**5.1 Biochemical parameter**

The severity is linked to recurrence risk in ATD-treated GD patients. Partly the biochemical parameters help to determine the seriousness of GD. The parametric increase of serum T3, which is affected by increased intrathyroid type 1 deiodinase activity, is significant in untreated GD. Independent GD factors influenced free thyroxine-to-free triiodothyronine ratio (FT3 andFT4) is predictive for the ATD treatment outcome for patients with GD. Hyperthyroidism symptoms observed after the treatment with beta-blockers. Patients with a higher T3/FT3 or FT3/ T4 serum ratio have been found to be more at recurrence, requiring a longer and more additional dose in the treatment. The risk of relapsed treatment is increased for patients with a higher serum T3 and FT3/FT4 ratio. When a patient has a high T3/T4 ratio, therapy should be continued for at least one year after the ATD has been removed. Serum thyroid-stimulating hormone (TSH) should be measured. However, as it is known, the thyroid hormone has a negative feed-back influence on the TSH. Thus, prior research has established that drug discontinuation is associated with elevated levels of TSH. These findings suggest that treatment with a prolonged ATD may be indicated for GD patients who do not normalize their thyroid-stimulating hormone levels quickly.

## **5.2 Immune parameters**

The GD is the result of hyper-activation by TRAb of the TSH receptor in follicular thyroid cells. In approximately 95% of newly diagnosed GD patients, TRAb is positive and higher TRAb levels are indicative of serious immune disorder. Recent times have demonstrated TRAb as a helpful and qualitative prognostic indicator for ATD therapy. At the time of GD diagnosis, patients with high TRAb levels had a considerably higher recurrence risk, while TRAb patients were often more likely to get long-term recovery. Switching from positive to negative TRAb in GD patients involves a reduced immune disorder after ATD therapy. In the prognosis of GD patients, TRAb levels were also observed at ATD withdrawal. Recurrence risk was noted to be increased in TRAb-positive GD during the time of drug discontinuation. New assays can be used to distinguish the stimulating (stimulating) and blocking (disturbing) effects of medications on antigen responses. Thyroid stimulating antibodies (TSAb) antibodies are found to be predominant in GD patients. Recently, the value of TRAb for patients on GD treatments for recurrence risk with prediction has been shown to be greater than that of GD, particularly TSAb. GD patients with thyroiditis from Hashimoto appear to be remission after Hashimoto's thyroiditis due to advanced harm. The prevalence of peroxidase/ peroxidase antibodies is highest in people with Hashimoto's thyroiditis. Few studies have analyzed whether the existence of Thyroid peroxidase antibodies (TPOAb) and Thyroglobulin antibodies (TgAb) autoantibodies is linked to the risk of a subsequent relapse in those with GD. People with GD may also show low TPOAb and TgAb levels, and in such cases, the clinical and laboratory findings are not completely consistent with the diagnosis of Hashimoto's disease.

#### **5.3 Goiter size**

A major clinical manifestation found in GD patients is the large goiter. Previous studies show a large predictor of increased risk of recurrence in GD patients after the removal of ATD, goiter size. Findings from 5 years of trail follow-up have shown that the rate of remission for normal or mild-goiter patients is higher than for largegoiter patients. GD patients with significantly lower goiter sizes tend to have higher rates of remission after ATD treatment. Enlarged goiter size at the time of GD diagnosis and drug withdrawal is associated with a higher recurrence risk of GD.

#### **5.4 Graves' orbitopathy**

At the time of diagnosis of GD, Graves' orbitopathy is observed in 35% of patients. Sometimes, the presence of the Graves orbitopathy indicated that the immune system gets worsen. Previous studies show that the risk of GD recurrence after withdrawal of ATD in patients with Graves' orbitopathy is higher [38]. An Eckstein et al. study even found that GD patients with severe Graves' orbitopathy only received a 7% remission rate. Although the recurrence rate is higher, the ATD treatment remains a preferred therapeutic option for GD patients with orbitopathy of Graves because Graves's orbitopathy improves as well as a steady eutyroid status achieved and reduces inflammatory markers of the TRAb. Recent studies have demonstrated that the continuous low dose of ATD has helped to improve GD disease in Graves orbitopathy patients.

#### **5.5 Genetic factors**

Genetic factors plays a key role in the pathogenesis of GD and increase the risk of recurrence to the development of GD. Several studies supports both cytotoxic T-lymphocyte-associated factor 4 (CTLA4) rs231775 and rs231779 polymorphisms were strongly associated with recurrence of GD even after ATD withdrawal in Asians, while there is no association in Caucasians for developing GD. In Caucasian patients with GD, the recurrence risk after ATD withdrawal was observed with the polymorphisms of HLA DQA2, HLA DRB1∗03, and HLA DQB1∗02. The HLA region majorly contains immune response genes and tHLA polymorphisms might also influence the outcome of GD patients by regulating the immune system.

#### **5.6 Environmental factors**

GD starts with some environmental factors in the predisposed genetic association in individuals. Stress is one of the important environmental considerations, and a majority of the studies have supported the association between stress and recurrence in GD patients after ATD therapy. The overall stress score for large life events was significantly higher in the recurrence group in a prospective study that examined the recurrence risk of GD in patients than in the remission. Another trial showed that the recurrence group was more stressful than the remission patients, and that the total number of stressful events is linked to the number of the recurrence. Psychosocial stress is an important part of a stressful event. It is worth mentioning. Previous trials showed that the risk of GD recurrence is higher than that of GD patients without such a disease for patients with psychiatric disorders as depression and hypochondriasis. Therefore, reducing stress is an essential way of improving the prognosis of ATD-treated GD patients. Another ecological factor is iodine intake.

The synthesis of the thyroid hormone is based on Iodine. Increased content of iodine in thyrocytes has promoted degradation of ATD and reduced uptake of ATD. The supplementation of iodine increased the GD recurrence rate. After ATD withdrawal hyperthyroidism in euthyroid GD patients arose when pharmaceutical doses of iodine were taken. Epidemiologic studies have shown, however, that in iodine-adequate countries, recurrence rates in GD patients do not exceed those in iodine-deficient areas following ATD withdrawal.
