Predictors of euthyreosis in hyperthyroid patients treated with radioiodine ¹³¹I⁻: a retrospective study

Hyperthyroidism is one of the most prevalent thyroid disorders, affecting 0.5–2% of women (tenfold more than man) in iodine-replete environments [1]. The most common causes of this condition are Graves’ disease (GD), toxic multinodular goiter (TMNG) and thyroid adenoma (TA) [1, 2]. Currently, there are three possible approaches to treatment of hyperthyroidism: antithyroid drugs (ATDs), radioiodine (RAI) therapy, and thyroidectomy. In case of GD, RAI therapy remains the most popular choice of the physicians in the United States, while ATDs are preferred in Europe, Latin America and Japan [3, 4]. RAI therapy is increasingly used as a first-line treatment of hyperthyroidism as data accumulates proving its efficacy and safety [5, 6]. According to the American Society of Endocrinology, radioiodine treatment may be used in case of all three major causes of hyperthyroidism, depending on the disease’s progression [7]. The outcome of RAI therapy, however, is difficult to predict. An optimal dose that would both eliminate the risk of developing hypothyroidism and maximize the chance of curing hyperthyroidism is individual and difficult to determine [8] (Fig. 1).

The success of RAI therapy in hyperthyroidism – meant as rendering the patient hypo- or euthyroid - correlates strongly with the activity of administered radioiodine [7]. There are several studies comparing the efficacy of treatment using a fixed dose versus a calculated dose, showing little differences between the two approaches [9‐14]. Thus, the choice of the method depends solely on the physician [7]. Undoubtedly, the outcome of the RAI therapy is not fully predictable and may result in hypothyroidism, euthyroidism or unchanged hyperthyroidism [7]. In an attempt to determine possible factors that could influence the outcome of the treatment, several studies have been conducted, proving e.g. gender, age, presence of ophthalmopathy and serum free T3 concentration to be relevant [11‐13, 15‐18].

Radioiodine therapy is the only non-operative treatment modality that provides a possibility of rendering a patient euthyroid without the necessity of further pharmacological management. There are, however, not much data on the predictors of achieving euthyreosis in the patients after RAI therapy, presence of which may facilitate the choice of treatment [19‐21]. Thus, in our research we aim to find predictors of specifically euthyreosis in patients who underwent the RAI treatment.

All the important clinical data are presented in Table 1. After 12 months of follow-up, 81 patients were rendered hypothyroid (group 1), requiring further hormonal supplementation, 52 achieved euthyreosis (group 2) and 11 remained in the state of hyperthyroidism (group 3). There were 98 females and 46 males in the studied group. Majority of the patients (eighty-one) were diagnosed with toxic nodular goiter and sixty-three with Graves’ disease. Among the patients, who achieved normal thyroid function after the therapy, only 8 were diagnosed with GD. Age of patients varied significantly from 53.5 ± 16.3 and 50.9 ± 16.4 in hypo- and hyperthyroid groups respectively to 67.3 ± 12.7 among subjects who achieved normal thyroid function. Among the patients who underwent thyroidectomy in the past, none became euthyroid after the treatment.

Treatment with radioiodine has been one of the most important therapeutic modalities in case of hyperthyroidism for many years [7]. Many physicians prefer to use large quantities of the isotope in order to achieve early hypothyroidism and avoid the necessity of administering another dose of ¹³¹I⁻. Prompting stability with hormonal supplementation in case of hypothyroid patients is a common clinical practice, however, makes the patient fully dependent on the medications. There have been studies aiming to depict an optimal dose of ¹³¹I⁻ that would maximize the chances of rendering a patient euthyroid, however, they did not take into consideration other factors predictive of such an outcome [22, 23]. In our study we have presented three such predictors: iodine uptake level, subjects’ age and the thyroid gland volume.

The statistical analysis showed that pre-therapeutic RAI uptake level correlated inversely with the chances of achieving euthyreosis in our patients. In further analysis, it has been shown, however, that it only occurs in case of TMNG patients and not in the GD group. This finding is partially in concordance with the study by M.A. Walter et al., where an inverse correlation was presented in both GD and TMNG patients [24]. There have also been studies proving low RAIU to contribute to a successful outcome of the therapy, meant by hypo- or euthyroidism, however, exclusively in GD [16, 17]. On the other hand, RAIU> 50% also has been shown to increase the incidence of hypothyroidism in case of patients with solitary pretoxic or toxic adenomas treated with radioiodine ¹³¹I⁻ [18]. Moreover, in patients with toxic goiter and high radioiodine uptake, RAI therapy resulted in a failure more frequently than in subjects with lower or moderate RAIU levels [25]. Authors suggested that this phenomenon could be attributed to the stunning effect, although normally such a situation occurs, when larger quantities of radioiodine are administered. It could be also explained by the fact that patients with larger RAIU levels could have a more active disease, which results in lower susceptibility to thyroid ablation with radioiodine. The reason for developing hyperthyroidism in patients with very high iodine uptake levels may be due to progressive destruction of the thyroid gland with subsequent release of the free hormones.

Etiology of the hyperthyroidism also contributes to the outcome of the therapy. We have shown that patients with TMNG have more predictors of achieving euthyroidism than patients with GD. Moreover, it seems that TMNG patients were more prone to achieving normal thyroid function than subjects in the GD group. This finding is in accord with observations made by other researchers [20]. It has also been shown that, conversely, in patients with GD hypothyroidism is a more frequent outcome of RAI therapy than in subjects with TMNG [12, 20]. The explanation of our finding could be that the extranodal tissue in TMNG exhibits less iodine uptake. As a consequence, it does not suffer as much damage as the nodules, which allows the gland to maintain its function after the therapy has ended [10]. In other words, ablated thyroid tissue in GD patients may not able to maintain its hormonal function after the radioiodine treatment.

In our study we also found that the more advanced age in the patients was a significant predictor of achieving euthyreosis. As other studies usually focus on depicting factors contributing to the success of RAI therapy (and not euthyreosis exclusively), we had little material to compare our results with [11, 12, 26‐32]. Nonetheless, some papers have shown that younger patients were more likely to present persistent hyperthyroidism after RAI therapy [9, 18, 26, 33]. The reason behind it may be that younger thyroid tissue is more resistant to radiation than in older patients [18]. Similar observations were made by other researchers, who found early age of onset of hyperthyroidism to be a negative predictor of the treatment success [12, 34]. This, however, was strongly connected to the severity of hyperthyroidism, rather than with the young age itself. Schneider et al. also noted a positive correlation between the older age and the success of RAI treatment having performed univariate analysis, but after multivariate analysis patients’ age was no longer significant [27]. Moreover, there have also been studies proving younger individuals to have an increased risk of presenting hypothyroidism [19, 28, 29].

There are certain factors that, undoubtedly, have an effect on the outcome of ¹³¹I⁻ therapy, e.g. use of ATDs, corticosteroids, goiter size, severity of hyperthyroidism, low-iodine diet or smoking habits. We must not forget, however, that these modulators are influenced by age and an overall condition of the patient. Thus, the patient’s advanced age and the final result of treatment are linked, though in an indirect manner [35]. Our result could be attributed to the fact, that 84.6% of patients who responded positively to the treatment, were diagnosed with TMNG, which prevalence increases in elderly patients and is more frequent than GD [7].

We have also proven that individuals with larger volumes of thyroid were more prone to achieving euthyreosis than patients with smaller glands. In contrast, many studies showed an inverse correlation between thyroid gland size and a successful outcome of treatment (again hypo- or euthyroid) [12, 32, 33, 36‐38]. On the other hand, no significant impact of the above-mentioned factor was noted in other researches or results turned out to be statistically insignificant after performing regression analysis [9, 11, 20, 27, 39, 40]. Differences between various papers may be explained by lack of an objective method of measuring thyroid gland size. Clinical examination or scintigraphy are less precise than ultrasound [41, 42]. Marković et al. suggested that an influence of the gland size on the outcome of therapy was present in case of normo-echogenic glands only [21]. Our data show that 22.6 cm3 was the mean volume for hypothyroid outcome group and is in concordance with results presented by Catarina Machado et al. (24.3 cm3) [43]. Similarly, mean thyroid volume of persistently hyperthyroid patients’ (54 cm3) was comparable with findings by Pfeilschifter et al., who observed failure of RAI therapy in individuals with thyroid’s volume larger than 50 cm3 [19].

Since the focus in this paper is on the predictors of achieving euthyreosis exclusively, the literature review was severely narrowed as the great number of the scientific papers depict factors contributing to overall success of the RAI therapy. It is, undoubtedly, one of the limitations of our discussion. We also need to mention that although a group of 144 patients is big enough to draw statistically significant conclusions, in order to make our findings more credible, a larger cohort should be examined – preferably in a prospective study. Moreover, it needs to be underlined that even after rendering a patient euthyroid, there is a low risk of converting to hypothyroid state in the subsequent years after therapy, especially in patients pretreated with ATDs, eventually requiring hormonal supplementation [44]. Lack of control group is another limitation.

As a follow-up to this research, we consider using the measurements of the effective thyroidal half-life and uptake of ¹³¹I⁻ as shown by Kobe C. et al. [45]. This approach has been shown to provide high therapy success rates in patients with GD [46]. It seems that this individual dosimetric approach not only gives a more precise data on the radiation exposure, but also may be more beneficial than the classical dosimetric methods.

In summary, in our research we depicted predictors of achieving euthyreosis after treatment with a fixed dose of ¹³¹I⁻ in hyperthyroid patients. The more advanced age, larger volume of thyroid gland and lower iodine uptake values contribute to rendering the patient euthyroid. In our opinion, physicians should take these three factors into consideration, while discussing the treatment modality with the patient, especially in case of TMNG diagnosis. It seems that subjects with higher RAIU levels should require special attention, since high failure rates are prevalent among them. Perhaps larger doses of radioiodine or longer pre-treatment with ATDs to prompt stabilization could be beneficial in these cases. In patients with e.g. smaller thyroid volumes, individual dosimetric methods may be useful to maximize the chances of achieving therapeutic success. GD patients with mild intensity of the disease could benefit from a longer use of ATDs before transferring them for radioiodine treatment, as older age seems to contribute to rendering a normal thyroid function in these patients. Further studies on predictors of normal thyroid function in the individual dosimetric approach, would help elucidate, whether the same factors also play a role in achieving euthyroidism, using this method.