To cite this article:
Orgiazzi Jacques. Clinical Thyroidology. May 2016, 28(5): 136-139. doi:10.1089/ct.2016;28.136-139.
Kahaly GJ, Diana T, Glang J, Kanitz M, Pitz S, König J. Thyroid stimulating antibodies are highly prevalent in Hashimoto's thyroiditis and associated orbitopathy. J Clin Endocrinol Metab. March 10, 2016 [Epub ahead of print].
Autoimmune thyroid diseases (AITDs) comprise two main clinical presentations, Graves’ disease (GD) and Hashimoto's thyroiditis (HT), both characterized by lymphocytic infiltration of the thyroid parenchyma. In GD, thyrotropin-receptor antibodies (TRAb) stimulate thyroid follicular cell growth and function, ultimately leading to hyperthyroidism. Extrathyroidal manifestations, e.g., Graves’ orbitopathy or thyroid-associated orbitopathy (TAO; prevalence around 25%) are also part of the disease. In HT, the more severe and longer-lasting lymphocytic preclinical infiltration of the thyroid causes destruction of the follicular cells and subsequent hypothyroidism. However, interconnections are obvious between GD and HT, possibly supported by their related inheritance. Specifically, four types of combinations of the two diseases have been observed, (i) TAO in a patient, usually TRAb-positive, with hypothyroid HT, initially referred to as “hypothyroid Graves’ disease” (1, 2); (ii) detection of TRAb in about 5% of the patients with HT, sometimes of the blocking type (3); whether these blocking antibodies are responsible for the hypothyroidism is unclear, except in pregnant women giving birth to a newborn with transient congenital hypothyroidism (4) ; (iii) occurrence of the biphasic sequence: spontaneous hypothyroid thyroiditis followed by Graves’ hyperthyroidism, uncommon but observed even in children and adolescents (5); and (iv) the so-called Hashitoxicosis syndrome, first described by Fatourechi et al., a clinically and biologically typical GD presentation with spontaneous evolution within 3 to 24 months to permanent hypothyroidism (6). Taking advantage of a large database of patients with AITD, the present contribution compares patients with HT associated with TAO with patients with HT not associated with TAO. Besides the clinical aspects, the study questions the potential role of TRAb in the occurrence of TAO in this non-GD pathology.
The data of 700 consecutive unselected patients with a diagnosis of HT (anti-TPOAb with or without anti-TgAb, heterogeneous hypoechoic thyroid ultrasound imaging, euthyroidism or hypothyroidism and, when available, low radionuclide uptake) followed at the endocrine outpatient clinic and at the joint thyroid–eye clinic of the Johannes Gutenberg University Medical Center in Mainz, Germany, were analyzed. All patients were screened for TAO, which was classified as clinically active or inactive, and as mild, moderate-to-severe, or sight-threatening (7). For comparison, a group of 53 patients with GD (26 without and 27 with TAO) and 302 healthy control subjects were also included in this study. In addition to the regular thyroid biologic tests, serum TRAbs were assayed with three different methods: (i) thyrotropin-binding inhibitory immunoglobulins (TBIIs) with the automated Kryptor assay (Thermo Scientific, Henningsdorf, Germany); (ii) thyroid-stimulating antibody (TSAb), expressed as a percentage of the reference value, with the Thyretain bioassay (median value in controls, 52%; range, 42.8 to 62.3) (Quidel, San Diego, CA); and (iii) TSH receptor blocking activity with the method based on the use of CHO cells expressing a chimeric TSH receptor (8, 9).
TAO was present in 44 (6%) of the 700 patients with HT. Compared to the patients without TAO, those with TAO tended to be older (49.3 yr vs. 35.2 yr); the proportion of patients <18 yrs of age was 9.1% among the 44 with TAO and 26.1% among the 656 without TAO. Also, patients with TAO had HT of longer duration (2.4 yr vs. 0.9 yr), were heavier smokers, and were less likely to present with another associated autoimmune disease (only thyroid disease: 75% vs. 52.6%; associated type 1 diabetes, 2.3% vs. 16.3%). TAO was mild and inactive in two thirds of the patients. TAO activity/severity was independent of sex, age, thyroid function, and smoking. No differences were noted in the prevalence of hypothyroidism or rate of levothyroxine replacement. However, baseline serum TSH was lower in patients with TAO than in those without it. There were no differences in serum free T4 and free T3 or in titers of anti-Tg and anti-TPO autoantibodies. The prevalence of TSAb was 68.2% in the HT patients with TAO and 5.5% in those without TAO. Detected as TBIIs, TRAb prevalence was 5% and 51% for the patients without and those with TAO, respectively. The titers of TSAb were higher in the group with TAO (range, 115% to 455% vs. 35% to 63%), and more so among the smokers with TAO. Interestingly, while TSAb was more likely to be detected in cases of HT of recent onset, TSAb levels tended to decrease with time in the absence of TAO but remained stable in patients with TAO. The prevalence and levels of TSAb were higher in patients with active and moderate-to-severe than in those with inactive and mild TAO. All sera were negative for blocking TSH receptor antibodies. In the GD group, the prevalence of TSAb and TBII was 100%. The titers of TSAb were higher than in the patients with HT and TAO, and, among patients with GD, notably higher in those with TAO (range, 588% to 864% vs. 306% to 520%).
In this very large series of patients with HT, the prevalence of TAO was 6%. In two thirds of the 44 cases, TAO was inactive (i.e., noninflammatory) and mild (not requiring glucocorticoid or radiation therapy). Patients with HT and TAO were somewhat older, had HT for a longer time, were less likely to have another associated autoimmune disease, and were more likely to be smokers. The presence of TAO was not correlated with functional thyroid status. The study confirms the link of TAO with TRAb, more specifically with TSAb, the presence and levels of which are strongly correlated with the occurrence and activity/severity of TAO. Of note, no instance of blocking TRAb was observed in this series of patients.
ANALYSIS AND COMMENTARY
This article raises several points concerning the relationship between HT and GD on one hand and the role of TRAb in the pathogenesis of TAO on the other. TRAbs are the hallmark of GD. Therefore, in a patient with HT, the presence of TRAbs suggests an association with GD. In that case, whether or not hyperthyroidism is expressed depends on the biologic activity of TRAb and on the degree of residual functionality of the diseased thyroid tissue. The prevalence and bioactivity of TRAbs in patients with HT have been previously studied. Chiovato et al. assayed blocking TRAbs in 140 patients with HT, 26 with thyroid atrophy, and 114 with goitrous HT: the prevalence of blocking TRAbs was much higher in atrophic than in goitrous thyroiditis (46% vs. 21%) as well as in patients with hypothyroidism, suggesting a potential role of TRAbs in both hypothyroidism and thyroid atrophy (3). Cho et al. reported similar results on a series of 185 patients (10). In contrast, in a study of 144 patients from Denmark diagnosed with hypothyroid HT, the prevalence of TBIIs (radiocompetition assay) averaged 10% and showed no correlation with the volume of the thyroid (11). In none of these studies was the orbital status analyzed.
Association of TAO with HT is certainly uncommon, and the 6% prevalence observed in the present study is likely a reflection of the bias inherent in referral to a joint thyroid–eye clinic. Anyhow, the comparison of the 44 patients with HT and TAO with the 656 without TAO illustrated some differences: more smokers, older age, longer duration of HT, and less polyautoimmunity in the TAO group. No information on the family history of thyroid diseases is available in the study. However, the main difference between the two groups concerned the prevalence and levels of TRAbs. Low levels of TRAbs were present in only 5% of patients with HT who did not have TAO, but in 51% to 68.2% (depending on the assay) of the patients with HT who did have TAO. Among the patients sequentially studied (228 of 700), in those without TAO TRAbs seemed to be detected relatively soon after HT diagnosis, then subsequently waned, while TRAb remained essentially unchanged in the patients with TAO. Although the prevalence and levels of TRAb were not as high in the group of patients with HT and TAO as in the patients with GD, they were correlated with the inflammatory activity and severity of TAO. This indicates that, in patients with HT and TAO, as in patients with GD, TRAbs are related to TAO without this indicating the mechanism of the link, which so far remains elusive. In that respect, it should be mentioned that blocking TRAbs were not detected in any of this large group of patients with or without TAO, which could have helped unravel the role of the biologic activity of the antibody. Finally, it is interesting that in the study by Solomon et al. in 1977, of 17 patients with euthyroid Graves’ orbitopathy (12), 6 had a combination of Graves’ orbitopathy, Graves’ disease, and Hashimoto's thyroiditis; 5 presented with “isolated” Graves’ orbitopathy; and the remaining 6 had unclassified abnormalities with dissociation of thyroid functional and autoimmune markers. Despite the biologic test imperfections of that time (thyroid suppressibility for thyroid function, long-acting thyroid stimulator [LATS]–protector assay for TRAb), it is obvious that an improved understanding of the pathogeny of TAO is necessary in order to better characterize the various modalities of TAO-thyroid disease combinations.
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