Radioiodine and Graves Orbitopathy

H.X. Li’s 2016 Journal of Endocrinolog Investigation meta-analysis of nine trials with 1773 patients suggested that radioiodine therapy is a significant risk factor for development or worsening of GO in GD. But GO progression can be prevented by prophylactic glucocorticoids in patients with preexisting GO. (Steroids however have health risks.)

Compared with Thyroidectomy alone, Total thyroid ablation induces an earlier and steadier GO improvement in patients with mild to moderate-severe and active GO. Whether this is sufficient to offer Total Thyroid Ablation to patients needs further investigation. (TTA: achieved by near total thyroidectomy followed by radioiodine)

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Older articles:

N Engl J Med . 1998 Jan 8;338(2):73-8. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy.

Bartalena L et al.

Source

Istituto di Endocrinologia, University of Pisa, Italy.

METHODS: We studied 443 patients with Graves’ hyperthyroidism and slight or no ophthalmopathy who were randomly assigned to receive radioiodine, radioiodine followed by a 3-month course of prednisone, or methimazole for 18 months. The patients were evaluated for changes in the function and appearance of the thyroid and progression of ophthalmopathy at intervals of 1 to 2 months for 12 months. Hypothyroidism and persistent nyperthyroiaism were promptly corrected.

RESULTS: Among the 150 patients treated with radioiodine, ophthalmopathy developed or worsened in 23 (15 percent) two to six months after treatment. The change was transient in 15 patients, but it persisted in 8 (5 percent), who subsequently required treatment for their eye disease. None of the 55 other patients in this group who had ophthalmopathy at base line had improvement in their eye disease. Among the 145 patients treated with radioiodine and prednisone, 50 (67 percent) of the 75 with ophthalmopathy at base line had improvement, and no patient had progression. The effects of radioiodine on thyroid function were similar in these two groups. Among the 148 patients treated with methimazole, 3 (2 percent) who had ophthalmopathy at base line improved, 4 (3 percent) had worsening of eye disease, and the remaining 141 had no change.

CONCLUSIONS: Radioiodine therapy for Graves’ hyperthyroidism is followed by the appearance or worsening of ophthalmopathy more often than is therapy with methimazole. Worsening of ophthalmopathy after radioiodine therapy is often transient and can be prevented by the administration of prednisone.

British Medical Journal. 1999 July 10; 319(7202): 68–69.

Radioiodine and thyroid eye disease. Use with caution

John P Walsh, Locum lecturer

Colin M Dayan, Consultant senior lecturer

University Department of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW (Email:

Michael J Potts, Consultant ophthalmic surgeon

Ophthalmopathy is a characteristic feature of Graves’ disease, although it is usually mild or subclinical. Enlargement of the extraocular muscle can be shown by computed tomography or magnetic resonance scanning in most patients with autoimmune hyperthyroidism, but only in 10-25% of cases does this result in clinically important problems such as proptosis, conjunctival oedema, or ophthalmoplegia—and the dreaded complication of optic nerve compression is mercifully rare.¹ When it does occur, however, severe thyroid eye disease is difficult to treat and may result in disfigurement, diplopia, or visual loss. Radioactive iodine (I-131) is widely used to treat the thyrotoxicosis of Graves’ disease, but, despite its demonstrable efficacy and safety,² there have long been concerns about its possible adverse effect on thyroid eye disease. Recently definitive evidence for this link has been presented.³ As a result, all doctors should now be aware that radioiodine should be used with caution in patients with ophthalmopathy. In their large, well designed study Bartalena et al treated 443 patients with Graves’ hyperthyroidism and mild or no ophthalmopathy with methimazole until euthyroid, then randomly allocated them to continued methimazole treatment, radioiodine, or radioiodine with adjuvant corticosteroid therapy.³The groups were well matched at baseline, and hypothyroidism or persistent hyperthyroidism after radioiodine treatment was corrected promptly. The results of the study were clear cut. After radioiodine treatment 15% of patients developed new or worsened ophthalmopathy, whereas this occurred in only 3% of patients treated with methimazole and in none treated with radioiodine plus prednisone. In the radioiodine group 24% of those with pre-existing ophthalmopathy suffered an exacerbation, whereas only 8% of patients without eye disease at baseline developed it. In most cases the adverse effect was transient, lasting two to three months, but eight patients, seven of whom had ophthalmopathy at baseline, required orbital radiotherapy and high dose corticosteroids. The trial excluded patients with pre-existing moderate or severe eye disease, in whom such an exacerbation could have been disastrous. The study conclusively shows an adverse effect of radioiodine on thyroid eye disease compared to methimazole. It confirms the results of a previous randomised trial,⁴ which was criticised on methodological grounds.⁵ The mechanism by which radioiodine exacerbates ophthalmopathy is poorly understood, as is the pathogenesis of thyroid eye disease in general. Two plausible theories have been advanced.¹ The first is that radiation induced thyroid damage releases one or more antigens which are shared by thyroid and retro-orbital tissues, resulting in immune mediated ophthalmopathy. Putative antigens include a 64 kDa protein which has been isolated from eye muscle and thyroid¹^,6 and the receptor for thyroid stimulating hormone, which is expressed in retro-orbital tissues as well as in thyrocytes.⁷ Recently an animal model for thyroid eye disease has been developed in mice treated with syngeneic lymphocytes sensitised to the human thyroid stimulating hormone receptor.⁷ This strengthens the role of the receptor in thyroid eye disease and should lead to further productive research. The second mechanism by which radioiodine may exacerbate ophthalmopathy is by the rapid induction of hypothyroidism, causing increased secretion of thyroid stimulating hormone.¹ This in turn may stimulate antigen production by thyrocytes or induce proliferation or differentiation in retro-orbital preadipocytes which express the receptor for thyroid stimulating hormone. We believe that the study by Bartalena et al³ has important implications for clinical practice. Firstly, since radioiodine treatment carries a substantial risk of exacerbating pre-existing thyroid eye disease it should be avoided as far as possible in patients with active or severe ophthalmopathy, in whom medical therapy with a thionamide drug such as carbimazole is preferable. Radioiodine may be used in patients with mild eye disease but adjuvant corticosteroids should be prescribed. Oral prednisone at a dose of 0.4-0.5 mg/kg daily for one month, tapered over the following two months, was effective in this study; lower doses may also be effective but have not been tested. Secondly, patients without clinical evidence of thyroid eye disease have a small risk (8% in this study) of developing ophthalmopathy and a very low risk (<1%) of developing severe eye disease. It may be prudent to warn all patients of this possible complication, but the risks do not justify denying most patients the benefits of definitive treatment with radioiodine when indicated. In addition, the risks do not justify the routine use of corticosteroids in patients without ophthalmopathy.

Finally, it is known from previous research that smoking, a raised serum tri-iodothyronine concentration, and uncorrected hypothyroidism are also risk factors for thyroid eye disease after radioiodine.¹^,4 To minimise the risk of thyroid ophthalmopathy as far as possible, patients should therefore be advised not to smoke, be rendered euthyroid with a thionamide before radioiodine, and be followed closely to detect and correct early hypothyroidism or persistent thyrotoxicosis.

British Medical Journal. 1999 October 23; 319(7217): 1133.

James Ahlquistconsultant endocrinologist editor—The relation between treatment with radioiodine and thyroid eye disease, discussed in Walsh et al’s editorial, troubles many endocrinologists and patients.¹ There have been concerns that the use of radioiodine for thyrotoxicosis due to Graves’ disease may be associated with a deterioration in ophthalmopathy, raising the question of whether radioiodine is safe for patients with mild ophthalmic Graves’ disease. This question has been addressed recently by Bartalena et al, who showed that there is a small but significant risk of deterioration in mild ophthalmopathy after the use of radioiodine and that this risk may be reduced by simultaneous administration of systemic glucocorticoids.²

Walsh et al go further and advocate that high dose prednisone, as used in Bartalena et al’s trial, should be used routinely in all patients with mild ophthalmopathy who are to receive radioiodine, to reduce the risk of deterioration in eye disease. Surely this is not yet justified. No account has been taken of the appreciable adverse effects of giving prednisone for three months (typically 30-40 mg/day for the first month and then reducing over the next two months). In Bartalena et al’s study under a tenth of patients (7/72) with mild pre-existing ophthalmopathy who received radioiodine had a deterioration that was more than transient and required treatment.

Routine use of glucocorticoids exposes all patients who receive them to important adverse effects, while the benefit is limited to a few. Certain clinical features (for example, mild but active or progressive ophthalmopathy) are likely to mark out those who are at risk. Further studies are needed to examine this and to determine the minimum dose and duration of glucocorticoid treatment that protects against deterioration of eye disease.

At present there is a case for limiting treatment with glucocorticoids to those who have an appreciable symptomatic worsening of ophthalmopathy rather than treating all routinely. Bartalena et al did not go so far as to advocate routine glucocorticoid treatment for all patients with mild ophthalmopathy who receive radioiodine, and with good reason. Clinical trials showing that a treatment is effective are immensely useful but need to be supported by further, balanced evaluation of the risks and benefits of treatment before the original demonstration of efficacy is translated directly into routine clinical practice—a message for all clinicians, not just endocrinologists. First do no harm.