Thyroid Disease. I have no disclosures. Overview TSH. Matthew Kim, M.D. July, 2012

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1 Thyroid Disease I have no disclosures Matthew Kim, M.D. July, 2012 Overview Thyroid Function Tests Hyperthyroidism Hypothyroidism Subclinical Thyroid Disease Thyroid Nodules Questions TSH Best single screening test for hypothyroidism or thyrotoxicosis! TSH can detect mild hypothyroidism or thyrotoxicosis before T4 is outside of the normal range Small changes in T4 correspond to large changes in TSH ( log- linear relationship) Pitfalls: Rare pituitary causes of hypothyriodism or hyperthyroidism Severe illness (nonthyroidal( illness) Drugs: dopamine, glucocorticoids (acutely), octreotide, bexarotene

2 T4 and T3 >99% circulating T4 and T3 are bound to proteins Thyroxine-binding globulin (TBG) Transthyretin Albumin Unbound or free hormone available to cells Total T4 and total T3 measure both free and bound Total T4 and total T3 levels altered by protein binding disorders as well as thyroid diseases Free T4 Index Free T4 Index = total T4 THBR Total T4 THBR = 8mcg/dL 1.0 = 8.0 Allows assessment of binding protein status Free T4 Single test Estimates are method dependent Can be inaccurate in severe illness and pregnancy THBR = patient T3 resin uptake/control serum T3 resin uptake Common Causes of Protein Binding Abnormalities Increased TBG T3 RU and THBR Estrogens Tamoxifen/Raloxifene Acute/subacute hepatitis HIV early stage Inherited TBG excess Opioids Decreased TBG T3RU and THBR Androgens Glucocorticoids Nicotinic Acid Inherited TBG deficiency TFTs in Nonthyroidal Illness Less severe More severe Thyroid Antibodies Thyroglobulin Antibodies Thyroid Peroxidase Antibodies (TPO Ab) Marker of thyroid autoimmunity TPO Ab more sensitive (nearly all patients with Hashimoto s s have positive TPO Ab) However up to 20% of all women have positive antibodies Common Causes of Thyrotoxicosis Overproduction of thyroid hormone Graves disease Toxic adenoma Toxic multinodular goiter Leakage of thyroid hormone Thyroiditis Exogenous thyroid hormone

3 Uncommon Causes of Thyrotoxicosis Graves Disease TSH-secreting pituitary adenomas HCG induced Struma ovarii Usually diagnosed clinically If unsure: 24 hr radioactive iodine uptake( RAIU) normal high in Graves disease low in thyroiditis I-123 Scan Treatment for Graves Disease Antithyroid Drugs: chance of permanent remission Propylthiouracil (PTU) Methimazole (MMI) I-131: permanent hypothyroidism Surgery: permanent hypothyroidism Antithyroid Drugs Lower thyroid hormone levels in wks ~30-60% remission rate reported after months of Rx ~50% relapse 18 months after cessation Potential drug related side effects Rash ( ~5%) Agranulocytosis ( 1 in ) Hepatitis and liver failure (recent additional reports to FDA adverse reporting system with PTU, especially in children) Requires frequent monitoring Cooper DS, Rivkees SA. J Clin Endocrinol Metab 2009; 94 :1881. Antithyroid Drugs PTU Methimazole Serum half life 75 min 4-6 hrs Duration of action 4-6 hrs hrs Dosing bid tid bid to qd Typical dosage tid qd Relative potency 1x 15x T4-T3 inhibition Yes No Methimazole is the drug of choice, except in early pregnancy

4 I-131 for Graves Disease Takes months to work Dose based on 24 hour RAIU Expect permanent hypothyroidism Must not be pregnant! Avoid pregnancy for 6 months post Rx May exacerbate preexisting opthalmopathy (especially in smokers) May cause transient exacerbation of hyperthyroidism Surgery for Graves Disease Subtotal thyroidectomy with permanent hypothyroidism Patients with severe drug reaction requiring euthyroidism rapidly Pregnant women requiring high doses of antithyroid drugs Toxic Nodules I-131 is ideal for restoring euthyroidism and reducing nodule volume in patients with suppressed serum TSH values Hypothyroidism rates low (<10-30%) in most studies Hyperthyroidism due to Thyroiditis Transient due to leakage of preformed thyroid hormone Low 24 hour RAIU Hyperthyroid phase usually lasts months Beta blockers if needed Hyperthyroidism due to Thyroiditis Autoimmune (silent, lymphocytic, painless) TPO Ab association Postpartum ( 5%-10% of pregnancies, up to 25% in diabetic patients) Drugs: lithium, amiodarone, interferon-alfa, interleukin-2 Subacute (painful, granulomatous, de Quervains) Pain may initially be unilateral Elevated ESR, ± fever Viral or post viral Can use NSAIDs or prednisone for pain

5 Causes of Hypothyroidism Primary hypothyroidism Destruction of thyroid tissue Hashimoto s: s: most common cause of hypothyroidism in U.S. Neck external beam irradiation: dose dependent Defects in biosynthesis Iodine deficiency Central hypothyroidism (very rare) Pituitary disease Hypothalamic disease Transient hypothyroidism Thyroiditis Age < 60: Therapy for Hypothyroidism Initiation of Levothyroxine Rx 0.8 mcg/lb ideal body wt/day Age > 60: mcg/day Cardiac disease: mcg/day Subclinical Hypo: May require only 50 mcg/day Therapy for Hypothyroidism Monitoring Rx Retest TSH 6 weeks after starting T4 Once TSH is normal, retest 3 months later Then retest TSH annually For central hypothyroidism, follow free T4 Thyroid Hormone Preparations other than Levothyroxine T3 (Cytomel( ) T3 and T4 mixtures (Thyrolar( - contains T4 and T3 in a ratio 4:1) Dessicated thyroid hormone (porcine thyroid glands - Armour ) T4 versus T4 plus T3? Randomized cross-over over trial (NEJM 1999) T4 vs reduced T4 dose + T3 ( 12.5mcg) T4 plus T3 arm had improved mood and neuropyschological function Most subsequent studies have not found a benefit Meta-analysis analysis of 11 randomized controlled studies found no benefit T3 is not recommended for the treatment of hypothyroidism Bunevicius et al. NEJM 1999; 340: 424. Grozinsky-Glasberg et al. J Clin Endocrinol Metab 2006; 91: Causes of Increased Levothyroxine Dose Drugs that interfere with absorption Calcium Ferrous sulfate Proton pump inhibitors Cholestyramine Infant soy formula Lovastatin? Drugs that increase hepatic metabolism Phenytoin Carbamazepine Rifampin Phenobarbitol Sertraline (probably other SSRIs,,? mechanism)

6 Causes of Increased Levothyroxine Dose Drugs that block T4 T3 conversion Amiodarone Malabsorption Celiac sprue Crohns Estrogen Pregnancy OCPs,, HRT Hypothyroidism and Pregnancy Hypothyroid pregnant woman have an increase in thyroid hormone requirement of ~30-50% Increase appears to be greatest in athyreotic patients Dose returns to baseline postpartum Separate levothyroxine from prenatal vitamins Hypothyroidism and Pregnancy Alexander et al N Engl J Med 351:241. ~ 40% Half of the women required a dose increase by the 8 th week of gestation Is Maternal Euthyroidism Important for the Fetus? Serum TSH was measured in stored blood from 25,000 pregnant women during the 2 nd trimester 62 hypothyroid women detected IQ of the offspring compared to 124 euthyroid controls 19% of the offspring of untreated hypothyroid women had an IQ less than 85 compared to 5% of the control group Haddow et al. N Engl J Med 1999; 341:549 Hypothyroidism and Pregnancy The Rarely-Seen Patients! Most recommend adjusting TSH to < 2.5mU/L preconception in hypothyroid women Measure TSH at week intervals during pregnancy? Empiric increase of dose at dx of pregnancy in all hypothyroid women (2 extra pills per week) Universal screening of all pregnant women not yet recommended but most recommend targeted case finding in early pregnancy (TPO Ab pos, personal or family h/o thyroid disease) Abalovich et al. J Clin Endocrinol Metab 2007; 92: 1.

7 Subclinical Thyroid Disease: Definition Laboratory disease with no clinical signs or symptoms specific to thyroid disease Subclinical Hypothyroidism TSH above normal (usually < 10mU/L) Free T4 levels within normal Subclinical Hyperthyroidism TSH less than normal (usually < 0.4mU/L) Free T4 levels within normal Subclinical Thyroid Disease: Prevalence Subclinical Hypothyroidism 4%- 8.5% Up to 20% in women older than 60 years Subclinical Hyperthyroidism 2% (using TSH of < 0.4mU/L) 0.7% (using TSH of < 0.1mU/L) Subclinical hyperthyroidism present in 14% - 21% of patients on T4 Rx Subclinical Hypothyroidism: Does it Progress to Overt Hypothyroidism? 20 year follow-up study of women TSH and +TPO Ab TSH only Progression to overt disease 4.3%/year 2.6%/year Subclinical Hypothyroidism: Untreated Adverse cardiac endpoints: Recent large prospective cohort study found no association with CV disorders or mortality Total and LDL cholesterol: Many studies show total and LDL chol Meta-analysis analysis suggests T4 Rx lowers T Chol and LDL Clinical benefit unclear Vanderpump et al Clin Endocrinol 1995;43:55 Cappola et al JAMA 2006;295: 1033 Danese et al. J Clin Endocrinol Metab 2000;85:2993 Subclinical Hypothyroidism: Treatment Guidelines TSH < 10mU/L Repeat at month intervals TSH > 10mU/L T4 Rx reasonable Pregnant women or women planning a pregnancy should be treated for any TSH elevation Surks et al. JAMA 2004; 291: 228 Subclinical Hyperthyroidism: Untreated Increased risk of atrial fibrillation in older patients Relative risk of 3.1 over 10 yrs ( TSH < 0.1) Relative risk 1.98 over 12 yrs ( TSH < 0.44) Increased fracture risk Increase in hip and vertebral fractures in postmenopausal woman > 65 yrs ( TSH < 0.1) Sawin et al NEJM 1994;331:1249 Cappola et al JAMA 2006;295: 1033 Bauer et al. Ann Intern Med 2001;134:561

8 Subclinical Hyperthyroidism: Treatment Guidelines Repeat to confirm TSH suppression is persistent If due to exogenous T4, reduce T4 dose Treat older patients and those at risk for cardiac disease or osteoporosis if TSH < 0.1mU/L Younger patients with TSH < 0.1mU/L, may be offered treatment or observation Thyroid Nodules Prevalence: palpable nodule found in 6.4% of adult women and 1.5% of adult men in Framingham data Rate of Malignancy: low 4-10% 4 Factors that increase the risk of malignancy: Childhood head or neck radiation Men > women Age < 20 or > 70 years Surks et al. JAMA 2004; 291: 228 Prevalence of Thyroid Nodules Check TSH TSH low TSH normal or high Radionuclide scan FNA cold hot Consider I-131 Malignant Benign Nondiagnostic Indeterminate Surgery Follow Repeat FNA Radionuclide scan cold hot Mazzaferri, N Engl J Med 1993; 328:553 Surgery Follow Results Of Fine Needle Aspiration In 9,119 Patients Benign 74% Malignant 4% Indeterminate 11% (Follicular/Hurthle cell) Nondiagnostic 11% Mazzaferri, N Engl J Med 1993; 328:553

9 Thyroid Nodule Key Points TSH is the most sensitive index of thyroid function Graves disease is usually diagnosed clinically Pregnancy is associated with increased levothyroxine dose requirements Treatment of subclinical thyroid disease is optional in most cases Fine needle aspiration is the most informative approach to the evaluation of thyroid nodules Question 1 30 year old woman is seen for anxiety symptoms which began one month ago. On further questioning she complains of mild heat intolerance and intermittent palpitations. She has no prior history of anxiety. She is 7 months postpartum and is nursing her infant. Meds: MVI only PE: Pulse 90. Her eyes are normal. Her thyroid is enlarged to twice the normal size. It is symmetric with no nodules and no bruit. She has no tremor. LABS: TSH < 0.01 mu/l (normal ) Free T4 is 2.3 ng/dl (normal ) Question 1 TSH < 0.01mU/L Free T4 2.3ng/dl What is the most appropriate next step? a. Perform RAIU with I-123 b. Start PTU 50 mg TID and repeat free T4 in 5 weeks c. Repeat TFTs in one month, offer beta blockers to be used as needed d. Start prednisone e. Recommend she stop nursing and start Methimazole 10 mg per day Question 2 45 year old woman found incidentally to have a 2 cm left thyroid nodule on an MRI done for posterior neck pain. She is unaware of the nodule. Her physician ordered a thyroid US which shows a 2.2 cm partially cystic left thyroid nodule and a right 0.8 cm solid nodule. PE: Pulse 72. She has a 2 cm left nodule. The remainder of the thyroid is normal. She has no cervical adenopathy. She has no tremor. Labs: TSH 0.22 mu/l (normal ) Free T4 1.1 ng/dl (normal ) Question 2 TSH 0.22mU/L Free T4 1.1ng/dl What is the most appropriate next test? a. Reassure her and recommend a repeat US in one year as this is an incidental finding b. Fine needle aspiration of both nodules c. Recommend bone mineral density to determine if treatment is needed for subclinical hyperthyroidism d. Evaluate further with radionuclide scanning e. Recommend I-131 therapy for presumed toxic multinodular goiter

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