Best Practice & Research Clinical Endocrinology & Metabolism
2Graves’ disease: Epidemiology, genetic and environmental risk factors and viruses
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.
References (104)
- et al.
Autoimmune thyroid disorders
Autoimmun Rev
(2015) - et al.
Chemokines in hyperthyroidism
J Clin Transl Endocrinol
(2019) - et al.
Graves’ disease: introduction, epidemiology, endogenous and environmental pathogenic factors
Ann Endocrinol
(2018) - et al.
Epidemiologic aspects of Hashimoto’s thyroiditis and Graves’ disease in Rochester, Minnesota (1935-1967), with special reference to temporal trends
Metabolism
(1972) - et al.
Defining and analyzing geo epi-demiology and human autoimmunity
J Autoimmun
(2010) - et al.
Surgical therapy of the thyroid papillary carcinoma in children: experience with 56 patients < or =16 years old
J Pediatr Surg
(2004) - et al.
Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity
Ann Endocrinol
(2011) - et al.
The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology
J Autoimmun
(2008) - et al.
Regression mapping of association between the human leukocyte antigen region and Graves disease
Am J Hum Genet
(2005) - et al.
Immunogenetics of autoimmune thyroid diseases: a comprehensive review
J Autoimmun
(2015)
Smoke and autoimmunity: the fire behind the disease
Autoimmun Rev
Agent Orange exposure and disease prevalence in Korean Vietnam veterans: the Korean veterans health study
Environ Res
Letter: viral antibodies in thyrotoxicosis
Lancet
Latent autoimmune thyroid disease in patients with chronic HCV hepatitis
J Hepatol
Thyroid disorders in chronic hepatitis C
Am J Med
The association of other autoimmune diseases in patients with Graves’ disease (with or without ophthalmopathy): review of the literature and report of a large series
Autoimmun Rev
HCV E2 protein binds directly to thyroid cells and induces IL-8 production: a new mechanism for HCV induced thyroid autoimmunity
J Autoimmun
Interferon induced thyroiditis. Best practice & research
Clin Endocrinol Metabol
Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia
Autoimmun Rev
Alpha-chemokine CXCL10 and beta-chemokine CCL2 serum levels in patients with hepatitis C-associated cryoglobulinemia in the presence or absence of autoimmune thyroiditis
Metabolism
High values of CXCL10 serum levels in patients with hepatitis C associated mixed cryoglobulinemia in presence or absence of autoimmune thyroiditis
Cytokine
The association of other autoimmune diseases in patients with autoimmune thyroiditis: review of the literature and report of a large series of patients
Autoimmun Rev
Cardiovascular complications in patients with pheochromocytoma: a mini-review
Biomédecine & pharmacothérapie
Graves’ disease
N Engl J Med
The Th1/Th2 paradigm and allergic disorders
Allergy
Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity
Endocr Rev
Diagnosis and management of thyrotoxicosis
BMJ : Br Med J/Br Med Assoc
Thyrotropin receptor antibodies-an overview
Ophthalmic Plast Reconstr Surg
Functional TSH receptor antibodies in children with autoimmune thyroid diseases
Autoimmunity
Thyrotropin receptor blocking antibodies
Horm Metab Res
Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease
Clin Exp Immunol
Prospective trial of functional thyrotropin receptor antibodies in graves’ disease
J Clin Endocrinol Metabol
High-dose intravenous immunoglobulin treatment in Graves’ ophthalmopathy
Acta Endocrinol
Clinical presentation of hyperthyroidism in a large representative sample of outpatients in France: relationships with age, aetiology and hormonal parameters
Clin Endocrinol
Incidence of hyperthyroidism in Sweden
Eur J Endocrinol
The incidence of autoimmune thyroid disease: a systematic review of the literature
Clin Endocrinol
Disease burden and outcome in children and young adults with concurrent graves disease and differentiated thyroid carcinoma
J Clin Endocrinol Metabol
Primary cell cultures from anaplastic thyroid cancer obtained by fine-needle aspiration used for chemosensitivity tests
Clin Endocrinol
Twin studies as a model for exploring the aetiology of autoimmune thyroid disease
Clin Endocrinol
Race/ethnicity and the prevalence of thyrotoxicosis in young Americans
Thyroid : Off J Am Thyroid Assoc
Certain HLA alleles are associated with stress-triggered Graves’ disease and influence its course
Endocrine
Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves’ disease
Clin Endocrinol
Gene expression of estrogen receptor-alpha in orbital fibroblasts in Graves’ ophthalmopathy
Arch Endocrinol Metabol
X chromosome inactivation and autoimmunity
Clin Rev Allergy Immunol
High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity
J Clin Endocrinol Metabol
Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis
J Clin Endocrinol Metabol
Fetal cell microchimerism: a protective role in autoimmune thyroid diseases
Eur J Endocrinol
Environmental issues in thyroid diseases
Front Endocrinol
Iodine excess and hyperthyroidism
Thyroid : Off J Am Thyroid Assoc
Cigarette smoke extract-induced oxidative stress and fibrosis-related genes expression in orbital fibroblasts from patients with graves’ ophthalmopathy
Oxidative medicine and cellular longevity
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