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Marshall Dahl MD PhD FRCPC cert Endo

Clinical Professor, University of British Columbiamarshall.dahl@vch.ca

Tel 604 875 5577Fax 604 875 5188

• Faculty: Marshall Dahl

• Relationships with commercial interests:– None– Nada– Nil

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• None

CFPC CoI Templates: Slide 2

Not applicable

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Review endocrine physiology ofthyroid gland

Five selected types of thyrotoxicosis-understand: Pathophysiology Clinical presentation Investigations Treatment

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Multiple Etiologies 5 are common Diagnosis needed for

appropriatemanagement

Differentiation canoften be made throughhistory and physicalexamination

23 woman presents for care Chief Complaint: “I went to the fitness club and a guy came up to

me and said that I should get my thyroidchecked!”

“I looked on the internet- I think that it’soveractive!”

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Some findings ofthyrotoxicosis are presentregardless of the etiology

What symptoms? What physical findings?

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She wants you to know thather mother and sister have“overactive thyroids”.

She has noticed that hereyes have become moreprominent

She’s pretty sure from herreading that she hasGraves’ disease

What findings are specificto this condition?

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Weetman, A. P. N Engl J Med 2000;343:1236-1248

Clinical Manifestations of Graves' Disease

Pathogenesis of Graves' Disease.

Weetman AP. N Engl J Med 2000;343:1236-1248.

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Weetman, A. P. N Engl J Med 2000;343:1236-1248

Bahn, R. S. et al. N Engl J Med 1993;329:1468-1475

Computed Tomographic Scans of the Orbits (Axial Views) in a Patient with Graves' Ophthalmopathy(Panel A) and a Normal Subject (Panel B)

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>60% of cases of thyrotoxicosis HLA-DR, CTLA-4, but 20% concordance

monozygotic twins Women in North America: 0.5/1000 (20 year

incidence) Women:Men 10:1 Peak: age 40-60, but any age possible

Disease Etiology SpecificSymptoms

Signs Lab Tests Other tests

Graves’ TSI Orbitopathy,Dermopathy

Firm, rubberygland +/-orbitpathy

↓ TSH↑ Free T4TSH receptorantibody*

Third generation assay sens 97%, spec 99%. JCEM 98, 6, June 2013, Barbesino

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Radioiodine Two day procedure Isotope limited: Tuesday, Wednesday

Good for etiology Good for structure Good if planning

iodine therapy

Pertechnetate Same day procedure Short notice Quick result Good for high uptake Not good for structure

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Disease Etiology SpecificSymptoms

Signs Lab Tests Uptake #Pattern

Graves’ TSI Orbitopathy,Dermopathy

Firm, rubberygland +/-orbitpathy

↓ TSH↑ Free T4+ve TSHrAb

HighDiffuse

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Contra-indicated in pregnancy and breast-feeding

Can’t be performed in the face of recent radio-contrast dye: IVP CT Angiography

Tracer can’t compete with large exogenousiodine dose for uptake Kelp pills

57 year old woman Chief Complaint:

“It’s the worst flu I’veever had! I’ve got afever, I ache all overand I’ve got the worstsore throat andearache!”

“Can I get someantibiotics?”

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“Flu” started withrunny nose and cough

Progressed to fever,generalized myalgia,ear pain, pain withswallowing

Thyroid is enlarged,tender, firm, no nodes

Pearce, E. N. et al. N Engl J Med 2003;348:2646-2655

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Pearce, E. N. et al. N Engl J Med 2003;348:2646-2655

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Disease Etiology SpecificSymptom

s

Signs Lab Tests Uptake #Pattern

Graves’Disease

TSI Orbitopathy,Dermopathy

Rubberygland +/-orbitpathy

↓ TSH↑ Free T4

HighDiffuse

Sub-acuteThyroiditis

Auto-immune+/-viral

Pain,tenderness

Firm,tendergland

↓ TSH↑ Free T4

NoneNone

58 year old woman Symptoms of

thyrotoxicosis Enlarged neck for

many years 2010:

TSH 0.1 (0.5-5.5), Free T4 20 (11-22)

2014: TSH < 0.01, Free T4 35

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General Appearance: thyrotoxic HR 100, BP 150/80 Lid-lag, stare, no proptosis Thyroid asymmetrically enlarged It is quite firm, irregular, non-tender with no

adenopathy

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Worldwide: iodine deficiency Developed world: genetic and non-immune Early: diffuse goitre Later: nodularity Slow growth with gradual functional

“autonomy”- dropping TSH with normal T4 Minority: biochemical and clinical

thyrotoxicosis Some may have local obstructive signs

Avoid exogenous iodine Jod-Basedow phenomenon Iodine causes autonomous nodules to overproduce

thyroxine

Often older patients Weight loss, atrial fibrillation, palpitations

No increased risk of malignancy Biopsy if dominant nodule or increasing size

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Disease Etiology SpecificSymptoms

Signs Lab Tests Uptake #Pattern

Graves’Disease

TSI Orbitopathy,Dermopathy

Rubbery gland+/- orbitpathy

↓ TSH↑ Free T4

HighDiffuse

Sub-acuteThyroiditis

Auto-immune+/-viral

Pain,tenderness

Firm, tendergland

↓ TSH↑ Free T4

NoneNone

Toxic Multi-nodularGoitre

“Autonomy” Slow goitregrowth

Asymmetric,nodular

↓ TSH↑ Free T4

HighPatchy

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Disease Etiology SpecificSymptoms

Signs Lab Tests Uptake #Pattern

Graves’Disease

TSI Orbitopathy,Dermopathy

Rubbery gland+/- orbitpathy

↓ TSH↑ Free T4

HighDiffuse

Sub-acuteThyroiditis

Auto-immune+/-viral

Pain,tenderness

Firm, tendergland

↓ TSH↑ Free T4

NoneNone

Toxic Multi-nodular Goitre

“Autonomy”Multifactorial

Slow goitregrowth

Asymmetric,nodular

↓ TSH↑ Free T4

HighPatchy

Toxic Nodule TSH receptormutation

Singlenodule?

Nodule,remainder ofthyroid small

↓ TSH↑ Free T4

HighNodule

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49 year old man withhistory majordepression treatedwith medication

Improved mood, butweight loss,tachycardia,diaphoresis, tremour

TSH < 0.01

Sertraline Cytomel TSH <0.01 Free T4 8 (11-22) Free T3 9.3 (3.5-6.5)

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Disease Etiology SpecificSymptoms

Signs Lab Tests Uptake #Pattern

Graves’Disease

TSI Orbitopathy,Dermopathy

Rubbery gland+/- orbitpathy

↓ TSH↑ Free T4

HighDiffuse

Sub-acuteThyroiditis

Auto-immune+/-viral

Pain,tenderness

Firm, tendergland

↓ TSH↑ Free T4

NoneNone

Toxic Multi-nodular Goitre

“Autonomy”Multifactorial

Slow goitregrowth

Asymmetric,nodular

↓ TSH↑ Free T4

HighPatchy

Toxic Nodule TSH receptormutation

Single nodule? Nodule,remainder ofthyroid small

↓ TSH↑ Free T4

HighNodule

Factitious,Iatrogenic

Exogenousthyroidhormone

History maynot beobvious

Thyroid notpalpable

↓ TSH↑ Free T4 or T3

NoneNone

Surgery Sub-total

thyroidectomy Rarely performed Special cases: Pregnancy and

intolerance of anti-thyroid drugs

<2% recurrence rate Hypothyroidism

common

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Thionamides: propylthiouracil, carbimazole and active

metabolite methimazole(Tapazole)

Inhibit TPO: reducingoxidation andorganification of iodide

This image cannot currently be displayed.

Methimazole Propylthiouracil

Serum Half-life 4-6 hrs 75 minutes

Tissue concentration 100X serum (gives 20 hrduration of action)

Dosing Single daily 3X/day

Time to normalizationT3,T4

5.8 weeks 16.8 weeks

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Measure Free T4monthly (TSHunreliable)

Titrate dose down tomaintenance

Maximum remissionrate by 18-24 months Discontinue and monitor

for relapse

Methimazole starting dose: 20-40 mg

daily Maintenance: 2.5-10

PTU Starting dose: 100-200

TID Maintenance: 50-100

daily in divided doses

~4%: rash, urticaria <3:1,000 agranulocytosis

“Sore throat, high fever- notify physician” Less common with low dose methimazole

Rarer: PTU: hepatocellular necrosis Methimazole: reversible cholestatic jaundice PTU: vasculitis Methimazole: scalp defect in neonates

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Either as initial treatment or second-line afterrelapse following drugs

Progressive destruction of thyroid cells Calculated dose based on uptake value and

size of gland Hypothyroidism common Time to normalization 4- 8 weeks Worsen orbitopathy?

Radioiodine is treatment of choice Concentrates within toxic nodule Remainder of thyroid is suppressed and unaffected Normal thyroid tissue recovers

Surgical resection is also effective Some centres use repeat injection of ethanol

solutions

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During acute inflammation: If marked local or systemic symptoms: Prednisone 40-60 mg daily tapered over 6-8 weeks

If less symptomatic: NSAIDs or ASA

If hypothyroid phase is prolonged andsymptomatic: Thyroxine at modest dose 50-100 ug daily 2-3

months

Three additional references?