Graves’ disease is an autoimmune disorder in which hyperthyroidism (over active thyroid) is caused by the autoantibodies against the TSH receptor. It is mainly characterized by the appearance of goiter. The symptoms are wide ranging as thyroid hormone affects many body systems. It is common in women and in people with age below than 40. Graves’ disease is caused by a combination of genetic and environmental factors while genetics being the main cause. Graves’ disease is not a single gene defect but has a complex pattern of inheritance. Today it is clear that genetic predisposition to Graves’ disease is caused by multiple genes. HLA gene is one the most studied gene predisposing to Graves’ disease. Lot of polymorphisms in this gene has been to be associated with the disease. Lymphoid tyrosine phosphatase encoded by the gene PTPN22 has been found to increase the risk of many autoimmune diseases including Graves’ disease. The best documented association of PTPN22 variants to autoimmune disorders including GD is rs2476601 (C1858T). Other genes associated with the risk of GD are thyrotropin receptor (TSHR), thyroglobulin gene, FCRL3, SCGB3A2, and CTLA4. This chapter will discuss in detail the genetics, pathophysiology, diagnosis and treatment of Graves’ hyperthyroidism.
- graves’ disease
- HLA region
Graves’ Disease (GD) was named after
GD with an annual incidence of 20 to 50 cases per 100,000 persons is the most common cause of hyperthyroidism . The incidence of GD peaks between 30 to 50 years of age, but people can be affected at any age. The lifetime risk for women is 3% and for men it is 0.5%. The risk of GD is not influenced by Long-term variations in iodine intake, but rapid repletion can transiently increase the incidence. The GD–associated incidence of ophthalmopathy is 16 cases per 100,000 in women and in men it is 3 cases per 100,000 annually. It is more common in whites than in Asians . Older men develop severe ophthalmopathy more likely than younger persons . Subtle abnormalities are revealed in 70% of patients by orbital imaging with GD . In up to 50% of patients in specialized centres, clinically consequential ophthalmopathy is detected with GD, and as a consequence of corneal breakdown or optic neuropathy in 3 to 5% of such patients, sight is threatned . The thyroid levels remain normal or autoimmune hypothyroidism develops either in 10% of the persons with ophthalmopathy [10, 11, 12]. In the
3. Pathophysiology of Graves’ Disease
In GD, four standard thyroid antigens: thyroglobulin, thyroid peroxidase, sodium-iodide symporter and the thyrotropin receptor are recognized to direct B and T lymphocyte-mediated autoimmunity. However, the primary auto antigen of GD is the thyrotropin receptor itself and is responsible for the manifestation of hyperthyroidism. In this disease, the antibody and cell-mediated thyroid antigen-specific immune responses are properly defined. The development of hyperthyroidism in healthy subjects by transferring thyrotropin receptor antibodies in serum from patients with GD and the passive transfer of thyrotropin receptor antibodies to the foetus in pregnant women are the direct proof of an autoimmune disorder that is mediated by means of autoantibodies. By circulating autoantibodies against the thyrotropin receptor, the thyroid gland is under continuous stimulation, and because of the increased production of thyroid hormones pituitary thyrotropin secretion is suppressed . In the immunoglobulin G1 subclass, the stimulating activity of thyrotropin receptor antibodies is found mostly. The release of thyroid hormone and thyroglobulin that is mediated via 3,'5′-cyclic adenosine monophosphate (cyclic AMP) are caused by these thyroid-stimulating antibodies, and they also stimulate iodine uptake, protein synthesis, and thyroid gland growth. In the etiology of hyperthyroidism in GD the anti-thyroglobulin, anti-sodium-iodide symporter, and anti-thyroid peroxidase antibodies seem to have a very little role. However, against the thyroid, these are markers of autoimmune disease. In persons with autoimmune thyroid disease, intrathyroidal lymphocytic infiltration is the initial histologic abnormality which has a direct correlation with thyroid antibodies’ titer [17, 18]. In addition to autoantigens, the cells of thyroid produce specific immune mediators such as cytokines and Fas which are involved in various immune process including complement legislation and T cell adhesion. Those individuals who are suffering from Graves’ Disease have lesser percentage of CD4 lymphocytes in thyroid as compared to their peripheral blood. In addition, the CD4 reduction in these patients may also be related to the elevated Fas expression in intrathyroidal CD4 T lymphocytes.
4. Genetics of Graves’ Disease
GD is a complex autoimmune disorder which affects the functioning of the thyroid gland, which is the butterfly shaped gland in the lower neck. Specific antibodies targetting the thyrotropin receptor are found in about 95% of patients with GD. GD is thought to result from a combination of environmental and genetic factors most of which are unknown. A number of genes predispose to the GD which include
4.1 HLA region
Human leukocyte antigen (HLA) region (6p21) within the human genome codes for 252 expressed loci including numerous key immune response genes is the most gene dense region . This region contains the highest degree of polymorphism within the genome and is divided into different classes which includes the extended class I, classical class I, classical class III, classical class II and extended class II  (Figure 3). The densest linkage disequilibrium (LD) is also shown by this gene, extending up to 540 kb , which compares with distances of between 1 and 173 kb seen in the rest of the genome . When trying to tease out the exact site of etiological variants, the degree of LD within the region is challenging. Most studies highlights the importance on the role of HLA class II encoded HLA-DR and –DQ molecules, which present exogenous antigens for recognition by CD4+ T helper (Th) cells. Including GD, strong associations of
4.2 Protein tyrosine phosphatase-22 (PTPN22)
Protein tyrosine phosphatase, non-receptor type 22 (lymphoid) is also known as PTPN22. This in humans is encoded by the
4.3 Cluster of differentiation 40 (CD40)
The Cluster of Differentiation (CD) are cell surface proteins with each of them assigned a specific number thereby allowing cell phenotypes to be recognized. Surface expression of a particular CD molecule is functional for the characterization of cell phenotypes. These molecules can act either as receptors or ligands. Some CD proteins though do not play role in cell signaling, but do have other functions, such as cell adhesion. CD for humans is numbered upto 371 with their specific functions. CD40 is a costimulatory protein found on the antigen- presenting cells and results in their activation. The binding of CD154 (CD40L) on helper T cells to CD40 activates antigen presenting cells and induces a variety of downstream effects. Deficiency can lead to Hyper-IgM syndrome type3. It is located on chromosome 20 in humans and chromosome 2 in mouse. Disruption of the CD40- CD40L co-stimulatory pathway has been found in many autoimmune diseases, including GD. on the basis of a genome-wide linkage study in GD,
4.4 The cytotoxic T lymphocyte-associated factor 4 (CTLA4 Or CD152)
It is a protein receptor that functions as an immune checkpoint and downregulates immune responses. It is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation; a phenomenon which is particularly notable in cancers . It is homologous to the T-cell co-stimulatory protein, CD28, and both molecules bind to CD80 and CD86, also called B7-1 and B7-2 respectively, on antigen-presenting cells. CTL4-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands. CTLA4 transfers an inhibitory signal to T cells,  whereas CD28 transmits a stimulatory signal . CTLA4 is also found in regulatory T cells and thereby contributing to their inhibitory function. CTLA4 consists of four exons encoding different functional domains such as a leader sequence and extracellular, transmembrane as well as cytoplasmic domains. The most reliable associations with GD within
4.5 The thyrotropin receptor (TSHR)
The thyrotropin receptor (TSHR) responding to thyrotropin (thyroid-stimulating hormone, TSH) is a Gs-protein coupled receptor and stimulates the production of thyroxin (T4) and triiodothyronine (T3). It is primarily found on the surface of the thyroid epithelial cells , but also found on adipose tissue and fibroblasts. A G protein signal cascade is activated upon the binding of circulating ligand TSH which activates adenylyl cyclase that synthesizes cAMP from ATP and subsequently resulting in increased intracellular levels of cAMP. cAMP functions as a secondary messenger and activates all functional aspects of the thyroid cells which include thyroglobulin synthesis, iodine pumping, endocytosis, iodination, proteolysis, thyroid peroxidase activity and hormone release.
4.6 FCRL3 (FC receptor-like-3)
Fc receptor-like protein 3 is a protein that in humans is encoded by
4.7 Secretoglobin 3A2 (SCGB3A2) gene
This gene is present on chromosome 5 in humans and chromosome 18 in mouse. It is a homodimeric protein thought to play a role in the modulation of inflammation and tumorigenesis. SCGB3A2 is a member of secretoglobin superfamily, a family of small, secreted proteins found in animals exclusively of mammalian lineage.
There are other genes which have strong association with GD such as cytokine genes:
5. Diagnosis of Graves’ Disease
The diagnosis to confirm the cause of Graves’ hyperthyroidism is based on the clinical and biochemical manifestations of hyperthyroidism and on the clinical and laboratory features. For the presence of hyperthyroidism, measurement of serum thyrotropin is a useful screening test, because the secretion of thyrotropin is reduced by very small increase in thyroid secretion, so by the measurement of serum free thyroxine the diagnosis of hyperthyroidism must be confirmed . Patients may have only increased secretion of triiodothyronine in the earliest stage of Graves’ hyperthyroidism; therefore, patients with normal serum free thyroxine concentrations and low serum thyrotropin concentrations, serum free triiodothyronine should be measured. Because of the use of certain drugs and increase in thyroid hormone–binding proteins, measurements of serum total thyroxine and triiodothyronine are less reliable as it can cause high values . In patients with hyperthyroidism and a diffuse goiter, the signs of ophthalmopathy or dermopathy are sufficient to confirm the diagnosis of GD. In patients with GD, other autoimmune disorders occur more frequently (Type 1 diabetes mellitus, Addison’s disease, Vitiligo, Pernicious anemia Alopecia areata, Myasthenia gravis, Celiac disease) and their presence therefore supports this diagnosis. Occasionally, in patients with pre-existing nodular goiter, GD occurs which causes confusion. The presence of a high serum concentration of thyroid peroxidase antibody which is present in about 75 percent of patients with Graves’ hyperthyroidism, or a thyroid radionuclide scan demonstrating a diffuse goiter provides evidence of GD, when the diagnosis is unclear clinically. Occasionally, to distinguish between Graves’ hyperthyroidism and thyrotoxicosis caused by painless, destructive (autoimmune) thyroiditis, thyroid radionuclide studies may be indicated especially in women post-partum. Patients may have a small diffuse goiter with painless thyroiditis, like those with GD. However, it is very unlikely that thyrotoxicosis due to painless thyroiditis will last longer than two months .
5.1 Measurement of thyrotropin-receptor antibodies in serum
It is largely a matter of individual preference, whether serum thyrotropin-receptor antibodies should be measured in the differential diagnosis of GD, some argue that a test for the antibodies should be done routinely, and others that a diagnosis of GD can nearly always be inferred correctly on the basis of the clinical findings. The immunoglobulin-mediated inhibition of the binding of radiolabeled thyrotropin to thyrotropin receptors is most widely used assay for thyrotropin-receptor antibodies and is positive approximately in 80% of individuals suffering for Graves’ hyperthyroidism . Up to 99% sensitivity is shown by newer assays. Even though a positive result might specify the occurrence of either thyroid- stimulating antibodies or thyrotropin-receptor– blocking antibodies, it is rational to conclude that a positive test in the individual suffering from hyperthyroidism is owing to thyrotropin-receptor–stimulating antibodies. With time as the mechanism of the interactions of antibodies with the thyrotropin receptor improves, it would be possible to develop simple, precise immunoassays for thyroid-stimulating antibodies for routine use. The antibodies identified by bioassays that measure the synthesis of cAMP in retort to the stimulation of thyrotropin receptors are only thyroid-stimulating antibodies — for instance, in cells transfected with thyrotropin receptor— but such assays are relatively expensive and not widely available .
5.2 Computed tomography (CT) or magnetic resonance imaging (MRI)
CT and/or MRI of the orbits is indicated if there is any uncertainty about the cause of ophthalmopathy, particularly in a patient with unilateral exophthalmos, to rule out a retrobulbar tumor or arteriovenous malformation. Approaches used in assessing the activity of ophthalmopathy are very helpful in determining which individuals will be benefitted from immunosuppressive treatment. Measurement of the relaxation time for extraocular muscles on T2-weighted MRI, Clinical activity scores (CAS), and orbital scanning with indium In 111 pentetreotide  have all been suggested for this purpose but have not been fully assessed. These above tests are not needed for the majority of individuals, who have only mild or moderate Graves’ ophthalmopathy .
6. Therapy for Graves’ Disease
According to age, severity of hyperthyroidism, goiter size, presence and degree of ophthalmopathy, as well as patient’s personal preference, GD treatment should be tailored in each individual patient. Medical treatment with anti-thyroid medicine (thionamides) is usually suggested in all patients to revive euthyroidism at first. Once euthyroidism is achieved, the long strategy comprises many choices, including relatively long-term (usually twelve to twenty four months) course of anti-thyroid drugs, radioactive iodine or surgery. Beta-blockers, if not inadvisable are time and again used prior to restoration of euthyroidism to reduce the symptoms of thyrotoxicosis. The thyroid hormone formation is blocked by specific thionamides or antithyroid drugs (propylthiouracil and methimazole). These drugs prevent the thyroid hormone production by inhibiting iodine organification and coupling of iodotyrosines. Treatment of this disease with these drugs is usually well tolerated. Some of the side effects like skin rash and, hardly Granulopenia, Hepatits and Arteritis may occur. Methimazole is currently most well liked over propylthiouracil, owing to the proof of a lower prevalence of severe side-effects, particularly hepatitis , with the exception of the first trimester of pregnancy, when propylthiouracil is preferred due to the increased rate of congenitalmal formations, especially aplasia cutis, which has been reported with the utilization of methimazole . Due to the high probability of recurrence of hyperthyroidism after the withdrawal of therapy, this method is not suggested to individuals having large goiters. Contrary, in individuals with thyroid eye disease (ophthalmopathy), we tend to like a surgical removal of all or part of the thyroid gland (thyroidectomy), radioiodine ablation, or both owing to the pathogenetic role of cross-reactive antigens between the thyroid and orbital tissues . In some centers, the methimazole is used at higher doses than desirable amounts needed to correct hyperthyroidism in coalition with thyroid hormone for block and replacement treatment. This tactic relies on plausible immunosuppressive methimazole action, which still has not been incontestable in studies related to humans . Radioiodine is ideally administered after the accomplishment of euthyroidism with the help of anti-thyroid drugs. Hypothyroidism is induced to attain a stable remission of GD, this is the goal of the treatment. To calculate the appropriate radioactive iodine dose to be given, 24 hour radioactive iodine uptake is usually performed before treatment and used together with gland volume. However, a fixed radioiodine dose may also be given without interfering with the outcome . Radioiodine treatment, when using appropriate dose, within 1 to 6 months in the majority of patients (about 80%), it leads to hypothyroidism. Those Patients having large goiter the radioiodine therapy should not be used as it has low success rate unless repeated treatments are planned. It has been seen that radioiodine has acute side effects which are mild, well tolerated and generally self-limiting. Radioactive therapy for the treatment of hyperthyroidism sometimes causes a transitory pain and swelling of the neck and subsequently requires a treatment with oral glucocorticoids. During this process, for a short period of time the symptoms of thyrotoxicosis may exacerbate due to the release of preformed thyroid hormones. After radioiodine treatment, a transient worsening or more rarely, the fresh appearance of thyroid eye disease may occur, but it can be easily prevented by the administration of oral prednisone after radioiodine for 8–12 weeks. After radioiodine therapy in adults with Graves, there is no evidence of an increased risk of thyroid cancer and other solid tumors as well as of leukemia . No major studies are available in children unfortunately. So, radioiodine treatment is not recommended before the age of 18–20 years. With the exception of a transitory decrease in testosterone levels in men, no effects on the reproductive system in male and female have been described . A patient with a large goiter has been indicated by Thyroidectomy. The surgical procedures most commonly recommended in patients with GD are near total thyroidectomy (NT) or total thyroidectomy (TT), consisting in the removal of most or all visible thyroid tissue, respectively. Both procedures result in hypothyroidism. Recurrence of hyperthyroidism is extremely rare. The rate of post-operative complications (e.g. surgical hypoparathyroidism, laryngeal nerve paralysis) is not increased compared with that observed using other less aggressive surgical procedures . Briefly, the treatment of choice depends on the seriousness and activity of GD. In individuals with moderately severe thyroid eye disease, the usage of intravenous glucocorticoids is the first-line treatment and if this intravenous glucocorticoids treatment fails, orbital decompression is performed . And this rehabilitative surgery (orbital decompression, muscle or eyelid surgery) must be considered when the eye disease is inactive. No major treatments are required for the majority of patients having a mild ophthalmopathy, and patients are given local measurement (e.g. eye lubricants, sun glasses) or, based on a recent study, selenium .
Since the incidence of Graves’ Disease is increasing at pace and already told in the above chapter that it has an unpropitious effects on the quality of life as it causes weight loss, fatigue irritability, goiter (swelling in the thyroid gland) and much more. It also affects skin and eyes the conditions called Graves’ dermopathy and Graves’ ophthalmopathy respectively. As explained earlier this disease is thought to result from a combination of environmental and genetic factors most of which are unknown. So it is necessary to understand those factors, which will help us in the better management of this disease in future.