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Editor,—The pathogenesis of thyroid eye disease is believed to derive from fibroblast stimulation by cytokines released by activated T lymphocytes. There is evidence of abnormal cell mediated autoimmunity and humoral autoimmunity resulting in infiltration of lymphocytes and adipocytes into the extraocular muscles.1 The success of therapeutic immunosuppressants (steroids/azathioprine/radiotherapy) strengthens this hypothesis. A single definitive cross reacting (thyroid/retro-orbital) autoantibody has not been identified. Zhang et alfound that sera from 50% of patients with thyroid eye disease reacted with an eye muscle specific protein of 55 kDa relative molecular weight.2 Pittsburgh data showed 67% patients with active Graves' ophthalmopathy have antibodies against a 67 kDa mitochondrial flavoprotein subunit although it has been subsequently found in 20% of controls.3 They also identified a 220 kDa cell membrane specific protein known as G2S specific to eye muscle and thyroid tissue, but antibodies to this have been demonstrated in both thyroid eye disease patients and normal people.4 No autoantibody has been demonstrated in every case and all lack specificity. Our case demonstrates that whatever the autoimmune process may be, the presence of normal thyroid tissue or autoimmune disease afflicted thyroid is not essential at the time of onset and development of clinical disease.
At age 30, this woman underwent partial thyroidectomy for papillary thyroid cancer. At 36 years she underwent radioactive ablation (2.2 GBq iodine-131) of the residuum for suspected recurrence. At this time there was no evidence of orbital disease.
At 70 years, she presented with 6 months' diplopia and “puffy, gritty” eyes.
She was clinically euthyroid on thyroxine, with bilateral proptosis (worse on the left) with conjunctival congestion, periorbital oedema, a divergent strabismus (Fig 1) and limitation of upward gaze. A clinical diagnosis of thyroid eye disease was made, which was confirmed by orbital computed tomography (Fig2).
Both her sister and paternal grandmother had goitres without thyroid eye disease. Her sister had thyroid microsomal antibodies.
Normal triiodothyronine 1.44 nmol/1 (range 1.2–2.2), mildly elevated thyroxine (174 nmol/1, normal range 58–140) in an attempt to suppress the thyroid stimulating hormone (0.9 mU/l, normal range 0.3–4.0). A technetium-99 uptake scan showed no thyroid remnant. An iodine-123 tracer scan showed borderline evidence of uptake in the thyroid bed but avid uptake in the lower thoracic spine suggesting residual thyroid cancer with a vertebral metastasis. Her serum thyroglobulin was elevated at 28 ng/ml (normal range <1 in athyria) but there were no antithyroglobulin antibodies. Thyroid stimulating hormone antibodies were negative, as were her thyroglobulin antibodies and thyroid microsomal antibodies. All human and porcine retrobulbar autoantigens were negative including the aforementioned 55, 67, and 220 kDa protein antibodies despite the presence of metastatic thyroid tissue. Her general autoantibody profile was negative for antinuclear antibodies, gastric parietal cell, smooth muscle, liver/kidney microsomal, mitochondrial and reticulin. The RA latex was weakly positive and the Rose-Waaler was <1:32.
Her thyroid eye disease was treated with radiotherapy to good effect. Her asymptomatic metastatic thyroid cancer is being treated with radioiodine.
This woman, with a family history of thyroid disease and whose sister has thyroid autoantibodies, has developed thyroid eye disease while possessing no significant normal thyroid tissue for 36 years. She was negative for the full array of routine and experimental thyroid autoantibodies and no other autoimmune disease were demonstrable.
If a humoral mechanism is relevant, than there are several possible explanations; firstly the autoantibody could be related to the sodium-iodine symporter in the thyroid cancer cells. That the recurrent thyroid cancer took up iodine may suggest the sodium-iodine symporter protein was present. An antibody to this protein may be a candidate for the cross reacting autoantibody but is not measured. Against this hypothesis is the fact that her sera did not cross react with porcine and human thyroid tissue screening test. Secondly, this observation could be explained by a separate or non-specific, non-thyroid specific immune response cross reacting with the orbital muscles to instigate the pathogenic process. More than one autoantibody may be able to produce thyroid eye disease or this may be part of a multifactorial immune process. Further, it is known that the severity of thyroid eye disease is not related to autoantibody titres but rather to environmental factors such as smoking and iatrogenic factors such as radioiodine treatment of thyrotoxicosis.5 6
While we accept that much current interest in the pathogenesis of this disease lies, not with humoral mechanisms, but with a T cell mediated cellular immune response, it is equally pertinent that any such event was initiated and progressed in a patient with athyria.
Our observations in this case are relevant to the understanding of the aetiology of thyroid eye disease in so far as the disease occurred in the presence of differentiated thyroid cancer but in the absence of any normal thyroid tissue or thyroid currently afflicted by autoimmune disease (and absence of any detectable amounts of the panoply of currently measurable serum autoantibodies)—this dissociation has not hitherto been recognised.