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A Population-Based Study of Chronic Autoimmune Hypothyroidism in Danish Twins¹

Department of Endocrinology M, Odense University Hospital (T.H.B., L.H.), and the Danish Twin Register, Odense University (T.H.B., K.O.K.), DK-5000 Odense C, Denmark

Address all correspondence and requests for reprints to: Dr. Thomas Heiberg Brix, The Danish Twin Register, Odense University, Winsløwparken 15 st., DK 5000 Odense C, Denmark. E-mail: tBRIX{at}HEALTH SDU.OK.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hashimoto’s thyroiditis (HT), atrophic thyroiditis (AT), and Graves’ disease are autoimmune thyroid diseases in which genetic factors are suspected to play an important role in disease susceptibility. In a recent population-based twin study we rendered it probable that a substantial part of the susceptibility to Graves’ disease is attributable to genetic factors. At present there are no population-based twin studies supporting such a genetic influence in the etiology of HT/AT.

To elucidate whether there is a genetic influence in the etiology of HT/AT, we studied the distribution of HT/AT in a population-based sample of 2945 Danish female-female twin pairs (5890 individuals) born between 1953 and 1972. Information on hypothyroidism was obtained from a nationwide questionnaire survey in 1994. Information from hospitals, out-patient clinics, general practitioners, and specialists was sought to verify the diagnosis.

The overall prevalence of autoimmune hypothyroidism was 0.41% (24 of 5890). The prevalence did not differ between monozygotic and dizygotic twins (0.42% and 0.40%, respectively). The crude probandwise concordance rates were significantly higher for monozygotic compared to dizygotic twin pairs: 0.55 (95% confidence interval, 0.23–0.83) vs. 0.0 (95% confidence interval, 0.0–0.25; P = 0.01). All of the healthy cotwins (n = 15) of twins with clinically overt autoimmune hypothyroidism were biochemically euthyroid. Overall, regardless of zygosity 53% (8 of 15) of the healthy cotwins were positive for antithyroid antibodies. The prevalence of autoantibodies among the monozygotic cotwins was 80% (4 of 5) and 40% (4 of 10) among dizygotic cotwins (P = 0.36).

In conclusion, the higher concordance rate in monozygotic compared to dizygotic pairs indicates that genetic factors play a role in the etiology of HT/AT among Caucasian women living in areas with borderline iodine deficiency. However, the fact that the concordance rate among MZ twins was below 1 suggests that environmental factors also are of etiological importance.

	Introduction

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AUTOIMMUNE thyroid disease (AITD) comprises several clinical variants. Roughly, patients can be divided into those with hyperthyroidism [Graves’ disease (GD)] and those with hypothyroidism with [Hashimoto’s thyroiditis (HT)] or without [atrophic thyroiditis (AT)] goiter. Although, GD and HT/AT have very different phenotypes, it is generally believed that they share a number of common etiological factors. Clearly, GD and HT/AT frequently occur in the same family, and some individuals progress from one form to another (1, 2). Moreover, there are descriptions of monozygotic (MZ) twin pairs in which one twin has GD and the cotwin has HT/AT (3, 4).

The etiology of AITD seems to involve complex interactions among genetic, environmental, and endogenous factors (5, 6). A role for genetic factors in the etiology is suggested by the aggregation of AITD within families (1, 7, 8). In addition, recent studies indicate that a number of genetic markers with association and/or linkage with phenotypic AITD, especially GD, may exist (2, 5, 6). However, the relative contribution of the genetic influence on disease susceptibility largely remains to be defined.

In a recent population-based twin study we rendered it probable that a substantial part of the familial aggregation of GD is attributable to genetic factors (9). This is based on the probandwise concordance rates being significantly higher in MZ than in dizygotic (DZ) twins (9). Whether this is also true for HT/AT, as suggested by observations in individual twin pairs (10, 11), remains to be investigated. The present study was undertaken to determine the concordance rates for autoimmune hypothyroidism in a cohort of Danish twins from a nationwide population-based twin register.

	Subjects and Methods

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Subjects

The twins were recruited from the young part of the Danish Twin Register. The ascertainment procedure of this nationwide population-based register was described in detail previously (12).

The study population consisted of 2945 female same sex twin pairs (5890 individuals) born between 1953 and 1972; both twins in a pair had participated in a questionnaire survey in 1994. This questionnaire survey was performed in all twins born between 1953 and 1982 as a part of a nationwide project about health and psycho-social conditions among twins. The response rate was 86%, and there was no difference in the response rate across the birth cohorts. All of the respondents were residents of Denmark, which is a nonendemic goiter area with borderline iodine deficiency (median urinary iodine excretion of 70–100 µg/24 h) (13).

The screening questions for thyroid disease were the following. Do you have or have you ever had hyperthyroidism, hypothyroidism, or goiter? Informed consent was obtained from all participants, and the study was approved by all of the regional scientific-ethical committees in Denmark (case file 96/150 PMC).

One hundred and fifty subjects indicated present or previous hypothyroidism. These subjects and their cotwins were sent a second more detailed questionnaire in 1996. This questionnaire contained questions about signs and symptoms of thyroid disease in general. The name and address of the general practitioner, specialists, or hospitals attended by the twin because of thyroid disorders were also requested. After 1 reminder, 108 subjects (72%) responded. In 84 subjects the presence of autoimmune hypothyroidism was excluded, the main reasons being errors when filling out the 1994 questionnaire (46 subjects) or other thyroid disease (38 subjects). In 42 subjects () verification of the self-reported hypothyroidism as stated in the 1994 questionnaire was impossible due to nonresponse to the 1996 questionnaire. However, in an attempt to verify or exclude the presence of the self-reported hypothyroidism as stated in the 1994 questionnaire, information on thyroid disease was sought from the National Discharge Register as part of a record linkage between The Twin Register and the National Discharge Register. Three of the 42 nonresponders (7.1%) were recorded in the National Discharge Register with a thyroid-specific International Classification of Disorders, World Health Organization Code; one had thyroid cancer and two had postpartum thyroiditis with temporary hypothyroidism. The twin with thyroid cancer was not considered further. The 2 twins with postpartum thyroiditis were both DZ (representing 2 discordant pairs). These pairs were also excluded from further consideration because they only had temporary hypothyroidism. Thus, a total of 24 subjects (21 twin pairs) could be classified as having autoimmune thyroiditis (7 HT and 17 AT). Table 1 gives the characteristics of these subjects stratified by zygosity.

Determination of zygosity was primarily based on self-reported answers to specific questions about similarity and mistaken identity, which is a well established and valid method (14). Moreover, the zygosity of the concordant pairs was verified by means of DNAtyping of nine short tandem repeat systems with the PE Applied Biosystems AmpFISTR Profiler Plus Kit (Foster City, CA) (15).

Analysis of data

In the classical twin study the comparison of the degree of concordance in MZ and DZ twin pairs indicates whether the disease is genetically influenced. A higher concordance rate in MZ than DZ pairs suggests that genetic factors are important, whereas similar concordance rates in MZ and DZ pairs indicates an environmental cause (16). Concordance was assessed by the probandwise concordance rates, which reflects the risk of disease for a twin given that the cotwin is affected (17). This concordance rate can be interpreted as the prevalence of disease in cotwins of probands and can be compared directly to the disease prevalence in the background population and to estimates of recurrence risks in other types of relatives (17). The 95% confidence intervals (CI) for concordance were calculated based on the binomial distribution.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The overall prevalence of clinically overt autoimmune hypothyroidism was 0.41% (24 of 5890). The prevalence did not differ between MZ and DZ twins (0.42% in MZ vs. 0.40% in DZ). Results regarding concordance rates are summarized in Table 1. There were 3 MZ and 0 DZ pairs concordant for autoimmune hypothyroidism, giving a crude probandwise concordance rate of 0.55 (95% CI, 0.23–0.83) for MZ pairs and 0 (95% CI, 0.0–0.25) for DZ pairs (P = 0.01).

Among the 3 MZ pairs concordant for autoimmune hypothyroidism, the time from diagnosis in the first affected twin until diagnosis in the cotwin was around 2 yr in 2 pairs and 4 yr in the remaining pair. The follow-up period (time span between disease onset in the proband and last contact with the cotwin) tended to be lower in MZ than in DZ pairs (Table 1). However, this difference was not statistically significant (5.5 vs. 7.7 yr; P = 0.42). In 2 of the 18 discordant pairs, the cotwin to the twin with autoimmune hypothyroidism had simple goiter. In both cases the cotwin was biochemically euthyroid, and there was no evidence of coexisting autoimmunity, as the cotwins were antibody negative. In the remaining 16 discordant pairs the cotwin had no history of past or present thyroid disease.

Prevalence of antithyroid antibodies in healthy cotwins

In 15 of the 18 discordant pairs, serum from the healthy cotwin was available for analysis of antithyroid antibodies (thyroid peroxidase and/or thyroglobulin). Due to emigration (1 pair) and unwillingness to give a blood sample (2 pairs) serum was not available in the remaining 3 pairs (representing 3 DZ pairs). All of the healthy cotwins (n = 15) to twins with clinically overt autoimmune hypothyroidism were biochemically euthyroid. Overall, regardless of zygosity, 53% (8 of 15) of the healthy cotwins were positive for antithyroid antibodies. The prevalence of autoantibodies among the monozygotic cotwins was 80% (4 of 5) and 40% (4 of 10) among DZ cotwins (P = 0.36).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The complex nature of HT/AT has made the identification of a possible susceptibility gene(s) problematic, and despite several large investigations the pattern of inheritance and major susceptibility genes have yet to be identified. It seems likely that HT/AT, like other organ-specific autoimmune diseases, is polygenic, with no single gene being either necessary or sufficient for disease development. Most previous studies of genetic factors in HT/AT have focused on human leukocyte antigen genes, and there are significant, but weak, associations with certain class II alleles that, on the other hand, seem to vary between racial groups and even within the same race (5). Furthermore, there is no evidence of linkage of HLA alleles and clinical HT/AT (5, 18). Thus, HLA genes may increase susceptibility to HT/AT, but other genetic loci appear to represent major disease susceptibility and/or severity factors. Other possible candidate genes, such as the TSH receptor, CTLA-4, Ig heavy chain gene, and the T cell receptor gene complexes, have recently been examined, but no consistent associations have been demonstrated, and linkage analysis has shown that these genetic loci do not cosegregate with phenotypic HT/AT (18, 19). Thus, the influence, if any, of these new candidate genes in the etiology of HT/AT seems at best weak.

The goal of this population-based twin study was to examine whether there is a genetic contribution to the etiology of HT/AT. The higher concordance rate among MZ pairs compared to DZ pairs indicates that genetic factors play a role in the etiology of HT/AT, at least in women living in areas with borderline iodine deficiency. However, the fact that the concordance rate among MZ twins was below 1 suggests that environmental factors are also of etiological importance. A detailed description of possible environmental factors in the etiology of autoimmune hypothyroidism is beyond the scope of this article. Clearly, recent reviews point toward certain infectious agents (20), smoking (21), and iodine intake (22) as some of the possible nongenetic factors. Unfortunately, our twin cohort does not comprise enough individuals with HT/AT to give a plausible estimate of the relative influence of genetic and environmental factors in the etiology of HT/AT. Moreover, it is important to point out that our finding of a probandwise concordance rate of 0.0 among the DZ twin pairs reflects the small number of affected twins and not the lack of a genetic contribution to HT/AT in DZ twins or siblings. In fact, according to the 95% confidence interval, the concordance rate for the DZ twins could lie anywhere between 0.0–0.25. Assuming that the degree of familial aggregation in HT/AT is the same as that reported in Graves’ disease (7), one would expect a probandwise concordance rate of 0.03–0.06 among DZ twins, which is clearly within the 95% confidence interval of our concordance rate in DZ twins.

The prevalence of thyroid autoantibodies among young Danish women is about 10–15% (23, 24). In the present study, however, as many as 80% of the MZ cotwins and 40% of the DZ cotwins to twins with clinically overt autoimmune hypothyroidism were positive for thyroid autoantibodies. Clearly, the prevalence of autoantibodies among the healthy cotwins is much higher than that in the background population. This is consistent with the results of family studies, which repeatedly demonstrate a much higher prevalence of thyroid autoantibodies among first degree relatives of patients with autoimmune hypothyroidism than in the general population (1, 25). This familial accumulation of thyroid autoantibodies could be due to shared genes or shared environment within the family. Unfortunately, our twin sample does not comprise enough twin pairs to evaluate the precise nature of the familial clustering of thyroid autoantibodies.

Our results should be interpreted in the context of a number of potential limitations. The data in this study were obtained from Caucasian women living in Denmark, among whom cultural background and living conditions are generally homogeneous. Thus, the results of this study cannot uncritically be extrapolated to other groups or populations. Although the Danish Twin Register is population based, our final study sample is unlikely to be completely representative of the entire twin population. Twins who did not answer/return the questionnaires were not included. However, based on record linkage between the Danish Twin Register and the National Discharge Register, it seems unlikely that twins with thyroid disease were less willing to answer/return the questionnaires than healthy twins. Moreover, we used the probandwise concordance rate. One of the great advantages of this concordance rate is that it is independent of ascertainment (26). Thus, it is not crucial that all twins be studied, as long as there is no systematic bias in the ascertainment procedure.

The information on the presence or absence of hypothyroidism was based on self-reports. This may result in recall bias. However, the diagnosis was confirmed by review of medical records from hospitals, out-patient clinics, and general practitioners. Additionally, record linkage between the Twin Register and the National Discharge Register did not indicate a systematic underreporting of disease by twins with hypothyroidism. In fact, the prevalence of confirmed HT/AT in our study (0.42%) is comparable to that found in women of a similar age group (<45 yr) in the Whickham Survey (27) (The prevalence of HT/AT in Denmark among women aged 20–40 yr is unknown.) The prevalence of HT/AT was similar in MZ (0.42%) and DZ (0.40%) twins. Thus, there is no evidence of overrepresentation of either zygosity class and no evidence of any systematic bias in the ascertainment procedure.

The follow-up period was not long in the healthy cotwins. That is, not much time was allowed for the cotwin to develop HT/AT, and hence, the concordance rates might be expected to increase with increasing follow-up time. However, this is a complex process, because new discordant pairs may also appear with increasing follow-up time, and it seems unlikely that such a potential increased concordance should be restricted to DZ compared to MZ twins. Indeed, the fact that the follow-up time tended to be longer in DZ pairs in whom concordance was lowest further strengthens our findings.

It could be argued that two of our patients did not have autoimmune thyroiditis. In these subjects antibodies were not measured initially, and both subjects turned out to be antibody negative. However, 5–10% of patients with clinical and ultrasound characteristics of chronic thyroiditis are thyroid antibody negative (28). Furthermore, it has repeatedly been reported that treatment with levothyroxine in patients with autoimmune thyroiditis can lead to a significant reduction in the serum concentrations of thyroid antibodies (29). Additionally, iatrogenic causes of hypothyroidism were ruled out in both subjects, making any other diagnosis highly unlikely.

In conclusion, our data indicate that genetic factors play a role in the etiology of HT/AT among Caucasian women living in areas with borderline iodine deficiency.

	Footnotes

 
¹ This work was supported by grants from the Agnes and Knut Mørks Foundation, the Dagmar Marshalls Foundation, the A. P. Møller and Hustru Chastine McKinney Møllers Foundation, the Novo Nordisk Foundation Committee, and the Clinical Research Institute, Odense University.

Received October 13, 1998.

Revised June 25, 1999.

Revised October 18, 1999.

Accepted October 22, 1999.

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