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Proliferation of retroocular fibroblasts play a major role in the induction
of TAO. This proliferation is thought to be induced by T-lymphocyte stimulation.
Burch et al., Washington, DC, found abundant expression of the enzyme manganese
superoxide dismutase in these fibroblasts, reflecting a high level of superoxide
radicals. When retroocular fibroblasts in culture were exposed to superoxide
radicals, proliferation was induced, but preincubation with methimazole
in a dose of 25 µM inhibited proliferation by 50%, whereas PTU was
less effective. It is concluded that the ameliorative effect of methimazole
on TAO could be explained by action as a freeradical scavenger.
Another phenomenon of TAO is the production of glycoaminoglycans (GAG), produced by the proliferating fibroblasts under the induction of released cytokines. Boucher et al., Montreal, Canada, tested the effects of calcitriol (vitamin D3, VD3) as this vitamin is known for its regulatory effects on cell proliferation and differentiation. They found that VD3 inhibited fibroblast proliferation, cytokine production, and GAG formation, both in fibroblasts in retroocular tissue of control patients, as of TAO patients. (Comment: Although vitamin D has shown to inhibit fibroblast proliferation etc. in controls and TAO patients, it is not advised to treat patients with vitamin D when there is no vitamin D deficiency. However, it would be interesting to investigate the vitamin D status of patients with TAO). Eyelid retraction in TAO is explained due to sympathetic overactivity secondary to thyrotoxicosis. However, eyelid retraction is sometimes also present in euthyroid TAO. If sympathetic overactivity is present, it can be evaluated by measurement of visual accomodation. Hamada et al., Osaka and Tokyo, Japan, measured visual accomodation in three patients with euthyroid TAO. Subject A without a previous history of hyperthyroidism, patient B with subnormal TSH, but normal free T4 and free T3, and patient C who was biochemically also euthyroid (normal TSH). Accomodation was low in patient A, but rose to just below the normal level when timolol malleate drops were locally applied and eyelid retraction disappeared after application of guanethidine drops. In patient B accomoda-tion was normal and local treatment had no effect on eyelid retraction, but this disappeared after 2 years methimazole treatment. Also patient C had normal accomodation and retraction did not react to local treatment, but disappeared after methylprednisolon pulse therapy. The authors suggest that measurement of accomodation may be helpful in the selection of therapy for eyelid retraction in euthyroid TAO. (Comment: It is doubtful if prednisone therapy is always indicated when only eye retraction is present. It is my experience that eyelid retraction often disappears over time.) The autoantigen, causing TAO, has to date not been detected. Several authors claim that the TSH receptor (TSH-R) is also present in retroorbital tissues and may act as an autoantigen to cause TAO. TSH-R mRNA has been detected only by amplification of mRNA by the PCR reaction. This reaction is not always considered to be highly specific. Bahn et al., Rochester, MN, estimated the amount of TSH-R mRNA by direct methods (thus without PCR) in cultured fibroblasts from patients with TAO. They concluded that the mRNA level is too low to be able to measure directly, if present at all. It is therefore still uncertain if TSH-R is present in retroorbital tissues and thus if it is the autoantigen that causes TAO. Kahaly et al., Mainz, Germany, evaluated three different radiation protocols for treatment of moderate to severe (ATA classes 2- 5) TAO in 62 consecutive patients with untreated active TAO, who had been euthyroid for 6 weeks. Patients with compressive optic neuropathy were excluded. Group A (n = 18) received 20 times 1 Gy divided over 20 weeks. Group B (n = 22) 10 times 1 Gy daily in 2 weeks, and group C (n = 22) 10 times 2 Gy daily over 2 weeks. Eye status was evaluated before and 6 months after the start of radiotherapy by ophthalmological investigation and quantitative MR imaging. A successful outcome was observed in 12 A (67%), in 13 B (59%), and in 13 C (59%) treated patients. Response to therapy was independent of duration of eye and/or thyroid disease. Subjective and objective signs decreased most in group A. (Comment: It should be noted that the effect in patients of group B, who received 10 Gy in total, is comparable to that in the other two groups who received each 20 Gy in total. This study is important and invites indeed to evaluate the effect of even lower doses in for instance patients with milder TAO.) Mühlberg et al., München and Leipzig, Germany, studied the effect of dexamethasone and UV-irradiation on the production of the antagonist of interleukin-1 (IL-1) i.e. IL-1 receptor antagonist (IL-1RA) by cultured retroorbital fibroblasts of euthyroid patients with severe active TAO. They found that with increasing concentrations of dexamethasone IL-1RA gene expression by fibroblasts was inhibited in a dose-dependent manner. In contrast, UV-irradiation dose-dependently upregulated IL-1RA expression. The authors conclude that induction of this antagonist to IL-1 may represent an important mechanism, by which orbital radiotherapy exerts its beneficial therapeutic effects in patients with TAO, because IL-1 plays a prominent role in the evolution of TAO by its capacity to stimulate cell proliferation, glycosaminoglycans synthesis and prostaglandine production. (Comment: Corticosteroids, like dexamethasone, also have a beneficial effect on development of TAO, apparently by a different mechanism than through its effects on IL-1RA gene expression.) The same group studied the effect of smoking on soluble (s) IL-1RA serum concentration in 27 consecutive smokers and non-smokers with active moderate to severe TAO, undergoing orbital radiotherapy (OR). All patients were euthyroid at the time of OR while on carbimazole. Eye status was assessed and scored according to the ATA concensus committee classification. Patients (18 smokers, 9 non-smokers) were evaluated prior to and 3 and 6 months following OR. Baseline sIL-1RA levels were negatively correlated with the number of cigarettes smoked during the 6 months preceding OR. Patients with no or minor therapeutical response, who were all smokers, had baseline sIL-1RA levels of 114 pg/ml, that increased to 172 and 149 at 3 and 6 months respectively. By contrast patients with moderate or good response (10 smokers and 9 non-smokers) had significantly higher baseline sIL-1RA levels of 294, which increased to 845 and 634pg/ml at 3 and 6 months respectively. It is concluded that a low baseline and an impaired search of sIL-1RA serum levels following OR were strongly correlated with smoking status. Patients who smoked, had a less favourable therapeutic response. (Comment: It seems wise, not only for the well-known reasons, but also to favour a therapeutical response, to advise patients to stop smoking before radiotherapy, and also during other treatment modalities?) Salvi et al., Parma, Italy, studied IL-6 and soluble IL-6 receptor (sIL-6R) concentrations in serum of 23 patients with Graves' disease (GD) and 14 patients with Hashimoto's thyroiditis (HT) when patients were euthyroid. TAO was active in 23 patients (15 GD and 8 HT), and inactive or absent in 14 patients (8 GD and 6 HT). No differences in median IL-6 and sIL-6R concentrations were found in group A and B patients, and also not in GD patients from group A versus group B. In group A patients with positive anti-TPO antibodies serum IL-6 concentration was higher than in group B patients with positive anti-TPO antibodies. (Comment: The only significant finding was a higher concentration of IL-6 in active TAO patients with positive TPO as compared to inactive or absent TAO with positive TPO. On the other hand, when all active and non-active TAO patients are compared, there is no difference.) |
