J-L Wémeau

Beron Amandine
email: amandine.beron@chru-lille.fr

Iodine 131 in the treatment of large goiters. L'Iode 131 dans le traitement des volumineux goitres

The treatment of large, complicated goiters with iodine 131 constitutes an interesting alternative to surgery. It is minimally invasive, safe, and effective in most cases, and is particularly valuable in elderly, fragile patients with multiple co-morbidities. Also, it does not preclude the possibility of surgery, should it become a necessary alternative, for whatever reason in the future. The precise pre-treatment evaluation includes thyroid scintigraphy, calculation of thyroid volume and tracheal surface measurement. Patients who are most at risk of acute complications (very small cross sectional tracheal area, underlying respiratory pathology, and hyperthyroidism) should be managed during hospitalization for possible respiratory distress, or rhythm disturbances induced by hormone release. The choice of the iodine 131 activity depends on individual routine practice, either standardized or modulated by thyroid mass. Administration may be repeated depending on the effect obtained and the cumulative dose. Efficacy in terms of volume reduction is practically constant at an early stage. Its effectiveness is difficult to predict, often less in the case of large size goiters. It can be improved by increasing iodine fixation, for example, using synthetic antithyroid drugs.

Permanent hypothyroidism is the most frequent and minor complication of the treatment. It involves biological monitoring in order to introduce hormone replacement therapy to avoid thyroid growth stimulation and negate the benefits of radioiodine treatment. thyroid, treatment, iodine 131, goiter.

Résumé

Le traitement par iode 131 des goitres volumineux, compliqués, constitue une alternative tout à fait intéressante à la chirurgie. Peu invasif, sûr, et efficace dans la majorité des cas, il est particulièrement précieux chez les patients âgés, fragiles, avec de multiples comorbidités. Il ne coupe pas du recours possible un jour ou l'autre à la chirurgie, si celle-ci s'avérait souhaitable pour quelque raison que ce soit. L'évaluation préthérapeutique rigoureuse comporte notamment la scintigraphie thyroïdienne, la mesure du volume thyroïdien et de la surface trachéale. Les patients les plus à risque de complications aigues (surface trachéale très diminuée, pathologie respiratoire sous-jacente, hyperthyroïdie) doivent recevoir le traitement par iode 131 cours d'une hospitalisation pour prendre en charge une éventuelle détresse respiratoire, ou des troubles du rythme induits par la libération hormonale. Le choix de l'activité d'iode 131 est fonction des habitudes, soit modulée par la masse, soit standardisée. L'administration peut être répétée selon l'effet obtenu et la dose cumulée. L'efficacité en termes de réduction de volume est pratiquement constante, précoce. Son importance est difficilement prévisible, souvent moindre en cas de goitres très volumineux. Elle peut être améliorée par l'augmentation de la fixation iodée par exemple sous antithyroïdien de synthèse. L'hypothyroïdie définitive est la complication la plus fréquente et la plus vénielle du traitement. Elle implique une surveillance biologique en vue d'introduire une hormonothérapie substitutive pour ne pas favoriser à nouveau la croissance du parenchyme thyroïdien et altérer le bénéfice du traitement par Iode 131. thyroïde, traitement, iode 131, goitre.

Introduction

A goiter is a diffuse hypertrophy of the thyroid gland. Despite international programs for the correction of iodine deficiency, its prevalence remains high, close to 10% in adults, affected by genetic predisposition, female gender, pregnancy, smoking, medication (i.e. lithium) etc. [START_REF] Wemeau | Les maladies de la thyroïde[END_REF]. Initially diffuse and homogenous, clinically latent or responsible for a slight esthetic deformity, goiters are organized in the form of nodules and increase by 0 to 20% per year [START_REF] Hegedüs | Management of simple nodular goiter: current status and future perspectives[END_REF].

It is often from the fifth decade that its volume exceeds 100 cm 3 [START_REF] Manders | Radioiodine therapy of euthyroid multinodular goiters[END_REF], and that multinodular goiter becomes symptomatic and at risk of complications: compression, hyperthyroidism, or cancer.

At this stage a total thyroidectomy is considered as first-line treatment [START_REF] Hegedüs | Management of simple nodular goiter: current status and future perspectives[END_REF][START_REF] Stokkel | EANM procedure guidelines for therapy of benign thyroid disease[END_REF][START_REF] Clerc | Recommandations de la SFMN ; procédure pour la scintigraphie thyroïdienne diagnostique[END_REF]. It is sometimes debated or rejected in elderly, fragile patients with comorbidities that make anesthesia and surgery excessively risky. Levothyroxine suppressive therapy is then practically ineffective, exposing patients to the risk of fracture and atrial fibrillation [START_REF] Wesche | A randomized trial comparing levothyroxine with radioactive iodine in the treatment of sporadic nontoxic goiter[END_REF]. In the case of toxic goiter, long-term treatment with synthetic anti-thyroid drugs could be proposed, but the normalization of TSH increases the volume of the goiter and its compressive risk [START_REF] Azizi | Treatment of Toxic Multinodular Goiter: Comparison of Radioiodine and Long-Term Methimazole Treatment[END_REF].

Treatment with iodine 131 has been an alternative treatment used since the 1950s in Germany, then widely promoted in the Benelux and Nordic countries [START_REF] Huysmans | Large, compressive goiters treated with radioiodine[END_REF][START_REF] Bonnema | Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome[END_REF]. It has also been adopted in Lille for almost 30 years [START_REF] Velayoudom | 131 iodine for the treatment of benign goiters[END_REF]. It allows both thyroid volume reduction and hyperfunctional nodules eradication.

The aim of our study was to specify the indications for radioisotopic treatment of bulky goiters, the practical modalities (in particular the measures likely to increase thyroid iodine 131 fixation), the constraints, the efficacy and possible complications.

Which patients could benefit from radioisotopic treatment?

Typically, iodine 131 treatment concerns:

-Patients with bulky goiters requiring therapeutic management because they are progressive, plunging, complicated by compressive signs and thyroid hyperfunction, -Subjects for whom the risks of surgery and anesthesia appear excessive (i.e. elderly subjects, cardiac and respiratory insufficiency, anticoagulant treatment, etc.), -Patients who refuse surgery, -Recurrences of nodular goiter after partial thyroidectomy, due to an increased risk of operative complications in cases of new surgery.

In addition to the standard contraindications of iodine 131, the suitability of radioisotopic treatment should be questioned in the following situations:

-presence of a thyroid nodule on ultrasound and cytologically suspected of being an epithelioma, -coincidence of primary hyperparathyroidism when its operative indication appears evident (symptomatic forms, serum calcium > 110 mg/L or 2.75 mmol/L) -Need for a rapid halting of tracheal compression.

Table 1, based on recent articles [START_REF] Knobel | Which is the ideal treatment for benign diffuse and multinodular non-toxic goiters ?[END_REF][START_REF] Bonnema | The role of radioiodine therapy in benign nodular goitre[END_REF], summarizes the therapeutic direction based on patients' data.

3 How should the practical modalities of treatment be considered?

Before scheduling radioisotopic treatment, the patient should undergo routine evaluation: clinical, biological (thyroid, phosphocalcic, and calcitonin measurement), morphological and scintigraphic tests.

Clinical evaluation

The clinical examination assesses the importance of the compression of nearby organs [START_REF] Wemeau | Les maladies de la thyroïde[END_REF] and will search in particular for:

-Phonation disorders (fragile, muffled or bitonal voice, by recurrent paralysis), -Dysphagia (trouble swallowing liquids or solids), -Respiratory discomfort (inspiratory dyspnea, wheezing, due to tracheal compression [START_REF] Bonnema | Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome[END_REF]), -Venous compression (collateral circulation, jugular turgescence, facial erythrosis triggered by a Pemberton maneuver: raised arms pressed firmly against the ears for one minute).

The clinical examination also evaluates the general and especially cardiovascular repercussions of a possible associated hyperthyroidism.

At the end of this evaluation and before administration of the isotope:

-In the case of multiple comorbidities, attention should be paid to the risk of iodine overload, either transient due to the iodinated contrast agent injection [START_REF] Clerc | Recommandations de la SFMN ; procédure pour la scintigraphie thyroïdienne diagnostique[END_REF], or prolonged with amiodarone, -Dysphagia should be taken into account. An ingestion test with a placebo capsule should then be proposed. If necessary, iodine 131 can be administered in liquid form (injectable iodine 131 will not be available in France until September 2020 at the earliest), -The usual radiation protection guidelines and a low iodine diet are specified so as not to reduce thyroid uptake of iodine 131.

Morphological and scintigraphic evaluation

Prior to the validation of iodine 131 treatment, several points should be considered:

-Screening for nodules suspected of epithelioma, -Evaluate thyroid volume, and if necessary the impact on the surrounding structures, -Measure the tracheal surface in its smallest dimensions, i.e. where the reduction by the goiter is most significant, -Assess the quality of iodine fixation by the thyroid parenchyma (intensity and homogeneity).

This evaluation must at least include a cervical ultrasound, possibly supplemented by cytological study of suspected thyroid nodules (growing nodules, EuTIRADS 4 or 5, and nodules > 2 cm EuTIRADS 3), thyroid scintigraphy, cervico-thoracic tomodensitometry (without injection of contrast agent), which can be performed either by hybrid imaging during thyroid scintigraphy (SPECT-CT) or on dedicated equipment.

In the case of intrathoracic extension, MRI is recommended to determine the thyroid volume and its relationship to the surrounding structures [START_REF] Hegedüs | Management of simple nodular goiter: current status and future perspectives[END_REF][START_REF] Bonnema | The role of radioiodine therapy in benign nodular goitre[END_REF]. How can the therapeutic activity of iodine 131 be envisaged?

There is no universal approach as to how the scintigraphic protocol should be performed, or as to the method of determining iodine 131 activity to be administered [START_REF] Bonnema | Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome[END_REF].

As regards scintigraphy, iodine 123 is often preferred to 99m Tc for the following reasons [START_REF] Stokkel | EANM procedure guidelines for therapy of benign thyroid disease[END_REF][START_REF] Clerc | Recommandations de la SFMN ; procédure pour la scintigraphie thyroïdienne diagnostique[END_REF]:

-It permits molecular and functional imaging, reflecting both the process of cell uptake and organification of iodine, and the creation of a binding curve, -99m Tc has only cell uptake that can lead to nodules incorrectly considered as autonomous.

The French Society of Nuclear Medicine [START_REF] Clerc | Recommandations de la SFMN ; procédure pour la scintigraphie thyroïdienne diagnostique[END_REF] has issued several recommendations concerning scintigraphic explorations in patients with goiter:

-increase the diagnostic activity administered (20 MBq of 123 I or 110 MBq of 99m Tc),

-perform an additional acquisition on the neck and thorax with a parallel collimator to specify the endothoracic extension of the goiter. This avoids underestimating the thyroid volume in cases of ultrasound evaluation alone, -perform multimodal imaging : computed tomography scan associated with tomoscintigraphy (SPECT-CT) to assess the anatomical ratios of plunging goiters, evaluate tracheal caliber and specify the volume.

In the literature, and in European recommendations [START_REF] Stokkel | EANM procedure guidelines for therapy of benign thyroid disease[END_REF], the feasibility of the treatment is validated by measuring the uptake rate 24 hours (TF24) after administration of a tracer dose of iodine 131 (from 0.6 to 3.7 MBq, no longer marketed in France). A TF24 of less than 20 % leads to reject treatment with iodine 131 alone, or to consider methods to increase iodine fixation.

The choice of the therapeutic activity of iodine 131 can be determined in several ways:

-In case of dosimetry calculation, it is necessary to perform at least one further measurement of the uptake rate (at best at 96 hours [START_REF] Bonnema | The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function[END_REF]), which is more constraining for the patient. The target absorbed dose (AD) to the thyroid is estimated from 100 to150 Gy for non Grave disease goiters, whether toxic or not.

-The most commonly used alternative is the calculation of activity taking into account thyroid mass to deliver between 3.7 and 4.44 MBq per gram of thyroid tissue (i.e.

between 1 and 1.2 mCi/g), corrected for the uptake rate (TF24 in the majority of publications).

-Finally, in an even simpler way, it is possible to alternatively choose a fixed dose of iodine 131 (555 to 925 MBq), in a single or repeated dose, depending on the volume of the goiter and the observed efficacy.

5

What are the expected benefits of iodine 131 treatment?

Treatment with iodine 131 reduces thyroid volume and compressive symptoms for the vast majority of patients, whether the goiter is basically cervical or intra-thoracic [START_REF] Bonnema | The role of radioiodine therapy in benign nodular goitre[END_REF]. The volume reduction is on average 30-50% in the year following treatment, and may continue beyond [START_REF] Baczyk | Therapy of large multinodular goitre using repeated doses of radioiodine[END_REF][START_REF] Bachmann | Radioiodine therapy for thyroid volume reduction of large goiters[END_REF] (figure 1).

Individual response is not necessarily predictable. However, in most surveys, it appears that the larger the goiter, the more limited the volume reduction [START_REF] Bonnema | The role of radioiodine therapy in benign nodular goitre[END_REF][START_REF] Moli | Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goitre[END_REF]. The response is also influenced by the presence of a hyperfunctional dominant nodule due to the lower irradiation of the rest of the thyroid [START_REF] Baczyk | Therapy of large multinodular goitre using repeated doses of radioiodine[END_REF][START_REF] Moli | Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goitre[END_REF], or the low dose of iodine 131 delivered [START_REF] Bonnema | Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome[END_REF][START_REF] Moli | Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goitre[END_REF].

Although the data are heterogeneous in terms of dose, thyroid volumes, proportion of hyperthyroidism, and iodine binding rate, the overall results appear satisfactory and show similar volume reductions (Table 2).

In the case of a normally functioning goiter, the administration of 4 fixed doses of iodine 131 every 3 months [START_REF] Baczyk | Therapy of large multinodular goitre using repeated doses of radioiodine[END_REF], can produce results equivalent at one year to the use of a single capsule of iodine 131, adjusting the activity to the mass and the uptake rate. With repeated fixed doses the volume reduction predominates 3 months after the first treatment; thereafter the therapeutic effect of the other doses is more limited. These data suggest that for normally functional goiters, it would be preferable to carry-out an initial treatment with a standard activity (800 MBq for example). Secondarily if the iodine binding and the 3 months morphological response are sufficient, radioiodine treatment can be repeated according to the evolution of the symptomatology.

The benefit usually obtained is the improvement or disappearance of compressive symptoms.

In Baczyk et al.'s study [START_REF] Baczyk | Therapy of large multinodular goitre using repeated doses of radioiodine[END_REF], in which all patients had a goiter of more than 100 ml, dyspnea had decreased by 50 to 75% after one year and at two years 90% of initially symptomatic patients had noted a disappearance of dysphagia and/or local discomfort. Globally, studies indicate that approximately 75% of patients experience an improvement in compressive symptomatology [START_REF] Huysmans | Large, compressive goiters treated with radioiodine[END_REF][START_REF] Howarth | Outpatient management of patients with large multinodular goiters treated with fractionated radioiodine[END_REF].

These data are in agreement with the increase in tracheal surface area and inspiratory capacity using spirometry measurement. In Bonnema et al. 1999 study [START_REF] Bonnema | The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function[END_REF], one year after treatment, the tracheal surface area had increased by 17.9% on average (37.5-126 mm 2 before versus 53-164.5 mm 2 at one year) and inspiratory capacity by 21.7%. In Huysmans et al. survey [START_REF] Huysmans | Large, compressive goiters treated with radioiodine[END_REF], the smallest tracheal surface area increased by 36% (+38%) on average one year after irradiation.

Quality of life questionnaires also show a significant improvement in the overall health status of patients one year after treatment, with a lower degree of satisfaction in the older subjects.

At the same time, dyspnea, respiratory signs and cervical discomfort improved, without a correlation with the extent of goiter size reduction and initial goiter size [START_REF] Kaniuka-Jakubowska | Nontoxic Goiter (NTG) and Radioiodine: What Do Patients Think About It? Quality of Life in Patients with NTG Before and After 131-I Therapy[END_REF].

6

Can iodine binding be increased?

Iodine uptake by the thyroid parenchyma depends on the iodine load, the state of stimulation of the thyroid parenchyma, and the degree of autonomy of nodular formations.

When iodine uptake is insufficient, treatment activity can be potentiated either by stimulating uptake (rhTSH, synthetic antithyroid drugs) or by increasing iodine retention within the thyroid follicles (Lithium salt).

Lithium salts

Lithium salts, particularly in its carbonate form, increases iodine retention by reducing thyroglobulin proteolysis and the release of iodothyronines into the blood flow [START_REF] Vannucchi | Radioiodine treatment of non-toxic multinodular goitre: effects of combination with lithium[END_REF].

They are particularly used in cases of severe thyrotoxicosis to achieve a rapid (usually transient) reduction in hyperhormonemia prior to radical treatment (total thyroidectomy or iodine 131), or in the treatment of metastatic differentiated thyroid cancers to increase the effectiveness of radiotherapy with iodine 131.

Only one study evaluated the interest of associating lithium salts with iodine 131 treatments for euthyroid nodular goiters [START_REF] Vannucchi | Radioiodine treatment of non-toxic multinodular goitre: effects of combination with lithium[END_REF]. In 62 patients with thyroid volume between 20 and 128.1 mL, the reduction in thyroid volume was equivalent in a group treated with iodine 131 alone, and in a similar group receiving iodine 131 + lithium salt for 6 days. The addition of lithium was found to prevent early radiation-induced thyrotoxicosis, which is potentially dangerous in cases of cardiovascular fragility.

This advantage must be weighed against the specific risks of lithium overdosage, increased in low-salt diet and drug interactions (diuretics, enzyme conversion inhibitors, non-steroid antiinflammatory drugs, etc.). Lithium is therefore an adjunctive therapy rarely used for the treatment of large goiters by iodine 131 in elderly, polymedicated subjects.

rh-TSH

Recombinant human recombinant TSH (rh-TSH) is a thyrostimulin which, at a dose of 0.9 mg, increases iodine 131 binding by a factor of 2 to 4 and makes its distribution more homogeneous within the thyroid parenchyma (Figure 2) [START_REF] Knobel | Which is the ideal treatment for benign diffuse and multinodular non-toxic goiters ?[END_REF][START_REF] Bonnema | The role of radioiodine therapy in benign nodular goitre[END_REF]. It therefore appears likely to accentuate the decrease in size of benign goiters submitted to radiodine.

In fact, the combined treatment with rh-TSH and iodine 131 generally produces an equivalent or superior efficacy to the treatment with iodine 131 alone, depending on the dose of recombinant TSH, which has been demonstrated in several studies [START_REF] Knobel | Which is the ideal treatment for benign diffuse and multinodular non-toxic goiters ?[END_REF][START_REF] Bonnema | The role of radioiodine therapy in benign nodular goitre[END_REF][START_REF] Fast | Prestimulation with recombinant human thyrotropin (rhTSH) improves the long-term outcome of radioiodine therapy for multinodular nontoxic goiter[END_REF][START_REF] Silva | Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goiters[END_REF]. In a comparative survey in 2012 [START_REF] Fast | Prestimulation with recombinant human thyrotropin (rhTSH) improves the long-term outcome of radioiodine therapy for multinodular nontoxic goiter[END_REF], 42 patients were treated with 0. In contrast, hypothyroidism was 3 to 4 times more frequent in patients pretreated with recombinant TSH. In the study of Fast et al. [START_REF] Fast | Prestimulation with recombinant human thyrotropin (rhTSH) improves the long-term outcome of radioiodine therapy for multinodular nontoxic goiter[END_REF] after 0.3 mg of rh-TSH + 131 I, 43% of hypothyroidism was observed at one year, and 52% after 5 years after treatment. For patients treated with 131 I alone (at an equivalent dose) there was 9% and 16% of hypothyroidism respectively. In the protocol with mrh-TSH [START_REF] Fast | Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study[END_REF], 13% of patients treated with 131 I alone developed hypothyroidism, compared to 33% and 45% of patients who received 0.01 mg and 0.03 mg mrh-TSH before iodine 131, respectively.

Thus rh-TSH was shown to achieve a better reduction of bulky goiters, at the cost of an increased risk of hypothyroidism. This treatment is not recommended in patients with hyperthyroidism, especially if they have cardiac comorbidities and in cases of severe tracheal compression.

In other situations, the best compromise recommended by Bonnema et al. [START_REF] Bonnema | The role of radioiodine therapy in benign nodular goitre[END_REF] is a single injection of 0.1-0.3 mg rh-TSH 24h before iodine 131. In France recombinant TSH is not approved for this indication and is marketed only in its 0.9 mg form.

Synthetic antithyroid drugs

Synthetic antithyroid drugs reduce the synthesis and serum concentration of thyroid hormones, thereby increasing endogenous TSH levels. Studer et al. have shown that prolonged treatment with antithyroid drugs can restore initially impaired iodine binding [START_REF] Studer | Recovery of initially suppressed thyroidal radioiodine uptake during long-term antithyroid treatment of euthyroid volunteers and hyperthyroid patients[END_REF].

For these reasons, this treatment could be used to reinforce the action of iodine 131, whether

or not the subjects are hyperthyroid, but there is currently very little data reported in the literature to rely on.

In 2020, [START_REF] Szumowski | Enhancing the efficacy of 131I therapy in non-toxic multinodular goitre with appropriate use of methimazole : an analysis of randomised controlled study[END_REF] the effect on thyroid volume and the risk of hypothyroidism were compared in 16 patients treated for 6 weeks with 10 mg methimazole (MMI) followed by iodine 131 four days after stopping MMI, and 15 patients treated with placebo followed by iodine 131. The activity of iodine 131 was set at 800 MBq; one or more additional treatments of 800 MBq were delivered every 6 months as long as the thyroid volume remained above 40 mL (mean initial thyroid volume = 61.9 + 19.8 mL in the MMI group, 68.3 + 12.3 mL in the placebo group). For patients treated with MMI + Iodine 131 binding rates at 24 and 48 hours were doubled. The difference of average volume reduction between the two groups was 34% at 6 months and 22% at 2 years, in favor of the MMI group. In the MMI group, 4 patients received more than one dose of iodine 131, compared to 10 patients in the 131 I group alone. The number of patients who developed hypothyroidism was equivalent in both groups, approximately 30%.

Premedication with synthetic antithyroid drugs is an attractive alternative, since these drugs are available in France, with a modest and manageable risk of undesirable effects (particularly hematological). However, its interest and tolerance still remain to be assessed in patients with larger goiters than those in the previously reported study.

7

Are there any side effects?

Acute or subacute adverse reactions are quite rare.

In less than 25% of patients, particularly those with a very bulky goiter, an early and transient increase in thyroid volume up to +25% of the initial volume can be observed, usually without any clinical consequences (Figure 3) [START_REF] Bonnema | The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function[END_REF][START_REF] Nygaard | Acute changes in thyroid volume and function following 131 I therapy of multinodular goitre[END_REF].

In one study [START_REF] Bonnema | The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function[END_REF], five out of 23 patients experienced early worsening of dyspnea requiring glucocorticoid treatment. These were patients with the lowest tracheal surfaces. A Danish team recommended combined corticosteroid therapy with iodine 131 in patients with a tracheal surface area lower than 50-60 mm 2 [START_REF] Bonnema | The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function[END_REF]. In these patients with marked tracheal narrowing or respiratory insufficiency, it is preferable to deliver the treatment during an inpatient stay of at least 48 hours to ensure monitoring and early management of possible worsening.

Transient hyperthyroidism may occur within the first 15 days after treatment. It often appears to be clinically moderate, with an increase in the order of 20% for FT4 and 13% for FT3 [START_REF] Nygaard | Acute changes in thyroid volume and function following 131 I therapy of multinodular goitre[END_REF],

but careful clinical monitoring should be performed if there is a history of heart disease.

Later in life, there is a risk of autoimmune hyperthyroidism associated with the development of autoantibodies stimulating TSH receptors. These radio-induced Graves diseases generally occur within 3 to 6 months following the IRAtherapy. Their risk is estimated to be just below 5% in patients treated for toxic goiter [START_REF] Roque | 131I-Induced Grave's disease in patients treated for toxic multinodular goitre : systematic review and descriptive analysis[END_REF]. These situations occur more frequently in patients with initially increased titers of antithyroperoxidase antibodies or even TSH receptor antibodies. The treatment is most often medical using temporary and adapted prescription of a synthetic antithyroid drug, to avoid any TSH release. Though a new therapeutic dose of iodine 131 should be avoided in the acute phase because of the increased risk of orbitopathy, it is possible to resort to it subsequently.

Hypothyroidism is finally the most frequent undesired effect. It occurs in 20-50% of patients (Table II) and most often appears within 2 years after treatment. Its incidence increases over the years, but is less frequent than in Graves disease [START_REF] Metso | Long-term follow-up study of radioiodine treatment of hyperthyroidism[END_REF]. Small volume goiters, increased antithyroid antibody titers and a family goiter context are the main predisposing factors for radiation-induced hypothyroidism [START_REF] Moli | Determinants of longterm outcome of radioiodine therapy of sporadic non-toxic goitre[END_REF]. This risk implies prolonged thyroid biological monitoring and the introduction of hormone replacement therapy if necessary, especially to avoid the re-increase in thyroid volume by the trophic effect of TSH.

Finally, for these multinodular goiters, reduced but not eradicated by radio-isotopic treatment, there is still a risk of revealing a malignant tumor (even malignant degeneration or anaplasic dedifferentiation of an unknown papillary or vesicular epithelioma). This is a theoretical risk that has long led to prefer surgery. It is minimized by the extensive preoperative morphological evaluation, as well as by clinical and ultrasound monitoring, which should be maintained for a long time. Blood calcium levels should also be monitored, because of a theoretical risk of radiation-induced late primary hyperparathyroidism [32]. These are the reasons that lead the medical community to reject iodine 131 in the treatment of simple goiter in young adults. Whereas Danish teams who use radioiodine more frequently have shown that the best morphological results are obtained at the stage of homogeneous goiter [START_REF] Hegedüs | Management of simple nodular goiter: current status and future perspectives[END_REF].

Conclusion

Reduction in the size of large, benign, symptomatic, possibly hyperfunctioning goiters can be effectively achieved with iodine 131, and should be considered for the treatment of elderly, frail, surgically at risk patients. Prior clinical and morpho-functional evaluations have to be extensive to validate the indication and to select patients to monitor more closely. Posttreatment follow-up is important to ensure functional benefit and to detect hypothyroidism.

The efficacy of iodine 131 could be enhanced by prior treatment with synthetic antithyroid drugs if preliminary data are confirmed and demonstrate their usefulness in the cases of large goiters.

32. Colaço SM, Si M, Reiff E, Clarck OH. Hyperparathyroidism after radioactive iodine therapy. Am J Surg 2007;194:323-7.

Figure 3 2 TF

 32 Figure 3

Acknowledgement

Sincere thanks to Prof. Xavier Marchandise and Dr. Georges Lion, for their sound advice and pertinent remarks.

Conflict of Interest:

Béron A: Conferences: Invitations in the capacity of an auditor (travel and accommodation expenses paid by a company on his behalf) for Genzyme.

Wémeau J-L:

No conflict of interest.


Judith Cottin
email: judith.cottin@chu-lyon.fr

Sabrina Pierre

Véronique Pizzoglio

Corinne Simon

Geneviève Durrieu

Nathalie Bleyzac

Aurore Gouraud

Jérôme Dumortier

Cottin Judith

Methylprednisolone-related liver injury: A descriptive study using the French pharmacovigilance database

Keywords: liver injury, methylprednisolone, pharmacovigilance, safety

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Glucocorticoids are compounds that have long been used for a variety of diseases, both as chronic therapy and in acute cases. Methylprednisolone (MP) pulses are recommended for critical events that require urgent treatment for an exacerbation of a known disease or when vital organs are compromised [START_REF] Bone | A controlled clinical trial of highdose methylprednisolone in the treatment of severe sepsis and septic shock[END_REF] .

Although generally well tolerated, several side effects are attributed to MP, many of which are dose and duration dependent [START_REF] Mcdonough | The epidemiology of glucocorticoid-associated adverse events[END_REF] . Before June 2018, the summary of product characteristics for MP mentioned transient increase in serum liver enzyme levels and hepatomegaly, but not clinically relevant hepatotoxicity [START_REF]Résumé des caractéristiques du produit -METHYLPREDNISOLONE MYLAN 1 g, poudre pour solution injectable (IV) -Base de données publique des médicaments[END_REF] . However, over the past 20 years, many case reports of hepatotoxicity induced by MP and a few case series have been published ; all concerned the use of high-dose intravenous (IV) MP, mainly in patients with multiple sclerosis or Basedow disease. MP-induced seems rare, but the reintroduction of this drug in the majority of reported cases illustrates the under-recognition of this effect.

In 2016, a case of high-dose MP-induced acute hepatitis in a 27-year-old with multiple sclerosis notified to the pharmacovigilance centre of Lyon (France) [START_REF] Dumortier | Methylprednisolone liver toxicity: A new case and a French regional pharmacovigilance survey[END_REF] led us to retrospectively analyse all cases of liver damage associated with the use of IV or oral MP registered in the French pharmacovigilance database (FPVD); a particular focus was made on the route of MP administration.

Methods

This study was performed in the FPVD, in which spontaneously reported cases have been registered since 1985 by 31 French pharmacovigilance centres. The present dataset analysis was approved by 31 regional pharmacovigilance centres and the French medicines agency (Agence nationale de sécurité du médicament et des produits de santé, ANSM), which manages the database and helped us with data extraction.

For each reported ADR, information on patient (e.g. age, gender), description of the ADR (e.g. date of occurrence, progression) and drug exposure (e.g. dates of introduction and withdrawal, dose) are recorded in the FPVD, along with a summary of the clinical report. The regional pharmacovigilance centre analyses each ADR (coded according to the Medical Dictionary for Regulatory Activities, MedDRA -version 21 [START_REF] Brown | The medical dictionary for regulatory activities (MedDRA)[END_REF] ) and evaluates the relationship between drugs and ADR. For each report, causality is assessed according to the French national pharmacovigilance system's standard procedure [START_REF] Bégaud | Imputation of the unexpected or toxic effects of drugs. Actualization of the method used in France[END_REF] . If a drug is considered probably responsible for the ADR, it is defined as "suspect"; if not, it is defined as "concomitant". If an ADR is considered probably caused by drug-drug interaction, drugs are coded as "interacting" drugs. An ADR is categorized as "serious" when it leads to hospitalization or prolongation of hospitalization, permanent disability/incapacity, is lifethreatening, or leads to the death of the patient. Concerning outcome, a favourable outcome of ADR is defined as full or on-going recovery at the time of notification

Selection of cases

All cases with MP coded as suspected, concomitant, or interacting drug associated with liver injury as ADR reported since 1985 up to 22 May 2016 were extracted from the FPVD. Cases were identified using the broad-ranging "Drug related hepatic disorders" standardized another MedDRA term.

Selected cases were then checked individually by a pharmacologist, irrespective of the level of MP causality and filtered by applying the following exclusion criteria: MP associated with any cytotoxic agent in cancer protocols, cases other than liver injury, cases with a possible other cause, chronology of events incompatible with MP causality (MP intake occurring after liver injury), cases insufficiently documented.

Liver injury criteria

Diagnosis criteria described by Aithal et al., considering transaminase above 5N as clinically significant, were used [START_REF] Aithal | Case Definition and Phenotype Standardization in Drug-Induced Liver Injury[END_REF] . We also used their classification of liver injuries into 4 grades of severity (Table 1) and only retained grade ≥1 cases. When laboratory normal values of liver enzymes were not documented, the following were used: alanine aminotransferase (ALT) [ The type of liver injury was defined according the ratio R=ALT/ALP: R ≥ 5 for hepatocellular pattern, R ≤ 2 for cholestasis pattern, 2 < R < 5 for mixed liver injury [START_REF] Bénichou | Criteria of drug-induced liver disorders. Report of an international consensus meeting[END_REF] . When R could not be calculated, information was drawn from MedDRA codes or the narrative.

Results

The first search using the "drug induced liver disorders" SMQ found 414 cases; among these 97 were included in the final analysis (Figure 1).

Demographic data

Among the 97 patients, 58.8% were female (sex ratio H/F: 0.7) and the mean age was 45.7 years (SD=18.3); patients were most frequently aged 40-49 and 50-59 years. The most frequent route of MP administration was IV (79.4%) followed by the oral route (17.5%); the intramuscular route concerned 3 cases (3.1%). The most frequent MP indication was multiple sclerosis (26.8%), followed by other auto-immune diseases (20.6%, including thyroiditis, polyarthritis, alopecia areata, Crohn's disease…; Table 2).

Characteristics of liver injuries

The most frequent type of liver injury was hepatocellular (73.2%), and most cases were of grade 1 (45.4%) or 2 (30.9%) irrespective of injury type; higher grades (≥3) were found in 6 cases (Table 3) :

-fulminant hepatitis (prothrombin rate 27 %) which recovered spontaneously but slowly after stopping suspected drugs (amoxicillin/clavulanic acid and IV MP) -cholestasis and decreased prothrombin rate in a patient treated by oral MP for 3 months.

Liver recovered after stopping all the drugs recently introduced excepted MP.

-severe liver cytolysis (prothrombin rate 32%, factor V 37%, transaminases x30 N) after the third course of MP for alopecia aerata -severe liver deficiency with encephalopathy and hypovolemic shock, leading to death, occurring 3 weeks after one dose of cyclophosphamide and a course of IV MP for multiple sclerosis -severe liver deficiency thirteen days after the patient received piperacillin/tazobactam, tobramycin, ciprofloxacin and IV MP.

-hepatocellular failure 2 months after the 4th course of IV MP for alopecia aerata. The evolution was not known.

Outcomes

Favourable outcome (n=82) was observed for 92% of cases with known outcome (n=89).

Deaths were reported in 3 cases, 2 of which had multiple potent causes and could not be reliably attributed to MP. The first one was a patient with metastatic prostate cancer, hospitalised for bilateral bronchopneumopathy, presenting with hepatocellular liver injury 3 days after administration of IV MP (120 mg/d), leading to death 5 days later; other drugs, including leuprorelin, paracetamol, morphine, ofloxacin, ceftriaxone, and midazolam, could be suspected. The second case was a patient with progressive glioma who presented with hepatitis 21 days after initiation of oral MP (100 mg/day); other drugs could also have been responsible for liver injury, including temozolomide, esomeprazole, and levetiracetam. The third case was woman presenting with acute hepatocellular liver injury, occurring 3 weeks after one dose of cyclophosphamide and a course of IV MP for multiple sclerosis; this rapidly progressed to severe liver deficiency with encephalopathy and hypovolemic shock, leading to death. According to the time to onset after cyclophosphamide introduction only MP was retained as the suspect drug. In addition, 4 patients did not recover at the time of last followup (one month), which was too short to draw any conclusion.

Intravenous MP

Among the 77 (79.4%) cases in which MP was used intravenously it was the only suspected drug in 17 cases (22%), making causality more probable. Liver injuries occurred a median 9.5 days (range: 1-267 days) after starting MP treatment. Moreover, 46.8% of liver injuries (n=36) were observed >24 hours after the end of MP course. The median number of MP courses before the first liver event was 1 (range: 0-35), the median cumulative dose (since the first dose of MP) was 2 g (range: 0.06-42.7), and 23 patients developped liver toxicity after the first exposure of IV MP. When available, the daily dose at the moment of liver injury was <100 mg for 16 patient, included between 100 mg and 1 g for 18 patients, <1 g for 23 patients and > 2g for 1 patient (median daily dose 500 mg (range 10-3000 mg)).

The distribution of liver injury types was similar to that observed in the total population analysis: 79.2% hepatocellular and 11.7 % of both cholestasis and hepatocellular. Most cases were of grade 1 (45.5%, n=35) or 2 (28.6%, n=22) irrespective of injury type; higher grades (≥3) were found in 5 cases (Table 3). Clinical signs were observed in 18 cases (23.3%) and were mainly asthenia (27.8%) and digestive disorders (38.9%). Among the 38 cases with data available the duration of liver injury was a median of 38 days (range: 4-140 days); two of these patients died, but only one death could be related to MP (see above).

Liver biopsy was performed in 13 patients (16.9%). It was not contributory in 2 cases and found mainly fibrosis (n=1), necrosis (n=1), lymphocytic infiltrate (n=2), undefined infiltrate (n=2), inflammatory disorders (n=1). In 2 cases, histology was compatible with autoimmune hepatitis despite a negative auto-immune blood tests, but also with a toxic event for one of them owing to centrolobular damage and eosinophils. Non drug-related causes were investigated in 51 cases (66.2%), without success: viral serology was measured in 43 cases (all were negative), abdominal ultrasound was performed in 36 cases (all without abnormalities), and auto-immune blood tests in 17 cases (all negative). Data regarding MP rechallenge were available for 19 patients (24.7%); MP was not reintroduced for 6 patients, and was re-introduced for 13 patients. Among the latter, 10 had a new episode of liver injury (76.9%). One recurrence was reported for 5 patients, and ≥ 2 recurrences for the remaining 5 patients (4 in one patient); there were a total 18 recurrences in 10 patients. All recurrences were hepatocellular liver injury (which was the initial injury for all patients concerned) and the grade was the same in all but one patient who had severe liver deficiency (prothrombin rate 36%) after the second MP course. Autoimmune blood tests were positive, and histology was compatible with autoimmune hepatitis. Liver recovered without specific treatment in all patients in whom a recurrence was reported (n=10). In one case of recurrence, a lower single dose of MP was re-introduced, and for a second case MP was reintroduced orally.

Oral MP Among the 17 (17.5%) cases in which MP was used orally, 52.9% (n=9) of liver injuries were hepatocellular and 29.4% (n=5) were mixed. Most cases were of grade 1 (n=7, 41.2%) or 2 (n=8, 47%). Only one case could be classified as severe, with a decreased prothrombin rate (value unknown) (Table 3). Clinical signs were mentioned in 7 cases (31.2%) and were digestive disorders in 57.1% (n=4).

Liver injuries occurred a median 13 days (range: 2-3360) after starting MP treatment, or 2 to 15 days from MP discontinuation in 6 cases. The median cumulative dose before liver injury was 0.864 g (range: 0.004-3). When available, the daily dose at the moment of liver injury was <10mg for 1 patient, included between 20 and 50 mg for 5 patients and > 50mg for 2 patients (median daily dose 40 mg (range 4-240 mg) . Among the 16 for whom MP was continued and who had outcome data, 6 (37.5%) recovered without sequelae. No positive reintroduction of MP was reported.

In the majority of cases (94.1%), MP was associated to at least one other drug classified as chronologically suspect: 8 cases with antibiotics (47.1%), 3 cases with temozolomide (17.6%). Viral serology, abdominal ultrasound, autoimmune blood tests were negative (47.1%).

MP was the only suspected drug and the only potent cause of liver injury in one case: a 26year-old woman receiving MP (daily dose not available) for Gougerot-Sjogren disease and who presented with hepatocellular liver injury 3 days after treatment initiation. One month previously, she had corticosteroids (unknown drug name) which were discontinued after 6 days owing to abnormal serum liver enzymes (without any further detail). Histology at the time of this event was found to be compatible with toxic hepatitis. The patient later had a similar event without any drug exposure. Prednisolone was re-introduced later and was well tolerated.

Discussion

The present study found that liver injury associated with MP was more frequently reported with MP administered intravenously. A majority were female and this is probably due to the indication of MP (multiple sclerosis in over a quarter of cases). For nearly three-quarters of patients liver injury was hepatocellular, the severity of which was mainly evaluated as mild or moderate. Most patients spontaneously and fully recovered, and, among the 3 deaths reported, only one could be reliably related to MP. Mortality herein was thus 1%, which is concordant with a previously published observational study [START_REF] Sisti | Age and Dose Are Major Risk Factors for Liver Damage Associated with Intravenous Glucocorticoid Pulse Therapy for Graves' Orbitopathy[END_REF] . The responsibility of IV MP was supported by 10 cases of positive re-introduction or the absence of other suspected drugs in nearly a quarter of cases. With regards to MP delivered via the oral route, it is difficult to draw any conclusion as many other suspect drugs were associated with MP and there was no case of re-introduction. It is of note that the summary of product characteristics have been recently updated to consider this adverse reaction [START_REF]Résumé des caractéristiques du produit -METHYLPREDNISOLONE MYLAN 1 g, poudre pour solution injectable (IV) -Base de données publique des médicaments[END_REF] .

The results are consistent with the 38 published cases of MP-related liver injuries (4-7,10- 23,25,26,32,34-36) (Table 4). These were reported between 2000 and 2018, and the main indications were auto-immune (multiple sclerosis, n=25, 64.1%; Basedow ophthalmopathy, n=10, 28.2%), patients were aged from 11 to 71 years, and the majority were female (n=31, 79.5%). This can be explained by the high incidence of MS and thyroid disorders among women [START_REF] Alonso | Temporal trends in the incidence of multiple sclerosis[END_REF] . Most received high-dose IV MP pulse therapy; only in two cases MP was administrated orally. Clinical presentation varied from isolated increase in transaminases to fulminant hepatitis, with fatal outcome in 4 cases [START_REF] Weissel | Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease[END_REF][START_REF] Marinó | Acute and Severe Liver Damage Associated with Intravenous Glucocorticoid Pulse Therapy in Patients with Graves' Ophthalmopathy[END_REF] . The time to liver injury onset varied greatly, occurring during MP treatment up to a few days to several months after the end of pulse therapy. There were 13 cases of re-introduction (all IV), 12 of which were positive, strengthening the causal link, in particular for IV MP. These positive rechallenges occurred between a few weeks [START_REF] Davidov | Methylprednisolone-induced liver injury: Case report and literature review[END_REF][START_REF] Melamud | Methylprednisolone-induced liver injury: a diagnostic challenge[END_REF] and several years (1 to 4 years) [START_REF] Carrier | Acute liver toxicity due to methylprednisolone: Consider this diagnosis in the context of autoimmunity[END_REF][START_REF] D'agnolo | High-dose methylprednisolone-induced hepatitis in a patient with multiple sclerosis: a case report and brief review of literature[END_REF][START_REF] Furutama | Recurrent High-Dose Intravenous Methylprednisolone Succinate Pulse Therapy-Induced Hepatopathy in a Patient with Multiple Sclerosis[END_REF][START_REF] Grilli | Incomplete septal cirrhosis after highdose methylprednisolone therapy and regression of liver injury[END_REF][START_REF] Rivero Fernández | Recurrent acute liver toxicity from intravenous methylprednisolone][END_REF][START_REF] Adamec | Toxic liver injury after high-dose methylprednisolone in people with multiple sclerosis[END_REF][START_REF] Hofstee | Acute hepatitis related to prednisolone[END_REF] after the last liver injury event. As found herein, MP dosage regimens varied, making it difficult to evaluate the correlation between the treatment duration or the cumulative dose and the risk for liver injury. However, published data does suggest a dose effect, and in particular for IV MP. For instance, in a prospective observational study that included 29 patients with Graves' ophthalmopathy with either dysthyroid optic neuropathy (treated with high-dose IV MP) or moderately severe disease (low-dose IV MP) and followed for 24 weeks, AST and ALT were increased in 38% of the high-dose group, and 14% of the low-dose group (relative risk: 1.8, 95% CI [1.2; 2.6]) (38) . A similar finding was found in a study conducted in the World Health Organization database; liver injuries occurred in 3.6% of those receiving high-doses IV MP (≥2g) versus 0.9% of those receiving low-doses (≤1g) [START_REF] Caster | Methylprednisolone-induced hepatotoxicity: experiences from global adverse drug reaction surveillance[END_REF] . Some authors have proposed a systematic monitoring of liver enzymes during and after the administration of MP bolus [START_REF] Davidov | Methylprednisolone-induced liver injury: Case report and literature review[END_REF][START_REF] Moli | Determinants of Liver Damage Associated with Intravenous Methylprednisolone Pulse Therapy in Graves' Ophthalmopathy[END_REF] , because of the delayed discovering of the liver injury. In our study, liver injuries were discovered after discontinuation of MP in 46.8% of patients receiving MP intravenously and in 35.3% patients receiving MP orally. In the setting of long treatment protocols, such as for thyroid-induced orbitopathy for which weekly MP infusions (500 mg) are given for 6 weeks, followed by another 6 weeks at 250 mg [START_REF] He | Comparison of two different regimens of intravenous methylprednisolone for patients with moderate to severe and active Graves’ ophthalmopathy: a prospective, randomized controlled trial[END_REF] , early identification during treatment of increased liver function test values may allow prompt withdrawal of MP. Conversely, the treatment protocol for multiple sclerosis is 1g daily for 3 days, and changes in liver function tests were generally discovered when patients had symptoms, late after MP administration. For both situations, therefore, performing liver function test routinely during MT administration could be beneficial, as the timely recognition of this complication and early drug withdrawal may prevent progression of necrosis hepatic injury. In general, monitoring of liver enzymes can be provided during and after treatment. This would make it possible to better document these cases of liver damage and the responsibility of MP. Considering the appreciable number of positive rechallenge, prescribers should be informed about the possible and delayed toxic effect of MP to avoid re-introduction as very severe liver failure is possible although not frequent. In any case, liver function test should be performed systematically in case of symptoms.

The mechanism of methylprednisolone-induced liver injury is unclear due to the small number of reported cases. Use of steroids may cause three forms of hepatic injury: steatosis/ steatohepatitis, hepatitis B virus reactivation and DILI (drug-induced liver injury) (41).

However, the cases in our study or those found in the literature do not support viral reactivation or steatosis. The cause of this apparent hepatotoxicity it may represent severe autoimmune hepatitis triggered by the sudden profound immunosuppression and subsequent immune reconstitution (26).

Conclusion

In conclusion, the results suggest that IV MP causality should be considered in case of acute liver injury while data for oral MP is insufficient. It would be interesting to further investigate the value of systematic liver monitoring for high-dose IV MP. Non-concordant cases (coagulation disorders, respiratory distress, jaundice, pancreatitis…) n=74

Incomplete diagnosis criteria n=61

Non-concordant chronology n=53

Other etiology (cardiac hepatopathy, hepatitis B reactivation, macrophage activation syndrome…) n=35

Cancelled cases n=1 No Methylprednisolone intake n=1

Table 1. Criteria of liver injury severity according to Aithal et al. [START_REF] Aithal | Case Definition and Phenotype Standardization in Drug-Induced Liver Injury[END_REF]

Grade

  10-50 UI/l], alkaline phosphatase (ALP) [0-120 UI/l], total bilirubin [5-17 μmol/l].

Figure 1 :

 1 Figure 1: Flow chart

Table 2 .

 2 Characteristics of the study population

		Severity		Criteria
	1	Mild		ALAT ≥5N or ALP ≥2N and TB <2N
	2	Moderate		ALAT ≥3N or ALP ≥2N and TB ≥2N or
				symptomatic hepatitis
	3	Severe		ALAT ≥3N or ALP ≥2N and TB ≥2N
				+ one of following criteria:
				INR ≥1.5;
				Ascites and/or encephalopathy;
				Other organ failure due to liver injury
	4	Life	threatening	or
		transplantation
	ALT: alanine aminotransferase; ALP: alkaline phosphatase; TB: total bilirubin

Table 3 .

 3 Characteristics of liver injuries

	Intravenous MP	Oral MP	Total population
			n = 97

Table 4 .

 4 Published cases of methylprednisolone-induced liver injury

	Reference	Age/	Indication	Route	Cumulative	Time after	ALT	PAL	R	Recovery time	Histology	Rechallenge Outcome
		sex			dose/	treatment	(xN)	(xN)	value	(weeks)
					treatment	initiation
					duration	(days)
	Weissel et al.	71/F	Basedow	IV	3g/3 days	28	NA	NA	NA	NA	Post-mortem: hepatic	NA	Death
	2000 ( 22)		ophthalmopathy								parenchymal necrosis
	Marino et al.	56/NA Basedow	IV	15g/NA	During	49.8	4.2	12.0	NA	Hepatic necrosis	NA	Death
	2004 (32)		ophthalmopathy			treatment
	Marino et al.	63/NA Basedow	IV	9.3g/NA	During	3.6	0.8	4.3	NA	NA	NA	Death
	2004 (32)		ophthalmopathy			treatment
	Marino et al.	47/NA Basedow	IV	8.3g/NA	29	NA	NA	NA	NA	NA	NA	Death
	2004 (32)		ophthalmopathy										after liver
													transplan
													tation
	Marino et al.	45/NA Basedow	IV	9.3g/NA	During	39.4	1.5	26.6	22	Hepatic necrosis	NA	Recovery
	2004 (32)		ophthalmopathy			treatment
	Marino et al.	30/NA Basedow	IV	7.2g/NA	45	18.6	2.0	9.4	18	Lymphocyte and	NA	Recovery
	2004 (32)		ophthalmopathy								eosinophil infiltration
	Marino et al.	55/NA Basedow	IV	10.7g/NA	29	20.9	2.0	10.2	9	NA	NA	Recovery
	2004 (32)		ophthalmopathy
	Marino et al.	54/NA Basedow	IV	4g/NA	During	36.3	1.5	23.8	20	Lymphocyte and	NA	Recovery
	2004 (32)		ophthalmopathy			treatment					plasma cell infiltration
	Salvi et al.	43/F	Hashimoto	IV	7.5 mg/kg/NA	77	23.0	NA	NA	30	Lobular hepatitis with	NA	Recovery
	2004 (19)		thyroiditis								central lobular necrosis,
											lymphomonocytic and
											plasmacellular
											infiltrates, acidophil
											bodies, and Kupffer cell
											hyperplasia
	Marino et al.	43/F	Basedow	IV	4.7g/NA	42	28.4	NA	NA	9	Lymphocyte and	NA	Recovery
	2005 (35)		ophthalmopathy								plasma cell infiltration,
											involving mainly one
											interlobular bile duct.
											Focal centrilobular
											necrosis
	Hofstee et al.	46/F	Multiple sclerosis	IV	3g/3 days	42	21.9	1.2	18.8	18	NA	Positive	Recovery
	2005 (34)
	Das et al.	48/F	Multiple sclerosis	IV	NA/NA	42	32.0	1.7	19.2	NA	Lymphocyte and	NA	Recovery
	2006 (6)										eosinophil infiltration,

NA: not available, F: female, M: male, IV: intravenous, O: oral; g: grams, ALT: alanine aminotransferase, PAL, phosphatase alkaline, R: rati 468

Acknowledgements

We thank Philip Robinson (DRCI, Hospices Civils de Lyon) for help in manuscript preparation.


MD Stéphane Bardet
email: s.bardet@baclesse.fr

31I Radioiodine therapy in Graves' disease: us et coutumes, controversies and guidelines Traitement à l'iode 131 dans la maladie de Basedow: us et coutumes, controverses et recommandations

Keywords:

For almost 80 years 131I radioiodine (RAI) therapy has proven to be an efficient and welltolerated therapeutic option in patients with Graves' disease (GD). Along with anti-thyroid drugs (ATD) and thyroidectomy, RAI is one the three major therapeutic tools for this autoimmune disease. The objective of this article is to review how RAI treatment is usually conducted in clinical routine and to discuss the main controversies surrounding this treatment in the light of recent national or international guidelines. This will be an opportunity to discuss the indications and contraindications for this treatment, its advantages and limits, and more generally its practical organization by a specialized team.

radioiodine therapy, Graves'disease

Résumé

Depuis près de 80 ans, il est bien démontré que le traitement à l'Iode 131 (irathérapie) est une option thérapeutique efficace et bien tolérée chez les patients atteints de la maladie de Basedow.

Avec les anti-thyroïdiens de synthèse et la thyroïdectomie, l'irathérapie constitue l'un des trois principaux outils thérapeutiques de cette maladie auto-immune. L'objectif de cet article est de faire le point sur l'utilisation de l'Iode 131 en routine clinique et de discuter des principales controverses concernant ce traitement à la lumière des récentes recommandations nationales ou internationales. Ce sera l'occasion de d'examiner les indications et contre-indications de ce traitement, de discuter de ses avantages et inconvénients, et plus généralement, de discuter de son organisation pratique par une équipe spécialisée.

Introduction

Graves' disease (GD) is the most frequent cause of overt hyperthyroidism, generally affecting relatively young women [START_REF] Smith | Graves' Disease[END_REF]. The therapeutic options for GD, i.e. antithyroid drugs, radioactive iodine (RAI) and total thyroidectomy, have been used for several decades. As all these options are efficient and most often well-tolerated, with no clear superiority of one over the other [START_REF] Torring | Graves' hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. Thyroid Study Group[END_REF],

treatment strategies are not uniform and vary across countries and thyroid specialists. In this article, we will focus on the use of RAI therapy. Firstly, we will discuss how patients with GD can be managed in clinical practice using RAI therapy. After this "us et coutumes" chapter, we will briefly tackle the main controversies which continue to agitate the world of nuclear medicine and thyroidology regarding the use of RAI in patients with GD. Lastly, the main recommendations of recent national or international guidelines will be presented.

Us et coutumes

The first recommendation of the French Guidelines on GD management specifies that the "choice of treatment for GD should be made in discussion with the patient, after explanation of the respective advantages and drawbacks of the three classical options. Specialist opinion is needed to choose the appropriate treatment and determine the monitoring program" [START_REF] Corvilain | Treatment of adult Graves' disease[END_REF]. The main advantage of RAI treatment is to definitely cure hyperthyroidism, generally after a one-day treatment, with uncommon and modest side-effects. The drawbacks are the common occurrence of hypothyroidism, possible exacerbation of Graves' orbitopathy (GO), risk of failure needing a second, even a third RAI treatment, and the radiation-related risks. The constraint is to deliver RAI treatment in a nuclear medicine department approved for therapy, respecting contraindications before treatment and enforcing radiation protection rules after treatment.

Although controversy on the role of RAI in first-line persists, RAI treatment in France is generally considered in the event of relapse after a 12-18 months well-conducted course of ATD, ATD side-effects such as leukopenia or allergy, or poor adherence to ATD therapy.

Schematically, when hyperthyroidsim relapses after ATD treatment, iratherapy is favored in patients with low thyroid volume, without suspicious nodules or active/severe GO, while total thyroidectomy is preferred in those with large goiter and/or suspicious nodules or significant GO.

Once RAI therapy is considered, a visit should be planned associated with a thyroid scintigraphy (Tc99m or I123) in order to rule out contraindications, to explain the objectives and process of treatment, and to determine the optimal conditions of RAI treatment.

The absolute contraindications are pregnancy and breast-feeding. Women of child-bearing age should be informed of the need of effective contraception at the time of RAI treatment and for 6 months after. They will also be informed that a pregnancy test will be systematically carried out in the 3 days preceding RAI treatment [START_REF] Stokkel | EANM procedure guidelines for therapy of benign thyroid disease[END_REF]. Breast-feeding should be stopped at least 4 to 6 weeks before treatment [START_REF] Leide-Svegborn | Excretion of radionuclides in human breast milk after nuclear medicine examinations. Biokinetic and dosimetric data and recommendations on breastfeeding interruption[END_REF]. RAI treatment can be also contraindicated in a patient totally urinary incontinent. If there is only moderate urinary leakage, the patient will be informed to stock soiled diapers for 2-3 months at home before putting them in the normal waste stream to avoid contaminating the recycling centers. It is also essential to ask patients if radiological examinations with iodinated contrast agents have recently been performed, as this would require delaying RAI treatment by a few weeks. Considering RAI treatment in a patient with GD should also take into account the presence of active GO and to ask the patient if he (she) smokes. There is indeed clear evidence that RAI treatment increases the risk of preexisting GO, especially in smokers [START_REF] Ma | Radioiodine therapy versus antithyroid medications for Graves' disease[END_REF][START_REF] Stiebel-Kalish | Treatment modalities for Graves' ophthalmopathy: systematic review and metaanalysis[END_REF][START_REF] Bartalena | Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy[END_REF][START_REF] Tallstedt | Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. The Thyroid Study Group[END_REF]. The risk of developing GO in patients without eye disese before treatment is also possible, particularly in smokers [START_REF] Traisk | Thyroid-associated ophthalmopathy after treatment for Graves' hyperthyroidism with antithyroid drugs or iodine-131[END_REF]. Iatrogenic hypothyroidism is another important risk factor for worsening GO after RAI treatment, especially when it is not quickly replaced [START_REF] Stan | Risk factors for development or deterioration of Graves' ophthalmopathy[END_REF]. Therefore, it is best to reserve RAI treatment for patients without or with mild GO, and to emphasize the need to quit smoking, carry out close biological monitoring to avoid hypothyroidism and if necessary, to have the opinion of an ophthalmologist [START_REF] Bartalena | Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy[END_REF]. Also, corticosteroid treatment is highly recommended in case of mild GO to prevent aggravation [START_REF] Bartalena | Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy[END_REF] and may be considered in presence of risk factors (elevated TSH-R antibidies, smoking) without GO [START_REF] Watanabe | Radioiodine-Associated Exacerbation of Graves' Orbitopathy in the Japanese Population: Randomized Prospective Study[END_REF]. At least two corticosteroid regimens, 0.4-0.5 mg/kg/day prednisolone for 3 months or 0.2-0.3 mg/kg/day for 6 weeks, have been shown to be effective in mild/moderate pre-existing GO [START_REF] Shiber | Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis[END_REF]. There is conflicting data regarding the usefulness of early thyroxine treatment after RAI to prevent hypothyroidism and GO worsening [START_REF] Perros | A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimally active graves' ophthalmopathy[END_REF][START_REF] Taieb | Quality of life, clinical outcomes and safety of early prophylactic levothyroxine administration in patients with Graves' hyperthyroidism undergoing radioiodine therapy: a randomized controlled study[END_REF].

Before treatment, it is also important to explain to patients how the production of thyroid hormones can be affected by RAI treatment in the following weeks, months or years, and to plan short and long-term follow-up with them and practioners.

Patients should be informed of the significant risk of permanent hypothyroidism leading to hormone replacement therapy. However, the time to onset of hypothyroidism is variable. It may be very early in the 3-6 weeks after treatment, with the risk of symptoms and GO exacerbation as previously discussed. As the hypothalamus-pituitary axis takes several weeks or months to recover, short-term biological monitoring, for example at 6 weeks and 3 months, must include FT4 +/-FT3 measurements in addition to TSH. More often, hypothyroidism is detected at 3 months. If the patient is euthyroid at this time, monitoring of TSH remains necessary in the following months or years as delayed hypothyroidism is possible. In rare cases, early hypothyroidism is transient with secondary return to euthyroidism, and sometimes, recurrence of hyperthyroidism [START_REF] Uy | Pattern of recovery of the hypothalamic-pituitarythyroid axis following radioactive iodine therapy in patients with Graves' disease[END_REF].

In contrast, persistence of hyperthyroidism can be observed after the first RAI treatment. This may be a real treatment failure, but in some patients it may reflect delayed treatment effectiveness. In practice, a clinical and biological evaluation is often carried out at 3 months. If hyperthyroidism is clearly documented at this time without improvement compared to baseline, a second RAI course is indicated. If hyperthyroidism persists but with less intensity, the patient can be closely monitored over the next 3 months and a second RAI treatment will be discussed at the end of this period.

Consultation prior to RAI treatment is also an opportunity to inform the patient, orally and in written form, on the radioprection rules to respect the days after treatment. These rules aim both requires administering an RAI activity of less than 740 Mbq (20 mCi) on an outpatient basis. If higher activity is planned, hospitalization in a radioprotected room will be required.

Controversial issues on RAI therapy in patients with GD

Although RAI has been used since 1941, there is still debate about when and how to use it in patients with GD. These controversies are at least partly linked to the lack of high quality data, in particular prospective randomized controlled trials in large patient samples.

Should ATD be used before RAI treatment?

Since ATD impair RAI efficacy by reducing iodine uptake [START_REF] Bonnema | Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome[END_REF] and free radical production [START_REF] Wilson | The effect of carbimazole therapy on interleukin 2, interleukin 2 receptors and free radicals[END_REF],

it is theoretically best to administer RAI in patients who are naive to ATD or who have stopped ATD for a sufficient time. In a large and well-conducted meta-analysis, it was confirmed that pretreatment with ATD, with no differences between thiouracil and imidazole derivatives, increased the rates of treatment failure when administered within 7 days before or after RAI treatment [START_REF] Walter | Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials[END_REF].

In routine practice, many clinicians prescribe ATD for a certain period of time to patients who will have RAI treatment with the aim of improving comfort and preventing a possible exacerbation of thyrotoxicosis after RAI treatment which is, if present, transient and modest [START_REF] Burch | The effect of antithyroid drug pretreatment on acute changes in thyroid hormone levels after (131)I ablation for Graves' disease[END_REF].

Although UK guidelines recommend pretreatment with ATD, others recommend that pretreatment be considered in symptomatic and/or fragile patients but stopped for at least 2 to 7 days before RAI treatment (Table 1). It should be noted that there is no robust data regarding the optimal duration of interruption of ATD treatment before RAI therapy. The option of increasing the RAI activity to be administered when stopping ATD treatment is deemed possible, even if this raises other concerns regarding radiation protection or potential side-effects. Although not widely used, lithium has also been shown to improve treatment efficacy allowing administration of lower activity [START_REF] Bogazzi | Impact of lithium on efficacy of radioactive iodine therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal[END_REF]. Beta-adrenergic blockers, such as propanolol (20-40 mg every 8h), are useful to control adrenergic symptoms (palpitations, tremor) and do not affect RAI uptake and efficacy. Unless contraindicated, they should be prescribed several weeks before and after RAI treament, until it restores euthyroidism.

"

Ablative" or "dose-adjusted" strategy, and "fixed" or "calculated" dose RAI:

which are the best?

There are at least two entangled concepts which preside over the choice of the RAI activity to be adminerested. One is related to the goal of treatment which can be to restore euthyroidism and to minimize the risk of hypothyroidism (often named "dose-adjusted" strategy), or to cure hyperthyroidism even at the cost of hypothyroidism ("ablative" strategy). The other one is related to the method of determining RAI activity, either calculated or fixed, the former being mostly associated with the "dose-adjusted" strategy, and the latter with the "ablative" strategy.

Theoretically, an individualized approach to deliver the lowest effective dose is the best way to proceed, not only for the patient but also for the persons around the patient after treatment and the environment. Calculation of adjusted activity is based on thyroid uptake, usually at two times, with estimation of thyroid volume on ultrasound. A technical chapter is devoted to this dosimetric approach in this review (joined paper, Piron B). Although good long-term data has been reported [START_REF] Chen | Striving for euthyroidism in radioiodine therapy of Graves' disease: a 12-year prospective, randomized, open-label blinded end point study[END_REF], the risk with this option is to fail and have to repeat RAI treatment. The other option is to administer a standardized fixed activity, generally between 185 and 555 MBq. Although easier to implement, there is a significant risk of hypothyroidism and unnecessary radiation exposure both for the patient, family and the public [START_REF] Jönsson | Excess radiation absorbed doses from non-optimised radioiodine treatment of hyperthyroidism[END_REF]. A systematic review of eight studies found no difference in patient outcome between the two approaches, although studies were methodologically highly heterogeneous [START_REF] De Rooij | Clinical outcomes after estimated versus calculated activity of radioiodine for the treatment of hyperthyroidism: systematic review and meta-analysis[END_REF]. The ETA and SFE guidelines recommend an "ablative" strategy rather than a "dose-adjustment" strategy using a RAI activity to achieve hypothyroidism (Table 1). For the ETA, a fixed actvity is fully acceptable while the ATA, SFE and UK NICE endorse both fixed and calculated methods.

RAI for primary therapy or for relapse?

Another area of controversy is whether or not RAI treatment should be used for primary therapy.

All guidelines insist that treatment decisions should be reached with the patient, after explanation of the respective advantages and drawbacks of the three classical options, namely ATD, RAI therapy or thyroidectomy. This applies to primary therapy or relapse, and a decision shared by the patient and a multidiscipilanry team would be best. This decision should also take into account a number of parameters including age, sex, the presence of large goiter, suspicious nodules, GO, smoking, presence of young children and desire for pregnancy, life and professional conditions and urinary continence. In France and more generally in Europe, the most common option for primary therapy is a 12-18 months course of ATD, with RAI treatment being considered in case of relapse. In the US, although the trend has changed in recent years, RAI treatment has long been the most-used first-line treatment. Recently, our British colleagues have recommended RAI for primary therapy. This recommandation mainly relies on recently reported data on cardiovascular morbidity and mortality in hyperthyroid patients treated with RAI compared to other modalities [START_REF] Okosieme | Primary therapy of Graves' disease and cardiovascular morbidity and mortality: a linked-record cohort study[END_REF][START_REF] Boelaert | Comparison of mortality in hyperthyroidism during periods of treatment with thionamides and after radioiodine[END_REF]. The British study, conducted in 4189 GD patients treated with RAI or ATD, interestingly showed that successful RAI treatment was associated with reduced mortality compared to ATD alone, and that the positive impact of RAI treatment on major cardiovascular events was significantly better when hypothyroidism was present at one year [START_REF] Okosieme | Primary therapy of Graves' disease and cardiovascular morbidity and mortality: a linked-record cohort study[END_REF]. This confirms a previous study where patients treated with RAI showed reduced mortality when they became hypothyroid [START_REF] Boelaert | Comparison of mortality in hyperthyroidism during periods of treatment with thionamides and after radioiodine[END_REF]. In contrast, other recent studies have shown increased all-cause and cardiovascular mortality in patients treated with RAI compared to thyroidectomy [START_REF] Ryodi | Cardiovascular Morbidity and Mortality After Treatment of Hyperthyroidism with Either Radioactive Iodine or Thyroidectomy[END_REF][START_REF] Giesecke | All-cause and cardiovascular mortality risk after surgery versus radioiodine treatment for hyperthyroidism[END_REF]. More generally, cardiovascular events are well correlated to the development of hypothyroidism, highlighting the benefit to rapidly control hyperthyroidism whichever first-line treatment is chosen. The fact that RAI has been shown to be more cost-effective than ATD and total thyroidectomy for the primary treatment of GD in a recent study has also been seen as an argument to promote RAI in first-line [START_REF] Donovan | Cost-utility analysis comparing radioactive iodine, anti-thyroid drugs and total thyroidectomy for primary treatment of Graves' disease[END_REF].

RAI therapy and the risk of second cancer?

Until recently, and despite conflicting data, concerns about risk of second cancer after RAI treatment were limited to patients with differentiated thyroid cancer in whom relatively high RAI activities can be administered. Recently, the paper by Kitahara et al. [START_REF] Kitahara | Association of Radioactive Iodine Treatment With Cancer Mortality in Patients With Hyperthyroidism[END_REF] caused considerable reaction, suggesting that RAI treatment may be associated with excess mortality from solid cancer in hyperthyroid patients, whereas previous reports did not find any evidence for an increased incidence of non-thyroid cancers [START_REF] Ryodi | Cancer Incidence and Mortality in Patients Treated Either With RAI or Thyroidectomy for Hyperthyroidism[END_REF][START_REF] Franklyn | Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study[END_REF][START_REF] Doody | Cancer mortality following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group[END_REF][START_REF] Hoffman | Cancer incidence following treatment of hyperthyroidism[END_REF][START_REF] Holm | Cancer risk after iodine-131 therapy for hyperthyroidism[END_REF]. This controversial issue will be thoroughly discussed in another article of this review (Elif Hindie), pointing out the limitations of that study [START_REF] Hindie | Association of Radioactive Iodine Treatment of Hyperthyroidism With Cancer Mortality: An Unjustified Warning?[END_REF] and providing an objective view of the risk of cancer in hyperthyroid patients treated with RAI.

Guidelines

In the last few years, national and international guidelines for the management of patients with GD have been published including the French consensus [START_REF] Corvilain | Treatment of adult Graves' disease[END_REF], the guidelines from the American Thyroid Association (ATA) [START_REF] Ross | American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis[END_REF] and the European Thyroid Association [START_REF] Kahaly | European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism[END_REF] and more recently, the recommendations from the UK NICE [START_REF] Nice | Thyroid Disease Guidelines[END_REF]. Although these general recommendations on GD discuss the use of all available treatment options in this autoimmune disease, a full and specific focus on RAI treatment is provided in French guidelines [START_REF] Corvilain | Treatment of adult Graves' disease[END_REF]. For most of the topics, these guidelines give converging recommendations. Recommendations may differ on some points, especially for controversial issues already discussed. Table 1 aims to summarize the key points of these recommendations.

Conclusion

For almost 80 years RAI therapy has proven to be an efficient and well-tolerated therapeutic option in patients with GD. The indications for RAI therapy, and the conditions under which treatment should be performed, should be discussed by a specialized team. The expected short and long-term consequences of this treatment must be clearly explained to patients before treatment, and special attention regarding radiation protection is required. In the future, welldesigned studies could help resolve some long-standing controversies and allow RAI therapy to continue to play a key role in the treatment of patients with GD.

Pre-treatment with ATD before RAI

Reco 17b: Medical preparation by ATD is helpful when not contraindicated or poorly tolerated, especially in fragile patients (elderly, highly symptomatic, with thyroid hormone elevation or cardiovascular history). When prescribed, ATD should be interrupted during 3-7 days around RAI treatment, although there is no consensus on optimal interruption duration.

Reco 19: If ATD are used before RAI therapy they should be paused around 1 week before and after therapy in order not to decrease the efficacy of RAI therapy.

"Ablative" or "doseadjustment" strategy

Reco 18a: In GD, an "ablative" strategy is more appropriate than a "dose-adjustment" strategy. The administered RAI dose should be such as to achieve hypothyroidism. Reco 20: No dose calculation can secure long-term euthyroidism and it is fully acceptable to offer a fixed dose of RAI. Reco 8: Sufficient activity of RAI should be administered in a single application, typically a mean dose of 10-15 mCi (370-555 MBq), to render the patient with GD hypothyroid.

Not addressed

Fixed or calculated RAI activity

Reco 18b: There is no preferable method for determining RAI dose: fixed or adjusted dose methods may both be used. However, fixed or semi-fixed dose methods have the advantage of simplicity Reco 20: No dose calculation can secure long-term euthyroidism and it is fully acceptable to offer a fixed dose of RAI.

Fixed or calculated RAI activity are possible.

No specific recommendation

The evidence did not identify a clinically important difference between a calculated or fixed strategy in terms of RAI dosing. No specific recommendation RAI: Radioiodine; GD:Graves' disease ;ATD : Antithyroid drugs ; MMI :Methimazole

  to minimize the exposure to ionizing radiation of individuals in the family, at work, or in public transport, especially young children and pregnant women, and the risk of radioactive contamination by urine during the 3 to 4 days following the administration of RAI. The recommendations relating to radioprotection and, if necessary, the prescription of sick leave, must be personalized taking into account the patient's lifestyle, profession or the presence of children at home or at work. In 2006, the French Society of Nuclear Medicine (SFMN) proposed restricted contact duration according to RAI activity : http://www.sfmn.org/index.php/accueil/70societe/guides-des-procedures/traitements/213-le-traitement-des-hyperthyroidies-par-l-iode-131?showall=1&limitstart=. The Decree 2003-2070 of March 24, 2003, limits the irradiation of the public exposed to ionizing radiation for medical reasons to 1 mSv. This ceiling of 1 mSv

Reco 5 :

 5 In addition to b-adrenergic blockade, pretreatment with MMI prior to RAI therapy for GD should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism. MMI should be discontinued 2-3 days prior to RAI. Pre-treatment recommended until specialist's decision, particularly in older adults who are symptomatic or severely thyrotoxic. No specific recommendation about ATD interruption before RAI treatment

Table 1 SFE

 1

		(3)	ETA (39)	ATA (38)	UK NICE (40)
	RAI for	Reco 1: Choice of treatment for GD should be	Reco 5: Patients with newly	Reco 3: Patients with overt Graves'	1.6.8: Offer RAI as first-line
	primary	made in discussion with the patient, after	diagnosed GD should be treated with	hyperthyroidism should be treated	treatment for adults with GD,
	therapy or for	explanation of the respective advantages and	ATD. RAI therapy or thyroidectomy	with any of the following	unless ATD are likely to achieve
	relapse	drawbacks of the three classical options.	prefer this approach. may be considered in patients who	thyroidectomy. modalities: RAI therapy, ATDs, or	remission or it is unsuitable.
		Reco 15: In case of recurrence of
		hyperthyroidism after termination of ATD	Reco 17: There are no absolute	Reco 23: If a patient with GD
		treatment, treatment options (second classical	indications for RAI therapy, but	becomes hyperthyroid after
		ATD course or radical treatment by RAI or	it is often recommended for patients	completing a course of MMI,
		surgery) should be discussed again with the	with side-effects to or recurrence	consideration should be given to
		patient in the light of the clinical data.	after a course of ATD.	RAI treatment or thyroidectomy.

Acknowledgement:

We are grateful to Helen Lapasset for her assistance in reviewing the manuscript

Conflict of interest statement:

The author has no conflict of interest to declare.