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

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1 ORIGINAL ARTICLE Endocrine Care Thyroid Volume in Hypothyroidism due to Autoimmune Disease Follows a Unimodal Distribution: Evidence against Primary Thyroid Atrophy and Autoimmune Thyroiditis Being Distinct Diseases Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Torben Jørgensen, and Peter Laurberg Department of Endocrinology and Medicine (A.C., I.B.P., P.L.), Aalborg Hospital, Aarhus University Hospital, DK-9000 Aalborg, Denmark; Endocrine Unit (N.K., H.P.), Department of Internal Medicine I, Bispebjerg Hospital, DK-2400 Copenhagen V, Denmark; National Heart Foundation (L.O.), DK-1127 Copenhagen K, Denmark; and Research Centre for Disease Prevention and Health (T.J.), DK-2600 Glostrup, Copenhagen, Denmark Context: Primary overt autoimmune hypothyroidism is often divided into primary idiopathic hypothyroidism with thyroid atrophy (Ord s disease) and hypothyroidism with goitre (Hashimoto s disease). Objective: The aim of the present study was to characterize the two subtypes of disease. Design and Setting: This was a population-based study identifying patients newly diagnosed with overt autoimmune hypothyroidism. Patients: We prospectively identified all patients with incident overt autoimmune hypothyroidism in a Danish population cohort, and 247 patients were invited to join a comprehensive program including thyroid ultrasonography and measurements of thyroid autoantibodies. Of the 144 patients investigated (58% of all invited), 139 were compared with 556 sex-, age-, and region-matched controls from the cohort. Results: Patients had lower median (11.6 ml vs ml, P 0.001) and a more dispersed distribution of thyroid volumes compared with controls (P 0.001). Log thyroid volume showed a Gaussian distribution in both males and females with no bimodal pattern. Nearly all patients had measurable thyroid autoantibodies, but with increasing thyroid volume (quartile I, II, III, and IV), levels of circulating antibodies were higher (median thyroid peroxidase autoantibody 1540, 3122, 4686, and 7058 ku/liter; median thyroglobulin autoantibody 72, 143, 119, and 1195 ku/liter), and thyroid volume correlated negatively with echogenicity (r 0.21, P 0.011). Patients with the smallest volumes were biochemically more hypothyroid at diagnosis (median serum T , 45.5, 45.0, and 36.7 nmol/liter; median serum TSH 81.0, 40.9, 45.4, and 55.6 mu/liter). No difference between groups was observed in prevalence of TSH receptor autoantibody (14.7, 5.6, 14.7, and 8.3%) or duration of symptoms before hypothyroidism was diagnosed. Conclusions: In primary autoimmune hypothyroidism, thyroid volume follows a normal distribution. Cases with thyroid atrophy and goiter are only extremes within this distribution and do not represent separate disorders. However, patients with low vs. high thyroid volume differ with respects to several characteristics. (J Clin Endocrinol Metab 94: , 2009) ISSN Print X ISSN Online Printed in U.S.A. Copyright 2009 by The Endocrine Society doi: /jc Received June 26, Accepted December 4, First Published Online December 16, 2008 Abbreviations: DanThyr, Danish Investigation of Iodine Intake and Thyroid Diseases; HLA, human leukocyte antigen; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TRAb, TSH receptor antibody. J Clin Endocrinol Metab, March 2009, 94(3): jcem.endojournals.org 833

2 834 Carlé et al. Thyroid Volume in Autoimmune Hypothyroidism J Clin Endocrinol Metab, March 2009, 94(3): Primary overt hypothyroidism is a common disease worldwide, and it may be subclassified into a number of disorders. The most common entity is autoimmune hypothyroidism (1), which is divided into primary atrophic hypothyroidism and hypertrophic autoimmune hypothyroidism (2). The atrophic variant was described in the late 1890s by Ord as dependent on a destructive affection of the thyroid gland (3). In 1912 Hashimoto (4) described the hypertrophic variant later to be known as Hashimoto s disease. No strict criteria exist to separate the atrophic and the goitrous form of hypothyroidism, and classification is often based on the presence or absence of goitre by clinical examination (5, 6). Ord s and Hashimoto s diseases have been reported to be distinct diseases (7 9), differing in human leukocyte antigen (HLA) types [HLA-DR3/B8 in atrophic hypothyroidism vs. HLA-DR5 in goitrous hypothyroidism (9, 10)], involvement of antibody-dependent cell-mediated cytotoxicity (7), the specific autoantibodies involved [TSH receptor antibody (TRAb) in the atrophic type of hypothyroidism (11 15), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) in the hypertrophic form (16)], and importance of humoral vs. cellular immunity for disease development (17). Moreover, Ord s disease has been suggested to be the end stage of Hashimoto s disease, but repetitive biopsies of thyroid glands have not supported this idea (18, 19), and no difference has been recorded in age at presentation of the two disorders (7). We studied thyroid volume measured by ultrasonography in a cohort of patients with incident autoimmune hypothyroidism diagnosed in a population to characterize in more detail the two subtypes with thyroid atrophy and goiter. In particular, we aimed to verify or disprove whether Ord s and Hashimoto s in fact are two distinct disorders. Patients and Methods This study is part of the Danish Investigation of Iodine Intake and Thyroid Diseases (DanThyr) (20). The DanThyr monitoring program was implemented in 1997 to monitor iodine intake and occurrence of thyroid disease before and after mandatory salt fortification with iodine, which was implemented in Denmark in the second half of year In the present study, two subsets of subjects were included: patients newly diagnosed with spontaneous autoimmune overt hypothyroidism in the population under study and healthy control subjects from the same population. All subjects were included and investigated before iodization of salt. Patients A register was linked to diagnostic laboratory databases in two areas of Denmark with a small difference in iodine intake, in and around the city of Aalborg (moderate iodine deficiency, n 311,102) and in Copenhagen (mild iodine deficiency, n 227,632). The register recorded every thyroid function test (serum TSH and serum T 4 ) requested by hospitals and general practitioners in the two regions representative of the Danish population (1). The diagnostic criteria used to identify patients with overt hypothyroidism, the algorithm for final verification of incident hypothyroidism, and the various subtypes of disease have been described in detail previously (1). The diagnosis was based on elevated serum TSH ( 5 mu/liter) in combination with a T 4 estimate below the laboratory reference range (1). It was required either that L-T 4 replacement had been immediately initiated or that the combination of high serum TSH and low T 4 was observed in an independent laboratory evaluation at least 3 wk after the initial sample. In the period March 1997 to December 2000, we identified 685 subjects with incident overt hypothyroidism. Of these, 578 were classified as having spontaneous autoimmune hypothyroidism. In selected periods, during which staff was available, we invited patients newly diagnosed with overt autoimmune hypothyroidism (n 247) to participate in a comprehensive investigation program as described in detail previously (16). Of these, 147 (59.5%) participated in the program including thyroid ultrasound investigation (n 144) and measurement of thyroid autoantibodies (TPOAb, n 142; TgAb, n 142; TRAb, n 141). The register database, which was connected to the laboratories performing the thyroid function tests, provided information on sex, age, region of inhabitancy, results of serum TSH (n 144) and total T 4 (n 143, one patient was diagnosed with low free T 4 without total T 4 measurement) at diagnosis, i.e. before treatment was initiated. In the initial phase of the study, we invited all patients aged up to 85 yr of age. Unfortunately, very few patients aged 70 yr attended the investigational program. For practical reasons, we changed the procedure, and for most of the study period, only patients aged up to 70 yr were invited. Thus, among the 331 patients with autoimmune hypothyroidism who were not invited, 105 were diagnosed in the period with no staff available for performing the investigation, 162 were not invited because of age above 70 yr, 45 patients were not invited because their general practitioner did not recommend the participation mostly because of concomitant disease, and 19 patients died before the scheduled investigation could be performed. Controls For each patient we planned to include four control subjects matched on age, sex, and region. In the period , a cross-sectional study was performed in Aalborg and Copenhagen (21). Women aged 18 22, 25 30, 40 45, and yr, and men aged yr were invited. From this group of healthy control subjects, we included for the present study age-, sex-, and region-matched controls (n 210) fulfilling criteria of no prior or current overt hypo- or hyperthyroidism. In the period , additional control subjects were recruited (n 346) to match patients outside these age groups. They were randomly invited from the same population using identical methods. We managed to find controls in a 4:1 ratio for almost all patients with hypothyroidism (cases: n 139; controls: n 556, for the remaining five cases we did not find four controls). Thus, only 139 of the 144 patients investigated were included in the case-control comparison. Thyroid ultrasound investigation An ultrasound investigation of the thyroid gland was performed using a Sonoline Versa Pro 7.5-MHz, 70-mm linear transducer with an effective length of 62 mm (Siemens, Munich, Germany). Patients were examined in supine position with the neck slightly hyperextended. Transverse and longitudinal scans of the thyroid gland were performed, and various measures were recorded. Total thyroid volume was calculated using the three-axis method. Volume was the sum of the two lobes each calculated according to the formula: /6 maximal length width depth (22). Thyroid enlargement was defined as thyroid volume exceeding 18 ml in women and 25 ml in men (23). The echostructure of the thyroid gland was compared with adjacent muscles and connective tissue, and it was classified into one of five categories with a span from severely hypoechogenic to severely hyperechogenic. There was one sonographer in Aalborg and one in Copenhagen. The accuracy and reproducibility of the various measures obtained from the ultrasound investigation have been validated in a previous DanThyr study (22). This study showed a good correlation and agreement between observers was found for thyroid volume (r 0.98) and the prevalence of thyroid nodules ( 0.72), whereas echogenecity and echopattern showed little agreement. The interobserver coefficient of variation was 9.6% for thyroid volume estimation.

3 J Clin Endocrinol Metab, March 2009, 94(3): jcem.endojournals.org 835 Controls and patients diagnosed with autoimmune hypothyroidism underwent the same investigational program including ultrasound investigation by the same investigators. Blood specimen analyses Four laboratories were in charge of analyzing blood specimens for thyroid function in the population monitored. For all patients newly diagnosed with autoimmune hypothyroidism, we recorded TSH and T 4 values at diagnosis, i.e. before treatment was initiated (1). The assays from the four laboratories used to measure serum TSH and T 4 have previously been described in detail (24, 25). A direct interlaboratory comparison did not reveal important differences in TSH or T 4 values (26). Blood samples were collected from all patients and controls who attended the special program. The samples were stored 20 C, and all thyroid autoantibodies were analyzed with samples in random order after the study had been completed. Patients and controls had TPOAb and TgAb measured, whereas TRAb was assessed only in patients. TPOAb and TgAb were measured using sensitive methods manufactured by BRAHMS (Berlin, Germany) as published previously (16, 27). Subjects with antibody concentration above the functional sensitivity given by the manufacturer (TPOAb: 30 ku/liter, TgAb: 20 ku/liter) were regarded as antibody positive (TPOAb and TgAb, respectively). TRAb was measured using a competitive assay using recombinant human TSH receptors (DYNO test; BRAHMS) (28). The limit of positivity for TRAb was 1.0 ku/liter (28). Questionnaire All patients who attended the investigational program filled out a questionnaire including information on various symptoms and symptom duration in months before hypothyroidism was diagnosed. The specific question used for evaluation was: have you experienced symptoms that may be related to hypothyroidism? If yes, for how many months? Statistics We used Statistical Package for Social Sciences (SPSS, Chicago, IL) for calculation of medians and value ranges. Groups of subjects were compared using Mann-Whitney U test or Kruskal-Wallis H test (continuous variables), or using Pearson s 2 test or Fischer s exact test (discrete variables). Variables were correlated using Spearman s. To test for trend in ordered variables between groups, we used the Jonckheere- Terpstra test. A multivariate linear regression model was used to identify predictors for thyroid volume. For all statistical analyses, P 0.05 was regarded as statistically significant. Ethical approval This study was approved by Regional Ethics Committee in North Jutland and Copenhagen. Registry permission was obtained from the Danish Data Protection Agency. All participants gave their written informed consent. No conflicts of interest have occurred during implementation or completion of the study. Results The thyroid volume distribution in both patients and controls was skewed to the right, and data were analyzed after log transformation of results of volume measurements. This provided a Gaussian distribution in both groups (Fig. 1). Patients diagnosed with autoimmune hypothyroidism had a somewhat smaller median thyroid volume compared with the controls (11.6 vs ml, P 0.001, Mann-Whitney U test). Of all patients investigated, 20.8% of the patients had thyroid enlargement (22.7% of women had thyroid volume 18 ml; 12.0% of men had thyroid FIG. 1. Distribution of thyroid volumes (log scaled) in patients with autoimmune hypothyroidism (n 139) (A) and age-, region-, and sex-matched healthy controls (n 556) (B). Median volume was lower (11.6 vs ml, P 0.001) and values more dispersed (P 0.001, ANOVA test) in patients compared with controls. volume 25 ml). This frequency of thyroid enlargement was not significantly different from that obtained in the controls (21.9%, P 0.82, Fischer s exact t test). Calculation on logaritmized volume values revealed different variances between the two groups (F 15.6, P 0.001, ANOVA test). Thus, the dispersion of thyroid volume values was considerably larger in patients than in controls (Fig. 1). The inclusion criterion for controls was no prior overt hypo- or hyperthyroidism. We studied how the inclusion of TPOAb-positive controls had influenced the result. Controls with measurable TPOAb (TPOAb,n 126) and TPOAb negative controls (n 434) had similar thyroid volume (median: 13.5 vs ml, P 0.79), age (53.3 vs yr, P 0.34), and

4 836 Carlé et al. Thyroid Volume in Autoimmune Hypothyroidism J Clin Endocrinol Metab, March 2009, 94(3): gender distribution (men/women: 14/112 vs. 78/356, P 0.08). However, similar to previous observations, controls from the area with the most severe iodine deficiency (Aalborg) were more often TPOAb positive (P 0.005) compared with controls from the area of only mild iodine deficiency (Copenhagen). Thyroid volume in cases diagnosed with autoimmune hypothyroidism was further studied. Figure 2 shows the Q-Q plots of the log-transformed thyroid volumes in patients newly diagnosed with autoimmune hypothyroidism. In both men and women, plots were linear, corresponding to a Gaussian distribution. Thus, no sign of a bimodal thyroid volume pattern was A Expected Normal Value B Expected Normal Value 0,0 0,0 Women (n = 119) Observed Value Men (n = 25) Observed Value FIG. 2. Q-Q plots of log-transformed thyroid volumes in female (A) and male (B) patients with newly diagnosed overt autoimmune hypothyroidism. The linear plots illustrate the Gaussian distribution of thyroid volumes in both sexes. evident. We found no statistically significant difference in thyroid size between hypothyroid patients from Aalborg vs. Copenhagen (median: 12.6 vs ml, P 0.256, Mann- Whitney U test). To evaluate characteristics of hypothyroid patients with a small vs. those developing a large thyroid gland, we stratified according to sex and split up the groups of patients into quartiles based on thyroid volumes. Patient characteristics in the four groups, each comprising both men and women, are listed in Table 1. The patients with the smallest thyroid volumes were biochemically more hypothyroid with a lower serum total T 4 (I vs. II III IV: P 0.004) and a higher serum TSH at diagnosis (I vs. II III IV: P 0.004). We found no statistically significant difference between patients belonging to groups II-IV with regard to neither serum TSH levels (II vs. III: P 0.87; II vs. IV: P 0.10; III vs. IV: P 0.16) nor serum T 4 levels (II vs. III: P 0.69; II vs. IV: P 0.20; III vs. IV: P 0.29). The majority of patients had measurable TPOAb and/or TgAb in blood irrespective of thyroid volume. However, patients with a higher thyroid volume had higher circulating levels of TPOAb (P 0.001) and TgAb (P 0.03). We found no difference in TRAb concentrations or the proportion of patients being TRAb positive in the groups with different thyroid volumes. With progressively larger thyroid volume, the thyroid gland was more hypoechogenic (Spearman s :r 0.21, P 0.011). When serum concentrations of TPOAb, TgAb, and TSH and thyroid echogenicity were entered into a multivariate model as explanatory variables with thyroid volume (log transformed) as outcome variable, a positive association was seen with TPOAb (standardized -coefficient 0.17, P 0.030) and TgAb ( 0.19, P 0.016), whereas thyroid volume was negatively correlated to serum TSH levels ( 0.24, P 0.003) and echogenicity ( 0.24, P 0.003). The explanatory variables explained only 18% of the variance in thyroid volume (r 0.43). Age and gender were not associated with thyroid volume, and inclusion of age and gender into the model did not alter the main findings. Discussion In this population-based study, we compared thyroid volume between patients diagnosed with primary overt autoimmune hypothyroidism and healthy controls. After log transformation, thyroid volume followed a normal distribution in both groups of subjects. Average volume was slightly lower in patients, and values were more dispersed. In the patients, thyroid volume correlated positively with levels of TPOAb and TgAb in serum and negatively with thyroid echogenicity and serum TSH. Thyroid volume distribution in hypothyroid patients vs. controls A right-skewed distribution of thyroid volume was observed in both patients and controls, which is in accordance with other studies (29, 30) reporting this in patients with autoimmune thyroiditis, independent of biochemical status (euthyroid, subclinically hypothyroid, or overtly hypothyroid). Patients had a sta-

5 J Clin Endocrinol Metab, March 2009, 94(3): jcem.endojournals.org 837 TABLE 1. Characteristics of patients newly diagnosed with overt autoimmune hypothyroidism Thyroid volume in quartiles I(n 36) II (n 36) III (n 36) IV (n 36) P value Thyroid volume (ml) Range (males) Range (females) Sex Females/males 30/6 30/6 30/6 29/7 Region Aalborg/Copenhagen 24/12 14/22 24/12 24/ a Age Median b (Range) (23 81) (31 71) (20 74) (27 84) Serum total-t 4 (nmol/liter) Median b (Range) (2 59) (0.5 59) (5 59) (2 59) Serum TSH (mu/liter) Median b (Range) (6 469) (5 144) (6 260) (10 202) TPOAb (ku/liter) Median 40 3,122 4,686 7, b (Ab, %) (91.2) (97.2) (94.4) (100) 0.30 a TgAb (ku/liter) Median , b (Ab %) (76.4) (75.0) (88.9) (83.3) 0.41 a TRAb (ku/liter) Median b (Ab %) (14.7) (5.6) (14.7) (8.3) 0.52 a Echogenicity (ultrasound) Severely low Low c Normal High/severely high Duration of symptoms (months) Median b (Range) (1 84) (0 72) (1 30) (3 30) Patient material was stratified according to sex and split into quartiles according to thyroid volumes. a Pearson s 2 test. b Kruskal-Wallis H test. c Jonckheere-Terpstra test. tistically lower thyroid volume than controls but with a large overlap. The dispersion of thyroid volumes was considerably larger in hypothyroid patients than in controls, illustrating that indeed some patients tend to have an increase and other a decrease in thyroid volume. On the other hand, the distribution of thyroid volumes was Gaussian with no sign of distinct subgroups. This finding was somewhat unexpected because primary autoimmune hypothyroidism is often divided into two clinical subtypes (2): Ord s hypothyroidism with atrophic thyroid gland, and Hashimoto s hypothyroidism with glandular hypertrophy and/or goiter. The volume distribution in patients diagnosed with autoimmune hypothyroidism was the same in both sexes, and Q-Q plots illustrated a pearls-on-a-string pattern with no sign of a bimodal distribution. Our findings indicated that patients with a small or large thyroid gland represent only extremes of a continuous Gaussian distribution. It has been suggested that atrophic hypothyroidism should be an end-stage disease of Hashimoto s disease. This was not supported by our findings because we found no difference in age or duration of symptoms between the groups with different thyroid volumes (Table 1). Our results are in accordance with Hayashi et al. (18), who performed time-sequential fine-needle aspiration in patients with Hashimoto s disease. These investigators found no change in histological pattern over time. Relation between thyroid volume and other characteristics in hypothyroid patients To evaluate in more detail the possible causes for the different development in thyroid volume in patients, we studied the distribution of various patient characteristics in four groups of patients differing with respect to total thyroid volume (groups I-IV, as illustrated in Table 1). Patients with the lowest thyroid volume had the highest degree of biochemical hypothyroidism, and it cannot be entirely excluded that this cluster of patients represents a subgroup with a special pathogenesis. A similar finding was reported in some (15) but not all studies (11), but the pathological substrate for the phenomenon remains unknown. One possibility is that a patient with an enlarged thyroid gland would be diagnosed with hypothyroidism at an earlier stage of the disease. This would not explain why patients with a small thyroid were

6 838 Carlé et al. Thyroid Volume in Autoimmune Hypothyroidism J Clin Endocrinol Metab, March 2009, 94(3): more hypothyroid at the time of diagnosis than those with a normal thyroid volume. Possibly thyroid insufficiency tends to progress more rapidly in patients with thyroid fibrosis and atrophy than in those dominated by lymphocytic tissue. Nearly all patients had measurable amounts of TPOAb and TgAb in blood, but the concentrations were progressively higher with higher thyroid volume, which is in accordance with findings from Mariotti et al. (31). This is biologically plausible because parts of the antibodies presumably are produced in the intrathyroidal lymphoid tissue. Higher serum concentrations of TPOAb and TgAb in participants with large thyroid glands were also found in a DanThyr study of control subjects from the population but only in the fraction of subjects with subclinical hypothyroidism (high serum TSH and normal serum T 4 ) (32). Several studies reported higher TRAb prevalence and concentration in Ord s compared with Hashimoto s hypothyroidism (11 14). We did not find such a correlation, and our study is in accordance with the study by Tamaki et al. (15). Some of the discrepancy between studies may be caused by differences in analytical methods. The TRAb assay used by us measured both stimulatory and blocking thyroid receptor antibodies. Study strengths and limitations We studied a cohort of patients, all newly diagnosed with primary overt autoimmune hypothyroidism. Other studies on thyroid volume in autoimmune hypothyroidism included patients with subclinical hypothyroidism (7, 11, 13, 30, 32) and euthyroid patients with thyroid autoantibodies (7, 11, 13, 30). The patients were diagnosed in a population cohort and included independent on referral to specialized hospital departments. Hypothyroid patients referred to a hospital unit may differ substantially from the entire population of patients with regard to age (33) but also presence of goiter, difficulty in swallowing, and neck discomfort (34). Some of the patients had received L-T 4 replacement therapy for a short period before they joined our investigation. Therapy may influence the echopattern (35), thyroid volume (18, 36), and antibody concentration (35, 36), although this is not a consistent finding (14, 37). We split the entire group of patients into those who joined the comprehensive program (antibody measurement, ultrasound investigation, and questionnaires) within 50 d after the first blood test indicating hypothyroidism had been taken (n 72) vs. later (n 68). Comparing the two groups, we found no difference in concentrations of TPOAb (4838 vs ku/ liter, P 0.22) or TgAb (112.6 vs ku/liter, P 0.26) and no difference in the prevalence of TRAb (12.5 vs. 10.4%, P 0.71). Thus, initiation of L-T 4 therapy before the ultrasound investigation did not introduce major bias on thyroid volume estimates. We searched for four age-, sex-, and region-matched controls for each of the 144 hypothyroid patients who after invitation attended the investigational program. Unfortunately, we were able to include matching controls for only 139 patients. Thus, 4% of the patients were not included in the case-control comparison. Only 13 of the 144 patients included in the present study was above 75 yr. The incidence of hypothyroidism increases steeply with age (1), and 45% of all patients newly diagnosed with hypothyroidism are 70 yr or older. Thus, the external validity of the present study is robust only for patients aged up to 70 yr. In this age group, 318 patients were diagnosed with spontaneous autoimmune hypothyroidism, 205 were invited, and 134 patients underwent the full investigational program. Patients with autoimmune thyroiditis may be biochemically euthyroid, subclinically hypothyroid, or overtly hypothyroid. Our study gives insight only into the fraction of patients being overtly hypothyroid. Conclusion In patients with primary autoimmune hypothyroidism, thyroid atrophy and goiter do not represent separate disorders. They are only extremes within a normal distribution of thyroid volumes. Thus, the combined term Ord-Hashimoto s disease as proposed by Davies (2) may be appropriate. Acknowledgments We are indebted to the clinical chemical laboratories and general practitioners in Copenhagen and Northern Jutland for their helpful collaboration and BRAHMS (Berlin) for assistance with thyroid autoantibody measurements. Address all correspondence and requests for reprints to: Allan Carlé, M.D., Ph.D., Department of Endocrinology and Medicine, Aalborg Hospital, Aarhus University Hospital, DK-9000 Aalborg, Denmark. carle@dadlnet.dk. This study was part of 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. Disclosure Statement: A.C., I.B.P., N.K., H.P., L.O., T.J., and P.L. have nothing to declare. References 1. Carle A, Laurberg P, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Rasmussen LB, Jorgensen T 2006 Epidemiology of subtypes of hypothyroidism in Denmark. Eur J Endocrinol 154: Davies TF 2003 Ord-Hashimoto s disease: renaming a common disorder again. Thyroid 13: Report on Myxoedema. Clinical Society of London. London; Longmans 4. Hashimoto H 1912 Zur kenntniss der lymphomatosen verandering der schilddruse (struma lymphomatosa). Arch Klin Chir 97: Dayan CM, Daniels GH 1996 Chronic autoimmune thyroiditis. 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