HYPERTHYROIDISM

2. HYPERTHYROIDISM Maryam Vasheghani , MD Assistant Professor of Internal medicine _ Endocrinologist National Research Institute of Tuberculosis and Lung Disease Shahid Beheshti University of Medical Sciences, Tehran, Iran. JULY 2015

3. Definitions • Thyrotoxicosis • The clinical syndrome of hypermetabolism that results when the serum concentrations of free T4, T3, or both are increased • Hyperthyroidism • Sustained increases in thyroid hormone biosynthesis and secretion by the thyroid gland “The two terms are not synonymous” Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Dr. MVasheghani

4. Prevalence Women 2% Men 0.2% Dr. MVasheghani

5. Pathogenesis • genetic factors • polymorphisms in HLA-DR, CTLA-4, and PTPN22 (a T cell regulatory gene) • environmental • Stress • Smoking • Sudden increases in iodine intake • Autoimmunity • TSI • Anti-TPO • cytokines such as IFN-, TNF, and IL-1 Dr. MVasheghani

6. Autoimmune characteristics • Autoimmune thyroid disease is characterized by • The presence of antibodies against: - Thyroid peroxidase (Microsomal Ag) - Thyroglobulin - TSH receptor (disease specific) • T-cell mediated autoimmunity is also present. • Lymphocytes infiltrate thyroid gland. • Prevalence: 2.7% in female in U.K (F/M: 10/1) • Incidence: 1/1000 per year in female. Dr. MVasheghani

7. Pathogenesis of Graves orbitopathy and dermopathy Local lymphocytes Cytocines (IF) Fibroblast Glycosaminoglycan in E.O.M and adipose tissue Swelling Functional impairment in muscle Dr. MVasheghani Fibrosis of muscle

8. Hypothesis: Immune system recognizes an antigen common to the thyroid gland and retroorbital tissue (and skin) and is likely to be TSHR itself, the main antigen of Grave’s disease. Dr. MVasheghani

9. Clinical Symptoms • Depends on • Age of patient • Severity of the disease • Magnitude of hormonal excess • Presence of co-morbid condition • Clinical manifestations of hyperthyroidism are largely independent of its cause. • However, causing disorder may have other effects. • Older patient presents with lack of clinical signs and symptoms, which makes diagnosis more difficult Dr. MVasheghani

10. Mechanism of Clinical Symptoms • Catabolism • Enhancement of sensitivity to catecholamines Dr. MVasheghani

11. Clinical symptoms Dr. MVasheghani

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14. Toxic MNG (Diffuse) Graves Dr. MVasheghani

15. Ophthalmopathy in Graves Occular muscle palsy Lid Lag Dr. MVasheghani

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17. Palmarerythema Dermopathy Dr. MVasheghani

18. Thyroid Acropathy Clubbing and Osteoarthropathy Dr. MVasheghani

19. Onycholysis Dr. MVasheghani

20. Ophthalmopathy & Dermopathy • Risk factors in ophtalmopathy • All of the same risk factors apply to the onset of both thyroid and eye involvement in Grave’s disease. • Smoking • Radioiodine • Natural course of Grave’s disease • Variable • Dermopathy is a late manifestation 99% of patients have orbitopathy. Dr. MVasheghani

21. Histopathology • Thyroid gland is enlarged and uniformly affected (diffuse toxic goiter). • - Consistency • - Outer surface • Microscopy: Follicles are small and lined by hyperplastic columar epithelium and contain scant colloid. Papillary projections of epith. in to lumen of follicles coma vascularity is increased. • Infiltration of lymphocytes and plasma cells which may form germinal centers. • Treatment with iodine or antithyroid drugs causes involution & TSH Abs decrease. Dr. MVasheghani

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23. ETHIOLOGY • Increased hormone production • Primary Hyperthyroidism • Gravies disease (60-80% of thyrotoxicosis) • Toxic multinodular goiter • Toxic adenoma • Iodine-induced (Jod - Basedow) • Trophoblastic tumor • Scondary Hyperthyroidism • Extra-thyroidal hormone production • Increased hormone release • Exogenous Dr. MVasheghani

24. ETIOLOGIES OF THYROTOXICOSIS Dr. MVasheghani

25. PRIMARY HYPERTHYROIDISM • Grave’s disease • Autoimmune disease caused by antibodies to TSH receptors • Can be familial and associated with other autoimmune diseases • Graves' disease accounts for 60–80% of thyrotoxicosis. • Toxic multi-nodular goiter • 5% of all cases • 10 times more common in iodine deficient area • Typically occurs in older than 40 with long standing goiter Dr. MVasheghani

26. Risk factors for Grave’s disease • Genetic susceptibility • Infection • Stress • Gender and Gonadal steroids • Pregnancy • Iodine & drugs Dr. MVasheghani

27. Toxic adenoma • More common in young patients • Autonomically functioning nodule Dr. MVasheghani

28. Subacute Thyroiditis • Abrupt onset due to leakage of hormones • Follows viral infection • Resolves within eight months • Can re-occur • Lymphatic and postpartum Thyroiditis • Transient inflammation • Postpartum can occur in 5-10% cases in the first 3-6 months • Transient hypothyroidism occurs before resolution Dr. MVasheghani

29. Treatment Induced Hyperthyroidism • Iodine Induced • Excess iodine indirect • Exposure to radiographic contrast media • Medication • Excess iodine increases synthesis and release of thyroid hormone in iodine deficient and older patients with pre-existing goiters • Amiodarone Induced Thyroiditis • Up to 12% of patients, especially in iodine deficient cases • Most common cause of iodine excess in US. Dr. MVasheghani

30. Thyroid Hormone Induced • Factitious hyperthyroidism in accidental or intentional ingestion to lose weight • Tumors • -Metastatic thyroid cancer • -Ovarian tumor that produces thyriod hormone (struma ovarii) • -Trophoblastic tumor • -TSH secreting tumor Dr. MVasheghani

31. DIAGNOSIS • Typical clinical presentation • Abnormal TFT • Markedly suppressed TSH (<0.05 µIU/mL) • Elevated FT4 and FT3 (Markedly in Graves) • Thyroid antibodies by Elisa Positive (anti-TPO, TSI) • Nuclear Scintigraphy to differentiate the causes Dr. MVasheghani

32. Algorithm for Hyperthyroidism Measure TSH and FT4  TSH, FT4 N  TSH,  FT4 N TSH, FT4 N  TSH,  FT4 FNAC, N Scan Primary (T4) Thyrotoxicosis Pituitary Adenoma Measure FT3 High T3 Toxicosis Features of Grave’s Normal Sub-clinical Hyper Yes No  RAIU Low RAIU F/u in 6-12 wks Rx. Grave’s Sub Acute Thyroiditis, I2, ↑ Thyroxine Single Adenoma, MNG Dr. MVasheghani

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34. TFT Dr. MVasheghani

35. Etiology • Hyperthyroidism with low RIU • - Subacute thyroiditis • - Exogenous harmone intake • - Ectopic ovarii • - Metastatic follicular thyroid CA • - Radiation thyroiditis • - palpation thyroiditis • - Amiodarone induced Dr. MVasheghani

36. Etiology • Hyperthyroidism with high RIU • - Grave’s disease • - Toxic adenoma • - Toxic multinodular goiter • - TSH- producing pituitary adenoma • - Hyperemesis gravidarum • - Trophoblastic disease Dr. MVasheghani

37. DDX • panic attacks • Mania • Pheochromocytoma • weight loss associated with malignancy Dr. MVasheghani

38. Treatment • Treatment depends upon • -Cause and severity of disease • -Patients age • -Goiter size • -Comorbid condition • -Treatment desired • The goal of therapy is to correct hyper-metabaolic state consists of both rapid amelioration of symptoms with a beta blocker and measures aimed at decreasing thyroid hormone synthesis with fewest side effects and lowest incidence of hypothyroidism. Dr. MVasheghani

39. Treatment Options • Treatment of thyrotoxicosis • Control adrenergic symptoms • Anti coagulation • Anti-thyroid drugs • Radioactive iodine • Surgery • Beta-blocker and iodides are adjuncts to above treatment • Treatment of ophthalmopathy • High dose of glucocorticoids ±cyclosporine • Surgery • Retro orbital radiation Dr. MVasheghani

40. Beta Blockers • Prompt relief of adrenergic symptoms • Propranolol widely used • Any beta blocker can be used, but non-selectives have more direct effect on hyper-metabolism • Start with 10-20 mg q6h • Increase progressively until symptoms are controlled • Most cases 80-320 mg qd is sufficient • CCB can be used if beta blocker not tolerated or contraindicated Dr. MVasheghani

41. Iodides • Iodide blocks peripheral conversion of T4 to T3 and inhibits hormone release.These are used as adjunct therapy • Before emergency non-thyroid surgery • Beta blockers cannot curtail symptoms • Decrease vascularity before surgery for Grave’s disease • Iodides are not used for routine Rx. because of paradoxical increase of hormone release with prolonged use • Commonly used: • Radiograph contrast agents (Iopanoicacid,Ipodate sodium, Potassium iodide) Dr. MVasheghani

42. Anti-thyroid Drugs • They interfere with oxidation and organification of iodine  suppress thyroid hormone levels • Large dose of PTU ,MMI impairs T4T3 • Two agents: • -Tapazole (methimazole) • -PTU (propylthiauracil) • Remission rate: 60% when therapy continued for two yrs • Relapse in 50% of cases. • Relapse more common in -smokers -elevated TS antibodies at end of therapy Dr. MVasheghani

43. THIONAMIDS • Remission rate: 60% when therapy continued for two years • Relapse in 50% of cases. • Relapse more common in -smokers -elevated TS antibodies at end of therapy Dr. MVasheghani

44. Methimazole Drug of choice for non-pregnant patients because of : • Low cost • Long half life • Lower incidence of side effects • Can be given in conjunction with beta-blocker • Beta-blockers can be tapered off after 4-8 weeks of therapy • Dose 15-30 mg/day • Monthly Free T4 or T3 until euthyroid • Maintenance dose 5-10 mg/day • TSH levels may remain undetectable for months after euthyroid and not to be used to monitor the therapy Dr. MVasheghani

45. PTU • Prefered for pregnant patients(1ST trimester) • Methimazole is associated with rare genetic abnormalities Dose 100 mg t.i.d Maintenance 100-200 mg/day Goal: Keep Free T4 at upper level of normal Dr. MVasheghani

46. Anti-thyroid Drugs Complications • Agranulocytosis up to 0.5% • High with PTU • Can occur suddenly • Mostly reversible with supportive Tx • Routine WBC monitoring controversial • Some people monitor WBC every two weeks for first month then monthly • Advised to stop drug if they develop sudden fever or sore throat Dr. MVasheghani

47. Radioactive Iodine • Treatment of choice for Grave’s dis. and TMNG • Inexpensive and Safe • Highly effective and Easy to administer • Dose depends on estimated weight of gland • Higher dose increases success rate but higher chance of hypothyroidism and is favored in older patient • Cardiac disease • Other group needs prompt control • Toxic nodular goiter or toxic adenoma • Some studies have shown increase of hypothyroidism irrespective of dose • Higher dose Dr. MVasheghani

48. Radioactive Iodine Side effects • 50% of Grave’s ophthalmology can develop or worsen by use of radioactive iodine • Use 40-50 mg Prednisone for at least three months can prevent or improve severe eye disease in 2/3 of patients • Use lower dose in ophthalmology because post Tx hypothyroidism may be associated with exacerbation of eye disease • Smoking makes ophthalmopathy worse. Dr. MVasheghani

49. Radioactive Iodine • Use of anti-thyroid drugs with iodine is not recommended in most cases • May improve safety for severe or complicated cases • Withdraw three days before iodine Tx • Beta blockers used to control symptoms before radioactive iodine and can be combined throughout Tx • Iodine containing meds need to be stopped several weeks before therapy Dr. MVasheghani

50. Radioactive Iodine Safety • Most radioactive iodine is eliminated in the urine, saliva and feces in 4-8 weeks. • Have double flushing of toilet and frequent hand washing for several weeks • No close contact with children and pregnant patients for 48-72 hours • Additional Tx may be needed after three months if indicated Dr. MVasheghani