Levothyroxine in Euthyroid Autoimmune Thyroiditis and Type 1 Diabetes: A Randomized, Controlled Trial

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1 X/07/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 92(5): Printed in U.S.A. Copyright 2007 by The Endocrine Society doi: /jc Levothyroxine in Euthyroid Autoimmune Thyroiditis and Type 1 Diabetes: A Randomized, Controlled Trial Beate Karges, Rainer Muche, Ina Knerr, Waldemar Ertelt, Thomas Wiesel, Regine Hub, Andreas Neu, Albrecht Klinghammer, Julia Aufschild, Andrea Rapp, Andreas Schirbel, Bernhard O. Boehm, Klaus M. Debatin, Eberhard Heinze, and Wolfram Karges Division of Pediatric Endocrinology and Diabetes (B.K., J.A., A.R., K.M.D., E.H.), University Children s Hospital Ulm, D Ulm, Germany; Institute of Biometrics (R.M.) and Division of Endocrinology (B.O.B.), Clinic for Internal Medicine I, University of Ulm, D Ulm, Germany; University Children s Hospital Erlangen (I.K.), D Erlangen, Germany; Children s Hospital Heidenheim (W.E.), D Heidenheim, Germany; Children s Hospital Datteln (T.W.), D Datteln, Germany; University Children s Hospital Tübingen (R.H., A.N.), D Tübingen, Germany; Children s Hospital Chemnitz (A.K.), D Chemnitz, Germany; Department of Nuclear Medicine (A.S.), University of Würzburg, D Würzburg, Germany; and Division of Endocrinology and Diabetes (W.K.), RWTH Aachen University, D Aachen, Germany Context: Patients with type 1 diabetes (T1D) have an increased risk of autoimmune thyroiditis (AIT). Objective: Our objective was to determine whether levothyroxine (L-T 4 ) treatment prevents the clinical manifestation of AIT in euthyroid subjects with T1D. Design and Setting: We conducted a prospective, randomized, open, controlled clinical trial at six tertiary care centers for pediatric endocrinology and diabetes. Patients: Of 611 children and adolescents with T1D, 89 individuals (14.5%) were identified with positive thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), or both. Of these, 30 patients (age, yr) met the inclusion criteria and were randomized to receive L-T 4 (n 16 patients) or no treatment (n 14 patients). Intervention: L-T 4 (1.3 g/kg daily) was given for 24 months in the treatment group, followed by an additional observation period of 6 months in both groups. AUTOIMMUNE THYROIDITIS (AIT) and type 1 diabetes mellitus (T1D) are considered T-cell-mediated autoimmune disorders with strong and partially overlapping genetic backgrounds. Patients with T1D have a 5-fold increased risk to develop AIT compared with the general population (1 4). Because AIT is a frequent cause of acquired hypothyroidism (5) interfering with metabolic control of diabetes (6), early diagnosis and treatment is particularly important for patients with T1D. Treatment of euthyroid patients with AIT has remained controversial, although preventive short-term treatment with levothyroxine (l-t 4 ) has shown favorable effects on First Published Online February 13, 2007 Abbreviations: AIT, Autoimmune thyroiditis; BMI, body mass index; GAD, glutamate decarboxylase; HbA 1c, glycated hemoglobin A 1c ; IA-2, tyrosine phosphatase; l-t 4, levothyroxine; SDS, sd score; T1D, type 1 diabetes; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community Main Outcome Measures: Thyroid gland volume (as determined by ultrasound), serum levels of TSH, thyroid hormones, TPOAb, and TgAb were assessed every 6 months for 30 months. Results: Mean thyroid volume decreased in the treatment group after 24 months ( 0.60 SD score) and increased in the observation group ( 1.11 SD score; P ). Serum thyrotropin, free T 4, TPOAb, and TgAb levels were not significantly different in both groups during the entire study period. Hypothyroidism developed in three individuals treated with L-T 4 and in four untreated patients (conversion rate, 9.3% per year). Conclusions: In this study in euthyroid patients with AIT and T1D, L-T 4 treatment reduced thyroid volume but had no effect on thyroid function and serum autoantibody levels. (J Clin Endocrinol Metab 92: , 2007) serological and cellular markers of AIT in adults (7, 8). It has been hypothesized that l-t 4 may reduce or prevent goiter and hypothyroidism by decreasing serum TSH and thyroid autoantigen expression, associated with decreased antibody production and cellular immunity of AIT (9, 10). In infancy and childhood, a normal thyroid function is pivotal to ensure optimal physical and mental development. Because of the lack of randomized controlled trials, it is still under debate whether l-t 4 treatment decreases the risk of hypothyroidism and goiter and improves immunological thyroid markers in children and adolescents with euthyroid AIT. We designed a prospective, randomized trial to determine whether a daily dose of l-t 4 would reduce the volume of the thyroid gland, the risk of hypothyroidism, and levels of thyroid autoantibodies in children and adolescents with T1D, who have an excess risk of AIT. Patients Patients and Methods Between September 1, 2002, and December 30, 2003, 611 unselected consecutive children and adolescents with T1D who attended the dia-

2 1648 J Clin Endocrinol Metab, May 2007, 92(5): Karges et al. L-T 4 in Euthyroid Autoimmune Thyroiditis betes clinic in six tertiary care centers for children and adolescents were screened for AIT and eligibility in this prospective, randomized trial. Patients (n 317 males, n 294 females) had a mean age of 12.7 yr (range, yr) and a mean diabetes duration of 5.2 yr (range, 1 17 yr). Inclusion criteria were T1D (defined clinically by insulin dependence and ketonuria/ketonemia at onset), positive antibodies ( 100 U/ml) against thyroid peroxidase (TPOAb) and/or thyroglobulin (TgAb), age 6 18 yr, euthyroid function (TSH 6.0 mu/liter, normal values for free T 4 ) and the patient s or parents written informed consent. The diagnosis of AIT was based on the presence of positive antibodies against TPO and/or thyroglobulin in this cohort of T1D patients, all of whom were antibody-positive for one or more islet cell antigens. Exclusion criteria were current treatment with l-t 4, positive serum antibodies against TSH receptor, Turner or Down syndrome, and severe illness. Dropout criteria were withdrawal of consent, undesirable event, and l-t 4 discontinuation of longer than 2 wk. The study protocol was approved by the local institutional review boards and was conducted in accordance with the Declaration of Helsinki. This trial was registered by the Federal Institute for Pharmaceuticals and Medical Products (BfArM no ). Study protocol Patients with AIT and T1D were randomly assigned to the treatment group, receiving l-t 4 during 24 months or to the observation group without treatment. Assignment was performed by stratified block randomization for patients with enlarged or normal-sized thyroid gland. l-t 4 was given by mouth once daily in the morning starting with a dose of 50 g for patients with a body weight less than 50 kg, 75 g for individuals between 50 and 75 kg, 100 g for patients between 75 and 100 kg, and 150 g for adolescents above 100 kg. If necessary, the l-t 4 dose was adjusted until TSH values were within the normal range ( mu/liter). Accordingly, l-t 4 dose was decreased in two patients and increased in two individuals. After 24 months, l-t 4 treatment was discontinued in euthyroid patients. Individuals in the observation group received l-t 4 in case of hypothyroidism (TSH 6.0 mu/liter or free T 4 values below normal range). Clinical and laboratory assessments were performed at baseline and every 6 months until month 30, including clinical examination, ultrasound of the thyroid, measurement of thyroid hormones, organ-specific autoantibodies (as specified below), and serum biochemical analyses. Laboratory measurements TSH, free T 4, and T 3 were determined with commercial immunometric reagent kits in each center. Iodide excretion in the urine was measured at baseline in a reference laboratory using HPLC. Glycated hemoglobin A 1c (HbA 1c ) was determined by HPLC (A1c2.2 Plus; TOSOH Corp. Europe, Amsterdam, The Netherlands). Measurement of serum autoantibodies was performed at the University of Ulm for all patients. Enzyme-linked immunometric assays were used for TPOAb (Pharmacia, Freiburg, Germany), TgAb (Vita Diagnostica, Freiburg, Germany), IgA antibodies to tissue transglutaminase, and parietal cell antibodies (Pharmacia). Serum gastrin was determined by RIA. Adrenal cell antibodies were measured by indirect immunofluorescence using monkey adrenal slides. Antibodies to glutamate decarboxylase (GAD65) and tyrosine phosphatase (IA-2) were determined by radioimmunometric assays. Islet cell antibodies (ICA) were measured by indirect immunofluorescence with detection limit and upper limit of normal 5 and 20 or more Juvenile Diabetes Foundation (JDF) units, respectively. Primary and secondary study parameters The primary study parameter was thyroid volume at 24 and 30 months. Determination of thyroid volumes was performed by ultrasound using standard procedures (11). sd scores (SDS) were calculated to adjust for age- and gender-related differences in thyroid volumes according to normal volumes in iodine-sufficient German children and adolescents (11). The mean intraobserver coefficient of variation for thyroid volume measurement was 8.2%. There were three prespecified secondary study parameters: conversion to hypothyroidism (TSH 6.0 mu/liter or free T 4 values below the normal range), thyroid function, and concentration of antibodies (TPOAb and TgAb) at 24 and 30 months. Statistical analysis Analyses were performed on an intention-to-treat basis with conservative assessment. For patients who withdrew before month 30, the last-observation-carried-forward principle was applied. Parameters in the treatment group and observation group were compared by the Mann-Whitney U exact test. For the analysis of nominal data, Fisher s exact test was used. Dynamics of thyroid volume in each group was calculated with nonparametric ANOVA for repeated measurements (Friedman test). All analyses involved two-tailed tests of significance and were performed with the use of SAS or SAS-Analyst Software (SAS, version 9.1.3). P values 0.05 were considered to indicate statistical significance. Results Study population Of 611 serologically screened patients with T1D, 89 eligible patients with positive serum thyroid autoantibodies were identified (prevalence, 14.5%). Of these individuals, 59 patients were not included because of current treatment with l-t 4, lack of consent, or other exclusion criteria (Fig. 1). Thus, 30 patients (mean age, yr) were enrolled in the study and randomly assigned to the l-t 4 treatment group or the observation group without l-t 4 therapy. The mean l-t 4 starting dose of the l-t 4 group was 1.3 g/kg d (range, g/d). Baseline characteristics were not different in both groups (Table 1), and no iodine deficiency or excess was detectable in any subject. Within the l-t 4 treatment group, thyroid volume at baseline was enlarged ( 2.0 SDS) in 11 individuals and normal ( 2.0 SDS) in five patients. Thyroid volume at baseline was elevated in eight patients of the observation group and normal in six cases. One patient of the observation group moved and was lost to follow-up in the second year of the study, and one individual lost interest in the study after 18 months. Two individuals in the l-t 4 group reported discontinuation of l-t 4 medication for longer than 2 wk and eventually withdrew from the study after 12 and 18 months, respectively. Effects on thyroid volume The dynamics of thyroid volumes was assessed by nonparametric ANOVA for repeated measurements and revealed no significant time-dependent effects in the l-t 4 group and observation group (P and P , respectively). When the difference in thyroid size in both groups was directly compared after 24 months in relation to baseline size (Fig. 2), treatment with l-t 4 was associated with a decrease of thyroid volumes, whereas in the observation group an increase of thyroid size was observed (P , Mann-Whitney U test; Table 2). This finding was attributable to an l-t 4 treatment effect in individuals with enlarged thyroid gland (SDS 2.0) compared with cases with a normal sized thyroid gland (SDS 2.0). In patients with goiter, a mean reduction of thyroid volume by 0.91 SDS was observed after treatment with l-t 4 during 24 months, whereas a mean increase of thyroid size by 1.33 SDS was noted in the observation group (P , Mann-Whitney U test). In patients with normal-sized thyroid gland at baseline, mean

3 Karges et al. L-T 4 in Euthyroid Autoimmune Thyroiditis J Clin Endocrinol Metab, May 2007, 92(5): FIG. 1. Trial design and assignment of patients. R, Randomization. enlargement was 0.79 SDS in the treatment group and 0.83 SDS in the observation group (P ). At month 30, 6 months after discontinuation of treatment, there was no significant difference in thyroid volumes in the l-t 4 group and the observation group (P , Mann-Whitney U test; Table 3). Thyroid function and autoantibodies To study the effect of l-t 4 on thyroid function and autoantibody levels, we compared serum levels of free T 4, TSH, TABLE 1. Clinical characteristics of patients with euthyroid AIT and T1D at baseline L-T 4 group (n 16) TPOAb, and TgAb after 24 months in relation to baseline between both groups (Table 2). No significant differences were observed for thyroid hormone and autoantibody levels between the l-t 4 group and the observation group throughout the study period. TSH levels at months 0, 6, 12, 24, and 30 were , , , and mu/liter in the l-t 4 group, and , , , , and mu/liter in the observation group (means sd). TPOAb and TgAb were positive in 24 (80%) and 22 (73.3%) individuals, respectively, and 16 patients had Observation group (n 14) P value a Male/female (n) 4/12 8/ Age (yr) Body weight (BMI SDS) b Tanner stage (I V) Thyroid volume (SDS) c FT 4 (pmol/liter) T 3 (nmol/liter) TSH (mu/liter) TPOAb (U/ml) TgAb (U/ml) Urinary iodide ( mol/liter) Diabetes duration (yr) HbA 1c (%) Insulin dose (units/kg d) Values are means SD. Reference ranges are as follows free T 4 (FT 4 ), pmol/liter; T 3, nmol/liter; TSH, mu/liter; TPOAb, less than 100 U/ml; TgAb, less than 100 U/ml; urinary iodide, mol/liter; HbA 1c, %. a Mann-Whitney U test, except for gender and Tanner stage (Fisher s exact test). b For BMI SDS, 0 indicates normal weight, and greater than 2.0 indicates obesity. c For SDS for thyroid volume (cm 3 ), 0 indicates normal thyroid volume, and greater than 2.0 indicates enlarged thyroid gland.

4 1650 J Clin Endocrinol Metab, May 2007, 92(5): Karges et al. L-T 4 in Euthyroid Autoimmune Thyroiditis FIG. 2. Changes of thyroid volumes in patients with AIT and T1D at 24 and 30 months compared with baseline (month 0). In the L-T 4 group, treatment with L-T 4 (months 0 24, shaded area) was followed by an observation (washout) period (months 24 30). Data are means SD of thyroid SDS, with positive (negative) values indicating increase (decrease) of thyroid volume. positive antibodies against both thyroid antigens (53.3%). The rate of positive antibodies remained unchanged during the observation period within both groups. Thyroid function was assessed 6 months after the discontinuation of l-t 4 treatment. At this time point, there were no significant changes in thyroid volume, thyroid hormone, and autoantibody levels compared with baseline or month 24 in individuals from the l-t 4 group and the observation group (Table 3). Conversion into hypothyroidism (TSH 6.0 mu/ liter or free T 4 below normal range) was observed in three individuals of the treatment group and in four patients of the observation group at 30 months after study entry, corresponding to an annual conversion rate of 9.3%. Clinical and metabolic parameters l-t 4 treatment may potentially influence metabolic control of diabetes and body weight. We assessed the course of HbA 1c and body mass index (BMI, kg/m 2 ) SDS in the l-t 4 group and observation group. After 24 months, HbA 1c increased in the treatment group by % and in the observation group by % (P , Mann-Whitney U test). The dose of injected insulin was not different in the l-t 4 group and the observation group at baseline ( vs U/kg d, P , Mann-Whitney U test), month 12 ( vs U/kg d, P ), and month 24 ( vs U/kg d, P ). A small decrease of BMI SDS was equally observed in the l-t 4 group and observation group ( and , respectively, P ). l-t 4 treatment was overall well tolerated with no adverse events. Islet cell and other organ-specific autoantibodies At baseline, all patients had at least one positive autoantibody against islet antigen (Table 4), confirming autoimmune T1D. Positive antibodies against GAD65 ( 0.9 U/ml) were more prevalent than those against IA-2 ( 0.75 U/ml) or islet cells (ICA). In addition, seven patients had positive antibodies against transglutaminase ( 8 U/ml), seven individuals had positive antibodies against parietal cell antigens ( 10 U/ml), and seven patients had elevated gastrin values ( 100 pg/ml). No individual had positive adrenal cortex antibodies (Table 4). The rate for positive antibodies against organ-specific antigens remained unchanged during the entire observation period of 30 months. Two transglutaminase antibody-positive individuals underwent duodenoscopy, with no histological evidence of celiac disease. No patient presented clinical signs or symptoms or other evidence of autoimmune disease other than diabetes and AIT. Discussion This prospective, randomized trial demonstrates that early treatment with l-t 4 reduces the size of the thyroid gland in euthyroid children and adolescents with AIT and T1D. Although goiter is a main symptom of AIT in children and adolescents (10), its treatment and prevention in euthyroid subjects is still under debate. In our study, the overall benefit of l-t 4 in terms of the reduction of thyroid size was significant in euthyroid patients, with a more pronounced effect in individuals with enlarged thyroid gland. Our data are in accordance with a recent retrospective study performed in patients with AIT of the same age group where a decrease of thyroid volume by l-t 4 was mostly confined to individuals with goiter (12). From a cohort of 611 children and adolescents with T1D screened in our study, 14.5% of individuals were identified to have positive serum antibodies to thyroid peroxidase (TPOAb), thyroglobulin (TgAb), or both. The high prevalence of thyroid antibodies in this pediatric cohort is similar to previous observations (1, 2), highlighting the high risk of thyroid autoimmunity in patients with T1D, with euthyroid function present in 70 85% of individuals at baseline (13, 14). The mean daily intake of l-t 4 (1.3 g/kg) for 24 months was not associated with changes in autoantibody levels in the treatment group, with no differences to the observation group. This finding is in contrast to a smaller cohort of euthyroid adults in which similar l-t 4 doses were used for a treatment period of 12 months (7). Our data may indicate that higher l-t 4 doses are needed in children and adolescents TABLE 2. Changes of primary and secondary study parameters in euthyroid patients with AIT and T1D after L-T 4 treatment at month 24 L-T 4 group (n 16) Observation group (n 14) P value a Change of thyroid volume (SDS) Change of FT 4 (pmol/liter) Change of TSH (mu/liter) Change of TPOAb (U/ml) Change of TgAb (U/ml) Data shown are the differences between values at 24 months and at baseline. Values are means SD, with positive (negative) values indicating increase (decrease) of each variable. Reference ranges are as follows: free T 4 (FT 4 ), pmol/liter; TSH, mu/liter; TPOAb, less than 100 U/ml; TgAb, less than 100 U/ml. a Mann-Whitney U test.

5 Karges et al. L-T 4 in Euthyroid Autoimmune Thyroiditis J Clin Endocrinol Metab, May 2007, 92(5): TABLE 3. Changes of primary and secondary parameters at month 30 after discontinuation of L-T 4 in euthyroid patients with AIT and T1D compared with adults to modify autoimmune activity in AIT, and they do not support the hypothesis that exogenous T 4 at nonsuppressive doses is suitable to down-regulate antibody markers of ongoing thyroid autoimmunity. Unlike insulin used in prevention trials of autoimmune T1D, T 4 is not an immunological target antigen in patients with AIT. l-t 4 may down-regulate TSH-dependent expression of thyroid peroxidase, a central autoantigen in AIT (15), as well as the metabolic and proliferative activity of thyroid follicular cells. Effects of l-t 4 in AIT thus putatively involve thyroid cell rest and, less likely, the induction of immune tolerance, but additional experimental evidence is clearly required to support this view. Recognition and treatment of thyroid dysfunction is a central goal in management of T1D, because this condition may interfere with glycemic control in affected individuals (6, 16). Our study was not powered to assess the effect of l-t 4 on thyroid function and prevention of hypothyroidism independently, but during the prospective observation period of 30 months, no significant differences were found between both groups. A rate of conversion from normal thyroid function to hypothyroidism of 9.3% per year was observed in our study with three patients from the treatment group and four patients from the observation group. This conversion rate is higher than reported in previous studies (13, 17). However, the limited number of individuals with an overall low rate of events and the limited observation period do not allow definite conclusions from our data concerning potential effects of l-t 4 on the prevention of hypothyroidism. The high rate of positive organ-specific autoantibodies in the study population was similar to other large series of TABLE 4. Prevalence of organ-specific autoantibodies in euthyroid patients with AIT and T1D at baseline Autoantibody L-T 4 group (n 16) Observation group (n 14) L-T 4 group (n 16) All patients (n 30) TPOAb (80%) TgAb (73%) GAD65 Ab (83%) IA-2 Ab (66%) Islet cell Ab (30%) t-transglutaminase Ab a (23%) Parietal cell Ab (23%) Adrenal gland Ab Ab, Antibody. a No evidence of celiac disease (clinical, laboratory, or histopathological) was detected in any of the patients. Observation group (n 14) patients with AIT and T1D (18 20). The observed absence of other clinical autoimmune disease may be explained by the young age and the selection of euthyroid patients in our trial, because it has been shown that subjects with overt hypothyroidism have a higher risk of a third autoimmune condition than euthyroid individuals (13). In conclusion, l-t 4 treatment is effective to reduce thyroid volume in pediatric patients with AIT and T1D. Our data support the clinical utility of l-t 4 at a non-tsh-suppressive dose for the treatment, and likely secondary prevention, of goiter in such individuals, even in the absence of latent or overt hypothyroidism. Acknowledgments Received November 13, Accepted February 7, Address all correspondence and requests for reprints to: Beate Karges, M.D., Division of Pediatric Endocrinology and Diabetes, University Children s Hospital, University of Ulm, Eythstrasse 24, D Ulm, Germany. beate.karges@uniklinik-ulm.de. This work was supported by the German Diabetes Foundation Das zuckerkranke Kind (to B.K.) and by the Research Training Group Molecular Diabetology and Endocrinology GRK 1041, Deutsche Forschungsgemeinschaft (to B.O.B.). 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