SIGNS & SYMPTOMS OF TED

Hello. I'm Dr. Terry Smith

In thinking about Graves' disease of the thyroid, and Thyroid Eye Disease, one is struck by not only the similar disease mechanisms underlying each, but also the divergence between the two diseases, and how the effective treatment of each is quite distinct. Remember, TED can present in patients with Graves' disease who are euthyroid, hyperthyroid, or hypothyroid, depending upon a number of factors, not least of importance is where in the disease temporality the patient might be at the time of presentation.

Because TED is separate, and distinct from Graves' disease, treating the hyperthyroidism, or hypothyroidism of Graves' disease does not address the pathophysiology or the symptomology of TED.

We've learned a lot about TED, its pathogenesis, and its natural course, over the last few decades. What we've learned is that the disease has, as its core, the interplay between multiple signaling pathways, receptors, and the molecular mechanisms involved in the activation of receptors.

Current research has shown that the IGF-1 receptor, when activated, may drive the pathophysiology of TED throughout the course of the disease. Patients with TED have increased receptor expression, and activation.

This cooperativity between the two receptors becoming activated results in the release of many pro-inflammatory cytokines, chemokines, and the subsequent infiltration of immune cells to the orbit. In addition, there is a coordinate overproduction of extracellular matrix molecules, including glycosaminoglycans, of which hyaluronan is the dominant specie. Fibroblast proliferation and terminal differentiation also result from activation of the receptor complex. In a patient with TED, auto-antibodies activate this receptor complex signaling, which stimulates orbital fibroblasts and the biosynthesis of a multitude of mediators of the disease.

We've also come to understand that the connective tissues in the orbits of patients with TED are unique. They are uniquely infiltrated with monocyte derived progenitor cells, known as fibrocytes. These fibrocytes are quite interesting cell types, because they're highly inflammatory. They express auto-antigens that may help us explain the localization of TED to the tissues around the eye.

So, what are the inflammatory effects of—of fibroblast activation? We need to remember that each of the components of pathophysiology of TED translates into the signs and symptoms of the disease, as we encounter in our clinical patients. Once activated, fibroblasts cause severe inflammation and over-expansion of tissue, muscle, and fat cells behind the eye. Inflammation and swelling and expansion of extraocular muscles, soft tissue, and fat in the context of a fixed bony orbit, can lead to clinical manifestations, including inflammation, a foreign body sensation, excessive tearing, dry eye, conjunctival or eyelid redness and swelling, orbital pain, chemosis, proptosis, and diplopia.

With regard to the importance of recognizing TED as early as possible, and when to begin instituting medical therapies, I can't stress enough the importance of recognizing the disease as early as possible. It just makes sense that since the disease, at its very core, has to do with remodeling of tissues, the earlier that the disease is recognized, and that potentially beneficial measures can be taken, the better.