Endocrinology: Thyroid Disorders

1. Southwest Ohio Regional Updates in Internal Medicine 2018 Endocrinology: Thyroid Disorders Abid Yaqub MD, FACE, FACP, ECNU Associate Professor Division of Endocrinology University of Cincinnati College of Medicine

2. Thyroid Gland Largest single organ endocrine gland of the body Primary function is synthesis, storage, and secretion of thyroid hormones which are necessary for growth, development and normal body metabolism Thyroid hormone controls various metabolic processes and helps the body utilize energy and stay warm Influences functions of multiple organs in the body

3. Hypothalamic-Pituitary-Thyroid Axis • TRH from the hypothalamus stimulates the pituitary gland to secrete TSH • TSH then binds to receptors in the thyroid gland to stimulate secretion of T4 and T3 at a molar ratio of 14:1 • T3 is the active thyroid hormone • 80% of T3 is formed by conversion from T4 in extra-thyroidal tissues

4. Thyroid Stimulating Hormone-TSH Initial test of choice to detect thyroid dysfunction Normal range is 0.5-4.5 mU/L Important limitations : Central hypothyroidism /non-thyroidal illness In patients with central or secondary hypothyroidism, TSH is an unreliable target for diagnosing or treating hypothyroidism When there is suspicion of pituitary disease Free T4 should be checked Upper normal range of TSH in healthy elderly population may extend up to 7.5 mIU/L Those elderly patients already on Levothyroxine replacement, it may be appropriate to keep TSH in 4-6 range

5. Total T4 and T3 T4 and T3 circulate bound to proteins-Thyroxine binding globulin (70%), Thyroxine binding pre-albumin (10%) and Albumin (15%) Widely available and accurate for assessment of most patients with thyroid disease Usually measured by automated assays Major limitation is false positives and false negatives resulting from changes in the concentration and binding affinity of thyroid hormone binding proteins

6. Free T4 and Free T3 Only 0.04% of T4 and 0.4% of T3 are unbound or free Assays measured only the unbound fraction of thyroid hormones Mostly not influenced by binding protein abnormalities High Free T4 indicates hyperthyroidism and low-low normal points towards hypothyroidism Free T4 usually normal in milder forms of hypo- and hyperthyroidism Free T3 is useful in patients with hyperthyroidism being high in many cases-not helpful in hypothyroidism

7. Hypothyroidism Hyperthyroidism Conditions associated with insufficient thyroid hormone action Common: 4.3% (5-8 times more common in women) Increased incidence with age Free T4: Low or normal (Subclinical) TSH: High Overproduction of thyroid hormone Thyrotoxicosis- the clinical manifestations of excess thyroid hormone action Common: 1.3% (5 times more common in women) Incidence increases with age Free T4: Normal (Subclinical) or High TSH: Low or undetectable NHANES III

8. Etiology of Hypothyroidism Primary Secondary -Hypopituitarism due to tumor, surgery, radiation, hypophysitis -Hypothalamic damage -Autoimmune (Hashimoto’s Thyroiditis) With goiter No goiter (Atrophic Thyroiditis) - Radioiodine ablation - Thyroidectomy - Iodide deficiency - Inborn errors of thyroid hormone synthesis - Drugs (Lithium, amiodarone, interferon-, TKI, checkpoint inhibitor immonotherapy)

9. Hypothyroidism: Therapy LT4 pills contain synthetic hormone T4 and is the recommended form of replacement therapy TSH to be checked every 6 weeks after dose adjustment or initiation Target TSH in the normal range T4 or T3 not targets for therapy except in secondary hypothyroidism In secondary hypothyroidism, it is recommended that Free T4 should be maintained in upper half of normal range Older patients and those with cardiac disease are usually started on a low dose which is raised gradually Calcium, iron, soy can block absorption. Estrogen, antidepressants, anti-seizure meds, reflux meds increase requirements

10. Subclinical (Mild) Hypothyroidism Defined as a T4 in the normal range with slightly high TSH that ranges from 4-10 mU/L Few or no symptoms. No clear consensus on who to treat in this group Treat patients with mild hypothyroidism and positive anti-TPO antibodies, significant symptoms, goiter, high cholesterol, pregnancy planning or pregnancy There is observational data evidence that elderly patients > 80 years of age have lower cardiovascular mortality and improved measures of generalized well being with higher than ‘normal’ range TSH of 0.4-5 Therefore, it is recommended that elderly patients > 70 years of age with TSH < 7 mIU/L should not be started on Levothyroxine

11. Subclinical (Mild) Hypothyroidism Treatment is recommended in all patients with TSH > 10 due to increased cardiovascular morbidity and mortality Treatment is also recommended for non-elderly patients in TSH 7-9.9 mIU/L range due to some evidence of increased CV morbidity and mortality in untreated patients in this range Treatment may be considered in elderly patients with TSH in 7-9.9 mIU/L range in the presence of significant symptoms There is increased risk of cardiac arrhythmia and osteoporosis in patients on excessive thyroid replacement

12. Hypothyroidism in Pregnancy Thyroxine is safe in pregnancy Requirements usually increase during pregnancy by 30-50% Fetus can not make thyroid hormone during first trimester so early aggressive treatment to achieve target TSH is critical Uncontrolled hypothyroidism especially during early pregnancy can potentially have adverse impact on fetal neurological development and subsequent cognitive functioning of child Thyroid functions have to be tested several times during pregnancy to ensure appropriate levels Normal range for TSH-1st trimester (0.1-2.5), 2nd trimester (0.2-3) and 3rd trimester (0.3-3)

13. Etiology of Thyrotoxicosis • Graves Disease • Toxic Multi-nodular Goiter • Toxic Adenoma • Subacute thyroiditis • Silent thyroiditis • TSH secreting adenoma • Struma ovarii • Factitious/ Iatrogenic • ~ 90% of endogenous hyperthyroidism in persons < 50 years is Graves’ disease with female predominance (8:1)-GO clinically evident in 50% of patients with GD • TMNG is 2nd most common cause of hyperthyroidism and the most common cause in patients > 60 years

14. Thyroiditis A diverse group of disorders characterized by some form of thyroid inflammation Painful or with tenderness Painless Hashimoto’s thyroiditis Silent thyroiditis Postpartum thyroiditis-occurs within one year after parturition Drugs: Amiodarone, Lithium, Interferon, TKI, Immune check point inhibitor therapy • Subacute thyroiditis (de Quervain’s thyroiditis)-Often recent Hx of viral upper RTI • Infectious thyroiditis • Radiation-induced thyroiditis • Trauma induced thyroiditis-including surgery or vigorous palpation during PE can be a cause Riedel’s thyroiditis: Fibrosing condition with extensive fibrosis, discomfort and compression

15. Thionamides not indicated • Beta blockers for symptomatic control is the mainstay of treatment • NSAIDs & Steroids may be indicated for painful thyroiditis

16. Factitious Thyrotoxicosis Prescribed or factitial ingestion of supraphysiologic doses of T4 and/or T3 Suspect in a thyrotoxic patient without palpable goiter and suppressed radioiodine uptake Ingestion of iodides (kelp and seaweeds) Ingestion of ground meat with thyroid tissue Serum Thyroglobulin maybe used to differentiate from thyroiditis -Exogenous Thyrotoxicosis-has low thyroglobulin -Destructive Thyroiditis-has high thyroglobulin

17. Radio-iodine Uptake in Thyrotoxicosis Increased uptake Decreased uptake (< 5%) Thyroiditis Exogenous thyroid hormone Iodinated contrast • Graves Disease (> 40%) • Toxic MNG • Toxic Adenoma

18. Hyperthyroidism Treatment OptionsThionamides Methimazole and propylthiouracil (PTU) block thyroid hormone synthesis Given to control thyrotoxicosis due to hyperthyroidism Remission of hyperthyroidism in Graves possible with thionamides However TA or TMNG will need definitive therapy for long term cure Therapy titrated to normalized T4 and T3-TSH is not target for Rx PTU: also decreases T4 to T3 conversion Serious side effects rare: agranulocytosis, hepatitis, vasculitis, aplastic anemia (0.2 – 0.5%)

19. Hyperthyroidism Treatment OptionsRAI-131 RAI-131: safe, effective ablative therapy Preferred definitive treatment for adults in U.S. Absolute contraindication: pregnancy and breast feeding Maximal effect in 2-3 months 80-90% rendered euthyroid or hypothyroid Major drawback: eventual hypothyroidism May cause transient worsening of hyperthyroidism Elderly or impaired cardiac reserve: Use anti-thyroid drugs to render patient euthyroid before RAI therapy

20. Hyperthyroidism Treatment OptionsSurgery Thyroidectomy can be considered for following: -Large compressive goiter -Nodules with suspicious FNA -Pregnancy-2nd trimester when not responsive to medications -Anti-Thyroid drug complications/ineffective and patient refuses RAI -Patient preference -Best to prepare patient with anti-thyroid drugs to render euthyroid -Potassium Iodide given 7-10 days preoperatively decreases vascularity -Recurrent laryngeal nerve or parathyroid damage < 1-2%

21. Hyperthyroidism during pregnancy There is increase in thyroxine binding globulin (TBG) during pregnancy resulting in increase in total T4 and T3 which are elevated about 1.5X hCG bears structural homology with TSH and stimulates production of thyroid hormones leading to decrease in TSH hCG peaks at 10-12 weeks with transient subclinical hyperthyroidism-a normal physiologic finding (hyperemesis gravidarum exaggerates this) Clinically significant hyperthyroidism requiring treatment is associated with symptoms, goiter, ophthalmopathy (in Graves’), elevated Free T4, T4 and T3 (>1.5 times) and TSH<0.03 in most cases

22. Hyperthyroidism during pregnancy Methimazole use in 1st trimester may be associated with fetal congenital malformations (Aplasia cutis, choanal atresia, trachea-esophageal fistulas) but preferred in 2nd and 3rd trimesters PTU use is less likely to be associated with fetal abnormalities but may be more likely associated with fatal hepatotoxicity Low doses of ATD drugs recommended Goal for treatment is to maintain Free T4 at or just above upper limit of normal range (T4 and T3 at 1.5x or slightly above) and TSH in 0.1-0.3 range to prevent fetal goiter or hypothyroidism TRAb or TSI check recommended in patients with Graves’ disease to predict occurrence of neonatal/fetal thyrotoxicosis 2017 ATA guidelines for management of Thyroid disease in pregnancy and the post-partum

23. Thyroid Storm • Thyroid storm is rare but is life threatening with high mortality rate • Characterized by hyperpyrexia, tachycardia, altered mentation or agitation in setting of significantly elevated thyroid hormones • A precipitating factor is frequently apparent • Intensive monitoring and supportive care in ICU is recommended • Aggressive therapy with Thionamides, iodine (SSKI), beta-blockers and glucocorticoids is essential • Propylthiouracil (PTU) is the preferred thionamide because it also inhibits conversion of T4 to T3 2016 ATA Hyperthyroidism management guidelines

24. Thyroid Storm • Iodine (SSKI) inhibits release of thyroid hormones from thyroid and also inhibits thyroid hormone synthesis in acute setting • PTU should be given at least 1 hour before SSKI • Beta-blockers decrease the accentuated adrenergic tone and ameliorate tachycardia associated with thyrotoxicosis • Propranolol is the preferred beta-blocker due to it inhibitory effect on type 1 deiodinase at high doses reducing T4 to T3 conversion • Glucocorticoids also block T4 to T3 conversion, may affect autoimmune process of Graves’ disease and treat possible relative adrenal insufficiency • IV Hydrocortisone or Dexamethasone preferred over oral Prednisone • Plasmapheresis or emergency surgery may be considered if needed 2016 ATA Hyperthyroidism management guidelines

25. Myxedema Coma • Myxedema coma is a life-threatening emergency with high mortality rate (up to 40%) • Characterized by hypothermia and decreased level of consciousness in the setting of significantly low thyroid hormones • There is marked slowing of metabolic processes resulting in multi-organ dysfunction • Associated with markedly high TSH values but secondary hypothyroidism may be associated with normal or low TSH values • Presence of precipitating illness should be looked for and treated • Management should be in ICU setting with cardiopulmonary support, fluid management and passive rewarming provided as appropriate 2014 ATA Guidelines for treatment of Hypothyroidism

26. Myxedema Coma • Due to the possibility of concomitant adrenal insufficiency, IV bolus of 100 mg Hydrocortisone should be administered before initiating thyroid hormone replacement therapy • Ideally a cortisol level should be drawn before giving IV Hydrocortisone bolus • A loading dose of 200-400 mcg of IV Levothyroxine is recommended followed by 50-100 mcg IV daily • Due to possible decreased T4 to T3 conversion in myxedema coma, IV Liothyronine 5-20 mcg bolus may also be given followed by 2.5-10 mcg every 8 hours • Response should be measured by improvement in clinical parameters (temperature, mental status, respiratory, cardiac, renal and electrolytes) • Usually takes about 7 days to significant improvement 2014 ATA Guidelines for treatment of Hypothyroidism

27. Thyroid functions in Non-thyroidal illness (Sick-Euthyroid Syndrome) Type 1 & Type 2-deiodinase catalyzes T4 to T3 conversion Type 3-deiodinase catalyzes T4 to rT3 conversion

28. Common Presentations of Sick Euthyroid Syndrome 1. Decreased 5’-deiodinase (free fatty acids, cytokines)Low T3 2. Decreased TBG ( glucocorticoids, nephrotic syndrome)Low T3,T4 3. Plasma inhibitors to binding (free fatty acids, cytokines)Low T3,T4 4. Increased TBG ( estrogens, hepatitis)Elevated T3, T4 5. Suppression of TSH ( transient central hypothyroidism, Dopamine, glucocorticoids)Low TSH

29. Thyroid functions in Non-thyroidal illness (Sick-Euthyroid Syndrome) Changes in thyroid function tests in non-thyroidal illnesses

30. Thyroid nodules are very common 6.4% of women and 1.5% men with clinically apparent nodules 20-76% on US exams 5-15% chance of malignancy Benign causes include Hashimoto’s, MNG and follicular adenomas Not all thyroid nodules are the same! 2015 ATA Thyroid nodules and differentiated cancer guidelines

31. If TSH subnormal Thyroid scintigraphy No FNA if nodule is ‘hot’ 2015 ATA Thyroid nodules and differentiated cancer guidelines

32. Thyroid Cancer • Thyroid Follicular Epithelial derived cancers: • Papillary Thyroid Cancer-85% • Follicular Thyroid Cancer-12% • Anaplastic-<3% (Uniformly fatal, older patient, mean survival 4-6 months) • Non-follicular epithelial derived cancers: • Medullary Thyroid Cancer-1-2% of thyroid cancers • Thyroid Lymphoma

33. Papillary Thyroid Carcinoma • Most common with best prognosis • More common in women • 10-year risk of mortality-7% • Produces thyroglobulin • Lymphatic spread with nodal metastasis common • Distal metastases in 10% • Psammoma bodies, papillary formations, nuclear grooves and pseudo-inclusions • Can be diagnosed with FNA

34. Follicular Thyroid Carcinoma • Good prognosis • More common in women • 10 year mortality-15% • Produces thyroglobulin • Hematologic spread more common, especially bone • Distant metastases in 25-35% • Requires histology for diagnosis -Vascular or capsular invasion • Tightly packed small follicles with scant colloid (pictured above) • Occasionally get cells with abundant granular, eosinophilic cytoplasm (Hürthle cell variant)

35. Medullary Thyroid Carcinoma immunostain for calcitonin • Neuroendocrine carcinoma arising from C cells • Produces calcitonin • Equal sex distribution-5 year survival 95% in Stage 1 and 68% in Stage IV • Sporadic vs hereditary • Most are sporadic (~70%) • ~30% are hereditary (MEN IIa, MEN IIb, FMTC) • autosomal dominant with >90% penetrance • often multiple and bilateral • RET mutation testing diagnostic of germline mutation • FNA diagnostic sensitivity is ~80% Organoid appearance with nests and cords

36. Treatment of Thyroid Cancer • Near total / total thyroidectomy • Most cases get surgery • Postop, patient will be hypothyroid (need LT4) • use LT4 to your advantage by suppressing TSH to below normal levels • Radioiodine (131I)-Well Differentiated Thyroid Cancer (WDTC) • For WDTC with intermediate to high risk features • Done subsequent to surgery as initial treatment • Treatment of recurrent cancer • External beam radiation (rarely used) • Locally invasive T4 tumors with possible residual disease

37. TSH suppression in WDTC • TSH has trophic effect on thyroid cellular growth • Well differentiated thyroid cancer cells express TSH receptors and growth may be accelerated with high TSH levels • Aggressive TSH suppression (<0.1) has been shown to improve overall survival in patients with high risk of recurrence and mortality • Mild TSH suppression (0.1-0.5) has been associated with improved outcomes in patients with intermediate risk of recurrence • TSH goal should be relaxed in patients with low BMD, atrial fibrillation and cardiac dysfunction • No role in Medullary thyroid cancer or Anaplastic thyroid cancer 2017 ATA Thyroid Cancer Management Guidelines

38. Case 1 A 32 year female is seen in office for routine physical exam. She feels well with no throat pain, dysphagia, choking sensation, or change in voice. She is on no medications and there is no personal or family history of thyroid disease. No history of radiation exposure. Exam: Alert, comfortable at rest Vitals: P 72 BP 126/74 RR 16. She is afebrile. No tremors. No lid lag or retraction. Neck palpation reveals a palpable right thyroid lobe nodule. There is no tenderness. Tendon reflexes are normal. Rest of physical exam is within normal limits Labs: TSH 1.3 mIU/L (0.5-5) Free T4 1.2 ng/dl (0.8-1.8)

39. Case 1 US thyroid: Normal sized gland with a 1.9 cm mixed solid cystic nodule with honey comb appearance in right thyroid lobe. No microcalcifications. Minimal peripheral vascularity. Not taller than wider. Margins are regular. Ultrasound

40. Question 1What should be the most appropriate next step? • Fine needle aspiration of nodule to rule out malignancy • Right thyroid lobectomy to r/o malignancy as FNA can have high false negative rate in such nodules • Thyroid antibodies to r/o Hashimoto’s thyroiditis • Conservative follow-up; consider repeat US in one year • Thyroid uptake & scan to find out if nodule is hot or cold

41. Question 1: Answer choices discussion Incorrect: FNA is not indicated as nodule has very low suspicion for malignancy (<3%) and below the cut-off size of 2 cm for FNA What should be the most appropriate next step? • Fine needle aspiration of nodule to rule out malignancy • Right thyroid lobectomy to r/o malignancy as FNA can have high false negative rate in such nodules • Thyroid antibodies to r/o Hashimoto’s thyroiditis • Conservative follow-up; consider repeat US in one year • Thyroid uptake & scan to find out if nodule is hot or cold Incorrect: Thyroid lobectomy is not indicated without preceding FNA Incorrect: Thyroid antibody (TPO) testing is not indicated in work-up of thyroid nodule Correct: Conservative management with consideration of follow-up US in appropriate for spongiform nodules 1-1.9 cm in size Incorrect: Thyroid scintigraphy is indicated for evaluation of thyroid nodule when TSH is subnormal

42. Case 2 A 27 year old woman presents early in her first pregnancy for a routine check-up. She is 10 weeks pregnant. She has mild intermittent nausea but no vomiting. She has occasional palpitations and ‘fluttering’ in her chest not lasting for more than a few seconds. She has some heat intolerance. She has no tremors. She has no diarrhea. No visual complaints. No skin rash. No personal or family history of thyroid disease. She is on no medications except prenatal multivitamin.

43. Case 2 Examination Labs TSH 0.11 mIU/L (0.5-5) Free T4 1.8 ng/dl (0.8-1.8) T4 17 mcg/dl (4.6-12) T3 280 ng/dl (70-200) Alert, comfortable at rest Vitals: P 80 BP 110/70 RR 16. She is afebrile. No tremors. No exophthalmos, lid lag or retraction. Mild thyroid fullness on exam. Normal tendon reflexes. Rest of physical exam is within normal limits

44. Question 2What is the best next management step at this stage? • Order thyroid uptake and scan to elucidate etiology of hyperthyroidism • Start low dose Methimazole therapy to keep T4 in middle of normal range to decrease risk of miscarriage • Start low dose Propylthiouracil to aim for T4 in middle of normal range • No intervention now, repeat thyroid function tests in 4 weeks • Obtain TSH receptor and TPO antibodies

45. Question 2: Answer choices discussion Incorrect: Thyroid uptake & scan in contraindicated during pregnancy What is the best next management step at this stage? • Order thyroid uptake and scan to elucidate etiology of hyperthyroidism • Start low dose Methimazole therapy to keep T4 in middle of normal range to decrease risk of miscarriage • Start low dose Propylthiouracil to aim for T4 in middle of normal range • No intervention now, repeat thyroid function tests in 4 weeks • Obtain TSH receptor and TPO antibodies Incorrect: Anti-thyroid medication prescribed in pregnancy only when there is clinically significant hyperthyroidism resulting from Graves’ disease. T4 is normal for pregnancy in this case. Incorrect: Anti-thyroid medication prescribed in pregnancy only when there is clinically significant hyperthyroidism resulting from Graves’ disease. T4 is normal for pregnancy in this case. Correct: Thyroid functions appear appropriate for pregnancy stage. Continued monitoring may be recommended Incorrect: TRAb or TSI check recommended in patients with Graves’ disease to predict occurrence of neonatal/fetal thyrotoxicosis

46. Case 3 A 56 female with Graves’ disease is transferred from surgical step- down unit to ICU, 1 day after an emergent appendectomy for a ruptured appendix. Graves’ disease was diagnosed 3 months ago and she was started on Methimazole 10 mg bid along with Atenolol 25 mg daily. However she has been non-compliant with therapy and did not follow-up on blood work and office visits. She smokes 1 ppd. She has no family history of thyroid disease. She has no other medical problems and was not on any medications when she presented to the emergency room with abdominal pain.

47. Case 3 Examination Labs TSH <0.01 mIU/L (0.5-5) Free T4 14 ng/dl (0.8-1.8) T3 1200 ng/dl (70-200) CBC, renal and hepatic profile within normal limits • Exam: Visibly anxious and agitated. Temp 102 F, BP 130/77, P 130, regular, RR 23. • Cardiac: 2/6 systolic murmur. Thyroid moderately enlarged with bruit heard over it. Abd: Mild tenderness around surgical scar, bowel sounds are normal. Tendon reflexes are brisk. 1+ ankle edema. Skin is warm and moist. Tremors noted. Rest of exam is normal.

48. Question 3Besides aggressive systemic ICU support, which of the following set of measures will be the most appropriate for this patient? • Methimazole first, followed by SSKI (Iodine), Atenolol and Prednisone • SSKI (Iodine) first, followed by Methimazole, Atenolol and Prednisone • SSKI (Iodine)first, followed by PTU, Propranolol and IV Hydrocortisone • PTU first, followed by SSKI (Iodine), Propranolol and IV Hydrocortisone • PTU first, followed by SSKI (Iodine), Atenolol and Prednisone

49. Question 3: Answer choices discussion Incorrect: PTU is the preferred thionamide because it also inhibits conversion of T4 to T3 and results in significantly greater acute reduction in T3 as compared to Methimazole Besides aggressive systemic ICU support, which of the following set of measures will be the most appropriate for this patient? • Methimazole first, followed by SSKI (Iodine), Atenolol and Prednisone • SSKI (Iodine) first, followed by Methimazole, Atenolol and Prednisone • SSKI (Iodine)first, followed by PTU, Propranolol and IV Hydrocortisone • PTU first, followed by SSKI (Iodine), Propranolol and IV Hydrocortisone • PTU first, followed by SSKI (Iodine), Atenolol and Prednisone Incorrect: PTU should be given at least 1 hour before SSKI to prevent iodine from being used as a substrate for new thyroid hormone synthesis Incorrect: PTU should be given at least 1 hour before SSKI to prevent iodine from being used as a substrate for new thyroid hormone synthesis Correct: Right sequence. Parenteral Dexamethasone or Hydrocortisone preferred over oral Prednsione. Propranolol preferred over Atenolol. Incorrect: Propranolol is the preferred beta-blocker due to it inhibitory effect on type 1 deiodinase at high doses reducing T4 to T3 conversion

50. Case 4 76 year old woman is brought to ER by EMS with decreased level of consciousness. She lives alone with no family. One of her neighbors called 911 after she failed to open her main door despite repeated prompts. EMS found her in her bed in unarousable condition. Past medical history is not available in ER.