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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
1. How would you characterize her hypothyroidism?
2. What are the ramifications of pregnancy to thyroid function/dysfunction?
TSH
LowHigh
FT4 FT4 & FT3
Low
1° Hypothyroid
Low
Central Hypothyroid
TRH Stim.
Ifequivocal
MRI, etc.
High
1° Thyrotoxicosis
High
2° thyrotoxicosis
•Endo consult•FT3, rT3•MRI, α-SU
RAIU
TRH Stimulation test
A) 1° HypothyroidismB) Central HypothyroidismC) EuthyroidD) 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
1. Thyroid Function
2. Iodine Kinetics
3. Thyroid Structure
4. FNA
5. Thyroid Antibodies
6. Thyroglobulin
T4
T3
80% (peripheral)
20%
Protein* binding + 0.03% free T4
Protein* binding + 0.3% free T3 (10-20x less than T4)
Total T4 60-155 nMTotal T3 0.7-2.1 nMT3RU/THBI 0.77-1.23
TBG 75%TBPA 15%Albumin 10%
*
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
1. How would you characterize her hypothyroidism?
2. 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 pregnantStarting 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:• 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 ThyroiditisHOW: 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
1. When to treat “Subclinical” thyroid dysfunction?
2. Naturopathic thyroid remedies
3. Hypothryoidism Rx other than Levothyroxine
4. 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
1. When to treat “Subclinical” thyroid dysfunction?
2. Naturopathic thyroid remedies (Thyrosol)
3. Hypothryoidism Rx other than Levothyroxine
4. 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:• 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
1. When to treat “Subclinical” thyroid dysfunction?
2. Naturopathic thyroid remedies
3. Hypothryoidism Rx other than Levothyroxine
4. 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” ?
T4
T3
85% (peripheral conversion)
15%
Protein* binding + 0.03% free T4
Protein* binding + 0.3% free T3 (10-20x less than T4)
Normal Daily Thyroid Secretion Rate:T4 = 100 ug/dayT3 = 6 ug/day
( ratio T4:T3 = 14:1 )
T4 T3
Potency 1 10
Protein Bound 10-20 1
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!
“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
1. When to treat “Subclinical” thyroid dysfunction?
2. Naturopathic thyroid remedies
3. Hypothryoidism Rx other than Levothyroxine
4. What is Wilson’s Thyroid Disease?
“Wilson’s Syndrome”
• Wilson’s disease: copper toxicity liver failure• “Wilson’s Syndrome”
• 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
1. What is difference between thyrotoxicosis and hyperthyroidism?
2. What is “apathetic” hyperthyroidism?
3. Amiodarone induced thyrotoxicosis?
4. Thyroid & drug-interactions (warfarin)?
5. 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 EFFECTS1) 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.)
Thyroid U/SBenign
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%
Cold nodule16-20% malignant
“Warm” Nodule (indeterminant) 5% malignant
Hot NoduleTc-99m < 5% malignantI123 < 1% malignant
only 5-10% of nodules
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
FNASurgical Specimen
Follicular Lesions on FNA: Can’t Distinguish!
Thyroid NodulePalpable>15mm
TSH
Low Normalor High
Scan
HotNotHot
FNA
MalignantSuspicious(Follicular)
Benign
InsufficientSample
Repeat FNA+/- U/S guide
Clin suspicionLow
Clin suspicionHigh
TotalThyroidectomy
RAI
Hemithyroidectomywith quick section+
-Close
Rx Plummer’s•Surgery•RAI
FollowU/S q1y
Thyroid NodulePalpable>15mm
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
No
FollowU/S q1y ?
YesTSH
Low Normalor High
Scan
HotNotHot
FNA
MalignantSuspicious(Follicular)
Benign
InsufficientSample
Repeat FNA+/- U/S guide
Clin suspicionLow
Clin suspicionHigh
TotalThyroidectomy
RAI
Hemithyroidectomywith quick section+
-Close
Rx Plummer’s•Surgery•RAI
FollowU/S q1y
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 stim
Graves’ Dx
(hyperthyroid)
TSH-R ab block
Thyroglobulin ab
Microsomal ab
Hashimoto’s
(hypothyroid)
Thyroid Antibodies
• Hashimoto’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
