Original Article
Occurrence of Ophthalmopathy after Treatment for Graves' Hyperthyroidism
N Engl J Med 1992; 326:1733-1738June 25, 1992
- Abstract
- Abstract
Background.
Ophthalmopathy caused by Graves' disease may first appear or worsen during or after treatment for hyperthyroidism. It is not known, however, whether choosing to treat hyperthyroidism with antithyroid drugs, iodine-131, or surgery affects the development or aggravation of Graves' ophthalmopathy.
Methods.
We studied 168 patients with hyperthyroidism caused by Graves' disease, stratified into two age groups — 20 to 34 years (54 patients, group 1) and 35 to 55 years (114 patients, group 2). The patients in group 1 were randomly assigned to treatment with methimazole for 18 months or subtotal thyroidectomy, and those in group 2 to either of these two treatments or to iodine-131 therapy. All the patients received thyroxine to avert hypothyroidism, except those treated with iodine-131, who received thyroxine only if hypothyroidism developed. The duration of follow-up was at least 24 months.
Results.
Twenty-two patients (13 percent) had infiltrative Graves' ophthalmopathy at randomization. During follow-up, ophthalmopathy developed for the first time in 22 patients (13 percent) and worsened in 8 patients (5 percent). The frequency of the development or worsening of ophthalmopathy was similar among the patients in group 1 (medical therapy, 4 of 27 patients [15 percent]; and surgery, 3 of 27 patients [11 percent]). In group 2, ophthalmopathy developed or worsened in 4 of the 38 patients (10 percent) treated medically, 6 of the 37 patients (16 percent) treated surgically, and 13 of the 39 patients (33 percent) given iodine-131 (P = 0.02 for the comparison between the iodine-131 subgroup and the others combined). The risk of the development or worsening of ophthalmopathy increased as pretreatment serum triiodothyronine concentrations increased.
Conclusions.
As compared with other forms of antithyroid therapy, iodine-131 is more likely to be followed by the development or exacerbation of Graves' ophthalmopathy. (N Engl J Med 1992;326:1733–8.)
Media in This Article
Figure 1
Kaplan–Meier Plots of the Development or Worsening of Ophthalmopathy in Patients with Hyperthyroidism Caused by Graves' Disease.Figure 2
Probability of the Development or Worsening of Ophthalmopathy in Patients with Hyperthyroidism Caused by Graves' Disease.Article Activity
- Article
THE two most common components of Graves' disease are hyperthyroidism and ophthalmopathy. There is usually a close temporal relation between the onset of the two conditions, but ophthalmopathy can develop long before or after the onset of hyperthyroidism.1 , 2 A consistent pathogenic link between them has not been identified, and the cause of Graves' ophthalmopathy is not known.
The choice of an antithyroid drug, thyroidectomy, or iodine-131 for the treatment of hyperthyroidism caused by Graves' disease is usually dictated by the patient's preference, age, the size of the thyroid gland, the severity of hyperthyroidism, and local resources and practice. To our knowledge, there has been no controlled clinical trial evaluating the effects of the different forms of antithyroid therapy on the course of the ophthalmopathy. The results of other types of studies vary widely. In some studies no worsening of ophthalmopathy has been found in patients treated with an antithyroid drug,3 , 4 but others have found that exophthalmometer readings increased more among patients given an antithyroid drug than among those given other treatments.5 Ophthalmopathy occurred more often among patients given iodine-131 than among those treated medically or surgically in one study,6 but not in another study comparing surgery with iodine-131 therapy.7 In two retrospective studies of a total of 662 patients with hyperthyroidism caused by Graves' disease who were treated with an antithyroid drug, subtotal thyroidectomy, or low-dose iodine-131, the choice of therapy had no influence on the frequency of either the development or the exacerbation of Graves' ophthalmopathy.8 , 9
In 1983 we undertook a clinical trial in which patients with hyperthyroidism caused by Graves' disease were randomly assigned to treatment with an antithyroid drug, subtotal thyroidectomy, or iodine-131 therapy. The trial was designed to answer two questions. First, is there a difference in the frequency of the development or aggravation of Graves' ophthalmopathy among young patients treated with an antithyroid drug as compared with subtotal thyroidectomy and among older patients treated with an antithyroid drug, subtotal thyroidectomy, or iodine-131? And second, can factors that predict the development of Graves' ophthalmopathy be identified?
Methods
Study Design and Evaluations
The study was approved by the ethics committee of the Karolinska Institute, and all the patients gave informed consent.
Between November 1983 and June 1990, all patients with hyperthyroidism caused by Graves' disease who were referred to us were evaluated for inclusion in the study. All 179 patients who agreed to enter the study were included. The diagnosis of hyperthyroidism caused by Graves' disease was based on the presence of symptoms and signs of hyperthyroidism, a diffuse goiter, elevated total and free thyroxine and total triiodothyronine (T3) concentrations in serum, detectable serum concentrations of thyrotropin-receptor antibodies, increased uptake of iodine-131 by the thyroid, and thyroid radionuclide scans showing a diffuse pattern of isotope uptake. Patients with a history of thyroid disease were excluded.
All the patients were examined by the study ophthalmologist before any therapy was begun. The eye examination included testing of visual acuity, tonometry, Hertel exophthalmometry, slitlamp examination, and tests of extraocular-muscle function with Lees' screen. The results of the examination were summarized as an ophthalmopathy-index score, which was based on a modification of the American Thyroid Association's classification of ocular changes in Graves' disease.10 Four categories of findings (soft-tissue involvement, exophthalmos, extraocular-muscle involvement, and sight loss) were scored from 1 to 3 according to their severity, giving a maximal overall score of 12. A score of 1 or more was considered to indicate the presence of ophthalmopathy. We omitted corneal changes from our index because they are not specific for Graves' ophthalmopathy.
Through May 1991, 173 of the 179 patients had been followed for at least 24 months after therapy began (range, 24 to 90; mean, 47), and 6 patients for less than 24 months. The latter six were therefore not included in this analysis. Five patients were withdrawn from the study shortly after randomization (three because of noncompliance, one who rejected the assigned iodine-131 treatment, and one in whom the diagnosis was not confirmed). A further six patients did not complete their treatment: two rejected the assigned treatment (iodine-131 in one case and surgery in the other), the diagnosis was not confirmed in two, and two had drug-induced skin rashes; the six were followed, however, and remained in the study. This report therefore includes 168 patients, analyzed according to intention to treat.
The patients were stratified into two groups according to age at entry into the study. Group 1 included the patients who were 20 to 34 years old, and group 2 those who were 35 to 55 years old. The patients in group 1 were randomly assigned to treatment with an antithyroid drug plus thyroxine (medical therapy) or subtotal thyroidectomy followed by thyroxine (surgery); in group 2, iodine-131 therapy was included as a third alternative. Randomization was performed with use of balanced lists, one for each age group. The mean age, number of tobacco smokers, and initial serum concentrations of T3, thyroxine, and thyrotropin-receptor antibodies were similar in the two groups, except for a significant difference in the level of thyrotropin-receptor antibodies between the patients who underwent surgery and those who received iodine-131 in group 2 (Table 1Table 1
Clinical and Demographic Characteristics of the Patients with Hyperthyroidism Caused by Graves' Disease.*). Apart from the patients who underwent surgery, all were treated as outpatients. The follow-up examinations were performed in the department in which therapy was given. These examinations included clinical evaluations, assessment of ophthalmologic status, and measurements of body weight and serum concentrations of T3, thyroxine, thyrotropin, and thyrotropin-receptor antibodies. The patients in the medical-therapy subgroups also had peripheral-blood leukocyte counts performed, and the patients in the surgery subgroups hemoglobin and serum calcium measurements.Therapy and Follow-up
Medical Therapy
Medical therapy consisted of the administration of 10 mg of methimazole four times daily for 18 months. To avert hypothyroidism, thyroxine (0.1 to 0.3 mg daily; mean, 0.17) was added after three to five weeks in a dose that resulted in a normal serum T3 and a low serum thyrotropin concentration. Propranolol (60 to 240 mg per day) or metoprolol (50 to 300 mg per day) was given initially for a few weeks. Methimazole and thyroxine were discontinued simultaneously. The patients were examined monthly for two months after the initiation of treatment and then every three months. After treatment was discontinued, the patients were examined twice during the first year and then once yearly.
Surgery
The patients who underwent surgery were given propranolol before the operation in a dose of at least 40 mg three to four times daily, or an equivalent dose of metoprolol. The median duration of this therapy before surgery was 26 days. The operation was a bilateral subtotal thyroidectomy, leaving the posterior capsule and approximately 1 g or less of each thyroid lobe. After surgery all the patients were given thyroxine to avert hypothyroidism (0.1 to 0.3 mg daily; mean in both age groups, 0.17 mg). The patients were seen after five weeks, then every three months during the first year after surgery and once yearly thereafter.
Iodine-131
A single oral dose of iodine-131 was administered to the patients in the iodine subgroup. The dose was based on the size of the thyroid, the 24-hour iodine-131 uptake, and the estimated effective half-life of the isotope in the thyroid. The dose was intended to deliver 120 Gy to the thyroid; the calculations have been described elsewhere.11 Unless contraindicated, propranolol or metoprolol was given to all the patients. The patients were examined 6 and 10 weeks after iodine-131 therapy, and the 24-hour uptake of iodine-131 by the thyroid was measured at 10 weeks. Eighteen patients were given more than one dose of iodine-131 from 10 weeks to 23 months after the initial treatment. Seven of these 18 patients had persistent hyperthyroidism at 10 weeks, 3 had recurrent hyperthyroidism without ophthalmopathy, 5 had recurrent hyperthyroidism and developing ophthalmopathy, and 3 had ophthalmopathy and no evidence of hyperthyroidism but continued to have iodine-131 uptake in the thyroid despite thyroxine therapy. Among the 18 patients who received more than one dose of iodine-131, ophthalmopathy worsened in 2 and developed in 10. Of the 10 patients, 3 received the second dose of iodine-131 before the ophthalmopathy developed. The patients who were euthyroid 10 weeks after iodine-131 therapy were examined every 3 months until they had biochemical evidence of hypothyroidism. All the patients eventually had hypothyroidism and received thyroxine (0.1 to 0.3 mg daily; mean, 0.15); thereafter, they were examined twice yearly for two years and then once yearly.
Ophthalmologic Follow-up
The patients were examined and their ophthalmopathy-index scores determined by the ophthalmologist after one year if the first examination had not revealed any signs of ophthalmopathy (i.e., an index score of 0). Patients were referred to the ophthalmologist if eye symptoms or signs developed during follow-up. Patients with ophthalmopathy (index score, ≥1) had monthly ophthalmologic examinations until their condition improved or stabilized; they were then examined one year later. The ophthalmologist was unaware of the type of therapy given except in the cases of patients who underwent surgery and those referred because of ocular problems.
Laboratory Studies
Serum T3 and thyroxine concentrations were measured by radioimmunoassay with kits obtained from Pharmos Group (Turku, Finland). Serum free thyroxine concentrations were measured by radioimmunoassay with kits from Diagnostic Products (Los Angeles). Serum thyrotropin concentrations were measured by immunometric assay with kits from Delfia (Kabi-Pharmacia, Uppsala, Sweden), and thyrotropin-receptor antibodies by radioreceptor assay with kits provided by Dr. B. Rees Smith (Cardiff, United Kingdom). The normal reference ranges were as follows; T3, 1.1 to 2.5 nmol per liter; thyroxine, 75 to 150 nmol per liter; free thyroxine, 9 to 21 pmol per liter; thyrotropin, 0.4 to 4.5 mU per liter; and thyrotropin-receptor antibodies, <10 percent. Measurements of 24-hour iodine-131 uptake by the thyroid, thyroid radionuclide scanning with iodine-131 or [99mTc]pertechnetate, and fine-needle aspiration biopsies of the thyroid were performed before therapy in all the patients. Biopsy was successful in 155 patients. The results were recorded as "lymphocytes present" (a higher number in the thyroid specimen than in the blood in the aspirate) or "lymphocytes not present."
Statistical Analysis
All the data were stored with use of Medlog software (Information Analysis, Mountain View, Calif.). The hypothesis that there were no differences among treatments with regard to the occurrence of ophthalmopathy within two years after the initiation of therapy was tested by chi-square analysis. Kaplan–Meier survival curves (Fig. 1Figure 1
Kaplan–Meier Plots of the Development or Worsening of Ophthalmopathy in Patients with Hyperthyroidism Caused by Graves' Disease.) were used to illustrate the pattern of occurrence of ophthalmopathy according to treatment group. When searching for prognostic factors, we applied logistic-regression analysis, with the outcome variable defined as the development or worsening of ophthalmopathy within two years after treatment. Using the regression coefficients from this analysis, we could draw the risk functions (Fig. 2Figure 2Probability of the Development or Worsening of Ophthalmopathy in Patients with Hyperthyroidism Caused by Graves' Disease.) by means of Minitab software. In a final regression analysis, all the available follow-up information for each patient was used.Results
The mean serum T3, thyroxine, and free thyroxine concentrations were within the normal reference intervals in all subgroups within six weeks after the initiation of therapy (data not shown). The serum concentrations of thyrotropin-receptor antibodies decreased gradually during the first year in the surgically and medically treated subgroups. In the iodine-131 subgroup, however, serum thyrotropin-receptor antibodies increased during the first year, after which they decreased (mean peak value, 66 percent).
During follow-up after the discontinuation of medical therapy, 10 of the 27 patients (37 percent) in group 1 and 12 of the 38 patients (32 percent) in group 2 who received this therapy had recurrent hyperthyroidism. Eight patients who received medical therapy had skin rashes, and one had symptoms similar to those of systemic lupus erythematosus; no patient had agranulocytosis. None of the patients treated surgically had permanent hypoparathyroidism or recurrent laryngeal-nerve damage.
Ophthalmopathy
Twenty-two patients (13 percent) had ophthalmopathy (i.e., an index score ≥1) at the time of the initial ophthalmologic examination, before any antithyroid treatment. The distribution of the index scores at that time is shown in Table 2Table 2
Pretreatment Ophthalmopathy-Index Scores of Patients with Hyperthyroidism Caused by Graves' Disease, According to Treatment.. Of the 22 patients, 4 were among the 54 patients in group 1 (7 percent) and 18 were among the 114 patients in group 2(16 percent). Eighty-seven of the 168 patients (52 percent) had ophthalmologic abnormalities (including those with only lid retraction and lid lag).New ophthalmopathy developed in 22 patients (13 percent), and 8 patients (5 percent) had worsening of preexisting ophthalmopathy after therapy. The distribution of the patients with regard to the changes in ocular status is shown in Table 3Table 3
Changes in the Ophthalmopathy-Index Score after Treatment and the Risk of Development or Worsening of Ophthalmopathy.. There was no significant difference in the frequency of the development or worsening of ophthalmopathy among the medically and surgically treated patients in group 1 (chi-square, 0.16; P>0.05). In group 2, however, ophthalmopathy developed or worsened in 33 percent of the patients treated with iodine-131, as compared with 10 percent of those treated medically and 16 percent of those treated surgically (chi-square, 6.75 with 2 df; P = 0.03 [P = 0.02 for the comparison of the iodine-131 subgroup with the others combined]). The probability of the development or worsening of ophthalmopathy within the first five years is shown in Figure 1.The ophthalmopathy was mild in the majority of the 30 patients in whom it developed or worsened (Table 4Table 4
Characteristics of the 30 Patients with Hyperthyroidism Caused by Graves' Disease in Whom Ophthalmopathy Developed or Worsened.). The mean maximal index score ranged from 1.8 (group 1, medical-therapy subgroup) to 3.3 (group 2, medical-therapy subgroup), and the highest score in any patient was 7. Only 6 of the 168 patients (4 percent), all in group 2, required treatment for ophthalmopathy. One of these patients belonged to the medical-therapy subgroup, one to the surgical subgroup, and four to the iodine-131 subgroup. All six patients were treated with prednisolone, and the patient in the medical-therapy subgroup and three of those in the iodine-131 subgroup also received orbital radiotherapy. No patient lost vision because of optic-nerve compression, and none needed orbital decompression or eye-muscle surgery. Five patients had eyelid surgery. The ophthalmopathy developed or worsened in 24 patients within the first year after therapy began and in 6 patients during the second year.Cytologic Studies
The frequency with which lymphocytes were detected in the fine-needle aspirates of the thyroid ranged from 26 to 48 percent in the five subgroups (P>0.05). Among the 51 patients with lymphocytes in the fine-needle aspirates, ophthalmopathy developed in only 3 (6 percent), whereas it developed in 25 of the 104 patients (24 percent) whose aspirates did not contain lymphocytes. Among the patients who underwent biopsies, ophthalmopathy developed in 21 and worsened in 7; the proportions of biopsy specimens containing lymphocytes were 14 percent (3 patients) and 0 percent, respectively (P>0.05).
Predictive Factors
By means of a series of logistic-regression analyses, we sought possible predictive factors for the development or worsening of ophthalmopathy. Apart from the treatment, the variables that proved important were the pretreatment serum T3 concentration and the degree of lymphocytic infiltration of the thyroid. The influence of the T3 concentration and the type of treatment on the risk of the development or worsening of ophthalmopathy is shown in Figure 2.
A proportional-hazards regression analysis based on all available follow-up information and including the background variables of sex and age for all patients revealed that the following explanatory variables were statistically significant: treatment with iodine-131 (relative risk, 3.6; 95 percent confidence interval, 1.6 to 8.2; P = 0.002), serum T3 concentration before treatment (P = 0.002), and the presence of lymphocytes in the thyroid (relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.8; P = 0.02). When this analysis was performed for the patients in group 2 alone, the pattern was the same, and the relative risk of ophthalmopathy associated with iodine-131 treatment was 4.1 (95 percent confidence interval, 1.7 to 10.0; P = 0.02).
The importance of the pretreatment serum T3 concentration is further demonstrated in Table 5Table 5
Patients with Hyperthyroidism Caused by Graves' Disease According to Pretreatment Serum T3 Concentrations and the Development or Worsening of Ophthalmopathy., which shows that a concentration of ≥5 nmol per liter was associated with an increased risk of the development or worsening of ophthalmopathy. Among the patients treated with iodine-131, the risk increased from 10 percent (2 of 20 patients) to 58 percent (11 of 19 patients). Among all the other patients the corresponding increase was from 2 percent (1 of 57 patients) to 22 percent (16 of 72 patients).There was a positive correlation between the pretreatment serum concentrations of T3 and thyrotropin-receptor antibodies, but in the regression analyses the level of thyrotropin-receptor antibodies was not a significant determinant of ophthalmopathy.
Discussion
There is no entirely satisfactory classification of the ocular changes in Graves' disease. The original classification of the American Thyroid Association10 has been modified several times,12 , 13 and several ophthalmopathy indexes have been constructed to allow a quantitative evaluation of ophthalmopathy.14 15 16 17 In this study we quantified the ocular changes using an index derived by summing the scores for each of four of the components of ophthalmopathy,14 and all evaluations were performed by one ophthalmologist. This type of index gives the same weight to the different components of ophthalmopathy, but the magnitude of the score does not necessarily correlate with the extent of subjective symptoms in an individual patient.
We included patients in our study regardless of the presence or absence of Graves' ophthalmopathy. During follow-up, relatively more patients (22) had new ophthalmopathy than had worsening of preexisting ophthalmopathy (8). Thus, most patients had no ophthalmopathy initially and it did not develop in most during follow-up, whatever their antithyroid treatment.
The risk of the development or worsening of ophthalmopathy was greater with increasing pretreatment serum T3 concentrations. The serum total thyroxine concentration did not have the same predictive value, although it was significant in some analyses that did not include serum T3; the serum free thyroxine concentration had no predictive value. It is unlikely that T3 itself induces or aggravates ophthalmopathy; it has no effect on the synthesis of hyaluronate by orbital fibroblasts in vitro.18 It is more likely that high serum T3 concentrations indicate the presence of severe metabolic or immunologic disturbances that predispose a patient to Graves' ophthalmopathy.
The method of treatment also influenced the course of the eye changes. The risk of the development or worsening of ophthalmopathy was significantly greater for a patient with a high serum T3 concentration who was treated with iodine-131 than for a patient treated with methimazole or surgery. The reason for this relation is unknown. It has been suggested that post-treatment hypothyroidism is important in the development of ophthalmopathy.19 None of the patients treated with methimazole or surgery had post-treatment hypothyroidism, however, because all were treated with thyroxine soon after surgery or the initiation of methimazole therapy. On the other hand, in the iodine-131 group biochemical hypothyroidism was allowed to develop before thyroxine therapy was initiated. A possible relation between the development of hypothyroidism after treatment and ophthalmopathy thus cannot be ruled out, but such a correlation was not found (data not shown).
The patients given methimazole received a relatively high daily dose of the drug throughout the 18-month treatment period, with thyroxine added soon after the start of therapy to prevent iatrogenic hypothyroidism. We and others20 have used this combination routinely for several decades; it is safe and convenient and requires a minimum of follow-up visits during treatment. In addition, a high dose of methimazole may produce a higher rate of remission of hyperthyroidism than a low dose.21
The presence or absence of lymphocytes in the thyroid was also predictive of the development or worsening of ophthalmopathy, the risk being lower if lymphocytes were present. None of the study patients had a history or any signs of thyroiditis, and all had an elevated 24-hour uptake of iodine-131 by the thyroid before treatment.
Many questions remain as to how patients with hyperthyroidism caused by Graves' disease should be treated. One concerns the influence of the severity of hyperthyroidism on the choice of therapy. We found that the risk of the development or worsening of ophthalmopathy increased from 10 to 58 percent among the older patients if their serum T3 concentrations before treatment were ≥5 nmol per liter and they were treated with iodine-131. For the other patients the corresponding increase was from 2 to 22 percent. In the patients with high serum T3 concentrations who were given methimazole, the risk of ophthalmopathy was lower, but there is a risk of relapse of hyperthyroidism in such patients after the drug is withdrawn.22 , 23 Similarly, if patients are treated surgically, ophthalmopathy is not likely to develop or worsen, but this treatment has more risks than methimazole or iodine-131. Furthermore, the three treatments for hyperthyroidism can be carried out in a multitude of ways, and opinions about the treatment of choice vary, as surveys of physicians have shown.20 , 24 In the final analysis, one must also consider the rates of relapse as well as the morbidity caused by the treatment.
It is possible that the risk of the development or worsening of ophthalmopathy can be reduced by modifying the iodine-131 therapy. For example, administering glucocorticoids before iodine-131 therapy may limit the progression of ophthalmopathy.25 Pretreatment with an antithyroid drug or the administration of thyroxine soon after iodine-131 therapy might have the same effect.
Supported by grants from the Swedish Medical Research Council (5992 and 02330), the Gustav V Jubilee Foundation, and the Foundation of the Karolinska Institute.
We are indebted to the Oncology Center and the staff of the Departments of Oncology, Endocrinology, and Surgery at the Karolinska Hospital and to the Department of Immunology, National Laboratory of Bacteriology, which performed all the thyrotropin-receptor-antibody analyses.
Source Information
From St. Erik's Eye Hospital, Stockholm (L.T.); the Departments of General Oncology, Radiumhemmet (G.L., H.B.), Endocrinology (O.T.), and Surgery (G.W.), Karolinska Hospital, Stockholm; the Department of Medicine, St. Goran's Hospital, Stockholm (J.-G.L.); and the Department of Statistics, University of Uppsala, Uppsala (A.T.) — all in Sweden. Address reprint requests to Dr. Tallstedt at the Department of Ophthalmology, Huddinge University Hospital, S-141 86, Huddinge, Sweden.
*The members of the study group are listed in the Appendix.
Appendix
The Thyroid Study Group also included the following institutions and investigators: Department of Endocrinology, Karolinska Hospital: H.E. Sjöberg, M. Sääf, and M. Thorén; Department of Internal Medicine, Sabbatsberg's Hospital, Stockholm: I. Ålinder; Department of Surgery, Karolinska Hospital: L.-O. Farnebo and B. Hamberger; Department of General Oncology, Radiumhemmet, Karolinska Hospital: P. Hall; St. Erik's Eye Hospital: B. Tengroth; Department of Pathology, Karolinska Hospital: T. Löwhagen; Department of Immunology, National Laboratory of Bacteriology, Stockholm: R. Norberg; and Department of Chemistry, Karolinska Hospital: T. Curstedt.
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