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Graves’ disease: Epidemiology, genetic and environmental risk factors and viruses

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Graves’ disease (GD) is the most common cause of hyperthyroidism in developed Countries. It is more common between 30 and 60 years; 5–10 times more frequent in women. The genetic predisposition accounts for 79% of the risk for GD, while environmental factors for 21%. About 70% of genes associated with autoimmune thyroid disorders (AITD) are implicated in T-cell function. Among GD endogenous factors, estrogens, X-inactivation and microchimerism are important. Among environmental risk factors, smoking, iodine excess, selenium and vitamin D deficiency, and the occupational exposure to Agent Orange have been associated with GD. Many studies showed that HCV is associated with thyroid autoimmunity and hypothyroidism, in patients with chronic HCV hepatitis (CHC); a significant link has been shown also between HCV-related mixed cryoglobulinemia and risk for GD. Moreover, IFN-α-treated CHC patients develop GD more frequently. Novel studies are needed about possible risk factors to reduce the occurence of GD in West Countries.

Introduction

Graves’ disease (GD) is an organ-specific autoimmune disorder leading to the overproduction of thyroid hormones (hyperthyroidism). Although many disorders result in hyperthyroidism, GD is the most frequent cause in West Countries with an annual incidence of 20 cases/100,000 persons [1,2].

GD is one of the main autoimmune thyroid disorders (AITD), that are characterised by the breakdown of immune tolerance against thyroid antigens [3,4]. GD is clinically characterised by thyrotoxicosis, and by the presence of serum anti-thyroid antibodies (ATA) and of autoreactive lymphocytes in the gland [5]. The thyroid-stimulating hormone (TSH) receptor (TSH-R), thyroid peroxidase (TPO), and thyroglobulin (Tg) have unusual properties (“immunogenicity”) contributing to the breakdown of tolerance [4].

Thyroid hormones affect several different body systems, and for this reason, signs and symptoms associated with GD can vary strongly and significantly influence the general well-being. Common symptoms are: tremor, heat sensitivity and warm, weight loss, even if with normal eating habits, anxiety and irritability, enlargement of the thyroid gland (goiter), alterations in menstrual cycles, erectile dysfunction or decreased libido, fatigue, frequent bowel movements, palpitations, and others [6].

As already stated above, the onset of GD implicates a breakdown of immune tolerance towards the thyroid, through an autoimmune multifactorial process, involving environmental and endogenous factors in genetically predisposed subjects [7].

In GD, autoimmune reaction causes the production of anti-TSH-R autoantibodies (TRAb) by B-cell clones, that infiltrate the gland. Depending on their respective actions on the TSH-R, TRAb antibodies can be classified as: thyroid stimulating antibodies (TSAb); thyroid blocking antibodies (TBAb); neutral antibodies [8]. TRAb antibodies are implicated in GD pathogenesis and its extrathyroidal manifestations, i.e. Graves’ ophthalmopathy (GO) and pretibial myxedema (PTM)/Graves’ dermopathy. Hyperthyroidism is associated with TSAb [[9], [10], [11], ∗[12]].

TSAb lead to similar downstream effects as the binding of TSH to TSH-R, inducing thyrocytes proliferation, thyroid growth, and secretion of thyroid hormones (T4 and T3) [8]. The role of TBAb and neutral antibodies is less understood in thyroid autoimmune pathophysiology [8]. TBAb can bind to the A subunit of the TSH-R and block the TSH action and its effects on the follicular cells, whilst the neutral antibodies bind to the receptor with no impact on cAMP generation or TSH binding [8].

Antithyroid drugs are the first-line therapy for GD. Ablative therapy, either from radioactive iodine or surgical thyroidectomy, can cause hypothyroidism and leads to lifelong thyroid hormone replacement [2]. High dose intravenous immunoglobulins [13], or corticosteroids (CS) reduce inflammation and orbital congestion in patients with active GO.

Section snippets

Epidemiology

Although GD may affect anyone, it is more common among women, between 30 and 60 years of age. The risk of GD is 3% for women and 0.5% for men. The annual incidence of GO is 16 cases/100,000 women and 3 cases/100,000 men, and the age of appearance is between 30 and 60 years [2].

In particular, a study from Minnesota showed a peak age-specific incidence in patients with 20–39 years of age [14]. Among 1572 hyperthyroid patients in France, in a study published in 2016, 73.3% had GD, 85% of whom were

Genetic factors

A family history of GD is considered a risk factor. The concordance rate of GD in monozygotic twins in different studies is varied from 0.29 to 0.36, while in the same studies the concordance rate in dizygotic twins was between 0.00 and 0.04. Using structural equation modeling, it was found that the risk for GD development can be attributed to heritability for about 79% [22], while environmental factors can explain 21% of the risk [23]. The genetic susceptibility might elucidate the ethnic

Infections and viruses

The development of AITD may be triggered by infectious agents [48]. An increased prevalence of non-secretors (subjects who are unable to secrete the watersoluble glycoprotein form of the ABO blood group antigens into saliva) is present in GD patients. Since non-secretors have a raised susceptibility to infection [49], this leads to hypothesize that an infective agent can be implicated in the pathogenesis of GD. Furthermore, Valtonen et al. found evidence for a recent bacterial or viral

Immune-pathogenesis of AITD in chronic HCV infection, cryoglobulinemia, and IFN-α treatment

The pathogenesis of AITD has not yet been completely described. Among the involved triggers (i.e. iodine, medications, infections), a strong association of AITD with HCV infection and IFN-α has been reported. Furthermore, HCV and IFN appear to act in synergism to induce AITD. Actually, clinical or subclinical disease occurs in about 40% of HCV patients during IFN-α therapy. IFN-induced thyroiditis can be of a non-autoimmune type (such as destructive thyroiditis, or non-autoimmune

Conclusion

Graves’ disease (GD) is an organ-specific autoimmune disorder associated with the presence of circulating TSH-R autoantibodies, and it is the most common cause of hyperthyroidism in developed countries, with an annual incidence of 20 cases/100,000 persons [1,2].

Although GD may affect anyone, it is more common between 30 and 60 years of age and is 5–10 times more frequent in women than in men. In fact, the lifetime risk is 3% for women and 0.5% for men. GD is associated with extrathyroidal

Role of the funding source

The Authors have nothing to declare.

Summary

Graves’ disease (GD) is an organ-specific autoimmune disorder, associated with the presence of circulating TSH-R autoantibodies, and it is the most common cause of hyperthyroidism in developed Countries.

The GD risk factors include genetic predisposition, and interactions between endogenous and environmental factors. About 70% of genes associated with autoimmune thyroid disorders are implicated in T-cell function. Among GD endogenous factors, estrogens, X-inactivation and microchimerism are

Declaration of Competing Interest

The Authors have nothing to declare.

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