Do bone turnover markers reflect changes in bone microarchitecture during treatment of patients with thyroid dysfunction?

PURPOSE: This study aimed to compare changes in the bone turnover markers (BTMs)-C-terminal telopeptide of type I collagen (CTX-I) and procollagen I N-terminal peptide (PINP)-with changes in the bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), during treatment of patients with thyroid dysfunction. METHODS: In women with newly diagnosed hypo- or hyperthyroidism, HR-pQCT variables, obtained from the tibia and the radius, were compared with BTMs. Data were collected at diagnosis and after at least 12 months of euthyroidism. RESULTS: 73 women completed the study (hypothyroidism, n = 27; hyperthyroidism, n = 46). Among hyperthyroid patients, correlations were found between changes in BTMs and HR-pQCT variables, primarily for cortical variables in the tibia, i.e. cortical thickness (CTX-I, p < 0.001; PINP, p < 0.001), and volumetric bone mass density (vBMD) (CTX-I, p < 0.001; PINP, p < 0.001). Moreover, correlations between BTMs and estimated bone strength were found. In the hypothyroid subgroup, no significant findings existed after adjustment. Following treatment, less decrease in tibial vBMD was seen among patients with increasing CTX-I compared to those with a decreasing CTX-I level (p = 0.009). Opposite findings applied to PINP, as patients with decreasing PINP showed an increase in tibial vBMD, in contrast to a decline in this parameter among patients with increasing PINP (p < 0.001). CONCLUSION: Changes in CTX-I and PINP correlated with HR-pQCT variables during the treatment of women with thyroid dysfunction. To some extent, these BTMs reflected the restoration of bone microarchitecture. CTX-I seems to be the most sensitive BTM in treatment-naïve thyroid diseases, while PINP is more useful for monitoring during treatment. TRIAL REGISTRATION NUMBER: NCT02005250. Date: December 9, 2013.

Antithyroid drugs in Graves' hyperthyroidism: differences between "block and replace" and "titration" regimes in frequency of euthyroidism and Graves' orbitopathy during treatment.

PURPOSE: Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves' hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD. To evaluate whether 'Block and Replace' (B + R) and 'Titration' (T) regimes are equivalent in terms of frequency of euthyroidism and Graves' Orbitopathy (GO) during ATD therapy. METHODS: A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution's policy. RESULTS: Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27-0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%. CONCLUSION: The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

Asymmetry indicates more severe and active disease in Graves' orbitopathy: results from a prospective cross-sectional multicentre study.

PURPOSE: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy. METHODS: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented. RESULTS: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]. CONCLUSION: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

Hyperthyroid patients without Graves' orbitopathy are not at increased risk of developing glaucoma: a nationwide Danish register-based case-control study.

PURPOSE: Graves' disease (GD) and toxic nodular goiter (TNG) are associated with various comorbidities. However, it is unclarified whether TNG and GD without orbitopathy are associated with glaucoma. METHODS: This was a case-control study using record-linkage data from nationwide Danish health registers. 28,461 patients with GD and 17,283 with TNG were included. Each case was age and sex matched with four non-hyperthyroid controls and followed over a mean period of 8 years. Data on glaucoma was obtained by record linkage within the National Danish Patient Register and/or the Danish National Prescription Registry. Logistic and Cox regression models were used to assess the risk of glaucoma before and after the diagnosis of GD and TNG. RESULTS: Compared to controls, there was a significantly increased frequency of glaucoma in patients with GD (4.6 vs. 4.2%, P = 0.006) and in patients with TNG (6.2 vs. 5.7%, P = 0.003). Prior to the diagnosis of hyperthyroidism, the odds ratio (OR) for glaucoma was non-significant in GD (1.09, 95% CI: 1.00-1.18) but slightly increased in TNG (1.13, 95% CI: 1.02-1.24). However, in TNG the OR attenuated completely when only including patients without co-morbidity in the analysis (1.03, 95% CI: 0.93-1.14). After adjustment for pre-existing co-morbidity, the hazard ratio (HR) for glaucoma following GD and TNG was not significantly increased (HR 1.08, 95% CI: 0.98-1.18 and HR 1.10, 95% CI: 0.99-1.21, respectively). CONCLUSIONS: Neither prior to nor following the diagnosis of GD and TNG had any significant association with glaucoma.

Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status. Current evidence suggests that the incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse. Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682). The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare. Recent published data on the incidence of GO and Graves' hyperthyroidism in Europe were used to estimate the prevalence of GO. The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves' Orbitopathy. The prevalence of GO in Europe is about 10/10,000 persons. The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000. CONCLUSION: GO has a prevalence that is clearly above the threshold for rarity in Europe. However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology. EUGOGO considers this area of academic activity a priority.

Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity.

By means of large twin cohorts, it has been possible to provide relatively valid and unbiased data regarding the influence of genetic and to some extent epigenetic factors in the aetiology of thyroid autoimmunity. The comparison of concordance rates between monozygotic and dizygotic twins provides irrefutable evidence of a genetic component in the aetiology of both Graves' disease and Hashimoto's thyroiditis, as well as for harbouring thyroid autoantibodies. Biometric modelling shows that approximately 75% of the total phenotypic variance in autoimmune thyroid disease is due to genetic effects. Despite the well known gender difference in the prevalence of autoimmune thyroid disease, the analyzes suggest that it is the same set of genes that operate in males and females. The lack of complete phenotypic concordance in monozygotic twin pairs indicates that also environmental and/or epigenetic factors are of importance. The impact of specific environmental and epigenetic exposures can be evaluated by investigating disease discordant twin pairs. Our studies show that skewed X chromosome inactivation is associated with clinically overt AITD but not with the presence of TPOAb in euthyroid individuals. It is now recognized that twin studies offer several features that uniquely enhance our ability to localize genes and understand their function. Future twin studies will incorporate information on genetic and epigenetic variation making it possible to quantify the precise effect of specific susceptibility genes and/or epigenetic variation on estimates of heritability.

Yersinia enterocolitica infection does not confer an increased risk of thyroid antibodies: evidence from a Danish twin study.

Understanding of the aetiological basis of thyroid autoimmunity may be gained by studying the early stages of the disease process. We aimed to (1) investigate the relationship between thyroid antibody status and Yersinia enterocolitica (YE) infection in euthyroid subjects and (2) explore the relative importance of genetic and environmental risk factors in the acquisition of YE infection. The association between thyroid antibody status and YE infection was explored using a case-control design. Furthermore, thyroid antibody-positive twins were compared with their thyroid antibody-negative co-twin. In 468 twins, IgA and IgG antibodies to virulence-associated outer-membrane proteins (YOPs) of YE were measured. Of these, 147 were thyroid antibody-positive (cases). A total of 147 age- and gender-matched twins were chosen as controls. The prevalence of YOP antibodies was lower among thyroid antibody-positive individuals than among controls. Yersinia infection was not associated with a positive thyroid antibody status: the odds ratio (with 95% CI) for YOP IgA-ab was 0.66 (0.42-1.05), P = 0.078 and for YOP IgG-ab it was 0.95 (0.60-1.50), P = 0.816. Within discordant twin pairs, the thyroid antibody-positive twin did not have an increased risk of Yersinia infection compared to the thyroid antibody-negative co-twin [odds ratio: YOP IgA-Ab: 0.94 (0.49-1.83), P = 0.866, and YOP IgG-Ab: 1.35 (0.72-2.53), P = 0.345]; 41% (95% CI 10-67% of the liability of being YOP antibody-positive was due to genetic effects. In conclusion, Yersinia infection does not confer an increased risk of thyroid antibodies. The genetic contribution in the acquisition of Yersinia infection is modest.

A next generation, pilot-scale continuous sterilization system for fermentation media.

A new continuous sterilization system was designed, constructed, started up, and qualified for media sterilization for secondary metabolite cultivations, bioconversions, and enzyme production. An existing Honeywell Total Distributed Control 3000-based control system was extended using redundant High performance Process Manager controllers for 98 I/O (input/output) points. This new equipment was retrofitted into an industrial research fermentation pilot plant, designed and constructed in the early 1980s. Design strategies of this new continuous sterilizer system and the expanded control system are described and compared with the literature (including dairy and bio-waste inactivation applications) and the weaknesses of the prior installation for expected effectiveness. In addition, the reasoning behind selection of some of these improved features has been incorporated. Examples of enhancements adopted include sanitary heat exchanger (HEX) design, incorporation of a "flash" cooling HEX, on-line calculation of F(o) and R(o), and use of field I/O modules located near the vessel to permit low-cost addition of new instrumentation. Sterilizer performance also was characterized over the expected range of operating conditions. Differences between design and observed temperature, pressure, and other profiles were quantified and investigated.

A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease.

CONTEXT: Autoimmune thyroid diseases (AITD), comprising Graves' disease and autoimmune hypothyroidism, are characterized by loss of immunological self-tolerance to thyroid antigens. These are complex diseases arising from a combination of genetic and environmental factors. An understanding of the genetic susceptibility factors for AITD could help to target treatments more effectively and identify people at risk for these conditions. OBJECTIVE: The objective of this study was to identify regions of genetic linkage to AITD that could potentially harbor genetic susceptibility factors for these conditions. DESIGN: The study design was a genome-wide screen performed on affected relative pairs with AITD. SETTING: Patients were recruited through hospital endocrinology clinics. PARTICIPANTS: Some 1119 Caucasian relative pairs affected with AITD (Graves' disease or autoimmune hypothyroidism) were recruited into the study. INTERVENTION: Blood samples were obtained from each participant for DNA analysis, and clinical questionnaires were completed. MAIN OUTCOME MEASURE: The study aimed to identify regions of genetic linkage to AITD. RESULTS: Three regions of suggestive linkage were obtained on chromosomes 18p11 (maximum LOD score, 2.5), 2q36 (maximum LOD score, 2.2), and 11p15 (maximum LOD score, 2.0). No linkage to human leukocyte antigen was found. CONCLUSIONS: The absence of significant evidence of linkage at any one locus in such a large dataset argues that genetic susceptibility to AITD reflects a number of loci, each with a modest effect. Linkage analysis may be limited in defining such loci, and large-scale association studies may prove to be more useful in identifying genetic susceptibility factors for AITD.

Relationship between cigarette smoking and Graves' ophthalmopathy.

Environmental triggers in the development of Graves' disease (GD) have been suggested from the very first description of the disease. Since 1987 a number of studies from various countries, have assessed the risk for Graves' ophthalmopathy (GO) associated with smoking, and found an odds-ratio of approximately 4 associated with smoking. Smokers have a higher risk for more advanced GO and a dose response relation is evident. Temporality is suggested by a few prospective studies, as is reversibility since former smokers had a lower risk of developing GO than current smokers, even with a comparable lifetime tobacco consumption. In view of the biological plausibility of the association (suggested mechanisms include tissue hypoxia, modulation of circulating pro- and anti-inflammatory cytokines and accentuation of fibroblast HLA-DR expression) it seems that the association is, indeed, causal. Treatment effect of GD/GO is also influenced by cigarette smoking. It is an independent risk factor for relapse of GD after antithyroid drug treatment. Furthermore, it attenuates the effect of orbital radiotherapy and high-dose systemic glucocorticoids in GO and causes a higher rate of progression of eye disease after radioiodine therapy. The possibility of hindering GO or attenuating its course suggests that counselling on smoking cessation should be an integral part of the treatment of any patient with GD.

Design and installation of a next generation pilot scale fermentation system.

Four new fermenters were designed and constructed for use in secondary metabolite cultivations, bioconversions, and enzyme production. A new PC/PLC-based control system also was implemented using GE Fanuc PLCs, Genius I/O blocks, and Fix Dynamics SCADA software. These systems were incorporated into an industrial research fermentation pilot plant, designed and constructed in the early 1980s. Details of the design of these new fermenters and the new control system are described and compared with the existing installation for expected effectiveness. In addition, the reasoning behind selection of some of these features has been included. Key to the design was the goal of preserving similarity between the new and previously existing and successfully utilized fermenter hardware and software installations where feasible but implementing improvements where warranted and beneficial. Examples of enhancements include strategic use of Inconel as a material of construction to reduce corrosion, piping layout design for simplified hazardous energy isolation, on-line calculation and control of nutrient feed rates, and the use of field I/O modules located near the vessel to permit low-cost addition of new instrumentation.

Validity of self-reported hyperthyroidism and hypothyroidism: comparison of self-reported questionnaire data with medical record review.

Studies that aim at identifying genes or environmental factors contributing to the development of autoimmune thyroid disease (AITD) demand that several hundred patients and control subjects be assessed. In these large studies, the laboratory methodology is often described in detail whereas little attention is given to an accurate description of the study population. Usually, a diagnosis of AITD in the control group is based on self-reported disease status. Although such studies have been criticized for diagnostic inaccuracy, no study has evaluated the validity of self-reported hyperthyroidism and hypothyroidism in detail. We have assessed the validity of self-reported hyperthyroidism and hypothyroidism in 401 twin pairs from among 6,628 same gender pairs, ages 18-41 years who participated in a nationwide questionnaire survey in 1994. The self-reported questionnaire data were compared with information from medical records and the 1/kappa coefficient, sensitivity, and specificity were determined. Overall, there was only a slight to fair agreement between the self-reported questionnaire data and medical record data as shown by kappa values of 0.18, 0.21, and 0.26 for hyperthyroidism and hypothyroidism as a group, hyperthyroidism and hypothyroidism, respectively. For both hyperthyroidism and hypothyroidism, the sensitivity of the self-reported diagnosis was 0.98, whereas the specificity was 0.57 and 0.67 for self-reported hyperthyroidism and hypothyroidism, respectively. In conclusion, the validity of self-reported hyperthyroidism and hypothyroidism is unsatisfactorily low. However, by combining self-reports with valid retrospective data on diagnostic findings it can be used as a sampling method in large epidemiological or genetic studies.

Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts.

The etiology of Graves' disease (GD), affecting up to 2% of a population in iodine-sufficient areas, is incompletely understood. According to current thinking, the development of GD depends on complex interactions among genetic, environmental, and endogenous factors. However, the relative contributions of the genetic and environmental factors remain to be clarified. In this study we report probandwise concordance rates for GD in a new cohort of same sex twin pairs born between 1953 and 1976 (young cohort), ascertained from the nationwide population-based Danish Twin Register. To elucidate the magnitude of the genetic and environmental influence in the etiology of GD, these new twin data were pooled with our previously published twin data on GD (old cohort). The old cohort consisted of 2338 same sex twin pairs born between 1870 and 1920 who had participated in questionnaire surveys during the 1950s, 1960s, and 1970s. The young cohort included 6628 same sex twin pairs born between 1953 and 1976 who had participated in a questionnaire survey in 1994. In the young cohort there were four monozygotic (MZ) pairs and one dizygotic (DZ) pair concordant for clinically overt GD, giving an overall probandwise concordance rate of 0.35 [95% confidence interval (CI), 0.16--0.57] for MZ pairs and 0.07 (95% CI, 0.01--0.24) for DZ pairs (P < 0.02). In the combined twin cohorts there were eight MZ pairs and one DZ pair concordant for clinically overt GD, giving a crude concordance rate of 0.35 (95% CI, 0.21--0.50) for MZ pairs and 0.03 (95% CI, 0.01--0.12) for DZ pairs (P < 0.02). Model-fitting analysis on the pooled twin data showed that 79% of the liability to the development of GD is attributable to genetic factors. Individual specific environmental factors not shared by the twins could explain the remaining 21%. In conclusion, our study strongly supports the idea that genetic factors play a major role in the etiology of GD and suggest that a further search for susceptibility genes is worthwhile.

Low birth weight is not associated with clinically overt thyroid disease: a population based twin case-control study.

OBJECTIVE: In recent years low birth weight has been proposed as a risk factor for the development of several chronic diseases in adult life, including diabetes and subclinical autoimmune thyroid disease. The association could, however, also be due to genetic or environmental factors affecting both birth weight and adverse health outcomes in adult life. Moreover, it is at present unknown whether or not low birth weight is associated with an increased risk of developing clinically overt thyroid disease. The aim of the present study was to investigate the impact of birth weight and several other birth characteristics on the development of clinically overt thyroid disease. DESIGN: A twin case-control study of same sex twin pairs. PATIENTS: One hundred and thirty-one same sex twin pairs (262 twin individuals) discordant for clinically overt thyroid disease, ascertained from a population based nation-wide twin register. MEASUREMENTS: Information about birth weight, birth length, birth order (first vs. second born), and prematurity was obtained from the original midwife records. RESULTS: Forty-nine twin pairs were discordant for clinically overt autoimmune thyroid disease (Graves' disease = 35 and Hashimoto's thyroiditis = 14) and 82 pairs were discordant for overt nonautoimmune thyroid disease (Simple goitre = 79 and toxic nodular goitre = 3). Overall, there was no difference in birth weights between probands and the healthy co-twins in monozygotic (MZ, n = 39) or in dizygotic (DZ, n = 92) pairs (MZ: mean +/- SE: 2619 +/- 93 g vs. 2553 +/- 89 g, P = 0.40; DZ: 2576 +/- 45 g vs. 2585 +/- 49, P = 0.86). By means of logistic regression, the impact of other birth characteristics such as birth length, birth order (first vs. second born), and prematurity was tested. None of the variables reached statistical significance. Subdividing the twin pairs into those discordant for clinically overt Graves' disease, Hashimoto's thyroiditis, and nonautoimmune thyroid disease did not change the results. CONCLUSIONS: This is the first study of the effect of birth weight and other birth characteristics on the subsequent development of clinically overt thyroid disease in which maternal, socioeconomic, and to a high degree, genetic factors have been controlled for. Our study did not show any effect of birth weight or any of the other birth characteristics on the risk of developing clinically overt autoimmune or nonautoimmune thyroid disease.

Genetic and environmental factors in the aetiology of simple goitre.

The aetiology of simple goitre, affecting up to 5% of a population in iodine-sufficient areas and over 10% in endemic areas, is incompletely understood. It is generally believed that the development of simple goitre, whether endemic or sporadic, depends on complex interactions between genetic, environmental and endogenous factors. The importance of genetic factors is evident from the clustering of simple goitre within families and from a higher concordance rate for goitre in monozygotic than in dizygotic twins. Recently, studies assessing the role of specific candidate genes or genetic markers in the aetiology of simple goitre have given conflicting data in various families. However, there may well be single genes playing a major role within certain families, eg the thyroglobulin (Tg) gene, the thyroid-stimulating hormone receptor (TSHR) gene, the Na+/I- symporter (NIS) gene, and the multinodular goitre marker 1 (MNG1) on chromosome 14, but the genes will vary from family to family. In addition, family and twin studies also indicate a modest to major role for environmental factors in the aetiology of simple goitre. Clearly, iodine deficiency and cigarette smoking are the most important environmental risk factors associated with the genesis of simple goitre. Other suggested risk factors include naturally occurring goitrogens, emotional stress and certain drugs and infections. Ongoing studies focus on whole-genome screening in multiplex families as well as on large population-based case-control studies. However, the possibility that simple goitre is a heterogeneous disease without a single well-defined genotype and phenotype should be left open.

Cigarette smoking and risk of clinically overt thyroid disease: a population-based twin case-control study.

BACKGROUND: The effects of cigarette smoking on the thyroid gland have been studied for years. However, the effect of smoking on thyroid function and size is still controversial. OBJECTIVE: To determine the impact of cigarette smoking on the development of clinically overt thyroid disease. METHODS: Matched case-control study of 132 same-sex twin pairs (264 individuals) discordant for clinically overt thyroid disease, ascertained from a population-based nationwide twin register. Information on thyroid disease and smoking habits was gathered by questionnaire, and the patients' endocrinologist or general practitioner verified the diagnosis. RESULTS: Overall, smoking was associated with an increased risk of developing clinically overt thyroid disease (odds ratio, 3.0; 95% confidence interval, 1.4-6.6; P = .003). This association remained statistically significant in monozygotic and dizygotic disease-discordant pairs. The effect of smoking was more pronounced in monozygotic vs dizygotic pairs (odds ratio, 5.0 vs 2.5; P= .04 for both). Essentially similar results were obtained after subdividing the twin pairs into groups discordant for clinically overt autoimmune (49 pairs) and nonautoimmune (83 pairs) thyroid disease. Among twin pairs concordant for smoking, probands with clinically overt autoimmune thyroid disease smoked significantly more than did their healthy co-twins (17 pairs; P= .03), whereas no difference was found between probands with nonautoimmune thyroid disease and their healthy co-twins (34 pairs; P= .20). CONCLUSIONS: Smoking is associated with an increased risk of developing clinically overt thyroid disease. Furthermore, our data suggest that cumulative cigarette consumption is a risk factor, most pronounced in autoimmune thyroid disease.

A population-based study of chronic autoimmune hypothyroidism in Danish twins.

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 proband-wise 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.

Major role of genes in the etiology of simple goiter in females: a population-based twin study.

The etiology of simple goiter, affecting up to 5% of a population in nonendemic areas, is incompletely understood. It is generally believed to be multifactorial in origin, but the relative contributions of genetic and environmental factors remain to be clarified. Therefore, we investigated a well defined population of Danish twins. We performed a historical cohort study of 5.479 same sex twin pairs born between 1953 and 1972. Information on goiter was obtained from a nationwide questionnaire survey in 1994. Information from hospitals, out-patient clinics, and the subjects' general practitioners was sought to verify the diagnoses. Concordance rates, tetrachoric correlations, and heritability were determined. The crude probandwise concordance rates were 0.42 [95% confidence interval (CI), 0.26-0.591 and 0.13 (95% CI, 0.06-0.24) for female monozygotic and female dizygotic pairs, respectively. The age-adjusted cumulative probandwise risk for simple goiter from birth to age 43 yr was 0.53 (95% CI, 0.23-0.83) for female monozygotic twins and 0.18 (95% CI, 0.05-0.35) for female dizygotic twins (P = 0.003). The tetrachoric correlations were substantially higher in monozygotic (0.82; SE, 0.07) than in dizygotic twins (0.47; SE, 0.12). Model-fitting analysis suggested that the heritability of the liability to the development of simple goiter in women is approximately 82%. Individual-specific environmental factors not shared by cotwins seemed to explain the remaining 18%. We conclude that the etiology of clinically overt simple goiter is multifactorial. Genetic factors play a major role in the etiology of simple goiter in females, but environmental factors are also of importance.

What is the evidence of genetic factors in the etiology of Graves' disease? A brief review.

Graves' disease (GD) is generally thought of as a multifactorial disorder in which genetic susceptibility interacts with environmental and endogenous factors to cause disease. The importance of genetic factors is suggested by the clustering of GD within families and by a higher concordance rate for disease in monozygotic than dizygotic twins. This has, however, recently been shown to be less pronounced than previously thought. During the last decade, much effort has been put into characterization of the genetic background of GD. Until recently most studies have examined associations between GD and the human leukocyte antigen (HLA) region, but recent advances in molecular techniques have opened the way for whole-genome screening. A number of HLA and non-HLA candidate genes have been proposed, but despite several large investigations within multiplex families no major susceptibility genes have been identified. This brief review discusses relevant articles published from 1940 through 1997 regarding the influence of genetic factors in the etiology of GD. Ongoing studies will focus on whole genome screening in multiplex families as well as population based twin studies. However, the possibility of GD being a heterogeneous disease without a single well-defined genotype and phenotype should be left open.

What is the evidence of genetic factors in the etiology of Graves' disease? A brief review.

Graves' disease (GD) is generally thought of as a multifactorial disorder in which genetic susceptibility interacts with environmental and endogenous factors to cause disease. The importance of genetic factors is suggested by the clustering of GD within families and by a higher concordance rate for disease in monozygotic than in dizygotic twins. This has, however, recently been shown to be less pronounced than previously thought. During the last decade much effort has been put into characterization of the genetic background of GD. Until recently, most studies have examined associations between GD and the human leukocyte antigen (HLA) region, but recent advances in molecular techniques have opened the way for whole genome screening. A number of HLA and non-HLA candidate genes have been proposed, but despite several large investigations within multiplex families no major susceptibility genes have been identified. This brief review discusses relevant articles published from 1940 through 1997 regarding the influence of genetic factors in the etiology of GD. Ongoing studies focus on whole genome screening in multiplex families as well as population-based twin studies. However, the possibility of GD being a heterogeneous disease without a single well-defined genotype and phenotype should be left open.