Glucocorticoids and outcome of radioactive iodine therapy for Graves’ hyperthyroidism

in European Journal of Endocrinology
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  • 1 Department of Clinical Medicine, University of Insubria, Division of Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy

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Radioactive iodine (RAI) is a well established and very effective method of treatment for Graves’ hyperthyroidism (1). RAI is given preferentially after pretreatment with antithyroid drugs to restore euthyroidism, or, especially in mild forms of hyperthyroidism and in young patients, without pretreatment (2). Its effectiveness can be increased by a short adjuvant treatment with lithium carbonate, which allows a prompter control of thyrotoxicosis and an earlier shrinkage of goiter (3).

Why should glucocorticoids be given concomitantly with RAI therapy? One possible reason is the occurrence of radiation thyroiditis, heralded by pain in the anterior neck region after RAI administration. This is a rare event, and non-steroidal anti-inflammatory agents for a few days are usually enough to control this transient phenomenon (1). The most important reason to use glucocorticoids concomitantly with RAI administration is to prevent the possible RAI-associated worsening of Graves’ ophthalmopathy (GO). RAI therapy causes GO progression in about 15% of cases, although this event is often transient (4). GO progression after RAI is more likely to occur in patients who already have GO prior to RAI therapy, smoke, have more severe hyperthyroidism and high levels of thyrotropin (TSH) receptor antibody (TRAb), or whose post-RAI hypothyroidism is not promptly corrected by l-thyroxine replacement therapy (5). In these at-risk patients a relatively short course of moderate doses of oral glucococorticoids prevents progression of eye disease and often cures preexisting GO (6).

An important problem, addressed by Jensen et al. in this issue of the European Journal of Endocrinology (7), is whether the concomitant administration of glucocorticoids may influence the outcome of RAI therapy and reduce its effectiveness. High doses of glucocorticoids have multiple effects on pituitary-thyroid function. These include transient inhibition of TSH secretion, reduced peripheral monodeiodination of thyroxine to triiodothyronine, and a decrease in thyroxine-binding globulin circulating levels (8). These effects are unlikely to affect the outcome of RAI therapy. In addition, glucocorticoids enhance – modestly – urinary clearance of iodide (8); this might somehow decrease recycling of RAI and, thereby, reduce its effectiveness. However, the demonstration that this is indeed the case is lacking. Interestingly, in FRTL-5 cells, dexamethasone has been shown to decrease sodium iodide symporter (NIS) expression, NIS RNA steady-state levels and iodide accumulation (9). This might provide the basis for a decreased RAI effect owing to glucocorticoid treatment. On the other hand, in prostate cancer cells expressing NIS, dexamethasone enhances the cytotoxic effects of RAI therapy (10). Cytotoxic effects of RAI are related to the formation of reactive oxygen species, which are responsible for DNA damage and ultimately cause cell death. Whether glucocorticoids affect production of reactive oxygen species is controversial, and conflicting results have recently been reported in the literature. While inhibition of intracellular production of reactive oxygen species was shown in platelets (11), glucocorticoid excess induced superoxide production in vascular endothelial cells, thereby contributing to vascular endothelial dysfunction (12). In addition, glucocorticoid treatment did not inhibit cardiac production of reactive oxygen species after reperfusion during conventional cardiac surgery (13); in the same study steroids decreased lipid peroxidation, but did not affect the occurrence of arrhythmias (13).

Thus, experimental data do not provide an unequivocal basis to predict a possible effect, either positive or negative, of glucococorticoids on the outcome of RAI therapy for hyperthyroidism. What do we know from the few clinical studies in which this aspect was evaluated? In a prospective study of 40 patients with Graves’ disease, betamethasone, given for 3 weeks before and 4 weeks after RAI therapy, delayed, but did not abolish, the RAI-associated rise in thyroid autoantibody levels, and caused a decrease in total serum IgG (14). At the end of the 12-month follow-up period, 9 out of 20 (45%) betamethasone-treated patients and 17 out of 20 (85%) placebo-treated patients developed hypothyroidism (14). Because the latter is considered a desirable goal of RAI therapy, one may argue that this regimen of glucocorticoid therapy does reduce the effectiveness of RAI therapy. In a study of 31 Graves’ patients submitted to RAI therapy, no differences in the outcome of treatment were observed in the subgroup of patients treated with glucocorticoids after RAI administration, as compared with patients not receiving steroid treatment (15). In our large study of the effects of RAI on GO, the prevalence of permanent hypothyroidism after RAI therapy was superimposable in patients treated with RAI alone (62%) or with RAI followed by glucocorticoid coverage (66%) (4); likewise, treatment failure, i.e. persistent hyperthyroidism, was similar in the two groups (14 and 12%, respectively) (4). The present study by Jensen et al. lends further support to the above results by showing that the cure rate (euthyroidism + hypothyroidism) in patients treated with RAI alone or with RAI followed by glucocorticoids was identical (60 and 59%, respectively) (7).

Therefore, available data suggest that post-RAI treatment with glucocorticoids, usually given to prevent GO progression, does not affect the outcome of RAI therapy for hyperthyroidism (Table 1). Accordingly, no increase in the dose of RAI is required. Conversely, pretreatment with glucocorticoids may reduce the effectiveness of RAI therapy and should, therefore, be avoided (Table 1). In conclusion, in patients in whom it is required (smokers with preexisting GO, severe hyperthyroidism, high TRAb titers), glucocorticoid therapy can be safely administered without any fear of compromising the outcome of RAI therapy.

Acknowledgements

This work was partly supported by grants from the University of Insubria (Fondi d’Ateneo per la Ricerca) and from the Ministry for Education, University and Research (MIUR, Rome, Project ‘Novel pathogenic, clinical and therapeutic aspects of Graves’ ophthalmopathy’) to Professor Bartalena.

Table 1

Effect of glucocorticoid therapy on the outcome of radioactive iodine therapy (RAI) for Graves’ hyperthyroidism.

AuthorYearGlucocorticoid regimenCure rate (Eu + Hypo)
Eu, euthyroidism; Hypo, hypothyroidism.
Gamstedt & Karlsson (14)1991Pre- and post-RAI45 vs 85% in patients receiving placebo
Chiovato et al. (15)1998Post-RAINo different outcome compared with patients not receiving steroids
Bartalena et al. (4)1998Post-RAI66 vs 62% in patients receiving RAI alone
Jensen et al. (7)2005Post-RAI60 vs 59% in patients not receiving steroids

References

  • 1

    Cooper DS. Treatment of thyrotoxicosis. In Werner & Ingbar’s The Thyroid – a Fundamental and Clinical Text, edn 9, ch 45, pp 665–694. Eds LE Braverman & RD Utiger. Philadelphia, PA: Lippincott Williams & Wilkins, 2005.

  • 2

    Bogazzi F, Martino E & Bartalena L. Antithyroid drug treatment prior to radioiodine therapy for Graves’ disease: yes or no? Journal of Endocrinological Investigation 2003 26 174–176.

    • Search Google Scholar
    • Export Citation
  • 3

    Bogazzi F, Bartalena L, Campomori A, Brogioni S, Traino C, De Martino F, Rossi G, Lippi F, Pinchera A & Martino E. Treatment with lithium prevents serum thyroid hormone increase after thionamide withdrawal and radioiodine therapy in patients with Graves’ disease. Journal of Clinical Endocrinology and Metabolism 2002 87 4490–4495.

    • Search Google Scholar
    • Export Citation
  • 4

    Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E & Pinchera A. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. New England Journal of Medicine 1998 338 73–78.

    • Search Google Scholar
    • Export Citation
  • 5

    Bartalena L, Pinchera A & Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocrine Reviews 2000 21 168–199.

    • Search Google Scholar
    • Export Citation
  • 6

    Bartalena L, Marcocci C, Bogazzi F, Panicucci M, Lepri A & Pinchera A. Use of corticosteroids to prevent progression of Graves’ ophthalmopathy after radioiodine therapy for hyperthyroidism. New England Journal of Medicine 1989 321 1349–1352.

    • Search Google Scholar
    • Export Citation
  • 7

    Jensen BE, Bonnema SJ & Hegedus L. Glucocorticoids do not influence the effect of radioiodine therapy in Graves’ disease. European Journal of Endocrinology 2005 153 15–21.

    • Search Google Scholar
    • Export Citation
  • 8

    Dluhy RG. The adrenal cortex in hypothyroidism. In Werner & Ingbar’s The Thyroid – a Fundamental and Clinical Text, edn 9, ch 59, pp 811–816. Eds LE Braverman & RD Utiger. Philadelphia, PA: Lippincott Williams & Wilkins, 2005.

  • 9

    Spitzweg C, Joba W, Morris JC & Heufelder AE. Regulation of sodium iodide symporter gene expression in FRTL-5 rat thyroid cells. Thyroid 1999 9 821–830.

    • Search Google Scholar
    • Export Citation
  • 10

    Scholz IV, Cengic N, Goke B, Morris JC & Spitzweg C. Dexamethasone enhances the cytotoxic effect of radioiodine therapy in prostate cancer cells expressing the sodium iodide symporter. Journal of Clinical Endocrinology and Metabolism 2004 89 1108–1116.

    • Search Google Scholar
    • Export Citation
  • 11

    Sanner BM, Meder U, ZidekW& Tepel M. Effects of glucocorticoids on generation of reactive oxygen species in platelets. Steroids 2002 67 715–719.

    • Search Google Scholar
    • Export Citation
  • 12

    Iuchi T, Akaike M, Mitsui T, Ohshima Y, Shintani Y, Azuma H & Matsumoto T. Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circulation Research 2003 92 81–87.

    • Search Google Scholar
    • Export Citation
  • 13

    Volk T, Schmutzler M, Engelhardt L, Pantke U, Laule M, Stangl K, Grune T, Wernecke K-D, Konertz W & Kox WJ. Effects of different steroid treatment on reperfusion-associated production of reactive oxygen species and arrhythmias during coronary surgery. Acta Anaesthesiologica Scandinavica 2003 47 667–674.

    • Search Google Scholar
    • Export Citation
  • 14

    Gamstedt A & Karlsson A. Pretreatment with betamethasone of patients with Graves’ disease given radioiodine therapy: thyroid autoantibody response and outcome of therapy. Journal of Clinical Endocrinology and Metabolism 1991 73 125–131.

    • Search Google Scholar
    • Export Citation
  • 15

    Chiovato L, Fiore E, Vitti P, Rocchi R, Rago T, Dokic D, Latrofa F, Mammoli C, Lippi F, Ceccarelli C & Pinchera A. Outcome of thyroid function in Graves’ patients treated with radioiodine: role of thyroid-stimulating and thyrotropin-blocking antibodies and of radioiodine-induced thyroid damage. Journal of Clinical Endocrinology and Metabolism 1998 83 40–46.

    • Search Google Scholar
    • Export Citation

 

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  • 1

    Cooper DS. Treatment of thyrotoxicosis. In Werner & Ingbar’s The Thyroid – a Fundamental and Clinical Text, edn 9, ch 45, pp 665–694. Eds LE Braverman & RD Utiger. Philadelphia, PA: Lippincott Williams & Wilkins, 2005.

  • 2

    Bogazzi F, Martino E & Bartalena L. Antithyroid drug treatment prior to radioiodine therapy for Graves’ disease: yes or no? Journal of Endocrinological Investigation 2003 26 174–176.

    • Search Google Scholar
    • Export Citation
  • 3

    Bogazzi F, Bartalena L, Campomori A, Brogioni S, Traino C, De Martino F, Rossi G, Lippi F, Pinchera A & Martino E. Treatment with lithium prevents serum thyroid hormone increase after thionamide withdrawal and radioiodine therapy in patients with Graves’ disease. Journal of Clinical Endocrinology and Metabolism 2002 87 4490–4495.

    • Search Google Scholar
    • Export Citation
  • 4

    Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E & Pinchera A. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. New England Journal of Medicine 1998 338 73–78.

    • Search Google Scholar
    • Export Citation
  • 5

    Bartalena L, Pinchera A & Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocrine Reviews 2000 21 168–199.

    • Search Google Scholar
    • Export Citation
  • 6

    Bartalena L, Marcocci C, Bogazzi F, Panicucci M, Lepri A & Pinchera A. Use of corticosteroids to prevent progression of Graves’ ophthalmopathy after radioiodine therapy for hyperthyroidism. New England Journal of Medicine 1989 321 1349–1352.

    • Search Google Scholar
    • Export Citation
  • 7

    Jensen BE, Bonnema SJ & Hegedus L. Glucocorticoids do not influence the effect of radioiodine therapy in Graves’ disease. European Journal of Endocrinology 2005 153 15–21.

    • Search Google Scholar
    • Export Citation
  • 8

    Dluhy RG. The adrenal cortex in hypothyroidism. In Werner & Ingbar’s The Thyroid – a Fundamental and Clinical Text, edn 9, ch 59, pp 811–816. Eds LE Braverman & RD Utiger. Philadelphia, PA: Lippincott Williams & Wilkins, 2005.

  • 9

    Spitzweg C, Joba W, Morris JC & Heufelder AE. Regulation of sodium iodide symporter gene expression in FRTL-5 rat thyroid cells. Thyroid 1999 9 821–830.

    • Search Google Scholar
    • Export Citation
  • 10

    Scholz IV, Cengic N, Goke B, Morris JC & Spitzweg C. Dexamethasone enhances the cytotoxic effect of radioiodine therapy in prostate cancer cells expressing the sodium iodide symporter. Journal of Clinical Endocrinology and Metabolism 2004 89 1108–1116.

    • Search Google Scholar
    • Export Citation
  • 11

    Sanner BM, Meder U, ZidekW& Tepel M. Effects of glucocorticoids on generation of reactive oxygen species in platelets. Steroids 2002 67 715–719.

    • Search Google Scholar
    • Export Citation
  • 12

    Iuchi T, Akaike M, Mitsui T, Ohshima Y, Shintani Y, Azuma H & Matsumoto T. Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circulation Research 2003 92 81–87.

    • Search Google Scholar
    • Export Citation
  • 13

    Volk T, Schmutzler M, Engelhardt L, Pantke U, Laule M, Stangl K, Grune T, Wernecke K-D, Konertz W & Kox WJ. Effects of different steroid treatment on reperfusion-associated production of reactive oxygen species and arrhythmias during coronary surgery. Acta Anaesthesiologica Scandinavica 2003 47 667–674.

    • Search Google Scholar
    • Export Citation
  • 14

    Gamstedt A & Karlsson A. Pretreatment with betamethasone of patients with Graves’ disease given radioiodine therapy: thyroid autoantibody response and outcome of therapy. Journal of Clinical Endocrinology and Metabolism 1991 73 125–131.

    • Search Google Scholar
    • Export Citation
  • 15

    Chiovato L, Fiore E, Vitti P, Rocchi R, Rago T, Dokic D, Latrofa F, Mammoli C, Lippi F, Ceccarelli C & Pinchera A. Outcome of thyroid function in Graves’ patients treated with radioiodine: role of thyroid-stimulating and thyrotropin-blocking antibodies and of radioiodine-induced thyroid damage. Journal of Clinical Endocrinology and Metabolism 1998 83 40–46.

    • Search Google Scholar
    • Export Citation