Infectious trigger
Since Graves disease is an autoimmune disease which appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals. In the 1990s, it was suggested that Y. enterocolitica may be associated with Graves disease. More recently, the role for Y. enterocolitica has been disputed.Epstein–Barr virus (EBV) is another potential trigger. Mechanism
Thyroid-stimulating immunoglobulins recognize and bind to the thyrotropin receptor (TSH receptor) which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3). Thyroxine receptors in the pituitary gland are activated by the surplus hormone, suppressing additional release of TSH in a negative feedback loop. The result is very high levels of circulating thyroid hormones and a low TSH level. Pathophysiology
Graves disease is an autoimmune disorder, in which the body produces antibodies that are specific to a self-protein: the receptor for thyroid-stimulating hormone. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.) These antibodies cause hyperthyroidism because they bind to the TSHr and chronically stimulate it. The TSHr is expressed on the thyroid 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.
When heated to decomposition it emits very toxic fumes of hydrogen chloride and nitrogen oxides. History
Nitrogen mustards arose from the derivatization of sulphur mustard gas after military personnel exposed to it during World War I were observed to have decreased white blood cell counts. Since the sulphur mustard gas was too toxic to be used in humans, Gilman hypothesized that by reducing the electrophilicity of the agent, which made it highly chemically reactive towards electron-rich groups, then less toxic drugs could be obtained. To this end, he made analogues that were less electrophilic by exchanging the sulphur with a nitrogen, leading to the nitrogen mustards.With an acceptable therapeutic index in humans, nitrogen mustards were first introduced in the clinic in 1946. Aliphatic mustards were developed first, such as mechlorethamine hydrochloride (mustine hydrochloride), which is still used in the clinic today. In the 1950s, aromatic mustards like chlorambucil were introduced as less toxic alkylating agents than the aliphatic nitrogen mustards, proving to be less electrophilic and react with DNA more slowly. Additionally, these agent can be administered orally, a significant advantage. Chlorambucil was first synthesized by Everett et al. References
External links
Leukeran (manufacturers website)
"Chlorambucil". Drug Information Portal. U.S. National Library of Medicine.