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

2. 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 LT  TSH < 0.01 mU/L
FT4 12 pM, FT3 2.1 pM

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

4. 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.

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

6. 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

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

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

9. Thyroid Function Tests
TSH –5.0 mU/L
Free T4 (thyroxine) – 23.8 pM
Free T3 (triiodothyronine) pM

10. 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

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

12. 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

14. 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): , Aug 31, 2001)

15. 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 ug/d
TSH > 20
Increase dose by 100 ug/d

16. 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

17. 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
3-6 mos
20% mortality, persistant brain dysfunction

18. 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

20. 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 mg od
Hypothyroid symptoms: LT 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)

21. 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

22. 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”

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

24. 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.

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

27. 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)

28. 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)

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

30. 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” ?

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

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

33. 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

34. Levothyroxine (T4) Average dose 1.6 ug/kg
Age > 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

35. 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!

36. 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

37. 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!)

38. 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

39. 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)

40. “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

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

42. “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)

43. Sick Euthyroid Syndrome, not Wilson’s syndrome!

44. “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

45. 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

46. 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

47. 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

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

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

50. 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)

52. 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)

53. “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

54. 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)

55. 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.

56. 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).

57. 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)?

59. 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

60. 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.

61. 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

62. 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 cm
TSH < 0.05 mU/L, FT4 19 pM, FT3 6.9 pM
RAIU/Scan: 45% RAIU, hot nodule on Left

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

64. Thyroid Structure
Physical Exam
Thyroid Ultrasound
Thyroid Scan

65. 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.)

66. 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)

67. 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

68. 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%

69. 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

70. Benign Lesions

71. Papillary Carcinoma
Surgical Specimen
FNA

72. Follicular Lesions on FNA: Can’t Distinguish!

73. + - 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

74. 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

75. 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

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

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

78. 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

79. 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