Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Graves’ Disease
M. Bradley Evans, M.D. October 23, 2002 The objectives of my talk this morning is a brief history, epidemiology, pathogenesis, predisposing factors, clinical manifestation, diagnosis, and the treatment options available for Graves’ disease. Although the namesake of Graves’ disease is attributed Dr. Robert James Graves of Dublin, Ireland, in his report Three Females with Goiter, Palpations, and Exophthalmus in 1835, the disease was actually discussed several years earlier by Caleb Hillier Parry of Bath, England, in his Eight Patients with Diffuse Goiter and Hyperthyroidism; however, this report was not published until 1825 which was three years after his death. Some experts believe that this disease should be called Parry's disease instead of Graves’ disease. It is also interesting to note that Karl A. von Basedow in 1840, in Wurzburg, Germany, described what became known as the Wurzburg triad of exophthalmus, stroma or goiter, and palpitations of the heart, and in most of Europe it is known as Basedow's disease instead of Graves’ disease. Graves’ disease is the most prevalent autoimmune disorder in the United States, with an annual incidence in women of 0.5:1,000 over 20 years. Between 40 and 60 years of age is when the highest risk of onset occurs, and in all patients who present with hyperthyroidism 60-80% will end up having Graves’ disease. It is five to ten times more common in women, and there is a similar prevalence among whites and Asians with a lower prevalence among Blacks. Although much recent research has been done in this disease, the exact pathogenesis still has yet to be elucidated. It is very complex. What is known is that Graves’ disease is an autoimmune disease with production of several autoantibodies against thyroid antigens, the most important of which is the TSH receptor. There are also antibodies directed toward thyroglobulin, thyroid peroxidase and the iodide cotransporter in thyroid tissue. The key to the pathogenesis of Graves’ disease are the thyroid-stimulating antibodies which were identified by Adams and Purves in 1956. They are present in 90% of patients with the disease. It is felt by most experts, however, that all patients with Graves’ disease have these antibodies in their serum, and it is due to the insensitivity of the assays that are available today that 10% of the patients are not found to have them. These antibodies bind to and stimulate the TSH receptor that produces the clinical signs of Graves’ disease. These signs include increased circulating levels of thyroid hormone and the hypertrophy and hyperplasia of thyroid volatiles. And as in most autoimmune diseases, the production is a highly complex one, depending on T cells and various cytokines which will be talked about in just a second. This chart shows the many different nomenclatures you will see when reading the literature on Graves’ disease. The original description was that of LAP, long-acting thyroid stimulator. This is not used anymore; however, the most commonly used terms in literature nowadays are thyroid-stimulating antibodies and thyroid-stimulating immunoglobulin. It is also interesting to note that not only are there stimulating antibodies in a share of patients with Graves’ disease, but there are also blocking antibodies albeit at a lower level which suggests that there is a link between autoimmune hyperthyroidism and autoimmune hypothyroidism or Hashimoto's. Also important in the pathogenesis of Graves’ disease is the TSH receptor and, although much recent research has been done on this, the precise mechanism defining and stimulating this receptor is still unknown. Studies have shown mutated receptors that the antibodies bind to at sites that are distinct to those of TSH; however, they are felt to overlap those of TSH. These are two configurations of the thyrotropin receptor which have been proposed, and this figure just shows that binding sites for TSH and antibodies are on the same receptor; however, they perform different effects, which suggests that they bind to different subtypes of receptors. The binding stimulates the production of intracellular cGMP which causes hyperthyroidism and goiter. Overall, the pathogenesis for Graves’ disease is very complex with interactions of various cytokines which are produced by infiltrating cells into the thyroid including key lymphocytes, dendritic cells, and macrophages which interact with several different molecules on the thyroid cell to produce the effect of Graves’ disease. When a piece of thyroid tissue is looked at under the microscope in a patient with untreated Graves’ disease, it will be noted by diffuse hyperplasia of the gland with increased cellularity, a relative absence of colloid, and a marked lymphocytic infiltration. This lymphocytic infiltration has been shown to be a major source of the autoantibodies with contributions also from the cervical lymph nodes and bone marrow. Some of the environmental factors which have been associated with Graves’ disease are female gender, which seems to be a result of the modulation of autoimmune effects by estrogen. Although controversial, some patients that have a recent onset of Graves’ disease admit to adverse life events preceding the onset of their symptoms. There have been multiple studies to confirm this although it is controversial. And although smoking is equally associated with hyperthyroidism, it is strongly associated with ophthalmopathy. Some other environmental or endogenous factors which have been shown not to be major contributors in Graves’ disease include iodine supplementation and reasons of iodine deficiency, antiretroviral therapy in patients with AIDS, and patients with multiple sclerosis who are treated with specific monoclonal antibodies. When one presents with Graves’ disease it is that of the typical picture of hyperthyroidism with the most common symptoms being nervousness, increased sweating, heat intolerance, palpitations, and weight loss. The most frequent signs will be tachycardia, goiter, and tremor. Once again, about half the patients will present with eye changes or ophthalmopathy and a smaller percentage will have dermopathy which will be described in more detail. The goiter which is associated with Graves’ disease is present in approximately 75-90% of patients. It is typically symmetrical, smooth, firm, and rubbery on palpation and may have a bruit or a thrill on auscultation. It is typically 2-10 times larger than normal; however, it is important to remember that it may be normal size in elderly patients. In 4% of patients they will present with what has been termed the Maureen Lenhart Syndrome which is one or more nodules in an otherwise diffuse goiter. These nodules are found to be cold on radioiodine scanning, and it is imperative that malignancy be ruled out in these lesions. One of the more obvious signs of Graves’ disease is the ophthalmopathy which is associated. It is clinically evident in only half the patients; however, if antigen studies are obtained it can be seen in up to 90%. The most common signs include eyelid retraction or lid lag and periorbital edema. Exophthalmos is present in about a third of the patients, and diplopia is present in 5-10%. Ophthalmopathy is characterized by edema and inflammation of the extraocular muscles with increased orbital connective tissue and fat. As you can see on this CT scan, there is hypertrophy of the medial rectus muscle along with some hypertrophy of the lateral rectus muscle and proptosis of the globe. The ophthalmopathy results from an autoimmune response to one or more antigens which are shared by the thyroid and orbit. The most likely candidate for this is the TSH receptor, which has been shown to be expressed by fibroblasts in the orbit. The end result of this whole process is fibrosis which is caused by cytokine-activated fibroblasts, not unlike that seen in the thyroid disease with the T cells, dendritic cells, and macrophages releasing cytokines to produce the symptoms of ophthalmopathy on the fibroblast. Also associated with Graves’ disease, albeit at a lower percentage, is dermopathy which is present in 1-2% of patients although it has been reported in up to 8% of patients. The most frequent site is over anterolateral aspect of the shin, although it can occur at other sites especially after trauma. It is characterized by lymphocytic infiltration of the dermis with resulting edema. As always, the history and physical examination are the most important aspects in the diagnosis of Graves’ disease. In a patient with the typical signs and symptoms of hyperthyroidism, along with a diffuse goiter felt on physical examination, this is usually sufficient to make the diagnosis. However, laboratory evaluations should be used to confirm the hyperthyroidism. Serum TSH should be drawn first, and if this is low, then hyperthyroidism should be confirmed with a serum T 4. In some cases the T 4 can be normal, and if this is the case then T 3 should be measured. I think that in some patients T 3 thyrotoxins can be present. I put this slide up just to show that although 60-80% of the patients with hyperthyroidism will have Graves’ disease, it is not the only diagnosis that must be entertained. There are several other conditions which can cause hyperthyroidism. So, if the diagnosis is still unclear after routine laboratory investigation and history and physical, there are other tests which can be obtained using thyroperoxidase antibodies and TSH receptor antibodies which are present in 75% and 90% of patients, respectively. Also, if a radioactive iodine scan is obtained in these patients, it will show a diffuse increased uptake in a diffusely enlarged gland. Although many people argue about what treatment should be tried first or which treatment should not be tried, the fact is that really there is no perfect treatment for Graves’ disease at this time. Antithyroid drugs have been in clinical use for the last 50 years. These include methimazole and propylthiouracil or PTU. They work by inhibiting thyroid peroxidase and the release thyroid hormone. PTU has the additional effect of inhibiting the peripheral conversion of T 4 to T 3 although the clinical significance of this has been questioned recently. Although antithyroid drugs will cause euthyroidism in almost all patients, it is important to remember that when these drugs are withdrawn that 40% of those treated will fail treatment. And if their hyperthyroidism does recur, a permanent remission is unlikely with a second course. There are some negative predictors of remission which include young patients, those with large goiters, those with ophthalmopathies, and those with high serum concentrations of TSH receptor antibodies. In any of these patients that present with this, they would most likely benefit from another treatment other than antithyroid drugs. The side effects of drugs used to treat Graves’ disease are rash, fever, urticaria and joint pain which have been seen in up to 15% of patients. In a much smaller percentage of patients, a granulocytosis can occur. If any signs of infection develop, such as sore throat, the medications must be discontinued immediately and treatment should be aggressive with broad spectrum antibiotics and supported measures. An extremely rare complication of antithyroid drugs is cytotoxicities which can manifest as acute hepatic necrosis or cholestatic hepatitis. The problem with this is that it continues to affect the patient despite the discontinuation of the drug and it is often fatal. Fortunately, it is extremely rare. Radioactive iodine is the most common treatment for Graves’ disease in the United States at the current time. It is ablative treatment for the thyroid gland. It is the delivery of a radioactive substance to the patient and is contraindicated in pregnant and breast-feeding women. It can induce or worsen ophthalmopathy, especially in those who smoke. Although much study has been done over the teratogenicity of radioactive iodine, it is not shown to be of any significance; however, the current recommendation is that conception should be delayed for at least four months following radioactive iodine treatment. There have also been many studies performed to determine if radioactive iodine increases the risk of cancer, and that also has not been firmly shown to be true. However, it has been shown that in patients who are treated with radioactive iodine and develop a thyroid cancer, the aggressiveness of this cancer is increased; however, it is unclear whether this is due to the Graves’ disease or the radioactive iodine treatment. And also, children should probably not be treated with radioactive iodine. The most common side effect of radioactive iodine treatment is hypothyroidism. There is a 10-30% risk in the first two years with a 5% risk per year thereafter, and it is important to remember that antithyroid drugs cannot be used immediately before or after treatment with radioactive iodine because of the radioprotective effect of these drugs. Some experts feel that surgery is an under-utilized primary treatment for Graves’ disease, and there have been some studies that propose that surgery should be a first-line treatment for Graves’ disease. There are some very strong indications for surgery. These include suspicious or confirmed malignant thyroid nodules, pregnant patients who are poorly controlled by or allergic to antithyroid drugs in which radioactive iodine would be contraindicated, women who wish to become pregnant soon after treatment—As I mentioned before, the current recommendation is that conception be delayed for at least four months—those with local compressive symptoms such as pain or dysphagia or hoarseness, and those who refuse radiation. Also children may benefit from thyroidectomy as a primary treatment option. Some other indications for surgery are patients who are poorly compliant, those in whom rapid control of symptoms is desired—there is about a four- to six-week lag time with antithyroid drugs before euthyroidism is achieved and radioactive iodine can take up to four to six months to produce euthyroidism. Also, patients with large thyroid glands and relatively low radioactive iodine uptake and patients with severe manifestations of ophthalmopathy have a relative indication for surgery. It has been shown that radioactive iodine can actually worsen ophthalmopathy, whereas surgery has its benefit in some patients with ophthalmopathy. It is very important that before the patient is taken to the operating room for a thyroidectomy that they are adequately prepared preoperatively to avoid complications such as thyroid storm. This can be accomplished with antithyroid medications given four to six weeks before the operation to correct the hyperthyroidism and Beta-blockers such as propanolol for one week before the operation to control the cardiovascular response to the catecholamines. Lugol’s solution—which is iodine with potassium iodide—or potassium iodide alone can be given to these patients before surgery to decrease the vascularity and the friability of the gland. When surgery is chosen as the primary treatment for Graves’ disease, the question then comes up, "What operation to perform?" Total or subtotal thyroidectomies are the options. Some of the indications for total thyroidectomy are coexistent thyroid malignancy, compressive symptoms, severe ophthalmopathy, those unwilling to accept the re-operation for possible recurrence, and the surgeon's preference and/or experience in subtotal and total thyroidectomy. If subtotal thyroidectomy is undertaken, then it must be remembered that there is a wide range of variation of incidence of hypothyroidism, anywhere from 3-48% in different studies that you look at. The factors for hypothyroidism can be explained by the remnant size which is left, the autoimmune activity, and the definition of hypothyroidism. What is meant by the autoimmune activity is the lymphocytic infiltration of the gland can actually cause the destruction of the thyroid gland which will increase the incidence of hypothyroidism when thyroid tissue is left behind. Some clinicians report subclinical hypothyroidism as frank hypothyroidism. When performing a subtotal thyroidectomy, it is recommended currently that about four to five grams of thyroid tissue is left behind, and this is a delicate balance because if less than four grams are left, then there is a greater than 50% incidence of hypothyroidism where if greater than seven grams are left then there is a 15% incidence of recurrent hyperthyroidism. The complications of surgery, which are well known by everyone in this room, are bleeding, infection, and scarring. Also with the more severe complications of recurrent laryngeal nerve injury and hypocalcemia. All complications in thyroidectomy should not exceed 2%. And if there has been shown to be no significant difference in the rate of complications between subtotal and total thyroidectomy in those studies, this has prompted many surgeons to perform a total thyroidectomy in Graves’ disease as opposed to subtotal thyroidectomy. I would like to say just a brief word about Graves’ disease and malignancy. It is controversial whether the overall incidence of cancer is increased in patients with Graves’ disease; however, it has been shown that patients who do present with nodules in the thyroid gland have an eightfold higher risk of thyroid cancer than those patients without Graves’ disease, and the cancer does seem to follow a more aggressive course. And, as in patients without Graves’ disease, the most common type of cancer is papillary carcinoma. In summary, Graves’ disease is a relatively common autoimmune disease with an unclear etiology. It presents with hyperthyroidism, as well as the extra thyroidal manifestations of ophthalmopathy and dermopathy. It is diagnosed by history and physical, thyroid function test, and assays for thyroid-stimulating antibodies and/or radioiodine scan when the diagnosis is unclear. Treatment options available include antithyroid medications, radioactive iodine therapy, and subtotal or total thyroidectomy. And there is an increased incidence in more aggressive course of cancer in patients with hypothyroid nodules in Graves’ disease. Case Presentation R.R. is a 48-year-old African-American male with a past medical history significant for hypertension, and aortic insufficiency with ascending aortic aneurysm status post aortic root replacement in December 1999, who presented to the VAMC in April 2002 with a two-month history of intermittent palpitations, heat intolerance, urinary frequency, shortness of breath, diarrhea, and goiter. The patient was found to be hyperthyroid by laboratory investigation and a diagnosis of Graves’’ disease was made. He was treated by endocrinology with propylthiouracil for six weeks followed by methimazole. The patient was rendered euthyroid; however, he continued to have a diffuse goiter of increasing size. A thyroid ultrasound was performed, which showed no discrete nodules, and the patient was followed in endocrine clinic. The patient continued to have increasing size of his goiter with compressive symptoms of dysphagia and hoarseness and the otolaryngology service was consulted to evaluate for thyroidectomy. On physical examination, the patient was noted to have a large goiter with mild exophthalmos and lid lag. The true vocal folds were mobile bilaterally. Laboratory evaluation revealed a TSH of <0.01, with T4 and T3 values within normal limits. Thyroid stimulating immunoglobulins were obtained, which were shown to be markedly elevated. 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