1. BENIGN DISEASES OF THE THYROID Rivka Dresner Pollak M.D Endocrinology.

2. Thyroid gland- anatomy

3. sternocleidomastoid thyroid esophagus trachea jugular v. carotid a. strap muscles vertebra

5. Recommended and Typical Values for Dietary Iodine Intake Recommended Daily Intakeμg I/day Adults150 During pregnancy200 Children90-120 Typical Iodine intakes North America75-300 Europe (Germany, Belgium)50-70 Switzerland130-160 Chile <50-150

7. Thyroid secretion P Protein Bound Thyroid hormone Free T 4, T 3 Tissue action Hormone metabolism Fecal excretion Serum thyroid hormone binding Feedback control

8. TBG = thyroxine binding globulin TTR = transthyretin % binding- mostly to TBG T4 - 99.5 T3- 95 DEIODINASE TYPE 1 & 2 THYROXINE BINDING GLOBULIN Estrogen  Androgen =  Glucocorticoids =  Acute illness N Chronic illness  Liver dis.  METABOLISM TRANSPORT THYROID HORMONES TRANSPORT AND METABOLISM

9. Serum protein binding of thyroid hormones Total T 4 TBG T4T4 T4T4 T4T4 T4T4 T4T4 T4T4 T4T4 T4T4 “Pill effect” Bound Free  synthesis By liver

11. Regulation of Thyroid hormone secretion Hypothalamus T 4, T 3 TSH (-) (+) TRH (+) (-) Pituitary Thyroid

12. Assessment of bioactive thyroid hormones Check free hormone levels: Free T 4 Free T 3 Check thyroid hormone “biosensor’: TSH

13. Thyroid function tests Hypo Hyper 1 o Hypo 1 o Hyper 1 o Hypo 1 o Hyper TSH FT 3 nmol/L FT 4 pmol/L 0.15 4 3.0 1.2 21 10

14. Laboratory tests in thyroid disease Anti-thyroid antibodies: Anti-thyroid peroxidase (TPO) Thyroid stimulating antibodies: TSI-Thyroid stimulating imunoglobulins TSH receptor Antibody Thyroglobulin

15. 2. Thyroid scanning Radioactive isotopes of I ( 131 I, 123 I) Pertechnetate Generates Data on: - Anatomy - Physiology

16. Normal thyroid scan

17. “Hot nodule”

18. “Cold” nodule

19. Multinodular goiter (MNG) Pertechnetate scanCHEST X-RAY

20. Radio Active Iodine Uptake (RAIU) 06121824 0 10 20 30 40 50 Time (hours) Hyperthroidism Normal Hyperthyroidism with Rapid turnover Hypothroidism 2

21. Thyroid abnormalities FunctionStructure HyperthyroidismHypothyroidism Etiology RXRXRXRX Thyroiditis Goiter Nodular Diffuse BenignMalignant Function nl 

22. Hyperthyroidism-Etiology Diffuse toxic goiter (Graves’ disease)- most common in young people Toxic adenoma (Plummers’ diesease) Toxic mulitinodular goiter (MNG) Subacute thyroiditis-Hyperthyroid phase Hyperthyroid phase of Hashimotos’ thyroiditis (“Hashitoxicosis) Factitious hyperthyroidism Rare causes:-TSHoma -Hydatidiform mole/choriocarcinoma - Multiplex pregnancy - Struma ovarii

23. Graves’ disease Diffuse toxic goiter Opthalmopathy Opthalmopathy Dermopathy Dermopathy Acropathy (clubbing)Acropathy (clubbing) Etiology:Autoimmune Anti-TSH receptor antibodies (stimulating, blocking, neutral) Anti-thyroid antibodies  expression of HLA-DR3  association with: - diabetes mellitus-type 1myasthenia gravis -Addison’s diseaselupus - pernicious anemia

24. Epidemiology : incidence 0.3-1.5/1000 Female: Male 5:1 Most Common cause of hyperthyroidism Graves’ disease

25. Thyroid and pituitary function in Graves’ disease  T 4,  T 3  TSH (+) (-) (+) Thyroid Stimulating Immunoglobulins (TSI)

26. Graves’ disease- Clinical features Symptoms: Fatigue palpitations Weight loss Heat intolerance Frequent bowel movements Sweating hyperkinesia Signs: Tachycardia Muscle wasting  pulse pressure Eye signs Diffuse goiter Lymphadenopathy Splenomegaly Hyperreflexia In the elderly:cardiovascular symptoms, myopathy

27. Graves’ Disease- Goiter

28. Graves disease- Opthalmopathy Extrathyroidal TSHR is present in retro-orbital adipocytes, muscle cells and fibroblasts

29. Grave’s Opthalmopathy Class 0 — No symptoms or signs Class I — Only signs, no symptoms (eg, lid retraction, stare, lid lag) Class II — Soft tissue involvement Class III — Proptosis Class IV — Extraocular muscle involvement Class V — Corneal involvement Class VI — Sight loss (optic nerve involvement)

30. Graves’ disease dermopathy

31. Graves disease- diagnosis Clinical hyperthyroidism Biochemistry:FT 4 , TT 3 , TSH  cholesterol  Serology:anti-TSH receptor antibodies anti-thyroid antibodies

32. Graves’ disease- therapy 1. Antithyroid drugs: Propylthiouracil (PTU) Thionamides-Propylthiouracil (PTU) Methimazole (MMI)  -blockers 3. Definitive therapy: 131 I- side effects: hypothyroidism Surgery-subtotal thyroidectomy side effects:anesthesia morbidity hypoparathyroidism recurrent laryngeal nerve damage hypothyroidism Treat for 12 months ~30%remission 70% Recurrence Or non-remission Follow-up

33. Anti-thyroid thionamide drugs PTU (propylthiouracil)MMI (methimazole) Dosage:TIDOnce daily Effect:  T 4, T 3  synthesis  T 4, T 3  synthesis inhibits T4→T3(high dose)(slow) Agranulocytosis*:Non-dose dependentDose dependent (> 40 mg/day)   > 40 yrs Pregnancy:  placental transfer  placental transfer aplasia cutis *occurrence 0.3-0.6%

34. Treatment of Graves' Orbitopathy Treatment of patients with Graves' orbitopathy has three components: Reversal of hyperthyroidism, if present Symptomatic treatment Treatment with a glucocorticoid, orbital irradiation, orbital decompression surgery to reduce inflammation in the periorbital tissues Anti thyroid drugs and thyroidectomy are safe; Radioactive iodine may worsen the situation.

35. The effect of high- dose PTU 0123456 20 25 30 35 40 45 50 FT 4 3 0 1 2 3 4 5 6 7 8 9 10 Days 1200 600 PTU dose mg/day: Upper limit of normal Normal range 140 120 100 80 Pulse rate:

36. Subacute thyroiditis Etiology:(Post) viral inflammation of thyroid Symptoms & signs:Hyperthyroidism Painful swelling of thyroid Pain irradiation to ear Fever Sometimes “silent” Laboratory:  ESR  acute phase reactants (CRP)

38. Subacute thyroiditis- therapy A self limited disease Therapy depends on symptoms/signs Non-steroid anti-inflammatory agents (NSAIDS)  -blockers Corticosteroids Outcome - in 6 months 90% euthytroid

39. Hypothyroidism- classification 1. Hashimoto’s thyroiditis 2. Post 131 I therapy for Grave’s disease 3. Post thyroidectomy 4. Excessive I intake (amiodarone-procor) Primary - TSH↑ Secondary TSH ↓ or normal: Hypopituitarism due to adenoma, destructive lesion, ablation TSH↓ Tertiary: Hypothalamic dysfunction (rare)

40. Hypothyroidism- clinical features Symptoms: Fatigue Weakness Weight gain Cold intolerance Constipation Cramps Paresthesias (carpal tunnel) Signs: Coarse features Bradycardia Myxedema Anemia Laboratory:  serum thyroid hormones,  cholesterol anemia (iron def., megaloblastic)

41. Hypothyroidism

42. Hypothyroidism- myxedema

43. Hypothyroidism- differential diagnosis Serum FT 4 and TSH FT4 , TSH  Primary hypothyroidism FT4 , TSH normal/low Secondary hypothyroidism TRH test Excessive response

44. Hypothyroidism- therapy Levothyroxine 0.05-0.3 mg/day Combined L-T 4 and L-T 3 may be beneficial with respect to well-being In elderly patients (at high risk for CVD), “go low, go slow”

45. Hypothyroidism- treatment Before After

46. Thyroid Storm and Myxedema Coma – rare endocrine emergencies

47. THYROID STORM Clinical setting History of Graves’ disease and discontinuation of medications/ previously undiagnosed hyperthyroidism. Acute onset of hyperpyrexia (over 40 ˚C) Sweating Marked tachycardia, often with atrial fibrillation Nausea, vomiting, diarrhea Agitation, tremulousness, delirium Occasionally “apathetic” – without restlessness and agitation, but with weakness, confusion, and cardio-vascular dysfunction. Acute life threatening exacerbation of thyrotoxicosis

48. THYROID STORM DIAGNOSIS: Largely based on the clinical findings and clinical suspicion. Elevated serum FT 4, FT 3. Low TSH MANAGEMENT 1. Supportive care Fluids, Oxygen, Cooling blanket,cetaminophen 2. Specific measures Propranolol, 40-80 mg every 6 hours. Antithyroid drugs – PTU. Glucocorticoids - Dexamethasone, 2 mg every 6 hours (due to reduction in glucocorticoids half life)

49. Myxedema Coma Extreme hypothyroidism: Coma Hypothermia Hypoventilation Hypoglycemia Hyponatremia Bradycardia Laboratory:FT 4 , FT 3 , TSH  Co 2 retention

50. Myxedema Coma- therapy Treat: Ventilation Precipitating factors T 4 or T 3 I.V. Corticosteroids-50-100mg hydrocortisone every 8 hours

51. Subclinical Hypothyroidism TSHFT4 AND FT3 NORMAL Biochemical definition WHEN TO TREAT? WHEN TSH > 10 AND WHAT ABOUT 4.5<TSH<10????

52. TSH 4.5-10

53. Subclinical hyperthyroidism TSH below lower limit of normal (<0.3) Free T3 & Free T4 – normal Make sure not over treatment of hypothyroidism Associated with increased risk of atrial fibrillation in subjects > age 60 and accelerated bone loss in postmenopausal women

54. Always repeat the test before initiating therapy!

55. Amiodarone (Procor)-induced thyroid dysfunction Each Procor tablet (200 mg) has 75 mg Iodine Procor can cause: hypothyroidism- does not require discontinue the medication (thyroxine can be added) Hyperthyroidism- anti thyroid drugs have limited efficacy; radioactive iodine doesn’t work Thyroiditis- may require steroids »