Ординатура / Офтальмология / Английские материалы / Graves' Orbitopathy A Multidisciplinary Approach_Wiersinga, Kahaly_2007

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61Trobe JD: Optic nerve involvement in dysthyroidism. Ophthalmology 1981;88:488–492.

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Dr. A. Jane Dickinson

Eye Department, Claremont Wing, Royal Victoria Infirmary Queen Victoria Road

Newcastle upon Tyne, NE1 4LP (UK)

Tel. 44 191 282 4410, Fax 44 191 2825446 E-Mail Jane.Dickinson@nuth.nhs.uk

Table 1. Synonyms for Graves’ orbitopathy

Graves’ eye disease

Graves’ ophthalmopathy

Ophthalmic Graves’ disease

Thyroid-associated ophthalmopathy (TAO)

Thyroid exophthalmos

Thyroid eye disease (TED)

Thyroid-related eye disease

Von Basedow’s ophthalmopathy

50

Onset of thyroid disease

Onset of eye disease simultaneously with thyroid disease

Fig. 1. Temporal relationship between the onset of Graves’ hyperthyroidism and the onset of Graves’ ophthalmopathy in 99 patients [2].

therapy (fig. 1). Similar data have also been found by the Pisa group [3]. In a pooled analysis over 40% of Graves patients developed orbitopathy after the onset of hyperthyroidism [4].

Patients may also develop GO in the absence of hyperthyroidism and never develop the high circulating thyroid hormone levels at all. This euthyroid GO

(also called ophthalmic Graves’ disease) occurs in 5–10% of patients. However, when these patients are extensively evaluated they are often found to have some features of thyroid disease, ranging from a positive family history through to the presence of TSH-receptor-stimulating antibodies. In addition, they may have isolated positive TPO antibodies or an abnormal response to TRH. Up to 50% of these initially euthyroid patients will develop hyperthyroidism within 18 months of presentation [4]. In addition to the euthyroid group around 10% of GO patients have primary autoimmune hypothyroidism characterised by the presence of moderate or high titres of TPO antibodies. These patients are receiving levothyroxine substitution therapy and are usually found to have TSH receptor antibodies. The severity of the orbitopathy in patients with primary hypothyroidism is as great or sometimes greater than that seen in those with overt Graves’ hyperthyroidism [5].

Do All Patients with Graves’Disease Have Graves’Orbitopathy?

The prevalence or orbitopathy in Graves’ disease depends on the sensitivity of the testing methodology, the inclusion of patients with lid changes only and selection bias of patients.

About 30% of unselected patients with Graves’ disease will have clinical evidence of GO. This may consist of mild symptomatology such as irritation, watering and discomfort or more significant complaints of ocular protrusion, diplopia and pain on eye movement or even at rest. The remainder of the patients are asymptomatic from the eye point of view and careful clinical examination does not reveal any obvious sign of GO. However, an abnormal elevation of intraocular pressure on upgaze has been found in 68% of patients without gross evidence of ophthalmopathy [6]. Imaging studies have shown extraocular muscle involvement in 90.5% of Graves’ patients when assessed by CT [7] but the generally accepted figure is that CT abnormalities occur in about 2/3 of the patients.

What Comes First in Graves’Disease? The Eye Changes or the Hyperthyroid Symptoms?

As indicated above, a small proportion of patients do develop eye changes prior to the onset of hyperthyroidism but in the majority of patients with GO the eye symptoms occur concurrently with the hyperthyroidism or after treatment has been started (fig. 1). Note that in euthyroid GO, an analysis has shown that 89% may have any thyroid abnormality [4].

Do TSH Receptor Antibodies Also Cause GO?

It has been long debated whether GO and Graves’ disease share a common cause, namely autoimmunity against the same antigens. Thus, most investigators believe that the reason why GO and Graves’ disease are associated relies on the fact that either the same proteins or proteins that are similar in their structure are expressed both in the thyroid gland and in orbital tissues, thereby representing a common target for the immune system [8]. Among the various proteins that have been involved, the most reasonable candidate is the TSH receptor, which is well known to be the major target of the immune system in Graves’ disease [9]. Several studies have shown that the TSH receptor is actually expressed in orbital tissues, especially fibroadipose cells. Thus, mRNA encoding the TSH receptor can be found there by RT-PCR [9]. However, TSH receptor mRNA was also found in unrelated tissues [10], raising the question whether its presence in orbital tissue actually reflects a true expression of the receptor or if it may be due to technical artifacts, such as the so-called illegitimate transcription. In this regard, a key point is to understand whether the protein (i.e. the TSH receptor itself) rather than the mRNA encoding it is expressed in orbital tissues. In fact, studies performed with several antibodies against the TSH receptor, either polyclonal or monoclonal, have generated conflicting results [9]. A piece of evidence in support of the expression of TSH receptor in orbital tissues is provided by functional studies in cultured fibroblasts. When primary cultures of fibroblasts derived from fibroadipose orbital tissues of GO patients are cultured under certain conditions, they undergo profound changes, resulting in a pre-adipocyte or adipocyte-like phenotype, following which a higher expression of TSH receptor can be observed together with a functional TSH-receptor-like response [11]. Thus, when challenged with TSH or TSHreceptor stimulating antibodies, differentiated fibroblasts show an increased release of cyclic AMP, suggesting an activation of the cyclic AMP cascade, as it occurs in thyroid cells once the TSH receptor is stimulated. When dealing with autoimmune diseases, the best way to show that a given protein is the responsible autoantigen is to reproduce the disease in animals immunized with the same protein. However, evidence is not available concerning the TSH receptor in GO. Although in some studies genetic immunization of mice with the TSH receptor resulted to some extent in a Graves’ like phenotype (hyperthyroidism), certain eye changes that had been originally interpreted as resembling GO [12] were confirmed only in part in subsequent studies [13]. It is unquestionable that GO is almost always associated with the presence of autoantibodies against the TSH receptor in the serum, and that these also correlate with the stage of GO [14]. Based on all the above considerations, it remains uncertain whether the TSH receptor is the antigen responsible for GO. Although the functional receptor is

Fig. 2. Pretibial myxedema.

probably expressed in orbital tissues, there is no direct proof for it to be the responsible autoantigen, although it remains the most reasonable candidate. Development of new animal models of Graves’ disease is needed in order to finally address this issue.

Are There Any Other Extrathyroidal Manifestations of

Graves’Disease Apart from Graves’Orbitopathy?

The two extrathyroidal manifestations are localised myxedema and thyroid acropachy [15].

Localised Myxedema

Also called pretibial myxedema because of its usual location, this condition is characterised by skin thickening and is often asymptomatic but may be associated with pruritus and occasional pain. The lesion, which is a raised yellow brown area, is usually localised to the pretibial area but has been seen on the feet, toes and upper extremities as well as the forehead and ear (fig. 2). About 90% of patients with pretibial myxedema have a history of hyperthyroidism but it is observed in patients with GO who have never had hyperthyroidism. Approximately 4% of patients with clinical GO will have pretibial

myxedema with an incidence of up to 12% in severe GO. Occasionally, the dermopathy occurs in the absence of clinical ophthalmopathy. Histological and biochemical examination of the lesion shows that the main constituent is an accumulation of glycosaminoglycans in the dermis. There is only minimal lymphocyte infiltration. The excess glycosaminoglycans are thought to cause dermal edema which will compress lymphatics thereby aggravating the edema.

Thyroid Acropachy

Thyroid acropachy presents with digital clubbing of fingers (but not toes) and swelling of digits and toes together with a periosteal reaction of extremity bones. It is rare, occurring in approximately 1% of patients with Graves’ disease. It is probably more common in females and may postdate hyperthyroidism, ophthalmopathy and dermopathy in that order. Similar to ophthalmopathy, it may occur in euthyroid or hypothyroid patients. A review of 178 patients with dermopathy showed that more than one fifth had acropachy and that this condition is an indicator of the severity of ophthalmopathy and dermopathy. Like dermopathy, it is nearly always associated with high titres of thyroid hormone receptor-stimulating antibodies.

References

1Means JH: Hyperophthalmic Graves’ disease. Ann Intern Med 1945;23:779–789.

2Wiersinga WM, Smit T, Van der Gaag R, Koornneef L: Temporal relationship between onset of Graves’ ophthalmopathy and onset of thyroidal Graves’ disease. J Endocr Invest 1988;11:615–619.

3Marcocci C, Bartalena L, Bogazzi F, Panicucci M, Pinchera A: Studies on the occurrence of ophthalmopathy in Graves’ disease. Acta Endocrinol (Copenh) 1989;120:473–478.

4Burch HB, Wartofsky L: Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev 1993;14:747–793.

5Gleeson H, Kelly W, Toft A, Dickinson J, Kendall Taylor P, Fleck B, Perros P: Severe thyroid eye disease associated with primary hypothyroidism and thyroid-associated dermopathy. Thyroid 1999;11:1115–1118.

6Gamblin GT, Harper DG, Galentine P, Buck DR, Chernow B, Eil C: Prevalence of increased

intraocular pressure in Graves’ disease: evidence of frequent subclinical ophthalmopathy. N Engl J Med 1983;308:420–424.

7Enzmann DR, Donaldson SS, Kriss JP: Appearance of Graves’ disease on orbital computed tomography. J Comp Assist Tomogr 1970;3:815–819.

8Prabhakar BS, Bahn RS, Smith TJ: Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr Rev 2003;24:802–835.

9Bahn RS: TSH receptor expression in orbital tissue and its role in the pathogenesis of Graves’ oph-

thalmopathy. J Endocrinol Invest 2004;27:216–220.

10Agretti P, Chiovato L, De Marco G, Marcocci C, Mazzi B, Sellari-Franceschini S, Vitti P, Pinchera A, Tonacchera M: Real-time PCR provides evidence for thyrotropin receptor mRNA expression in orbital as well as in extraorbital tissues. Eur J Endocrinol 2002;147:733–739.

11Agretti P, De Marco G, De Servi M, Marcocci C, Vitti P, Pinchera A, Tonacchera M: Evidence for protein and mRNA TSHr expression in fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) after adipocytic differentiation. Eur J Endocrinol 2005;152:777–784.

12Many MC, Costagliola S, Detrait M, Denef F, Vassart G, Ludgate MC: Development of an animal model of autoimmune thyroid eye disease. J Immunol 1999;162:4966–4974.

13Baker G, Mazziotti G, von Ruhland C, Ludgate M: Reevaluating thyrotropin receptor-induced mouse models of Graves’ disease and ophthalmopathy. Endocrinology 2005;146:835–844.

14Eckstein AK, Plicht M, Lax H, Neuhauser M, Mann K, Lederbogen S, Heckmann C, Esser J, Morgenthaler NG: Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 2006;91:3464–3470.

15Fatourechi V Localized myxedema and thyroid acropachy; in Braverman LE, Utiger RD (eds): The Thyroid: A Fundamental and Clinical Text, ed 9. New York, Lippincott Williams & Wilkins, 2005, pp 488–499.

Prof. J.H. Lazarus

Centre for Endocrine and Diabetes Sciences, Cardiff University Cardiff CF14 4XN, Wales (UK)

Tel. 44 29 2071 6900, Fax 44 29 2071 2045, E-Mail Lazarus@cf.ac.uk

Conversely, respondents who considered that the prevalence of GO increased originated from countries such as Poland and Hungary, where the prevalence of smoking had increased since 1989 [5].

Is the Age and Sex Distribution of Graves’ Orbitopathy

Similar to that of Graves’ Disease?

GO patients are older than patients with Graves’hyperthyroidism, with a mean age of 46.4 years for patients with GO and Graves’hyperthyroidism, but 40.0 years for patients with Graves’ hypothyroidism only [4, 6]. In 152 newly referred GO patients from 8 EUGOGO centers, the mean age of GO patients was 49 years [7].

Graves’ ophthalmopathy, like Graves’ hyperthyroidism, is more common in women than in men. The female to male ratio was 9.3 in patients with mild ophthalmopathy, 3.2 in those with moderate ophthalmopathy, and 1.4 with severe ophthalmopathy [1–4].

A sex-related difference in the severity of GO has been noted, with men comprising a relatively greater proportion of cases of severe ophthalmopathy. Eye disease tends to be more severe in older patients and in men. The reason for this effect of gender is not clear but the higher prevalence of smoking among men likely plays a role.

Are There Ethnic Differences?

Europeans have a substantially greater risk of developing GO than Asians, with a prevalence of 42% compared to 7.7% in Asians [8].

The reasons for this difference are not clear. Recent genetic studies suggest that the common 318 C/T polymorphism in the promoter region of CTLA4 gene is associated with a reduced risk of ophthalmopathy in Chinese Graves’ patients [9]. However, extended analyses with large sample sizes should be carried out in patients of different ethnic origin to verify this association. Environmental or anatomic factors are more likely to be involved. Adequate adjustments of normal and abnormal values of exophthalmos are important for a correct diagnosis of TAO [10].

What Are the Risk Factors for the Occurrence of Graves’ Orbitopathy?

Several factors may increase the risk of ophthalmopathy in patients with Graves’ disease, namely tobacco, gender, genetics, type of treatment for hyperthyroidism, TSH receptor antibodies, drugs, advanced age and stress.