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MANAGEMENT OF THYROTOXICOSIS Michael D. Puricelli, MD Jeffrey B. Jorgensen, MD Overview • Case • Thyroid physiology • Etiology and pathophysiology of Thyrotoxicosis • Work-up of Thyrotoxicosis • Complications of Thyrotoxicosis • Management of Thyrotoxicosis Case • 31 y/o female patient is referred for “hyperthyroidism” • What are key historical and examination findings? History and Physical Exam • Comprehensive history: • Diagnostic clues: duration of symptoms, the degree and pattern of thyroid enlargement, autoimmune disease, ocular symptoms, other malignancies • Factors that impact treatment:prior neck surgery, therapeutic irradiation with I 131, External beam radiation, • Comprehensive physical examination • Measurement of pulse rate, blood pressure, respiratory rate, and body weight • Thyroid size; presence or absence of thyroid tenderness, symmetry, and nodularity • Pulmonary, cardiac, and neuromuscular function • Presence or absence of peripheral edema, ocular signs, or pretibial myxedema should be assessed. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Case • 6 months, progressively worsening • Rapid heart • • • • • beat/Palpitations Irritability, anxiety, fatigue Increased bowel movements Weight loss Heat intolerance No ocular changes • Physical Exam: • Tachycardia • Moist, warm skin • Fine tremor • Enlarged thyroid, nontender and no nodules palpated • Normal vision, no exophthalmos Case • Referring doctor obtained a TSH which was undetectable and Free T4 which is 3x normal. • What further diagnostic testing is appropriate? I-123 Uptake Scan Reference Normal Patient’s study Diagnosis? http://emedicine.medscape.com/article/121865-workup Case • Graves’ Disease • What are treatment options? • Which option is best for her? • I-131 • Antithyroid drugs • Surgery • If she chooses surgery, how should she be prepared prior to the procedure? Overview • Case • Thyroid physiology • Etiology and pathophysiology of Thyrotoxicosis • Work-up of Thyrotoxicosis • Complications of Thyrotoxicosis • Management of Thyrotoxicosis Thyroid Physiology • Two hormones are produced by the thyroid gland: • 3,5,3′-triiodothyronine (T3) . • 3,5,3′,5′-tetraiodothyronine or thyroxine (T4). • Created via iodination of tyrosine within tissue specific thyroglobulin. • Active hormone and precursors are stored within the follicular lumen. Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. http://www.chiro.org/nutrition/FULL/Peripheral_Metabolism_of_Thyroid.html Thyroid Physiology Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Thyroid Physiology • 100 micrograms of exogenous iodine is required daily to ensure adequate thyroid hormone production. • Thyroid gland concentrates iodine for use via sodium/iodide symporter in the basal membrane. • A sodium potassium antiporter maintains low intracellular sodium concentration. • Iodine travels to the apical membrane. • Pendrin is a protein which aids in release of iodine into the follicular lumen • Hypothyroidism, goiter, hearing loss Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Thyroid Physiology • Hormone synthesis occurs at the apical surface (thyroperoxidase). • Iodine is oxidized and transferred to thyrosyl residues on thyroglobulin • Making monoiodotyrosine (MIT) and di-iodotyrosine (DIT). • Iodotyrosine molecules are coupled • MIT + DIT = T3 • DIT + DIT = T4 Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Thyroid Physiology • Micropinocytosis is used to retrieve thyroglobulin into small vesicles • In lysosomes, the hormones and iodotyrosine precursors are cleaved from the polypeptide backbone • MIT and DIT are deiodinated and the iodine returns to the free iodine pool. • Some T4 is deiodinated to T3 prior to release. • T4 and T3 are released from the thyroid gland. Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Thyroid Physiology Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Thyroid Physiology • In the plasma <1% of thyroid hormones are free iodo- amino acids • The remainder are bound to proteins: thyroxine binding globulin (70%), transthyretin (10%), albumin (10-20%). • Thyroxine binding globulin has a lower affinity for T3 than T4 so there is a higher percentage of T3 is free (0.3% versus 0.2%). Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Thyroid Physiology • T4 must be deiodinated to T3 to exert much of its biological activity. • Three iodothyronine deiodinase enzymes • Type I deiodinase: Liver, kidney and thyroid – activated by TSH. Produces most circulating T3 • Inhibited by propylthiouracil • Type II deiodinase: CNS, pituitary, placenta, skin, thyroid. Produces T3 for local activity • Negatively regulated by thyroid hormone • Unaffected by PTU • Type III deiodinase: inactivates T4 and T3 by forming reverse T3. Present in brain, skin, placenta, fetal tissues Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Kumar: Robbins and Cotran Pathologic Basis of Disease, Professional Edition, 8th ed. Thyroid Physiology • TSH stimulates G protein receptor • Efflux of iodide into the follicle and uptake of colloid into the thyrocyte as well as release of T4, T3. • Increases synthetic enzyme expression • Increased T3 production relative to T4. • Increasing doses of iodine • Increases hormone synthesis initially, but then reverses as intrathyroid levels of iodide reach a critical level, and further organification is inhibited. • With prolonged TSH-stimulation cell proliferation eventually leads to goiter Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Overview • Case • Thyroid physiology • Etiology and pathophysiology of Thyrotoxicosis • Work-up of Thyrotoxicosis • Complications of Thyrotoxicosis • Management of Thyrotoxicosis Definitions • Thyrotoxicosis • Clinical state from excessive thyroid hormone action in tissues • Hyperthyroidism • Type of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone from the thyroid gland. Thyrotoxicosis • Prevalence estimated 2% in the US based upon cross- sectional study. • More common in older individuals and women (10:1) • Hyperthyroidism • Overt: • High T4 and T3 with low TSH • Subclinical: • Normal T4 and T3 with low TSH Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5 th Ed. Canaris GJ, et al: The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160:526. Helfand M, Redfern CC. Clinical guideline, part 2. Screening for thyroid disease: an update. American College of Physicians. Ann Etiology of Thyrotoxicosis • Inappropriate thyroid stimulation by trophic factors • Constitutive activation of thyroid hormone synthesis and secretion • Stores of preformed hormone are passively released in excessive amounts • Exposure to extra-thyroidal sources of thyroid hormone Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Etiology of Thyrotoxicosis • Inappropriate thyroid stimulation by trophic factors (60- 85%) • Graves Disease • Thyrotropin receptor antibodies stimulate the TSH receptor causing increased hormone production Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Etiology of Thyrotoxicosis • Constitutive activation of thyroid hormone synthesis and secretion leading to autonomous release of excess thyroid hormone • Activating mutations in genes regulating thyroid hormone synthesis • Activating mutations of the TSH receptor • Toxic multinodular goiter in 10-30% of patients • Toxic Adenomas in 2-20% of patients Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Etiology of Thyrotoxicosis • Stores of preformed hormone are passively released in excessive amounts • Inflammation of thyroid tissue due to autoimmune, infectious, chemical, or mechanical insult • Painless thyroiditis is the etiology of about 10% of hyperthyroidism in the post-partum period (post partum thyroiditis) • Subacute thyroiditis is thought to arise from viral infection • Drugs: Lithium, interferon-alpha, amiodarone Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Etiology of Thyrotoxicosis • Exposure to extra-thyroidal sources of thyroid hormone • Endogenous • Struma ovarii • Metastatic differentiated thyroid cancer • Exogenous • Factitious thyrotoxicosis Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet. 2012 Mar 24;379(9821):1155-66. doi: 10.1016/S0140-6736(11)60782-4. Epub 2012 Mar 5. Review. PubMed PMID: Overview • Case • Thyroid physiology • Etiology and pathophysiology of Thyrotoxicosis • Work-up of Thyrotoxicosis • Complications of Thyrotoxicosis • Management of Thyrotoxicosis Work-up of Clinically or Incidentally Discovered Thyrotoxicosis • TSH concentrations • Circulating thyroid hormone levels • Thyroidal I-123 uptake scan Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Biochemical Evaluation • • There is an inverse log-linear relationship between free T4 and TSH such that small changes in free T4 result in large changes in TSH. Third generation assays represent the most sensitive test for TSH offering ability to detect differences of 0.01 mU/L. de los Santos ET, Starich GH, Mazzaferri EL. Sensitivity, specificity, and cost-effectiveness of the sensitive thyrotropin assay in the diagnosis of thyroid disease in ambulatory patients. Arch Intern Med. 1989 Mar;149(3):526-32. PubMed PMID: 2493228. Biochemical Evaluation • If hyperthyroidism is strongly suspected, diagnostic accuracy improves if serum TSH and T4 are measured at the same time. • In early stages of hyperthyroidism (usually from adenomas), T3 may be elevated and free T4 normal. • Called “T3 toxicosis” • Free T3 measures are less well validated than free T4 so total T3 is usually preferred Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet. 2012 Mar 24;379(9821):1155-66. doi: 10.1016/S0140-6736(11)60782-4. Epub 2012 Mar 5. Review. PubMed PMID: Radioactive Iodine Uptake Test • Indicated when the clinical presentation of thyrotoxicosis is not • • • • diagnostic of Graves’ disease (symmetric enlarged thyroid, recent onset of ophthalmopathy, and moderate to severe hyperthyroidism). Performed by administering an isotope of iodine (usually I-123) orally and measuring the percentage of the I-123 trapped by the thyroid gland. The test is usually performed 24 hours after administration of the isotope, although this may be done earlier. The principal usefulness of this test is in differentiating hyperthyroidism into high-uptake (focal vs diffuse) or low uptake states with uncertain diagnosis. Not to be done in pregnancy. Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Radioactive Iodine Uptake Test Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Pattern of Uptake is Diagnostically Useful (A) Normal thyroid • http://emedicine.medscape.com/article/2094805-overview Pattern of Uptake is Diagnostically Useful (A) Normal thyroid (B) Graves disease (C) Plummer disease (toxic multinodular goiter) (D) Toxic adenoma (E) Thyroiditis • http://emedicine.medscape.com/article/2094805-overview Additional Diagnostic Testing • Indicated when radioactive iodine uptake test is contraindicated or not useful (pregnancy, recent iodine exposure etc.) • Measurement of thyrotropin receptor antibodies (TRAb) • TRAb: Sensitive (99%) and specific (95%) for Graves’ Disease • Ratio of total T3 to total T4 • Elevated >20 (T3/T4) in Graves’ Disease and Toxic nodular goiter, while <20 in painless or postpartum thyroiditis • Factitious thyroiditis • Associated with low thyroglobulin level • Ultrasonography • Flow may differentiate between Graves’ Disease and Destructive thyroiditis Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Thyroid Scan • A thyroid scan should be done in patients with thyrotoxicosis and thyroid nodularity. • Thyroid cancer in Graves’ Disease has a frequency of 2% or less. • When a palpable, a hypofunctional thyroid nodule is found in a patient with Graves’ disease, it has about 45% probability of being a malignancy. Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5th Ed. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Overview • Case • Thyroid physiology • Etiology and pathophysiology of Thyrotoxicosis • Work-up of Thyrotoxicosis • Complications of Thyrotoxicosis • Management of Thyrotoxicosis Complications of Thyrotoxicosis • Interestingly, there is only moderate correlation between elevation in thyroid hormone concentration and clinical signs/symptoms. • In 25 patients with Graves’ Disease, Hyperthyroid Symptom Scale scores: • Correlate inversely with age and thyroid size • Scores did not correlate with free T4 or T3 Trzepacz PT, Klein I, Roberts M, Greenhouse J, Levey GS. Graves' disease: an analysis of thyroid hormone levels and hyperthyroid signs and symptoms. Am J Med. 1989 Nov;87(5):558-61. PubMed PMID: 2816972. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Complications of Thyrotoxicosis • Weight loss • Osteoporosis • There are also increased fracture rates in post menopausal women with subclinical hypothyroidism • Bone mineral density is improved after treatment with antithyroid drugs or radioactive iodine. • Atrial fibrillation • Among those with subclinical hypothyroidism, 2.8 fold higher risk of atrial fibrillation among those >60 years • Improvement is noted with restoration of euthyroid state or beta blockers. • Embolic events • Cardiovascular collapse Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Overview • Case • Thyroid physiology • Etiology and pathophysiology of Thyrotoxicosis • Work-up of Thyrotoxicosis • Complications of Thyrotoxicosis • Management of Thyrotoxicosis Management of Thyrotoxicosis • Symptomatic control • Disease Specific Management • Graves’ Disease • Toxic Multinodular Goiter • Toxic Adenoma • Special Considerations Symptomatic Control • Beta blockers are useful in almost all forms of thyrotoxicosis, while antithyroid drugs are useful only in some. • Decrease in heart rate, systolic blood pressure, muscle weakness, and tremor. • It improves irritability, emotional variability, and exercise intolerance • Beta-adrenergic blockade should be given to thyrotoxic patients with resting heart rates >90 beats per minute or cardiovascular disease • Beta-adrenergic blockade should be given to children with symptoms of hyperthyroidism or HR >100 bpm • Beta-adrenergic blockade should be considered in all patients with symptomatic thyrotoxicosis Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Management of Thyrotoxicosis • Symptomatic control • Disease Specific Management • Graves’ Disease • Toxic Multinodular Goiter • Toxic Adenoma • Special Considerations Graves’ Disease • In a randomized controlled trial, patients receiving treatment with antithyroid medication, I-131 or surgery were compared. • • • • • 20-34 yr: received antithyroid drugs for 18 months (medical) or subtotal thyroidectomy 35-55 yr of age, received medical, surgical, or radioiodine (iodine-131) treatment Follow-up time was at least 48 months All treatments normalized the mean serum hormone levels within 6 weeks The risk of relapse was highest in the medically treated young and old adults (42% vs. 34%), followed by that in those treated with iodine-131 (21%) and than in the surgically treated young and old adults (3% vs 8%), respectively Torring O, Tallstedt L, Wallin G, et al. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine—a prospective, randomized study. Thyroid Study Group. J Clin Endocrinol Metab 1996; 81: 2986–93. Graves’ Disease • Torring et al continued: • Satisfaction (below) • Conclusion: The increased risk of ophthalmopathy in patients with high serum T3 levels, especially when treated with iodine-131, and the relatively high frequency of relapse after treatment with antithyroid drugs are important factors to consider when selecting therapy for Graves' disease. • Patients with overt Graves’ hyperthyroidism should be treated with any of the following modalities: I-131 therapy, antithyroid medication, or thyroidectomy Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Anti-thyroid Drugs for Graves’ Disease Favorable Considerations: • High likelihood of remission • • • • • (females, with mild disease, small goiters, and negative or low-titer TRAb) Elderly or others with comorbidities increasing surgical risk or with limited life expectancy Individuals in nursing homes or other care facilities who may have limited longevity and are unable to follow radiation safety regulations Patients with previously operated or irradiated necks Lack of access to a high-volume thyroid surgeon Moderate to severe active Graves’ Ophthalmopathy. Contraindications: • Previous known major adverse reactions to ATDs. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. Anti-thyroid Drugs • Goal in Graves’ Disease is to achieve euthyroidism while awaiting spontaneous remission (~30% in Graves’ Disease, higher in selected populations). • Methimazole and propylthiouracil • Inhibit thyroid hormone biosynthesis by inhibiting the oxidation and organification of iodine and the coupling of iodotyrosines (thyroid peroxidase) • Propylthiouracil also inhibits the thyroidal and extrathyroidal conversion of T4 to T3 • Neither drug has an effect on the release of thyroid hormones stored in the thyroid gland. • Most patients have normalized T4 in 8-12 weeks. • Methimazole and PTU have immunosuppressive actions that may contribute to the occurrence of remissions of Graves’ disease. Pellitteri, PK. Ing, S. Jameson, B. Chapter 123 Disorders of the Thyroid Gland. Cummings Otolaryngology Head & Neck Surgery. 5 th Ed. Anti-thyroid Drugs • Methimazole should be used in virtually all patients choosing antithyroid drug therapy except during the first trimester of pregnancy, treatment of thyroid storm, and in patients with minor reactions to methimazole who refuse I-131 and surgery. • Methimazole is dosed once daily, while propylthiouracil requires multiple daily administrations • Methimazole compliance 83%. • Propylthiouracil compliance 53%. • Methimazole use in the first trimester is associated with choanal and esophageal atresia • A “block and replace” therapeutic strategy has been executed in some cases, however, this is not recommended due to increased adverse effects Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Adverse Effects of Antithyroid Drugs • A CBC with differential should be obtained during febrile illness and at the onset of pharyngitis in all patients taking antithyroid medications. • Liver function and hepatocellular integrity studies (CMP) should be checked with evidence of hepatic dysfunction. Duration of Anti-thyroid Drug Therapy • If methimazole is chosen as primary therapy for Graves’ Disease, it should be continued for 12-18 months and then tapered/stopped if the TSH is normal • Thyrogen receptor antibodies should be measured prior to cessation, as normal levels predict greater chance for remission. • Mild disease, small goiters and negative TRAb have remission rate >50% • If remission is not achieved in patients with Graves’ Disease by 12-18 months, consideration should be given to alternative treatments, though methimazole may be continued if patients prefer this approach. • Remission rate does not improve with treatment longer than 18 mo Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 I-131 For Graves’ Disease Favorable Considerations: • Females planning a pregnancy • • • • in the future (more than 4–6 months following radioiodine therapy, provided thyroid hormone levels are normal). Individuals with comorbidities increasing surgical risk. Previously operated or externally irradiated necks. Lack of access to a highvolume thyroid surgeon. Contraindications to antithyroid drug use. Contraindications: • Pregnancy, lactation, females planning a pregnancy within 4–6 months. • Coexisting thyroid cancer, or suspicion of thyroid cancer. • Individuals unable to comply with radiation safety guidelines Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. I-131 Administration • Sufficient radiation should be administered in a single dose to make the patient hypothyroid • 10 mCi leads to hypothyroidism in 69% at 1 year • 15 mCi leads to hypothyroidism in 75% at 6 mo. • Hypothyroidism may occur as soon as within 4 weeks, but most commonly between 2-6 months post treatment • If hyperthyroidism persists >6 mo or response if minimal after 3 mo, retreatment with I-131 is recommended. • Surgery should be considered in patients with refractory hyperthyroidism to several treatments. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 I-131 Administration • Once, euthyroid, there is no evidence of reduced fertility and offspring show no increased rate of congenital anomalies • Women should stop breastfeeding at least 6 weeks prior to treatment to prevent concentration in the breast tissue • There is a long-term increase in cardiovascular and cerebrovascular deaths after I-131 therapy • Thought to be due to hyperthyroidism rather than treatment • One study showed an increase in cancer deaths following treatment, however, other studies have failed to demonstrate this finding. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Malignancy After I-131 Treatment • The pediatric study with the longest follow-up reported 36- year outcomes of 116 patients. • The patients ranged in age at treatment from 3 to 19 years. No patient developed thyroid cancer or leukemia. • A study using phantom modeling, estimated that at 0, 1, 5, 10, and 15 years of age, and adulthood, respective total body radiation activities are 11.1, 4.6, 2.4, 1.45, 0.90, and 0.85 rem (1 rem = 0.1 Sv) Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Theoretical Projections of Cancer Incidence for I-131 Therapy I-131 should be avoided in children <5 yr, though it is acceptable for ages 5-10 yr if the calculated dose is <10 mCi. I-131 is acceptable for children >10 years if the activity is >150 mCi/g thyroid tissue. Toohey RE, Stabin MG, Watson EE. The AAPM/RSNA physics tutorial for residents: internal radiation dosimetry: principles and applications. Radiographics. 2000 Mar-Apr;20(2):533-46; quiz 531-2. PubMed PMID: 10715348. Mortality after I-131 • A population-based study of mortality in a cohort of 7209 subjects with hyperthyroidism who were treated with radioactive iodine. Causes of death were compared with data on age-specific mortality. • During 105,028 person-years of follow-up, • Standardized mortality ratio, 1.1; 95 percent confidence interval, 1.1 to 1.2; P<0.001). • The risk was increased for deaths related to the following: • Thyroid disease (standardized mortality ratio, 24.8; 95 percent confidence interval, 20.4 to 29.9), • Cardiovascular disease (standardized mortality ratio, 1.2; 95 percent confidence interval, 1.2 to 1.3) • Cerebrovascular disease (standardized mortality ratio, 1.4; 95 percent confidence interval, 1.2 to 1.5) • Fracture of the femur (26 excess deaths; standardized mortality ratio, 2.9; 95 percent confidence interval, 2.0 to 3.9). Franklyn JA, Maisonneuve P, Sheppard MC, Betteridge J, Boyle P. Mortality after the treatment of hyperthyroidism with radioactive iodine. N Engl J Med. 1998 Mar 12;338(11):712-8. PubMed PMID: 9494147. Antithyroid Drugs vs I-131 • Prospective observational population based study of 1,086 subjective age >40 yr treated with either antithyroid drugs of I-131 • 12 868 person-years of follow-up • Standardized mortality ratio 1.15 for the population • All-cause mortality was increased during thionamide treatment (SMR, 1.30 [95% CI, 1.05-1.61]) and after 131-I not associated with hypothyroidism (SMR, 1.24 [95% CI, 1.04-1.46]; P = .01) • After I-131 treatment requiring T4 replacement (SMR, 0.98 [95% CI, 0.82-1.18]; P = .85). Boelaert K, Maisonneuve P, Torlinska B, Franklyn JA. Comparison of mortality in hyperthyroidism during periods of treatment with thionamides and after radioiodine. J Clin Endocrinol Metab. 2013 May;98(5):1869-82. doi: 10.1210/jc.2012-3459. Epub 2013 Mar 29. PubMed PMID: 23543662. Surgery for Graves’ Disease Favorable Considerations: • Symptomatic compression or large • • • • • goiters (≥80 g) Thyroid malignancy is documented or suspected (e.g., suspicious or indeterminate cytology) Large nonfunctioning, photopenic, or hypofunctioning nodule Coexisting hyperparathyroidism requiring surgery Females planning a pregnancy in <4–6 months (i.e., before thyroid hormone levels would be normal if radioactive iodine were chosen as therapy), especially if TRAb levels are particularly high Patients with moderate to severe active Graves’ Ophthalmopathy. Contraindications: • Substantial comorbidity such as cardiopulmonary disease, end-stage cancer, or other debilitating disorders • Pregnancy is a relative contraindication and should only be used in this circumstance, when rapid control of hyperthyroidism is required and antithyroid medications cannot be used. • Thyroidectomy is best avoided in the first and third trimesters of pregnancy because of teratogenic effects associated with anesthetic agents and increased risk of fetal loss in the first trimester and increased risk of preterm labor in the third. • Optimally, thyroidectomy is performed in the latter portion of the second trimester. Although it is the safest time, it is not without risk (4.5%–5.5% risk of preterm labor) Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. Surgery • Near total or total thyroidectomy may be performed for treatment of Graves’ Disease. • Near total: 8% recurrence at 5 years post-op • Total: nearly 0% recurrence. • Surgery should be done by a high volume thyroid surgeon. • Thyroid procedures in Maryland between 1991 and 1996 reviewed by surgeon volume. • <10 Cases • Length of stay 1.9 days • Complications 8.6% • 10-100 Cases length of stay • Length of stay 1.7 days • Complications 6.1% • >100 Cases length of stay • Length of stay 1.4 days • Complications 5.1% Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Nov;22(11):1195. PubMed PMID: 21510801. Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R. The importance of surgeon experience for clinical and economic Graves’ Ophthalmopathy • Present in approximately 50% of patients with Graves’ Disease, severe in 5% • Natural history: rapid deterioration followed by gradual improvement • Quality of life is impaired by the condition and current therapeutic approaches fail to significantly improve quality of life • Prevention is the focus of treatment • Several retrospective cohort studies and randomized trials have compared the risk of Graves’ Ophthalmopathy development or progression after therapy (15% and 33%) • One RCT found that risk to be 23/150 (15%) for radioactive iodine, compared with 4/148 (3%) for antithyroid drugs • Another RCT 13/39 (33%) for radioactive iodine compared with 4/38 (10%) for antithyroid drugs and 6/37 (16%) for surgery • In contrast, one prospective but nonrandomized cohort study identified no difference among antithyroid drugs, surgery, and radioactive iodine treatment, with an overall 4.9%–7.1% frequency of GO development Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. Graves’ Ophthalmopathy • All therapies (antithyroid drugs, I-131 and surgery) are considered appropriate for patients with Graves’ Ophthalmopathy except in certain situations. • Patients with Graves’ hyperthyroidism and active moderate-tosevere or sight-threatening ophthalmopathy should be treated with either methimazole or surgery • Comparison of two different surgical approaches (total thyroidectomy vs. subtotal thyroidectomy) for patients with moderate-to-severe GO showed that the eye disease improved over 3 years of follow-up in all patients. • In another series of 42 patients with progressive GO treated with total thyroidectomy, exophthalmos was stable in 60% of cases and improved in the remainder • Limited data of other treatments in this population, however, antithyroid drugs are also felt to be safe. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Surgery - Preparation • Thyroid storm is a risk from the stress of surgery, anesthesia, or thyroid manipulation. • Patients undergoing surgery for Graves’ Disease, TMNG, or TA should be rendered euthyroid with methimazole prior to surgery whenever possible. • Typically takes 4-6 weeks • Potassium iodide should be given in the immediate pre-operative period in Graves’ Disease. • Iodide administration pre-operatively decreases thyroid blood flow, vascularity, and intraoperative blood loss during thyroidectomy. • Mechanism: reduced thyroglobulin proteolysis and inhibited thyroidal iodine transport, oxidation, and organification. • When it is not possible to render a patient with Graves’ Disease euthyroid prior to thyroidectomy, beta blockade should be initiated along with potassium iodide. • Antithyroid drugs should be stopped at the time of thyroidectomy and betablockers weaned following surgery. • Following thyroidectomy, levothyroxine should be started at a daily dose appropriate for the patient’s weight (0.8 microgram/pound or 1.7 microgram/kg) and TSH measured at 6-8 weeks post-operatively. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Thyroid Storm Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Thyroid Storm • Multimodality treatment approach is indicated • • • • • • • • Beta blockade Antithyroid drug therapy Inorganic iodide Corticosteroids Antipyretics Cooling blankets Volume resuscitation Respiratory support. Toxic Multinodular Goiter & Toxic Adenoma • Patients with TMNG or TA should be treated with either I-131 or thyroidectomy. On occasion, low dose treatment with methimazole may be appropriate. • TMNG • <1% risk of needing further treatment following total or near total thyroidectomy, cessation of thyroid hormone secretion within days, need for exogenous thyroid replacement in 100%, 100% improvement in compressive symptoms • I-131 therapy has a 20% retreatment rate, 50-60% response by 3 months and 80% by 6 months, and hormone replacement in 3% at one year and 64% at 24 years, 46% improvement in compressive symptoms • TA • Surgical treatment failure <1%, following lobectomy 2.3% have hypothyroidism • I-131 there is a 6-18% risk of persistent hyperthyroidism and 5.5% risk of recurrent hyperthyroidism, 75% response rate within 3 months, risk of hypothyroidism increases with time (8% by 1 year and 60% by 20 years), reduction in nodule volume noted up to 24 months after treatment Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of Antithyroid Drugs for TMNG or TA • No spontaneous/induced remission as in Graves’ Disease, however, this may be the best choice for some patients. Alternative Treatments • Toxic adenoma: Percutaneous ethanol injection under sonographic guidance demonstrated cure rate (absent uptake of the nodule) in 93% and major complication rate of 3% • Reduced volume of nodules by 66%. • Limited experience, “PEI or alternative treatments should be employed only in the very rare situation when standard therapies have failed, are contraindicated or refused”. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN; American Thyroid Association; American Association of Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593-646. doi: 10.1089/thy.2010.0417. Epub 2011 Apr 21. Erratum in: Thyroid. 2011 Oct;21(10):1169. Thyroid. 2012 Summary Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet. 2012 Mar 24;379(9821):1155-66. doi: 10.1016/S0140-6736(11)60782-4. Epub 2012 Mar 5. Review. PubMed PMID: 22394559.