0021-972X/98/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1998 by The Endocrine Society
Vol. 83, No. 5 Printed in U.S.A.
Hashimoto’s Thyroiditis and Insulin-Dependent Diabetes Mellitus: Differences among Individuals with and without Abnormal Thyroid Function* ERIN MCCANLIES, LESLIE A. O’LEARY, THOMAS P. FOLEY, M. KAYE KRAMER, JAMES P. BURKE, ASTRID LIBMAN, JENNIFER S. SWAN, ANN R. STEENKISTE, BRIDGET J. MCCARTHY, MASSIMO TRUCCO, AND JANICE S. DORMAN Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh (E.M., L.A.O., M.K.K., J.P.B., J.S.S., A.R.S., J.S.D.), Pittsburgh, Pennsylvania 15261; the Department of Pediatrics, University of Pittsburgh School of Medicine (T.P.F., M.T.), Pittsburgh, Pennsylvania 15261; the Faculty of Medical Sciences, National University of Rosario (A.L.), Rosario 2000, Argentina; and the Department of Epidemiology, University of Illinois School of Public Health (B.J.M.), Chicago, Illinois 60612 ABSTRACT Insulin-dependent diabetes mellitus probands from the Familial Autoimmune and Diabetes Study were evaluated for autoimmune thyroid disease (n 5 265). The prevalence of Hashimoto’s thyroiditis was 26.6%; 42.0% of these individuals were euthyroid, and 58.0% were hypothyroid. There was a female predominance among hypothyroid and euthyroid Hashimoto’s cases compared to those with no thyroid disease (75% vs. 72.4% vs. 41.6%; P , 0.001). Insulin-dependent diabetes mellitus patients with hypothyroid Hashimoto’s thyroiditis were more likely to report another autoimmune disease compared to euthyroid Hashimoto’s patients or individuals with no thyroid disease (30.8% vs. 17.2% vs. 13.9%; P , 0.01). Sex-specific analysis revealed that this difference was significant for men but not for women. Both
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NDIVIDUALS with insulin-dependent diabetes mellitus (IDDM) frequently develop Hashimoto’s thyroiditis, defined by high titers of thyroid peroxidase or thyroglobulin antibodies, elevated TSH in the absence of medications, and/or a positive history or examination (1–3). Although many persons with Hashimoto’s thyroiditis are hypothyroid, there is a subgroup of euthyroid cases with high titers of thyroid autoantibodies and normal thyroid function who do not require medication. However, some of these individuals may become hypothyroid as they age. Should this occur among persons with IDDM, the decrease in basal metabolic rate due to untreated hypothyroidism may cause serious illness and further complicate lipid disturbances, metabolic control, and risk of adverse pregnancy outcomes (4 – 6). Given the high prevalence of Hashimoto’s thyroiditis among IDDM individuals (7–38%) (1–3) compared to that in the general population (,1% to 7%) (7–9), the characterization of potential risk factors for hypothyroidism has impor-
Received May 12, 1997. Revision received December 31, 1997. Accepted January 20, 1998. Address all correspondence and requests for reprints to: Janice S. Dorman, Ph.D., Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261. Email:
[email protected]. * This work was supported by NIH Grants RO1-DK-44590, R01-DK49588, RO1-DK-24021, and T32-DK-7410.
euthyroid and hypothyroid Hashimoto’s cases were more likely to have a family history of the disease (66.7% vs. 69.2% vs. 47.7%; P , 0.05). No differences were observed in the prevalence of DQA1*0501DQB1*0201 or DQA1*0301-DQB1*0302 across the three groups. Body mass index, lipid levels, glycemic control, and diabetes complications were also similar. However, euthyroid Hashimoto’s women were more likely to report spontaneous abortions than those with hypothyroid Hashimoto’s thyroiditis or no thyroid disease (23.8% vs. 61.5% vs. 29.1%; P , 0.05). These data suggest that gender-specific risk factors may be primary determinants of Hashimoto’s thyroiditis and other autoimmune diseases among women. However, diseasespecific determinants may also increase susceptibility to other autoimmune diseases. (J Clin Endocrinol Metab 83: 1548 –1551, 1998)
tant clinical implications for the diabetic population. A better understanding of the etiology and natural history of Hashimoto’s thyroiditis among IDDM cases could improve detection and treatment and might prevent the complications described above. The current report focuses on potential environmental, genetic, and immunological differences that distinguished hypothyroid and euthyroid Hashimoto’s thyroiditis among IDDM participants in the Familial Autoimmune and Diabetes (FAD) Study. The clinical characteristics potentially affected by the natural history of the disease were also evaluated. Experimental Subjects The FAD study is based on the Children’s Hospital of Pittsburgh IDDM Registry for the years 1950 –1964 (n 5 671). This cohort was originally defined in 1981 for a study of IDDM mortality. Individuals were eligible if they were 1) receiving insulin therapy at hospital discharge, 2) less than 17 yr of age at disease onset, 3) diagnosed between 1950 and 1964, and 4) seen at Children’s Hospital of Pittsburgh for a diabetes evaluation within 1 yr of IDDM onset. During 1990, registered cases from the 656 unique families in this cohort were recontacted to update the 1981 survey. Information was obtained for 86% (n 5 561) of the family cohort. In 1993, living IDDM cases who completed the 1990 survey (n 5 375) and their families were recruited for the FAD Study. Those who agreed (n 5 265; 71%) were evaluated for autoimmune thyroid disease. To determine whether our survivor cohort represented the original study sample, we first compared the 375 FAD Study eligible subjects to those who were deceased (n 5 181) or ineligible because of
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HASHIMOTO’S THYROIDITIS AND IDDM imprisonment, etc. (n 5 5). No differences in race or gender were observed. However, the average IDDM duration was shorter for the FAD Study eligible subjects (22.5 vs. 23.9 yr; P , 0.001), which was not unexpected. We also compared the 265 FAD Study participants with those who were eligible but refused to participate (n 5 110). No difference in race, gender, or IDDM duration was observed, suggesting that the final sample was representative of the original cohort.
Materials and Methods Hashimoto’s thyroiditis with hypothyroidism was defined by the presence of high titers ($10 U/mL) of thyroid peroxidase (TpAb) or thyroglobulin antibodies, elevated levels of TSH (.5 mU/L) in the absence of medications, a positive medical history, and/or a positive clinical examination. Euthyroid Hashimoto’s thyroiditis was defined as elevated TpAb or thyroglobulin antibodies and normal TSH without the positive medical history or clinical examination seen with hypothyroidism. Graves’ disease was defined by high titers of TSH receptor antibodies (.10%), undetectable TSH (,0.1 mU/L), high T3 (.250 mg/dL), a positive medical history, and/or a positive clinical examination. Autoimmune thyroid disease status could not be determined for 6 of the 265 IDDM probands. Serum samples obtained from participants were used for assessments of lipid levels, glycosylated hemoglobin, and the presence of antinuclear autoantibodies (ANA). In addition, participants completed several questionnaires to assess past medical history, lifestyle habits, gynecological and reproductive history, etc. HLA-DQA1 and DQB1 molecular typing was also performed from DNA extracted from peripheral blood lymphocytes using standardized laboratory methods (10, 11). Eight DQA1 alleles and 14 DQB1 alleles were evaluated using the nomenclature of the WHO Nomenclature Committee for Factors of the HLA System (12). x2 tests and analyses of variance were employed to evaluate univariate associations for discrete and continuous variables, respectively, among the three groups (i.e. hypothyroid Hashimoto’s thyroiditis, euthyroid Hashimoto’s thyroiditis, and no thyroid disease) (13). Haplotype frequencies were obtained by gene counting. Exact and nonparametric tests were employed when necessary.
Results Prevalence of Hashimoto’s thyroiditis and its potential risk factors
The prevalence of Hashimoto’s thyroiditis among the IDDM probands was 26.6%. Among those with Hashimoto’s thyroiditis, 42.0% were euthyroid, and the remaining 58.0% were hypothyroid. Graves’ disease was present in 9.3% (n 5 24) of the IDDM probands. As this paper focuses on IDDM and Hashimoto’s thyroiditis, all Graves’ cases were excluded from further analyses. As illustrated in Table 1, IDDM probands with hypothyroid Hashimoto’s, euthyroid Hashimoto’s, and no thyroid disease were similar with regard to race, age at clinic visit, age at IDDM onset, and diabetes duration. However, there TABLE 1. Demographic characteristics of IDDM probands with and without Hashimoto’s thyroiditis Characteristic
Hypothyroid Hashimoto’s
Euthyroid Hashimoto’s
No thyroid disease
n Gender (% female) Race (% Caucasian) Age at clinic visit (yr) Age at IDDM onset (yr) IDDM duration (yr)
40 75.0 97.5 42.8 6 5.2 7.1 6 4.1 35.7 6 3.7
29 72.4 96.6 42.9 6 3.9 7.8 6 2.7 35.0 6 4.2
166 41.6a 98.8 42.0 6 5.2 6.7 6 3.9 35.3 6 4.0
Data are percentages or the mean 6 SD. Cases with Graves disease (n 5 24) or missing information (n 5 6) were not included. a P , 0.001 for hypothyroid Hashimoto’s thyroiditis vs. euthyroid Hashimoto’s thyroiditis vs. no thyroid disease.
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were significantly more females among those with hypothyroid and euthyroid Hashimoto’s thyroiditis. Potential risk factors for Hashimoto’s thyroiditis were also compared across the three groups (Table 2). IDDM subjects with hypothyroid Hashimoto’s were significantly more likely to report another autoimmune disease than those with euthyroid Hashimoto’s thyroiditis or no thyroid disease. The conditions reported were quite diverse and included rheumatoid arthritis, pernicious anemia, multiple sclerosis, systemic lupus erythematosus, Crohn’s disease, IgA deficiency, narcolepsy, vitiligo, mixed connective tissue disease, and psoriasis. Sex-specific analyses revealed that this difference was significant for males (33% vs. 25% vs. 8.3%; P , 0.05), but not females (30% vs. 14.3% vs. 21.7%; P . 0.05). IDDM probands with hypothyroid or euthyroid Hashimoto’s thyroiditis were significantly more likely to have a positive family history of Hashimoto’s thyroiditis than those without thyroid disease. However, no statistically significant differences were observed for high titer antinuclear antibodies, smoking, or HLA DQA1-DQB1 haplotype. Differences in clinical and reproductive characteristics
Individuals with hypothyroid Hashimoto’s thyroiditis, euthyroid Hashimoto’s thyroiditis, and no thyroid disease were also similar with regard to body mass index; and total, low density lipoprotein, and high density lipoprotein cholesterol, and triglycerides (data not shown). Moreover, there were no significant differences in glycemic control, as reflected by glycosylated hemoglobin levels, or reported microvascular or macrovascular complications, suggesting that with proper treatment, complications of Hashimoto’s thyroiditis are unlikely to occur. The reproductive characteristics of women with hypothyroid Hashimoto’s thyroiditis, euthyroid Hashimoto’s thyroiditis, and no thyroid disease were also compared. There were no statistically significant differences in reported age at menarche, age at menopause, infertility, or proportion ever pregnant (data not shown). However, IDDM women with euthyroid Hashimoto’s thyroiditis were significantly more likely to report one or more spontaneous abortions compared to those with hypothyroid Hashimoto’s thyroiditis or no thyroid disease (61.5%, vs. 23.8%, vs. 29.1%, respectively; P , 0.05). Discussion
A female predominance was observed among IDDM cases with hypothyroid and euthyroid Hashimoto’s thyroiditis compared to those with no thyroid disease. Given that IDDM is equally prevalent among males and females in most Caucasian populations (14), this gender distribution suggests that etiological risk factors, unrelated to those for insulindependent diabetes, are associated with Hashimoto’s thyroiditis. Female sex hormones, reproductive history, etc., are likely determinants (15). These gender-specific factors may also explain the higher observed prevalence of other autoimmune diseases among hypothyroid Hashimoto’s cases, most of whom were women. However, stratified analyses revealed a statistically significant difference for men, but not women. Thus, IDDM women, in general, were more likely to
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MCCANLIES ET AL.
TABLE 2. Potential risk factors for Hashimoto’s thyroiditis among IDDM probands Characteristic
Hypothyroid Hashimoto’s
Euthyroid Hashimoto’s
No thyroid disease
n Another autoimmune disease (%)a Family history of Hashimoto’s (%) ANA (% with titer $160) Smoking (% ever smoked) HLA-DQA1-DQB1 haplotype (%) *0501-*0201/*0301-0302 *0501-*0201/Xd *0301-*0302/Xd X/X
40 30.8 66.7 15.0 32.4
29 17.2 69.2 17.2 40.7
166 13.9b 47.7c 7.8 53.8
20.0 25.0 37.5 17.5
31.0 20.7 41.4 6.9
37.3 21.2 27.1 14.5
a
Self-report of an autoimmune disease other than IDDM or Hashimoto’s thyroiditis. P , 0.01. P , 0.05 for hypothyroid Hashimoto’s thyroiditis vs. euthyroid Hashimoto’s thyroiditis vs. no thyroid disease. d X, Not DQA1*0501-DQB1*0201 or DQA1*0301-DQB*0302. b c
develop other autoimmune diseases, whereas only men with Hashimoto’s thyroiditis appeared to be predisposed to these disorders. One explanation for these findings is that genderspecific risk factors are responsible for a higher baseline prevalence of these conditions in women relative to men. Therefore, the contribution of disease-specific risk factors (i.e. those associated with hypothyroid Hashimoto’s thyroiditis) may be easier to detect among men because their overall risk of the disease is low. In addition, the diverse group of other conditions reported among women and men with and without Hashimoto’s thyroiditis indicates that common risk factors may influence susceptibility for a variety of autoimmune diseases, including Hashimoto’s thyroiditis. IDDM cases with euthyroid and hypothyroid Hashimoto’s were likely to report a positive family history of Hashimoto’s thyroiditis, confirming other reports of the familial clustering of these diseases (16 –19). Thus, the factors associated with the development of autoimmunity may also aggregate in IDDM families. There are few data regarding the role of HLA-DQ in IDDM and Hashimoto’s thyroiditis. A recent publication revealed that among IDDM cases with DQB1*0201, DQB1*0302 was less likely to be the second allele among those with Hashimoto’s thyroiditis compared to those with Graves’ disease or no thyroid disease (20). This difference, however, was not statistically significant, which is consistent with the current findings. Our data are also supportive of a study that revealed no statistically significant haplotype differences among young-onset IDDM cases with or without TpAb (21). Because these alleles are strong markers of IDDM susceptibility, their contributions to Hashimoto’s thyroiditis may be more difficult to identify among IDDM cases than among unaffected individuals in the general population. With regard to adverse pregnancy outcomes, our findings indicated that IDDM women with euthyroid, but not hypothyroid Hashimoto’s thyroiditis were more likely to report spontaneous abortions than women with no thyroid disease. Thus, the presence of autoantibodies may be associated with an increased likelihood of spontaneous abortion, even in the absence of overt disease (5, 6). This emphasizes the importance of identifying euthyroid cases before the development of thyroid dysfunction, as they may be at high risk for reproductive failure. Future research in this area is likely to evolve in several
directions. First, investigations such as the FAD Study will begin to expand their evaluations of other autoimmune diseases and autoantibodies (i.e. gastric parietal cell, ovarian, islet cell, etc.) to more completely evaluate the spectrum of autoimmunity among IDDM and nondiabetic individuals. Such analyses may reveal specific patterns for particular autoimmune disease clusters. Secondly, prospective investigations of younger cohorts are required. This would permit an accurate evaluation of the determinants of the natural history of Hashimoto’s thyroiditis in IDDM adults. By necessity, such studies will be extensive due to the relatively low incidence of the disorder, even among high risk individuals. Finally, studies of men should be undertaken. Despite the potential difficulties associated with identifying affected men, they may represent an important subgroup for which genetic or environmental effects, in the absence of sex hormones, may be detected. Acknowledgment The authors acknowledge the assistance of Ms. Cindy Niznik in the preparation of this manuscript.
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