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Editorial |
Department of Clinical Medicine University of Insubria Division of Endocrinology Ospedale di Circolo 21100 Varese, Italy
Address all correspondence and requests for reprints to: Professor Luigi Bartalena, Department of Clinical Medicine, Section of Endocrinology, University of Insubria at Varese, Division of Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy. E-mail: l.bartalena{at}libero.it or luigi.bartalena{at}uninsubria.it.
Graves’ ophthalmopathy or orbitopathy (GO) is the complex of ocular manifestations of autoimmune origin (1, 2, 3) found in a large proportion of patients with Graves’ disease, in some patients with Hashimoto’s thyroiditis, or occasionally without any apparent signs of thyroid autoimmune disease in so-called "Euthyroid Graves’ Disease" (4). About half of Graves’ patients have no clinically apparent eye involvement and some 45% have mild ocular manifestations, whereas 3–5% have severe GO, which requires aggressive treatments (4). It is worth noting that the quality of life of GO patients is markedly impaired (5).
Glucocorticoids are used for GO in two different clinical settings: 1) moderately severe to severe eye disease; and 2) mild eye disease, for which radioiodine therapy is given to treat concomitant hyperthyroidism.
Moderately Severe to Severe GO
Moderately severe to severe GO can be treated by either nonsurgical or surgical approaches, mostly depending on the clinical stage of disease (6). Although the natural history of eye disease is incompletely understood, GO undergoes an initial phase of activity, during which clinical manifestations appear and progressively worsen; it then stabilizes (plateau phase) and then spontaneously tends to improve, although residual eye involvement of different degrees is almost inevitably apparent in the majority of patients when GO becomes inactive ("burnt out") (4). In the minority of patients whose GO is moderately severe to severe but inactive, nonsurgical treatments are essentially useless; in contrast, surgery, either orbital decompression to correct residual marked proptosis, eye muscle surgery to cure eye muscle dysfunction and strabismus, or eyelid surgery to manage lid retraction, represents the treatment of choice (4). If moderately severe to severe GO is active, medical treatments are often very effective, although orbital decompression may be indicated also in these cases if proptosis is severe or optic neuropathy is unresponsive to medical treatment (4). After many decades of clinical experience, systemic high-dose glucocorticoids and orbital radiotherapy, used alone or in combination, remain the most effective medical treatments (6). Recent years have witnessed lively debate on the true efficacy of orbital radiotherapy (7), but the results of several randomized, controlled studies have, with one exception (8), documented its effectiveness (9) and safety (10). Glucocorticoids have been employed either orally or parenterally, with the rationale for their use being their antiinflammatory and immunosuppressive actions. In a review we published 5 yr ago (4), we reported an overall rate of favorable response in 63% of GO patients treated with oral glucocorticoids. In the last two decades, as with other autoimmune disorders, there has been increasing use of iv glucocorticoids for GO. The results of several small, mainly uncontrolled trials suggested a higher effectiveness of iv glucocorticoids compared with the oral route. In a prospective, single-blind, randomized study of 82 patients, we confirmed this impression: both oral and iv treatments (associated with orbital radiotherapy) produced favorable results, which were, however, more frequent (88 vs. 63%) and pronounced in the iv group (11). The latter route of administration also appeared to be better tolerated by the patients, especially in terms of a much lower prevalence of iatrogenic Cushing’s syndrome (11). The cumulative dose of iv steroids we used varied, based on body weight, between 9 and 12 g, with no oral glucocorticoids between iv pulses or at the end of the entire 14-wk cycle of treatment (11). After a wider experience with this therapeutic protocol, however, we observed seven cases of acute and severe liver damage (about 0.8% of 
800 patients so treated); three patients died (12). The reasons for this hepatotoxicity remain unclear, but direct dose-related hepatotoxicity—viral hepatitis after immunosuppression, preexisting liver steatosis, or autoimmune hepatitis precipitated by a sudden reactivation of the immune system after steroid withdrawal—represent possible explanations for this phenomenon. In the last few years, we reduced the cumulative dose of iv steroids to no more than 6 g, using a small dose of oral glucocorticoids (5–10 mg prednisone in the interpulse period and for a few weeks after completion of iv pulses); in addition, we routinely check for liver steatosis, viral markers, and autoantibodies before initiation of treatment, and we carefully monitor patients during and after treatment. Using these restrictive measures, we have not observed additional cases of acute liver damage in the last 3 yr (12).
The randomized, single-blind trial by Kahaly et al. (13) published in the present issue provides additional important information. It confirms our previous finding that the iv route of glucocorticoid administration is more effective than the oral route. A treatment response was observed in 77% of iv treated patients vs. 51% of orally treated patients, with a better outcome in terms of final disease activity, disease severity, quality of life, and need for subsequent treatments. Most importantly, these positive results were achieved using even lower cumulative doses of iv glucocorticoids (4.5 g) than those we currently use. Furthermore, no oral interpulse steroids were given in this study, and it is worth noting that side effects were limited; in particular, no instances of increased liver enzymes were observed (13).
What can we conclude from our previous study (and subsequent larger experience) and from this study? First, glucocorticoids still represent an effective treatment for moderately severe to severe active GO, and the iv route is preferable to the oral route. Second, iv glucocorticoids should be used at much lower doses than previously (4.5- to 6-g cumulative dose), possibly with a small dose of oral prednisone (or equivalent) in the interpulse period and for a few weeks after completion of iv treatment. Third, a careful assessment of patients before treatment for identification of possible risk factors of liver toxicity is mandatory. And, fourth, monitoring of patients, particularly for liver function, is warranted during and after therapy.
Mild GO
Patients with nonsevere ophthalmopathy rarely require aggressive treatments. Local measures, including dark lenses for photophobia, artificial tears and ointments for gritty sensation and lacrimation, and prisms for mild diplopia, are usually sufficient to control these mild ocular manifestations (4). Prompt control of thyroid dysfunction (both hyper- and hypothyroidism) (14) and refraining from smoking (15) are probably the most important means to avoid progression of mild GO to more severe disease. Glucocorticoids are usually not indicated in patients with mild GO, with one relevant exception: in patients who receive radioiodine therapy for hyperthyroidism. Two randomized, prospective, controlled clinical trials by Tallstedt et al. (16) and our own group (17) clearly demonstrated that radioiodine administration may be associated with a progression of the ophthalmopathy. This admittedly occurs in a minority of patients (15%) and is often transient (17). Although worsening of GO is relatively uncommon, glucocorticoids play a role in this clinical setting, because, as shown in two randomized clinical trials (17, 18), they can prevent, at relatively low doses and for short periods of time, exacerbations of eye disease and can effectively cure preexisting ocular manifestations. A major question is: should "preventive" glucocorticoids be used in all patients receiving radioiodine therapy for hyperthyroidism? Certainly, some risk factors for GO progression after radioiodine have been identified; these include preexisting eye disease, severity of hyperthyroidism, high serum TSH levels (implying delayed correction of postradioiodine hypothyroidism), high TSH-receptor antibody titers, and, most important, cigarette smoking (4). Patients with one or more of these risk factors (especially smokers) should, in my opinion, be covered by glucocorticoids when treated with radioiodine (19). On the other hand, patients who have no clinical evidence of ocular involvement before radioiodine do not need glucocorticoid treatment. The prospective study of 72 GO patients treated by radioiodine therapy published by Perros et al. (20) in the present issue of the JCEM provides interesting and novel information. A large proportion of these patients (41 of 72) had previously had active ophthalmopathy (including optic neuropathy in 10 cases), but had minimally active (some might say inactive) GO when radioiodine therapy was given. None of them had ophthalmological deterioration nor did any require glucocorticoid treatment. Particular attention was paid to prompt correction of postradioiodine hypothyroidism with L-T4 replacement.
What can we conclude from this (20) and previous studies (16, 17)? Radioiodine therapy can cause GO progression in a certain proportion of Graves’ patients. Patients who smoke or have active (although mild to moderate) GO or severe hyperthyroidism are good candidates for receiving glucocorticoid coverage. Patients who have no ocular involvement or whose GO has become inactive, either following specific treatments or as the consequence of the natural history of eye disease, probably do not need glucocorticoids, unless they have other relevant risk factors for GO progression or a posttreatment flare-up. Another conclusion stemming from the Perros et al. study (20) might be that radioiodine ablation therapy for hyperthyroidism might be postponed until GO is completely burnt out, as previously suggested by Wiersinga (21). Whether this approach is appropriate or whether Graves’ patients with significant ocular manifestations should receive early thyroid ablative therapy (radioiodine, thyroidectomy, or both) in view of the putative pathogenic link between the thyroid and the orbit remains a matter of debate and conjecture.
Footnotes
This work was partly funded by grants from the University of Insubria at Varese (Fondi d’Ateneo per la Ricerca) and from the Ministry for Education, University and Research (MIUR, Rome, Italy) Project "Novel pathogenic, clinical and therapeutic aspects of Graves’ ophthalmopathy."
1 This article is dedicated to my family and all my friends who are supporting me in a very difficult struggle against cancer. 
Abbreviation: GO, Graves’ ophthalmopathy or orbitopathy.
Received July 13, 2005.
Accepted July 19, 2005.
References
This article has been cited by other articles:
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  L. Bartalena, L. Baldeschi, A. Dickinson, A. Eckstein, P. Kendall-Taylor, C. Marcocci, M. Mourits, P. Perros, K. Boboridis, A. Boschi, et al. Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO Eur. J. Endocrinol., March 1, 2008; 158(3): 273 - 285. [Full Text] [PDF]
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 A. Toft and T. C Sandeep Radioiodine treatment of hyperthyroidism BMJ, March 10, 2007; 334(7592): 483 - 484. [Full Text] [PDF]
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