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Levothyroxine Treatment Reduces Thyroid Size in Children and Adolescents with Chronic Autoimmune Thyroiditis

Department of Pediatrics (J.S., B.L., S.-A.I.), Pediatric Endocrinology Research Unit (J.S., B.L., S.-A.I.), and Department of Endocrinology (U.-B.E.), Malmö University Hospital, Lund University, SE-205 02 Malmö, Sweden; Department of Diagnostic Radiology (P.N.), Copenhagen University Hospital, DK-2650 Copenhagen, Denmark; Department of Diagnostic Radiology (C.O.), Helsingborg Hospital, S-25187 Helsingborg, Sweden; and Department of Women’s and Children’s Health (B.J.), Uppsala University, SE-751 05 Uppsala, Sweden

Address all correspondence and requests for reprints to: Johan Svensson, M.D., Department of Pediatrics, Malmö University Hospital, SE-205 02 Malmö, Sweden. E-mail: johan.svensson{at}med.lu.se.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: The use of levothyroxine to reduce thyroid size in pediatric patients with goiter due to chronic autoimmune thyroiditis (AIT) remains controversial. In overtly hypothyroid patients, reductions in thyroid volume have been reported, whereas the effect in subclinically hypothyroid and euthyroid patients is less clear.

Objective: The objective of the study was to evaluate the effect of levothyroxine treatment on thyroid size (determined with thyroid ultrasonography) in children and adolescents with AIT.

Design and Setting: This study included patients with AIT treated at a university hospital outpatient clinic between 1987 and 2004.

Patients: Ninety children with AIT (73 girls and 17 boys, aged 6.1–17.7 yr) were included in the study.

Intervention: Intervention was treatment with levothyroxine for a median 2.8 yr (range 0.5–10.2).

Main Outcome Measure: Change in thyroid volume SD score (SDS) during the study period was measured.

Results: Median thyroid volume SDS was reduced in patients euthyroid (–0.4 SDS, P < 0.001), subclinically hypothyroid (–1.4 SDS, P < 0.001), and overtly hypothyroid (–1.8 SDS, P < 0.002) at diagnosis of AIT. Both hypothyroid and euthyroid patients with goiter (thyroid volume > 2.0 SDS) at baseline reduced their median thyroid volume SDS (–1.6 and –0.9, respectively, P < 0.001). Hypothyroid patients without goiter also reduced median thyroid volume SDS (–1.2, P < 0.004), whereas no change was noticed in euthyroid children without goiter.

Conclusions: Levothyroxine treatment is effective in reducing thyroid volume in pediatric patients and is suggested in treatment of goiter caused by AIT, especially in cases of hypothyroid, but also in euthyroid children.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CHRONIC AUTOIMMUNE THYROIDITIS (AIT) is the most common cause of thyroid impairment among children and adolescents in the iodine-sufficient parts of the world. A major symptom in pediatric patients with the disease is goiter (1). It is well established that levothyroxine and iodine treatment efficiently reduces thyroid volume in children and adolescents and adults with nontoxic goiters in geographic areas with iodine deficiency (2, 3, 4). In goiter caused by AIT, significant reductions in thyroid volume during treatment with levothyroxine have been reported for adults (5). However, the treatment effect is less clear for children and adolescents. Treatment of goiter with levothyroxine is currently recommended only in children with coexisting overt hypothyroidism (1, 6). Only a few studies (6, 7) have been performed, and none of these have used thyroid ultrasonography to evaluate changes in thyroid size.

One of the major difficulties when interpreting changes in thyroid volume during levothyroxine treatment in growing children and adolescents is taking into consideration the child’s expected normal thyroid growth during the study period. Because both chronological age and auxological parameters significantly influence thyroid volume independently of each other, both parameters need to be taken into account when interpreting changes in thyroid volume (8, 9).

In this study we investigated the effect of levothyroxine treatment on thyroid size in 90 children with AIT using a multivariate model to interpret changes in thyroid volume during treatment. When calculating the treatment effect, sex, age, and auxological parameters were used, and a child’s expected normal thyroid growth during the study period was taken into consideration.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

This study included children and adolescents with AIT treated at our outpatient clinic between 1987 and 2004. The patients were traced using the hospital’s diagnosis registries. Medical records were reviewed, and patients were considered to have AIT if they were seropositive for at least one of either thyroglobulin autoantibodies (TgAb) or thyroid peroxidase autoantibodies, in addition to exhibiting morphological changes consistent with AIT, as diagnosed by thyroid ultrasound (hypoechogenicity) or fine-needle biopsy (lymphocytic infiltration).

Patients with thyroid ultrasound performed at baseline and at least one more thyroid ultrasound performed during levothyroxine treatment were included. Because several patients had started treatment before the initial ultrasonography of the thyroid gland was performed, examinations before and within 6 months after commencement of treatment were considered the baseline examination. The children and adolescents had been treated with levothyroxine in increasing dosages until TSH levels within the lower part of the normal range were reached.

Thyroid volume and levels of TSH, T₄, and/or free T₄, as well as a patient’s height and weight at the time of each ultrasound examination, were recorded.

Because the reference used for the interpretation of thyroid size was based on children and adolescents younger than 19 yr of age, all ultrasound examinations performed after the age of 19 yr were excluded from analysis. A total of 90 children and adolescents fulfilled the inclusion criteria and comprised the study group.

Individuals were classified as subclinically hypothyroid at diagnosis of AIT if they had elevated serum TSH (TSH > 4 mIU/ml) and normal serum T₄ or free T₄ concentrations (T₄ > 50 nmol/liter or free T₄ > 9 pmol/liter). If an elevated serum TSH concentration was associated with a decreased serum T₄ or free T₄ concentration, the patient was considered to be overtly hypothyroid.

The study was approved by the Research Ethics Committee of the Medical Faculty at Lund University.

Thyroid ultrasound

Thyroid volume and morphology were determined by two experienced members of the team (P.N. and C.O.), using real-time sonography.

Examinations were performed in a supine position with the neck hyperextended. Hitachi EUB 400 (Tokyo, Japan), Acuson XP 128 (Mountain View, CA), Acuson Sequoia, Siemens Elegra (Issaquah, WA), and ATL HDSI 5000 (Seattle, WA), with 5- to 9-MHz transducers, were used during the study period (1987 to 2004). Thyroid volume was calculated according to Brunn et al. (10). Repeated measurements were made until reproducible figures were obtained (9). The ultrasonographic diagnosis of thyroiditis was carried out by subjective measurements of the thyroid echogenicity in reference to the strap muscle of the neck (11, 12, 13).

As described earlier, a reference for normative thyroid volumes, based on a multivariate model by sex that took both auxological parameters and age into account, was used for interpretation of thyroid volumes (9). SD scores (SDS) for thyroid volume were calculated for each ultrasound examination. Equations for calculation of thyroid volume SDS are given in Table 1. The patients were considered to be goitrous at baseline if they had a thyroid volume SDS greater than 2.0.

Over the study period, several different methods to determine thyroid hormones and thyroid autoantibodies were in clinical use.

TSH, T₄, and free T₄

TSH and T₄ were analyzed using an in-house RIA between 1987 and 1993. After 1993 a commercial RIA was used (Amerlite TT4 and TSH-30 assay; Kodak Clinical Diagnostics, Amersham, UK). Between 1995 and February 2004, TSH, T₄, and free T₄ were analyzed using a heterogeneous sandwich magnetic separation assay (Immuno 1 immunoassay; Bayer Corp., Tarrytown, NY), and from February 2004 these analyses were performed using chemiluminescence (chemiluminescent Access immunoassay system; Beckman Coulter, Fullerton, CA).

Thyroid peroxidase autoantibodies

Between 1987 and November 1995, a commercial kit using semiquantitative microtiter particle agglutination (Serodia-AMC; Fujirebio, Tokyo, Japan) was used. From December 1996 until May 2002 a commercial RIA was used (DYNOtest, AntiTPO; Brahms Diagnostic, Henningsdorf, Germany). Subsequent to May 2002, the Immulite 2000 chemiluminescent analyzer (Diagnostic Products Corp., Los Angeles, CA) has been used for detection of these autoantibodies.

TgAb

An in-house RIA method was in use between 1987 and May 2002 (14), and in part overlapping this method was a commercial kit (Thymune-T; Murex, London, UK) using hemagglutination of tanned turkey red cells. Since May 2002, TgAbs have been analyzed on the Immulite 2000 chemiluminescent analyzer (Diagnostic Products Corp.).

Statistics

Arithmetic means, medians, and ranges were used unless otherwise stated. Nonparametric statistical methods have been applied. The Mann-Whitney test was used when analyzing differences between groups and Wilcoxon tests when analyzing two related samples (changes within groups). Correlation analyses were done by means of the nonparametric Spearman’s rho. P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
An analysis of the treatment effect was made on the whole group of patients and after dividing them into two groups based on the occurrence of goiter at the baseline investigation.

All patients

The study included 90 subjects, 73 girls (81%) and 17 boys (19%). The mean age at baseline was 12.2 yr (range 6.1–17.6) for the girls and 14.0 yr (range 8.6–17.6) for the boys. The median duration of levothyroxine treatment from baseline to final ultrasound examination was 2.8 yr (range 0.5–10.2). The boys were older than the girls at baseline (P < 0.05); otherwise, there were no significant differences between them with regard to thyroid volume SDS at baseline, TSH levels at baseline, or reduction in thyroid volume SDS during the study period (Table 3).

View larger version (10K): [in this window] [in a new window]   FIG. 1. Change in thyroid volume SDS between baseline and final ultrasound investigation among all patients (n = 90). Results are presented as median, range, and interquartile range.

View larger version (17K): [in this window] [in a new window]   FIG. 2. Thyroid volume SDS at baseline and in subgroups based on duration of levothyroxine treatment. Each patient is represented only once in each group and compared with the baseline investigation. Results are presented as median, range, and interquartile range.

Of the 90 patients in the study, 35 were euthyroid, 42 subclinically hypothyroid, and 13 overtly hypothyroid at diagnosis of AIT. In all of these groups, significant reductions in thyroid volume SDS were shown (Fig. 3). Median thyroid volume SDS was reduced from 2.5 (range –0.2 to 5.9) to 1.8 (range –0.1 to 5.7) in the euthyroid group (P < 0.001), from 2.8 (range–1.5 to 7.5) to 1.5 (range –2.8 to 6.0) in the subclinically hypothyroid group (P < 0.001), and from 3.1 (–1.1 to 6.4) to 0.9 (range –2.2 to 3.0) in the group of children overtly hypothyroid at diagnosis (P < 0.002). At baseline there were no significant differences in thyroid volume SDS, and treatment duration did not differ significantly between hypothyroid (subclinical or overt hypothyroidism) and euthyroid patients. However, the reduction in thyroid volume SDS was significantly larger among the subclinically and overtly hypothyroid patients when compared with the euthyroid patients (median reduction in thyroid volume SDS –1.5 and –2.1 vs. –0.4, P < 0.004 and P < 0.001, respectively).

View larger version (12K): [in this window] [in a new window]   FIG. 3. Change in thyroid volume SDS between baseline and final thyroid ultrasound in euthyroid, subclinically hypothyroid, and overtly hypothyroid children and adolescents at diagnosis of AIT. Results are presented as median, range, and interquartile range.

Sixty-one patients (68%) were goitrous at baseline. In these patients, median thyroid volume SDS decreased from 3.7 (range 2.0–7.5) at baseline to 2.0 (range –2.8 to 6.0) at the final ultrasound examination (P < 0.001) (Fig. 4).

View larger version (13K): [in this window] [in a new window]   FIG. 4. Change in thyroid volume SDS between baseline and final ultrasound in patients with goiter at baseline. Results are presented as median, range, and interquartile range.

Patients without goiter

Twenty-nine of the 90 patients (32%) had thyroid volumes less than 2 SDS at baseline. During treatment the median thyroid volume SDS in this group of nongoitrous patients was reduced from 1.2 (range –1.5 to 2.0) at baseline to 0.6 (range –2.2 to 2.2) at the final investigation (P < 0.005).

Seventeen of the patients were hypothyroid at baseline with TSH levels ranging from 4.1 to 939 mIU/liter (median TSH 9.0), whereas 12 patients were euthyroid on entering the study, with a median TSH level of 1.8 mIU/liter (range 0.1–3.8). The hypothyroid patients decreased their median thyroid volume SDS significantly from 1.0 (range –1.5 to 2.0) at baseline to –0.8 (range –2.2 to 2.2) at the final investigation (P < 0.004), whereas no significant difference was found in the euthyroid group (Fig. 5).

View larger version (13K): [in this window] [in a new window]   FIG. 5. Change in thyroid volume SDS between baseline and final thyroid ultrasound in patients without goiter at baseline. Results are presented as median, range, and interquartile range.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In this study we investigated the effect of levothyroxine treatment on thyroid volume in children and adolescents with AIT. Using a multivariate approach when interpreting changes in thyroid volume enabled us to take a child’s expected thyroid growth into consideration when calculating the treatment effect. Significant reductions in thyroid volume SDS were found, irrespective of thyroid parameters or presence of goiter at diagnosis of AIT.

Some of our results are in contrast with earlier published reports. Rother et al. (6) retrospectively investigated the effect of levothyroxine treatment in 65 goitrous children and adolescents with AIT during a treatment period of 3.5 ± 2.5 yr. They (6) reported, as we do here, a clear decrease in thyroid size among children with overt hypothyroidism, whereas thyroid size remained unchanged among the majority of compensated hypothyroid or euthyroid children throughout the treatment period. One possible explanation for the disparity between our data and the data presented by Rother et al. regarding the euthyroid and subclinically hypothyroid children may be the rapid increase in thyroid volume that normally takes place during puberty, with maximum growth rate at 12.5 yr of age (15). The mean age at diagnosis in the study by Rother et al. was 12.1 yr for girls and 11.6 yr for boys. In their study, thyroid size in the majority of euthyroid or compensated hypothyroid patients remained unchanged during the treatment period, a period during which normal thyroid growth is at its most intense. If the child’s expected thyroid growth had been taken into account, thyroid volume SDS most likely would have decreased in both of these groups. Another explanation may be the use of thyroid ultrasonography in our study. Several studies have shown it superior to palpation for estimating thyroid size, especially in children and adolescents (16), and therefore thyroid ultrasonography has supplanted palpation as the preferred technique for estimating thyroid volume.

Hypothetically, the decrease in thyroid volume SDS found in our study could be an effect of the natural course of the disease as well as the result of the levothyroxine treatment. Changes in thyroid volume have been studied prospectively in euthyroid and subclinically hypothyroid patients with AIT untreated by levothyroxine. Maenpaa et al. (17) studied the course of AIT in 46 children and adolescents during a 6.5-yr period and reported unchanged, increased, and decreased thyroid size in euthyroid and subclinically hypothyroid patients during the period of investigation. This indicates a variable natural course with regard to thyroid size in children and adolescents with AIT. However, Jaruratanasirikul et al. (7) followed up 28 euthyroid and eight subclinically hypothyroid patients for 5.9 ± 0.3 yr and found that goiter size remained unchanged without levothyroxine treatment in the majority of these patients and that no spontaneous decrease in thyroid size took place. In the same study, the effect of levothyroxine treatment on thyroid volume in 14 patients with overt hypothyroidism was investigated, and a significant reduction in thyroid size was reported in nine patients. Discontinuation of levothyroxine treatment after 3 yr of treatment resulted in an increase in thyroid size, which was again diminished after reinstitution of levothyroxine therapy (7). It is unlikely that the significant reduction in thyroid volume SDS would be accounted for by the spontaneous development of the disease in our study, but it may be a contributing factor.

Prophylactic levothyroxine treatment of euthyroid patients with AIT has been found to reduce both serological and cellular markers of AIT. It has also raised the question of whether prophylactic levothyroxine treatment for euthyroid patients with AIT might arrest the progression or even the manifestation of the disease (18). In our study, a subgroup of 12 patients were both euthyroid and without goiter at the start of levothyroxine treatment. Thyroid volume SDS in this group of children remained unchanged during the study period, i.e. neither did thyroid volume SDS decrease nor was any development of goiter observed. Levothyroxine treatment might have contributed to the prevention of goiter development among these children, but to evaluate this, a prospective study with untreated controls would be needed.

Several studies have been performed to investigate the natural history of AIT in children and adolescents (7, 17, 19). The clinical course of the disease is highly variable. Rallison et al. (19) found that the disease resolved completely in one third of all patients, progressed to overt hypothyroidism in another third, and was unchanged in the remaining third of patients with AIT diagnosed during childhood and adolescence. In our study all patients remained autoantibody positive throughout the investigated period. We were not able to analyze changes in autoantibody levels because several different methods of detecting thyroid autoantibodies had been in use during the study period.

Our study revealed a significant negative correlation between the TSH level on diagnosis of AIT and the change in thyroid volume SDS during treatment. Reduction in thyroid volume SDS was significantly larger among patients who were hypothyroid at diagnosis, compared with those euthyroid at diagnosis.

During the study period, different methods for analysis of thyroid parameters and different sets of ultrasound equipment for determination of thyroid volume and morphological changes in the thyroid gland have been in use, a source of potential bias. However, before each change of laboratory method, the new method has been compared with the one in use and has been found congruent. Moreover, the same normal range for TSH and T₄ has been in use during the whole study period. The exchange of ultrasound equipment during the study period has not substantially influenced the calculations of thyroid volume because the new equipment has been calibrated and tested to ensure exact distance measurement. Furthermore, the same members of the team (P.N. and C.O.) performed the measurements throughout the study period.

Thus, using an objective method for estimation of thyroid volume and a reference enabling assessment of a subject’s expected thyroid growth during the study period, we found levothyroxine treatment efficient in reducing thyroid volume SDS, particularly in hypothyroid, but in euthyroid children and adolescents with goiter due to AIT as well. Based on these results, we suggest the use of levothyroxine therapy for the treatment of goiter in both euthyroid and hypothyroid children with AIT. Whether levothyroxine therapy can prevent development of goiter in euthyroid children without goiter is a subject for future investigation.

	Footnotes

 
This work was supported by grants from the Health Services Administration, Malmö University Hospital; the Skåne Council Foundation for Research and Development; the Novo Nordisk Foundation; Her Royal Highness Princess Lovisas Fund; the Axel Tielman Fund; the Anna-Lisa and Sven-Eric Lundgren Fund; and the Linnea and Josef Carlsson Fund.

Authors J.S., U.-B.E., P.N., C.O., B.J., B.L., and S.-A.I. have nothing to declare.

First Published Online February 28, 2006

Abbreviations: AIT, Autoimmune thyroiditis; SDS, SD score; TgAb, thyroglobulin autoantibody.

Received November 2, 2005.

Accepted February 21, 2006.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Svensson, J. Articles by Ivarsson, S.-A. Search for Related Content PubMed PubMed Citation Articles by Svensson, J. Articles by Ivarsson, S.-A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LEVOTHYROXINE LIOTHYRONINE Related Collections Pediatric Endocrinology Thyroid