Thyroid Disorders

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 LT4 0.05 ? TSH lt 0.01 mU/L
• FT4 12 pM, FT3 2.1 pM

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Case 1

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

4
TSH
Low
High
FT4 FT3
FT4
Low
Low
High
High
Central Hypothyroid
1 Thyrotoxicosis
1 Hypothyroid
If equivocal
2 thyrotoxicosis
RAIU
TRH Stim.

• Endo consult
• FT3, rT3
• MRI, a-SU

MRI, etc.
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TRH Stimulation test
A) 1 Hypothyroidism B) Central Hypothyroidism C)
Euthyroid D) 1 Thyrotoxicosis
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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

1. Thyroid Function
2. Iodine Kinetics
3. Thyroid Structure
4. FNA
5. Thyroid Antibodies
6. Thyroglobulin

8
T4
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
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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

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TSH Assay(0.4-5 mU/L)

• Early RIA lt 1.0 mU/L
• Thyrotoxicosis / 2º hypothyroidism
• Unable to detect lower range of normal
• Monoclonal SEN lt 0.1 mU/L
• Super SEN lt 0.01 mU/L

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Case 1

1. How would you characterize her hypothyroidism?
2. 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

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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)

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LT4 dose adjustment in PregnancyNeed TSH at
baseline q2mos while pregnantStarting LT4 2
ug/kg/d and check TSH q4wk until euthythyroid
TSH Dose Adjustment
TSH increased but lt 10 Increase dose by 50 ug/d
TSH 10-20 Increase dose by 50-75 ug/d
TSH gt 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

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Neonatal Graves

• Rare lt 2 infants born to Graves moms
• 2 types
• Transplacental trnsfr of TSH-R ab (IgG)
• Present at birth, self-limited
• Rx PTU, Lugols, 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 wont cross placenta)
• Child develops own TSH-R ab
• Strong family hx of Graves
• Present _at_ 3-6 mos
• 20 mortality, persistant brain dysfunction

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Postpartum Thyroid

• 5 (3-16) postpartum women (25 T1DM)
• Up to 1 year postpartum (most 1-4 months)
• Lymphocytic infiltration (Hashimotos)
• Postpartum ? Exacerbation of all autoimmune dx
• 25-50 persistant hypothyroidism
• Small, diffuse, nontender goitre
• Transiently thyrotoxic ? Hypothyroid

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Postpartum Thyroid

• Distinguish Thyrotoxic phase from Graves
• 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)

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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

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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 Wilsons Disease

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Case 2

• When to treat Subclinical thyroid dysfunction?
• Naturopathic thyroid remedies
• Hypothryoidism Rx other than Levothyroxine
• What is Wilsons Thyroid Disease?

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Subclincal Hypothyroidism

• ? TSH, normal FT4
• Most asymptomatic dont need Rx (monitor TSH
  q2-5y)
• Rx Indications
• Increased risk of progression
• TSH gt 10, Female gt 50 y.o.
• Anti-TPO Ab titre gt 1100,000 ?
• Goitre present ?
• Dyslipidemia?
• Total cholesterol (TC) ? 6-8 if TSH gt 10 and TC
  gt 6.2 nM
• Symptoms?
• Pregnancy, Infertility, Ovulatory Dysfn.

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Case 2

• When to treat Subclinical thyroid dysfunction?
• Naturopathic thyroid remedies (Thyrosol)
• Hypothryoidism Rx other than Levothyroxine
• What is Wilsons Thyroid Disease?

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Hashimotos Disease

• Most common cause of hypothyroidism in North
  America (not idodine defeciency!)
• Autoimmune
• lymphocytic thyroiditis
• Females gt Males, Runs in Families
• Antithyroid antibodies
• Thyroglobulin Ab
• Microsomal Ab
• TSH-R Ab (block)

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Hashimotos 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)

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Case 2

• When to treat Subclinical thyroid dysfunction?
• Naturopathic thyroid remedies
• Hypothryoidism Rx other than Levothyroxine
• What is Wilsons Thyroid Disease?

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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 ?

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Normal Daily Thyroid Secretion Rate T4 100
ug/day T3 6 ug/day ( ratio T4T3 141 )
T4
Protein binding 0.03 free T4
85 (peripheral conversion)
T3
Protein binding 0.3 free T3
15
(10-20x less than T4)
32
T4 T3
Potency 1 10
Protein Bound 10-20 1
Half-Life 5-7d lt 24h
Secreted by thyroid 100 ug/d 6 ug/d
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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 gt 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

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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!

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I still dont 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

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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!)

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T3/T4 Liotrix

• Thyrolar
• Combo pill of T3 and T4
• Ratio of T4T3 41 (not 141)
• 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 T4T3
• Variable
• Still not physiologic, often too high in T3
  (T4T3 31)

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In an ideal world

• Mixed compound with T4T3 141
• 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 Wilsons Thyroid Disease?

42
Wilsons Syndrome

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

43
Sick Euthyroid Syndrome, not Wilsons syndrome!
44
Wilsons 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

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Case 3

• TSH lt 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

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Case 3

• F/up _at_ 2 mos
• weight loss (more muscle, less fluid)
• Resolved Fatigue, SOB, SOA
• HR 76 irreg-irreg
• TSH lt 0.05, FT4 8 pM, FT3 2.1 pM
• INR 1.5

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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?

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RAIU

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

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RAIU

• Normal 4h RAIU 5-15
• 24h RAIU
• gt25 Hyperthyroid
• 20-25 Equivocal (check TSH)
• 9-20 Normal
• 5-9 Equivocal (check TSH)
• lt5 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)

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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 Graves still
  most common)
• Less likely to have a goitre
• Common symptoms
• Weight loss, anorexia
• Constipation despite thyrotoxic
• Tachycardia, Afib, CHF, angina
• Cognitive Dysfunction

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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)

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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)?

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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

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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 gt 60 (10 year risk AFIB 32, 10 if normal
  TSH)
• TMNG or toxic adenoma
• Osteoporosis

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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 lt 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
• Rxs offered
• RAI ablation versus thyroidectomy
• Patient chose Thyroidectomy

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Thyroid Structure

• Physical Exam
• Thyroid Ultrasound
• Thyroid Scan

65
Thyroid nodules

• U/S more sensitive than P.E., particularly for
  nodules that are lt 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.)

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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)
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Thyroid Scan
Thyroid nodule risk of malignancy 6.5
only 5-10 of nodules
Cold nodule 16-20 malignant
Hot Nodule Tc-99m lt 5 malignant I123 lt 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 gt 95

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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

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Benign Lesions
71
Papillary Carcinoma
FNA
Surgical Specimen
72
Follicular Lesions on FNA Cant Distinguish!
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Thyroid Nodule Palpable gt15mm
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 Plummers
• Surgery
• RAI

Hemithyroidectomy with quick section
Total Thyroidectomy

-
RAI
Close
74
Incidentaloma (Size lt 15mm) Hx of XRT
exposure? FHx of thyroid cancer? Malign features
on U/S? Age lt 20 or gt 60? Graves
Disease? Familial Adenomatosis Polyposis
Thyroid Nodule Palpable gt15mm
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 Plummers
• 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 lt 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 lt 2 ng/mL (undetectable)

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TSH-R ab block Thyroglobulin ab Microsomal
ab Hashimotos (hypothyroid)
Autoimmune Thyroid Disease
TSH-R ab stim Graves Dx (hyperthyroid)
78
Thyroid Antibodies

• Hashimotos
• Thyroglobulin AB (lt40 KIU/L)
• Thyroid peroxidase AB (lt 35 KIU/L)
• Graves
• TSI or TSH Receptor Ab (Stim) IgG antibody
• SEN 60 SPEC 90
• 2-3 month turn-around time
• Indications
• Pregnant present or past hx Graves check 2nd
  trimester
• (if hi-titre gt 5X normal needs PTU as TSI
  crosses placenta)
• ? Euthyroid Graves ophthalmopathy
• Alternating hyper/hypo function due to
  alternating Stim/Block TSI

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Thyroglobulin (Tg)

• Normal lt 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 Hashimotos patients
  may falsely elevate or decrease thyroglobulin
  levels