*2.3.1. Genetic factors for Graves' disease*

High prevalence of Graves' disease in family members and relatives of Graves' disease and Hashimoto's thyroiditis support that genetic factors are involved in causation of Graves' disease. There is also evidence that occurrence rate of Graves' disease is higher in monozygotic twins than dizygotic twins. The concordance rate in monozygotic twins is only 17-35% which indicate low penentrance of genes.

Graves' disease is a polygenic disease. Polymorphism in HLA-DR, CTLA-4 and PTPN-22 genes are associated with increased risk of Graves' disease. HLA-DR3 (HLA-DRB1\*03), HLA-DQA1\*0501 and HLA-B8 gives a risk ratio of three fold to fourfold in white population. HLA-DQ3 is involved in patients with African descent whereas HLA-BW46 is involved in patients with Asian descent. The other genes involved in pathogenesis of Graves' disease are CD40 gene, thyroglobulin gene, TSHR gene, immunoglobulin genes, GD-1 gene (on chromosome 14q13), GD-2 gene (on chromosome 20) and GD-3 gene (on chromosome Xq21-22).

### *2.3.2. Environmental Factors for Graves' disease*

#### *Infection*

From very early it has been suggested that Graves' disease is associated with infectious agents, but this hypothesis has not been confirmed. Incidence of recent viral infections are high in patients with Graves' disease. The association of Graves' disease with infectious

agents can be explained by molecular mimicry. Molecular mimicry implies structural similarity between infectious agent with a self antigen. Circulating antibody against Yersinia enterocolitica has been found in high percentage of patients with Graves' disease. Furthermore, serum from some patients recovering from Yersinia infections block the binding of TSH to its receptor. Low affinity binding sites for TSH have also been found with Leishmania and Mycoplasma species. However, no studies proved that infections agents have causative role in Graves' disease.

Thyroid Hormone Excess: Graves' Disease 163

Direct trauma to the thyroid gland, ethanol injection for the treatment of autonomously functioning thyroid nodules, or thyroid injury following radio-iodine treatment for toxic adenoma or toxic multinodular goiter are associated with an increased risk of Graves' disease. Radio-iodine treatment may also cause onset or worsening of ophthalmopathy. Possible explanation is that thyroid injury by any means cause massive release of thyroid antigens, which in turn stimulate an autoimmune reaction to TSHR in susceptible

Graves' disease onset and recurrence is also associated with iodine and iodine containing drugs like amiodarone and radio-contrast media especially in iodine deficient population.

Graves' disease is an example of organ specific autoimmune disorder in which both humoral and cell mediated immunity directed against different thyroid antigens are involved. TSHR is the primary autoantigen of Graves' disease, while other autoantigens like

TSHR is a member of GPCR super family and involves cAMP and phosphoinositol pathways for signal transduction. TSHR has large intracellular domain (subgroup B). It is a glycoprotein consisting of 744 amino acids and having molecular weight of 84 kd. Gene for TSHR is located on chromosome 14q31 and is formed by 10 exons. Circulating autoantibody directed against the TSHR is the primary factor responsible for Graves' disease. TSHR antibodies (TSHR-Ab) are of three types- namely stimulating antibody, blocking antibody and neutral antibody. Stimulating antibodies are those who after binding to TSHR activate adenylate cyclase and cause increased thyroid growth and vascularity, and increases the production of thyroid hormones. Blocking antibodies are those who after binding to TSHR act as an antagonist, whereas neutral antibodies does not have any functional activity.

Almost 50 years ago(in 1956) long acting thyroid stimulators (LATS) was discovered by Adams and Purves during a search for thyroid stimulating activity in patients with Graves' disease. 13 Later on it was found that LATS are nothing but immunoglobulin of IgG1

Transplacental transfer of TSHR stimulating antibodies (TSAb) from TSAb positive pregnant mother to fetus causes transient neonatal thyrotoxicasis that improves spontaneously after the disappearance of TSAb. 14 This provides the definite role of TSAb in

TSAb are produced mainly by the lymphocytes infiltrating the thyroid gland and lymphocytes present in the draining lymph nodes, and partly by the circulating blood lymphocytes.15,16 There is a positive correlation exists between the TSAb level and serum

thyroglobulin and thyroid peroxidase are secondarily involved.

the causation of Graves' disease. TSAb are oligoclonal.

*Other risk factors:* 

individuals.

subclass.

**3. Pathogenesis**

**3.1. Humoral immunity** 

#### *Stress*

In different studies, it has been found that stressful life events precedes the onset of Graves' disease. Severe emotional and physical stress, like separation from the loved one or following road traffic accident, cause release of cortisol ad corticotrophin releasing hormone. So, stress is a relatively immune suppression state. Immune system overcompensates once stress is over which can precipitate disease similar to postpartum period. In conclusion there is limited but significant evidence that stressful life events can precipitate the onset of Graves' disease in genetically susceptible individuals.

#### *Gender*

Typically Graves' disease is more prevalent in females than males. It is about 5-10 times more common in females at any age. 6,7 In children this difference is smaller. The exact cause for female preponderance is not known, but it is similar to other autoimmune disorders. In experimental animal models of autoimmune thyroiditis it has been seen that androgens appear to down regulate the immune system.8,9 Other possible explanation for female preponderance is female sex steroids. But Graves' disease also occurs in men and postmenopausal women. These observations have suggested that it is the X-chromosome, not the sex steroids, which is responsible. But most of the x-linked disorders are only present in man, it has been thought that a gene with dose dependent effect on X-chromosome is responsible.

#### *Pregnancy*

Postpartum period is an important risk factor for both the onset and relapse of Graves' disease. Postpartum period is associated with a fourfold to eightfold increased risk for the onset of Graves' disease. Rebound immunity is the likely explanation for this increased risk. Graves' disease is associated with low pregnancy rate because thyrotoxicosis decreases the fertility rate. However in women with Graves' disease who became pregnant, successful pregnancy outcome is low because Graves' disease causes increased pregnancy loss and its complications. Graves' disease exacerbates during the first trimester of pregnancy and postpartum period, while it improves during the second and third trimester of pregnancy.

#### *Smoking*

Smoking is a minor risk factor for Graves' disease; however it is a major risk factor for Graves' ophthalmopathy. There are number of studies showing relationship between Graves' disease, Graves' ophthalmopathy and smoking. 11,12

#### *Other risk factors:*

162 Thyroid Hormone

*Stress* 

*Gender*

*Pregnancy* 

*Smoking* 

have causative role in Graves' disease.

X-chromosome is responsible.

Graves' disease in genetically susceptible individuals.

agents can be explained by molecular mimicry. Molecular mimicry implies structural similarity between infectious agent with a self antigen. Circulating antibody against Yersinia enterocolitica has been found in high percentage of patients with Graves' disease. Furthermore, serum from some patients recovering from Yersinia infections block the binding of TSH to its receptor. Low affinity binding sites for TSH have also been found with Leishmania and Mycoplasma species. However, no studies proved that infections agents

In different studies, it has been found that stressful life events precedes the onset of Graves' disease. Severe emotional and physical stress, like separation from the loved one or following road traffic accident, cause release of cortisol ad corticotrophin releasing hormone. So, stress is a relatively immune suppression state. Immune system overcompensates once stress is over which can precipitate disease similar to postpartum period. In conclusion there is limited but significant evidence that stressful life events can precipitate the onset of

Typically Graves' disease is more prevalent in females than males. It is about 5-10 times more common in females at any age. 6,7 In children this difference is smaller. The exact cause for female preponderance is not known, but it is similar to other autoimmune disorders. In experimental animal models of autoimmune thyroiditis it has been seen that androgens appear to down regulate the immune system.8,9 Other possible explanation for female preponderance is female sex steroids. But Graves' disease also occurs in men and postmenopausal women. These observations have suggested that it is the X-chromosome, not the sex steroids, which is responsible. But most of the x-linked disorders are only present in man, it has been thought that a gene with dose dependent effect on

Postpartum period is an important risk factor for both the onset and relapse of Graves' disease. Postpartum period is associated with a fourfold to eightfold increased risk for the onset of Graves' disease. Rebound immunity is the likely explanation for this increased risk. Graves' disease is associated with low pregnancy rate because thyrotoxicosis decreases the fertility rate. However in women with Graves' disease who became pregnant, successful pregnancy outcome is low because Graves' disease causes increased pregnancy loss and its complications. Graves' disease exacerbates during the first trimester of pregnancy and postpartum period, while it improves during the second and third trimester of pregnancy.

Smoking is a minor risk factor for Graves' disease; however it is a major risk factor for Graves' ophthalmopathy. There are number of studies showing relationship between

Graves' disease, Graves' ophthalmopathy and smoking. 11,12

Direct trauma to the thyroid gland, ethanol injection for the treatment of autonomously functioning thyroid nodules, or thyroid injury following radio-iodine treatment for toxic adenoma or toxic multinodular goiter are associated with an increased risk of Graves' disease. Radio-iodine treatment may also cause onset or worsening of ophthalmopathy. Possible explanation is that thyroid injury by any means cause massive release of thyroid antigens, which in turn stimulate an autoimmune reaction to TSHR in susceptible individuals.

Graves' disease onset and recurrence is also associated with iodine and iodine containing drugs like amiodarone and radio-contrast media especially in iodine deficient population.
