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Marshall Dahl MD PhD FRCPC cert Endo
Clinical Professor, University of British Columbia
marshall.dahl@vch.ca
Tel 604 875 5577
Fax 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 of
thyroid gland
 Five selected types of thyrotoxicosis-
understand:
 Pathophysiology
 Clinical presentation
 Investigations
 Treatment

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 Multiple Etiologies
 5 are common
 Diagnosis needed for
appropriate
management
 Differentiation can
often be made through
history and physical
examination
 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 thyroid
checked!”
 “I looked on the internet- I think that it’s
overactive!”

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 Some findings of
thyrotoxicosis are present
regardless of the etiology
 What symptoms?
 What physical findings?

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 She wants you to know that
her mother and sister have
“overactive thyroids”.
 She has noticed that her
eyes have become more
prominent
 She’s pretty sure from her
reading that she has
Graves’ disease
 What findings are specific
to 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 Specific
Symptoms
Signs Lab Tests Other tests
Graves’ TSI Orbitopathy,
Dermopathy
Firm, rubbery
gland +/-
orbitpathy
↓ TSH
↑ Free T4
TSH receptor
antibody*
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 Specific
Symptoms
Signs Lab Tests Uptake #
Pattern
Graves’ TSI Orbitopathy,
Dermopathy
Firm, rubbery
gland +/-
orbitpathy
↓ TSH
↑ Free T4
+ve TSHr
Ab
High
Diffuse

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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 exogenous
iodine dose for uptake
 Kelp pills
 57 year old woman
 Chief Complaint:
 “It’s the worst flu I’ve
ever had! I’ve got a
fever, I ache all over
and I’ve got the worst
sore throat and
earache!”
 “Can I get some
antibiotics?”

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 “Flu” started with
runny nose and cough
 Progressed to fever,
generalized myalgia,
ear pain, pain with
swallowing
 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 Specific
Symptom
s
Signs Lab Tests Uptake #
Pattern
Graves’
Disease
TSI Orbitopathy,
Dermopathy
Rubbery
gland +/-
orbitpathy
↓ TSH
↑ Free T4
High
Diffuse
Sub-acute
Thyroiditis
Auto-
immune+/-
viral
Pain,
tenderness
Firm,
tender
gland
↓ TSH
↑ Free T4
None
None
 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 Specific
Symptoms
Signs Lab Tests Uptake #
Pattern
Graves’
Disease
TSI Orbitopathy,
Dermopathy
Rubbery gland
+/- orbitpathy
↓ TSH
↑ Free T4
High
Diffuse
Sub-acute
Thyroiditis
Auto-
immune+/-
viral
Pain,
tenderness
Firm, tender
gland
↓ TSH
↑ Free T4
None
None
Toxic Multi-
nodular
Goitre
“Autonomy” Slow goitre
growth
Asymmetric,
nodular
↓ TSH
↑ Free T4
High
Patchy

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Disease Etiology Specific
Symptoms
Signs Lab Tests Uptake #
Pattern
Graves’
Disease
TSI Orbitopathy,
Dermopathy
Rubbery gland
+/- orbitpathy
↓ TSH
↑ Free T4
High
Diffuse
Sub-acute
Thyroiditis
Auto-
immune+/-
viral
Pain,
tenderness
Firm, tender
gland
↓ TSH
↑ Free T4
None
None
Toxic Multi-
nodular Goitre
“Autonomy”
Multifactorial
Slow goitre
growth
Asymmetric,
nodular
↓ TSH
↑ Free T4
High
Patchy
Toxic Nodule TSH receptor
mutation
Single
nodule?
Nodule,
remainder of
thyroid small
↓ TSH
↑ Free T4
High
Nodule

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 49 year old man with
history major
depression treated
with medication
 Improved mood, but
weight 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 Specific
Symptoms
Signs Lab Tests Uptake #
Pattern
Graves’
Disease
TSI Orbitopathy,
Dermopathy
Rubbery gland
+/- orbitpathy
↓ TSH
↑ Free T4
High
Diffuse
Sub-acute
Thyroiditis
Auto-
immune+/-
viral
Pain,
tenderness
Firm, tender
gland
↓ TSH
↑ Free T4
None
None
Toxic Multi-
nodular Goitre
“Autonomy”
Multifactorial
Slow goitre
growth
Asymmetric,
nodular
↓ TSH
↑ Free T4
High
Patchy
Toxic Nodule TSH receptor
mutation
Single nodule? Nodule,
remainder of
thyroid small
↓ TSH
↑ Free T4
High
Nodule
Factitious,
Iatrogenic
Exogenous
thyroid
hormone
History may
not be
obvious
Thyroid not
palpable
↓ TSH
↑ Free T4 or T3
None
None
 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: reducing
oxidation and
organification of iodide
This image cannot currently be displayed.
Methimazole Propylthiouracil
Serum Half-life 4-6 hrs 75 minutes
Tissue concentration 100X serum (gives 20 hr
duration of action)
Dosing Single daily 3X/day
Time to normalization
T3,T4
5.8 weeks 16.8 weeks

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 Measure Free T4
monthly (TSH
unreliable)
 Titrate dose down to
maintenance
 Maximum remission
rate 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 after
relapse 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 and
symptomatic:
 Thyroxine at modest dose 50-100 ug daily 2-3
months
Three additional references?