In Young Patients with Turner or Down Syndrome,Graves' Disease Presentation Is Often Preceded by Hashimoto's Thyroiditis

Introduction

The fluctuations in thyroid function that sometimes occur in autoimmune thyroid diseases have been, in recent years, the theme of several editorials (1,2), clinical reports (3 –6), and letters to the editor (7,8), which have raised interesting questions about the metamorphosis of clinical phenotype in thyroid autoimmunity.

One possible and more common scenario concerns the evolution of Graves' disease (GD) to Hashimoto's thyroiditis (HT), while the other and less common scenario regards conversion of HT into GD. Understanding the basis of these changes is important, since the ultimate goal in treating thyroid autoimmunity is to counter the factors that induce thyroid dysfunction (1).

In order to elucidate the potential mechanisms involved in the conversion from HT to GD, we have investigated the frequency of HT antecedents in the clinical history of a study population (group A) consisting of young GD patients with either Turner syndrome (TS) or Down syndrome (DS)—that is, two conditions that are known to be associated with an increased risk of autoimmune thyroid diseases (9,10). The frequency of HT antecedents was also investigated in a population of age-matched GD patients with neither TS nor DS (group B).

The aim of our study was to ascertain whether the association with these chromosomal abnormalities may affect the switching process from HT to GD. The results of the present study may be useful in shedding some light on the potential mechanisms involved in the metamorphosis from HT to GD or vice versa, a theme that has been frequently discussed in recent years (1 –8).

Patients and Methods

Group A consisted of 28 children and adolescents with DS (14 female; median age at diagnosis of GD 10.3 years; range 3.2–20.0 years) and seven female patients with TS (median age at GD diagnosis 14.6 years; range 9.8–29.5 years). Group B consisted of 109 age-matched patients with neither TS nor DS (89 female) who had been previously reported elsewhere (3). Median ages at GD diagnosis in the two groups were not significantly different (Table 1).

In both groups, GD diagnosis was based on both clinical and laboratory data: (i) elevated free thyroxine (fT4) levels; (ii) suppressed thyrotropin (TSH) levels; and (iii) increased (>1.5 IU/mL) serum titers of TSH receptor autoantibodies (TRAbs).

At the time of GD diagnosis, all the recruited patients were retrospectively investigated in order to either confirm or exclude clinical antecedents of HT. These investigations were based on either the clinical records of our centers, in the cases with other preexisting autoimmune endocrine disorders, or questionnaires addressed to the family pediatricians, in the cases that were not being followed up in our centers at the time of GD presentation. The retrospective diagnosis of HT was based on the following findings: (i) thyroid enlargement; (ii) high titers of circulating antibodies against thyroid peroxidase (TPOAb) and/or thyroglobulin (TGAb); (iii) hypoechogenic thyroid pattern; and (iv) absent TRAbs (<0.5 IU/mL).

Retrospective investigations also aimed at ascertaining how many patients in each group exhibited a biochemical picture of either subclinical or overt hypothyroidism at the time of HT diagnosis, and how many had received levothyroxine (L-T4) therapy prior to the onset of GD. The definition of “overt hypothyroidism” was based on the coexistence of both an increased TSH and a low fT4 level, whilst that of “subclinical hypothyroidism” was based on the coexistence of an increased TSH and a normal fT4 level.

In both groups, all the patients with documented antecedents of HT underwent an assessment of their iodine status after GD diagnosis, aiming at evaluating possible influences of iodine deficiency or excess on the conversion from HT to GD. Iodine status was evaluated by measuring iodine excretion in morning urine samples, and results were interpreted according to the criteria of the World Health Organization (11).

Data are expressed as mean±standard devation (SD) or median and range, as appropriate. Statistical comparisons between the patient groups were performed by Student's unpaired t-test, Mann–Whitney U-test, or chi-square test, as appropriate.

Results

Antecedents of HT were significantly more common in group A than in group B (Table 1). Median ages at HT diagnosis were not significantly different in the two groups (Table 1). The median time interval between HT diagnosis and GD presentation was significantly greater in group A than in group B (Table 1). Hyperthyroidism was not caused by overtreatment of preexisting hypothyroidism in the patients in either group.

In all nine patients of group A, HT had presented with a biochemical picture of either overt (in two cases) or subclinical hypothyroidism (in seven cases), whereas in group B, at the time of HT diagnosis, one patient was euthyroid, two exhibited subclinical hypothyroidism, and the fourth exhibited overt hypothyroidism. After HT diagnosis, six of the nine patients in group A and three of the four patients in group B were treated with L-T4 (Table 1). Serum TSH, fT4, TPOAb, and TGAb values at HT diagnosis were not significantly different in the two groups (Table 2).

Median urine iodine excretion was not significantly different in the two groups (131 μg/L, range 120–180 vs. 140 μg/L, range 126–155, respectively). These results indicate an optimal iodine status in all the patients of both groups (11).

Discussion

Patients with DS and TS are known to be exposed to an increased risk of developing HT, GD, and other autoimmune disorders (9,10,12 –15), although the mechanisms responsible for these associations have not been clearly elucidated to date (16,17). To the best of our knowledge, this is the first study reporting that the conversion rate from HT to GD is also significantly increased in these two chromosomal abnormalities.

It has been already demonstrated that, in the general population, there exists a continuum between HT and GD within the spectrum of autoimmune thyroid diseases (1,4 –7). The present study is unique in that it shows, for the first time, that patients with either TS or DS are more likely to progress from HT to GD, although patients did not differ from the control group in terms of either thyroid function and autoimmunity tests at HT diagnosis, or in iodine status.

A mechanism that has been hypothesized to account for the change from HT to GD is the alteration in the biological activity of TRABs, from predominantly thyroid-blocking antibodies (TBAbs) during the HT phase to thyroid-stimulating antibodies (TSAbs) when GD manifests itself (1). According to this hypothesis, TSAb emergence after L-T4 therapy may be sufficient to counteract TBAb inhibition (2). This hypothesis, however, would not explain why, in the present study, the conversion from HT to GD was observed more frequently in patients with TS and DS, since the frequency of patients who underwent L-T4 treatment was not significantly different in the two groups.

The possible explanation could be that the switch was detected more frequently in the selected population with these chromosomopathies because these patients were already being monitored for thyroid disorders before GD presentation. Nevertheless, the gap between the two groups in terms of progression rate from HT to GD (25.7% vs. 3.7%) was too wide to be explained only by ascertainment bias, rather than true causation.

According to the present results, the shifting process from HT to GD seems to require more time in the patients with TS and DS than in those not diagnosed with TS and DS, a finding that is very difficult to explain, considering that, if genetic abnormalities played a role in the switch, one would predict that the switch occurs sooner when the abnormalities are present. One possible explanation for this observation might be a reduced thyroid reserve, which could account for a diminished gland responsiveness to TRAb stimulation. Nonetheless, this hypothesis is not substantiated by our results, according to which thyroid function impairment at HT presentation was not more severe in the patients in group A than in group B. Finally, it has to be considered that the immunological and pathophysiological mechanisms accounting for HT–GD conversion have not been clarified as of yet (1,2), and therefore it remains unclear why, in the patients with DS and TS included in this study, the conversion process took longer than in those without these conditions.

To sum up, although the retrospective design of the present study hampers the ability to draw firm conclusions about the significance of our findings, we believe that it may be a useful contribution to the specific literature on the relationships between HT and GD, since our data suggest that the investigated chromosomal abnormalities might favor metamorphosis from HT to GD.

We conclude that: (i) in young patients with TS or DS, GD presentation is often (25.7% of cases) preceded by HT; (ii) this evolution trend does not seem to be conditioned by thyroid function and autoimmunity tests at HT diagnosis, L-T4 treatment, or iodine status alterations; (iii) patients with these chromosomopathies and coexisting HT might be at high risk of progressing to GD; and (iv) the pathophysiological bases of these findings need to be clarified.