THYROID Volume 2, Number Mary Ann Liebert,
2, 1992 Inc., Publishers
Relationship Between Graves' Ophthalmopathy and Type of Treatment of Graves' Hyperthyroidism C. MARCOCCI, L. BARTALENA, F. BOGAZZI, G. BRUNO-BOSSIO, and A. PINCHERA
ABSTRACT The relationship between the treatment of Graves' hyperthyroidism and the course of ophthalmopathy is rather unclear. Antithyroid drugs may improve eye manifestations, possibly by restoring normal thyroid function and reducing orbit-directed autoimmune reactions, whereas ophthalmopathy may worsen after radioiodine administration or thyroidectomy. This might occur because of a treatment-related release of thyroid antigens and activation of the autoimmune response that might involve the orbit. On the other hand, some authors suggest that complete thyroid ablation, either by radioiodine or surgery, might be beneficial for ophthalmopathy. However, reported effects of radioiodine and thyroidectomy on Graves' ophthalmopathy are conflicting. This may be due, at least in part, to the retrospective feature of most studies and the lack of precise evaluation of ocular involvement. Two prospective studies were performed in which patients with Graves' disease with mild or no ophthalmopathy were randomly assigned to treatment by radioiodine or subtotal thyroidectomy alone or in association with systemic glucocorticoids. Both treatments were followed by a progression of pre-existing mild ophthalmopathy in a substantial proportion of cases: glucocorticoids prevented such an exacerbation. Ophthalmopathy did not develop in patients without clinical evidence of eye disease prior to therapy. Therefore, it is recommended that a course of glucocorticoids be instituted concomitantly with radioiodine therapy or thyroidectomy in Graves' patients with some degree of ocular involvement.
INTRODUCTION
Several origin
pieces OF evidence indicate the autoimmune of Graves' ophthalmopathy, but its precise pathogenesis still remains to be clarified, and it is unclear whether it is an integral part of Graves' disease or a separate entity (1,2). Severe eye manifestations occur only in a minority of Graves' patients, but orbital alterations can be shown by sophisticated techniques in almost all cases, with little, if any, clinical evidence of eye disease present (3). In most cases, there is a close temporal relationship between the onset of hyperthyroidism and that of ophthalmopathy, but ocular manifestations may begin after thyrotoxicosis (4,5). Because most patients in whom the eye disorder follows the onset of hyperthyroidism have already received treatment for thyrotoxicosis, the question has been raised as to whether the
Istituto di
hyperthyroidism might have any role in the appearance of ophthalmopathy or the course of preexisting eye disease. Available information on this issue is rather unclear and somewhat contradictory because of the small series of patients, the different methods of evaluation of eye involvement, and the limited number of prospective studies. This problem is complicated by the observation that the natural course of Graves' ophthalmopathy is highly variable, with unpredictable exacerbations and remissions. This makes it difficult to establish whether a given treatment for hyperthyroidism affects the course of ophthalmopathy. Any discussion on this issue should answer the following questions: What is the effect of thyroid status on the activity of the putative immune phenomenon responsible for the eye disease? Is there any specific mechanism by which treatment of hyperthyroidism, by either antithyroid drug ( ATD), radioiodine, or surgery, could influence the ophthalmopathy? management of
Endocrinología, Université di Pisa, 56018 Tirrenia-Pisa, Italy. 171
MARCOCCI ET AL.
172
INFLUENCE OF THYROID STATUS ON ACTIVITY OF IMMUNE SYSTEM AND ON GRAVES' OPHTHALMOPATHY The effects of thyroid status on the immune system are rather Most studies on human hyperthyroidism or hypothyroidism have been performed in patients with Graves' disease or Hashimoto's thyroiditis. Since these conditions are autoimmune diseases, it is often difficult to establish whether the immunologie abnormality is the consequence of the altered thyroid status or a manifestation of the underlying disturbance of immune surveillance. Several studies indicate that thyroid hormones stimulate the activity of the immune system, probably through depression of suppressor T cell number and functions (6,7). Restoration of euthyroidism in Graves' patients after treatment with antithyroid drugs of the thionamide group (methimazole, carbimazole, and propylthiouracil) is associated with a significant fall of TSHreceptor, antithyroglobulin (anti-Tg) and antithyroid peroxidase (anti-TPO) autoantibody titers (8-11). In apparent contrast with these findings is the observation of a marked decrease of serum anti-Tg and anti-TPO antibodies in patients with idiopathic myxedema or hypothyroid Hashimoto's thyroiditis submitted to L-thyroxine treatment (12,13). In the latter study (13), no significant effect of L-thyroxine was documented in patients with euthyroid Hashimoto's thyroiditis and normal circulating TSH concentrations before therapy. The mechanism by which correction of hyperthyroidism and hypothyroidism leads to a decreased activity of thyroid autoimmunity is still debated. As already discussed, thyrotoxicosis by itself may affect the immune system, possibly through a decrease in the number and function of generalized T suppressor lymphocytes (7,14,15). This explanation, however, is not supported by the observation of a fall in thyroid-stimulating antibodies (TSAb) (as assessed by LATS bioassay) in 2 euthyroid Graves' patients receiving methimazole (MMI) combined with T3 to maintain the euthyroid state (16). On the other hand, an important role of thyroid function itself is suggested by the observation that TSAb also decline in Graves' disease patients treated with potassium perchlorate (17), which has no recognized immunosuppressive effects ( 18). A direct effect of thyroid hormones on the immune system is suggested by the relationship between serum levels of soluble interleukin 2 receptor, a marker of activity of the immune system, and serum concentrations of free thyroid hormones (19). Alternatively, a direct suppressive effect of MMI on thyroid autoimmune reactions, independent of changes in the thyroid status, has been postulated on the basis of the results obtained in Hashimoto's patients treated with MMI and L-T4 to keep serum concentrations of thyroid hormone constant (20). However, a fall of circulating thyroid autoantibodies also was found in similar groups of patients given either MMI in combination with L-T4 or L-T4 alone (12,21), suggesting that in this model, the main active substance was actually thyroxine rather than MMI. At present, the hypothesis that ATD or thyroid hormones or both may interfere with the immune system by reducing thyroid autoantigen availability and presentation is the one that provides the best explanation for the fall in serum thyroid autoantibody levels observed in hypothyroid Hashimoto's patients after prolonged treatment with L-T4 (13) and in patients with Graves' disease after ATD therapy (11). Administration of thyroid
complex.
hormones or ATD is in fact associated with a decrease in serum TSH or TSAb levels, respectively, leading to reduced thyroid stimulation. In keeping with this concept are several in vitro studies providing evidence that TSH and TSAb increase the synthesis and expression of TPO by thyroid cells (22,23). It should be noted that both TSH (24) and TSAb (25) enhance the gamma-interferon-dependent HLA-DR expression by thyroid cells. It could be envisaged that both TSH and TSAb are very important in perpetuating mechanisms operating in Hashimoto's thyroiditis and Graves' disease, respectively. Whether MMI may modulate thyroid autoantigen expression by thyroid stimulators is still uncertain (26). One of the pathogenetic hypotheses of Graves' ophthalmopathy is that thyroid antigen, e.g., thyroglobulin, and thyroid autoantibodies can reach the orbit through the lymphatic system and trigger a local inflammatory reaction mediated by humoral and cellular mechanisms, eventually damaging the ocular structures (27). Alternatively, an autoimmune reaction against antigens shared by the thyroid and the orbital tissues may trigger the onset of or exacerbate eye disease. In either case, the thyroid tissue as a source of antigen(s) plays a central role in the development and eventually in the maintenance of ophthalmop-
athy (28). It might be expected, therefore, that following correction of thyrotoxicosis. Graves' ophthalmopathy should improve. This has proven to be the case in a study by Prummel at al. (29), who found that the simple correction of thyrotoxicosis in a few weeks by ATD was associated with an improvement of eye manifestations, particularly of soft tissue and extraocular muscle involvement, whereas no significant changes occurred in patients maintained euthyroid with MMI and followed for 20 weeks. Some authors have had the impression that ophthalmopathy is more likely to progress in patients who become hypothyroid (30,31). Karlsson
et al.
(32) found that
a
treatment-induced
hypothyroid phase could be identified in 6 of 15 patients developing severe eye disease following radioiodine therapy. The mechanism by which hypothyroidism would worsen ophthalmopathy is open to speculation. As already mentioned, TSH has been shown to increase the expression of thyroid specific antigens in vitro (22,23) and, in the presence of gammainterferon, to induce the expression of class II antigens on thyroid cells (24,25). Thus, the stimulation of thyroid cells through the TSH receptor either by TSH (hypothyroidism) or by an increase in TSH-receptor antibodies (radioiodine) might result in a pathogenetic signal leading to an exacerbation of eye disease. Radioiodine therapy might worsen ophthalmopathy not only by activation of the autoimmune thyroid disease by release and presentation of antigen or destruction of radiosensitive suppressor T lymphocytes but also by inducing hypothyroidism. Following this hypothesis, these authors have suggested the use of thyrostatic drugs combined with thyroxine in all patients who undergo radioiodine therapy to prevent the rise of thyroid autoantibodies and to prevent hypothyroidism (32). EFFECT OF VARIOUS TREATMENTS OF GRAVES' HYPERTHYROIDISM ON THE COURSE OF OPHTHALMOPATHY As already mentioned, even if there is a close temporal relationship between the onset of hyperthyroidism and that of
THYROID TREATMENT AND GRAVES' OPHTHALMOPATHY
No treatment
|
]
MMI Tx
131-1 Remission (after
MMI)
C «s
c ai
01
Temporal relationship between the onset of hyperthyroidism and the onset of ophthalmopathy in 108 Graves patients with severe ophthalmopathy. Pre, ophthalmopathy before hyperthyroidism; Cone, ophthalmopathy concomitant with hyperthyroidism; Post, ophthalmopathy after hyperthyroidism. MMI, methimazole; Tx, subtotal thyroidectomy; 131-1, radioiodine. FIG. 1.
ophthalmopathy,
in a significant proportion of patients the manifestations become evident only long after the onset of thyroid hyperfunction (4,5). To investigate whether in this group the onset of ophthalmopathy might be related to the treatment of hyperthyroidism, we have reviewed the medical records of 108 patients with severe ophthalmopathy occurring after hyperthyroidism (Fig. 1 ). About half of the patients had not received any treatment for hyperthyroidism when eye disease occurred. Of the remaining 50%, the majority had started methimazole therapy, and a few patients had been treated with radioiodine or surgery. Thus, ophthalmopathy may follow hyperthyroidism even in the absence of treatment. The finding that among the treated patients methimazole therapy was most often associated with the onset of ophthalmopathy is likely simply to reflect the fact that ATD is most commonly used as the first form of treatment of Graves' hyperthyroidism in Italy. Moreover, it is worth noting that in a substantial proportion of Graves' patients, ophthalmopathy may occur in the absence of hyperthyroidism (so-called euthyroid Graves' ophthalmopathy), suggesting that the mechanism underlying its onset, maintenance, and worsening may be independent of thyrotoxicosis and its treatment (5).
Antithyroid drug therapy We found that methimazole had no major effect on eye manifestations in a group of Graves' patients with mild ophthalmopathy, who were followed for 6-12 months after initiation of therapy. Over the same period of time, no clinical evidence of ophthalmopathy was found in another group of Graves' patients with no ophthalmopathy before therapy. These data are in agreement with those reported by Aranow and Day (33), who
'
retrospectively evaluated the course of ophthalmopathy in 129 patients with Graves' disease treated with ATD. Since in none of them did the eye disease worsen, these authors concluded that ATD therapy is less likely to be followed by a worsening of ophthalmopathy than is thyroidectomy or radioiodine. A similar conclusion was reached by Solem et al. (34), who prospectively evaluated 105 thyrotoxic Graves' patients during a 24-month course of carbimazole therapy. Treatment was supervised very closely to avoid iatrogenic hypothyroidism. None of the 69 patients with eye involvement had a progression of eye disease. Inflammatory changes usually subsided gradually with achievement of euthyroidism. None of the 34 patients without ophthalmopathy before treatment developed it after therapy. Thus, with the exception of Gwinup et al. (35), who found that propylthiouracil was associated more often than other treatments with a progression of ophthalmopathy (evaluated, however, only on the basis of changes of proptosis), there is a wide consensus that ATD therapy per se does not influence eye disease (33-36). The problem of medical treatment of Graves' hyperthyroidism, however, is that in most patients a relapse of thyrotoxicosis follows withdrawal of treatment. This occurs concomitantly with the reactivation of autoimmune phenomena responsible for thyroid disease and probably for ophthalmopathy, as indicated by the increase in TSH-receptor and other thyroid autoantibody levels at the time of relapse, generally associated also with an exacerbation of eye signs. In this regard, the low prevalence of recurrences of hyperthyroidism in patients in whom L-T4 was added to MMI after restoration of euthyroidism and was continued after MMI withdrawal might prove to be associated with a more favorable course of ophthalmopathy
(37).
MARCOCCI ET AL.
174 Table 1. Progression of Graves' Ophthalmopathy Following Radioiodine Therapy of Hyperthyroidism
Author Werner (53) Kriss et al. (39)a Hamilton et al. (30) Bartalena et al. (51)a Sridama and DeGroot (52) Vestergaard and Laurberg (48)a
No. of patients
Progression (%)
161 24 98 26 241 22
5 8-25 5 56 23 23
"Prospective study. Radioiodine
treatment
There are several reports in the literature suggesting that ophthalmopathy may worsen following therapeutic procedures associated with the leakage of antigens from the thyroid, such as thyroid surgery (38), radioiodine (39-41), and even irradiation of the neck for nonthyroidal diseases (42,43). It has been claimed that after thyroid injury (radioiodine or thyroid surgery), there is a liberation of thyroid antigen(s), leading to an increased production of autoantibodies, such as TSH-receptor, thyroglobulin, and thyroid peroxidase autoantibodies (44-47). This, in turn, may initiate the eye injury. An association between worsening of ophthalmopathy and radioiodine treatment was reported originally by Kriss et al. in 1967 (39), who found that the onset of ophthalmopathy coincided with the appearance of LATS in the serum of 3 patients. This observation has been confirmed subsequently by other authors (48,49), including ourselves in a prospective study (50,51). However, this view is not shared by all authors (30,33,52,53) (Table 1). In particular, Sridama and DeGroot (52), in a retrospective analysis of 573 patients with Graves'
disease, found that there was no difference in the occurrence of posttreatment ophthalmopathy among patients who did not have overt eye disease before treatment,
independent of the therapy
employed (radioiodine, antithyroid drug, or surgery; 4.9%, 6.7%, and 7.1%, respectively). The worsening of ophthalmop-
athy was more frequent in patients who had ocular signs before treatment, but the rate of progression was similar in the three groups (22.7%, 18.9%, and 19.2%, respectively). The discrepant data of the literature might be, at least in part, attributed to the fact that most reports were retrospective, precise measurement of ocular involvement often was lacking, and ophthalmopathy often was evaluated too long after radioiodine therapy, thus obscuring any possible relation between radioiodine administra-
tion and the outcome of eye disease. To address this problem, in 1987 we started a prospective study, in which hyperthyroid Graves' patients who had slight or no signs of ophthalmopathy and no change in their ocular status for at least 3 months before treatment were randomly assigned to a group treated with radioiodine alone (Group 1) or to a group concomitantly treated with radioiodine and systemic glucocorticoids (Group 2) (0.4-0.5 mg prednisone/kg body weight for 1 month, with subsequent tapering and withdrawal after 3 months) (50,51). Before treatment, 10 patients in Group 1 and5in Group 2 had no evidence of ophthalmopathy. In none of them did ocular symptoms appear after radioiodine therapy (Fig. 2).
Among the patients in Group 1 with clinical evidence of ophthalmopathy before therapy, ocular disease worsened in 9 of 16 (56%) and did not change in 6 of 16 (44%). In contrast, ophthalmopathy improved in 11 of 21 (52%) and did not change in 10of21 (48%) in Group 2. The worsening of ophthalmopathy occurred within 6 months in most cases and was persistent. Soft tissue changes and extraocular muscle function were the parameters mostly involved. In 4 patients of Group 1, the exacerbation was such as to require treatment with orbital irradiation combined with high doses of systemic glucocorticoids. The outcome of radioiodine therapy was similar in the two groups, the prevalence of hypothyroidism being about 30% at the end of the 18-month study period, and no relation was noted between the development of hypothyroidism and the worsening of ophthalmopathy in patients of Group 1. The progression of ophthalmopathy observed in patients of Group 1 might have been merely coincidental. However, the findings that ophthalmopathy was unchanged before radioiodine treatment, that exacerbation mostly occurred within 6 months after treatment, and that worsening did not occur in any patient receiving glucocorticoids concomitantly with radioiodine make this possibility unlikely and strongly suggest that the exacerbation of eye disease was related to radioiodine administration. We, therefore, recommend short-term administration of systemic glucocorticoids concomitantly with radioiodine in patients with Graves' hyperthyroidism, at least in those who already have sorqe degree of ocular involvement, who are more prone to have a worsening of their ophthalmopathy. Even though our data recently have been confirmed by other studies, some authors are skeptical and claim that in their experience in the treatment of Graves' disease they have not had the impression that radioiodine therapy carries the risk of worsening of ophthalmopathy. In this respect, a recent study by Barth et al. (49) reported that contrary to their previous clinical impression, a careful review of the records of 89 patients with Graves' disease treated with radioiodine could indeed demonstrate some progression of ophthalmopathy in one third of patients with ocular symptoms before treatment. In addition, half of them required special treatment for eye disease.
Thyroidectomy Based on the observation that reduction of thyroid mass is followed by remission of thyroid autoimmune phenomena, as indicated by the progressive decrease of circulating thyroid autoantibodies, Bauer and Catz (54) proposed that the ablation of thyroid tissue, either by surgery or radioiodine, might beneficially affect the course of eye disease. Indeed these authors reported in the mid-1960s that total thyroidectomy was followed by a complete regression of Graves' ophthalmopathy in 32 consecutive patients. In contrast, 15 patients treated by subtotal thyroidectomy had a progression of eye disease after surgery (55). In the latter group, the ablation of residual thyroid tissue was associated with a significant improvement of eye manifestations. A beneficial effect of total thyroid ablation (surgery, radioiodine, or both) on the course of ophthalmopathy has been confirmed by some (56-58) but not all authors (38,59-61 ), even though a tendency toward improvement more often followed ablative therapy with thyroid surgery than with radioiodine
(Table 2).
THYROID TREATMENT AND GRAVES' OPHTHALMOPATHY
80
G o; •13
60
O
40
175
-,
-
c
a»
ö
20
0-J
SG
SG
LZI Improvement E3
No
change
FIG. 2. Changes of eye manifestations after radioiodine treatment of Graves' clinical evidence of ophthalmopathy are not represented. SG—, patients treated radioiodine combined with systemic glucocorticoids. Table 2. Effects Author
of
Thyroid Ablation on No. of patients
Total thyroidectomy Catz and Perzik (55) Werner et al. (38) Marushak et al. (56) Grussendorf et al. (57)
88 4 4 30
Bauer and Catz (54) Pequegnat et al. (40) Volpé et al. (60) Boy le et al. (61)
18 57 13 2
the
Course
+
H Worsening
hyperthyroidism. Patients who initially had no by radioiodine alone; SG + patients treated by
of
,
Graves' Ophthalmopathy
Improvement
No
86% 50% 53%
change
Worsening
14% 100% 50% 33%
14%
I31|
One of the main problems in evaluating the role of thyroid ablation on the course of ophthalmopathy is the difficulty of defining ablation. In fact, even in patients developing severe hypothyroidism following total thyroidectomy or radioiodine administration, residual thyroid tissue frequently can be demonstrated by thyroid scan. This was considered by Catz the explanation for the lack of amelioration reported by some authors (62). Ablation of thyroid tissue is not a standard procedure for treating Graves' hyperthyroidism, and subtotal thyroidectomy generally is reserved only for a minority of patients (those with large goiters or with relapsing hyperthyroidism at a young age). Several studies (30,36,52,59,63) have tried to ascertain whether, as suggested by Catz and Perzik (55), subtotal thyroidectomy may be followed by a worsening of ophthalmopathy. As indicated in Table 3, it is difficult to draw a definite conclusion, and no study has confirmed the constant worsening observed by Catz and Perzik (55). As a matter of fact, in several instances, ophthalmopathy is not influenced or even improves after subtotal thyroidectomy.
90% 40%
26%
34% 100% 50%
50%
Table 3. Progression of Graves' Ophthalmopathy Following Subtotal Thyroidectomy Author Hamilton et al. (30) Barbosa et al. (36)a Sridama and DeGroot (52) Frilling et al. (63)a Levitt et al. (59)a
No.
of patients 54 14 81 78 18
Progression (%) 2 7
20 8 22
"Prospective study. We currently are investigating in a prospective study the effects of subtotal thyroidectomy and the possible protective role of glucocorticoids on eye manifestations in a series of 40 Graves' patients with mild or no signs of ophthalmopathy, treated by subtotal thyroidectomy. From the evaluation of the first 25 patients who have completed a 1-year follow-up period, it would appear that subtotal thyroidectomy was not followed by
176
MARCOCCI ET AL.
60
-i
50
H
G
.aM
40
rö
ÍX
30 C
m >-.
Du
20
H
10 H
0-1
SG
D Improvement
OU No change
+
Worsening
FIG. 3. Changes in eye manifestations in Graves' patients after subtotal thyroidectomy. Patients who initially had no clinical evidence of ophthalmopathy are not represented. SG—, patients treated by subtotal thyroidectomy alone; SG+, patients treated by subtotal thyroidectomy followed by systemic glucocorticoid administration.
the appearance of ophthalmopathy in 5 patients with no evidence of eye disease before surgery, independent of whether they were given glucocorticoids after thyroidectomy. The ophthalmopathy progressed in 6 of 11 patients not receiving glucocorticoids. The worsening was mild in 4 and marked in 2, involving soft tissue changes and extraocular muscle function. The eye manifestations remained stable in the other 5 patients of this group (Fig. 3). On the other hand no patient given glucocorticoids after surgery had an exacerbation of eye disease, which remained unchanged in 3 patients and improved in 6 (Fig. 3). All patients were followed carefully and promptly given L-thyroxine when hypothyroidism occurred. In view of the preliminary results of this prospective study, we recommend that patients with Graves' hyperthyroidism, at least those with some evidence of eye disease, be treated with a short-term administration of systemic glucocorticoids to prevent a possible exacerbation of their ophthalmopathy after thyroidectomy.
presence of ophthalmopathy, since this may cause a worsening of eye disease, and (c) protect the patient from possible exacerbation after thyroid surgery or radioiodine by the administration of short-term glucocorticoids. Our current therapeutic approach to treat Graves' hyperthyroidism is the following. In patients with no significant ophthalmopathy, the modality of treatment is based on standard criteria, and patients generally are given a long-term course of MMI, followed, if hyperthyroidism relapses, by radioiodine or, less frequently, by subtotal thyroidectomy. In patients with ophthalmopathy, we prefer a definitive treatment of hyperthyroidism (subtotal thyroidectomy or radioiodine, as indicated) under protection with systemic glucocorticoids if the ophthalmopathy is mild to moderate or followed by combined therapy with orbital irradiation and high-dose systemic glucocorticoids if the ophthalmopathy is severe (64-66).
REFERENCES
DISCUSSION The influence of treatment of hyperthyroidism on the course of Graves' ophthalmopathy remains uncertain. Circumstantial evidence suggests that (a) the course of eye disease is more favorable in patients rendered and maintained euthyroid, (b) an exacerbation may occur after radioiodine therapy or subtotal thyroidectomy, and (c) short-term treatment with systemic glucocorticoids prevents such exacerbations. The following therapeutic implications derive from these considerations: (a) render the patient euthyroid carefully, avoiding treatment-induced hypothyroidism, (b) avoid recurrence of hyperthyroidism in the
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Aguayo J, Iitaka M, Row VV, Volpé R 1988 Studies of HLA-DR expression on cultured human thyrocytes: Effect of antithyroid drugs and other agents on interferon gamma-induced HLA-DR expression. J Clin Endocrinol Metab 66:903-908. 27. Kriss JP, Konishi J, Herman N 1975 Studies on the pathogenesis of Graves' ophthalmopathy (with some related observations regarding therapy). Recent Prog Horm Res 31:533-566. 28. Bech K 1989 Thyroid antibodies in endocrine ophthalmopathy. Acta Endocrinol (Copenh) 121(suppl 2):117-122. 29. Prummel MF, Wiersinga WM. Mourits MPh, Koorneef L, Berghout A, Van derGaag R 1989 Amelioration of eye changes of Graves' ophthalmopathy by achieving euthyroidism. Acta Endocrinol (Copenh) 121(suppl 2):185-189. 30. Hamilton RD, Mayberry VE, McConahey WM, Hanson KC 1967 Ophthalmopathy of Graves' disease: A comparison between patients treated surgically and patients treated with radioiodine. Mayo 26.
Clin Proc 42:812-818. Almquist S, Algvere P 1972 Hypothyroidism in progressive ophthalmopathy of Graves' disease. Acta Ophthalmol 50:761-770. 32. Karlsson FA, Dahlberg PA, Jansson R, Westermark K^Enoksson P 1989 Importance of TSH receptor activation in the development of severe endocrine ophthalmopathy. Acta Endocrinol (Copenh) 31.
121(suppl2):132-141. 33. Aranow H Jr, Day RM 1965 Management of thyrotoxicosis in patients with ophthalmopathy: Antithyroid regimen determined primarily by ocular manifestations. J Clin Endocrinol Metab 25:1-10. 34. Solem JH, Segaard E, Ytteborg J 1979 The course of endocrine ophthalmopathy during antithyroid therapy in a prospective study. Acta Med Scand 205:111-114. 35. Gwinup G, Elias AN. Ascher MS 1982 Effect on exophthalmos of various methods of treatment of Graves' disease. JAMA 247:2136-2138. 36. Barbosa J, Wong E, Doe RP 1972 Ophthalmopathy of Graves' disease: Outcome after treatment with radioactive iodine, surgery or antithyroid drugs. Arch Intern Med 130:111-113. 37. Hashizume K, Ichikawa K. Sakurai A, et al 1991 Administration of thyroxine in treated Graves' disease—Effects on the level of antibody to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism. N Engl J Med 324:947-953. 38. Werner SC, Feind CR, Aida M 1967 Graves' disease and total thyroidectomy: Progression of severe eye changes and decrease in serum long acting thyroid stimulator after operation. N Engl J Med 276:132-138. 39. Kriss JP, Pleshakov V, Rosenblum AL, Holderness M, Sharp G, Utiger R 1967 Studies on the pathogenesis of the ophthalmopathy of Graves' disease. J Clin Endocrinol Metab 27:582-593. 40. Pequegnat EP, Mayberry WE, McConahey WM, Wyse EP 1967 Large doses of radioiodine in Graves' disease: Effect on ophthalmopathy and long-acting thyroid stimulator. Mayo Clin Proc 42:802-811. 41. Jones DIR, Munro DS, Wilson GM 1969 Observations on the course of exophthalmos after l3lI therapy. Proc R Soc Med 62:15-18. 42. Wasnich RD, Grumet FC, Payne RO, Kriss JP 1973 Graves' ophthalmopathy following external neck irradiation for nonthyroidal neoplastic disease. J Clin Endocrinol Metab 37:703-713. 43. Jackson R. Rosemberg C, Kleinmann R, Vagenakis AG, Braver-
MARCOCCI ET AL.
178 LE 1979 Ophthalmopathy after neck irradiation therapy Hodgkin's disease. Cancer Treat Rep 63:1393-1395.
man
for
44. Kriss JP, Pleshakov V, Chien JR 1964 Isolation and identification of the long-acting thyroid stimulator and its relation to hyperthyroidism and circumscribed pretibial myxedema. J Clin Endocrinol Metab 24:1005-1028. 45. Pinchera A, Pinchera MG, Stanbury JB 1965 Thyrotropin and long acting thyroid stimulator assays in thyroid disease. J Clin Endocrinol Metab 25:189-208. 46. Bech K, Madsen SN 1980 Influence of treatment with radioiodine and propylthiouracil on thyroid stimulating immunoglobulins in Graves' disease. Clin Endocrinol (Oxf) 13:417-424. 47. Pinchera A, Fenzi GF, Macchia E, Bartalena L, Mariotti S, Monzani F 1982 Thyroid stimulating immunoglobulins. Horm Res 16:317-328. 48. Vestergaard H, Laurberg P 1989 Radioiodine and aggravation of Graves' ophthalmopathy. Lancet 2:47. 49. Barth A, Probst P, Burgi H 1991 Identification of a subgroup of Graves' disease patients at higher risk for severe ophthalmopathy after radioiodine. J Endocrinol Invest 14:209. 50. Marcocci C, Bartalena L, Bogazzi F, Bruno-Bossio G, Lepri A, Pinchera A 1989 Radioiodine treatment of Graves' hyperthyroidism and progression of ophthalmopathy: Protective effect of systemic corticosteroids. Acta Endocrinol (Copenh) 121(suppl 2): 145-148. 51. Bartalena L, Marcocci C, Bogazzi F, Panicucci M, Lepri A, Pinchera A 1989 Use of corticosteroids to prevent progression of Graves' ophthalmology after radioiodine therapy for hyperthyroidism. N Engl J Med 321:1349-1362. 52. Sridama V, DeGroot U 1989 Treatment of Graves' disease and the course of ophthalmopathy. Am J Med 87:70-73. 53. Werner SC 1960 Experimentally induced changes in some of the manifestations of infiltrative ophthalmopathy (malignant exophthalmos). Trans Assoc Am Physician 73:314-324. 54. Bauer FK, Catz B 1966 Radioactive iodine therapy for progressive malignant exophthalmos. Acta Endocrinol (Copenh) 51:15-22. 55. Catz B, Perzik SL 1965 Subtotal vs total surgical ablation of the thyroid, malignant exophthalmos and its relation to remnant thyroid. In Cassano C, Andreoli M (eds) Current Topics in Thyroid Research: Proceedings of the Fifth International Thyroid Conference. Academic Press, New York, p 1183. 56. Marushak D, Faurschou S, Blichert-Toft M 1984 Regression of ophthalmopathy in Graves' disease following thyroidectomy. Acta Ophthalmol 62:767-779. 57. Grussendorf M, Inane Y, Goretzki PE, Roher HD. Horster FA,
58.
Kruskemper HL 1989 Effect of near total thyroidectomy on ophthalmopathy in patients with Graves' disease. In: Pickardt CR, Boergen KP (eds) Graves' Ophthalmopathy. Developments in Diagnostic Methods and Therapeutic Procedures. Karger, Basel, p86. White IL 1979 Total thyroid ablation: A prerequisite to orbital decompression for Graves' disease ophthalmopathy. Laryngoscope
84:1869-1875. 59. Levitt MD, Antony JE, Agnello R, McCormick CC 1988 The effect of subtotal thyroidectomy on Graves' ophthalmopathy. World J Surg 12:593-597. 60. Volpé R, Desbarats-Schonbaum ML, Schonbaum E, Row AA, Ezrin C 1969 The effect of radioablation of the thyroid in Graves' disease with high levels of long-acting thyroid stimulator (LATS). Am J Med 46:217-226. 61. Boyle IT, Greig WR, Thomson JA, Winning J, McGirr EM 1969 Effect of thyroid ablation on dysthyroid exophthalmos. Proc R Soc Med 62:19. 62. Catz B 1967 Remnant thyroid tissue. N Engl J Med 276:985-986. 63. Frilling A, Goretzki PE, Grussendorf M, Erbsloh M, Roher HD 1990 The influence of surgery on endocrine ophthalmopathy. World J Surg 14:442-446. 64. Bartalena L, Marcocci C, Chiovato L, et al 1983 Orbital cobalt irradiation combined with systemic corticosteroids for Graves ophthalmopathy: Comparison with systemic corticosteroids alone. J Clin Endocrinol Metab 56:1139-1144. 65. Marcocci C, Bartalena L, Panicucci M, et al 1987 Orbital cobalt irradiation combined with retrobulbar or systemic corticosteroids for Graves' ophthalmopathy: A comparative study. Clin Endocrinol (Oxf) 27:33-42. 66. Marcocci C, Bartalena L, Bogazzi F, Bruno-Bossio G, Lepri A, Pinchera A 1991 Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves' ophthalmology is more effective than radiotherapy alone: Results of a prospective randomized study. J Endocrinol Invest 12:853-860
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Relationship Between Graves' Ophthalmopathy and Type of Treatment of Graves' Hyperthyroidism C. MARCOCCI, L. BARTALENA, F. BOGAZZI, G. BRUNO-BOSSIO, and A. PINCHERA
ABSTRACT The relationship between the treatment of Graves' hyperthyroidism and the course of ophthalmopathy is rather unclear. Antithyroid drugs may improve eye manifestations, possibly by restoring normal thyroid function and reducing orbit-directed autoimmune reactions, whereas ophthalmopathy may worsen after radioiodine administration or thyroidectomy. This might occur because of a treatment-related release of thyroid antigens and activation of the autoimmune response that might involve the orbit. On the other hand, some authors suggest that complete thyroid ablation, either by radioiodine or surgery, might be beneficial for ophthalmopathy. However, reported effects of radioiodine and thyroidectomy on Graves' ophthalmopathy are conflicting. This may be due, at least in part, to the retrospective feature of most studies and the lack of precise evaluation of ocular involvement. Two prospective studies were performed in which patients with Graves' disease with mild or no ophthalmopathy were randomly assigned to treatment by radioiodine or subtotal thyroidectomy alone or in association with systemic glucocorticoids. Both treatments were followed by a progression of pre-existing mild ophthalmopathy in a substantial proportion of cases: glucocorticoids prevented such an exacerbation. Ophthalmopathy did not develop in patients without clinical evidence of eye disease prior to therapy. Therefore, it is recommended that a course of glucocorticoids be instituted concomitantly with radioiodine therapy or thyroidectomy in Graves' patients with some degree of ocular involvement.
INTRODUCTION
Several origin
pieces OF evidence indicate the autoimmune of Graves' ophthalmopathy, but its precise pathogenesis still remains to be clarified, and it is unclear whether it is an integral part of Graves' disease or a separate entity (1,2). Severe eye manifestations occur only in a minority of Graves' patients, but orbital alterations can be shown by sophisticated techniques in almost all cases, with little, if any, clinical evidence of eye disease present (3). In most cases, there is a close temporal relationship between the onset of hyperthyroidism and that of ophthalmopathy, but ocular manifestations may begin after thyrotoxicosis (4,5). Because most patients in whom the eye disorder follows the onset of hyperthyroidism have already received treatment for thyrotoxicosis, the question has been raised as to whether the
Istituto di
hyperthyroidism might have any role in the appearance of ophthalmopathy or the course of preexisting eye disease. Available information on this issue is rather unclear and somewhat contradictory because of the small series of patients, the different methods of evaluation of eye involvement, and the limited number of prospective studies. This problem is complicated by the observation that the natural course of Graves' ophthalmopathy is highly variable, with unpredictable exacerbations and remissions. This makes it difficult to establish whether a given treatment for hyperthyroidism affects the course of ophthalmopathy. Any discussion on this issue should answer the following questions: What is the effect of thyroid status on the activity of the putative immune phenomenon responsible for the eye disease? Is there any specific mechanism by which treatment of hyperthyroidism, by either antithyroid drug ( ATD), radioiodine, or surgery, could influence the ophthalmopathy? management of
Endocrinología, Université di Pisa, 56018 Tirrenia-Pisa, Italy. 171
MARCOCCI ET AL.
172
INFLUENCE OF THYROID STATUS ON ACTIVITY OF IMMUNE SYSTEM AND ON GRAVES' OPHTHALMOPATHY The effects of thyroid status on the immune system are rather Most studies on human hyperthyroidism or hypothyroidism have been performed in patients with Graves' disease or Hashimoto's thyroiditis. Since these conditions are autoimmune diseases, it is often difficult to establish whether the immunologie abnormality is the consequence of the altered thyroid status or a manifestation of the underlying disturbance of immune surveillance. Several studies indicate that thyroid hormones stimulate the activity of the immune system, probably through depression of suppressor T cell number and functions (6,7). Restoration of euthyroidism in Graves' patients after treatment with antithyroid drugs of the thionamide group (methimazole, carbimazole, and propylthiouracil) is associated with a significant fall of TSHreceptor, antithyroglobulin (anti-Tg) and antithyroid peroxidase (anti-TPO) autoantibody titers (8-11). In apparent contrast with these findings is the observation of a marked decrease of serum anti-Tg and anti-TPO antibodies in patients with idiopathic myxedema or hypothyroid Hashimoto's thyroiditis submitted to L-thyroxine treatment (12,13). In the latter study (13), no significant effect of L-thyroxine was documented in patients with euthyroid Hashimoto's thyroiditis and normal circulating TSH concentrations before therapy. The mechanism by which correction of hyperthyroidism and hypothyroidism leads to a decreased activity of thyroid autoimmunity is still debated. As already discussed, thyrotoxicosis by itself may affect the immune system, possibly through a decrease in the number and function of generalized T suppressor lymphocytes (7,14,15). This explanation, however, is not supported by the observation of a fall in thyroid-stimulating antibodies (TSAb) (as assessed by LATS bioassay) in 2 euthyroid Graves' patients receiving methimazole (MMI) combined with T3 to maintain the euthyroid state (16). On the other hand, an important role of thyroid function itself is suggested by the observation that TSAb also decline in Graves' disease patients treated with potassium perchlorate (17), which has no recognized immunosuppressive effects ( 18). A direct effect of thyroid hormones on the immune system is suggested by the relationship between serum levels of soluble interleukin 2 receptor, a marker of activity of the immune system, and serum concentrations of free thyroid hormones (19). Alternatively, a direct suppressive effect of MMI on thyroid autoimmune reactions, independent of changes in the thyroid status, has been postulated on the basis of the results obtained in Hashimoto's patients treated with MMI and L-T4 to keep serum concentrations of thyroid hormone constant (20). However, a fall of circulating thyroid autoantibodies also was found in similar groups of patients given either MMI in combination with L-T4 or L-T4 alone (12,21), suggesting that in this model, the main active substance was actually thyroxine rather than MMI. At present, the hypothesis that ATD or thyroid hormones or both may interfere with the immune system by reducing thyroid autoantigen availability and presentation is the one that provides the best explanation for the fall in serum thyroid autoantibody levels observed in hypothyroid Hashimoto's patients after prolonged treatment with L-T4 (13) and in patients with Graves' disease after ATD therapy (11). Administration of thyroid
complex.
hormones or ATD is in fact associated with a decrease in serum TSH or TSAb levels, respectively, leading to reduced thyroid stimulation. In keeping with this concept are several in vitro studies providing evidence that TSH and TSAb increase the synthesis and expression of TPO by thyroid cells (22,23). It should be noted that both TSH (24) and TSAb (25) enhance the gamma-interferon-dependent HLA-DR expression by thyroid cells. It could be envisaged that both TSH and TSAb are very important in perpetuating mechanisms operating in Hashimoto's thyroiditis and Graves' disease, respectively. Whether MMI may modulate thyroid autoantigen expression by thyroid stimulators is still uncertain (26). One of the pathogenetic hypotheses of Graves' ophthalmopathy is that thyroid antigen, e.g., thyroglobulin, and thyroid autoantibodies can reach the orbit through the lymphatic system and trigger a local inflammatory reaction mediated by humoral and cellular mechanisms, eventually damaging the ocular structures (27). Alternatively, an autoimmune reaction against antigens shared by the thyroid and the orbital tissues may trigger the onset of or exacerbate eye disease. In either case, the thyroid tissue as a source of antigen(s) plays a central role in the development and eventually in the maintenance of ophthalmop-
athy (28). It might be expected, therefore, that following correction of thyrotoxicosis. Graves' ophthalmopathy should improve. This has proven to be the case in a study by Prummel at al. (29), who found that the simple correction of thyrotoxicosis in a few weeks by ATD was associated with an improvement of eye manifestations, particularly of soft tissue and extraocular muscle involvement, whereas no significant changes occurred in patients maintained euthyroid with MMI and followed for 20 weeks. Some authors have had the impression that ophthalmopathy is more likely to progress in patients who become hypothyroid (30,31). Karlsson
et al.
(32) found that
a
treatment-induced
hypothyroid phase could be identified in 6 of 15 patients developing severe eye disease following radioiodine therapy. The mechanism by which hypothyroidism would worsen ophthalmopathy is open to speculation. As already mentioned, TSH has been shown to increase the expression of thyroid specific antigens in vitro (22,23) and, in the presence of gammainterferon, to induce the expression of class II antigens on thyroid cells (24,25). Thus, the stimulation of thyroid cells through the TSH receptor either by TSH (hypothyroidism) or by an increase in TSH-receptor antibodies (radioiodine) might result in a pathogenetic signal leading to an exacerbation of eye disease. Radioiodine therapy might worsen ophthalmopathy not only by activation of the autoimmune thyroid disease by release and presentation of antigen or destruction of radiosensitive suppressor T lymphocytes but also by inducing hypothyroidism. Following this hypothesis, these authors have suggested the use of thyrostatic drugs combined with thyroxine in all patients who undergo radioiodine therapy to prevent the rise of thyroid autoantibodies and to prevent hypothyroidism (32). EFFECT OF VARIOUS TREATMENTS OF GRAVES' HYPERTHYROIDISM ON THE COURSE OF OPHTHALMOPATHY As already mentioned, even if there is a close temporal relationship between the onset of hyperthyroidism and that of
THYROID TREATMENT AND GRAVES' OPHTHALMOPATHY
No treatment
|
]
MMI Tx
131-1 Remission (after
MMI)
C «s
c ai
01
Temporal relationship between the onset of hyperthyroidism and the onset of ophthalmopathy in 108 Graves patients with severe ophthalmopathy. Pre, ophthalmopathy before hyperthyroidism; Cone, ophthalmopathy concomitant with hyperthyroidism; Post, ophthalmopathy after hyperthyroidism. MMI, methimazole; Tx, subtotal thyroidectomy; 131-1, radioiodine. FIG. 1.
ophthalmopathy,
in a significant proportion of patients the manifestations become evident only long after the onset of thyroid hyperfunction (4,5). To investigate whether in this group the onset of ophthalmopathy might be related to the treatment of hyperthyroidism, we have reviewed the medical records of 108 patients with severe ophthalmopathy occurring after hyperthyroidism (Fig. 1 ). About half of the patients had not received any treatment for hyperthyroidism when eye disease occurred. Of the remaining 50%, the majority had started methimazole therapy, and a few patients had been treated with radioiodine or surgery. Thus, ophthalmopathy may follow hyperthyroidism even in the absence of treatment. The finding that among the treated patients methimazole therapy was most often associated with the onset of ophthalmopathy is likely simply to reflect the fact that ATD is most commonly used as the first form of treatment of Graves' hyperthyroidism in Italy. Moreover, it is worth noting that in a substantial proportion of Graves' patients, ophthalmopathy may occur in the absence of hyperthyroidism (so-called euthyroid Graves' ophthalmopathy), suggesting that the mechanism underlying its onset, maintenance, and worsening may be independent of thyrotoxicosis and its treatment (5).
Antithyroid drug therapy We found that methimazole had no major effect on eye manifestations in a group of Graves' patients with mild ophthalmopathy, who were followed for 6-12 months after initiation of therapy. Over the same period of time, no clinical evidence of ophthalmopathy was found in another group of Graves' patients with no ophthalmopathy before therapy. These data are in agreement with those reported by Aranow and Day (33), who
'
retrospectively evaluated the course of ophthalmopathy in 129 patients with Graves' disease treated with ATD. Since in none of them did the eye disease worsen, these authors concluded that ATD therapy is less likely to be followed by a worsening of ophthalmopathy than is thyroidectomy or radioiodine. A similar conclusion was reached by Solem et al. (34), who prospectively evaluated 105 thyrotoxic Graves' patients during a 24-month course of carbimazole therapy. Treatment was supervised very closely to avoid iatrogenic hypothyroidism. None of the 69 patients with eye involvement had a progression of eye disease. Inflammatory changes usually subsided gradually with achievement of euthyroidism. None of the 34 patients without ophthalmopathy before treatment developed it after therapy. Thus, with the exception of Gwinup et al. (35), who found that propylthiouracil was associated more often than other treatments with a progression of ophthalmopathy (evaluated, however, only on the basis of changes of proptosis), there is a wide consensus that ATD therapy per se does not influence eye disease (33-36). The problem of medical treatment of Graves' hyperthyroidism, however, is that in most patients a relapse of thyrotoxicosis follows withdrawal of treatment. This occurs concomitantly with the reactivation of autoimmune phenomena responsible for thyroid disease and probably for ophthalmopathy, as indicated by the increase in TSH-receptor and other thyroid autoantibody levels at the time of relapse, generally associated also with an exacerbation of eye signs. In this regard, the low prevalence of recurrences of hyperthyroidism in patients in whom L-T4 was added to MMI after restoration of euthyroidism and was continued after MMI withdrawal might prove to be associated with a more favorable course of ophthalmopathy
(37).
MARCOCCI ET AL.
174 Table 1. Progression of Graves' Ophthalmopathy Following Radioiodine Therapy of Hyperthyroidism
Author Werner (53) Kriss et al. (39)a Hamilton et al. (30) Bartalena et al. (51)a Sridama and DeGroot (52) Vestergaard and Laurberg (48)a
No. of patients
Progression (%)
161 24 98 26 241 22
5 8-25 5 56 23 23
"Prospective study. Radioiodine
treatment
There are several reports in the literature suggesting that ophthalmopathy may worsen following therapeutic procedures associated with the leakage of antigens from the thyroid, such as thyroid surgery (38), radioiodine (39-41), and even irradiation of the neck for nonthyroidal diseases (42,43). It has been claimed that after thyroid injury (radioiodine or thyroid surgery), there is a liberation of thyroid antigen(s), leading to an increased production of autoantibodies, such as TSH-receptor, thyroglobulin, and thyroid peroxidase autoantibodies (44-47). This, in turn, may initiate the eye injury. An association between worsening of ophthalmopathy and radioiodine treatment was reported originally by Kriss et al. in 1967 (39), who found that the onset of ophthalmopathy coincided with the appearance of LATS in the serum of 3 patients. This observation has been confirmed subsequently by other authors (48,49), including ourselves in a prospective study (50,51). However, this view is not shared by all authors (30,33,52,53) (Table 1). In particular, Sridama and DeGroot (52), in a retrospective analysis of 573 patients with Graves'
disease, found that there was no difference in the occurrence of posttreatment ophthalmopathy among patients who did not have overt eye disease before treatment,
independent of the therapy
employed (radioiodine, antithyroid drug, or surgery; 4.9%, 6.7%, and 7.1%, respectively). The worsening of ophthalmop-
athy was more frequent in patients who had ocular signs before treatment, but the rate of progression was similar in the three groups (22.7%, 18.9%, and 19.2%, respectively). The discrepant data of the literature might be, at least in part, attributed to the fact that most reports were retrospective, precise measurement of ocular involvement often was lacking, and ophthalmopathy often was evaluated too long after radioiodine therapy, thus obscuring any possible relation between radioiodine administra-
tion and the outcome of eye disease. To address this problem, in 1987 we started a prospective study, in which hyperthyroid Graves' patients who had slight or no signs of ophthalmopathy and no change in their ocular status for at least 3 months before treatment were randomly assigned to a group treated with radioiodine alone (Group 1) or to a group concomitantly treated with radioiodine and systemic glucocorticoids (Group 2) (0.4-0.5 mg prednisone/kg body weight for 1 month, with subsequent tapering and withdrawal after 3 months) (50,51). Before treatment, 10 patients in Group 1 and5in Group 2 had no evidence of ophthalmopathy. In none of them did ocular symptoms appear after radioiodine therapy (Fig. 2).
Among the patients in Group 1 with clinical evidence of ophthalmopathy before therapy, ocular disease worsened in 9 of 16 (56%) and did not change in 6 of 16 (44%). In contrast, ophthalmopathy improved in 11 of 21 (52%) and did not change in 10of21 (48%) in Group 2. The worsening of ophthalmopathy occurred within 6 months in most cases and was persistent. Soft tissue changes and extraocular muscle function were the parameters mostly involved. In 4 patients of Group 1, the exacerbation was such as to require treatment with orbital irradiation combined with high doses of systemic glucocorticoids. The outcome of radioiodine therapy was similar in the two groups, the prevalence of hypothyroidism being about 30% at the end of the 18-month study period, and no relation was noted between the development of hypothyroidism and the worsening of ophthalmopathy in patients of Group 1. The progression of ophthalmopathy observed in patients of Group 1 might have been merely coincidental. However, the findings that ophthalmopathy was unchanged before radioiodine treatment, that exacerbation mostly occurred within 6 months after treatment, and that worsening did not occur in any patient receiving glucocorticoids concomitantly with radioiodine make this possibility unlikely and strongly suggest that the exacerbation of eye disease was related to radioiodine administration. We, therefore, recommend short-term administration of systemic glucocorticoids concomitantly with radioiodine in patients with Graves' hyperthyroidism, at least in those who already have sorqe degree of ocular involvement, who are more prone to have a worsening of their ophthalmopathy. Even though our data recently have been confirmed by other studies, some authors are skeptical and claim that in their experience in the treatment of Graves' disease they have not had the impression that radioiodine therapy carries the risk of worsening of ophthalmopathy. In this respect, a recent study by Barth et al. (49) reported that contrary to their previous clinical impression, a careful review of the records of 89 patients with Graves' disease treated with radioiodine could indeed demonstrate some progression of ophthalmopathy in one third of patients with ocular symptoms before treatment. In addition, half of them required special treatment for eye disease.
Thyroidectomy Based on the observation that reduction of thyroid mass is followed by remission of thyroid autoimmune phenomena, as indicated by the progressive decrease of circulating thyroid autoantibodies, Bauer and Catz (54) proposed that the ablation of thyroid tissue, either by surgery or radioiodine, might beneficially affect the course of eye disease. Indeed these authors reported in the mid-1960s that total thyroidectomy was followed by a complete regression of Graves' ophthalmopathy in 32 consecutive patients. In contrast, 15 patients treated by subtotal thyroidectomy had a progression of eye disease after surgery (55). In the latter group, the ablation of residual thyroid tissue was associated with a significant improvement of eye manifestations. A beneficial effect of total thyroid ablation (surgery, radioiodine, or both) on the course of ophthalmopathy has been confirmed by some (56-58) but not all authors (38,59-61 ), even though a tendency toward improvement more often followed ablative therapy with thyroid surgery than with radioiodine
(Table 2).
THYROID TREATMENT AND GRAVES' OPHTHALMOPATHY
80
G o; •13
60
O
40
175
-,
-
c
a»
ö
20
0-J
SG
SG
LZI Improvement E3
No
change
FIG. 2. Changes of eye manifestations after radioiodine treatment of Graves' clinical evidence of ophthalmopathy are not represented. SG—, patients treated radioiodine combined with systemic glucocorticoids. Table 2. Effects Author
of
Thyroid Ablation on No. of patients
Total thyroidectomy Catz and Perzik (55) Werner et al. (38) Marushak et al. (56) Grussendorf et al. (57)
88 4 4 30
Bauer and Catz (54) Pequegnat et al. (40) Volpé et al. (60) Boy le et al. (61)
18 57 13 2
the
Course
+
H Worsening
hyperthyroidism. Patients who initially had no by radioiodine alone; SG + patients treated by
of
,
Graves' Ophthalmopathy
Improvement
No
86% 50% 53%
change
Worsening
14% 100% 50% 33%
14%
I31|
One of the main problems in evaluating the role of thyroid ablation on the course of ophthalmopathy is the difficulty of defining ablation. In fact, even in patients developing severe hypothyroidism following total thyroidectomy or radioiodine administration, residual thyroid tissue frequently can be demonstrated by thyroid scan. This was considered by Catz the explanation for the lack of amelioration reported by some authors (62). Ablation of thyroid tissue is not a standard procedure for treating Graves' hyperthyroidism, and subtotal thyroidectomy generally is reserved only for a minority of patients (those with large goiters or with relapsing hyperthyroidism at a young age). Several studies (30,36,52,59,63) have tried to ascertain whether, as suggested by Catz and Perzik (55), subtotal thyroidectomy may be followed by a worsening of ophthalmopathy. As indicated in Table 3, it is difficult to draw a definite conclusion, and no study has confirmed the constant worsening observed by Catz and Perzik (55). As a matter of fact, in several instances, ophthalmopathy is not influenced or even improves after subtotal thyroidectomy.
90% 40%
26%
34% 100% 50%
50%
Table 3. Progression of Graves' Ophthalmopathy Following Subtotal Thyroidectomy Author Hamilton et al. (30) Barbosa et al. (36)a Sridama and DeGroot (52) Frilling et al. (63)a Levitt et al. (59)a
No.
of patients 54 14 81 78 18
Progression (%) 2 7
20 8 22
"Prospective study. We currently are investigating in a prospective study the effects of subtotal thyroidectomy and the possible protective role of glucocorticoids on eye manifestations in a series of 40 Graves' patients with mild or no signs of ophthalmopathy, treated by subtotal thyroidectomy. From the evaluation of the first 25 patients who have completed a 1-year follow-up period, it would appear that subtotal thyroidectomy was not followed by
176
MARCOCCI ET AL.
60
-i
50
H
G
.aM
40
rö
ÍX
30 C
m >-.
Du
20
H
10 H
0-1
SG
D Improvement
OU No change
+
Worsening
FIG. 3. Changes in eye manifestations in Graves' patients after subtotal thyroidectomy. Patients who initially had no clinical evidence of ophthalmopathy are not represented. SG—, patients treated by subtotal thyroidectomy alone; SG+, patients treated by subtotal thyroidectomy followed by systemic glucocorticoid administration.
the appearance of ophthalmopathy in 5 patients with no evidence of eye disease before surgery, independent of whether they were given glucocorticoids after thyroidectomy. The ophthalmopathy progressed in 6 of 11 patients not receiving glucocorticoids. The worsening was mild in 4 and marked in 2, involving soft tissue changes and extraocular muscle function. The eye manifestations remained stable in the other 5 patients of this group (Fig. 3). On the other hand no patient given glucocorticoids after surgery had an exacerbation of eye disease, which remained unchanged in 3 patients and improved in 6 (Fig. 3). All patients were followed carefully and promptly given L-thyroxine when hypothyroidism occurred. In view of the preliminary results of this prospective study, we recommend that patients with Graves' hyperthyroidism, at least those with some evidence of eye disease, be treated with a short-term administration of systemic glucocorticoids to prevent a possible exacerbation of their ophthalmopathy after thyroidectomy.
presence of ophthalmopathy, since this may cause a worsening of eye disease, and (c) protect the patient from possible exacerbation after thyroid surgery or radioiodine by the administration of short-term glucocorticoids. Our current therapeutic approach to treat Graves' hyperthyroidism is the following. In patients with no significant ophthalmopathy, the modality of treatment is based on standard criteria, and patients generally are given a long-term course of MMI, followed, if hyperthyroidism relapses, by radioiodine or, less frequently, by subtotal thyroidectomy. In patients with ophthalmopathy, we prefer a definitive treatment of hyperthyroidism (subtotal thyroidectomy or radioiodine, as indicated) under protection with systemic glucocorticoids if the ophthalmopathy is mild to moderate or followed by combined therapy with orbital irradiation and high-dose systemic glucocorticoids if the ophthalmopathy is severe (64-66).
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DISCUSSION The influence of treatment of hyperthyroidism on the course of Graves' ophthalmopathy remains uncertain. Circumstantial evidence suggests that (a) the course of eye disease is more favorable in patients rendered and maintained euthyroid, (b) an exacerbation may occur after radioiodine therapy or subtotal thyroidectomy, and (c) short-term treatment with systemic glucocorticoids prevents such exacerbations. The following therapeutic implications derive from these considerations: (a) render the patient euthyroid carefully, avoiding treatment-induced hypothyroidism, (b) avoid recurrence of hyperthyroidism in the
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