Ординатура / Офтальмология / Учебные материалы / Эндокринная офтальмопатия - мультидисциплинарный подход 2007

Fig. 1. Combined thyroid-eye clinics at work: the resident in training (standing) presents the patient to the consultants in endocrinology and ophthalmology (both seen at the back); results of all laboratory tests, ophthalmological measurements and orbital CT scans can be viewed at the screen of the computer connected to the hospital patients’ database.

the most appropriate management plan. This requires combined thyroid-eye clinics of the two specialties (fig. 1). According to patient load, the combined clinics can be organized once weekly, every fortnight, or every month.

Why Is a Multidisciplinary Approach Recommended?

Accurate diagnosis and appropriate management of GO requires the combined expertise of endocrinologist and ophthalmologist. Although the expertise of the clinicians is critical and the setting perhaps less so, evidence from other clinical disciplines would suggest that a dedicated multidisciplinary clinic results in better outcomes [3, 4]. The European Group on Graves’ Orbitopathy (EUGOGO) therefore recommends that patients with GO should be managed in combined thyroid-eye clinics with input from endocrinologists and ophthalmologists [5]. EUGOGO strongly believes that multidisciplinary groups enhance

Table 1. High-speed track for patients with GO, operative in the Academic Medical Center, Amsterdam

the quality of care delivered to GO patients. Many patients with GO in Europe never reach specialist centres or are referred too late to benefit from treatments, which results in suboptimal outcomes [6]. It is therefore encouraging to notice that the number of combined thyroid-eye clinics all over Europe is steadily increasing over the last few years.

Can Patients-Support Groups Be Helpful?

Involvement of patients with GO in the combined thyroid-eye clinics can be very helpful. One may ask representatives of patient support groups to be present in a separate room, simultaneously with the combined thyroid-eye clinics. Patients may wish to get into immediate contact with fellow patients, who as experts by experience may share how it feels to be affected by GO and undergoing specific procedures. It may reduce anxiety for what is coming and offer a realistic view of what is to be expected in terms of outcome. Talking to fellow patients add a dimension not readily provided by the attending physicians. Patient support groups usually distribute very informative brochures on GO.

I Have Heard of a Fast-Track Clinic for Graves’

Orbitopathy Patients: What Is That?

When the patient attends the combined thyroid-eye clinic, he or she has already been seen separately by the ophthalmologist and the endocrinologist, and the results of specific laboratory investigations ordered by these two specialists are known. It means that the patient has already visited the hospital on

average 4–6 times for consultations with both specialists, with the orthoptist, the radiology department and the laboratory. To reduce the number of visits, a ‘high-speed track’ for GO patients can be organized, in which all investigations are being performed on the same day (table 1). The results are in at the end of the afternoon, and can be viewed in the consultation room on the monitor of the computer connected to the large hospital patients’ database. The patient is then seen simultaneously by both consultants, and a final diagnosis and management plan can be reached in almost all instances. The logistics of such a high-speed track should not be underestimated, but once it is operative it is very gratifying for doctors and patients alike. Our high-speed track accommodates two new referrals of GO patients every Tuesday [7].

References

1Bartley GB, Fatourechi V, Kadmas EF, Jacobson SJ, Ilstrup DM, Garrity JA, Gorman CA: The incidence of Graves’ ophthalmopathy in Olmsted Country, Minnesota. Am J Ophthalmol 1995;120:511–517.

2Wiersinga WM, Prummel MF: Graves’ ophthalmopathy: a rational approach to treatment. Trends Endocrinol Metab 2002;13:280–287.

3Ducharme A, Doyon O, White M, Rouleau JL, Brophy JM: Impact of care at a multidisciplinary congestive heart failure clinic: a randomized clinical trial. Cancer Med Ass J 2005;173:40–43.

4Sperk-Hillen JM, O’Connor PJ: Factors driving diabetes care improvement in a large medical group: 10 years of progress. Am J Management Care 2005;5:S177–S185.

5The European Group on Graves’ Orbitopathy (EUGOGO): Clinical assessment of patients with Graves’ orbitopathy: the European Group on Graves’ Orbitopathy recommendations to generalists, specialists and clinical researchers. Eur J Endocrinol 2006;155:387–389.

6Perros P, Baldeschi L, Boboridis K, Dickinson AJ, Hullo A, Kahaly GJ, Kendall-Taylor P, Krassas GE, Lane CM, Lazarus JH, Marcocci C, Marino M, Mourits MP, Nardi M, Orgiazzi J, Pinchera A, Pitz S, Prummel MF, Wiersinga WM: A questionnaire survey on the management of Graves’ orbitopathy in Europe. Eur J Endocrinol 2006;155:207–211.

7Wiersinga WM: The philosophy of Graves’ ophthalmopathy. Orbit 2005;24:165–171.

Prof. Wilmar M. Wiersinga

Department of Endocrinology and Metabolism, Academic Medical Center, Room F5–171 University of Amsterdam

Meibergdreef 9

NL–1105 AZ Amsterdam (The Netherlands)

Tel. 31 20 566 6071, Fax 31 20 691 7682, E-Mail w.m.wiersinga@amc.uva.nl

Fig. 1. Disappearance of lid retraction in a hyperthyroid patient (a) rendered euthyroid with methimazole thyroidectomy (b).

serum TSH-receptor autoantibody (TRAb) and other thyroid autoantibodies levels [1, 3]. Although the pathogenic link between thyroid and orbit autoimmune phenomena remains to be definitely proven, flare up of autoimmune reactions against antigen(s) share by thyroid and orbit might cause GO progression. This is one of the arguments used to advocate permanent control of hyperthyroidism by either radioiodine therapy or thyroidectomy in Graves’ patients with GO [9].

Radioiodine

Radioiodine therapy is the first-line treatment of Graves’ hyperthyroidism in the USA [5]. Opinions on its effects on GO are controversial [1, 10–12], but results of the few available randomized studies are more concordant, because they show GO progression after radioiodine therapy in 15–37% of patients [13–15] (fig. 2). GO exacerbation is more likely in patients who had GO prior to radioiodine therapy, and can be prevented by a concomitant course of oral glucocorticoids [see below, ‘Should the presence of Graves’ orbitopathy limit the use of radioiodine therapy?’], which also contribute to improve pre-existing eye manifestations [13, 15]. If radioiodine is given to patients with absent or minimally active/inactive GO, progression of the eye disease is unlikely, if other risk factors [see below, ‘Is there any risk factor which may predict worsening of Graves’ orbitopathy after radioiodine?’] are absent [16, 17].

Fig. 2. Outcome of GO after treatment of hyperthyroidism with methimazole, radioiodine or radioiodine prednisone in a randomized clinical trial [15].

The pathogenic mechanism responsible for radioiodine-associated progression of GO is probably related to the release of thyroid antigens after radiation injury, which might trigger or exacerbate autoimmune responses towards antigens shared by thyroid and orbit [1, 3], and/or to a transient phase of hypothyroidism associated with TSH receptor (TSHR) stimulation by TSH [18].

Although in the short-term radioiodine may be detrimental for GO, in the long-term it may have beneficial effects owing to antigen deprivation and removal of thyroid autoreactive T lymphocytes [19, 20].

Thyroidectomy

The issue of whether thyroidectomy affects the course of GO is also unsettled [1, 3, 7]. However, results of recent studies support the concept that thyroidectomy is not a disease-modifying treatment and does not influence the natural history of GO [1, 3, 7]. Accordingly, glucocorticoids are not needed after thyroidectomy for Graves’ disease [21].

Since thyroidectomy also causes leakage of thyroid antigens, why it is not followed, as in the case of radioiodine therapy, by GO progression? This is probably due to the different temporal modality of thyroid injury (long lasting after radioiodine therapy and short lasting after surgery) and to the consequent modification of the thyroid autoimmune response [21]. Moreover, at variance with radioiodine, the initiation of levothyroxine treatment shortly after surgery may protect surgical patients from the occurrence of hypothyroidism, which, as mentioned above, may adversely affect GO [21].

In summary, thionamides and thyroidectomy do not substantially affect the course of GO, whereas radioiodine therapy is associated with GO progression

Table 1. Advantages and disadvantages of different treatment of hyperthyroidism

1This can be avoided by using the block-replace regimen.

2Worsening can be prevented by protective glucocorticoid therapy (0.5 mg/kg body weight for 1 month, gradually withdrawn over 2 months) [13, 15].

in a minority of patients. Glucocorticoid coverage should be given in at-risk patients treated with radioiodine (table 1).

Are There Any Specific Criteria to Prefer One of the Treatment

Modalities for Hyperthyroidism in Graves’Orbitopathy?

Any hyperthyroid patient with GO, independent of its severity, should receive prompt treatment with thionamides in order to restore euthyroidism. The issue discussed herein is whether the choice of subsequent treatment of hyperthyroidism in patients with GO should be made, in addition to established criteria (goitre size, age, first episode vs. recurrence of hyperthyroidism, etc.), on the basis of other features related to the presence of GO. In any case, a coordinated approach to the treatment of Graves’ hyperthyroidism and orbitopathy should be taken.

The presence of active GO has generated two lines of thought in the last 20–30 years. The first suggests that when GO is active, it may be preferable to continue ATD treatment and, if needed, associate immunosuppression (glucocorticoids and/orbital irradiation) or orbital decompression as appropriate. The use of radioiodine or surgery would be delayed until the eye disease is burnt-out [22]. The second approach favours, in view of the pathogenic link between thyroid and orbit, definitive therapy of hyperthyroidism (radioiodine or surgery) and concomitant treatment for GO as appropriate [10]. No controlled studies are available to establish whether either approach is better.

The first approach is reasonable in mild cases of GO not requiring specific therapeutic measures (except for the local treatments) in that it allows the eye disease to run its natural course. In moderate-to-severe GO cases, the second approach might be preferred, because radioiodine or surgery might have, in the long run, a beneficial effect on GO following removal of shared thyroid antigens and autoreactive T lymphocytes [19, 20].

The identification of risk factors which are associated with an increased risk of GO worsening after radioiodine therapy should prompt to select thionamides (or thyroidectomy, when appropriate) as the treatment of choice for hyperthyroidism, or to associate glucocorticoids with radioiodine therapy.

Is There Any Risk Factor which May Predict Worsening of

Graves’Orbitopathy after Radioiodine?

GO progression after radioiodine therapy occurs only in a minority of patients ( 15%). Therefore, other risk factors must contribute to this outcome. Some of these factors have been identified, including the following:

(1)Pre-existing orbitopathy (especially if active): In one study GO worsened in 17 of 72 (24%) patients with pre-existing orbitopathy and appeared only in 6 of 68 (8%) patients without eye involvement prior to radioiodine therapy [15];

(2)Severity of hyperthyroidism prior to radioiodine therapy: GO aggravation of was more likely in patients with higher serum thyroid hormone concentrations before treatment (T3 level 5 nmo/l) [14];

(3)High serum TSH or TSHR antibodies levels: Circumstantial evidence suggests that high serum TSH [18] or TSHR antibodies [23, 24] may also play a role in the exacerbation of GO after radioiodine;

(4)Cigarette smoking: Worsening or de novo appearance of GO is quite rare in non-smokers (4 of 68 patients, 6%), but much more frequent in smokers

(19 of 82 patients, 23%) [25].

It is therefore important to collect adequate information regarding the above issues before using radioiodine therapy. In fact, identification of risk factors allows the identification of patients in whom GO is more likely to progress. In these patients, concomitant glucocorticoid therapy should be given after radioiodine therapy, since it avoids progression of eye disease [10, 13, 15, 17] [see below, ‘Should the presence of Graves’ orbitopathy limit the use of radioiodine therapy?’].

In addition to factors predicting the worsening of ophthalmopathy, it is very important to avoid late correction of hypothyroidism [26] [see below, ‘Does transient hypothyroidism following therapy influence the course of Graves’ orbitopathy?’].

Should the Presence of Graves’Orbitopathy Limit the

Use of Radioiodine Therapy?

As previously discussed [see above, ‘Does it matter for the eyes how the patient is rendered euthyroid?’)], radioiodine therapy carries a small but definite risk of causing progression of GO [1, 7, 13–15]. However, progression is usually observed in patients in whom other risk factors are present [see above, ‘Is there any risk factor which may predict worsening of Graves’ orbitopathy after radioiodine’] and can be prevented by protective glucocorticoid therapy (0.5 mg/kg body weight for 1 month, gradually withdrawn over 2 months) [13, 15]. Glucocorticoid can be safely administered after radioiodine since it does not affect the outcome of radioiodine therapy for hyperthyroidism [27]. The possible side effects of glucocorticoids and the need to complete the 2-month treatment once radioiodine has been given should be discussed with the patient before radioiodine is chosen as the treatment for hyperthyroidism.

A survey among European endocrinologists showed that the possible untoward effects of radioiodine on GO influenced their willingness to use it in GO patients with recurrent hyperthyroidism [28]. We do not share the view that radioiodine therapy should be avoided in GO patients [1, 9, 10]. Radioiodine is an effective procedure for permanent control of hyperthyroidism and can be safely used in patients with GO following the appropriate guidelines (table 2). In patients with no signs or symptoms of GO or when orbitopathy is inactive, concomitant glucocorticoid therapy may not be necessary, because a new appearance of GO is very rarely observed. Nevertheless, glucocorticoids may certainly be considered, especially if other risk factors (especially cigarette smoking) are present [7] [see above, ‘Is there any risk factor which may predict worsening of Graves’ orbitopathy after radioiodine?’]. In any case, patients given radioiodine should be informed of the low risk of developing GO and glucocorticoids should be offered. In patients with mild and active eye disease, a 2-month course of oral glucocorticoid is recommended [10, 17]. In patients with moderate-to-severe and active GO, radioiodine therapy should be promptly followed by appropriate treatments for GO, such as high-dose intravenous glucocorticoids and/or orbital radiotherapy [1].

Does Transient Hypothyroidism following Therapy

Influence the Course of Graves’Orbitopathy?

Maintenance of stable euthyroidism during therapy with thionamides and prompt restoration of normal thyroid status after radioiodine therapy or thyroidectomy is strongly recommended. Indeed, occurrence of a transient phase