Thyroid Disorders William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine, McMaster University

Case 1 31 year old female Somalia  Canada 3 years ago G2P1A0, 11 weeks pregnant Well except fatigue Hb 108, ferritin 7 (Fe and LT4 interaction?) TSH 0.2 mU/L, FT4 7 pM Started on LT4 0.05  TSH < 0.01 mU/L FT4 12 pM, FT3 2.1 pM

Case 1 How would you characterize her hypothyroidism? What are the ramifications of pregnancy to thyroid function/dysfunction?

TSH Low High FT4 & FT3 FT4 Low High Low High Central Hypothyroid 1° Thyrotoxicosis 1° Hypothyroid If equivocal 2° thyrotoxicosis RAIU TRH Stim. Endo consult FT3, rT3 MRI, α-SU MRI, etc.

TRH Stimulation test A) 1° Hypothyroidism B) Central Hypothyroidism C) Euthyroid D) 1° Thyrotoxicosis

Case 1 GH, IGF-1 normal LH, FSH, E2, progesterone, PRL normal for pregnancy 8 AM cortisol 345, short ACTH test normal MRI: normal pituitary TGAB, TPOAB negative LT4 increased until FT4 in hi-normal range Normal pregnancy, delivery, baby, lactation Considering TRH stim once done breast-feeding

Thyroid Tests Thyroid Function Iodine Kinetics Thyroid Structure FNA Thyroid Antibodies Thyroglobulin

T4 T3 * Total T4 60-155 nM Total T3 0.7-2.1 nM T3RU/THBI 0.77-1.23 Protein* binding + 0.03% free T4 80% (peripheral) T3 Protein* binding + 0.3% free T3 20% (10-20x less than T4) * TBG 75% TBPA 15% Albumin 10% Total T4 60-155 nM Total T3 0.7-2.1 nM T3RU/THBI 0.77-1.23

Thyroid Function Tests TSH 0.4 –5.0 mU/L Free T4 (thyroxine) 9.1 – 23.8 pM Free T3 (triiodothyronine) 2.23-5.3 pM

TSH Assay (0.4-5 mU/L) Early RIA < 1.0 mU/L Thyrotoxicosis / 2º hypothyroidism Unable to detect lower range of normal Monoclonal SEN < 0.1 mU/L Super SEN < 0.01 mU/L

Case 1 How would you characterize her hypothyroidism? What are the ramifications of pregnancy to thyroid function/dysfunction?

Thyroid & Pregnancy: Normal Physiology Increased estrogen  increased TBG Higher total T4, T3 (normal FT4, FT3 if thyroid gland working properly) hCG peak end of 1st trimester, weak TSH agonist so may cause slight goitre Fetal thyroid starts working at 11 wks T4 & T3 do NOT cross placenta (or do so minimally) Do cross placenta: PTU, MTZ, TSH-R Ab (stim or block) MTZ  aplasia cutis scalp defects

Thyroid & Pregnancy: Hypothyroidism Will need ~ 25% increase in LT4 during pregnancy due to increased TBG levels Risks: increased spont abort, HTN, preterm pregnancy, 7 IQ points for fetus (NEJM, 341(8):549-555, Aug 31, 2001)

LT4 dose adjustment in Pregnancy: Need TSH at baseline & q2mos while pregnant Starting LT4: 2 ug/kg/d and check TSH q4wk until euthythyroid TSH Dose Adjustment TSH increased but < 10 Increase dose by 50 ug/d TSH 10-20 Increase dose by 50-75 ug/d TSH > 20 Increase dose by 100 ug/d

Thyrotoxicosis & Pregnancy Risks: fetal anomalies, spont abort, preterm labor, fetal hyperthyoridism, thyroid storm in labor No RAI ever Rx options: ATD or 2nd trimester thyroidectomy PTU drug of choice (avoid MTZ due to scalp defects) Aim to keep FT4 levels in hi normal range OK to breast feed on PTU as does not go into breast milk

Neonatal Grave’s Rare < 2% infants born to Graves” moms 2 types: Transplacental trnsfr of TSH-R ab (IgG) Present at birth, self-limited Rx PTU, Lugol’s, propanolol, prednisone Prevention: TSI in mom 2nd trimester, if 5X normal then Rx mom with PTU (crosses placenta to protect fetus) even if mom is euthyroid (can give mom LT4 which won’t cross placenta) Child develops own TSH-R ab Strong family hx of Grave’s Present @ 3-6 mos 20% mortality, persistant brain dysfunction

Postpartum & Thyroid 5% (3-16%) postpartum women (25% T1DM) Up to 1 year postpartum (most 1-4 months) Lymphocytic infiltration (Hashimoto’s) Postpartum  Exacerbation of all autoimmune dx 25-50% persistant hypothyroidism Small, diffuse, nontender goitre Transiently thyrotoxic  Hypothyroid

Postpartum & Thyroid Distinguish Thyrotoxic phase from Grave’s: Rx: No Eye disease Less severe thyrotoxic, transient (repeat thyroid fn 2-3 mos) RAI (if not breast-feeding) Rx: Hyperthyroid symptoms: atenolol 25-50 mg od Hypothyroid symptoms: LT4 50-100 ug/d to start Adjust LT4 dose for symtoms and normalization TSH Consider withdrawal at 6-9 months (25-50% persistent hypothyroid, hi-risk recur future preg)

Postpartum & Thyroid Postpartum depression When studied, no association between postpartum depression/thyroiditis Overlapping symtoms, R/O thyroid before start antidepressents Screening for Postpartum Thyroiditis HOW: TSH q3mos from 1 mos to 1 year postpartum? WHO: Symptoms of thyroid dysfn. Goitre T1DM Postpartum thyroiditis with prior pregnancy

Case 2 47 year old female Concerned about weight gain over past 15 years (15 lbs). Otherwise asymptomatic BMI 25, Thyroid: 40 gm, rubbery firm. TSH 6.7 mU/L, FT4 13 pM, FT3 2.5 pM FHx: mother, sister – both on LT4 Medications: “Thyrosol” (health store) Wondering about hypothyroidism causing her weight gain Read on internet about “Wilson’s Disease”

Case 2 When to treat “Subclinical” thyroid dysfunction? Naturopathic thyroid remedies Hypothryoidism Rx other than Levothyroxine What is Wilson’s Thyroid Disease?

Subclincal Hypothyroidism  TSH, normal FT4 Most asymptomatic & don’t need Rx (monitor TSH q2-5y) Rx Indications: Increased risk of progression TSH > 10, Female > 50 y.o. Anti-TPO Ab titre > 1:100,000 ? Goitre present ? Dyslipidemia? Total cholesterol (TC)  6-8% if TSH > 10 and TC > 6.2 nM Symptoms? Pregnancy, Infertility, Ovulatory Dysfn.

Case 2 When to treat “Subclinical” thyroid dysfunction? Naturopathic thyroid remedies (Thyrosol) Hypothryoidism Rx other than Levothyroxine What is Wilson’s Thyroid Disease?

Hashimoto’s Disease Most common cause of hypothyroidism in North America (not idodine defeciency!) Autoimmune lymphocytic thyroiditis Females > Males, Runs in Families Antithyroid antibodies: Thyroglobulin Ab Microsomal Ab TSH-R Ab (block)

Hashimoto’s Disease Treatment: No benefit to giving iodine! Thyroid Hormone Replacement Levothyroxine (T4) T3?, T4/T3 combo?, dessicated thyroid? No benefit to giving iodine! In fact, iodine may decrease hormone production Wolff-Chaikoff effect (lack of escape)

Case 2 When to treat “Subclinical” thyroid dysfunction? Naturopathic thyroid remedies Hypothryoidism Rx other than Levothyroxine What is Wilson’s Thyroid Disease?

Treatment of Hypothyroidism Iodine only if iodine deficiency is the cause Rare in North America! Replacement thyroid hormone medication: T4? T3? T4 + T3 Mixture? Thyroid Hormone from “natural sources” ?

Normal Daily Thyroid Secretion Rate: T4 = 100 ug/day T3 = 6 ug/day ( ratio T4:T3 = 14:1 ) T4 Protein* binding + 0.03% free T4 85% (peripheral conversion) T3 Protein* binding + 0.3% free T3 15% (10-20x less than T4)

T4 T3 Potency 1 10 Protein Bound 10-20 Half-Life 5-7d < 24h Secreted by thyroid 100 ug/d 6 ug/d

Levothyroxine (T4) Synthroid (Abbott), Eltroxin (GSK) Synthetically made 50 ug white pill  no dye (hypoallergenic) Most commonly prescribed treatment for hypothyroidism No T3 (but 85% of T3 comes from T4 conversion) All patients made euthyroid biochemically Most (but not all) patients feel normal

Levothyroxine (T4) Average dose 1.6 ug/kg Age > 50-60 or cardiac disease: must start at a low dose (25 ug/d) Recheck thyroid hormone levels every 4-6 weeks after a dose change Aim for a normal TSH level

Levothyroxine (T4) Medical situations where T4 medication may be affected. Estrogen: Pregnancy, OCP, HRT Need to increase T4 dose! Drugs that interfere with T4 absorption Iron, Calcium Cholestyramine (cholesterol resin Rx) At least 4h between T4 and these drugs!

Tissue levels versus circulating levels? “I still don’t feel normal on Synthroid even though my blood tests are normal.” Free T4, Free T3 wide range of normal TSH (0.4 –5.0 mU/L) Narrow range of normal, but still a range! Adjust dose for a lower TSH still in the normal range? Tissue levels versus circulating levels? No human studies Rodents: High T4 and normal T3 tissue levels

Liothyronine (T3) Cytomel (Theramed) Shorter half-life Fluctuating levels (i.e. need a slow-release pill) Twice daily dosing often needed 10x more potent: palpitations & other cardiac side effects High T3 levels, low T4 levels (not physiologic either!)

T3/T4 Liotrix Thyrolar Combo pill of T3 and T4 Ratio of T4:T3 = 4:1 (not 14:1) T3 still not slow release Few small studies showing benefit 1999 NEJM study 33 patients Benefit: mood & cognitive function Not available in Canada

Desiccated Thyroid (Armour) Desiccated powder derived from thyroids of slaughtered pigs or cows Vegetarian? Mad Cow Disease? Contains T4 and T3 Still no slow-release of T3 Ratio of T4:T3 Variable Still not physiologic, often too high in T3 (T4:T3 = 3:1)

“In an ideal world…” Mixed compound with T4:T3 = 14:1 T3 component slow release formulation Resultant: Normal circulating TSH, FT4, FT3 Normal tissue levels of T4 and T3 Good, large studies (RCTs) demonstrating clear benefit over T4 alone

Case 2 When to treat “Subclinical” thyroid dysfunction? Naturopathic thyroid remedies Hypothryoidism Rx other than Levothyroxine What is Wilson’s Thyroid Disease?

“Wilson’s Syndrome” Wilson’s disease: copper toxicity  liver failure Dr. E. D. Wilson “discovered” this condition and named it after himself in late 1980’s Decreased body temperature (low normal range) Hypothyroid symptoms (nonspecific) Normal thyroid function tests “Impaired T4  T3 conversion” “Build up of reverse T3” Treat with “Wilson’s T3-therapy” (presumably T3)

Sick Euthyroid Syndrome, not Wilson’s syndrome!

“Wilson’s Syndrome” No scientific evidence that this condition exists No randomized trials proving safety or any benefit of giving people T3 when their thyroid hormone levels are normal This condition not endorsed by: Canadain Society of Endocrinology and Metabolism (CSEM) American Thyroid Association (ATA) Endocrine Society

Case 3 62 y male Afib: amiodarone, warfarin x 11 months 2 months: fatigue, muscle weakness, increasing dyspnea/edema, weight gain O/E: HR 110 irreg-irreg, appears malnourished,  JVP, SOA, lung crackles

Case 3 TSH < 0.05 mU/L, FT4 60 pM, FT3 24 pM INR 4.2, Echo: LVH, normal LV syst fn. RAIU 2%, Thyroid scan: no gland seen Rx: Methimazole 40 mg/d, lasix, aldactone, ramipril, reduced warfarin Cardiolgist: d/c amiodarone  bisoprolol

Case 3 F/up @ 2 mos: weight loss (more muscle, less fluid) Resolved: Fatigue, SOB, SOA HR 76 irreg-irreg TSH < 0.05, FT4 8 pM, FT3 2.1 pM INR 1.5

Case 3 What is difference between thyrotoxicosis and hyperthyroidism? What is “apathetic” hyperthyroidism? Amiodarone induced thyrotoxicosis? Thyroid & drug-interactions (warfarin)? Subclinical Thyrotoxicosis?

RAIU Oral dose of I131 5 uCi (or I123 200 uCi but more $) Measure neck counts @ 24h (+/- 4h if suspect high turnover) RAIU = neck counts – bkgd (thigh counts) x 100 pill counts - bkgd

RAIU Normal 4h RAIU = 5-15 % 24h RAIU: >25% Hyperthyroid 20-25% Equivocal (check TSH) 9-20% Normal 5-9% Equivocal (check TSH) <5% Hypothyroid Dependent on dietary iodine intake! Must be: not pregnant! (ß-hCG), no ATD x 7d, no LT4 x 4d, no large doses of iodine or radiocontrast for 2 wk (prefer 4-6 wk)

Thyrotoxicosis Treatment Beta-blockers (hyperadrenergic symptoms) Hyperthyroidism: Anti-thyroid Drugs Propylthiouracil (PTU), Methimazole Radioiodine Ablation Surgical Thyroidectomy Thyroiditis: ASA, NSAIDS, +/- corticosteroids Iodine (high doses Wolff Chaikoff effect)

“Apathetic Hyperthyroidism” Elderly population Lack of tremor, diaphoresis, heat-intolerance, hyperdefecation and other classic symptoms from sympathetic over-activity TMNG more likely than in young (but Grave’s still most common) Less likely to have a goitre Common symptoms: Weight loss, anorexia Constipation despite thyrotoxic Tachycardia, Afib, CHF, angina Cognitive Dysfunction

Amiodarone and Thyroid PHYSIOLOGIC EFFECTS 1) Increase iodine pool in body and therefore decrease RAIU. 2) Decrease peripheral deiodination of T4 to T3. 3) Decrease pituitary deiodination and therefore transient rise in TSH for 1st 3 mos of Rx. Amiodarone Induced Thyroid Dysfunction: 3 months to 4 years after starting amiodarone Hypothyroidism 8% (subclinical hypothyroidism 20%) Thyrotoxicosis 3% (10% iodine deficiency areas)

Amiodarone induced Hypothyroidism 1) Increased TSH (not useful 1st 3 mos). 2) Decreased FT4 3) Decreased FT3 (not neccesary to measure) 4) More common in areas of hi iodine intake (North America) d/t Wolff Chaikoff effect. 5) Rx: Stop amiodarone if possible. LT4 aim dose to keep FT4 level at high normal to slightly above normal. Unlike other types of hypothyroidism do NOT try to normalize TSH as this requires dose ~ 250 ug/d and clearly causes hyperthyroidism.

Amiodarone induced Thyrotoxicosis (AIT) 1) Decreased TSH 2) Increased FT4 3) Increased FT3 in some patients (inhibition of deiodinase) 4) More common in areas of low iodine intake (Europe) d/t Jodbasedow effect or iodine/amiodarone induced thyroid damage. 5) Two types of AIT: Hyperthyroidism (RAIU low but measurable) – Jodbasedow, often goitre/nodule(s) Thyroiditis (RAIU 0%) 6) May present without hyperthyroid symptoms and simply worsening of cardiac disorder (arrythmia, angina, CHF, etc).

Amiodarone induced Thyrotoxicosis (AIT) Rx: Stopping amiodarone may not help as amiodarone still present in body tissue stores for months May need amiodarone to still treat arrythmias made worse by thyrotoxicosis Radioactive I-131 useless d/t decreased RAIU. Thionamide ATDs (PTU, methimazole): Rx of choice Glucocorticoids if RAIU indicates thyroiditis & no response to ATD Prednisone 40 mg/d Surgery? Somewhat risky d/t unknown safety wrt thyroid storm & underlying heart condition that required amiodarone in the first place! KClO4 (potassium perchlorate)?

Thyroid & Drug Interactions 1) Warfarin T4 increases catabolism of vitamin K dependent clotting factors. Increase LT4/hyperthyroidism will increase sensitivity to warfarin (decrease dose). Decrease LT4/hypothyroidism will decrease sensitivity to warfarin (increase dose). 2) Cholestyramine Binds T4 & T3 4-5h between resin & LT4 or T3. 3) Iron or Calcium Also binds T4 & T3

Thyroid & Drug Interactions 4) Estrogens Increase TBG, decrease FT4 level Need to increase LT4 in some patients 5) Androgens/corticosteroids Decrease TBG, increase FT4 level Need to decrease LT4 in some patients 5) Diabetes Increase LT4/hyperthyroidism will increase insulin/OHA requirements. Decrease LT4/hypothyroidism will decrease insulin/OHA requirements.

Subclinical Hyperthyroidism  TSH, Normal FT4 and FT3 Progression to overt hyperthyroidism low: Men 0% per year Women 1.5% per year TMNG or toxic adenoma present 5% per year Indications to Rx: Any cardiac disease (CAD, AFIB, etc.) Age > 60 (10 year risk AFIB 32%, 10% if normal TSH) TMNG or toxic adenoma Osteoporosis

Case 4 29 year old female, engaged to be married T1DM Thyroid U/S: 2.9 cm R lower pole 2.0 cm L lower pole, Many others ranging from 0.5-1.5 cm TSH < 0.05 mU/L, FT4 19 pM, FT3 6.9 pM RAIU/Scan: 45% RAIU, hot nodule on Left

Case 4 FNA of 3cm nodule on Right: benign Rx’s offered: RAI ablation versus thyroidectomy Patient chose Thyroidectomy

Thyroid Structure Physical Exam Thyroid Ultrasound Thyroid Scan

Thyroid nodules U/S more sensitive than P.E., particularly for nodules that are < 1 cm or located posteriorly in the gland. U/S also more SEN than thyroid scan U/S too Sensitive? Thyroid Incidentaloma (Carotid duplex, etc.)

Malignant Characteristics Thyroid U/S Benign Characteristics Malignant Characteristics Regular border Halo (sonolucent rim) Irregular border No Halo Hyperechoic Hypoechoic (more vascular) Egg shell calcification Microcalcification N/A Intranodular vascular spots (color doppler)

Thyroid Scan Thyroid nodule: risk of malignancy 6.5% only 5-10% of nodules Cold nodule 16-20% malignant Hot Nodule Tc-99m < 5% malignant I123 < 1% malignant “Warm” Nodule (indeterminant) 5% malignant

Fine Needle Aspiration (FNA) 25G Needle, 10cc syringe Done in Office +/- Local 3-5 passes SEN 95-99% (False Negative rate 1-5%) SPEC > 95%

FNA Results Nondiagnostic: repeat FNA Benign: macrofollicular or "colloid" adenomas, chronic autoimmune (Hashimoto's) thyroiditis Suspicious or Indeterminant: microfollicular or cellular adenomas (follicular neoplasm) Malignant

Benign Lesions

Papillary Carcinoma Surgical Specimen FNA

Follicular Lesions on FNA: Can’t Distinguish!

+ - Thyroid Nodule Follow U/S q1y TSH Scan FNA Not Hot Hot Palpable >15mm Follow U/S q1y TSH Benign Clin suspicion Low Low Normal or High Scan FNA Insufficient Sample Repeat FNA +/- U/S guide Not Hot Hot Clin suspicion High Suspicious (Follicular) Malignant Rx Plummer’s Surgery RAI Hemithyroidectomy with quick section Total Thyroidectomy + - RAI Close

Familial Adenomatosis Polyposis Incidentaloma (Size < 15mm) Hx of XRT exposure? FHx of thyroid cancer? Malign features on U/S? Age < 20 or > 60? Grave’s Disease? Familial Adenomatosis Polyposis Thyroid Nodule Palpable >15mm Follow U/S q1y TSH No Yes Benign Clin suspicion Low Low Normal or High Follow U/S q1y ? Scan FNA Insufficient Sample Repeat FNA +/- U/S guide Not Hot Hot Clin suspicion High Suspicious (Follicular) Malignant Rx Plummer’s Surgery RAI Hemithyroidectomy with quick section Total Thyroidectomy + - RAI Close

Case 5 19 year old female PMHx: Eating Disorder, Bulimia Weight loss despite witnessed food intake Tachycardia, palpitations FHx: Hypothyroidism (mother) No palpable goitre TSH < 0.05 mU/L, FT4 23 pM, FT3 5.0 pM 24h RAIU 2%, Thyroid Scan: no gland seen

Case 5 TSH-R antibody negative Thyroglobulin < 2 ng/mL (undetectable)

Autoimmune Thyroid Disease TSH-R ab block Thyroglobulin ab Microsomal ab Hashimoto’s (hypothyroid) Autoimmune Thyroid Disease TSH-R ab stim Graves’ Dx (hyperthyroid)

Thyroid Antibodies Hashimoto’s Grave’s Thyroglobulin AB (<40 KIU/L) Thyroid peroxidase AB (< 35 KIU/L) Grave’s TSI or TSH Receptor Ab (Stim): IgG antibody SEN 60% SPEC 90% 2-3 month turn-around time Indications: Pregnant & present or past hx Grave’s: check 2nd trimester (if hi-titre > 5X normal needs PTU as TSI crosses placenta) ? Euthyroid Grave’s ophthalmopathy Alternating hyper/hypo function due to alternating Stim/Block TSI

Thyroglobulin (Tg) Normal < 40 ng/mL Increased in all thyroid disease Thyrotoxicosis factitia: low or undetectable Tg Useful for thyroid cancer surveillance post surgery & radioiodine ablation Not useful for thyroid cancer diagnosis Thyroglobulin antibodies in Hashimoto’s patients may falsely elevate or decrease thyroglobulin levels