Jamie Shelly, PharmD PGY1 Community Pharmacy Resident UNC Eshelman School of Pharmacy/Kerr Drug May 15, 2012

1. Hyperthyroidism: Walking the Thyroid Tightrope Jamie Shelly, PharmD PGY1 Community Pharmacy Resident UNC Eshelman School of Pharmacy/Kerr Drug May 15, 2012

2. Disclosure I have no relationships with commercial interests related to the content of this presentation.

3. Objectives • Describe the etiology and pathophysiology of hyperthyroidism • Identify symptoms associated with hyperthyroidism • Explain the use of non-pharmacologic, pharmacologic, and adjunctive treatment strategies in patients with hyperthyroidism • Given patient cases, formulate appropriate recommendations and counseling for patients with hyperthyroidism

4. Thyroid Hormone System http://www.differencebetween.net/wp-content/uploads/2009/12/thyroid-system.jpg

5. Hyperthyroidism Pathophysiology http://www.differencebetween.net/wp-content/uploads/2009/12/thyroid-system.jpg

6. Hyperthyroidism Pathophysiology http://www.differencebetween.net/wp-content/uploads/2009/12/thyroid-system.jpg

7. Etiology Am Fam Physician. 2005;72(4):623-30. J Fam Pract. 2011;60(7):388-95.

8. Causes of Drug-Associated Hyperthyroidism Endocr Pract. 2011;17(3):456-520.

9. Signs and Symptoms http://images.findthebest.com/sites/default/files/blog_images/resource/hyperthyroidism_655.jpg

10. Signs and Symptoms http://www.beltina.org/pics/graves_ophthalmopathy.jpg https://www.nursingunlimited.com/Online_Classes/Courses/Graves_Disease/Graves_Disease_page1_clip_image008.jpg

11. Signs and Symptoms http://dermimages.med.jhmi.edu/images/colloid_goiter_2_080613.jpg http://2.bp.blogspot.com/-LpOZUA9RZVw/Tjg9HPGOOPI/AAAAAAAAA-g/47E8HlqpP9M/s1600/goiter.png http://www.thyroidimaging.com/gozzo_5.jpg

12. Poll Question Which of the following symptoms is NOT typically associated with hyperthyroidism? a. Increased heart rate b. Decreased appetite c. Increased irritability d. Decreased heat tolerance

13. Complications • Thyroid hormones influence nearly every tissue and organ system in the body • Increasebasal metabolic rate and thermogenesis • Decreaseserum cholesterol and systemic vascular resistance • Therefore, untreated hyperthyroidism can cause: • Weight loss • Osteoporosis • Embolic events • Atrial fibrillation • Cardiovascular collapse/death Circulation. 2007;116:1725-35. Endocrinol Metab Clin North Am. 1993; 22:263-77. Acta Endocrinol. 1993;128:230-34.

14. A Trio of Treatment Options Surgical intervention Radioactive iodine (RAI) Antithyroid drugs (ATD) http://4.bp.blogspot.com/_bmTd42i0Occ/TUb_XN1797I/AAAAAAAAMqw/yAjIDXfwRQ8/s1600/tightrop%2Bwalker%2Bbrighton%2Bdaily%2Bphoto%2Bbeach%2B143.jpg

15. 1. Surgical Intervention Advantages • Rapid • Effective, especially in patients with large goiters Disadvantages • Most invasive option • Most costly • Pain • Scarring • Permanent hypothyroidism • Potential for complications (e.g. laryngeal nerve damage, hypoparathyroidism) http://www.bloggingjunction.com/wp-content/uploads/2010/11/Advantages-And-Disadvantages.jpg Lancet. 2003;362:459-68.

16. Surgical Intervention http://static.ddmcdn.com/gif/about-weight-loss-surgery-ga-1.jpg Reserved for certain situations: Pediatric patients with severe disease Patients requiring immediate normalization of thyroid functions Presence of clinically suspicious or potentially malignant thyroid nodule • Intolerance or poor response to antithyroid drugs • Refusal to undergo radioactive iodine therapy • Presence of very large goiter (compressive symptoms or cosmetic reasons) • Pregnancy Am Fam Physician. 2005;72(4):623-30. J Fam Pract. 2011;60(7):388-95.

17. 2. Radioactive Iodine Advantages • Cures hyperthyroidism • Most cost effective Disadvantages • Permanent hypothyroidism is almost inevitable • May worsen ophthalmopathy • Pregnancy must be deferred 6-12 months • No breast-feeding • Potential risk of hyperthyroidism exacerbation http://www.bloggingjunction.com/wp-content/uploads/2010/11/Advantages-And-Disadvantages.jpg Lancet. 2003;362:459-68.

18. Radioactive Iodine • Concentrates in thyroid gland and destroys tissue • Generally requires a single dose • Up to 20% of patients require a second dose, given ~6-12 months after first dose • Thyroid function returns to normal 2-6 months after treatment • Hypothyroidism usually develops within 4-12 months Am Fam Physician. 2005;72(4):623-30. Thyroid.1998;8:653–59.

19. 3. Antithyroid Medications Advantages • Noninvasive • Lower initial cost • Low risk of hypothyroidism • Possible remissions Disadvantages • Low cure rate • Adverse drug reactions • Compliance Lancet. 2003;362:459-68. http://www.medicalscale1.com/wp-content/uploads/2011/03/balance-weight-scale.jpg

20. Antithyroid Medications (thioamides) • Inhibit thyroid hormone synthesis http://doctorsgates.blogspot.com/2010_12_13_archive.html

21. Antithyroid Medications (thioamides) • Goal of treatment is to render the patient euthyroid as quickly and safely as possible • Can be used as: • Primary treatment • Usually given for 6-18 months • Adjunctive therapy • Before RAI or surgery • After RAI or surgery if hyperthyroidism recurs Am Fam Physician. 2005;72(4):623-30.

22. Antithyroid Medications Imidazoles Thiouracils Methimazole [Tapazole] (MMI) Propylthiouracil (PTU) Carbimazole -Available only in Europe -Metabolized to methimazole immediately following ingestion Lancet. 2003;362:459-68.

23. Methimazole (MMI) • Generally drug of choice • Compared to PTU: • Lower cost • Longer half life (6-8 hours vs. 1-2 hours for PTU) • Fewer adverse effects • Starting dose=15-30 mg PO daily • Maintenance dose=5-10 mg per day Am Fam Physician. 2005;72(4):623-30.

24. Propylthiouracil (PTU) • At higher doses, blocks peripheral conversion of thyroxine (T4) to triiodothyronine (T3) • Preferred for pregnant women • Starting dose=100 mg PO TID • Maintenance dose=100-200 mg per day Am Fam Physician. 2005;72(4):623-30.

25. Research: MMI vs. PTU in Graves’ Disease J Clin Endocrinol Metab. 2007;92(6):2157-62.

26. Research: MMI vs. PTU in Graves’ Disease J Clin Endocrinol Metab. 2007;92(6):2157-62.

27. Research: MMI vs. PTU in Graves’ Disease J Clin Endocrinol Metab. 2007;92(6):2157-62.

28. Antithyroid Medication Adverse Effects Minor • Rash, fever, gastrointestinal upset, arthralgias Severe • Agranulocytosis • Most serious complication of ATD • Patients should be notified to discontinue ATDs immediately if they develop a fever or sore throat • Liver damage • Patients should be notified to discontinue ATDs if jaundice, dark urine, malaise or light-colored stools develop Lancet. 2003;362:459-68.

29. Research: Is Agranulocytosis Dose Related? Thyroid. 2009;19(6):559-63.

30. Research: Is Agranulocytosis Dose Related? Thyroid. 2009;19(6):559-63.

31. Poll Question A new physician calls your pharmacy requesting a methimazole starting dose for a patient newly diagnosed with severe Graves’ disease. He has not yet seen a patient with Graves’ and wonders whether it will be best to start the patient on 15 mg or 30 mg daily. Which would you recommend and why? a. 15 mg/day; is associated with fewer serious side effects than 30 mg/day b. 15 mg/day; is as efficacious as 30 mg/day in severe Graves’ disease c. 30 mg/day; is more efficacious than 15 mg/day in severe Graves’ disease d. 30 mg/day; is recommended starting dose in Graves’ disease of any severity

32. Antithyroid Medication Monitoring • Thyroid function should be assessed every 4-6 weeks for the first 4-6 months • Doses are adjusted based on clinical status and free T4 and T3 levels • TSH may remain low or undetectable for months after a patient becomes euthyroid • Therefore, TSH should NOT be used to monitor therapy http://media.ebcu.com/product/imgage/Security&Protection/2010102613/5d2a40b5d0d836631ab61bc587adc214.jpg Lancet. 2003;362:459-68.

33. Antithyroid Medication Relapse • Can occur in up to 50% of patients who respond initially • Regardless of regimen used • More likely in patients who: • Smoke • Have large goiters • Have elevated thyroid-stimulating antibody levels at the end of therapy • If relapse occurs, RAI or surgery is recommended, although ATD therapy can be restarted Arch Intern Med. 2000;160:1067-71. Eur J Endocrinol. 2002;147:583-9.

34. Adjunctive Treatment—Beta Blockers • Relieve adrenergic symptoms (e.g. tremor, heat intolerance, palpitations, nervousness) • Propranolol used most widely • Initial dose: 10-20 mg PO q 6 h • Increase until symptoms are controlled • Doses from 80-320 mg per day are usually sufficient • Calcium channel blockers can be used to reduce heart rate in patients who cannot tolerate beta blockers Ann Surg. 2001;233:60-4. CMAJ.2003;168:575-85.

35. Adjunctive Treatment—Iodides • Inhibit thyroid hormone release and block peripheral conversion of T4 to T3 • NOT used in routine treatment due to paradoxical increases in hormone release that may occur with prolonged use • May see used to reduce gland vascularity before surgery for Graves’ disease and before emergency nonthyroid surgery if beta blockers cannot control hyperthyroidism Arch Intern Med. 2000;160:1067-71. Thyroid. 2001;11:561-7.

36. How Does One Decide which Treatment to Use? Depends on: • Cause • Severity • Comorbid conditions • Goiter size • Patient age • Patient preference • Physician preference http://www.tednguyenusa.com/wp-content/uploads/2011/01/Social-media-guideline-post.jpg Am Fam Physician. 2005;72(4):623-30.

37. What do the guidelines say? • Most recent“Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists” • Published in 2011 • 100 evidence-based recommendations Endocr Pract. 2011;17(3):456-520.

38. TMNG & TA • Graves’ disease • Thyroiditis Guidelines—Choosing Treatment • RAI, ATDs, or surgery • Note: guidelines differ for pts with Graves’ ophthalmopathy (based on disease activity, severity, and smoking status) • RAIor surgery • Prolonged ATD tx may be best in individuals with limited longevity or at increased surgical risk • Beta blockers and NSAIDs • Those failing to respond or with moderate-to-severe Sx should be treated with corticosteroids (prednisone 40 mg daily x 1-2 wks) Endocr Pract. 2011;17(3):456-520.

39. Guidelines—ATDs • Methimazole should be used in virtually every patient who chooses ATDs, except: • First trimester of pregnancy • Thyroid storm • Patients with minor reactions to methimazole who refuse RAI or surgery Endocr Pract. 2011;17(3):456-520.

40. Guidelines—ATDs • Patients should be informed of ATD side effects and the necessity of informing the physician promptly if they should develop symptoms suggestive of agranulocytosis or hepatic injury • Before starting ATDs and at each subsequent visit, patients should be alerted to stop the medication immediately and call their physician when there are symptoms suggestive of agranulocytosis or hepatic injury Endocr Pract. 2011;17(3):456-520.

41. Guidelines—Beta Blockers • Should be given to • Symptomatic elderly patients • Patients with resting heart rates above 90 bpm • Patients with coexistent cardiovascular disease • Beta blockers should be considered in ALL patients with symptomatic hyperthyroidism Endocr Pract. 2011;17(3):456-520.

42. Research: Beta Blockers Proc West Pharmacol Soc. 2003;46:125-6.

43. Research: Beta Blockers Proc West Pharmacol Soc. 2003;46:125-6.

44. Guidelines—Beta Blockers Endocr Pract. 2011;17(3):456-520.

45. Poll Question Which patient diagnosed with hyperthyroidism would beleastlikely to benefit from beta blocker therapy? a. 83 yom with tremor and palpitations b. 56 yof with CHF, edema, and heat intolerance c. 19 yof with a heart rate of 93 bpm d. 62 yom with goiter, weight loss, and Graves’ ophthalmopathy

46. Guidelines—Labs • Prior to initiating ATDs, patients should have: • Baseline CBC including white count with differential • Liver profile • A differential WBC count should be obtained: • During febrile illness • At onset of pharyngitis • Routine monitoring of white blood counts is not recommended • Following thyroidectomy: • Serum calcium or intact parathyroid hormone • Administer oral calcium and calcitriol based on results Endocr Pract. 2011;17(3):456-520.

47. Subclinical Hyperthyroidism • Occurs in 1-2% of the US population • Characterized by TSH <0.1mU/L and normal levels of T3 and T4 • Causes are similar to overt hyperthyroidism • Carries significant health risks • Atrial fibrillation • Systolic and diastolic cardiac dysfunction • Decreased bone density • Increased risk of dementia J Fam Pract. 2011;60(7):388-95.

48. Guidelines—Subclinical Hyperthyroidism • If subclinical hyperthyroidism is to be treated, treatment should be based on etiology and follow the same principles as overt hyperthyroidism Subclinical Hyperthyroidism: When to Treat Endocr Pract. 2011;17(3):456-520.

49. Guidelines—Smoking and Graves’ Disease • “Clinicians should advise patients with Graves’ disease to stop smoking and refer them to a structured smoking cessation program” • Smoking is the most important known risk factor for the development or worsening of Graves’ ophthalmopathy • Risk is proportional to the number of cigarettes smoked per day Endocr Pract. 2011;17(3):456-520. http://www.howtostopsmokinghelp.com/

50. Research: Smoking and Thyroid Disorders Eur J Endocrinol 2002 ;146(2):153-61.