Graves' Disease: Pathophysiology, Genetics and Management

*Mosin S. Khan, Suhail S. Lone, Sunia Faiz, Iqra Farooq and Sabhiya Majid*

#### **Abstract**

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.

**Keywords:** Graves' Disease, GD, HLA region, PTPN22, CD40, CTLA4, CD152, TSHR, Tg, FCRL3, SCGB3A2

#### **1. Introduction**

Graves' Disease (GD) was named after *Robert J. Graves,* who first recognized this disease in the 19th century as a syndrome with enlarged and overactive thyroid gland (hyperthyroidism due to circulating autoantibodies), an high heart rate, and eye abnormalities (**Figure 1**). On the quality of life, GD has unpropitious effects [1], as a consequence of somatic and psychiatric symptoms, an inability to work and is connected with an increased risk of death [2]. The autoimmune basis of the GD results from complex interactions between different factors which include genetic, endogenous and environmental factors, and this is compulsory for current understanding of this disease [3, 4]. The circulating antibodies (IgG) that binds and activates the G-protein–coupled thyrotropin receptor leads to hyperthyroidism in this disease [5]. In this disease the G-protein–coupled thyrotropin receptor after getting activated stimulates follicular cell growth and excessive development which results in the enlargement of thyroid gland and also increase in thyroid hormone production and the fraction of triiodothyronine (T3) relative to thyroxine (T4) in

**Figure 1.** *Graves' Disease.*

thyroid secretion [6]. In GD the suppressed serum thyrotropin level and elevated levels of serum T4 and T3 are revealed by the thyroid functioning tests. A term known as *subclinical hyperthyroidism* is referred when serum thyrotropin level is low as compared to normal serum levels of T4 and T3 [7].
