Thyroid hormone upregulates α, but downregulates β-chain in myocytes [14]. The final effect of thyroid hormones in animal studies is an increased rate of V1 isoform of MHC (MHCα/α) synthesis that is characteristically faster in myocardial fibre shortening [13,15]. A similar effect

Thyroid hormones also have effects on SERCA, which is responsible for the rate of calcium uptake during diastole, by actions on calcium activated ATPase and its inhibitory cofactor phospholamban [18,19]. Thyroid hormones enhance myocardial relaxation by upregulating expression of SERCA, and downregulating expression of phospholamban. The greater reduction in cytoplasmic calcium concentration at the end of the diastole increases the magnitude of systolic transient of calcium and augments its ability for activation of actinmyosin subunits. As a confirmation, phospholamban deficient mice showed no increase in

On the plasma membranes, T3 exerts direct extragenic actions on the functions other ion channels such as Na/K ATPase, Na/Ca++exchanger, and some voltage gated K channels (Kv

bring differing degrees of risks to patients.

66 Thyroid Disorders - Focus on Hyperthyroidism

the transcription [9].

The strong inotropic activity of thyroid hormones is probably due to an increased number of β-adrenergic receptors [28]. Circulating cathecholamine levels are in fact the same, but G protein and β-receptors increase [29]. The sensitivity of cardiovascular system to adrenergic stimulation does not change by thyroid hormones [30,31]. The changes in the heart rate result from both an increase in sympathetic tone and decrease in parasympathetic tone [32,33].

These genomic effects fail to explain the fast actions of thyroid hormones on the cardiovascular system. Non-genomic effects promote rapid changes, such as increased cardiac output [34-36]. The hemodynamic consequences of hyperthyroidism and nongenomic changes on plasma membranes occur acutely and contribute to these rapid changes. Studies indicate that thyroid hormone activates acute phosphorylation of phospholamban, and that also partly explains the homology between thyroid hormone and adrenergic system on the heart [32].

In an experimental study on rats, thyroid hormones upregulate connexin-40, a gap junction protein of myocardium important for the transport of electrical activity, and this may be one of the pathogenetic mechanisms of atrial fibrillation in hyperthyroidism [37]. In another animal study the authors suggested that the connexin-43 phosphorylation was downregulated by T3 in diabetic rats and decrease adaptation of heart to hyperglycemia and this may render the heart prone to ventricular arrythmias [38]. In fact thyroid hormone receptor alpha 1 is predominantly expressed in cardiac myocardium and may have an important role in cardiac myoblast differentiation by ERK kinase dependent process, but its clinical relevance is not known [39]. Also ERK (extracellular signal-regulated kinase) pathway may have a role in negative cardiac remodelling and decreased cardiac contractile function in hyperthyroidism, by inhibition of the Raf-1/ERK pathway by T3 [40,41].

Meanwhile, the thyroid hormone may have direct (without autonomous nervous system) effects on the sinoatrial node [42,43] and oxidative stress in animal studies [44]. The heart rate increases due to increased sinoatrial activity, a lower threshold for atrial activity, and a shortened atrial repolarisation [45,46]. Together with hemodynamic changes, i.e. the volume preload increases due to activation of the renin-angiotensin system [47], contractility increases due to increased metabolic demand and the direct effect of the thyroid hormone on heart muscle [48] and systemic vascular resistance decreases because of triiodotyronine-induced peripheral vasodilatation [49]. The result is a dramatic increase in cardiac output [50].

Local type 2 iodothyronine deiodinase up-regulation may also be involved in cardiac remod‐ elling via activation of thyroid hormone signalling pathways involving Akt and p38 MAPK (mitogen-activated protein kinase) in thyrotoxic-dilated cardiomyopathy [51]. Animal studies show the effects of thyroid hormones on soluble fractions of 5'-nucleosidase activity, via protein kinase C-related pathway [52]. Preclinical studies blocking Akt by angiotensin-II type 2 receptor blocker showed that this blockage might prevent thyroxine-mediated cardiac hypertrophy [53]. Meanwhile, hypertrophied myocytes may be susceptible to apoptotic stimulation by angiotensin II in hyperthyroidism [54].

sinusal tachycardia and shortened PR interval, and frequently intra-atrial conduction is prolonged, which is seen as increase in P wave duration. Intraventricular conduction delay in the form of right bundle branch block is present in around 15% of patients, and atrioventricular block may also occur due to unknown reasons. The most common rhythm disturbance in hyperthyroid patients is sinus tachycardia [32]. Its clinical impact however is overshadowed by that of patients with atrial fibrillation. The prevalence of atrial fibrillation (AF) and less common forms of supraventricular tachycardia in this disease ranges between 2 to 20 percent [64,65]. AF is generally accompanied by rapid ventricular response. It is more common in men and its significance increases by age, after 40 years [65]. As in the case of angina or heart failure, the development of AF should not be attributed only to hyperthyroidism, and the underlying

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 69

Atrial fibrillation usually reverses to a sinus rhythm by achievement of a euthyroid state, if the patient is younger and the duration of hyperthyroidism is not long. The beta-adrenergic blockade may be effective in controlling the ventricular rate. Increased plasma clearance of beta-blockers may necessitate higher doses [66]. Among them propranolol has the advantage of blocking the conversion of T4 to T3 in peripheral tissues, however other cardioselective betablockers have a longer half-life and can be equally effective on the heart. In cardiac arrhythmias intravascular infusion of calcium blockers should be avoided due to the risk of a further fall in PVR [67]. It is still controversial whether the patients with AF should have anticoagulant therapy to prevent systemic embolization. It is advised to evaluate each patient on a case-bycase basis, and determine the risk of bleeding over embolization [68,69]. In younger patients with hyperthyroidism and AF, who do not have other heart disease, hypertension, or inde‐ pendent risk factors for embolization, the risk of anticoagulant therapy may suppress its benefits. But it would be appropriate to administer anticoagulant agents to older patients with known or suspected heart diseases, or AF with longer duration. When oral anticoagulants will be used, it should be considered that hyperthyroid patients will need smaller doses than euthyroid ones, due to faster elimination of vitamin-K dependent clotting factors [70].

In the patients with AF the maintenance of sinus rhythm is not possible until the euthyroid state is restored, so electrical cardioversion is not recommended without confirming the

Many hyperthyroid patients experience exercise intolerance and exertional dyspnea, in part because of weakness in the skeletal and respiratory muscle [71] and also due to inability to increase heart rate or lower vascular resistance further, as normally occurs in exercise [72]. The tem "high output heart failure" has not been used in recent decades, because it is clear that the heart is still able to increase cardiac output at rest and with exercise. In the setting of low vascular resistance and decreased preload, the cardiac functional reserve is compromised and cannot rise further to accommodate the demands of submaximal or maximal exercise [73]. About 6% of thyrotoxic patients develop heart failure and less than 1% develop dilated cardiomyopathy with impaired left ventricular systolic dysfunction, due to the tachycardiamediated mechanism leading to an increased level of cytosolic calcium during diastole, with reduced contractility of the ventricle and diastolic dysfunction, often with tricuspid regurgi‐ tation [74]. In the recent study of Yue et al, diastolic dysfunction was more prominent in

organic heart diseases should be investigated.

euthyroid status.

Studies on rats show that mitochondrial ultrastructure was damaged in T3 treated hyperthy‐ roid rat heart, leading to energy depletion and cardiac dysfunction [55]. Another study on hamsters revealed that long term hyperthyroidism cause increased left ventricular interstitial fibrosis, significant cardiac hypertrophy and deleterious cardiac remodeling characterized by myocyte lengthening, chamber dilatation, decreased relative wall thickness, increased wall stress, and impaired global cardiac function whereas cardiomyocyte functions may be enhanced [56]. Some animal studies Show beneficial effects of angiotensin receptor blockers on myocytes as improved left ventricular longitudinal strain, heart rate and reduced cardio‐ myocyte width, affecting structural remodelling beyond the anti-tachycardic effect of betablockers [57].

#### **2.3. Hemodynamic effects of thyroid hormones**

Hemodynamic effects of thyroid hormones are generally nongenomic and faster, by direct effects on the heart and blood vessels. In the peripheral vascular system, the rapid use of oxygen, increased production of metabolic end products and relaxation of arterial smooth muscle fibres by thyroid hormone cause peripheral vasodilatation [21]. This fall in peripheral vascular resistance (PVR) plays the central role in all hemodynamic changes caused by thyroid hormones [58]. Decreased PVR causes an increase in heart rate and selective increase in blood flow of some organs (skin, skeletal muscles, heart), and a fall in diastolic pressure with consequent widening of pulse pressure. Vasodilatation without an increase in renal blood flow causes reduction in renal perfusion and activation of the renin-angiotensin system which causes sodium retention and increased blood volume [59]. In addition, thyroid hormones regulate erythropoietin secretion and increased red cell mass may also contribute to blood volume increase [60]. Improved diastolic relaxation and increased blood volume increased left ventricular end-diastolic volume (LVEDV). Reduced PVR and increased LVEDV means increased preload and decreased afterload, thus the stroke volume increases. Increased stroke volume and increased heart rate leads to a doubling or tripling of cardiac output which cannot be solely explained by the increased metabolic rate of the body [61].

The importance of the contribution of decreased systemic vascular resistance to the increase in systemic blood flow in patients with hyperthyroidism is evidenced by studies in which the administration of arterial vasoconstrictors, atropine and phenylephrine, decreased peripheral blood flow and cardiac output by 34% in patients with hyperthyroidism but not in normal subjects [62,63].

#### **2.4. Clinical aspects of hyperthyroidism and subclinical hyperthyroidism on heart**

Increased rate and strength of the heart contractility, together with an exaggerated response of heart rate to exercise is present in hyperthyroid patients who describe this as palpitations. Diurnal heart rate variations are generally preserved. The most common ECG abnormality is sinusal tachycardia and shortened PR interval, and frequently intra-atrial conduction is prolonged, which is seen as increase in P wave duration. Intraventricular conduction delay in the form of right bundle branch block is present in around 15% of patients, and atrioventricular block may also occur due to unknown reasons. The most common rhythm disturbance in hyperthyroid patients is sinus tachycardia [32]. Its clinical impact however is overshadowed by that of patients with atrial fibrillation. The prevalence of atrial fibrillation (AF) and less common forms of supraventricular tachycardia in this disease ranges between 2 to 20 percent [64,65]. AF is generally accompanied by rapid ventricular response. It is more common in men and its significance increases by age, after 40 years [65]. As in the case of angina or heart failure, the development of AF should not be attributed only to hyperthyroidism, and the underlying organic heart diseases should be investigated.

2 receptor blocker showed that this blockage might prevent thyroxine-mediated cardiac hypertrophy [53]. Meanwhile, hypertrophied myocytes may be susceptible to apoptotic

Studies on rats show that mitochondrial ultrastructure was damaged in T3 treated hyperthy‐ roid rat heart, leading to energy depletion and cardiac dysfunction [55]. Another study on hamsters revealed that long term hyperthyroidism cause increased left ventricular interstitial fibrosis, significant cardiac hypertrophy and deleterious cardiac remodeling characterized by myocyte lengthening, chamber dilatation, decreased relative wall thickness, increased wall stress, and impaired global cardiac function whereas cardiomyocyte functions may be enhanced [56]. Some animal studies Show beneficial effects of angiotensin receptor blockers on myocytes as improved left ventricular longitudinal strain, heart rate and reduced cardio‐ myocyte width, affecting structural remodelling beyond the anti-tachycardic effect of beta-

Hemodynamic effects of thyroid hormones are generally nongenomic and faster, by direct effects on the heart and blood vessels. In the peripheral vascular system, the rapid use of oxygen, increased production of metabolic end products and relaxation of arterial smooth muscle fibres by thyroid hormone cause peripheral vasodilatation [21]. This fall in peripheral vascular resistance (PVR) plays the central role in all hemodynamic changes caused by thyroid hormones [58]. Decreased PVR causes an increase in heart rate and selective increase in blood flow of some organs (skin, skeletal muscles, heart), and a fall in diastolic pressure with consequent widening of pulse pressure. Vasodilatation without an increase in renal blood flow causes reduction in renal perfusion and activation of the renin-angiotensin system which causes sodium retention and increased blood volume [59]. In addition, thyroid hormones regulate erythropoietin secretion and increased red cell mass may also contribute to blood volume increase [60]. Improved diastolic relaxation and increased blood volume increased left ventricular end-diastolic volume (LVEDV). Reduced PVR and increased LVEDV means increased preload and decreased afterload, thus the stroke volume increases. Increased stroke volume and increased heart rate leads to a doubling or tripling of cardiac output which cannot

The importance of the contribution of decreased systemic vascular resistance to the increase in systemic blood flow in patients with hyperthyroidism is evidenced by studies in which the administration of arterial vasoconstrictors, atropine and phenylephrine, decreased peripheral blood flow and cardiac output by 34% in patients with hyperthyroidism but not in normal

Increased rate and strength of the heart contractility, together with an exaggerated response of heart rate to exercise is present in hyperthyroid patients who describe this as palpitations. Diurnal heart rate variations are generally preserved. The most common ECG abnormality is

**2.4. Clinical aspects of hyperthyroidism and subclinical hyperthyroidism on heart**

stimulation by angiotensin II in hyperthyroidism [54].

68 Thyroid Disorders - Focus on Hyperthyroidism

**2.3. Hemodynamic effects of thyroid hormones**

be solely explained by the increased metabolic rate of the body [61].

blockers [57].

subjects [62,63].

Atrial fibrillation usually reverses to a sinus rhythm by achievement of a euthyroid state, if the patient is younger and the duration of hyperthyroidism is not long. The beta-adrenergic blockade may be effective in controlling the ventricular rate. Increased plasma clearance of beta-blockers may necessitate higher doses [66]. Among them propranolol has the advantage of blocking the conversion of T4 to T3 in peripheral tissues, however other cardioselective betablockers have a longer half-life and can be equally effective on the heart. In cardiac arrhythmias intravascular infusion of calcium blockers should be avoided due to the risk of a further fall in PVR [67]. It is still controversial whether the patients with AF should have anticoagulant therapy to prevent systemic embolization. It is advised to evaluate each patient on a case-bycase basis, and determine the risk of bleeding over embolization [68,69]. In younger patients with hyperthyroidism and AF, who do not have other heart disease, hypertension, or inde‐ pendent risk factors for embolization, the risk of anticoagulant therapy may suppress its benefits. But it would be appropriate to administer anticoagulant agents to older patients with known or suspected heart diseases, or AF with longer duration. When oral anticoagulants will be used, it should be considered that hyperthyroid patients will need smaller doses than euthyroid ones, due to faster elimination of vitamin-K dependent clotting factors [70].

In the patients with AF the maintenance of sinus rhythm is not possible until the euthyroid state is restored, so electrical cardioversion is not recommended without confirming the euthyroid status.

Many hyperthyroid patients experience exercise intolerance and exertional dyspnea, in part because of weakness in the skeletal and respiratory muscle [71] and also due to inability to increase heart rate or lower vascular resistance further, as normally occurs in exercise [72]. The tem "high output heart failure" has not been used in recent decades, because it is clear that the heart is still able to increase cardiac output at rest and with exercise. In the setting of low vascular resistance and decreased preload, the cardiac functional reserve is compromised and cannot rise further to accommodate the demands of submaximal or maximal exercise [73]. About 6% of thyrotoxic patients develop heart failure and less than 1% develop dilated cardiomyopathy with impaired left ventricular systolic dysfunction, due to the tachycardiamediated mechanism leading to an increased level of cytosolic calcium during diastole, with reduced contractility of the ventricle and diastolic dysfunction, often with tricuspid regurgi‐ tation [74]. In the recent study of Yue et al, diastolic dysfunction was more prominent in thyrotoxic patients older than 40 years of age, whereas in younger ones marked reduction in peripheral vascular resistance and increased cardiac output were prominent [75].

lid lag and retraction (or stare), or exposure keratitis may be detected [86]. Most patients experience only the minor congestive signs of TAO (chemosis, injection, lid edema), with improvement in several months without treatment. Approximately 28% of TAO cases are severe and symptomatic for several years. Symptoms and signs include, restricted motility leading to diplopia, exposure keratopathy, optic neuropathy and loss of vision [87,88].

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 71

TAO can be divided into two clinical stages; congestive and fibrotic. In the congestive or inflammatory stage, auto-immunity leads to inflammatory cellular infiltration of the muscles and transformation of fibroblasts into adipose tissue. The fibrotic stage is characterized by

In TAO, the most important pathological changes are enlarged extraocular muscles and increased orbital fat. These changes result from a complex interplay among orbital fibroblasts,

Patients with TAO, orbital tissue is infiltrated by inflammatory cells (T helper type 1 (Th1) and T helper type 2 (Th2) lymphocytes, B lymphocytes, mast cells, and macrophages) [91,92]. These cells release cytokines which participate in tissue reactivity and remodeling. Normally, the antigens to which lymphocytes respond are foreign, and several tolerance mechanisms act to prevent the development of reactivity to self-antigens or autoimmuni‐ ty, but these tolerance mechanisms sometimes fail and autoimmunity develops [93,94]. Fibroblasts are a highly interactive cell type, described as "sentinel cells" [95]. They, respond to immune stimulation and actively participate in the inflammatory pathway [96,97]. In patients with TAO, orbital fibroblasts synthesize excess glycosaminoglycans (GAGs), including hyaluronan. These can differentiate into adipocytes, leading to the accumula‐ tion of fat [98]. Orbital fibroblasts do not express the IL-1 receptor antagonist at levels found in other fibroblasts, but also display lymphocyte costimulatory molecules such as CD40. These differentations result in excessively high levels of Cox-2 and PGE2 in response to proinflammatory cytokines [99,100]. T lymphocytes in the orbital tissue interact with fibroblasts. This interaction results with activation and proliferation of fibroblasts, synthe‐ sis of extracellular macromolecules, and differentiation to adipocytes [101]. A summary of

Autoantigen expression by orbital fibroblasts results in T lymphocyte accumulation to the orbit [103]. The autoantigen may be a TSH receptor (TSH-R) or an insulin-like growth factor-1 receptor (IGF-1R) [103,104]. T lymphocytes in the orbital tissue induce fibroblast proliferation and hyaluronan synthesis. This result in orbital tissue remodeling [101]. Stimulation of orbital fibroblasts by T lymphocytes results in production of chemokines (e.g. IL-16, RANTES) and cytokines (e.g. IL-6). These molecules initiate migration of T and B lymphocytes to the orbital tissue and increase fibroblast presentation of autoantigens [97,101,105). Costimulatory molecules, adhesion molecules, and cytokines like IFN*γ*, IL-1*β*, and TNF*α* play an important role in the interaction between T lymphocytes and fibroblasts. One of the communication

immune cells, cytokines, auto-antibodies, genetics, and environmental factors [84].

this model for the pathogenesis of TED is depicted in Figure 1 [102].

**Interactions between orbital fibroblasts, immune cells, cytokines and autoantibodies**

fibrosis which causes proptosis and strabismus [89,90].

**3.2. Pathophysiology**

Hyperthyroidism may complicate or cause pre-existing cardiac disease because of increased myocardial oxygen demand, increased contractility and heart rate, and may cause silent coronary artery disease, anginas or compensated heart failure and even endothelial dysfunc‐ tion [76]. Treatment of heart failure with tachycardia should include a beta-blocker, by considering its contraindications in each patient. Furosemide may help to reverse the volume overload, but digoxin is less beneficial when compared with euthyroid heart failure patients because there may be relative resistance to its action, due to greater blood volume (distribution) and the need to block more Na-K-ATPase in myocardium [70].

Subclinical hyperthyroidism is a state characterised by low serum thyrotropin levels and normal serum thyroid hormone concentrations. Over recent decades this state has also been found to be associated with some abnormalities in cardiac function. Enhanced systolic function and impaired diastolic function due to slowed myocardial relaxation may cause increased left ventricular mass in these subjects, together with increased heart rate and arrhythmias by similar mechanisms as overt hyperthyroidism [77,78]. In people over 60 years of age subclinical hyperthyroidism was associated with a tripled risk of atrial fibrillation during a 10-year followup period [79]. In a recent cross-sectional study with 29 patients, subclinical hyperthyroidism was found to be related with impaired functional response to exercise with low oxygen consumption and exercise threshold, together with slower heart rate recovery [80].

Besides antithyroid treatment strategies, beta-blocker therapy reduces heart rate and improves left ventricular mass, but positive inotropic response persists. This subclinical hyperthyroidism is associated with increased cardiovascular mortality [81]. In the study of Heeringa et al with 1,426 patients, it was shown that even the high-normal thyroid function may increase the risk of AF [82]. Besides increased AF and thromboembolic events, increased left ventricular mass and left ventricular function may be the reason. Thus, it is advised to measure serum thyrotropin in all elderly patients with systolic hypertension, a widened blood pressure, recent-onset angina, atrial fibrillation and any exacerbation of ischemic heart disease and treat it [72,83].

#### **3. Progressive infiltrative ophtalmopathy in hyperthyroidism**

#### **3.1. Hyperthyroidism and eye disease**

Thyroid eye disease (TED), also called thyroid-associated ophthalmopathy (TAO) and Graves' ophthalmopathy (GO), affects 25–50% of patients with Graves' disease [84]. Regardless of whether hyperthyroidism occurs first, the signs and symptoms of GO become manifest in 85% of patients within 18 months [85]. The clinical features are usually mild. Most common symptoms are; ocular irritation with redness and tearing,, sensitivity to light, double vision, blurring of vision, and feeling a pressure sensation behind the eyes. On physical examination, extraocular muscle dysfunction, proptosis, periorbital and eyelid edema, conjunctival chemos, lid lag and retraction (or stare), or exposure keratitis may be detected [86]. Most patients experience only the minor congestive signs of TAO (chemosis, injection, lid edema), with improvement in several months without treatment. Approximately 28% of TAO cases are severe and symptomatic for several years. Symptoms and signs include, restricted motility leading to diplopia, exposure keratopathy, optic neuropathy and loss of vision [87,88].

TAO can be divided into two clinical stages; congestive and fibrotic. In the congestive or inflammatory stage, auto-immunity leads to inflammatory cellular infiltration of the muscles and transformation of fibroblasts into adipose tissue. The fibrotic stage is characterized by fibrosis which causes proptosis and strabismus [89,90].

#### **3.2. Pathophysiology**

thyrotoxic patients older than 40 years of age, whereas in younger ones marked reduction in

Hyperthyroidism may complicate or cause pre-existing cardiac disease because of increased myocardial oxygen demand, increased contractility and heart rate, and may cause silent coronary artery disease, anginas or compensated heart failure and even endothelial dysfunc‐ tion [76]. Treatment of heart failure with tachycardia should include a beta-blocker, by considering its contraindications in each patient. Furosemide may help to reverse the volume overload, but digoxin is less beneficial when compared with euthyroid heart failure patients because there may be relative resistance to its action, due to greater blood volume (distribution)

Subclinical hyperthyroidism is a state characterised by low serum thyrotropin levels and normal serum thyroid hormone concentrations. Over recent decades this state has also been found to be associated with some abnormalities in cardiac function. Enhanced systolic function and impaired diastolic function due to slowed myocardial relaxation may cause increased left ventricular mass in these subjects, together with increased heart rate and arrhythmias by similar mechanisms as overt hyperthyroidism [77,78]. In people over 60 years of age subclinical hyperthyroidism was associated with a tripled risk of atrial fibrillation during a 10-year followup period [79]. In a recent cross-sectional study with 29 patients, subclinical hyperthyroidism was found to be related with impaired functional response to exercise with low oxygen

consumption and exercise threshold, together with slower heart rate recovery [80].

**3. Progressive infiltrative ophtalmopathy in hyperthyroidism**

Besides antithyroid treatment strategies, beta-blocker therapy reduces heart rate and improves left ventricular mass, but positive inotropic response persists. This subclinical hyperthyroidism is associated with increased cardiovascular mortality [81]. In the study of Heeringa et al with 1,426 patients, it was shown that even the high-normal thyroid function may increase the risk of AF [82]. Besides increased AF and thromboembolic events, increased left ventricular mass and left ventricular function may be the reason. Thus, it is advised to measure serum thyrotropin in all elderly patients with systolic hypertension, a widened blood pressure, recent-onset angina, atrial fibrillation and any exacerbation of

Thyroid eye disease (TED), also called thyroid-associated ophthalmopathy (TAO) and Graves' ophthalmopathy (GO), affects 25–50% of patients with Graves' disease [84]. Regardless of whether hyperthyroidism occurs first, the signs and symptoms of GO become manifest in 85% of patients within 18 months [85]. The clinical features are usually mild. Most common symptoms are; ocular irritation with redness and tearing,, sensitivity to light, double vision, blurring of vision, and feeling a pressure sensation behind the eyes. On physical examination, extraocular muscle dysfunction, proptosis, periorbital and eyelid edema, conjunctival chemos,

peripheral vascular resistance and increased cardiac output were prominent [75].

and the need to block more Na-K-ATPase in myocardium [70].

70 Thyroid Disorders - Focus on Hyperthyroidism

ischemic heart disease and treat it [72,83].

**3.1. Hyperthyroidism and eye disease**

In TAO, the most important pathological changes are enlarged extraocular muscles and increased orbital fat. These changes result from a complex interplay among orbital fibroblasts, immune cells, cytokines, auto-antibodies, genetics, and environmental factors [84].

#### **Interactions between orbital fibroblasts, immune cells, cytokines and autoantibodies**

Patients with TAO, orbital tissue is infiltrated by inflammatory cells (T helper type 1 (Th1) and T helper type 2 (Th2) lymphocytes, B lymphocytes, mast cells, and macrophages) [91,92]. These cells release cytokines which participate in tissue reactivity and remodeling. Normally, the antigens to which lymphocytes respond are foreign, and several tolerance mechanisms act to prevent the development of reactivity to self-antigens or autoimmuni‐ ty, but these tolerance mechanisms sometimes fail and autoimmunity develops [93,94]. Fibroblasts are a highly interactive cell type, described as "sentinel cells" [95]. They, respond to immune stimulation and actively participate in the inflammatory pathway [96,97]. In patients with TAO, orbital fibroblasts synthesize excess glycosaminoglycans (GAGs), including hyaluronan. These can differentiate into adipocytes, leading to the accumula‐ tion of fat [98]. Orbital fibroblasts do not express the IL-1 receptor antagonist at levels found in other fibroblasts, but also display lymphocyte costimulatory molecules such as CD40. These differentations result in excessively high levels of Cox-2 and PGE2 in response to proinflammatory cytokines [99,100]. T lymphocytes in the orbital tissue interact with fibroblasts. This interaction results with activation and proliferation of fibroblasts, synthe‐ sis of extracellular macromolecules, and differentiation to adipocytes [101]. A summary of this model for the pathogenesis of TED is depicted in Figure 1 [102].

Autoantigen expression by orbital fibroblasts results in T lymphocyte accumulation to the orbit [103]. The autoantigen may be a TSH receptor (TSH-R) or an insulin-like growth factor-1 receptor (IGF-1R) [103,104]. T lymphocytes in the orbital tissue induce fibroblast proliferation and hyaluronan synthesis. This result in orbital tissue remodeling [101]. Stimulation of orbital fibroblasts by T lymphocytes results in production of chemokines (e.g. IL-16, RANTES) and cytokines (e.g. IL-6). These molecules initiate migration of T and B lymphocytes to the orbital tissue and increase fibroblast presentation of autoantigens [97,101,105). Costimulatory molecules, adhesion molecules, and cytokines like IFN*γ*, IL-1*β*, and TNF*α* play an important role in the interaction between T lymphocytes and fibroblasts. One of the communication pathways of T lymphocytes and orbital fibroblasts is the CD40-CD40 ligand pathway [97,100,101]. In TAO orbital fibroblasts express high levels of CD40 [97,106]. Activation by CD40L induces hyaluronan synthesis, IL-6 and IL-8, Cox-2 and PGE2 [97,101,107].

**Autoantibody (Anti-TSH receptor, Anti-IGF1 receptor)**

**Ab binds to orbital fibroblasts**

**B lymphocytes accumulate**

**Proliferation**

**Figure 1.** Pathophysiology of thyroid eye disease

autoimmunity might also predispose to TAO.

**Thymic stromal lymphopoietin (tslp) gene promoter polymorphisms**

(Data adapted from reference 102)

**3.4. Genetics**

**Activation and release of chemokines**

**MHC II IL-6 TCR**

For the development of TAO the presence of autoimmune thyroid disease appears to be necessary, but not sufficient [124]. The interaction between genetic and environmental factors plays a major role for the development of TAO in a patient with autoimmune thyroid disease. TAO and autoimmune thyroid disease share a common etiology; regardless of which occurs first, the other develops within 18 months in 80% of affected patients [125]. Polymorphic variations in individual somatic genes or groups of genes known to be involved in thyroid

The role of TSLP in Th17 cell differentiation implicates TSLP in the pathogenesis of TAO. Tsai et al. genotyped 470 patients with TAO at 3 single nucleotide polymorphisms (SNPs) in TSLP and determined the serum concentrations of TSLP in 432 patients and 272 controls. They showed that TSLP polymorphisms are associated with TAO and that expression levels of TSLP are higher in patients than in control subjects. In addition, they concluded that TSLP mediates

**Production of GAGs**

**IL-8 CXCL10**

**Orbital tissue**

**IL-16 RANTES CXCL10**

**CD 40 L**

**CD 40**

**IFN-γ TNF-α PGD2 PGJ2**

**Adipogenesis**

**T lymphocytes**

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 73

T lymphocyte-mediated activated fibroblasts release factors which promote and activate the proliferation of T lymphocytes. In this way fibroblasts perpetuate inflammation [101,108]. Antonelli et al. found that orbital fibroblasts from TAO patients may modulate the activity of T lymphocytes through the production of CXCL10. Serum CXCL10 levels were higher in active TAO patients than in those with inactive disease. CXCL10 release enhances the migration of T lymphocytes into the orbital tissue. These lymphocytes secrete IFN*γ* and TNF*α*. There is a positive feedback between CXCL10 and IFN*γ* – TNF*α.* Peroxisome proliferator-activated receptor-gamma (PPAR-*γ)* activation has an inhibitory role in this process [108]. Feldon et al. found that activated human T lymphocytes drive the differentiation of human fibroblasts to adipocytes. They showed that human T cells, when activated, strongly express Cox-2 and produce PGs, possibly 15d-PGJ2, that are PPAR-γ ligands and human T cells also produce PGD2. These findings showed that PGD2 converts to the PGJ series of PGs with the final product being 15d-PGJ2, a notable potent PPAR-γ ligand [109-111]. Feldon et al. also showed that human orbital fibroblasts express PPAR-γ and that 15d-PGJ2, PGD2, and 15d-PGD2 strongly induce adipogenesis [109]. Natural and synthetic activators of PPAR-*γ* stimulate lipid accumulation and the expression and secretion of adiponectin [112,113]. PPAR-*γ* levels are higher in orbital tissue from patients with active TAO [108,114].

Chen et al. showed higher mRNA levels of a macrophage chemoattractant called C-C motif chemokine ligand-2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1) and dense infiltra‐ tion with macrophages in the orbital fat compared with normal controls [115].

#### **3.3. Smoking**

There is a strong and consistent association between smoking and TAO [116]. But the exact mechanism by which smoking affects TAO is not known. Formation of superoxide radicals and tissue hypoxia could be responsible. Cigarette smoke either contains or can generate a variety of oxidants and free radicals [117]. Orbital fibroblasts can be induced by tissue hypoxia (5% CO2 and 95% N2) and superoxide radicals, thus they proliferate and synthesize GAGs [118,119]. Mack et al. cultured orbital fibroblasts, obtained from patients undergoing orbital decompression for severe GO. They showed that, inreased human leukocyte antigen (HLA-DR) expression of orbital fibroblasts occurred in response to nicotine and tar only in the presence of interferon-γ. These findings suggest that there is an interaction between smoking and orbital immune responses [120]. Many studies demonstrated a dose-response relationship between the numbers of cigarettes smoked per day and TAO [121]. Smokers suffer more severe TAO than non-smokers. Smoking increases the progression of TAO after radioiodine therapy for hyperthyroidism [116]. Eckstein et al. demonstrated that smoking influences the course of TAO during treatment in a dose dependent manner. The response to treatment is delayed and considerably poorer in smokers [122]. Pfeilschifter et al. showed that former smokers had a significantly lower risk for the occurrence of proptosis and diplopia than active smokers with a comparable lifetime cigarette consump

(Data adapted from reference 102)

#### **3.4. Genetics**

pathways of T lymphocytes and orbital fibroblasts is the CD40-CD40 ligand pathway [97,100,101]. In TAO orbital fibroblasts express high levels of CD40 [97,106]. Activation by

T lymphocyte-mediated activated fibroblasts release factors which promote and activate the proliferation of T lymphocytes. In this way fibroblasts perpetuate inflammation [101,108]. Antonelli et al. found that orbital fibroblasts from TAO patients may modulate the activity of T lymphocytes through the production of CXCL10. Serum CXCL10 levels were higher in active TAO patients than in those with inactive disease. CXCL10 release enhances the migration of T lymphocytes into the orbital tissue. These lymphocytes secrete IFN*γ* and TNF*α*. There is a positive feedback between CXCL10 and IFN*γ* – TNF*α.* Peroxisome proliferator-activated receptor-gamma (PPAR-*γ)* activation has an inhibitory role in this process [108]. Feldon et al. found that activated human T lymphocytes drive the differentiation of human fibroblasts to adipocytes. They showed that human T cells, when activated, strongly express Cox-2 and produce PGs, possibly 15d-PGJ2, that are PPAR-γ ligands and human T cells also produce PGD2. These findings showed that PGD2 converts to the PGJ series of PGs with the final product being 15d-PGJ2, a notable potent PPAR-γ ligand [109-111]. Feldon et al. also showed that human orbital fibroblasts express PPAR-γ and that 15d-PGJ2, PGD2, and 15d-PGD2 strongly induce adipogenesis [109]. Natural and synthetic activators of PPAR-*γ* stimulate lipid accumulation and the expression and secretion of adiponectin [112,113]. PPAR-*γ* levels are

Chen et al. showed higher mRNA levels of a macrophage chemoattractant called C-C motif chemokine ligand-2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1) and dense infiltra‐

There is a strong and consistent association between smoking and TAO [116]. But the exact mechanism by which smoking affects TAO is not known. Formation of superoxide radicals and tissue hypoxia could be responsible. Cigarette smoke either contains or can generate a variety of oxidants and free radicals [117]. Orbital fibroblasts can be induced by tissue hypoxia (5% CO2 and 95% N2) and superoxide radicals, thus they proliferate and synthesize GAGs [118,119]. Mack et al. cultured orbital fibroblasts, obtained from patients undergoing orbital decompression for severe GO. They showed that, inreased human leukocyte antigen (HLA-DR) expression of orbital fibroblasts occurred in response to nicotine and tar only in the presence of interferon-γ. These findings suggest that there is an interaction between smoking and orbital immune responses [120]. Many studies demonstrated a dose-response relationship between the numbers of cigarettes smoked per day and TAO [121]. Smokers suffer more severe TAO than non-smokers. Smoking increases the progression of TAO after radioiodine therapy for hyperthyroidism [116]. Eckstein et al. demonstrated that smoking influences the course of TAO during treatment in a dose dependent manner. The response to treatment is delayed and considerably poorer in smokers [122]. Pfeilschifter et al. showed that former smokers had a significantly lower risk for the occurrence of proptosis and diplopia than active smokers with

tion with macrophages in the orbital fat compared with normal controls [115].

CD40L induces hyaluronan synthesis, IL-6 and IL-8, Cox-2 and PGE2 [97,101,107].

higher in orbital tissue from patients with active TAO [108,114].

**3.3. Smoking**

72 Thyroid Disorders - Focus on Hyperthyroidism

a comparable lifetime cigarette consump

For the development of TAO the presence of autoimmune thyroid disease appears to be necessary, but not sufficient [124]. The interaction between genetic and environmental factors plays a major role for the development of TAO in a patient with autoimmune thyroid disease. TAO and autoimmune thyroid disease share a common etiology; regardless of which occurs first, the other develops within 18 months in 80% of affected patients [125]. Polymorphic variations in individual somatic genes or groups of genes known to be involved in thyroid autoimmunity might also predispose to TAO.

#### **Thymic stromal lymphopoietin (tslp) gene promoter polymorphisms**

The role of TSLP in Th17 cell differentiation implicates TSLP in the pathogenesis of TAO. Tsai et al. genotyped 470 patients with TAO at 3 single nucleotide polymorphisms (SNPs) in TSLP and determined the serum concentrations of TSLP in 432 patients and 272 controls. They showed that TSLP polymorphisms are associated with TAO and that expression levels of TSLP are higher in patients than in control subjects. In addition, they concluded that TSLP mediates

**Figure 1.** Pathophysiology of thyroid eye disease

the differentiation of CD4+T cells into Th17 cells. According to this study the *TSLP* gene may be a relevant candidate gene for susceptibility to TAO. *TSLP* genotypes may be used as genetic markers for the diagnosis and prognosis of TAO [126].

**PPAR-γ gene polymorphism**

**IL-23R polymorphisms**

signaling cascade [136].

larger studies.

**3.5. Cytokines**

**Protein tyrosine phosphatase-22**

**Nuclear factor (NF)-[kappa]B1**

**Human leukocyte antigen (HLA)**

patients than in the control groups.

A11,-B5,-DW12 and-DR14 and TAO has been found [141,142].

The PPAR-γ transcription factor is involved in both adipogenesis and inflammation which have been implicated in the pathogenesis of TAO. Alevizaki et al. found no difference in the distribution of the Pro(12)Ala PPAR-*γ* gene polymorphism between GD patients with and without TAO. But they showed that PPAR-γ polymorphism carriers had lower TSH-Rab levels and lower clinical activity scores (CAS). According to this study patients with TAO who have

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 75

Huber et al. demonstrated that two IL-23R polymorphisms (rs10889677 and rs2201841) were associated with TAO. According to this study we can speculate that these variants may induce TAO by changing the expression and/or function of IL-23R, by promoting a pro-inflammatory

Lymphoid protein tyrosine phosphatase (LYP, aka PTPN-22) represents another negative regulator of T cell activation. Syed et al. found an association between certain single nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase (PTP) called PTPN12 and in‐ creased risk of mild/moderate ophthalmopathy [137]. But this data should be confirmed in

Kurylowicz et al. showed a correlation between a polymorphism in the NF-[kappa]B1 gene promoter (-94ins/del adenine, thymine, thymine, guanine) and the development of TAO [138].

HLA class I-II genes are related for the development of TAO [139]. Akaishi et al. found TAO patients with major extraocular muscle involvement have had a higher frequency of the HLA-DRB1\*16 allele, but patients with minor extraocular muscle involvement have had a higher frequency of the HLA-DRB1\*03 allele [140]. In another study an association between HLA-

Autoimmune thyroid disease involves the activation of multiple cytokine networks. Serum IL-6 levels were greater in the patients with TAO than in those without eye disease [143] and both Th1-and Th2-derived cytokines were elevated in TAO patients compared with control samples [144]. Chen et al. found that the exaggerated capacity of orbital fibroblasts to express high levels of both IL-6 and its receptor in an anatomic site-selective manner could represent an important basis for immune responses in TAO [145]. Higher serum levels of IL-17 were obtained in TAO patients than in controls. Serum IL-17 concentration had significant correla‐ tion with CAS [146]. Significantly higher PAI-1 [147] and IgE levels [148] were found in TAO

this polymorphism are associated with less-severe and less-active disease [135].

#### **Toll-like receptor gene polymorphisms**

Toll-like receptors (TLRs) are a family of pattern-recognition receptors, which play a role in eliciting innate/adaptive immune responses and developing chronic inflammation. Liao et al evaluated 6 TLR-4 and 2 TLR-9 gene polymorphisms in 471 GD patients (200 patients with TAO and 271 patients without TAO) from a Taiwan Chinese population. There was no statistically significant difference in the genotypic and allelic frequencies of TLR-4 and TLR-9 gene polymorphisms between the GD patients with and without TAO. In the sex-stratified analyses they showed that the association between TLR-9 gene polymorphism and the TAO phenotype was more pronounced in the male patients. Their data suggest that TLR-9 gene polymorphisms are significantly associated with increased susceptibility of ophthalmopathy in male GD patients [127].

#### **Polymorphisms of B7 molecules (CD80 and CD86)**

Liao et al. evaluated genotypes of CD80 and CD86 polymorphism in GD patients. They found that the frequency of C allele at position rs\_9831894 of the CD86 gene is different in patients with GD (with and without TAO). They showed that the G-A haplotype has a protective effect in the development of TAO among patients with GD. Their data suggest that the polymor‐ phisms of the CD86 gene may be used as genetic markers for making the diagnosis and prognosis of TAO [128].

#### **Interleukin-1beta (IL1β) polymorphisms**

Recent studies have demonstrated that IL1β plays a role in the development of TAO by inducing adipogenesis and accumulation of GAGs and prostaglandin E2 (PGE2) [129,130]. Liu et al. found that the SNPs rs3917368 and rs1143643 in the 3′ UTR and intron regions of *IL1β* and patients with the genotypes containing both rs3917368 A/A and rs1143643 A/A may bear a higher risk of developing TAO. Thus we can speculate that *IL1β* polymorphisms can be related with the development of TAO in GD [131].

#### **Cytotoxic T lymphocyte antigen-4**

Vaidya et al. firstly reported an association between *CTLA-4A/G* polymorphism at codon 17 and TAO [132], but this data was not confirmed by Allahabadia et al. in a larger cohort of patients [133]. Daroszewski et al. evaluated the relation between soluable CTLA-4 level and clinical manifestation of TAO and CTLA-4 gene polymorphisms. They found higher levels of Serum sCTLA-4 in the TAO group than in controls. The level of sCTLA-4 was higher in severe TAO patients than in non-severe cases. They showed for the first time that the pres‐ ence of the *CTLA-4* gene polymorphisms Jo31 and CT60 were related with elevated sCTLA-4 levels [134]. These data suggest that the polymorphisms of the *CTLA-4* gene may be used as a genetic marker for making the diagnosis and prognosis of TAO. The role of sCTLA-4 and its full-length cell-bound analogue in autoimmunity remains uncertain.

#### **PPAR-γ gene polymorphism**

the differentiation of CD4+T cells into Th17 cells. According to this study the *TSLP* gene may be a relevant candidate gene for susceptibility to TAO. *TSLP* genotypes may be used as genetic

Toll-like receptors (TLRs) are a family of pattern-recognition receptors, which play a role in eliciting innate/adaptive immune responses and developing chronic inflammation. Liao et al evaluated 6 TLR-4 and 2 TLR-9 gene polymorphisms in 471 GD patients (200 patients with TAO and 271 patients without TAO) from a Taiwan Chinese population. There was no statistically significant difference in the genotypic and allelic frequencies of TLR-4 and TLR-9 gene polymorphisms between the GD patients with and without TAO. In the sex-stratified analyses they showed that the association between TLR-9 gene polymorphism and the TAO phenotype was more pronounced in the male patients. Their data suggest that TLR-9 gene polymorphisms are significantly associated with increased susceptibility of ophthalmopathy

Liao et al. evaluated genotypes of CD80 and CD86 polymorphism in GD patients. They found that the frequency of C allele at position rs\_9831894 of the CD86 gene is different in patients with GD (with and without TAO). They showed that the G-A haplotype has a protective effect in the development of TAO among patients with GD. Their data suggest that the polymor‐ phisms of the CD86 gene may be used as genetic markers for making the diagnosis and

Recent studies have demonstrated that IL1β plays a role in the development of TAO by inducing adipogenesis and accumulation of GAGs and prostaglandin E2 (PGE2) [129,130]. Liu et al. found that the SNPs rs3917368 and rs1143643 in the 3′ UTR and intron regions of *IL1β* and patients with the genotypes containing both rs3917368 A/A and rs1143643 A/A may bear a higher risk of developing TAO. Thus we can speculate that *IL1β* polymorphisms can be

Vaidya et al. firstly reported an association between *CTLA-4A/G* polymorphism at codon 17 and TAO [132], but this data was not confirmed by Allahabadia et al. in a larger cohort of patients [133]. Daroszewski et al. evaluated the relation between soluable CTLA-4 level and clinical manifestation of TAO and CTLA-4 gene polymorphisms. They found higher levels of Serum sCTLA-4 in the TAO group than in controls. The level of sCTLA-4 was higher in severe TAO patients than in non-severe cases. They showed for the first time that the pres‐ ence of the *CTLA-4* gene polymorphisms Jo31 and CT60 were related with elevated sCTLA-4 levels [134]. These data suggest that the polymorphisms of the *CTLA-4* gene may be used as a genetic marker for making the diagnosis and prognosis of TAO. The role of sCTLA-4 and

its full-length cell-bound analogue in autoimmunity remains uncertain.

markers for the diagnosis and prognosis of TAO [126].

**Polymorphisms of B7 molecules (CD80 and CD86)**

**Toll-like receptor gene polymorphisms**

74 Thyroid Disorders - Focus on Hyperthyroidism

in male GD patients [127].

prognosis of TAO [128].

**Interleukin-1beta (IL1β) polymorphisms**

**Cytotoxic T lymphocyte antigen-4**

related with the development of TAO in GD [131].

The PPAR-γ transcription factor is involved in both adipogenesis and inflammation which have been implicated in the pathogenesis of TAO. Alevizaki et al. found no difference in the distribution of the Pro(12)Ala PPAR-*γ* gene polymorphism between GD patients with and without TAO. But they showed that PPAR-γ polymorphism carriers had lower TSH-Rab levels and lower clinical activity scores (CAS). According to this study patients with TAO who have this polymorphism are associated with less-severe and less-active disease [135].

#### **IL-23R polymorphisms**

Huber et al. demonstrated that two IL-23R polymorphisms (rs10889677 and rs2201841) were associated with TAO. According to this study we can speculate that these variants may induce TAO by changing the expression and/or function of IL-23R, by promoting a pro-inflammatory signaling cascade [136].

#### **Protein tyrosine phosphatase-22**

Lymphoid protein tyrosine phosphatase (LYP, aka PTPN-22) represents another negative regulator of T cell activation. Syed et al. found an association between certain single nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase (PTP) called PTPN12 and in‐ creased risk of mild/moderate ophthalmopathy [137]. But this data should be confirmed in larger studies.

#### **Nuclear factor (NF)-[kappa]B1**

Kurylowicz et al. showed a correlation between a polymorphism in the NF-[kappa]B1 gene promoter (-94ins/del adenine, thymine, thymine, guanine) and the development of TAO [138].

#### **Human leukocyte antigen (HLA)**

HLA class I-II genes are related for the development of TAO [139]. Akaishi et al. found TAO patients with major extraocular muscle involvement have had a higher frequency of the HLA-DRB1\*16 allele, but patients with minor extraocular muscle involvement have had a higher frequency of the HLA-DRB1\*03 allele [140]. In another study an association between HLA-A11,-B5,-DW12 and-DR14 and TAO has been found [141,142].

#### **3.5. Cytokines**

Autoimmune thyroid disease involves the activation of multiple cytokine networks. Serum IL-6 levels were greater in the patients with TAO than in those without eye disease [143] and both Th1-and Th2-derived cytokines were elevated in TAO patients compared with control samples [144]. Chen et al. found that the exaggerated capacity of orbital fibroblasts to express high levels of both IL-6 and its receptor in an anatomic site-selective manner could represent an important basis for immune responses in TAO [145]. Higher serum levels of IL-17 were obtained in TAO patients than in controls. Serum IL-17 concentration had significant correla‐ tion with CAS [146]. Significantly higher PAI-1 [147] and IgE levels [148] were found in TAO patients than in the control groups.

#### **3.6. Imaging procedures in TAO**

#### **Ultrasound (US)**

US is of primary importance in orbital pathology because of its safety, non-invasiveness, short time of investigation, low cost, lack of radiation and application without need to prepare the patient. In endocrine orbitopathy; the A scan demonstrates echographical widening of the peripheral orbital space and a widening of the muscle echo, while the B scan shows a high internal echo of the connective tissue septa, increased reflection of the muscle belly and distension of the retrobulbar optic nerve sheaths, enlargement of lacrimal gland and dilatation of the superior ophthalmic vein [149]. Although it has many advantages, US cannot effectively display the muscles at the apex of the orbit. US is not as effective as other diagnostic procedures in delineating the relationship of orbital pathology to contiguous structures, nor is it reliable in imaging lesions of either the posterior orbit or those involving the bone walls [150].

is local blood pooling due to venous stasis by the orbital inflammation [158,159]. Krassas et al. found that OCT positivity is higher in Graves' patients with than in those without ophthalm‐ opathy, and higher in patients with active TAO than in those with inactive TAO [160]. Postema et al. demonstrated that OCT positivity correlates with activity of the TAO such as high CAS [161]. Thus, a positive orbital OCT means clinically active TAO, in which immunosuppressive treatment might be of therapeutic benefit [162]. However, limitations such as cost, nonnegligible radiation burden, non-specific examination for TAO, and finally, lack of evaluation of eye muscle swelling restrict the widespread use of this technique [163]. Orbital OCT is mainly indicated to select patients with TAO who will benefit from immunosuppression [162].

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 77

Kuo et al. were first described in a positron emission tomography (PET/CT) study in a patient with TAO. The detection of inflammation by 18F-fluorodeoxyglucose (FDG) uptake was sensitive and objectively demonstrable by this semi-quantitative imaging method [164]. García-Rojas et al. carried out the first prospective study. FDG uptake of extra-ocular muscles was statistically different between patients with and without TAO. In cases with TAO where clinical doubt exists, PET/CT provides valuable and useful information for the diagnosis, characterization, and therapeutic decision [165]. Further research is required to define the role

Another tool to measure orbital inflammation is the uptake of radioactively labeled substances, such as 67Gallium (Ga) citrate [166] and 99mTechnetium (Tc)-labeled agents [167,168]. In medical

The treatment for TAO varies according to the level of disease activity. Thus, methods have been proposed to determine whether TAO is active (33). There are two main scoring systems

**1.** NOSPECS (No signs or symptoms; Only signs; Soft tissue involvement with symptoms and signs; Proptosis; Eye muscle involvement; Corneal involvement; Sight loss)

Neither NOSPECS nor CAS are both specific and completely reliable, but CAS is a simple office-based tool. The modified NOSPECS criteria include lid retraction, soft tissue inflamma‐ tion, proptosis, size difference, extra-ocular muscle involvement, corneal defects, and optic nerve compression [169]. CAS demonstrates the presence or absence of seven symptoms or

The score ranges from 0 to 7, with 0 to 2 characteristics indicating inactive TAO and 3 to 7 characteristics indicating active TAO. The CAS has a high predictive value for the outcome of immunosuppressive treatment in TAO. The main determinant of therapeutic outcome is disease activity, not disease duration [172]. In addition, the severity of disease should be

literature there are few studies about these nuclear imaging techniques.

**3.7. Other diagnostic techniques**

of FDG-PET/CT in the management of TAO.

**3.8. Clinical classification systems**

**2.** CAS (Clinical Activity Score) systems.

signs that indicate inflammation (Table-1) [171].

[169,170]:

#### **Computed tomography (CT)**

According to differential X-ray absorption CT can differentiate normal and abnormal struc‐ tures of different tissue density. In CT orbital fat images as a black, low-density area, while in contrast to this extraocular muscles and the optic nerve image as higher-density areas [151]. The primary areas of orbital involvement are extraocular muscles, and CT findings correlate with clinical impressions of the severity of extraocular muscle enlargement [152]. Muscle involvement on CT of TAO is usually limited to the non-tendonous portion of the muscle. Due to compression of the optic nerve by enlarged extraocular muscles near the orbital apex, optic nerve dysfunction can be seen in TAO [153]. Other findings that may be noted on CT are lachrymal gland enlargement, a dilated superior opthalmic vein, muscle belly enlargement and increase in orbital fat volume [154,55]. CT imaging is a non-invasive, simple, fast, and cost effective imaging procedure. Furthermore, having high sensitivity and correlation with clinical findings, CT imaging should be considered first during diagnostic evaluation of TAO.

#### **Magnetic resonance imaging (MRI)**

Pulse sequences that examine T2 in MRI can estimate the water content of tissues. In TAO lymphocytes infiltrate the orbital tissue that causes fibroblast stimulation. Fibroblasts produce large amounts of GAGs.  Increased water content of thickened extra-ocular muscles cause elevated T2 [156]. In TAO there are two different phases with disease activity. Medical treatment can be effective in the active stage. Therefore, for predicting the outcome of medical management the evaluation of disease activity is important. Yokoyama et al. investigated whether MRI could assess the disease activity in TAO. They found that MRI is not only a useful tool for detection of extraocular muscle enlargement, but also for assessment of disease activity in TAO [157]. In conclusion, MRI is useful to assess TAO. But cost and availability are current limitations of this modality. Therefore, MRI should be used for the management of TAO in specialized patients and clinics.

#### **Octreoscan (OCT)**

It is thought that radionuclide accumulation is probably due to binding to somatostatin receptors on lymphocytes, myoblasts, fibroblasts and endothelial cells. Another explanation is local blood pooling due to venous stasis by the orbital inflammation [158,159]. Krassas et al. found that OCT positivity is higher in Graves' patients with than in those without ophthalm‐ opathy, and higher in patients with active TAO than in those with inactive TAO [160]. Postema et al. demonstrated that OCT positivity correlates with activity of the TAO such as high CAS [161]. Thus, a positive orbital OCT means clinically active TAO, in which immunosuppressive treatment might be of therapeutic benefit [162]. However, limitations such as cost, nonnegligible radiation burden, non-specific examination for TAO, and finally, lack of evaluation of eye muscle swelling restrict the widespread use of this technique [163]. Orbital OCT is mainly indicated to select patients with TAO who will benefit from immunosuppression [162].

#### **3.7. Other diagnostic techniques**

**3.6. Imaging procedures in TAO**

76 Thyroid Disorders - Focus on Hyperthyroidism

**Computed tomography (CT)**

**Magnetic resonance imaging (MRI)**

**Octreoscan (OCT)**

US is of primary importance in orbital pathology because of its safety, non-invasiveness, short time of investigation, low cost, lack of radiation and application without need to prepare the patient. In endocrine orbitopathy; the A scan demonstrates echographical widening of the peripheral orbital space and a widening of the muscle echo, while the B scan shows a high internal echo of the connective tissue septa, increased reflection of the muscle belly and distension of the retrobulbar optic nerve sheaths, enlargement of lacrimal gland and dilatation of the superior ophthalmic vein [149]. Although it has many advantages, US cannot effectively display the muscles at the apex of the orbit. US is not as effective as other diagnostic procedures in delineating the relationship of orbital pathology to contiguous structures, nor is it reliable in imaging lesions of either the posterior orbit or those involving the bone walls [150].

According to differential X-ray absorption CT can differentiate normal and abnormal struc‐ tures of different tissue density. In CT orbital fat images as a black, low-density area, while in contrast to this extraocular muscles and the optic nerve image as higher-density areas [151]. The primary areas of orbital involvement are extraocular muscles, and CT findings correlate with clinical impressions of the severity of extraocular muscle enlargement [152]. Muscle involvement on CT of TAO is usually limited to the non-tendonous portion of the muscle. Due to compression of the optic nerve by enlarged extraocular muscles near the orbital apex, optic nerve dysfunction can be seen in TAO [153]. Other findings that may be noted on CT are lachrymal gland enlargement, a dilated superior opthalmic vein, muscle belly enlargement and increase in orbital fat volume [154,55]. CT imaging is a non-invasive, simple, fast, and cost effective imaging procedure. Furthermore, having high sensitivity and correlation with clinical findings, CT imaging should be considered first during diagnostic evaluation of TAO.

Pulse sequences that examine T2 in MRI can estimate the water content of tissues. In TAO lymphocytes infiltrate the orbital tissue that causes fibroblast stimulation. Fibroblasts produce large amounts of GAGs.  Increased water content of thickened extra-ocular muscles cause elevated T2 [156]. In TAO there are two different phases with disease activity. Medical treatment can be effective in the active stage. Therefore, for predicting the outcome of medical management the evaluation of disease activity is important. Yokoyama et al. investigated whether MRI could assess the disease activity in TAO. They found that MRI is not only a useful tool for detection of extraocular muscle enlargement, but also for assessment of disease activity in TAO [157]. In conclusion, MRI is useful to assess TAO. But cost and availability are current limitations of this modality. Therefore, MRI should be used for the management of TAO in specialized patients and clinics.

It is thought that radionuclide accumulation is probably due to binding to somatostatin receptors on lymphocytes, myoblasts, fibroblasts and endothelial cells. Another explanation

**Ultrasound (US)**

Kuo et al. were first described in a positron emission tomography (PET/CT) study in a patient with TAO. The detection of inflammation by 18F-fluorodeoxyglucose (FDG) uptake was sensitive and objectively demonstrable by this semi-quantitative imaging method [164]. García-Rojas et al. carried out the first prospective study. FDG uptake of extra-ocular muscles was statistically different between patients with and without TAO. In cases with TAO where clinical doubt exists, PET/CT provides valuable and useful information for the diagnosis, characterization, and therapeutic decision [165]. Further research is required to define the role of FDG-PET/CT in the management of TAO.

Another tool to measure orbital inflammation is the uptake of radioactively labeled substances, such as 67Gallium (Ga) citrate [166] and 99mTechnetium (Tc)-labeled agents [167,168]. In medical literature there are few studies about these nuclear imaging techniques.

#### **3.8. Clinical classification systems**

The treatment for TAO varies according to the level of disease activity. Thus, methods have been proposed to determine whether TAO is active (33). There are two main scoring systems [169,170]:

Neither NOSPECS nor CAS are both specific and completely reliable, but CAS is a simple office-based tool. The modified NOSPECS criteria include lid retraction, soft tissue inflamma‐ tion, proptosis, size difference, extra-ocular muscle involvement, corneal defects, and optic nerve compression [169]. CAS demonstrates the presence or absence of seven symptoms or signs that indicate inflammation (Table-1) [171].

The score ranges from 0 to 7, with 0 to 2 characteristics indicating inactive TAO and 3 to 7 characteristics indicating active TAO. The CAS has a high predictive value for the outcome of immunosuppressive treatment in TAO. The main determinant of therapeutic outcome is disease activity, not disease duration [172]. In addition, the severity of disease should be assessed (Table-2). Dysthyroid optic neuropathy, corneal breakdown or both indicate that the TAO is sight-threatening and requires immediate treatment [116].

**Table 1.** Components of the Clinical Activity Score

**Table 2.** Assesment of Disease Severity

#### **3.9. Management**

#### **Smoking and TAO**

Patients should be encouraged to quit smoking. In an observational study smoking cessation has been associated with a decreased risk of the development of exophthalmos and diplopia in patients with Graves' disease [171].

#### **Management of hyperthyroidism in patients with TAO**

Uncontrolled thyroid functions (both hyper-and hypothyroidism) are related to severe TAO. Patients with hyperthyroidism can be treated with anti-thyroid drugs (ATDs), radioactive iodine (RAI) therapy and surgical therapy. Some different studies have shown improve‐ ment in TAO [173] by indirect beneficial effects [174] and a gradual decrease in TSHreceptor antibody (TRAb) levels during ATDs treatment [175]. There are confliciting reports in medical literature about RAI therapy and severe TAO [176,177]. But this association cannot be excluded. This risk can be eliminated by therapy with oral glucocorticoids (GCs) after RAI therapy and avoiding post-treatment hypothyroidism [116]. Thyroidectomy is an effective treatment choice for the definitive cure of hyperthyroidism. Wilhelm et al. showed that near-total/total thyroidectomy is safe and superior to subtotal thyroidectomy for management of hyperthyroidism in Graves' disease [178]. According to the European Group on Graves' Orbitopathy (EUGOGO) Consensus Statement; ATD therapy and thyroidecto‐

my do not affect the course of TAO. No particular ATD or regimen, nor any type of thyroidectomy (subtotal or total) has been demonstrated to have any advantages in terms

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 79

TAO represents a complex therapeutic problem. Currently available pharmacologic treatment options result in a partial or absent response of the ophthalmopathy. Up to date available

Glucocorticoids (GCs) are effective treatment options in TAO because of their antiinflamma‐ tory and immunosuppressive actions (96). Moreover they decrease GAGs synthesis and

GCs can be administrated by oral, local (retrobulbar or subconjunctival) and intravenous routes. Oral GCs are generally used in high doses (prednisone, 60–100 mg/day or equiva‐ lent doses of other steroids) and for long-time periods (several months). It has been demonstrated that high-dose oral GCs are effective on soft tissue changes and optic neuropathy. But when its dose is tapered down and/or withdrawn, recurrence of active eye disease is a frequent problem [181]. In slightly more than 60% of cases (range: 40–100%) favorable effects of high-dose oral GCs are reported. GCs have also been used intravenous‐ ly. In most studies effects have been observed on inflammatory signs and optic nerve involvement. But the effects on extra-ocular muscle involvement, and especially propto‐

In most studies patients treated with intravenous GCs have had more favorable results compared with patients treated with oral GCs [18,183]. But in almost all studies treatment with intravenous GCs have been associated with, in the interpulse periods, or followed by (often prolonged) treatment with oral GCs. Moreover there have been biases in patient selections (different degrees of disease activity and duration). Bartalena et al. compared the efficacy and safety of three doses of intravenous (IV) methylprednisolone (2.25, 4.98, or 7.47 g in 12 weekly infusions) in patients with moderate to severe and active TAO. They demonstrated that the use of a cumulative dose of 7.47 g of methylprednisolone provides short-term advantage over lower doses. This benefit was transient and associated with slightly greater toxicity. According to this study we can speculate that an intermediate-dose regimen be used in most cases and the high-dose regimen be reserved to the most severe cases of TAO [184]. Systemic glucocor‐ ticoid therapy relates with some side effects and complications. Therefore, local (retrobulbar or subconjunctival) glucocorticoid therapy has been raised. But in most studies local gluco‐ corticoid therapy had been less effective than systemic administration. As a result, local glucocorticoid therapy can be a treatment option in patients with active ophthalmopathy and

GCs are generally used for severe and active TAO [90]. Furthermore, patients with sightthreatening dysthyroid optic neuropathy should be treated with high-dose intravenous or oral

of outcome of TAO in hyperthyroidism [116].

**3.10. Pharmacologic treatments**

treatments for TAO are as follows:

secretion by orbital fibroblasts [180].

sis, have not been constantly impressive [90].

with major contraindications to the systemic administration [181].

**Glucocorticoids**

my do not affect the course of TAO. No particular ATD or regimen, nor any type of thyroidectomy (subtotal or total) has been demonstrated to have any advantages in terms of outcome of TAO in hyperthyroidism [116].

#### **3.10. Pharmacologic treatments**

TAO represents a complex therapeutic problem. Currently available pharmacologic treatment options result in a partial or absent response of the ophthalmopathy. Up to date available treatments for TAO are as follows:

#### **Glucocorticoids**

assessed (Table-2). Dysthyroid optic neuropathy, corneal breakdown or both indicate that the

∙ Exophthalmos

Patients should be encouraged to quit smoking. In an observational study smoking cessation has been associated with a decreased risk of the development of exophthalmos and diplopia

Uncontrolled thyroid functions (both hyper-and hypothyroidism) are related to severe TAO. Patients with hyperthyroidism can be treated with anti-thyroid drugs (ATDs), radioactive iodine (RAI) therapy and surgical therapy. Some different studies have shown improve‐ ment in TAO [173] by indirect beneficial effects [174] and a gradual decrease in TSHreceptor antibody (TRAb) levels during ATDs treatment [175]. There are confliciting reports in medical literature about RAI therapy and severe TAO [176,177]. But this association cannot be excluded. This risk can be eliminated by therapy with oral glucocorticoids (GCs) after RAI therapy and avoiding post-treatment hypothyroidism [116]. Thyroidectomy is an effective treatment choice for the definitive cure of hyperthyroidism. Wilhelm et al. showed that near-total/total thyroidectomy is safe and superior to subtotal thyroidectomy for management of hyperthyroidism in Graves' disease [178]. According to the European Group on Graves' Orbitopathy (EUGOGO) Consensus Statement; ATD therapy and thyroidecto‐

∙ Subjective diplopia score ∙ Eye muscle involvement ∙ Corneal involvement ∙ Optic nerve involvement

TAO is sight-threatening and requires immediate treatment [116].

∙ Spontaneous retrobulbar pain ∙ Pain with eye movement ∙ Redness of the eyelids ∙ Redness of the conjunctiva ∙ Swelling of the eyelids ∙ Swelling of the caruncle ∙ Conjunctival edema (chemosis)

78 Thyroid Disorders - Focus on Hyperthyroidism

∙ Lid aperture

∙ Swelling of the eyelids ∙ Redness of the eyelids ∙ Redness of the conjunctivae ∙ Conjunctival edema

**3.9. Management**

**Smoking and TAO**

∙ Inflammation of the caruncle or plica

**Table 2.** Assesment of Disease Severity

in patients with Graves' disease [171].

**Management of hyperthyroidism in patients with TAO**

**Table 1.** Components of the Clinical Activity Score

Glucocorticoids (GCs) are effective treatment options in TAO because of their antiinflamma‐ tory and immunosuppressive actions (96). Moreover they decrease GAGs synthesis and secretion by orbital fibroblasts [180].

GCs can be administrated by oral, local (retrobulbar or subconjunctival) and intravenous routes. Oral GCs are generally used in high doses (prednisone, 60–100 mg/day or equiva‐ lent doses of other steroids) and for long-time periods (several months). It has been demonstrated that high-dose oral GCs are effective on soft tissue changes and optic neuropathy. But when its dose is tapered down and/or withdrawn, recurrence of active eye disease is a frequent problem [181]. In slightly more than 60% of cases (range: 40–100%) favorable effects of high-dose oral GCs are reported. GCs have also been used intravenous‐ ly. In most studies effects have been observed on inflammatory signs and optic nerve involvement. But the effects on extra-ocular muscle involvement, and especially propto‐ sis, have not been constantly impressive [90].

In most studies patients treated with intravenous GCs have had more favorable results compared with patients treated with oral GCs [18,183]. But in almost all studies treatment with intravenous GCs have been associated with, in the interpulse periods, or followed by (often prolonged) treatment with oral GCs. Moreover there have been biases in patient selections (different degrees of disease activity and duration). Bartalena et al. compared the efficacy and safety of three doses of intravenous (IV) methylprednisolone (2.25, 4.98, or 7.47 g in 12 weekly infusions) in patients with moderate to severe and active TAO. They demonstrated that the use of a cumulative dose of 7.47 g of methylprednisolone provides short-term advantage over lower doses. This benefit was transient and associated with slightly greater toxicity. According to this study we can speculate that an intermediate-dose regimen be used in most cases and the high-dose regimen be reserved to the most severe cases of TAO [184]. Systemic glucocor‐ ticoid therapy relates with some side effects and complications. Therefore, local (retrobulbar or subconjunctival) glucocorticoid therapy has been raised. But in most studies local gluco‐ corticoid therapy had been less effective than systemic administration. As a result, local glucocorticoid therapy can be a treatment option in patients with active ophthalmopathy and with major contraindications to the systemic administration [181].

GCs are generally used for severe and active TAO [90]. Furthermore, patients with sightthreatening dysthyroid optic neuropathy should be treated with high-dose intravenous or oral glucocorticoid agents [116]. Additionally, there are some case reports in medical literature, who had severe complicatons related with high-dose glucocorticoid pulse therapy [185].

to this, treatment is quite expensive and is related with disease transmission using plasmaderived products. More prospective, randomized and controlled trials, which includes large

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 81

**a. Cyclosporine A (CyA):** The first report by Weetman et al. showed that CyA had positive effects on ocular-muscle function, visual acuity, exophthalmos and orbital muscle swel‐ ling [193]. Prummel et al. compared two groups of 18 patients each of which were treated with either cyclosporine or prednisone. At the end of the study, treatment response was observed in 11 patients treated with prednisone, but only in 4 patients treated with cyclosporine [194]. Weissel et al. treated 8 patients with TAO, all of whom had compres‐ sive optic nerve disease (CON), by a combined treatment with CyA and cortisone. CON disappeared completely in all patients [195]. In summary, the use of CyA has been reported in several studies. Given the side effects of CyA, some of which can be severe, it should not be considered as a first-line treatment in TAO. The use of CyA might be maintained in patients who are resistant to GCs alone, and in whom the persistent activity of the disease warrants a continuing medical intervention. According to the recent European Thyroid Association survey CyA or azathioprine were indicated as suitable therapeutic options by

**b. Methotrexate (MTX):** MTX is not a novel drug, but it has not systematically been evaluated in TAO management. Smith et al. carried out the unique study on the use of MTX for noninfectious orbital inflammatory disorders like TAO. They included 14 patients, and three of them had TAO. All three patients with TAO had an improvement in their ocular conditions after MTX treatment [196] According to the recent European Thyroid Association survey MTX was indicated as a therapeutic option by only 1% of respondents [197]. MTX has many dosedependent and reversible side effects and should not be used as a first-line treatment. In patients with GC dependency, it can be used at low doses with the aim of reducing the dose of GCs. However, to clarify the effectiveness of MTX in TAO management we need more

Bouzas et al. carried out a prospective, nonrandomized, comparative study on the effects of the antioxidant agents allopurinol and nicotinamide in TAO patients. Ocular conditions significantly improved in antioxidant-treated patients, more than placebo-treated patients [198]. Yoon et al. investigated the inhibitory effect of quercetin on inflammation in cultured whole orbital tissue. Quercetin had a significant suppression of tissue IL-6,IL-8, IL-1β and TNFα mRNA expression in cultured orbital tissues from three TAO samples relative to untreated control tissue [199]. Marcocci et al. demonstrated that selenium administration (100 μg twice daily) significantly improved quality of life, reduced ocular involvement, and slowed

There is limited data about treatment TAO with antioxidants. We need larger, prospective and

randomized trials to clarify the role of antioxidant agents in the treatment of TAO.

series of patients are required to obtain more accurate results.

only 6% and 2% of respondents respectively [196].

controlled and randomized prospective studies.

progression of the disease in patients with mild TAO [200].

**Antioxidants**

**Immunosuppressive drugs**

#### **Somatostatin (SST) analogues**

SST receptors (SSTR) are expressed in many tissues, including activated lymphocytes. OCT was proposed as a method to evaluate orbital inflammation in TAO. The use of the SST analog, octreotide, was first reported in TAO patients by Chang et al [186]. Uysal et al. evaluated the effect of octreotide treatment in nine patients with TAO. Seven of the patients showed improvement in CAS. Proptosis improved either slightly or significantly in seven patients. None of the patients has showed deterioration in the eye according to their findings [187]. A major disadvantage of octreotide is its short half-life, which requires multiple injections. To overcome this limitation, new long-acting SST analogs (lanreotide / octreotide-LAR) have been developed. Stan et al. carried out a randomized, double-blind, placebo-controlled trial of octreotide-LAR for treatment of TAO. In octreotide-LAR-treated patients, the CAS improved with a greater degree than in the placebo group. They noted improvement in eyelid fissure width, which suggest that octreotide LAR treatment may be effective in TAO patients with significant lid retraction [188]. In another study Krassas et al. aimed to investigate the orbital Indium-111-pentetreotide activity after treatment with octreotide and lanreotide in patients with TAO. All patients treated with SST analogs had a negative follow-up OCT, whereas controls had a positive OCT. Both NOSPECS score and CAS had improved in the treatment group, but there have been no changes in control subjects [189]. Most common side effects of SST analog therapy in TAO patients were mild gastrointestinal symptoms occurring during the first week of treatment. Because of minimal side effects and proven efficacy, SST analogs could be a treatment option in selected patients. But we need further large, multi-center, prospective and randomized clinical trials and a comparable series of patients with other established treatment options, to achieve more accurate outcomes. In addition, the high cost of this treatment must also be taken into account.

#### **Intravenous immunoglobulins (IVIG)**

Antonelli et al. was published as the first non-randomized study on the use of IVIGs for TAO. They treated 7 patients with high-dose IVIGs alone (400 mg/kg/day for 5 consecutive days; the cycle was repeated five times at 3-week intervals) and 7 patients with IVIGs associated with orbital radiotherapy. The results were compared with a historical group of patients previously treated with high-dose GCs and orbital radiotherapy. They found that IVIGs, either alone or combined with orbital radiotherapy, had improved the ocular conditions. This result did not differ from those obtained in the historical group [190]. In a randomized trial by Kahaly et al. 19 patients with active TAO were treated with a 20-week course of oral prednisolone (P, starting dose 100 mg/day), and 21 received 1g immunoglobulin/kg body weight for 2 consec‐ utive days every 3 weeks. The immunoglobulin course was repeated six times. The degree of clinical improvement between two groups was not significant. There was a marked reduction of thyroid antibody titres in the immunoglobulin group. Side effects were more frequent and severe during P than during immunoglobulin therapy [191]. But another study by Seppel et al. failed to show any beneficial effects of IVIGs in TAO [192]. In summary, treatment studies with IVIGs include small numbers of patients and all of them are not randomized. In addition to this, treatment is quite expensive and is related with disease transmission using plasmaderived products. More prospective, randomized and controlled trials, which includes large series of patients are required to obtain more accurate results.

#### **Immunosuppressive drugs**

glucocorticoid agents [116]. Additionally, there are some case reports in medical literature, who had severe complicatons related with high-dose glucocorticoid pulse therapy [185].

SST receptors (SSTR) are expressed in many tissues, including activated lymphocytes. OCT was proposed as a method to evaluate orbital inflammation in TAO. The use of the SST analog, octreotide, was first reported in TAO patients by Chang et al [186]. Uysal et al. evaluated the effect of octreotide treatment in nine patients with TAO. Seven of the patients showed improvement in CAS. Proptosis improved either slightly or significantly in seven patients. None of the patients has showed deterioration in the eye according to their findings [187]. A major disadvantage of octreotide is its short half-life, which requires multiple injections. To overcome this limitation, new long-acting SST analogs (lanreotide / octreotide-LAR) have been developed. Stan et al. carried out a randomized, double-blind, placebo-controlled trial of octreotide-LAR for treatment of TAO. In octreotide-LAR-treated patients, the CAS improved with a greater degree than in the placebo group. They noted improvement in eyelid fissure width, which suggest that octreotide LAR treatment may be effective in TAO patients with significant lid retraction [188]. In another study Krassas et al. aimed to investigate the orbital Indium-111-pentetreotide activity after treatment with octreotide and lanreotide in patients with TAO. All patients treated with SST analogs had a negative follow-up OCT, whereas controls had a positive OCT. Both NOSPECS score and CAS had improved in the treatment group, but there have been no changes in control subjects [189]. Most common side effects of SST analog therapy in TAO patients were mild gastrointestinal symptoms occurring during the first week of treatment. Because of minimal side effects and proven efficacy, SST analogs could be a treatment option in selected patients. But we need further large, multi-center, prospective and randomized clinical trials and a comparable series of patients with other established treatment options, to achieve more accurate outcomes. In addition, the high cost

Antonelli et al. was published as the first non-randomized study on the use of IVIGs for TAO. They treated 7 patients with high-dose IVIGs alone (400 mg/kg/day for 5 consecutive days; the cycle was repeated five times at 3-week intervals) and 7 patients with IVIGs associated with orbital radiotherapy. The results were compared with a historical group of patients previously treated with high-dose GCs and orbital radiotherapy. They found that IVIGs, either alone or combined with orbital radiotherapy, had improved the ocular conditions. This result did not differ from those obtained in the historical group [190]. In a randomized trial by Kahaly et al. 19 patients with active TAO were treated with a 20-week course of oral prednisolone (P, starting dose 100 mg/day), and 21 received 1g immunoglobulin/kg body weight for 2 consec‐ utive days every 3 weeks. The immunoglobulin course was repeated six times. The degree of clinical improvement between two groups was not significant. There was a marked reduction of thyroid antibody titres in the immunoglobulin group. Side effects were more frequent and severe during P than during immunoglobulin therapy [191]. But another study by Seppel et al. failed to show any beneficial effects of IVIGs in TAO [192]. In summary, treatment studies with IVIGs include small numbers of patients and all of them are not randomized. In addition

**Somatostatin (SST) analogues**

80 Thyroid Disorders - Focus on Hyperthyroidism

of this treatment must also be taken into account.

**Intravenous immunoglobulins (IVIG)**

**a. Cyclosporine A (CyA):** The first report by Weetman et al. showed that CyA had positive effects on ocular-muscle function, visual acuity, exophthalmos and orbital muscle swel‐ ling [193]. Prummel et al. compared two groups of 18 patients each of which were treated with either cyclosporine or prednisone. At the end of the study, treatment response was observed in 11 patients treated with prednisone, but only in 4 patients treated with cyclosporine [194]. Weissel et al. treated 8 patients with TAO, all of whom had compres‐ sive optic nerve disease (CON), by a combined treatment with CyA and cortisone. CON disappeared completely in all patients [195]. In summary, the use of CyA has been reported in several studies. Given the side effects of CyA, some of which can be severe, it should not be considered as a first-line treatment in TAO. The use of CyA might be maintained in patients who are resistant to GCs alone, and in whom the persistent activity of the disease warrants a continuing medical intervention. According to the recent European Thyroid Association survey CyA or azathioprine were indicated as suitable therapeutic options by only 6% and 2% of respondents respectively [196].

**b. Methotrexate (MTX):** MTX is not a novel drug, but it has not systematically been evaluated in TAO management. Smith et al. carried out the unique study on the use of MTX for noninfectious orbital inflammatory disorders like TAO. They included 14 patients, and three of them had TAO. All three patients with TAO had an improvement in their ocular conditions after MTX treatment [196] According to the recent European Thyroid Association survey MTX was indicated as a therapeutic option by only 1% of respondents [197]. MTX has many dosedependent and reversible side effects and should not be used as a first-line treatment. In patients with GC dependency, it can be used at low doses with the aim of reducing the dose of GCs. However, to clarify the effectiveness of MTX in TAO management we need more controlled and randomized prospective studies.

#### **Antioxidants**

Bouzas et al. carried out a prospective, nonrandomized, comparative study on the effects of the antioxidant agents allopurinol and nicotinamide in TAO patients. Ocular conditions significantly improved in antioxidant-treated patients, more than placebo-treated patients [198]. Yoon et al. investigated the inhibitory effect of quercetin on inflammation in cultured whole orbital tissue. Quercetin had a significant suppression of tissue IL-6,IL-8, IL-1β and TNFα mRNA expression in cultured orbital tissues from three TAO samples relative to untreated control tissue [199]. Marcocci et al. demonstrated that selenium administration (100 μg twice daily) significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild TAO [200].

There is limited data about treatment TAO with antioxidants. We need larger, prospective and randomized trials to clarify the role of antioxidant agents in the treatment of TAO.

#### **Cytokine antagonists**

Chang et al. aimed to determine the effects of pentoxifylline (Ptx); a cytokine antagonist, on fibroblasts derived from patients with Graves' ophthalmopathy. Ptx treatment caused a dosedependent inhibition of serum-driven fibroblast proliferation and glycosaminoglycan synthe‐ sis [201]. Balazs et al. showed that Ptx has had beneficial effects on inflammatory symptoms of TAO and associated laboratory parameters [202]. In another study Ptx has improved the quality of life (QOL) of patients in the inactive phase of TAO [203]. According to these studies Ptx may be an effective and promising drug in the treatment of TAO.

**Thalidomide**

**3.11. Radiotherapy**

radiation retinopathy [221].

clear cells in patients with TAO [213].

Thalidomide plays a role in inhibiting adipogenesis of orbital fibroblasts in TAO [212]. Han et al. demonstrated the immunoregulatory effect of thalidomide on peripheral blood mononu‐

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 83

Orbital fibroblasts from patients with TAO have treated with rosiglitazone, and the results suggested that TSHR expression in TAO orbital preadipocyte fibroblasts is linked to adipo‐ genesis [214]. Several case reports of TAO exacerbation following the initiation of PPAR agonists have been reported in the literature [215,216]. These findings suggest that novel drugs which antagonize the PPAR signalling system can also be considered as a treatment option in TAO. The effects of PPAR-*γ* activation on CXCL10, CXCL9 and CXCL11 secretion in orbital fibroblasts and preadipocytes were evaluated. The inhibitory role of PPAR-*γ* activation in the process demonstrated [217,218].These studies suggest that PPAR agonists can also be consid‐ ered as a treatment option in TAO. There are conflicting reports in the medical literature,

Radiotherapy (RT) is a treatment option in TAO because of its non-specific anti-inflammatory and specific immunosuppressive effects (lymphocytes infiltrating the orbital space are highly radiosensitive) [219]. Moreover RT reduces GAG production by orbital fibroblasts [220]. RT has especially benefical effects on soft tissue changes and optic neuropathy. Unfortunately, in longstanding TAO, the benefical effects for reduction in proptosis and the improvement in ocular motility are not satisfactory [90]. A systematic review and meta-analysis of eight randomized controlled trials showed that, in patients with moderate to severe TAO, RT 20 Gy is a valid therapeutic option which improves lots of ocular symptoms. According to medical literature the dose of 20 Gy can be considered the optimal dose for orbital RT of TAO. The cumulative dose is usually fractionated in 10 daily doses over a 2-week period to reduce the cataractogenic effect [221]. Higher cumulative doses of RT does not improve the effectiveness of treatment [222]. Combined use of GCs and orbital RT was found to be more effective than using either one alone (140). Orbital RT is usually well tolerated. It may be associated with a transient exacerbation of inflammatory eye signs and symptoms, but this is unlikely to occur if GCs are concomitantly administered. Cataract is a possible complication of irradiation to the lens. Radiation retinopathy is an extremely rare complication of RT. Systemic microvascular disease due to diabetes mellitus (DM) or to previous chemotherapy may increase the risk for

A major concern about orbital RT is carcinogenecity. In a small cohort of patients treated with RT for TAO, there was no significant evidence of radiation-induced cancer death [224]. Wakelkamp et al. evaluated the frequency of long-term complications of orbital RT for TAO (radiation-induced tumors, cataract, and retinopathy) in comparison with GCs. Mortality has obtained similarly in the irradiated and nonirradiated patients [225]. Haenssle et al. reported pigmented basal cell carcinomas 15 years after orbital RT therapy for TAO [226]. The long-

**Peroxisome proliferator-activated receptor (PPAR) agonists / antagonists**

regarding the use of PPAR agonists and antagonists in the treatment of TAO.

#### **TNF-α antagonists**

Paridaens et al. assessed the effect of etanercept on clinical signs in TAO. After treatment the mean CAS and ophthalmopathy index (OI) had decreased significantly. No adverse effects were noted [204]. İnfliximab administration resulted with a significant reduction of inflam‐ mation and improvement of visual function without noticeable short-term side effects in two patients with active TAO [205,206]. But randomized prospective clinical trials are needed to obtain whether TNF-α antagonists are effective in reducing the inflammatory symptoms of TAO, and can be administered safely for a long-term period without serious side effects.

#### **Rituximab (RTX)**

A patient with TAO, who was unresponsive to steroids, was treated with RTX. The CAS declined from 5 to 2 in 3 months and the patient had peripheral B-cell depletion [207]. When the effect of RTX therapy was compared with IV GCs, RTX had positively affected the clinical course of TAO, independently of either thyroid function or circulating antithyroid antibodies, including TSH receptor antibody [208]. Silkiss et al. demonstrated a statistically significant decrease in CAS from the baseline value. B-cell depletion had been observed and was well tolerated, and there were no adverse effects from the RTX infusions [206]. There is currently insufficient evidence to support the use of RTX in patients with TAO. We need large rando‐ mised conrolled trials (RCTs) for investigating the efficacy and safety of RTX versus placebo or corticosteroids in patients with active TAO to make adequate judgement of this novel therapy for this condition

#### **Rapamycin**

A case of TAO, with dysthyroid optic neuropathy, who was refractory to steroids and orbital decompression surgery reported. Symptoms, visual acuity, color plate testing, and visual fields of the patient had been improved; despite the prednisone tapering [210]. On the basis the pathogenesis of TAO, rapamycin can be considered as a therapeutic option. But we need more RCTs to assess the efficacy and safety of this drug.

#### **Colchicine**

A randomized clinical study showed that colchicine had a beneficial effect on the inflammatory phase of TAO. Therefore, it was equally effective when compared to the classic treatment with corticosteroids, but safer and better tolerated [211]. Due to the lack of controlled trials, it is not clear that these effects were related to the natural history of the ophthalmopathy or to the effects of the drug.

#### **Thalidomide**

**Cytokine antagonists**

82 Thyroid Disorders - Focus on Hyperthyroidism

**TNF-α antagonists**

**Rituximab (RTX)**

therapy for this condition

RCTs to assess the efficacy and safety of this drug.

**Rapamycin**

**Colchicine**

effects of the drug.

Chang et al. aimed to determine the effects of pentoxifylline (Ptx); a cytokine antagonist, on fibroblasts derived from patients with Graves' ophthalmopathy. Ptx treatment caused a dosedependent inhibition of serum-driven fibroblast proliferation and glycosaminoglycan synthe‐ sis [201]. Balazs et al. showed that Ptx has had beneficial effects on inflammatory symptoms of TAO and associated laboratory parameters [202]. In another study Ptx has improved the quality of life (QOL) of patients in the inactive phase of TAO [203]. According to these studies

Paridaens et al. assessed the effect of etanercept on clinical signs in TAO. After treatment the mean CAS and ophthalmopathy index (OI) had decreased significantly. No adverse effects were noted [204]. İnfliximab administration resulted with a significant reduction of inflam‐ mation and improvement of visual function without noticeable short-term side effects in two patients with active TAO [205,206]. But randomized prospective clinical trials are needed to obtain whether TNF-α antagonists are effective in reducing the inflammatory symptoms of TAO, and can be administered safely for a long-term period without serious side effects.

A patient with TAO, who was unresponsive to steroids, was treated with RTX. The CAS declined from 5 to 2 in 3 months and the patient had peripheral B-cell depletion [207]. When the effect of RTX therapy was compared with IV GCs, RTX had positively affected the clinical course of TAO, independently of either thyroid function or circulating antithyroid antibodies, including TSH receptor antibody [208]. Silkiss et al. demonstrated a statistically significant decrease in CAS from the baseline value. B-cell depletion had been observed and was well tolerated, and there were no adverse effects from the RTX infusions [206]. There is currently insufficient evidence to support the use of RTX in patients with TAO. We need large rando‐ mised conrolled trials (RCTs) for investigating the efficacy and safety of RTX versus placebo or corticosteroids in patients with active TAO to make adequate judgement of this novel

A case of TAO, with dysthyroid optic neuropathy, who was refractory to steroids and orbital decompression surgery reported. Symptoms, visual acuity, color plate testing, and visual fields of the patient had been improved; despite the prednisone tapering [210]. On the basis the pathogenesis of TAO, rapamycin can be considered as a therapeutic option. But we need more

A randomized clinical study showed that colchicine had a beneficial effect on the inflammatory phase of TAO. Therefore, it was equally effective when compared to the classic treatment with corticosteroids, but safer and better tolerated [211]. Due to the lack of controlled trials, it is not clear that these effects were related to the natural history of the ophthalmopathy or to the

Ptx may be an effective and promising drug in the treatment of TAO.

Thalidomide plays a role in inhibiting adipogenesis of orbital fibroblasts in TAO [212]. Han et al. demonstrated the immunoregulatory effect of thalidomide on peripheral blood mononu‐ clear cells in patients with TAO [213].

#### **Peroxisome proliferator-activated receptor (PPAR) agonists / antagonists**

Orbital fibroblasts from patients with TAO have treated with rosiglitazone, and the results suggested that TSHR expression in TAO orbital preadipocyte fibroblasts is linked to adipo‐ genesis [214]. Several case reports of TAO exacerbation following the initiation of PPAR agonists have been reported in the literature [215,216]. These findings suggest that novel drugs which antagonize the PPAR signalling system can also be considered as a treatment option in TAO. The effects of PPAR-*γ* activation on CXCL10, CXCL9 and CXCL11 secretion in orbital fibroblasts and preadipocytes were evaluated. The inhibitory role of PPAR-*γ* activation in the process demonstrated [217,218].These studies suggest that PPAR agonists can also be consid‐ ered as a treatment option in TAO. There are conflicting reports in the medical literature, regarding the use of PPAR agonists and antagonists in the treatment of TAO.

#### **3.11. Radiotherapy**

Radiotherapy (RT) is a treatment option in TAO because of its non-specific anti-inflammatory and specific immunosuppressive effects (lymphocytes infiltrating the orbital space are highly radiosensitive) [219]. Moreover RT reduces GAG production by orbital fibroblasts [220]. RT has especially benefical effects on soft tissue changes and optic neuropathy. Unfortunately, in longstanding TAO, the benefical effects for reduction in proptosis and the improvement in ocular motility are not satisfactory [90]. A systematic review and meta-analysis of eight randomized controlled trials showed that, in patients with moderate to severe TAO, RT 20 Gy is a valid therapeutic option which improves lots of ocular symptoms. According to medical literature the dose of 20 Gy can be considered the optimal dose for orbital RT of TAO. The cumulative dose is usually fractionated in 10 daily doses over a 2-week period to reduce the cataractogenic effect [221]. Higher cumulative doses of RT does not improve the effectiveness of treatment [222]. Combined use of GCs and orbital RT was found to be more effective than using either one alone (140). Orbital RT is usually well tolerated. It may be associated with a transient exacerbation of inflammatory eye signs and symptoms, but this is unlikely to occur if GCs are concomitantly administered. Cataract is a possible complication of irradiation to the lens. Radiation retinopathy is an extremely rare complication of RT. Systemic microvascular disease due to diabetes mellitus (DM) or to previous chemotherapy may increase the risk for radiation retinopathy [221].

A major concern about orbital RT is carcinogenecity. In a small cohort of patients treated with RT for TAO, there was no significant evidence of radiation-induced cancer death [224]. Wakelkamp et al. evaluated the frequency of long-term complications of orbital RT for TAO (radiation-induced tumors, cataract, and retinopathy) in comparison with GCs. Mortality has obtained similarly in the irradiated and nonirradiated patients [225]. Haenssle et al. reported pigmented basal cell carcinomas 15 years after orbital RT therapy for TAO [226]. The longterm treatment results seem to be satisfactory. But long-term follow up studies with greater numbers of patients are necessary to examine the risks and benefits more precisely. Orbital radiotherapy,whenproperlyperformed,appearstobeasafeprocedurewithlimitedsideeffects.

The studies in the medical literature could not make any meaningful comparisons between the surgical techniques. In the previous studies because of the risks of surgery, orbital decompression has been used in patients with marked proptosis and optic nerve compression, especially if no beneficial effect was obtained with other treatments. But in recent years the indications of orbital decompression has expanded. Garrity et al. reviewed the records of 428 consecutive eye surgery patients at the Mayo Clinic. These were; optic neuropathy, severe orbital inflammation, proptosis, and glucocorticoid side effects [238]. According to the EUGOGO consensus statement on TAO; orbital decompression for exophthalmos (rehabilita‐ tive surgery) could be delayed for at least 6 months, until the orbitopathy has been inactive for a period, because surgery yields the best results when TAO is inactive. But in patients with TAO who are intolerant or non-responsive to GCs, orbital decompression can be considered in the active phase. In conclusion, orbital decompression seems to be an effective and safe

Bartalena et al. within the EUGOGO consensus statement on TAO, published the set of medical

**All patients with TAO**

**Restore euthyroidism ,urge smoking withdrawal, refer to specialist centers (except for the mildest cases) local mesures**

**Mild Moderate to severe Sight-threatening (DON)**

**Commentary:** Rehabilitative surgery includes orbital decompression, squint surgery, lid lengthening, and blepharo‐ plasty/browplasty. I.V.GCs: intravenous glucocorticoids; OR: orbital radiotherapy; DON: dysthyroid optic neuropathy.

**Rehabilitive surgery**

**I.V GCS**

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 85

**Stable and inactive**

**surgery**

**Poor response (2 weeks)**

**Prompt decompression**

**(±OR) Rehabilitive**

**Still active**

**I.V GCS**

**Progression Active İnactive**

**I.V GCS (±OR)**

**Stable and inactive**

**Figure 2.** Management of Thyroid-Associated Oophthalmopathy (TAO)

treatment for patients with TAO [116].

**Local measures wait and see**

> **Stable and inactive**

**Rehabilitive surgery (if needed)**

**3.15. Medical and surgical recommendations**

and surgical recommendations shown in Figure 2.

#### **3.12. Plasmapheresis**

In the first report by Dandona et al., a patient with Graves's disease with acute progressive exophthalmos was treated with plasmapheresis. Their results has suggested that plasmaphe‐ resis could be a useful treatment option in acute and rapidly progressive ophthalmopathy [227]. Glinoer et al. observed significant clinical improvement immediately after plasmaphe‐ resis. The most significant effects were on soft tissue involvement, proptosis, intraocular pressure, and visual acuity [228]. In contrast to these, unfavorable effects of plasmapheresis have been reported [229,230]. Trials involving plasmapheresis provided conflicting results. We need RCTs to assess the efficacy and safety of plasmapharesis.

#### **3.13. Total thyroid ablation**

According to "shared" antigen(s) theory hypothesis; autoreactive T-lymphocytes which can recognize and interact with one or more antigens shared by the thyroid and the orbital tissue, trigger the event [231]. If this hypothesis is correct, in patients with appropriate genetic background and exposed to relevant environmental risk factors, the presence of thyroid tissue could be related with the development and progression of the ophthalmopathy [232,233]. A progressive decrease and disappearance of circulating auto-antibodies in initially antibodypositive thyroid cancer patients was demonstrated. This observation supports the theory that total thyroid ablation reduces thyroid autoimmunity [234]. Spinelli et al. reported major efficacy in the ophthalmopathy by total thyroidectomy(TT) [235]. De Bellis et al. evaluated the effect of TT alone or followed by post-surgical 131Iodine with respect to methimazole treatment on the activity and severity of TAO. Patients in TT and 131Iodine showed an early significant decrease and a further progressive reduction of the activity and severity of TAO during the follow-up, without statistically significant differences. These studies suggest that TT alone could be an appropriate alternative to improve TAO with a reduction of the cost/benefit ratio [236]. In conclusion, Total Thyroid Ablation (TTA) could be a possible treatment strategy for TAO. Its advantages are; better outcomes in the short term and a shorter period for the improvement of TAO. Because of its costs and risks TTA can not be recommended as a firstline treatment option in TAO.

#### **3.14. Surgical therapy**

#### **Orbital decompression**

The goal of orbital decompression is to provide increased space for the increased orbital tissue, by removing the bony or fatty components of the orbit. In this way it is effective on proptosis and on the other ocular manifestations. This treatment could not act on the pathogenesis of the diesease. Several techniques have been used to remove portions of one to four walls of the orbit. The decision for which surgical techniques could be used, depends on the experience of the orbit surgeon and the clinical situation of the patient [237].

The studies in the medical literature could not make any meaningful comparisons between the surgical techniques. In the previous studies because of the risks of surgery, orbital decompression has been used in patients with marked proptosis and optic nerve compression, especially if no beneficial effect was obtained with other treatments. But in recent years the indications of orbital decompression has expanded. Garrity et al. reviewed the records of 428 consecutive eye surgery patients at the Mayo Clinic. These were; optic neuropathy, severe orbital inflammation, proptosis, and glucocorticoid side effects [238]. According to the EUGOGO consensus statement on TAO; orbital decompression for exophthalmos (rehabilita‐ tive surgery) could be delayed for at least 6 months, until the orbitopathy has been inactive for a period, because surgery yields the best results when TAO is inactive. But in patients with TAO who are intolerant or non-responsive to GCs, orbital decompression can be considered in the active phase. In conclusion, orbital decompression seems to be an effective and safe treatment for patients with TAO [116].

#### **3.15. Medical and surgical recommendations**

term treatment results seem to be satisfactory. But long-term follow up studies with greater numbers of patients are necessary to examine the risks and benefits more precisely. Orbital radiotherapy,whenproperlyperformed,appearstobeasafeprocedurewithlimitedsideeffects.

In the first report by Dandona et al., a patient with Graves's disease with acute progressive exophthalmos was treated with plasmapheresis. Their results has suggested that plasmaphe‐ resis could be a useful treatment option in acute and rapidly progressive ophthalmopathy [227]. Glinoer et al. observed significant clinical improvement immediately after plasmaphe‐ resis. The most significant effects were on soft tissue involvement, proptosis, intraocular pressure, and visual acuity [228]. In contrast to these, unfavorable effects of plasmapheresis have been reported [229,230]. Trials involving plasmapheresis provided conflicting results.

According to "shared" antigen(s) theory hypothesis; autoreactive T-lymphocytes which can recognize and interact with one or more antigens shared by the thyroid and the orbital tissue, trigger the event [231]. If this hypothesis is correct, in patients with appropriate genetic background and exposed to relevant environmental risk factors, the presence of thyroid tissue could be related with the development and progression of the ophthalmopathy [232,233]. A progressive decrease and disappearance of circulating auto-antibodies in initially antibodypositive thyroid cancer patients was demonstrated. This observation supports the theory that total thyroid ablation reduces thyroid autoimmunity [234]. Spinelli et al. reported major efficacy in the ophthalmopathy by total thyroidectomy(TT) [235]. De Bellis et al. evaluated the effect of TT alone or followed by post-surgical 131Iodine with respect to methimazole treatment on the activity and severity of TAO. Patients in TT and 131Iodine showed an early significant decrease and a further progressive reduction of the activity and severity of TAO during the follow-up, without statistically significant differences. These studies suggest that TT alone could be an appropriate alternative to improve TAO with a reduction of the cost/benefit ratio [236]. In conclusion, Total Thyroid Ablation (TTA) could be a possible treatment strategy for TAO. Its advantages are; better outcomes in the short term and a shorter period for the improvement of TAO. Because of its costs and risks TTA can not be recommended as a first-

The goal of orbital decompression is to provide increased space for the increased orbital tissue, by removing the bony or fatty components of the orbit. In this way it is effective on proptosis and on the other ocular manifestations. This treatment could not act on the pathogenesis of the diesease. Several techniques have been used to remove portions of one to four walls of the orbit. The decision for which surgical techniques could be used, depends on the experience of

the orbit surgeon and the clinical situation of the patient [237].

We need RCTs to assess the efficacy and safety of plasmapharesis.

**3.12. Plasmapheresis**

84 Thyroid Disorders - Focus on Hyperthyroidism

**3.13. Total thyroid ablation**

line treatment option in TAO.

**3.14. Surgical therapy**

**Orbital decompression**

Bartalena et al. within the EUGOGO consensus statement on TAO, published the set of medical and surgical recommendations shown in Figure 2.

**Commentary:** Rehabilitative surgery includes orbital decompression, squint surgery, lid lengthening, and blepharo‐ plasty/browplasty. I.V.GCs: intravenous glucocorticoids; OR: orbital radiotherapy; DON: dysthyroid optic neuropathy.

**Figure 2.** Management of Thyroid-Associated Oophthalmopathy (TAO)

#### **4. Hyperthyroidism and bone**

In 1891 Von Recklinghausen firstly described reduced bone mass in untreated hyperthyroid‐ ism. Thyroid hormones (3,3',5-triiodothyronine [T3] and 3,3',5,5'-tetra iodothyronine [T4]) act on normal bone growth, development and turnover in both children and adults [239,240]. Hyperthyroidism increases bone turnover, acting mainly on bone resorption, but also on osteoblast activity [241,242] [Figure-3]. As a result, hyperthyroidism is an important etiology of secondary osteoporosis [243].

hyperthyroidism due to the increases of inhibitory IGFBPs that can counteract the anabolic effects and contribute to the observed net bone loss [249]. T3 activates fibroblast growth factor receptor-1 (FGFR1) in bone and this can be related with the pathogenesis of skeletal disorders

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 87

Thyroid hormones increase the activation of new remodeling cycles. These effects include predominantly increased osteoclastic activity. Although; excess osteoblastic activity, osteoid deposition (osteomalacia) and rarefaction (osteoporosis) were also described. These changes were observed both in trabecular and cortical bone ([51]. In 1978 Mosekilde & Melsen dem‐ onstrated a unique histomorphometric pattern; with evidence of both increased osteoblast and osteoclast activity in hyperthyroidism. These changes have given rise to a net loss of bone volume and were evident in both cortical and trabecular bone. But cortical bone has been rather more influenced (Figure-4) [252]. An *in-vitro* organ culture of fetal rat bone, demonstrated a

The majority of patients with hyperthyroidism have normal or near normal total serum calcium levels. However, ionized serum calcium levels are elevated in most of the patients. Changes in serum calcium levels correlate with serum T3 levels [253,254]. Generally hyper‐ calcemia in hyperthyroidism tends to be mild or asymptomatic. Severe (>15 mg/dl) and symptomatic hypercalcemia is rare [255]. Hypercalcemia usually resolves after attainment of euthyroid state by all therapeutic modalities, i.e. subtotal thyroid resection, antithyroid drugs and radioiodine therapy. Symptomatic hypercalcemia can be treated by rehydration, use of corticosteroids, calcitonin and phosphate therapy. Reduced renal tubular and intestinal calcium reabsorption leads to increased urinary and fecal calcium [241]. The hyperadrenergic state of hyperthyroidism contributes hypercalcemia [256]. These changes correlate positively with thyroid hormone levels and cortical osteoclastic activity. Hypercalcemia in hyperthyr‐

Most of the patients have increased serum phosphorous levels. But some studies have shown normal or low levels of serum phosphorous. Increased bone and tissue catabolisms which lead to excess input of phosphorous to the plasma, lower clearance and increased renal tubular reabsorption of phosphorous may lead to hyperphosphatemia in hyperthyroidism. These changes are related to suppressed PTH levels and direct effects of thyroid hormones. Antithy‐

The reduction of serum PTH levels has been reported for the first time by Bouillon and DeMoor [257]. This observation confirmed by other clinical trials. Increased serum calcium levels inhibit

direct stimulation of bone resorption by prolonged treatment with T4 or T3 [244].

oidism is unrelated to the parathyroid hormone (PTH) levels [253,254].

roid treatment normalizes serum phosphorous concentration [253].

**c. Parathyroid hormone secretion in hyperthyroidism**

**b. Phosphorous homeostasis in hyperthyroidism**

resulting from thyroid disease [250].

**Histological changes in hyperthyroidism**

**Biochemical changes in hyperthyroidism a. Calcium homeostasis in hyperthyroidism**

**4.2. Changes in hyperthyroidism**

(Data adapted from reference 252).

#### **4.1. Mechanism**

Direct stimulation of thyroid hormones on bone resorption in organ cultures have been demonstrated [244]. This action may be mediated by a nuclear T3 receptor [245,246]. Thyroid hormones may also affect bone calcium metabolism by a direct action on osteoclasts [247].

Besides the hormones of calcium metabolism, locally produced factors are important in maintaining normal bone metabolism. Serum interleukin-6 (IL-6) concentration increases in hyperthyroid patients and stimulates osteoclast production. Therefore, IL-6 may be an effector of the action of PTH on bone [248]. Thyroid hormones may influence the IGF-I/IGFBP system in vivo in hyperthyroidism. The anabolic effects of increased levels of IGF-I may be limited in hyperthyroidism due to the increases of inhibitory IGFBPs that can counteract the anabolic effects and contribute to the observed net bone loss [249]. T3 activates fibroblast growth factor receptor-1 (FGFR1) in bone and this can be related with the pathogenesis of skeletal disorders resulting from thyroid disease [250].

#### **4.2. Changes in hyperthyroidism**

**4. Hyperthyroidism and bone**

86 Thyroid Disorders - Focus on Hyperthyroidism

of secondary osteoporosis [243].

**0 0**

(Data adapted from reference 252).

**4.1. Mechanism**

**50**

**Figure 3.** Trabecular Bone Remoelling Cycle in (a) Hyperthyroid and (b) Normal Subjects

**30**

**0**

**Wall thickness (µm)**

**30**

**60**

**(a)**

**(b)**

**60**

In 1891 Von Recklinghausen firstly described reduced bone mass in untreated hyperthyroid‐ ism. Thyroid hormones (3,3',5-triiodothyronine [T3] and 3,3',5,5'-tetra iodothyronine [T4]) act on normal bone growth, development and turnover in both children and adults [239,240]. Hyperthyroidism increases bone turnover, acting mainly on bone resorption, but also on osteoblast activity [241,242] [Figure-3]. As a result, hyperthyroidism is an important etiology

**0 200**

**50 100 250**

**Net loss of trabecular thickness**

**100 200 250**

**Days**

Direct stimulation of thyroid hormones on bone resorption in organ cultures have been demonstrated [244]. This action may be mediated by a nuclear T3 receptor [245,246]. Thyroid hormones may also affect bone calcium metabolism by a direct action on osteoclasts [247]. Besides the hormones of calcium metabolism, locally produced factors are important in maintaining normal bone metabolism. Serum interleukin-6 (IL-6) concentration increases in hyperthyroid patients and stimulates osteoclast production. Therefore, IL-6 may be an effector of the action of PTH on bone [248]. Thyroid hormones may influence the IGF-I/IGFBP system in vivo in hyperthyroidism. The anabolic effects of increased levels of IGF-I may be limited in

#### **Histological changes in hyperthyroidism**

Thyroid hormones increase the activation of new remodeling cycles. These effects include predominantly increased osteoclastic activity. Although; excess osteoblastic activity, osteoid deposition (osteomalacia) and rarefaction (osteoporosis) were also described. These changes were observed both in trabecular and cortical bone ([51]. In 1978 Mosekilde & Melsen dem‐ onstrated a unique histomorphometric pattern; with evidence of both increased osteoblast and osteoclast activity in hyperthyroidism. These changes have given rise to a net loss of bone volume and were evident in both cortical and trabecular bone. But cortical bone has been rather more influenced (Figure-4) [252]. An *in-vitro* organ culture of fetal rat bone, demonstrated a direct stimulation of bone resorption by prolonged treatment with T4 or T3 [244].

#### **Biochemical changes in hyperthyroidism**

#### **a. Calcium homeostasis in hyperthyroidism**

The majority of patients with hyperthyroidism have normal or near normal total serum calcium levels. However, ionized serum calcium levels are elevated in most of the patients. Changes in serum calcium levels correlate with serum T3 levels [253,254]. Generally hyper‐ calcemia in hyperthyroidism tends to be mild or asymptomatic. Severe (>15 mg/dl) and symptomatic hypercalcemia is rare [255]. Hypercalcemia usually resolves after attainment of euthyroid state by all therapeutic modalities, i.e. subtotal thyroid resection, antithyroid drugs and radioiodine therapy. Symptomatic hypercalcemia can be treated by rehydration, use of corticosteroids, calcitonin and phosphate therapy. Reduced renal tubular and intestinal calcium reabsorption leads to increased urinary and fecal calcium [241]. The hyperadrenergic state of hyperthyroidism contributes hypercalcemia [256]. These changes correlate positively with thyroid hormone levels and cortical osteoclastic activity. Hypercalcemia in hyperthyr‐ oidism is unrelated to the parathyroid hormone (PTH) levels [253,254].

#### **b. Phosphorous homeostasis in hyperthyroidism**

Most of the patients have increased serum phosphorous levels. But some studies have shown normal or low levels of serum phosphorous. Increased bone and tissue catabolisms which lead to excess input of phosphorous to the plasma, lower clearance and increased renal tubular reabsorption of phosphorous may lead to hyperphosphatemia in hyperthyroidism. These changes are related to suppressed PTH levels and direct effects of thyroid hormones. Antithy‐ roid treatment normalizes serum phosphorous concentration [253].

#### **c. Parathyroid hormone secretion in hyperthyroidism**

The reduction of serum PTH levels has been reported for the first time by Bouillon and DeMoor [257]. This observation confirmed by other clinical trials. Increased serum calcium levels inhibit PTH secretion, so there is an inverse relationship between serum PTH and calcium levels. Additionally, serum parathyroid hormone-related peptide (PTH-rP) levels increase in hyperthyroidism. In hyperthyroid patients, a significant elevation in PTH-rP levels was obtained when compared with healthy controls. After treatment, levels of PTH-rP declined. PTH-rP could be a factor in the pathogenesis of hypercalcemia in hyperthyroid patients [258].

associated with bone loss and may be a risk factor for the development of osteoporosis in premenopausal women [273]. It has been well established that hyperthyroidism leads to reduced BMD in female patients, but there is lack of acceptable data in male patients. Majima et al. evaluated BMD and bone metabolism in male patients with hyperthyroidism. The study demonstrated a high prevalence of cortical bone loss in male patients with hyperthyroidism,

Complications of Hyperthyroidism http://dx.doi.org/10.5772/58196 89

Also, endogenous subclinical hyperthyroidism can be a risk factor for osteoporosis. In several cross-sectional studies, BMD was decreased at multiple sites in pre-and post-menopausal women with endogenous subclinical hyperthyroidism [275-277]. This finding, however, was not confirmed in other cross-sectional observations in endogenous conditions [278]. Földes et al. demonstrated that numbers of pre-menopausal patients with endogenous sub-clinical hyperthyroidism BMD of the lumbar spine, femoral neck and the midshaft of the radius were not significantly decreased. But in post-menopausal women with long-lasting endogenous sub-clinical hyperthyroidism mean densitometric values were slightly, but significantly, lower [279]. Whether endogenous sub-clinical hyperthyroidism significantly affects bone metabo‐

Prolonged hyperthyroidism due to L-thyroxine(L-T4) treatment has been associated with reduced bone mass and thus with the potential risk of premature development of osteoporosis. The effects of L-T4 treatment have been evaluated in many clinical trials. In several studies, bone mineral density was decreased at multiple sites in pre-and post-menopausal women treated with L-T4 [280,281]. In a study by Giannini et al. post-menopausal thyroidectomized patients showed significantly lower bone mass than pre-menopausal patients. A negative correlation between time since menopause and bone mass were obtained in post-menopausal L-T4 treated patients [282]. There is lack of acceptable data about the effects of L-T4 treatment on bone metabolism in male patients. A mild deleterious effect of thyroid hormone excess in the axial bone mass from male subjects obtained. Male patients with chronic TSH suppression by L-T4 or history of hyperthyroidism should be assessed by BMD [283]. However, several recent studies have failed to show such a harmful effect of L-T4 treatment on BMD [284-286].

It should be noted that other risk factors may affect BMD in hyperthyroid patients. These include a relative deficiency of insulin-like growth factor type I, dehydroepiandrosterone sulfate [287], vitamin D receptor (VDR) polymorphisms [288] and estrogen [289]. The question as to whether prolonged hyperthyroidism due to L-T4 treatment increases the risk of fractures