Autoimmune thyroid disease and thyroid function test fluctuations in patients with resistance to thyroid hormone

Objective Resistance to thyroid hormone-beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β ( THRB ) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum TSH. We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations. to a control. A study of the general Japanese population reported that thyroid autoantibodies were detected in 23.4% of women and 14.8% of men with non-palpable goiters (8). No study has reported the prevalence of AITD among Japanese patients with RTHβ.

Basal thyroid function tests were performed at least one month after patients who were misdiagnosed with Graves' disease discontinued anti-thyroid drugs. All participants except one unaffected relative were checked for thyroid autoantibodies (Table 4, supplementary Figure 1) using methods described as follows. Before March 2008, four patients and one unaffected relative were evaluated by hemagglutination assay kits (MCHA: Microsome test and TGHA: Thyroid test, Fuji Rebio Inc., Tokyo, Japan) and one patient was evaluated by radioimmunoassay for thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) (Cosmic Co, Hiroshima, Japan).
Data based on ultrasound examination were available in 56 patients with RTHβ and in 21 unaffected relatives who were at least 15 years old (Table 4, supplementary Figure 1). Thyroid volume was measured by ultrasound and was calculated using the equation as described previously (9). For evaluation of the malignant potential, we used the ultrasound classification system based on the shape and echo features of thyroid nodules as reported previously (10, 11) and measured the maximum diameter of nodule sizes.
The patients with AITD have satisfied the diagnostic criteria: positive values for TPOAb and/or TgAb, with either hypoechoic and/or inhomogeneous pattern in thyroid ultrasonography or lymphocytic infiltration in the thyroid gland with cytological examination.    (Table 3), the questionnaire showed that palpitations and goiter were the main chief complaints and were present in 38.8% and 34.3% of the patients, respectively. Medical history and electrocardiograms showed that 7.4% (5 of 68) of the patients had concurrent atrial fibrillation. Importantly, 13.2% (9/68) of the patients were misdiagnosed with Graves' disease at initial evaluation; consequently, nine patients were prescribed anti-thyroid drugs (6 with thiamazole and 2 with propylthiouracil) and one patient who had undergone subtotal thyroidectomy at a hospital elsewhere was also prescribed thiamazole after recurrence of thyroid enlargement to 62 mL.

Statistical analysis
FT4 and FT3 levels were significantly higher in patients with RTHβ compared to unaffected relatives (Table 4) (Table 3), the ultrasound data showed that twice as many patients (73.2%) had goiter with a thyroid volume ≥ 20 mL.
While nodules with solid components were detected in 42.9% of the RTHβ patients, malignancy was not suspected in any of them upon ultrasound evaluation and fine needle aspiration.
We evaluated the sequential thyroid function in 44 RTHβ patients who consulted our hospital more than twice (supplementary Figure 1). Among them, 13 patients (29.5%), eight with AITD and five without AITD, temporarily showed data inconsistent with RTHβ during the observation period (Table 5). Serial changes of data  (Table 6 and supplementary Figure 2) with elevated TSH and low FT4 levels and overt thyrotoxicosis (Table 7 (Tables 1 and 5). There were no over-represented mutations in the group with data inconsistent with RTH (Table 1)

Discussion
This study describes the characteristics of 68 Japanese patients with RTHβ in a single institute specializing in thyroid care. We found that RTHβ patients, especially men, showed a higher frequency of AITD. More than 20% of patients with RTHβ The presence of thyroid autoimmunity is generally more common in women; however, there was no difference in sex regarding the frequency of AITD in RTHβ patients in our study. Moreover, the frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives; however, this difference was not found in the female patients (Table 4). This result was consistent with the study of Barkoff et al (6). In addition, the prevalence of AITD in Japanese patients with RTHβ in this study (more than 40%) was higher compared to previous studies (~25%) (4, 6, 7). Japanese individuals are known to have a higher iodine intake than individuals from other countries (12). Although the relationship between iodine intake and the occurrence of AITD is undetermined, several studies have shown a direct relationship between iodine intake and AITD (13, 14). The mechanism of increased AITD in patients with RTHβ has not been elucidated. Gavin et al. have suggested that chronic TSH stimulation in RTHβ patients activates intra-thyroidal lymphocytes to produce

Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.    Genetic variants that include one or more members with AITD are shown in bold.  showing overt hypothyroidism due to chronic thyroiditis in Table 6 Arrows indicate the onset of hypothyroidism. Each vertical bar indicates a reference range.

Supplementary Figure 3. Serial thyroid function data of two patients with RTHβ
showing overt thyrotoxicosis in Table 7 Arrows indicate the onset of thyrotoxicosis. Each vertical bar indicates a reference range.