comments in NEJM about Dr. Bartalena's study

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Preventing Graves' Ophthalmopathy

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Graves' ophthalmopathy and Graves' hyperthyroidism are closely

linked, but the precise relation between these different expressions

of the same disease is poorly understood. One much-debated issue is

whether ophthalmopathy develops or becomes more severe as a result

of the treatment of hyperthyroidism with antithyroid drugs,

thyroidectomy, or radioiodine. The question must be considered in

the context of the natural history of Graves' ophthalmopathy. In

patients with Graves' hyperthyroidism, eye disease appears before

the onset of hyperthyroidism in about 20 percent, at the same time

as hyperthyroidism in about 40 percent, and after hyperthyroidism in

about 40 percent. Furthermore, this eye disease often improves

spontaneously. In a recent study of 59 patients with ophthalmopathy

who were followed for one year, the condition improved substantially

in 22 percent and slightly in 42 percent; 22 percent had no change,

and 14 percent had worsening.1

What factors underlie the development of Graves' ophthalmopathy?

Enlarged extraocular eye muscles are seen on computed tomographic

scans of the orbit in almost all patients with Graves'

hyperthyroidism, yet ophthalmopathy is clinically apparent in only

about half. In those who have ophthalmopathy, the changes are mild

(e.g., swollen eyelids and slight proptosis) in about 60 percent and

more severe (with diplopia and visual loss) in 40 percent. These

differences could be due to genetic or environmental factors. A

search for genetic markers specifically linked to susceptibility to

Graves' ophthalmopathy has so far been unsuccessful.2 More progress

has been made in delineating environmental factors. In a case–

control study, more patients with Graves' hyperthyroidism but

without ophthalmopathy were smokers than was the case among normal

subjects (odds ratio for Graves' hyperthyroidism among smokers as

compared with nonsmokers, 1.9), and the association was much

stronger for patients who had both Graves' hyperthyroidism and

ophthalmopathy (odds ratio, 7.7).3 The smokers also had more severe

ophthalmopathy than the nonsmokers. Smoking thus increases the risk

of Graves' ophthalmopathy.

The biologic explanation for this association is unknown, but recent

studies provide some interesting clues. First, orbital fibroblasts

synthesize more glycosaminoglycans when cultured under hypoxic

conditions.4 Glycosaminoglycans attract water, and excessive

production of glycosaminoglycans contributes to the characteristic

swelling of the eye muscles in Graves' ophthalmopathy. Second, serum

concentrations of soluble interleukin-1–receptor antagonist are

lower in smokers than in nonsmokers with Graves' ophthalmopathy, and

low concentrations are associated with a poor response to orbital

radiotherapy.5 The inference is that in smokers the proinflammatory

and fibrogenic effects of interleukin-1 are less inhibited. Finally,

in normal subjects smoking is associated with antibodies to heat

shock protein 72, a protein involved in autoimmune reactions that is

also expressed on orbital fibroblasts.6

The study by Bartalena and coworkers7 in this issue of the Journal

suggests that radioiodine is another nongenetic factor promoting

ophthalmopathy in patients with Graves' hyperthyroidism. These

investigators randomly assigned patients with Graves'

hyperthyroidism who had slight ophthalmopathy or none to treatment

with radioiodine, radioiodine plus prednisone, or methimazole.

Ophthalmopathy developed or worsened in 15 percent of the patients

treated with radioiodine, in none of those treated with radioiodine

and prednisone, and in 3 percent of those treated with methimazole.

The good results obtained with radioiodine plus prednisone indicate

only that prednisone is effective in patients with Graves'

ophthalmopathy. To evaluate which treatment for Graves'

hyperthyroidism entails the lowest risk of the development or

progression of eye disease, the proper comparison is between the

radioiodine and methimazole groups. The finding that ophthalmopathy

developed or worsened in patients treated with radioiodine more

often than in patients treated with methimazole confirms the results

of a previous randomized trial.8 That study, however, has been

criticized because all the radioiodine-treated patients became

hypothyroid and thyroxine therapy was slightly delayed. Subsequent

studies have demonstrated that high serum thyrotropin concentrations

after radioiodine therapy are associated with the development of

ophthalmopathy.9,10 In the study by Bartalena et al., the patients

were closely monitored for both hyperthyroidism and hypothyroidism

and either was quickly corrected. As a result, there was no relation

between thyroid status and the incidence of ophthalmopathy.

This study does not prove that the higher frequency of new or

worsened ophthalmopathy in the radioiodine group was caused by the

radioiodine therapy. It could still reflect the natural history of

ophthalmopathy, but in that case one has to assume that methimazole

has a beneficial effect on ophthalmopathy. I favor the view that

radioiodine is causally involved, because a plausible biologic

explanation exists. Destruction of the thyroid by radioiodine is

associated with an increase in thyrotropin-receptor antibody and

other thyroid antibodies in serum, presumably because of the release

of thyroid antigens and the activation of T and B lymphocytes. In

the orbit, activated T lymphocytes may bind to orbital fibroblasts

that express thyrotropin receptors or other antigens shared with

thyroid tissue. The resulting release of cytokines could stimulate

the production of glycosaminoglycans and collagen by orbital

fibroblasts, resulting in edema and fibrosis.

How should the finding that ophthalmopathy develops or worsens more

often after radioiodine therapy than after methimazole therapy be

applied to clinical practice? Should all patients with Graves'

hyperthyroidism receive prednisone for several months after

radioiodine treatment? I don't think so, for several reasons. First,

the changes in the eye after radioiodine therapy were often mild and

transient. Second, exposing many patients to the side effects of

prednisone in order to prevent eye changes in no more than 15

percent is inappropriate. The results should, however, lead to a

more thorough assessment of the risk that ophthalmopathy will

develop or worsen after radioiodine therapy in a particular patient.

In other words, what factors determine whether ophthalmopathy will

appear or become more severe after radioiodine therapy? Several can

be mentioned: preexisting active ophthalmopathy, smoking, high serum

triiodothyronine concentrations before treatment, and high serum

concentrations of thyrotropin-receptor antibodies and thyrotropin

after treatment. The patients in whom ophthalmopathy worsened after

radioiodine therapy were more often smokers than those without

worsening, and they had slightly more active ophthalmopathy. In the

study by Tallstedt et al.,8 a pretreatment serum triiodothyronine

concentration of at least 325 ng per deciliter (5 nmol per liter)

was a risk factor for ophthalmopathy, but a high concentration of

thyrotropin-receptor antibodies was not. Finally, it should be

recognized that the study by Bartalena et al. dealt with patients

who had little or no ophthalmopathy before radioiodine treatment. In

patients with more severe ophthalmopathy and especially those with

active eye disease, it seems prudent to treat hyperthyroidism with

an antithyroid drug or to administer prednisone if radioiodine is

given.

In my opinion, the study by Bartalena et al. provides conclusive

evidence that radioiodine treatment of Graves' hyperthyroidism

carries a small but definite risk of the development or worsening of

ophthalmopathy, whereas antithyroid-drug treatment does not. Even

though the changes in patients' eyes after radioiodine therapy are

usually mild and transient, I prefer to use antithyroid-drug therapy

in high-risk patients.

Wilmar M. Wiersinga, M.D.

University of Amsterdam

1100DE Amsterdam, the Netherlands

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