Diagnosis of Thyroid Disorders

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

www.drharper.ca

Case 1

31 year old female Somalia Canada 3 years ago G2P1A0, 11 weeks pregnant Well except fatigue Hb 108, ferritin 7 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.
2.

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

TSH High Low

FT4
High Low 1 Hypothyroid 2 thyrotoxicosis
Endo consult FT3, rT3 MRI, -SU
If equivocal

FT4 & FT3 Low

High

Central 1 Thyrotoxicosis Hypothyroid

TRH Stim. MRI, etc.

RAIU

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
1.
2. 3. 4. 5.

6.

Thyroid Function Iodine Kinetics Thyroid Structure FNA Thyroid Antibodies Thyroglobulin

Normal Daily Thyroid Secretion Rate: T4 = 100 ug/day T3 = 6 ug/day ( ratio T4:T3 = 14:1 )

T4
85% (peripheral conversion) 15%

Protein* binding

+ 0.03% free T4

T3

Protein* binding
(10-20x less than T4)

+ 0.3% free T3

Total T4 Total T3 T3RU/THBI

60-155 nM 0.7-2.1 nM 0.77-1.23

* TBG

75% TBPA 15% Albumin 10%

Thyroid Function Tests

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

TSH Assay
(0.4-5 mU/L)

Early RIA < 1.0 mU/L

Thyrotoxicosis / 2 hypothyroidism
Unable to detect lower range of normal

Monoclonal SEN < 0.1 mU/L Super SEN < 0.01 mU/L

Case 1
1.
2.

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 TSH > 20
Increase dose by 50-75 ug/d 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

Postpartum Thyroiditis

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

Postpartum Thyroiditis

Rx:

Hyperthyroid symptoms: atenolol 25-50 mg od Hypothyroid symptoms: LT4 50-100 ug/d to start
Adjust LT4 dose for symptoms and normalization of 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 Wilsons Disease

Case 2
1.
2. 3.

4.

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

Subclincal Hypothyroidism

TSH, normal FT4 Most asymptomatic & dont 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.

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 Any cardiac disease (CAD, AFIB, etc.) Age > 60 (10 year risk AFIB 32%, 10% if normal TSH) TMNG or toxic adenoma Osteoporosis

Indications to Rx:

Case 2
1.
2. 3.

4.

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

Hashimotos 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)

Hashimotos Disease

Treatment:

Thyroid Hormone Replacement Levothyroxine (T4) T3?, T4/T3 combo?, dessicated thyroid? In fact, iodine may decrease hormone production Wolff-Chaikoff effect (lack of escape)

No benefit to giving iodine!

Case 2
1.
2. 3.

4.

When to treat Subclinical thyroid dysfunction? Naturopathic thyroid remedies Hypothryoidism Rx other than Levothyroxine What is Wilsons 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
85% (peripheral conversion) 15%

Protein* binding

+ 0.03% free T4

T3

Protein* binding
(10-20x less than T4)

+ 0.3% free T3

T4 Potency Protein Bound Half-Life 1 10-20 5-7d

T3 10 1 < 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

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?
No human studies Rodents: High T4 and normal T3 tissue levels

Tissue levels versus circulating 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.
2. 3.

4.

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

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)

Sick Euthyroid Syndrome, not Wilsons syndrome!

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

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 Rxs offered:

RAI ablation versus thyroidectomy

Patient chose Thyroidectomy

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! (-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 ASA, NSAIDS, +/- corticosteroids

Thyroiditis:

Iodine (high doses Wolff Chaikoff effect)

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/S
Benign Characteristics Regular border Halo (sonolucent rim) Hyperechoic Malignant Characteristics Irregular border No Halo Hypoechoic (more vascular) Microcalcification
Intranodular vascular spots (color doppler)

Egg shell calcification

N/A

Thyroid Scan
Thyroid nodule: risk of malignancy 6.5%

only 5-10% of nodules

Cold nodule
16-20% malignant

Warm Nodule
(indeterminant) 5% malignant

Hot Nodule
Tc-99m < 5% malignant I123 < 1% 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%

Thyroid Nodule
Palpable >15mm

Follow U/S q1y

TSH
Low Normal or High Benign Clin suspicion Low

Scan Not Hot

FNA

Insufficient Repeat FNA Sample +/- U/S guide Clin suspicion High

Hot Rx Plummers Surgery RAI

Malignant

Suspicious (Follicular)

Total Thyroidectomy RAI

Hemithyroidectomy with quick section

Close

Incidentaloma
(Size < 15mm) Hx of XRT exposure? FHx of thyroid cancer? Malign features on U/S? Age < 20 or > 60? Graves Disease? Familial Adenomatosis Polyposis

Thyroid Nodule
Palpable >15mm

Follow U/S q1y

No Follow U/S q1y ?

Yes

TSH
Low Normal or High Benign Clin suspicion Low

Scan Not Hot

FNA

Insufficient Repeat FNA Sample +/- U/S guide Clin suspicion High

Hot Rx Plummers Surgery RAI

Malignant

Suspicious (Follicular)

Total Thyroidectomy RAI

Hemithyroidectomy with quick section

Close