Graves' disease pathophysiology
|
Graves' disease Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Medical Therapy |
|
Case Studies |
|
Graves' disease pathophysiology On the Web |
|
American Roentgen Ray Society Images of Graves' disease pathophysiology |
|
Risk calculators and risk factors for Graves' disease pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
Overview
Pathophysiology
Several factors may contribute in Graves' disease pathogenesis. Followings are the main aspects of Graves' diseases pathophysiology.
Initiating factors
Genetic factors are important in developing Graves' disease. These factors include genes encoding for,[1]
- Thyroglobulin
- Thyrotropin receptor
- HLA-DRβ-Arg74
- The protein tyrosine phosphatase nonreceptor type 22 (PTPN22)
- Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4)
- CD25
- CD40
Hypermethylation of genes involved in encoding thyrotropin receptor and proteins involved in T-cell signaling is another important factor.[2]
Anti Thyrotropin Receptor Antibodies
Graves' disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). These are IgG1 subclass of antibodies.[3]
These antibodies cause hyperthyroidism because they bind to the TSH receptor and chronically stimulate it. The TSH receptor is expressed on the follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This in turn causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter. These antibodies stimulate thyroid hormone production that is uncontrolled by the hypothalamic pituitary axis.[4]
The infiltrative exophthalmos that is frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.
The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.
There are 3 types of autoantibodies to the TSH receptor currently recognized:
- TSI, Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as LATS (Long Acting Thyroid Stimulants), activating the cells in a longer and slower way than TSH, leading to an elevated production of thyroid hormone.
- TGI, Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
- TBII, Thyrotrophin Binding-Inhibiting Inmunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor.
The trigger for auto-antibody production is not known. There appears to be a genetic predisposition for Graves' disease, suggesting that some people are more prone than others to develop TSH receptor activating antibodies due to a genetic cause. HLA DR (especially DR3) appears to play a significant role.[5]
Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in life, it is thought that a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor (a phenomenon known as antigenic mimicry, also seen in some cases of type I diabetes).
One possible culprit is the bacterium Yersinia enterocolitica (a cousin of Yersinia pestis, the agent of bubonic plague). However, although there is indirect evidence for the structural similarity between the bacteria and the human thyrotropin receptor, direct causative evidence is limited.[5] Yersinia seems not to be a major cause of this disease, although it may contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.[6] It has also been suggested that Y. enterocolitica infection is not the cause of auto-immune thyroid disease, but rather is only an associated condition; with both having a shared inherited susceptibility.[7] More recently the role for Y. enterocolitica has been disputed.[8]
The ocular manifestations of Graves disease are more common in smokers and tend to worsen (or develop for the first time) following radioiodine treatment of the thyroid condition. Thus, they are not caused by hyperthyroidism per se; this common misperception may result from the fact that hyperthyroidism from other causes may cause eyelid retraction or eyelid lag (so-called hyperthyroid stare) which can be confused with the general appearance of proptosis/exophthalmos, despite the fact that the globes do not actually protrude in other causes of hyperthyroidism. Also, both conditions (globe protrusion and hyperthyroid lid retraction) may exist at the same time in the hyperthyroid patient with Graves disease.
References
- ↑ Tomer Y (2014). "Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics". Annu Rev Pathol. 9: 147–56. doi:10.1146/annurev-pathol-012513-104713. PMC 4128637. PMID 24460189.
- ↑ Limbach M, Saare M, Tserel L, Kisand K, Eglit T, Sauer S, Axelsson T, Syvänen AC, Metspalu A, Milani L, Peterson P (2016). "Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling". J. Autoimmun. 67: 46–56. doi:10.1016/j.jaut.2015.09.006. PMID 26459776.
- ↑ Weetman AP, Yateman ME, Ealey PA, Black CM, Reimer CB, Williams RC, Shine B, Marshall NJ (1990). "Thyroid-stimulating antibody activity between different immunoglobulin G subclasses". J. Clin. Invest. 86 (3): 723–7. doi:10.1172/JCI114768. PMC 296786. PMID 2168443.
- ↑ Morshed SA, Latif R, Davies TF (2009). "Characterization of thyrotropin receptor antibody-induced signaling cascades". Endocrinology. 150 (1): 519–29. doi:10.1210/en.2008-0878. PMC 2630889. PMID 18719020.
- ↑ 5.0 5.1 Tomer Y, Davies T (1993). "Infection, thyroid disease, and autoimmunity" (PDF). Endocr Rev. 14 (1): 107–20. PMID 8491150.
- ↑ Toivanen P, Toivanen A (1994). "Does Yersinia induce autoimmunity?". Int Arch Allergy Immunol. 104 (2): 107–11. PMID 8199453.
- ↑ Strieder T, Wenzel B, Prummel M, Tijssen J, Wiersinga W (2003). "Increased prevalence of antibodies to enteropathogenic Yersinia enterocolitica virulence proteins in relatives of patients with autoimmune thyroid disease". Clin Exp Immunol. 132 (2): 278–82. PMID 12699417.
- ↑ Hansen P, Wenzel B, Brix T, Hegedüs L (2006). "Yersinia enterocolitica infection does not confer an increased risk of thyroid antibodies: evidence from a Danish twin study". Clin Exp Immunol. 146 (1): 32–8. PMID 16968395.