Introduction

Thyroid eye disease (TED) or thyroid-associated orbitopathy (TAO) is reported to affect 25 to 50% of patients with Graves’ disease (GD) and up to 2% of patients with chronic autoimmune thyroiditis. Annual incidence is estimated to be 16 per 100,000 in women and 2.9 per 100,000 in men. ^{1,​ 2} There is a bimodal age distribution with the highest incidence in the fifth and seventh decades. The major pathological features include expansion of orbital soft tissues and enlargement of extraocular muscles. These changes can lead to proptosis, exposure keratopathy, and restrictive strabismus with debilitating diplopia. In severe cases, crowding of the orbital apex can result in compression of the optic nerve with permanent vision loss if left untreated. ³ Currently available treatments for TED include medical therapy directed at treating hyperthyroidism and orbital inflammation, surgical therapy in the form of orbital decompression, eyelid surgery usually to recess the eyelids, strabismus surgery to realign the eyes, as well as radiation therapy as either radioactive iodine ⁴ or external beam orbital radiation. These treatments show variable efficacy over a wide spectrum of disease severity. This is at least in part due to our limited understanding of the pathophysiology behind TED. This chapter aims to provide a summary of the most current knowledge and evidence behind the pathogenesis of TED, clinical presentation, diagnostic studies, and treatment options.

6.2 Pathophysiology

Understanding the pathophysiology of TED begins with the mechanisms behind autoimmunity in GD. In GD, autoimmune response to the A-subunit of the thyroid-stimulating hormone receptor (TSHR), which is a G protein coupled receptor, results in autoantibodies known as thyroid-stimulating immunoglobulins (TSI). ⁵ TSI in circulation then bind the TSHR on the thyroid follicular cells, which then secrete thyroid hormone, leading to clinical hyperthyroidism. The cause or the trigger for the initiation of this autoimmune response, or loss of self-tolerance to TSHR, is unknown. There is, however, a close temporal correlation between onset of GD and TED, with the majority of patients developing eye symptoms within 18 months of autoimmune thyroid disease. This correlation is thought to suggest at least some overlapping common pathways underlying the two disease processes. ⁶

Pathogenesis of TED can be understood as a complex interaction between autoimmunity, inflammation, cytokine response, and how these affect the downstream effector cells within the orbit leading to the clinical findings. ⁶

6.2.1 Autoimmunity in Thyroid Eye Disease

As noted earlier, autoimmunity against TSHR is a fundamental component of GD. Given the temporal as well as many clinical correlations between TED and GD, autoimmunity against TSHR was assumed to play a role in TED. In fact, studies revealed that 98% of patients with TED have detectable TSHR autoantibodies. ⁷ With further improvement in sensitivity of modern assays for TSHR antibody detection, both TSI and second subtype TSHR binding inhibitory immunoglobulins (TBII) are detectable and highly correlated with clinical activity of TED. ⁸ Although TSHR was originally thought to be isolated to follicular cells within thyroid tissue, it has since been recovered in low levels in a variety of cell types, including orbital fibroblasts (OF). OF cultured from TED patients have higher levels of TSHR expression compared to controls, and those with active disease have higher levels of expression than those in inactive or chronic stage. ⁹ TSHR antibodies acting upon these upregulated TSHR within orbital tissue are thought to lead to downstream pathways as outlined below via the effector cells. ⁹

Another potential autoantigen that has been implicated in TED is insulinlike growth factor 1 receptor (IGF-1R). IGF-1R is a receptor tyrosine kinase with widespread expression and roles. Its expression is certainly not specific to GD, TED, or orbital tissues. It is, however, thought to form a functional complex with TSHR to propagate a synergistic response leading to changes in TED. ¹⁰ IGF-1R has a threefold higher expression in OF from TED patients compared to controls, and induce hyaluronan (HA) synthesis. ¹¹ However, the actual autoantibodies directed against IGF-1R have been shown to be equivalent in TED and healthy controls, ¹⁰ and the exact binding activity of IGF-1R antibodies on IGR-R1 on OF remains to be elucidated.

6.2.2 Effector Cells in Thyroid Eye Disease Orbit

The constellation of signs and symptoms of TED are attributable to volume expansion of extraocular muscles and orbital fat. Examination of this orbital tissue reveals increased deposition of glycosaminoglycans (GAG) in the form of HA. HA is a high-molecular-weight, highly anionic and hydrophilic polysaccharide that is present within the connective tissue throughout the body. HA deposition within the endomysium of extraocular muscle fibers leads to extracellular, interstitial edema and subsequent extraocular muscle enlargement. In terms of orbital fat expansion, there is de novo adipogenesis triggered by signaling pathways linked to TSHR and IGF-1R.

The main effector cell for both HA synthesis and adipogenesis carrying out the downstream signaling pathways for TSHR and IGF-1R is thought to be the OF. Fibroblasts are ubiquitous connective tissue cells. In the orbit, two subpopulations of fibroblasts are thought to exist: thymocyte antigen 1 positive (Thy1+) and Thy1-negative (Thy1–) OF. Thy1+ OF, when treated with transforming growth factor beta (TGF-β) differentiate into myofibroblasts with contractile properties, while Thy– OF differentiate into mature adipocytes when treated with peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist. ¹² Each of these subtypes are thought to be responsible for the heterogeneity in the presentation of TED, with some patients exhibiting enlargement of extraocular muscles predominantly versus proliferation of orbital fat.

The origin of these pluripotent OF is likely related to a population of progenitor cells known as fibrocytes, which are bone-marrow-derived cells expressing both fibroblastic and hematopoietic stem cell markers from monocyte lineage. They circulate in peripheral blood and are able to migrate to sites of injury, and in this case, orbital tissue in TED. In a similar manner to OF, fibrocytes are able to differentiate into myofibroblasts or adipocytes, express both TSHR and IGF-1R, and secrete a similar set of inflammatory cytokines. Fibrocytes are found in higher levels in the peripheral circulation of TED patients compared to controls, and the concentration of TSHR-expressing fibrocytes in TED is similar to that of thyroid follicular cells. ¹³

In response to both TSHR and IGF-1R activation, HA synthesis and adipogenesis pathways are triggered in OF and fibrocytes. For HA synthesis interleukin-1 beta (IL-1β), TGF-β1, and platelet-derived growth factor (PDGF) have all been separately shown to be potent activators. PDGF also further increases expression of TSHR in OF, forming a type of positive feedback loop to potentiate its effect. ¹⁴ Interestingly, IL-1β-mediated stimulation of HA synthesis can be blocked by steroids ¹⁵ and PDGF-mediated response can be mitigated by a number of tyrosine kinase inhibitors, suggesting possible venues for targeted therapy in TED. Adipogenesis in OF is carried out by PPAR-γ signaling. There is an overexpression of PPAR-γ in the adipose tissue of active TED. Rosiglitazone, an anti-diabetic drug that is a PPAR-γ agonist, has also been shown to increase TSHR expression, further potentiating this pathway. ¹⁶ Both TSHR and IGF-1R trigger differentiation of pre-adipocytic OF into mature adipocytes, leading to proliferation of orbital fat in TED.

6.2.3 Cellular Immunity and Role of Inflammation

Another component in the complex pathophysiology of TED is the role of cellular immunity and inflammation. In the active phase of TED, orbital inflammation is a key feature that manifests clinically as injection, chemosis, proptosis, lid edema, and pain, and is often acutely treated with steroids. Examination of enlarged extraocular muscles and orbital fat reveals extensive lymphocytic infiltration. While both T and B lymphocytes have been noted within the orbital tissue, CD4⁺ T-cell population predominates. There is a reciprocal signaling between OF and lymphocytes in that activated OF secrete T-cell chemoattractants that recruit T cells to the orbit, which in turn further activate OF. Within extraocular muscles, Th1-type cytokine expression is seen with interferon gamma (IFN-γ), tumor necrosis factor alpha (TNFα), and IL-1β and IL-6. Within orbital fat, Th2-type profile with IL-4 and IL-10 is thought to be more common. ¹⁷ Th1 type is also more common in active phase of TED, while Th2 is seen in the chronic, stable phase. ¹⁸ Activated OF respond robustly to these cytokines, and in turn also secrete more to form a potentiating positive feedback loop. Overexpression of IL-1β, TNFα, IFN-γ, IL-6, IL-10, and IL-8 has been shown in orbital tissue in TED. IL-6 in particular is known to further increase the expression of TSHR, as well as B-cell activation. B lymphocytes in turn are responsible for the generation of the autoantibodies. Rituximab, a monoclonal antibody against B-cell antigen CD20, has shown promise in treatment of TED in recent studies. ¹⁹

6.3 Clinical Presentation

The most salient clinical features of TED include unilateral or bilateral proptosis, eyelid retraction with “temporal flare,” lid lag, lagophthalmos, and restrictive strabismus ( ▶ Fig. 6.1). The disease can be symmetric or vastly asymmetric. With regard to strabismus, the inferior rectus and medial rectus muscles are typically the most frequently affected muscles and can produce corresponding supraduction and abduction deficits. Decreased vision results from exposure keratopathy from a combination of features mentioned earlier, and in severe cases, compressive optic neuropathy. Additional signs and symptoms depending on the relative activity of the disease include eyelid erythema and edema, conjunctival injection (frequently over extraocular muscle insertions), and chemosis and caruncular edema. The acuity and activity of the disease can also be evaluated by assessing the resistance to retropulsion where the surgeon gently presses on the globes over closed eyelids and determines the degree of resistance. When there is active inflammation, the resistance is generally higher than that of chronic fibrosis. According to an oft-cited cohort study, eyelid retraction is the most common feature of TED and is present in 90% of patients at some point during the clinical course. This was followed by proptosis, which was seen in 62%, restrictive extraocular motility (43%), and optic nerve dysfunction (6%). The most common subjective symptom was ocular pain, present in 30% of patients. ²⁰

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