez-CalvetLRegoAParamoCAndradeMA. Incidence of different forms of thyroid dysfunction and its degrees in an iodine sufficient area. Thyroidology199464954.

    • Search Google Scholar
    • Export Citation
  • 8

    Abraham-NordlingMTorringOLantzMHallengrenBOhrlingHLundellGCalissendorffJJorneskogGWallinG. Incidence of hyperthyroidism in Stockholm, Sweden, 2003–2005. European Journal of Endocrinology2008158823827doi:10.1530/EJE-07-0877.

    • Search Google Scholar
    • Export Citation
  • 9

    WilliamsIAnkrettVOLazarusJHVolpeR. Aetiology of hyperthyroidism in Canada and Wales. Journal of Epidemiology and Community Health198337245248doi:10.1136/jech.37.3.245.

    • Search Google Scholar
    • Export Citation
  • 10

    FurszyferJKurlandLTMcConaheyWMElvebackLR. Graves' disease in Olmsted County, Minnesota, 1935 through 1967. Mayo Clinic Proceedings197045636644.

    • Search Google Scholar
    • Export Citation
  • 11

    IversenK. Thyrotoxicosis in aged individuals. Journal of Gerontology195386569doi:10.1093/geronj/8.1.65.

  • 12

    LavardLRanlovIPerrildHAndersenOJacobsenBB. Incidence of juvenile thyrotoxicosis in Denmark, 1982–1988. A nationwide study. European Journal of Endocrinology1994130565568doi:10.1530/eje.0.1300565.

    • Search Google Scholar
    • Export Citation
  • 13

    ThjodleifssonB. A study of Graves' disease in Iceland. Acta Medica Scandinavica1975198309314doi:10.1111/j.0954-6820.1975.tb19546.x.

  • 14

    BerglundJChristensenSBHallengrenB. Total and age-specific incidence of Graves' thyrotoxicosis, toxic nodular goitre and solitary toxic adenoma in Malmo 1970–74. Journal of Internal Medicine1990227137141doi:10.1111/j.1365-2796.1990.tb00132.x.

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    • Export Citation
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    KalkWJKalkJ. Incidence and causes of hyperthyroidism in blacks. South African Medical Journal198975114117.

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    ReinweinDBenkerGKonigMPPincheraASchatzHSchleusenerA. The different types of hyperthyroidism in Europe. Results of a prospective survey of 924 patients. Journal of Endocrinological Investigation198811193200.

    • Search Google Scholar
    • Export Citation
  • 17

    ThommesenNNirellIKristensenHP. Material on hyperthyroidism from a five-year period in a central hospital. Ugeskrift for Laeger197113316631669.

    • Search Google Scholar
    • Export Citation
  • 18

    BulfoniA. Epidemiological assessment of thyrotoxicosis in a hospitalized population. Minerva Medica198677815818.

  • 19

    CarleALaurbergPPedersenIBKnudsenNPerrildHOvesenLRasmussenLBJorgensenT. Mainly the younger hypothyroid patients are referred to hospital – evidence for referral bias. Journal of Clinical Epidemiology200962446451doi:10.1016/j.jclinepi.2008.06.016.

    • Search Google Scholar
    • Export Citation
  • 20

    LaurbergPJorgensenTPerrildHOvesenLKnudsenNPedersenIBRasmussenLBCarleAVejbjergP. The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives. European Journal of Endocrinology2006155219228doi:10.1530/eje.1.02210.

    • Search Google Scholar
    • Export Citation
  • 21

    BulowPedersenIKnudsenNJorgensenTPerrildHOvesenLLaurbergP. Large differences in incidences of overt hyper- and hypothyroidism associated with a small difference in iodine intake: a prospective comparative register-based population survey. Journal of Clinical Endocrinology and Metabolism20028744624469doi:10.1210/jc.2002-020750.

    • Search Google Scholar
    • Export Citation
  • 22

    RasmussenLBOvesenLBulowIJorgensenTKnudsenNLaurbergPPertildH. Dietary iodine intake and urinary iodine excretion in a Danish population: effect of geography, supplements and food choice. British Journal of Nutrition2002876169doi:10.1079/BJN2001474.

    • Search Google Scholar
    • Export Citation
  • 23

    Statistics Denmark 2006. Available from http://www.danmarksstatistik.dk (accessed 26-1-2011) 2005.

  • 24

    Carle A. Subtypes of hypothyrodism PhD Thesis 2006. Faculty of Health Sciences University of Aarhus Denmark.

  • 25

    PedersenIBLaurbergPArnfredTKnudsenNJorgensenTPerrildHOvesenL. Surveillance of disease frequency in a population by linkage to diagnostic laboratory databases. A system for monitoring the incidences of hyper- and hypothyroidism as part of the Danish iodine supplementation program. Computer Methods and Programs in Biomedicine200267209216doi:10.1016/S0169-2607(01)00125-0.

    • Search Google Scholar
    • Export Citation
  • 26

    Pedersen IB. On the importance of small differences in iodine intake for thyroid function. PhD Thesis 2002. Faculty of Health Sciences University of Aarhus Denmark.

  • 27

    CarleALaurbergPPedersenIBKnudsenNPerrildHOvesenLRasmussenLBJorgensenT. Epidemiology of subtypes of hypothyroidism in Denmark. European Journal of Endocrinology20061542128doi:10.1530/eje.1.02068.

    • Search Google Scholar
    • Export Citation
  • 28

    PedersenIBKnudsenNPerrildHOvesenLLaurbergP. TSH-receptor antibody measurement for differentiation of hyperthyroidism into Graves' disease and multinodular toxic goitre: a comparison of two competitive binding assays. Clinical Endocrinology200155381390doi:10.1046/j.1365-2265.2001.01347.x.

    • Search Google Scholar
    • Export Citation
  • 29

    AmicoJARichardsonVAlpertBKleinI. Clinical and chemical assessment of thyroid function during therapy with amiodarone. Archives of Internal Medicine1984144487490doi:10.1001/archinte.144.3.487.

    • Search Google Scholar
    • Export Citation
  • 30

    ChenJShaoJ. Jackknife variance estimation for nearest-neighbour imputation. Journal of the American Statistical Association200196260269doi:10.1198/016214501750332839.

    • Search Google Scholar
    • Export Citation
  • 31

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    Kirkwood BR. The Poisson Distribution. In Essentials of Medical Statistics. 1st edn pp 124–130. Oxford: Blackwell Scientific Publications 1988.

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    • Search Google Scholar
    • Export Citation
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    JohannessenAC. Atypical thyrotoxicosis. Ugeskrift for Laeger198414627672769.

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    Iversen E. Temporary Rise if the Frequency of Thyreotoxicosis in Denmark 1941–1945. Doctoral dissertation pp 1–244 University of Copenhagen Denmark: Rosenkilde & Bagger 1948.

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    • Export Citation
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    HaraldssonAGudmundssonSTLarussonGSigurdssonG. Thyrotoxicosis in Iceland 1980–1982. An epidemiological survey. Acta Medica Scandinavica1985217253258doi:10.1111/j.0954-6820.1985.tb02691.x.

    • Search Google Scholar
    • Export Citation
  • 38

    BrownlieBEWellsJE. The epidemiology of thyrotoxicosis in New Zealand: incidence and geographical distribution in north Canterbury, 1983–1985. Clinical Endocrinology199033249259doi:10.1111/j.1365-2265.1990.tb00489.x.

    • Search Google Scholar
    • Export Citation
  • 39

    BerglundJEricssonUBHallengrenB. Increased incidence of thyrotoxicosis in Malmo during the years 1988–1990 as compared to the years 1970–1974. Journal of Internal Medicine19962395762doi:10.1046/j.1365-2796.1996.415757000.x.

    • Search Google Scholar
    • Export Citation
  • 40

    LundgrenEBorup ChristensenS. Fallande incidens av thyreotocixos i Jämtland län under perioden 1975–1984 (abstract). Hygiea198796154.

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    • Export Citation
  • 41

    HuangQJinRZouD. Study on the effects of increased iodized salt intake on the incidence of thyroid diseases. Zhonghua Liu Xing Bing Xue Za Zhi200122455458.

    • Search Google Scholar
    • Export Citation
  • 42

    FlynnRWMacDonaldTMMorrisADJungRTLeeseGP. The thyroid epidemiology, audit, and research study: thyroid dysfunction in the general population. Journal of Clinical Endocrinology and Metabolism20048938793884doi:10.1210/jc.2003-032089.

    • Search Google Scholar
    • Export Citation
  • 43

    RiccabonaGBauerHMathieFScholzK. Epidemiology and treatment of thyrotoxicosis in an endemic goitre district. Wiener Klinische Wochenschrift197284360363.

    • Search Google Scholar
    • Export Citation
  • 44

    StewartJCVidorGI. Thyrotoxicosis induced by iodine contamination of food – a common unrecognised condition?BMJ19761372375doi:10.1136/bmj.1.6006.372.

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    Number of patients with hyperthyroidism fulfilling the criteria used for verification (n=1682) in the DanThyr study in the period 1997–2000. A total of 909 patients had sustained hyperthyroidism after 3 weeks, 1313 patients had received treatment within 3 weeks and 138 had a history suggesting transient hyperthyroidism.

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    Age-specific incidence rates (IR) of the three most common nosological types of hyperthyroidism in Denmark (Graves' disease, multinodular toxic goitre and solitary toxic adenoma).

  • View in gallery

    Incidence rates (±s.e.m.) of hyperthyroidism according to age group, gender and region of inhabitancy.

  • 1

    CanarisGJManowitzNRMayorGRidgwayEC. The Colorado thyroid disease prevalence study. Archives of Internal Medicine2000160526534doi:10.1001/archinte.160.4.526.

    • Search Google Scholar
    • Export Citation
  • 2

    VanderpumpMPTunbridgeWMFrenchJMAppletonDBatesDClarkFGrimleyEJHasanDMRodgersHTunbridgeF. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clinical Endocrinology1995435568doi:10.1111/j.1365-2265.1995.tb01894.x.

    • Search Google Scholar
    • Export Citation
  • 3

    LaurbergPPedersenKMVestergaardHSigurdssonG. High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. Journal of Internal Medicine1991229415420doi:10.1111/j.1365-2796.1991.tb00368.x.

    • Search Google Scholar
    • Export Citation
  • 4

    LaurbergPBulowPIPedersenKMVestergaardH. Low incidence rate of overt hypothyroidism compared with hyperthyroidism in an area with moderately low iodine intake. Thyroid199993338doi:10.1089/thy.1999.9.33.

    • Search Google Scholar
    • Export Citation
  • 5

    BaltisbergerBLMinderCEBurgiH. Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency. European Journal of Endocrinology1995132546549doi:10.1530/eje.0.1320546.

    • Search Google Scholar
    • Export Citation
  • 6

    MostbeckAGalvanGBauerPEberOAtefieKDamKFeichtingerHFritzscheHHaydlHKohnHKonigBKoriskaKKroissALindPMarktBMaschekWPeslHRamschak-SchwarzerSRiccabonaGStockhammerMZechmannW. The incidence of hyperthyroidism in Austria from 1987 to 1995 before and after an increase in salt iodization in 1990. European Journal of Nuclear Medicine199825367374doi:10.1007/s002590050234.

    • Search Google Scholar
    • Export Citation
  • 7

    GalofreJCGarcia-MayorRVFluitersEFernandez-CalvetLRegoAParamoCAndradeMA. Incidence of different forms of thyroid dysfunction and its degrees in an iodine sufficient area. Thyroidology199464954.

    • Search Google Scholar
    • Export Citation
  • 8

    Abraham-NordlingMTorringOLantzMHallengrenBOhrlingHLundellGCalissendorffJJorneskogGWallinG. Incidence of hyperthyroidism in Stockholm, Sweden, 2003–2005. European Journal of Endocrinology2008158823827doi:10.1530/EJE-07-0877.

    • Search Google Scholar
    • Export Citation
  • 9

    WilliamsIAnkrettVOLazarusJHVolpeR. Aetiology of hyperthyroidism in Canada and Wales. Journal of Epidemiology and Community Health198337245248doi:10.1136/jech.37.3.245.

    • Search Google Scholar
    • Export Citation
  • 10

    FurszyferJKurlandLTMcConaheyWMElvebackLR. Graves' disease in Olmsted County, Minnesota, 1935 through 1967. Mayo Clinic Proceedings197045636644.

    • Search Google Scholar
    • Export Citation
  • 11

    IversenK. Thyrotoxicosis in aged individuals. Journal of Gerontology195386569doi:10.1093/geronj/8.1.65.

  • 12

    LavardLRanlovIPerrildHAndersenOJacobsenBB. Incidence of juvenile thyrotoxicosis in Denmark, 1982–1988. A nationwide study. European Journal of Endocrinology1994130565568doi:10.1530/eje.0.1300565.

    • Search Google Scholar
    • Export Citation
  • 13

    ThjodleifssonB. A study of Graves' disease in Iceland. Acta Medica Scandinavica1975198309314doi:10.1111/j.0954-6820.1975.tb19546.x.

  • 14

    BerglundJChristensenSBHallengrenB. Total and age-specific incidence of Graves' thyrotoxicosis, toxic nodular goitre and solitary toxic adenoma in Malmo 1970–74. Journal of Internal Medicine1990227137141doi:10.1111/j.1365-2796.1990.tb00132.x.

    • Search Google Scholar
    • Export Citation
  • 15

    KalkWJKalkJ. Incidence and causes of hyperthyroidism in blacks. South African Medical Journal198975114117.

  • 16

    ReinweinDBenkerGKonigMPPincheraASchatzHSchleusenerA. The different types of hyperthyroidism in Europe. Results of a prospective survey of 924 patients. Journal of Endocrinological Investigation198811193200.

    • Search Google Scholar
    • Export Citation
  • 17

    ThommesenNNirellIKristensenHP. Material on hyperthyroidism from a five-year period in a central hospital. Ugeskrift for Laeger197113316631669.

    • Search Google Scholar
    • Export Citation
  • 18

    BulfoniA. Epidemiological assessment of thyrotoxicosis in a hospitalized population. Minerva Medica198677815818.

  • 19

    CarleALaurbergPPedersenIBKnudsenNPerrildHOvesenLRasmussenLBJorgensenT. Mainly the younger hypothyroid patients are referred to hospital – evidence for referral bias. Journal of Clinical Epidemiology200962446451doi:10.1016/j.jclinepi.2008.06.016.

    • Search Google Scholar
    • Export Citation
  • 20

    LaurbergPJorgensenTPerrildHOvesenLKnudsenNPedersenIBRasmussenLBCarleAVejbjergP. The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives. European Journal of Endocrinology2006155219228doi:10.1530/eje.1.02210.

    • Search Google Scholar
    • Export Citation
  • 21

    BulowPedersenIKnudsenNJorgensenTPerrildHOvesenLLaurbergP. Large differences in incidences of overt hyper- and hypothyroidism associated with a small difference in iodine intake: a prospective comparative register-based population survey. Journal of Clinical Endocrinology and Metabolism20028744624469doi:10.1210/jc.2002-020750.

    • Search Google Scholar
    • Export Citation
  • 22

    RasmussenLBOvesenLBulowIJorgensenTKnudsenNLaurbergPPertildH. Dietary iodine intake and urinary iodine excretion in a Danish population: effect of geography, supplements and food choice. British Journal of Nutrition2002876169doi:10.1079/BJN2001474.

    • Search Google Scholar
    • Export Citation
  • 23

    Statistics Denmark 2006. Available from http://www.danmarksstatistik.dk (accessed 26-1-2011) 2005.

  • 24

    Carle A. Subtypes of hypothyrodism PhD Thesis 2006. Faculty of Health Sciences University of Aarhus Denmark.

  • 25

    PedersenIBLaurbergPArnfredTKnudsenNJorgensenTPerrildHOvesenL. Surveillance of disease frequency in a population by linkage to diagnostic laboratory databases. A system for monitoring the incidences of hyper- and hypothyroidism as part of the Danish iodine supplementation program. Computer Methods and Programs in Biomedicine200267209216doi:10.1016/S0169-2607(01)00125-0.

    • Search Google Scholar
    • Export Citation
  • 26

    Pedersen IB. On the importance of small differences in iodine intake for thyroid function. PhD Thesis 2002. Faculty of Health Sciences University of Aarhus Denmark.

  • 27

    CarleALaurbergPPedersenIBKnudsenNPerrildHOvesenLRasmussenLBJorgensenT. Epidemiology of subtypes of hypothyroidism in Denmark. European Journal of Endocrinology20061542128doi:10.1530/eje.1.02068.

    • Search Google Scholar
    • Export Citation
  • 28

    PedersenIBKnudsenNPerrildHOvesenLLaurbergP. TSH-receptor antibody measurement for differentiation of hyperthyroidism into Graves' disease and multinodular toxic goitre: a comparison of two competitive binding assays. Clinical Endocrinology200155381390doi:10.1046/j.1365-2265.2001.01347.x.

    • Search Google Scholar
    • Export Citation
  • 29

    AmicoJARichardsonVAlpertBKleinI. Clinical and chemical assessment of thyroid function during therapy with amiodarone. Archives of Internal Medicine1984144487490doi:10.1001/archinte.144.3.487.

    • Search Google Scholar
    • Export Citation
  • 30

    ChenJShaoJ. Jackknife variance estimation for nearest-neighbour imputation. Journal of the American Statistical Association200196260269doi:10.1198/016214501750332839.

    • Search Google Scholar
    • Export Citation
  • 31

    Rothman KJ & Greenland S. Modern Epidemiology 2nd edn pp 253–279. Philadelphia PA: Lippincott Williams & Wilkins 1998.

  • 32

    Kirkwood BR. The Poisson Distribution. In Essentials of Medical Statistics. 1st edn pp 124–130. Oxford: Blackwell Scientific Publications 1988.

  • 33

    MogensenEFGreenA. The epidemiology of thyrotoxicosis in Denmark. Incidence and geographical variation in the Funen region 1972–1974. Acta Medica Scandinavica1980208183186doi:10.1111/j.0954-6820.1980.tb01174.x.

    • Search Google Scholar
    • Export Citation
  • 34

    JohannessenAC. Atypical thyrotoxicosis. Ugeskrift for Laeger198414627672769.

  • 35

    Iversen E. Temporary Rise if the Frequency of Thyreotoxicosis in Denmark 1941–1945. Doctoral dissertation pp 1–244 University of Copenhagen Denmark: Rosenkilde & Bagger 1948.

  • 36

    BarkerDJPhillipsDI. Current incidence of thyrotoxicosis and past prevalence of goitre in 12 British towns. Lancet19842567570doi:10.1016/S0140-6736(84)90776-1.

    • Search Google Scholar
    • Export Citation
  • 37

    HaraldssonAGudmundssonSTLarussonGSigurdssonG. Thyrotoxicosis in Iceland 1980–1982. An epidemiological survey. Acta Medica Scandinavica1985217253258doi:10.1111/j.0954-6820.1985.tb02691.x.

    • Search Google Scholar
    • Export Citation
  • 38

    BrownlieBEWellsJE. The epidemiology of thyrotoxicosis in New Zealand: incidence and geographical distribution in north Canterbury, 1983–1985. Clinical Endocrinology199033249259doi:10.1111/j.1365-2265.1990.tb00489.x.

    • Search Google Scholar
    • Export Citation
  • 39

    BerglundJEricssonUBHallengrenB. Increased incidence of thyrotoxicosis in Malmo during the years 1988–1990 as compared to the years 1970–1974. Journal of Internal Medicine19962395762doi:10.1046/j.1365-2796.1996.415757000.x.

    • Search Google Scholar
    • Export Citation
  • 40

    LundgrenEBorup ChristensenS. Fallande incidens av thyreotocixos i Jämtland län under perioden 1975–1984 (abstract). Hygiea198796154.

    • Search Google Scholar
    • Export Citation
  • 41

    HuangQJinRZouD. Study on the effects of increased iodized salt intake on the incidence of thyroid diseases. Zhonghua Liu Xing Bing Xue Za Zhi200122455458.

    • Search Google Scholar
    • Export Citation
  • 42

    FlynnRWMacDonaldTMMorrisADJungRTLeeseGP. The thyroid epidemiology, audit, and research study: thyroid dysfunction in the general population. Journal of Clinical Endocrinology and Metabolism20048938793884doi:10.1210/jc.2003-032089.

    • Search Google Scholar
    • Export Citation
  • 43

    RiccabonaGBauerHMathieFScholzK. Epidemiology and treatment of thyrotoxicosis in an endemic goitre district. Wiener Klinische Wochenschrift197284360363.

    • Search Google Scholar
    • Export Citation
  • 44

    StewartJCVidorGI. Thyrotoxicosis induced by iodine contamination of food – a common unrecognised condition?BMJ19761372375doi:10.1136/bmj.1.6006.372.

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    • Export Citation
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