Slide notes: This presentation provides information on Graves disease, a systemic autoimmune disease. Epidemiology, pathology, complications,

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2 This presentation provides information on Graves disease, a systemic autoimmune disease. Epidemiology, pathology, complications, including ophthalmic complications, treatments (both permanent solutions and drug therapy), Graves disease in childhood and predictive factors for patient outcomes will be covered. 2

3 The number of people in the US affected by 24 autoimmune diseases was estimated by applying mean weighted prevalence and incidence rates from published articles to US Census data. Data from 1997 suggest that 8,511,845 persons from the US have one of the 24 autoimmune diseases targeted by this study, and that women are 2.7 times more likely than men to acquire an autoimmune disease. Reference: Jacobson DL, et al. Clin Immunol Immunopathol 1997;84:

4 A study of Caucasian patients with Graves disease (2020 female, 58 male) found the peak age for Graves disease diagnosis for both men and women was between the 4th and 6th decades of life. Median age for diagnosis was slightly younger in women than in men. Biochemical severity, measured as the amount of serum free T 4, was similar between the sexes. The frequency of goitre was significantly higher in women than in men (P<0.001), and the presence of goitre was associated with a lower mean age of diagnosis and a greater disease severity in both sexes. Reference: Manji N et al. J Clin Endocrinol Metab 2006;91:

5 Colour-flow Doppler sonography can be used to assess the health of the thyroid gland. An undiagnosed or poorly controlled overactive thyroid can occasionally lead to thyroid storm a severe and sudden onset of symptoms including a very rapid heart beat, fever, dehydration with diarrhoea and vomiting, jaundice, severe agitation and confusion, hallucinations, psychosis, excessive sweating, chest pain and muscle weakness. These are all symptoms of the metabolism going into overdrive, and is a medical emergency. It can be caused by an infection, pregnancy, incorrect medication or damage to the thyroid gland; for example, a blow to the throat. Source: Overactive thyroid complications. Available from: www://nhs.uk. Accessed February

6 The heart rate and arrhythmia profile was analysed by 24-hour Holter monitoring in 37 hyperthyroid patients before, during and after antihyperthyroid therapy of between 8 and 89 weeks duration. The triiodothyronine (T 3 ) hormone level was 331 ± 108 ng/ml before treatment, 202 ± 98 ng/ml during treatment and 149 ± 41 ng/ml after treatment; heart rate was 95 ± 13 beats/minute before treatment and decreased to 79 ± 9 beats/minute after treatment. Heart rate remained above that recorded for control subjects in the same trial (72 ± 8 beats/minute, P<0.001). Reference: Von Olshausen K et al. Am J Cardiol 1989;63:

7 This diagram shows normal thyroid function and feedback mechanisms (a), and the changes that occur when a patient has hyperthyroidism (b). Thyroid stimulating hormone (TSH) is secreted by the pituitary gland and acts on the thyroid to produce T 3 (triiodothyronine) and T 4 (thyroxine). The pituitary constantly monitors blood thyroid levels, and moderates its production of TSH accordingly. In those with Graves hyperthyroidism, usually blood levels of TSH are lower than normal and levels of T 3 and T 4 are higher than normal. This is caused by an antibody to the TSH receptor blocking TSH production causing the overproduction of the thyroid hormones. Source: Diseases of thyroid function: hyperthyroidism. Available from: Accessed February

8 There are a number of factors thought to be involved in the pathogenesis of Graves disease. Hereditary factors play a role, especially the inheritance of antigens DR3, DQ2 and DQA1*0501. Cigarette smoking increases the risk of Graves disease roughly 2-fold. Other causes include damage to the thyroid gland (radiation) and reduced numbers or dysfunctional regulatory T cells. The T lymphocyte suppressor cell (TSAb) and others bind to the thyrotrophin receptor, which stimulates the thyroid gland. This produces high levels of autoantibodies, thyroid damage and eventually cell death. The autoantibodies involved include antibodies and cell-mediated immunity to the thyroid stimulating hormone receptor, thyroid peroxidase and thyroglobulin. Also produced are antibodies to megalin (thyroid cell thyroglobulin receptor) thyroid iodide supporter and eye muscles and fibroblasts in patients with Graves ophthalmology. Autoimmunity, seen as elevation of ICAM-1, IL-6 and IL-8, also plays a role. Source: DeGroot LG. Thyroid Disease Manager, Graves disease and the manifestations of thyrotoxicosis. Updated July Available from: Accessed February

9 Silent (painless) thyroiditis is similar in presentation to Graves disease, is also an autoimmune condition, and can occur in both men and women. In silent thyroiditis, there may be a phase of high thyroid hormone levels, causing symptoms of an overactive thyroid gland, which may be followed by a phase of symptoms of an underactive thyroid, before the symptoms resolve, usually within months. Silent thyroiditis is not as serious as Graves disease; eye involvement is not a feature, and the two conditions can be separated by results of thyroid antibody tests. Source: Thyroiditis. Available from: Accessed February 2016.

10 Patients with Graves disease are at low risk of sudden cardiac arrest induced by thyroid storm. Most patients are treated for hyperthyroidism before symptoms are critical, and prompt recognition of the storm and agressive treatment has reduced mortality rates from the condition. Source: Bartalena L et al. Graves disease: complications, updated February Available from: Accessed February

11 Treatment of Graves disease with radioactive iodine or surgery necessitates lifelong levothyroxine replacement and monitoring of thyroid hormone levels. Surgery is favoured in patients with suspicious or malignant thyroid nodules, those with large goitres and those who cannot be treated with antithyroid drugs. Surgery is not without risk or potential complications. During pregnancy, antithyroid drugs are the primary therapy. Different countries vary in their choice of first-line therapy radioiodine is used more frequently in the US compared with Europe or parts of Asia. References: Burch HB et al. JAMA 2015;314: Abraham P et al. Ther Clin Risk Manag 2010;6:

12 This study followed 168 patients for 5 years after treatment of hyperthyroidism caused by Graves disease. Patients were treated with methimazole for 18 months, subtotal thyroidectomy, or iodine-131 therapy. The mean serum T 3, thyroxine and free thyroxine concentrations were within normal reference intervals for all subgroups within 6 weeks of the initiation of therapy. Worsening or the development of ophthalmopathy occurred in 33% of patients treated with iodine-131, compared with 10% of those treated with methimazole and 16% treated surgically. Reference: Tallstedt L et al. N Engl J Med 1992;326:

13 The benefits and risks of the three common treatments for Graves disease were assessed in this randomized clinical trial. The 179 patients were randomized according to age: those aged years (young adults) were treated with antithyroid drugs for 18 months (medical) or with subtotal thyroidectomy (surgical); the remaining 119 patients, aged years (old adults), received medical, surgical or radioiodine treatment. The risk of relapse was highest in medically treated young and old adults (42% and 34%), followed by those treated with radioiodine (21%) and then those treated surgically: young adults (3%) and old adults (8%). Reference: Tӧrring O et al. J Clin Endocrinol Metab 1996;81:

14 The effect of different therapies for Graves disease was tested in this group of newly diagnosed patients aged between 20 and 55 years. Patients received medical therapy for 18 months, thyroid surgery or radioiodine therapy (only if the patient was 35 years). L-thyroxine (L-T4) was added to therapy as needed to keep patients euthyroid. TSH-receptor antibodies (TRAb) were measured before and for 5 years after the initiation of therapy. The 48 patients receiving medical therapy and the 47 surgical patients had a gradual reduction in TRAb, with TRAb disappearing in 70-80% of patients after 18 months. The 36 patients receiving radioiodine experienced a 1-year long worsening of autoimmunity against the thyroid stimulating hormone receptor (TSH-r), but the number of patients with remission of TSH-r autoimmunity, with the disappearance of TRAb from serum, was lower than with the other types of therapy. Reference: Laurberg P et al. Eur J Endocrinol 2008;158:

15 Antithyroid drugs are used to block excess thyroid hormone production. Typically, a patient will take one of these two drugs for between 1 and 2 years. After this, the medication is stopped. If hyperthyroidism returns, as happens in 50% of patients, a more permanent solution to the disease is considered either radioiodine treatment or surgical removal of all, or part of, the thyroid gland. Source: Diseases of thyroid function: hyperthyroidism. Available from: endocrinediseases.org. Accessed February

16 Drug therapy for hyperthyroidism is used to prevent excess thyroid hormone production. The two drugs used most commonly are methimazole and propylthiouracil (PTU), with PTU being the preferred antithyroid agent during pregnancy. Less commonly used are perchlorate, which blocks iodine/iodide uptake into the thyroid gland, preventing the synthesis of thyroid hormones, and lithium, which causes biochemical hypothyroidism. Reference: Abraham P et al. Ther Clin Risk Manag 2010;6:

17 The pharmacological properties of the two most popular antithyroid drugs are compared in this slide. There is similarity between the drugs, but methimazole is generally the drug of preference due to its longer duration of action (so need for less frequent dosing), and its lower propensity to cause side-effects. References: Cooper DS. N Engl J Med 2005;352: Brent GA. N Engl J Med 2008;358:

18 Specific pharmacokinetic properties can determine the better drug in particular circumstances. Propylthiouracil is often preferred over methimazole during pregnancy and lactation due to its relatively lower propensity to cross the placenta and lower levels expressed in breast milk. Patients with concomitant liver disease may also preferentially be treated with propylthiouracil. Some women with Graves disease opt to receive radioiodine or surgical therapy prior to becoming pregnant, to avoid any potential teratogenic effects of antithyroid drugs during pregnancy. References: Cooper DS. N Engl J Med 2005;352: Brent GA. N Engl J Med 2008;358: Burch HB et al. JAMA 2015;314:

19 The two commonly used antithyroid medications, methimazole (MMI) and propylthiouracil (PTU) have similar side-effect profiles. Agranulocytosis occurs twice as often in patients taking PTU as in those taking MMI. With MMI therapy, the risk of agranulocytosis is dose-dependent the lower the dose, the lower the risk. Source: Milas K. Available from: Accessed February

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21 Beta blockers are often used in patients with Graves disease, despite not having any antithyroid effects themselves other than a slight decrease in the conversion of thyroxine to biologically active triiodothyronine. Graves disease patients have increased sensitivity to adrenaline, which, in conjunction with the increased thyroid hormone in their blood, can result in rapid heart beat, sweating, shakiness, anxiety, increased appetite, loss of weight and heat intolerance. These symptoms are alleviated by beta blockers when given in addition to antithyroid drugs or radioiodine. As the activity of the thyroid gland decreases from the antithyroid treatment, the dose of the beta blocker can be reduced and finally stopped. Source: DeCapito CA et al. Beta blockers in Graves disease, Graves disease and thyroid foundation. Available from: www://gdatf.org. Accessed February

22 This study examined consecutively presenting Graves disease patients between 1975 and 1998 to determine if simple clinical features, such as age, gender or smoking history could predict response to treatment. Patients (n=314) were initially treated with antithyroid drugs (carbimazole or propylthiouracil for 18 months), of whom 116 had successful medical treatment, and 198 needed to proceed to radioiodine or surgery. Factors predictive of a poor outcome included male gender, age <40 years, the presence of a medium or large goitre, high free T 3 levels and the presence of thyroid stimulating hormone receptor antibodies. A current history of smoking was associated with larger goitres and strongly associated with thyroid eye disease. Reference: Allahabadia A et al. J Clin Endocrinol Metab 2000;85:

23 This study was designed to test whether the addition of thyroxine (T 4 ) to antithyroid drugs reduced the rate of recurrence of hyperthyroidism in patients with Graves disease, as suggested by Hashizume et al in The study by McIver et al failed to find support for a reduction in the rate of recurrence, but did chart thyroid parameters (serum concentrations of thyrotropin, free T 3, T 4 and thyrotropin-receptor antibodies) in each patient every 3 months for 36 months. This showed that the administration of thyroxine did not interfere with the reduction in thyroid parameters, or the number of patients achieving a euthyroid state. Further work has suggested that the block and replace approach provides the patient with less fluctuation in their thyroid levels over the course of hyperthyroidism reduction. References: McIver B et al. N Engl J Med 1996;334: Hashizume K et al. N Engl J Med 1991;324: Vaidya B et al. Clin Endocrinol 2014;81:

24 Graves disease is a well-recognized condition. Most patients presenting with the condition will be effectively diagnosed and offered one of three treatments, depending on their age and individual health. Medical emergencies involving Graves disease are rare, and are more common in those undiagnosed. 24