Graves'+Disease

=Graves' Disease (Hyperthyroidism) =

Root cause of disease:
Graves disease is a thyroid-specific autoimmune disease that is caused by a genetic predisposition and in some cases thought to develop due to a reaction to a viral infection. In Graves’ disease, the body produces antibodies to the thyroid stimulating hormone receptor, causing abnormally high amounts of thyroid hormone to be synthesized and released, which ultimately leads to hyperthyroidism, goiter (enlarged thyroid) and, less commonly, ophthalmopathy and/or pretibial myxedema (dermopathy) [4]. The cellular and molecular factors involved in the onset of Graves’ disease are described in the flowchart below.

Affected cell types/tissues/organs/systems:
The organ most predominantly affected by Graves’ disease is the thyroid, which is part of the body’s endocrine system. Other than becoming enlarged, the thyroid itself isn’t harmed but the large amounts of hormones that it produces affect other areas of the body. Hyperthyroidism affects metabolism and essentially speeds up bodily processes [3]. This affects the heart by causing heart palpitations and the heart to race [3]. The nervous system is also affected. People tend to become nervous, irritable, anxious, have tremors and difficulty sleeping [3]. The digestive and reproductive systems can be affected as well since frequent bowel movements and weight loss are common and women may experience lighter or less frequent menstrual periods [3]. Ophthalmopathy, which occurs in approximately 40% of people with hyperthyroidism, is when the tissue surrounding the eyes is affected. The muscles around the eyes swell and the eyes themselves bulge outwards [4]. This can lead to vision problems. Approximately 2% of patients who experience ophthalmopathy also experience dermopathy consisting of raised, hyper-pigmented edemas. This usually manifests as pretibial myxedema on the shins but can be found on other parts of the body including the feet and hands [4].

Historical background:
Graves’ disease was first described in the 1830s by the Irish physician, Dr. Robert James Graves (1796-1853). He was the chief physician at Meath hospital in Dublin where he put great focus on the clinical observation of patients. In 1834, he gave series of lectures later published in 1835 about three patients with enlarged thyroids and symptoms of hyperthyroidism including heart palpitations. One of the patients had enlarged eyes [8]. Famous victims of Graves’ disease include comedian Marty Feldman [7] and both George H. W. Bush and Barbara Bush [6].

Common symptoms:
The inevitable symptom of Graves’ disease is hyperthyroidism. Other possible symptoms include ophthalmopathy (found in approximately 40% of patients) and pretibial myxedema (found in approximately 2% of patients exhibiting ophthalmopathy) [4]. Hyperthyroidism is when a person’s thyroid is producing abnormally high levels of thyroid hormones, which subsequently speeds up their metabolism. Symptoms of hyperthyroidism include racing heart, heart palpitations, nervousness, irritability, anxiety, trouble sleeping, frequent bowel movements, lighter or less frequent menstrual periods in women, excessive energy that eventually gives way to tiredness, muscle weakness, and weight loss [3]. Ophthalmopathy is when the muscle tissue surrounding the eyes is affected by the antibodies. The muscles around the eyes become swollen and the eyes bulge outwards, which can result in vision problems [4]. Pretibial myxedema is a type of dermopathy that afflicts the shins consisting of lumpy, red edemas [4]. In very rare cases, this can occur on other body parts including the hands and feet [5].

Standard treatments:
Treatments for hyperthyroidism include anti-thyroid drugs, beta-blockers, radioiodine, and surgery. Anti-thyroid drugs are used to decrease the thyroid’s production of thyroid hormones by interfering with their synthesis. The most common anti-thyroid drug is methimazole (Tapazole) [2]. This drug has the most minimal side effects [4]. 20-30% of patients treated with anti-thyroid drugs experience prolonged remission after 12-18 months of treatment [3]. However, there is a fairly high rate of remission when these drugs are used as the primary treatment [4]. Another class of drug utilized in the treatment of hyperthyroidism is the beta-blockers, or “beta adrenergic blocking agents”. Beta-blockers don’t lower the levels of thyroid hormones in a patient, but rather block them from acting on the body [3]. They work quickly at alleviating some symptoms such as high heart rate, heart palpitations, nervousness, and shakes, but are not recommended as a sole therapy for hyperthyroidism [3,4]. They are often used for immediate relief of symptoms while waiting for anti-thyroid drugs or another treatment to take effect [3] and are not effective treatments for ophthalmopathy.

A third treatment option for hyperthyroidism is called Radioiodine and is the most common treatment in North America [3]. It consists of swallowing a capsule or drinking a solution of radioactive iodine, which, is taken in by the overactive thyroid cells because they need iodine to function [3]. It slowly destroys those cells over a period of several months [3]. The goal of this treatment is to shrink nodules and return to normal levels of thyroid hormones but it rarely results in euthyroidism (normal thyroid functioning) [3,4]. Sometimes patients end up less hyperthyroid than before the procedure, but most become hypothyroid (under active thyroid) and must be treated with thyroid hormone supplements (usually Synthroid) for the rest of their lives [3]. Radioiodine is a low risk treatment but cannot be used if a woman is pregnant and can make ophthalmopathy worse if the patient already has it [4].

The most extreme, but also most effective treatment of hyperthyroidism is surgical removal of the thyroid gland, called a thyroidectomy. Thyroidectomies are performed in cases of very large goiters, intolerance or ineffectiveness of anti-thyroid drugs, refusal of radioiodine, pregnancy, and ophthalmopathy [4]. For this treatment to be safe, a patient must be rendered euthyroid using on of the other treatments prior to surgery [4]. Although thyroidectomies offer a permanent cure for hyperthyroidism, they usually result in hypothyroidism, which can to be treated for with thyroid hormone supplements (Synthroid) for the rest of a patient’s life and will get to them to a state of euthyroidism. Surgery is also useful in the instance of suspected or confirmed thyroid cancer because the gland can simply be removed. Overall, there are multiple treatment options for patients with Granves’ disease or hyperthyroidism. The treatments all function by restoring thyroid function rather than suppressing the immune response. The choice of treatment depends on age, type of thyroid issue, severity, and other medical conditions. Patients should see a specialist such as an internist or an endocrinologist for advice on the proper treatment. Any of these treatments are likely to result in hypothyroidism (even the anti-thyroid drugs), but hypothyroidism is much easier to treat.

Treatment for mild to moderate ophthalmopathy includes restoration of euthyroidism and lubricant and/or anti-inflammatory eye drops [4]. For more severe cases when vision is threatened, corticosteroids may be used [4]. In the most severe cases, surgery called orbital decompression is used to fix bulging eyes or eyelid surgery is used to allow eye lids to close and to help with dry eye. Orbital decompression surgery involves removing bone from the skull behind the eyes to make space for the muscles and fatty tissue.

References:
[1] Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2008). Molecular Biology of the Cell (5th ed., Reference ed.). New York: Garland Science, Taylor & Francis Group, LLC. [2] American Thyroid Association. (2012, June 4). Graves’ Disease. Retrieved May 13, 2013, from the American Thyroid Association website: http://www.thyroid.org/what-is-graves-disease/ [3]American Thyroid Association. (2012, June 4). Hyperthyroidism. Retrieved May 13, 2013, from the American Thyroid Association website: http://www.thyroid.org/what-is-hyperthyroidism/ [4] Ginsberg, J. (2003). Diagnosis and management of Graves’ disease. Canadian Medical Association Journal, 168(5), 575-585. [5] Johns Hopkins University. (n.d.) I have skin disease related to Graves’ disease: What is pretibial myxedema? Retrieved May 13, 2013, from the Johns Hopkins University Hyperthyroidism and Graves’ disease website: http://www.hopkinsmedicine.org/endocrine/graves/Answer.asp?QuestionID=61 [6] Parangi, S., & Phitayakorn, R. (2011). Thyroid Disease. Santa Barbara, California: Greenwood Publishing Group. [7] Ross, R. (2011). Marty Feldman: The Biography of a Comedy Legend. Titan Books Limited. [8] Smyth, P. P. A. (n.d.) Milestones in European Thyroidology (MET). Retrieved on May 15, 2013, from the European Thyroid Association’s website: http://www.eurothyroid.com/about/met/graves.php

References for flow chart:
[A] Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2008). Molecular Biology of the Cell (5th ed., Reference ed.). New York: Garland Science, Taylor & Francis Group, LLC. [B] Davies, T. F., Latif, R., & Yin, X. (2012). New Genetic Insights from Autoimmune Thyroid Disease. Journal of Thyroid Research, 2012, 6 pages. [C] Ginsberg, J. (2003). Diagnosis and management of Graves’ disease. Canadian Medical Association Journal, 168(5), 575-585. [D] Gough, S. C. (2000). The genetics of Graves’ disease. Endocrinology Metabolism Clinics of North America, 29(2), 255-266. [E] Johns Hopkins University. (n.d.) I have skin disease related to Graves’ disease: What is pretibial myxedema? Retrieved May 13, 2013, from the Johns Hopkins University Hyperthyroidism and Graves’ disease website: http://www.hopkinsmedicine.org/endocrine/graves/Answer.asp?QuestionID=61 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">[F] Lloyd, R. V. (Ed.). (2010). Endocrine Pathology: Differential Diagnosis and Molecular Advances. New York: Springer Science + Business Media.