Graves' Disease: Clinical Significance and Management

*Thenmozhi Paluchamy*

#### **Abstract**

Graves' Disease is an autoimmune disease characterized by hyperthyroidism due to circulating autoantibodies. Graves' Disease was originally known as "exophthalmic goiter" but is now named after Sir Robert Graves, an Irish doctor who first described the condition in 1835. A number of conditions can cause hyperthyroidism, but Graves' Disease is the most common, affecting around 1 in 200 people. It most often affects women under the age of 40, but it is also found in men. It affects an estimated 2–3 percent of the world's population. Thyroid-stimulating immunoglobulin (TSIs) binds to and activates thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicles to increase synthesis of thyroid hormone. The overproduction of thyroid hormones can have a variety of effects on the body causes exophthalmic goiter, Graves ophthalmopathy, Graves dermopathy etc.,. Thyroid profile including antithyroid antibodies, radioactive iodine uptake study, and thyroid scan are the main diagnostic investigations to rule out Graves' Disease. The major aim of the treatment is to inhibit the overproduction of thyroid hormones by targeting the thyroid gland, to reduce the symptoms, and prevention of complication is also major challenges.

**Keywords:** anti-thyroid drug, autoimmune thyroid disease, goiter, Graves' Disease, Graves ophthalmopathy, hyperthyroidism, thyroglobulin, thyroidectomy, thyrotropine receptor antibody, radioactive iodine

#### **1. Introduction**

Thyroid diseases are one of the most common endocrinopathies globally [1]. The thyroid gland is a small, butterfly-shaped endocrine gland located in the lower front of the neck synthesizes and secretes mainly two hormones i.e., T4 (Thyroxine) and T3 (Triiodothyronine) [2] into the blood and then carried to every tissues in the body. TSH stands for thyroid stimulating hormone, which is produced by the pituitary gland of the brain. This gland stimulates the thyroid to synthesize and release the thyroid hormones into the blood. Thyroid hormones act on almost all nucleated cells and are essential for normal growth and energy metabolism1. It also controls the body temperature, menstrual cycles, the functioning of the lungs, heart & muscle strength and ancillary vital organs [3]. When thyroid gland secretes either too much or too little of the thyroid hormones T4 and T3, it's called a thyroid disease. There are several different types of thyroid disease, including hyperthyroidism, hypothyroidism, thyroid cancer, thyroiditis, and autoimmune thyroid disease.

Graves' Disease is an autoimmune disorder that leads to overactivity of the entire thyroid gland due to circulating autoantibodies. The synonyms of Graves' Disease are Basedow disease, exophthalmic goiter, Graves' hyperthyroidism, Parry disease

and toxic diffuse goiter [4]. Graves' Disease is the commonest cause of hyperthyroidism. Graves' Disease was originally known as exophthalmic goiter but now it is named after Sir Robert Graves, an Irish physician, who described this form of hyperthyroidism in 1830s [5]. Autoimmune thyroid disease ranges from one end of Hashimoto's hypothyroidism (HH) to another end of Graves' hyperthyroidism (GH). Autoimmune diseases are characterized by the activity of autoreactive lymphocytes, which cause tissue or organ damage through the formation of antibodies that react against host tissues, or effector T cells, which are specific for endogenous self-peptides [6]. Thyroid peroxidase (TPO) and thyroglobulin (Tg) are the major autoantigens in Hashimoto's disease whereas in Graves' Disease TPO-Ab and Tg-Ab are also occur in 70% of patients with Graves' Disease [7], but The thyroid-stimulating hormone receptor (TSHR) is the major autoantigen in Graves' Disease. The antibody called thyrotropin receptor antibody (TRAb) and thyroid-stimulating immunoglobulins (TSIs) bind to and activate thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicles to increase synthesis of thyroid hormone.

Graves' Disease is not only affecting the thyroid and often affecting the skin and eyes named as Graves' dermopathy, Graves' orbitopathy and Graves' ophthalmopathy. The overproduction of thyroid hormones can have a variety of effects on the other body systems too. About 3 in every 4 people with an overactive thyroid gland have a condition called Graves' Disease [8]. Graves' Disease is considered to be an autoimmune disorder, but other causes may contribute to its development, including genetic, environmental, and/or other factors. Graves' Disease usually affects people between ages 30 and 50, but can occur at any age [9]. The disease is seven to eight times more common in women than men [10].

#### **2. Epidemiology**

Graves' Disease occurs in almost any part of the world. Graves' Disease is the most common causes of spontaneous thyrotoxicosis and it represents 60–90% of all causes of thyrotoxicosis in different regions of the world and it is estimated to affect 2–3 percent of the world's population [4]. Graves' Disease is the most common cause of hyperthyroidism in the United States. The incidence of Graves' Disease in Olmstead County was found to be 30 cases per 100,000 annually [11]. The overall prevalence of hyperthyroidism in the United States is 1.2% with an incidence of 20/100,000 to 50/100,000 in a study conducted in Olmstead County, Minnesota. The incidence of Graves' Disease was 24.8 cases per 100,000 with an adjusted female to male ratio of 3.9:1 [12, 13] but studies specifically on Graves' Disease are rare [14]. In Canada, Graves' Disease is the most common cause of hyperthyroidism affecting one in every 100 people. It appears to becoming even more common. In the Wickham Study in the United Kingdom, the incidence of Graves' Disease was reported to be 100–200 cases per 100,000 population per year which is significantly higher than previous estimates [15] and among women, it has been reported to be 80 cases 100,000 per year [16]. The age adjusted incidence of adult onset Graves' Disease in Sheffield, UK was 24.8 per 100,000 per year. It is more common in women than men and the most common in people with ages 20 to 50 years and the risk for Graves' Disease in women and men are 3% and 0.5%. The 12-year incidence of Graves' Disease among women with 25 to 42 years was as high as 4.6/1000 as per Nurses' Health Study II report. The ratio of 3.9:1 reported in this study is however in keeping with other studies in Iceland and Sweden that reported a gender ratio of 4:1 in hyperthyroidism in general [16]. In Sweden, the reported incidence of Graves' Disease (2003–2005) was 21.4 per 100,000 per year with a Female:Male ratio of 5.6:1 [17].

The prevalence of maternal thyrotoxicosis is approximately 1 case per 500 persons, with maternal Graves' Disease being the most common etiology [10]. Graves' Disease

*Graves' Disease: Clinical Significance and Management DOI: http://dx.doi.org/10.5772/intechopen.96418*

is observed with a rate of 0.1–0.4% in pregnant women [18]. Aside from the infrequent occurrence of postnatal thyrotoxicosis due to maternal antibodies, the incidence of spontaneous Graves' Disease in children before the age of ten is most unusual, but the incidence climbs with each decade until about age 60 [14–15, 19] . Pediatric Graves' Disease accounts for 10–15% of thyroid disorders in patients less than 18 years of age [20]. Graves' Disease is rare under the age of 5 years and has a peak incidence at 10–15 years of age [21]. The incidence of Graves' Disease is believed to be between 0.1 and 3 per 100,000 children [22] with a prevalence of 1 in 10,000 children in the United States [23]. A study found that out of 57 patients with the average age of the 32.8 years, male:female ratio of 1:3.3, 52 (91%) had subacute thyroiditis as the cause of thyrotoxicosis while Graves' Disease was seen in 9% [24]. The Graves' Disease affecting all countries and races equally across the world and it occurs eight times more common in women than men between 30 to 60 years of age group [14, 15].

#### **3. Causes**

Graves' Disease is caused by a malfunction in the body's disease-fighting immune system. The immune system usually produces antibodies against the target specific antigens such as bacteria, virus, or other foreign substance. In Graves' Disease, the immune system produces an antibody against the own cell of the thyroid gland. Normally, thyroid gland function is regulated by a hormone thyroidreleasing hormone (TRH) which is secreted from the posterior lobe of the pituitary gland. The immune system produces antibodies called thyrotropin receptor antibody (TRAb) that trigger the TSH receptor, tricking and dominance over the normal function of the thyroid gland and also causing an oversecretion of thyroid hormones. However the exact cause for Graves' Disease is not well understood. Despite there are risk factors like a combination of genetic and environmental factors which triggered the immune system against the thyroid.

#### **4. Risk factors**

**Genetic Environmental Agents** • Genetic background: family history of thyroid disease • Race • Age • Gender: Women • Other autoimmune disorders ○ Type 1 diabetes ○ Rheumatoid arthritis ○ Pernicious anemia ○ Lupus erthymatosus ○ Addison's disease ○ Vitiligo ○ Crohn's disease • Infectious agents • Dietary Iodine • Dietary Selenium • Pregnancy and the Postpartum Period • Medication: (amiodarone, • interferon-a (IFN-a), and CD52 MABs) • Smoking • Stress • Radiation Exposure • Toxicants

Although anyone can develop Graves' Disease, many factors (**Table 1**) can increase the risk of disease, including:

#### **4.1 Heredity/genetics**

Family history of Graves' Disease is a known risk factor; there is likely a gene or genes that can make a person more susceptible to the disorder. 70%–80% of susceptibility to autoimmune thyroid disease is based on genetics; individuals with a personal history of autoimmune disease or family history of autoimmune thyroid disease are the most susceptible. The specific genes involved include human leukocyte antigen-DR3, cytotoxic T lymphocyte-associated factor 4, CD40, protein tyrosine phosphotase-22 gene, thyroglobulin (Tg), and TSH receptor [25]. Graves' Disease include genes encoding thyroglobulin, thyrotropin receptor, HLA-DRβ-Arg74, the protein tyrosine phosphatase nonreceptor type 22 (PTPN22), and proteins involved in T cell signaling [26–28]. HLA-DRB1 and HLA-DQB1 also appear to be associated with Graves' Disease susceptibility. Cytotoxic T lymphocyteassociated molecule-4 (CTLA4) is a major thyroid autoantibody susceptibility gene, [29, 30] and it is a negative regulator of T-cell activation and may play an important role in the pathogenesis of Graves' Disease. Heredity increases genetic susceptibility to environmental triggers.

#### *4.1.1 Race*

The loci associated with autoimmune thyroid diseases are AITD1, CTLA4, GD1, GD2, GD3, HT1, and HT2 among white race and also different loci have been linked in persons of other races. The more susceptible to occur autoimmune thyroid disease is influenced by gene in human leukocyte antigen region on chromosome 6 and in *CTLA4* on band 2q33. It is associated with specific HLA haplotypes and vary with ethnicity [10].

#### *4.1.2 Gender*

Women are much more likely to develop Graves' Disease than are men. Women develop it seven to eight times more frequently than men [10] and are due to the production of special proteins (called antibodies) that attack the thyroid gland. The ratio of developing Graves' hyperthyroidism between women and men is 7:1 and is often mediated with either more estrogen or less testosterone and also observed that moderate amounts of estrogen enhance immunologic reactivity [31–33]. However, the X-chromosome is the source of the increased susceptibility rather than sex steroid since the susceptibility continues after the menopause and X-chromosome inactivation has been linked with autoimmune thyroid disease [34].

#### *4.1.3 Age*

Typically, Graves' Disease is a disease of young women, but it may occur in persons of any age. Graves' Disease is usually occur in people between ages 30 and 50 years but can occur at any age. The typical age range is 20–40 years and the most affected women are aged 30–60 years [35].

#### *4.1.4 Other autoimmune disorders*

People with other autoimmune disorders are more likely to develop Graves' Disease than people without these disorders such as type 1 diabetes, rheumatoid arthritis, pernicious anemia, lupus erthymatosus, addison's disease, vitiligo, or crohn's disease.

#### **4.2 Environmental agents**

The remaining 20%–30% contribution to the onset of autoimmune thyroid disease is thought to be due to environmental exposures or triggers. Interfere with thyroid function at multiple sites, including thyroid hormone synthesis, thyroid hormone metabolism and excretion, and thyroid hormone action [36–39]. Most of these agents may influence the pituitary and thyrotropin (TSH) secretion, or even be partial thyroid hormone receptor agonists. There are a number of exposures that have been identified and proposed, both from human and animal studies (11–14) [40–43]. These include infections, life stress, iodine intake, smoking, medications such as amiodarone and interferon, radiation, and environmental toxicants. The environmental parameters commonly reported as contributing factors are infectious agents, iodine, drugs (amiodarone, Interferon-a (IFN-a), and CD52 MABs), tobacco, and stress [44].

#### *4.2.1 Infection*

Autoimmune thyroiditis can be induced in experimental animals by certain viral infections. Graves' Disease has been associated with a variety of infectious agents such as Yersinia enterocolitica and Borrelia burgdorferi. Homologies have been shown between proteins of these organisms and thyroid autoantigens [45, 46]. Thyroid autoimmune disease is associated with infections in the thyroid gland itself such as subacute thyroiditis, congenital rubella etc., and could initiate class II molecule expression. When Hepatitis C infection is treated with interferon therapy is a well-recognized precipitator of autoimmune thyroid disease, although less commonly a Graves' Disease develops rather than thyroiditis [47].

#### *4.2.2 Stress*

Both physical and emotional stressful life events and illness may act as a trigger for the onset of Graves' Disease among people who have genes that increase their risk. A review of the literature including seven case–control studies has highlighted the preexistence of a 'negative' stressful event in patients with Graves' Disease [48–55]. In general, stress suppresses the immune function, possibly mediated by the actions of cortisol on immune cells. Stress-induced suppression may be followed by rebound immunologic hyperactivity which could precipitate autoimmune thyroid disease in genetically susceptible individuals. The major T helper cells involved in Graves' Disease is Th2 and more recently found that Th17 is favor for the production of the pathogenic antibody directed against the TSH receptor by B lymphocytes both in mice and humans. Stress hormones direct stimulate the Th2, and Th17 or Th1 and also induce IL4, IL6, and IL12 by dentritic cells. Stress causes immature DCs which induce apoptosis in Treg cells leads not to act like regulators of Th2 and Th17 effector cells. It has been found that patients with untreated Graves' Disease have low in Treg cells which is inversely correlated with serum concentration of TSH receptor antibodies [56].

#### *4.2.3 Pregnancy and the postpartum period*

Pregnancy or recent childbirth may increase the risk of the disorder, particularly among women who have genes that increase their risk. The immune suppression is associated with the onset of autoimmune diseases especially postpartum thyroiditis. Fetal microchimerism, fetal cells in maternal tissue has maternal immune response is recognized as a trigger for thyroid autoimmunity and development of postpartum autoimmune thyroid disease [57]. During pregnancy severe Graves' Disease is

uncommon because hyperthyroidism is associated with increased pregnancy loss pregnancy loss and reduced fertility. Even if pregnancy occurs it can cause complication to mother as well fetus. Both B-cell and T-cell functions are declined during pregnancy, while Tregs increase dampening the disease [44, 58]. After delivery, the slow rebound from immunosuppression results in immune reactivity which contributes to the occurrence of postpartum thyroid disease, including recurrence or the new onset of Graves' Disease [59]. Around 30 percent of young women have a history of pregnancy in the 12 months before the onset of Graves' Disease [60], which shows that postpartum Graves' Disease is a surprisingly common condition and that pregnancy is a major risk factor for susceptible women.

#### *4.2.4 Smoking*

Cigarette smoke contains cyanide, which is metabolized to thiocyante, and can interfere with iodine concentration in the thyroid [37]. Cigarette Smoking has been associated with an increased production of T3 and thyroglobulin [61, 62], affect the thyroid hormone action [63], enhanced sympathetic nervous activity, or by affecting thyroid-directed autoimmune responses [49, 62, 64–66]. Cigarette smoking causes complex interactions with the immune system which may increase cytokines in orbit and thyroid causes Graves' Disease and also smokers who have Graves' Disease exacerbating risk of developing Graves' ophthalmopathy [41, 67–68].

#### *4.2.5 Dietary iodine*

Iodine is essential for thyroid hormone production, although a number of regulatory factors allow a normal amount of thyroid hormone to be produced across a fairly wide range of iodine intake. Deficient iodine intake is well known to be associated with reduced thyroid hormone production. Excess iodine, however, can also have adverse effects depending on underlying thyroid function, as well as the extent and duration of iodine excess [69]. Patients with multinodular goiter and associated areas of autonomous, TSH-independent, thyroid hormone production can have excess thyroid hormone production in response to iodine, the Jod–Basedow effect. Increased immunogenicity of thyroglobulin, thyroid cell destruction, In response to iodine supplementation in areas of iodine deficiency, there is an increase in thyroid autoantibodies and in some cases autoimmune thyroid disease [42, 43, 70, 71]. The mechanism of stimulation of autoimmune thyroid disease in response to iodine supplementation is not established. Excess iodine intake is associated with highly iodinated Tg, which is thought to be more immunogenic than poorly iodinated Tg [42, 70].

#### *4.2.6 Dietary selenium*

Selenium interacts with immune response. Low selenium intake has been associated with an increase in thyroid autoantibodies, and selenium supplementation with a reduction in antibodies [41].

#### *4.2.7 Medications*

Medications associated with the onset of autoimmune thyroid disease include lithium, amiodarone, interferon α, interleukin 2, campath-1 h, and highly active anti-retroviral therapy [42]. Some medications, such as lithium, may not trigger

autoimmunity, but accelerate the autoimmune process by interfering with thyroid function. It may stimulate the immune response at multiple sites. Medications differ in their mechanisms of stimulating thyroid autoimmunity, as well as the relative effect on promoting hypothyroidism or Graves' Disease [41].

#### *4.2.8 Radiation Exposure*

Radiation exposure especially medical radiation is one of the environmental exposures linked to effects on the thyroid which stimulate thyroid autoantibodies, increases thyroid antigens, inflammation. Autoimmune thyroid disease has been linked to therapeutic medical radiation [72–74]. Patients receiving 131I for thyroid disorder develop Graves' Disease later in their life and, sometimes, it can lead Graves' ophthalmopathy [73]. Radiation therapy with 131I causes low level thyroid autoantibody positivity in a sensitive TSH receptor antibody measurement which was associated with the development of Graves' Disease [73].

#### *4.2.9 Toxicants*

The main sources of toxicants are industrial chemicals, pesticides and herbicides, toxins in consumer goods, and heavy metals which may impair the thyroid function by recruiting antibodies to attack the thyroid. Most municipal water sources are now closely monitored for a range of toxicants, including those that affect the thyroid and well water also to be tested regularly for contaminants [75, 76].

#### **5. Pathophysiology**

Hypothalamic–pituitary-thyroid axis feedback mechanism is controlled the secretion of thyroid hormone by involving the interaction of stimulatory and inhibitory factors. Hypothalamus secretes Thyrotropin-releasing hormone (TRH) which stimulates the anterior lobe of pituitary gland to release Thyroid Stimulating Hormone (TSH). TSH binds with receptors on the thyroid gland leads to the release of thyroid hormones primarily T4 and to a lesser extent T3. Elevated levels of these hormones act on the hypothalamus to decrease TRH secretion and thus the synthesis of TSH and vice versa. Iodine requires for the synthesis of thyroid hormone. Dietary inorganic iodide is carried to the thyroid gland by iodide transporter. In the presence of thyroid peroxidase enzyme inorganic iodide is converted to iodine and bound to thyroglobulin through a process called organification. This causes the formation of Monoiodotyrosine (MIT) and Diiodotyrosine (DIT) and coupled to form triiodothyronine (T3) and thyroxine (T4) and then stored in the thyroid's follicular lumen with thyroglobulin. These preformed hormones which diffuse into the peripheral circulation form thyroid gland. In the peripheral circulation more than 99.9% of T4 and T3 are in inactive form. However, free T3 is 20–100 times more biologically active than free T4. Free T3 acts by binding to DNA-binding proteins in cell nuclei which regulate the transcription of various cellular proteins [77]. Any causes that alter the process leads to an increase in the peripheral circulation of unbound thyroid hormone can cause hyperthyroidism.

Thyroid Stimulating Hormone – Receptor (TSH-R) is a G-protein coupled receptor with seven transmembrane-spanning domains which primarily seen thyroid gland. It is also present in adipocytes, fibroblasts, bone cells and a variety of additional sites [78, 79]. TSHR regulates thyroid growth and thyroid hormone production and secretion and TSH also acting via TSHR. Hyperthyroidism in Graves' Disease manifested by the production of autoantibodies against the TSHR. These autoantibodies mimic the effects of the hormone on thyroid cells thereby stimulating autonomous production of T3 and T4. The derangement of immune function also lead to the production of pathologic autoantibodies complex by involving B and T cells which enhance the several autoantigens in addition to TSH-R. In Graves' Disease, B and T lymphocyte-mediated autoimmunity are known to be directed at 4 well-known thyroid antigens: thyroglobulin (Tg), thyroid peroxidase (TPO), sodium-iodide symporter and the thyrotropin receptor. Thyroid stimulating immunoglobulin binds with thyroid-stimulating hormone (TSH) receptor on the thyroid cell membrane and stimulates the action of the thyroid-stimulating hormone. It stimulates both, thyroid hormone synthesis and thyroid gland growth, causing hyperthyroidism and thyromegaly [3] The stimulating activity of thyrotropin receptor antibodies is found in the immunoglobulin G. Circulating autoantibodies against the thyrotropin receptor continuously stimulate the thyroid gland to increase the secretion of thyroid hormone and thyroglobulin that is mediated by 3,'5′-cyclic adenosine monophosphate which suppresses the secretion of pituitary thyrotropin. These autoanitbodies also stimulate iodine uptake, protein synthesis, and thyroid gland growth [80].

Intrathyroidal lymphocytic infiltration observed in initial histologic examination in autoimmune thyroid disease and can be correlated with thyroid antibodies titer. The thyroid cells express molecules due to being the source of autoantigens that mediate T cell adhesion and complement regulation such as Fas and cytokines which interact the immune system and also the proportion of CD4 lymphocytes is lower in the thyroid than in the peripheral blood. Besides being the source of autoantigens, the thyroid cells express molecules that mediate T cell adhesion and complement regulation (Fas and cytokines) that participate and interact with the immune system. In these patients, the proportion of CD4 lymphocytes is lower in the thyroid than in the peripheral blood. The increased Fas expression in intrathyroidal CD4 T lymphocytes causes CD4 lymphocyte reduction. The autoimmune thyroid disease susceptibility genes are CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 [25, 81] which specific either Graves' Disease or Hashimoto thyroiditis. The two new susceptibility loci are RNASET2-FGFR1OP-CCR6 region at 6q27 and an intergenic region at 4p14 [82]. Positive Graves' Disease is strongly associated with thyroidstimulating hormone receptor and major histocompatibility complex variants with persistently thyroid stimulating hormone receptor autoantibodies. [83]

#### **5.1 Graves' thyroid gland**

The thyroid gland is diffusely enlarged but not always. The pathological change of the thyroid gland is follicular hyperplasia, intracellular colloid droplets, cell scalloping, a reduction in follicular colloid, and a patchy (multifocal) lymphocytic infiltration. The majority of intrathyroidal lymphocytes are T cells but plenty of B cells may be present. In some areas, thyroid epithelial cell size correlates with the intensity of the lymphocytic infiltrate, suggesting thyroid-cell stimulation by local B cells secreting stimulating TSHR-Ab [84].

#### **5.2 Autoantibodies of thyroid**

Thyroid autoantibodies, including TSHR-Abs secretes spontaneously from lymphocytes of Graves' thyroid tissue in activated state [85]. It may also secretes activated autoantibodies when decline in serum thyroid autoantibody concentrations after antithyroid drug treatment, after thyroidectomy, and late after radioactive iodine therapy.
