Thyroid Eye Disease: A Historical Perspective

Within the short period from 1802 to 1840 four physicians from four different countries (Flajani in Italy, Parry in England, Graves in Ireland and Basedow in Germany) independently described a hitherto unknown disease, the hallmark of which were tachycardia and enlargement of the thyroid. Three of the physicians also noted exophthalmos. In sequence, the disease was attributed to primary cardiac disease, then to increased sympathetic nerve discharge, and finally to thyroid hyper-function. The latter concept failed to explain the exophthalmos, which cannot be reproduced by over-dosage of thyroid hormone. Explanations for the exophthalmos went from cardiac failure (causing swelling of the thyroid and retro-orbital tissues), to sympathetic nerve discharge, to over-secretion of TSH, to production within the pituitary of TSH fragments with exophthalmogenic properties, and finally to shared auto-antigens of thyroidal and retroorbital tissue. The latter theory is favoured today, after it had been recognized that thyroid hyperfunction in Graves’ disease was due to auto-antibodies to the thyroidal TSH receptor; such receptors were postulated also to be present in retroorbital tissue. Thus, each generation of scientists explained the pathogenesis of exophthalmos with the methods and concepts available to medical research at any given time. Although big advances have been made, future research may be good for some unexpected surprises.