NORD gratefully acknowledges Alan P. Farwell, MD, Chief, Section of Endocrinology, Diabetes and Nutrition, Director, Endocrine Clinics,Boston Medical Center, Associate Professor of Medicine, Boston University School of Medicine, for assistance in the preparation of this report.
Onset of the symptoms associated with Graves’ disease is usually gradual, often taking several weeks or months to develop. Symptoms may include behavioral changes such as nervousness, irritability, anxiousness, restlessness and difficulty sleeping (insomnia). Additional symptoms include unintended weight loss, muscle weakness, an abnormal intolerance to heat, increased sweating, a rapid, irregular heartbeat (tachycardia) and fatigue
Graves’ disease is often associated with abnormalities affecting the eyes often referred to as Graves’ ophthalmopathy. While mild ophthalmopathy is present in the majority of people who have Graves’ hyperthyroidism at some point in their lives, less than 10% have significant eye involvement that requires therapy. Eye symptoms can develop before, at the same time or after the development of hyperthyroidism. In rare instances, individuals with eye symptoms never develop hyperthyroidism. In some instances, Graves’ ophthalmopathy may first become apparent or may worsen following treatment for Graves’ hyperthyroidism.
Graves’ ophthalmopathy is highly variable. In some individuals it may remain the same for many years, while in other individuals it may improve or worsen. It can also follow a pattern of worsening (exacerbations) and then going improving greatly (remission). Most individuals have mild disease with no progression.
Common eye abnormalities include swelling of the tissues surrounding the eye that may cause the eye to protrude or bulge out of its protective socket (orbit), a condition referred to as proptosis. Affected individuals may also experience dry eyes, puffy eyelids, eyelid retraction, inflammation, redness, pain, and irritation of the eyes. Some individuals describe a gritty sensation in the eyes. Less often, blurred or double vision, sensitivity to light, and/or diminished vision may also occur.
Very rarely, individuals with Graves’ disease develop a skin condition known as pretibial dermopathy or myxedema. This condition is characterized by the development of thickened, reddish skin on the front of shins. It is usually limited to the shins but, sometimes, may also occur on the feet. Rarely, soft-tissue swelling of the hands and clubbing of the fingers and toes (acropachy).
Additional symptoms associated with Graves’ disease include heart palpitations, slight tremors of the hands and/or fingers, hair loss, brittle nails, exaggerated reflexes (hyperreflexia), increased appetite, and an increase in the frequency of bowel movements. Females with Graves’ disease may experience an alteration in the menstrual cycle. Males may experience erectile dysfunction. In some instances, Graves’ disease may progress to cause congestive heart failure or abnormal thinning and weakness of the bones (osteoporosis) that leaves them brittle and susceptible to repeated fractures.
Graves’ disease is considered to be an autoimmune disorder, but other factors may contribute to its development, including genetic, environmental, and/or other factors.
Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. The immune system normally produces specialized proteins call antibodies. Antibodies react against foreign materials (e.g. bacteria, viruses, toxins) in the body bringing about their destruction. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen.
In Graves’ disease, the immune system creates an abnormal antibody called thyroid-stimulating immunoglobulin. This antibody mimics the function of normal thyroid-stimulating hormone. It attaches to the surface of thyroid cells and turns on the cells to produce thyroid hormones, leading to overproduction of these hormones (overactive thyroid). In Graves’ ophthalmopathy, these antibodies may also affect the cells surrounding the eyes.
Affected individuals may carry genes for, or have a genetic susceptibility to, Graves’ disease. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).
Various genes have been identified that are linked to Graves’ disease including genes that weaken or modify the response of the immune system (immunomodulators) such as the CD25, CD40, CD40, CTLA-4, FOXP3, and various HLA genes, particularly HLA-DR3. Genes that are directly linked to thyroid function such as the thyroglobulin (Tg) or the thyroid stimulating hormone receptor (TSHR) genes have also been linked to Graves’ disease. The Tg gene produces thyroglobulin a protein that is found only in thyroid tissue and plays a role in the production of thyroid hormones. The TSHR gene produces a protein that is a receptor and binds to thyroid stimulating hormone. The exact underlying manner that genetic and environmental factors interact to cause Graves’ disease is not fully understood. Additional genetic factors, known as modifier genes, may play a role in the development or expression of Graves’ disease.
Environmental factors that may trigger the development of Graves’ disease include extreme emotional or physical stress, infection, or pregnancy. Individuals who smoke are at a greater risk of developing Graves’ disease and Graves’ ophthalmopathy. Individuals who have other disorders caused by malfunction of the immune system such as diabetes type 1 or rheumatoid arthritis are at a greater risk of developing Graves’ disease.
Graves’ disease affects females more often than males by a ratio of 5-10 to 1. The disorder usually develops during middle age with a peak incidence of 40-60, but can also affect children, adolescents and the elderly. Graves’ disease occurs in almost any part of the world. Graves’ disease is estimated to affect 2%-3% of the general population. Graves’ disease is the most common cause of hyperthyroidism.
A diagnosis of Graves’ disease is made based upon a detailed patient and family history, a thorough clinical evaluation, identification of characteristic findings, and specialized tests such as blood tests that measure the levels of thyroid hormone and thyroid-stimulating hormone. Blood tests to detect the presence of specific antibodies that cause Graves’ disease can be performed to confirm a diagnosis, but are usually not necessary.
Treatment of Graves’ disease usually involves one of three methods, antithyroid drugs (thionamides), use of radioactive iodine, or surgery. The specific form of treatment recommended may be based upon the age of an affected individual and the degree of the illness.
The least invasive method of treating Graves’ disease is the use of drugs that reduce the release of thyroid hormone (antithyroid drugs). These drugs are especially preferred for the treatment of young children and pregnant women, individuals with mild cases of hyperthyroidism, or individuals in whom prompt control of hyperthyroidism is required. The most common antithyroid drug used to treat Graves’ disease is methimazole, which is recommended by the American Thyroid Association and the American Association of Clinical Endocrinologists as the initial treatment of choice for hyperthyroidism in children and adolescents. Propylthiouracil is sometimes used in specific instances, especially when Graves’ disease occurs early in pregnancy.
Definitive treatments for Graves’ disease are those that destroy the thyroid, frequently resulting in hypothyroidism. Definitive therapy with radioactive iodine is the most common treatment for Graves’ disease in the United States. Iodine is a chemical element used by the thyroid gland to create (synthesize) thyroid hormones. Nearly all of the iodine in a person’s body is absorbed by thyroid tissue. Affected individuals will swallow a solution containing radioactive iodine, which will travel through the bloodstream and collect in the thyroid gland where it will damage and destroy thyroid tissue. This will shrink the thyroid and reduce the overproduction thyroid hormones. If thyroid hormone levels fall too low, hormone therapy to regain adequate levels of thyroid hormone may be necessary.
The other definitive therapy is surgery to remove all or part of the thyroid gland (thyroidectomy). This a method of treatment for Graves’ disease is usually reserved for individuals in whom the other forms of treatment have not been successful or are contraindicated or with large glands or by those interested in the quickest resolution to the hyperthyroidism. Hypothyroidism is common after surgery; indeed, this may be the desired outcome.
In addition to the three above-mentioned treatments, drugs that block thyroid hormone that is already circulating in the blood from performing its functions (beta blockers) may be prescribed. Beta blockers such as propranolol, atenolol, or metoprolol can be used. When thyroid hormone levels return to normal, therapy with beta blockers can be stopped.
Lifelong follow up and laboratory studies are necessary in many cases. In some cases, lifelong hormone replacement therapy may be necessary.
Mild cases of Graves’ ophthalmopathy (eye abnormalities associated with Graves’ disease) may be treated with sunglasses, ointments, artificial tears, and/or prisms that are attached to glasses. More serious cases of Graves’ ophthalmopathy may be treated with corticosteroids, such as prednisone, to reduce the swelling of tissues surrounding the eyes.
Orbital decompression surgery and orbital radiotherapy may also be necessary in more severe cases. During orbital decompression surgery, a surgeon takes out the bone between the eye socket (orbit) and the sinuses. This allows the eye to fall back into its natural position within the eye socket. This surgery is generally reserved for individuals who are at risk of vision loss due to pressure on the optic nerve or in whom other treatment options have not worked. These therapies require management by ophthalmologists specializing in treatment of Graves’ ophthalmopathy.
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