My patient is

hyperthyroid
And I’m not sure why or what to do about it
Thyroid regulation
• Negative feedback primarily by free
T3/T4
• Decreases TRH secretion from hypothalamus
• Decreases sensitivity of anterior pituitary to
TRH
Thyroid hormone production

1. Iodide Uptake (I⁻)

• Iodide (I⁻) is actively transported from the blood into the
thyroid follicular cell via the sodium-iodide symporter
(NIS) on the basolateral membrane.
2. Iodide Transport to Follicular Lumen
• Iodide is then moved across the cell and into the
follicular lumen (colloid) where hormone synthesis
occurs.
3. Oxidation and Organification
• Iodide (I⁻) is oxidised to iodine (I₂) by the enzyme
thyroid peroxidase (TPO).
• Iodine is then organified—it is covalently bound to
tyrosine residues on thyroglobulin (TG) to form:
• MIT (monoiodotyrosine)
• DIT (diiodotyrosine)
4. Coupling Reaction
• Also catalyzed by TPO, this step combines:
• DIT + DIT → T₄ (thyroxine)
• MIT + DIT → T₃ (triiodothyronine)
These hormones remain stored in thyroglobulin within
the colloid.
5. Endocytosis of TG
• Thyroglobulin containing T₃ and T₄ is taken back into the
cell by endocytosis.
6. Proteolysis
• Inside the cell, proteases cleave T₃ and T₄ from
thyroglobulin.
7. Secretion
• Free T₃ and T₄ are released into the bloodstream to exert
systemic effects.
Hyperthyroidism
• Overall prevalence of 1.2%, 5x more common in women
• Causes
Graves disease
• The most common cause of hyperthyroidism
• mediated by thyroid stimulating immunoglobulins (TSI’s)
binding to the TSH receptor to mimic the effects of TSH
• Patients can have a diffuse non-tender goiter
• Patients can have a thyroid bruit due to increased blood flow
Two unique • Graves orbitopathy
extrathyroid • Pretibial myxoedema
al signs
Which patient at highest risk?
• TSH 0.06, T4 50
vs
• TSH < 0.03, T4 74
Caused by the underlying
autoimmune disease, not by thyroid
hormone excess
• Graves orbitopathy charactised by inflammation and edema of
retro-orbital tissues (extraocular muscles and fat), causes
forward protrusion of the globe (proptosis or exopththalmos)
• Pretibial myxoedema, a rare plaque-like thickening of the skin
over the shins, due to the accumulation of
glycosaminoglycans in the dermis

• The presence of orbitopathy or pretibial myxedema with or

without a symmetrically enlarged thyroid is highly suggestive
of Graves disease and no further testing is warranted.
Manifestations of graves
disease
Toxic multinodular goitre
• Most common cause of hyperthyroidism in older
patients
• Prevalence increases in settings of iodine deficiency
• decreased iodine leads to less thyroid hormone synthesis
• less T3/T4 causes less negative feedback -> high TSH
• chronic TSH stimulation leads to autonomous nodule
formation
• Characterised by areas of autonomous function within
an MNG that develop in response to somatic mutations
in genes regulating thyroid hormone synthesis and
secretion
Toxic adenomas
• Similar to toxic MNG, hyperthyroidism develops due to
autonomous function of a single nodule
• The presence of multiple nodules or a single nodule is
suggestive of a toxic MNG or adenoma, respectively.
• This diagnosis should be confirmed with a nuclear medicine
thyroid scan demonstrating a single or multiple areas of
radioisotope uptake
Iodine induced hyperthyroidism
• Precipitated by drugs such as amiodarone or
radiographic contrast media
• Occurs in up to 3% of patients treated with amiodarone
and typically in the setting of underlying thyroid
pathology, such as MNG
• RAIU is likely diminished
Amiodarone induced thyrotoxicosis
• Occurs via two mechanisms
• AIT1
• precipitated by excess iodine causing the Jod-Basedow phenomenon resulting in
increased thyroid hormone synthesis
• The Jod-Basedow phenomenon refers to iodine-induced hyperthyroidism,
typically occurring in individuals with underlying autonomous thyroid tissue
when they are exposed to a sudden increase in iodine.
• MNG
• Latent graves – TRAb positive
• Wolff-Chaikoff effect – protective autoregulation; sudden exposure to excess iodine
temporarily turns off thyroid peroxidase -> decreased T3/T4 production
• In iodine deficiency -> chronic TSH stimulation leads to autonomous nodule formation
• The nodules can become hyperfunctional when exposed suddenly to high iodine load
• Amiodarone is 37% iodine by weight, and its use releases a large iodine load into
the body, triggering excess thyroid hormone production in susceptible patients.
• Treatment - Carbimazole
AIT2
• destructive thyroiditis
• The cytotoxic effects of amiodarone on the thyroid
are primarily due to its direct toxic actions on
thyroid follicular cells, driven by its chemical
structure, lipophilicity, and metabolites.
• Treatment - glucocorticoids
Thyroiditis
• Transient hyperthyroidism results from release of
preformed thyroid hormone by inflamed thyroid tissue
• Subacute thyroiditis
• Causes by granulomatous inflammation in the setting of a viral
syndrome, resulting in a painful and tender goitre
• Can be supported by elevated ESR and serum thyroglobulin levels
• Painless thyroiditis
• Causes by an autoimmune process resulting in a nontender goitre.
• Most often observed in the postpartum period, up to a year postpartum
Factitious hyperthyroidism
• Surreptitious ingestion of thyroid hormone for the
purposes of weight loss
hCG induced
• Very high levels of human chorionic gonadotropin (hCG)
(which weakly cross-reacts with the TSH receptor)
• Pregnancy – Gestational transient thyrotoxicosis
• Trophoblastic tumors – choriocarcinoma, hydatidiform mole)
Differential diagnosis of hyperthyroidism
Differential diagnosis of
hyperthyroidism based on RAIU
Manifestatio
ns of
hyperthyroid
ism
Diagnostic testing
• Plasma TSH is the best initial diagnostic test
• Subnormal TSH should be followed by measurement of T3 and T4
• Subclinical hyperthyroidism is defined as a subnormal TSH in the
setting of normal thyroid hormone levels. Symptoms of hyperthyroidism
are often absent
• Other causes of TSH suppression
• Critical illness resulting in severe nonthyroidal illness. Patients have normal or low
plasma free T4 and low plasma T3
• Central hypothyroidism. fT4 levels are low or low-normal, and clinical signs of
hyperthyroidism are absent
• TSI / TRAb
• Thyroid ultrasound looking for nodules
• Nuclear medicine thyroid uptake
Treatment
• Goal of treatment
• manage symptoms related to increased adrenergic tone
• manage thyrotoxicosis
• radioactive iodine
• thionamides
• subtotal/total thyroidectomy
• Some forms of hyperthyroidism (subacute or
postpartum thyroiditis) are transient and require only
symptomatic therapy
Subclinical hyperthyroidism
• Increases the risk of AF in the elderly (particularly > 65)
• Predisposes to osteoporosis
• Treatment indicated if TSH <0.1 with additional risk
factor
• Age > 65
• Cardiovascular disease
• Osteoporosis
Beta blockers
• B-blockers are used to relieve symptoms such as
palpitations, tremor and anxiety
• Propranolol is a good non-selective B-blocker which can
block beta receptors and prevent peripheral conversion
by inhibiting type 1 deiodinase when 160mg/day is used
Thionamides

• Carbimazole and Propylthiouracil

inhibit thyroid hormone synthesis by
blocking thyroid peroxidase
• PTU also inhibits peripheral
conversion of T4 to T3 by type 1
deiodinase
• CBZ is preferred to PTU except in 1st
trimester
• Usual starting doses
• CBZ 10-40mg daily
• PTU 100-200mg TDS
• After 18 months of therapy, can
consider stopping if TSI is low
• Otherwise aim to continue for 5
years
Radioactive iodine

• Thyroid cells actively take up iodine,

including radioactive iodine, via the sodium-
iodide symporter.
• Overactive thyroid (Graves’ or toxic nodules)
takes up more iodine than normal tissue.
• Once inside the thyroid, ¹³¹I emits beta
particles, which:
• Cause local cytotoxicity
• Lead to gradual destruction of overactive
thyroid tissue
• This reduces the production of thyroid
hormones (T4 and T3) over time.
• Single dose of iodine-131 permanently
controls hyperthyroidism in about 80-90% of
patients
• further doses can be given if necessary
Side effects of RAI
• Permanent hypothyroidism in >50% of patients treated for Graves disease within the first year
• There is a slight exacerbation of hyperthyroidism following treatment because of release of stored
thyroid hormone
• relevant in patients with severe cardiac disease, can consider treating initially with thionamides to restore
euthyroidism first
• RAI can worsen graves orbitopathy and is contraindicated in moderative to severe graves orbitopathy
• Graves’ disease is an autoimmune condition where TSH receptor antibodies (TRAb) stimulate both:
• The thyroid gland
• Orbital fibroblasts, causing eye inflammation and tissue expansion
• After ¹³¹I therapy, thyroid cell destruction can cause:
• A release of thyroid antigens
• A transient increase in TRAb levels
• This stimulates orbital TSH receptors further, worsening inflammation and tissue swelling behind
the eyes.
Highest risk in:
• Smokers (strongest risk factor)
• Patients with pre-existing orbitopathy
• High baseline TRAb titres
Surgery
• Subtotal/total thyroidectomy provides long term control
• may trigger a perioperative exacerbation of hyperthyroidism
• For treatment of Graves
• achieve euthyroid with a thionamide pre-operatively
• Add supersaturated potassium iodide (SSKI) 2 weeks before surgery
• Wolff-Chaikoff effect:
• High levels of iodide temporarily inhibit thyroid hormone synthesis and release.
• Leads to rapid reduction in circulating T4 and T3 levels.
• Decreased thyroid vascularity:
• SSKI reduces blood flow to the gland by causing vasoconstriction and reducing
angiogenesis.
• This makes the gland less friable and easier to dissect, lowering intraoperative
bleeding risk.
• Thyroid size reduction:
• Modest decrease in gland size and firmness helps with safer surgical handling.
• Total thyroidectomy or near-total thyroidectomy are preferred in
management of toxic MNG or Graves disease
• Lobectomy may be sufficient in those with a single toxic adenoma
• Following total or near-total thyroidectomy -> need to replace
thyroid hormone with levothyroxine 1.6 mcg/kg
• Following subtotal thyroidectomy or lobectomy -> can wait to start
thyroxine replacement until persistent TSH elevation seen
• Surgery preferred in
• Moderate to severe active GO
• Suspected co-existent malignancy
• Graves planning pregnancy
• Symptomatic compression by large goitres or nodules >4cm
 Clinical
scenarios
Case 1
• A 28-year-old woman presents with palpitations, weight loss despite
increased appetite, heat intolerance, and anxiety. On exam, she has a
diffusely enlarged, smooth thyroid gland, lid lag, and a fine tremor.
She also has bilateral exophthalmos and pretibial myxedema.
• Investigations:
• TSH: <0.01 mIU/L (normal 0.4–4.0)
• Free T4: 45 pmol/L (normal 10–22)
• Free T3: 15 pmol/L (normal 3.5–6.5)
• TSH receptor antibodies: positive ( 8 IU/L; normal <1.5)
• Diffuse increased uptake on thyroid uptake scan
• Which of the following best explains the cause of this patient's
hyperthyroidism?
A) Destruction of thyroid follicles releasing preformed hormone
B) Autoimmune stimulation of the TSH receptor
C) Autonomous hormone production by thyroid nodules
D) Excess iodine intake stimulating thyroid hormone synthesis
E) Exogenous thyroid hormone ingestion
Case 1
• A 28-year-old woman presents with palpitations, weight loss despite
increased appetite, heat intolerance, and anxiety. On exam, she has a
diffusely enlarged, smooth thyroid gland, lid lag, and a fine tremor.
She also has bilateral exophthalmos and pretibial myxedema.
• Investigations:
• TSH: <0.01 mIU/L (normal 0.4–4.0)
• Free T4: 45 pmol/L (normal 10–22)
• Free T3: 15 pmol/L (normal 3.5–6.5)
• TSH receptor antibodies: positive ( 8 IU/L; normal <1.5)
• Diffuse increased uptake on thyroid uptake scan
• Which of the following best explains the cause of this patient's
hyperthyroidism?
A) Destruction of thyroid follicles releasing preformed hormone
B) Autoimmune stimulation of the TSH receptor
C) Autonomous hormone production by thyroid nodules
D) Excess iodine intake stimulating thyroid hormone synthesis
E) Exogenous thyroid hormone ingestion
Case 2
A 65-year-old man complains of intermittent palpitations and
mild weight loss over 6 months. On exam, he has an irregularly
enlarged thyroid with multiple palpable nodules. No eye signs or
dermopathy.
Lab results:
• TSH: <0.01 mIU/L
• Free T4: 28 pmol/L
• Free T3: 8.5 pmol/L
What is the most likely mechanism causing hyperthyroidism in
this patient?
A) Inflammation leading to follicular rupture
B) TSH receptor antibody stimulation
C) Autonomous hormone production by nodules independent of
TSH
D) Excess iodine-induced hormone synthesis
E) Exogenous thyroid hormone intake
Case 2
A 65-year-old man complains of intermittent palpitations and
mild weight loss over 6 months. On exam, he has an irregularly
enlarged thyroid with multiple palpable nodules. No eye signs or
dermopathy.
Lab results:
• TSH: <0.01 mIU/L
• Free T4: 28 pmol/L
• Free T3: 8.5 pmol/L
What is the most likely mechanism causing hyperthyroidism in
this patient?
A) Inflammation leading to follicular rupture
B) TSH receptor antibody stimulation
C) Autonomous hormone production by nodules independent of
TSH
D) Excess iodine-induced hormone synthesis
E) Exogenous thyroid hormone intake
Case 3
A 40-year-old woman presents with a painful, tender thyroid gland following a recent
upper respiratory tract infection. She has symptoms of hyperthyroidism (palpitations,
heat intolerance), but also fever and malaise.
Lab results:
• TSH: <0.01 mIU/L
• Free T4: 35 pmol/L (elevated)
• ESR: 65 mm/hr (elevated; normal <20)

Why is the thyroid uptake scan low in this condition?

A) The thyroid gland is being destroyed and not synthesizing new hormone
B) There is autoimmune stimulation of the gland
C) Exogenous thyroid hormone suppresses uptake
D) The nodules are producing excess hormone autonomously
E) Excess iodine inhibits hormone synthesis
Case 3
A 40-year-old woman presents with a painful, tender thyroid gland following a recent
upper respiratory tract infection. She has symptoms of hyperthyroidism (palpitations,
heat intolerance), but also fever and malaise.
Lab results:
• TSH: <0.01 mIU/L
• Free T4: 35 pmol/L (elevated)
• ESR: 65 mm/hr (elevated; normal <20)

Why is the thyroid uptake scan low in this condition?

A) The thyroid gland is being destroyed and not synthesizing new hormone
B) There is autoimmune stimulation of the gland
C) Exogenous thyroid hormone suppresses uptake
D) The nodules are producing excess hormone autonomously
E) Excess iodine inhibits hormone synthesis
Case 4
• A 63-year-old man with ischemic cardiomyopathy and atrial fibrillation presents with unintentional weight loss,
increased sweating, and worsening palpitations over several weeks. He has been taking amiodarone 200 mg
daily for the past 18 months. On exam, he is tachycardic with a resting heart rate of 112 bpm. There is no eye
disease or goitre.
• Lab results:
• TSH: <0.01 mIU/L (normal 0.4–4.0)
• Free T4: 55 pmol/L (normal 10–22)
• Free T3: 10 pmol/L (normal 3.5–6.5)
• TPO antibodies: negative
• TRAb: negative
• ESR: 50 mm/hr
• CRP: 35 mg/L
• Thyroid uptake scan: very low uptake
• Color flow Doppler shows reduced vascularity of the thyroid, nil nodules
• Which combination of findings most strongly supports a diagnosis of Type 2 Amiodarone-Induced
Thyrotoxicosis?
• A) Low radioactive iodine uptake, negative thyroid autoantibodies, increased vascularity on Doppler
B) High radioactive iodine uptake, suppressed TSH, longstanding goitre, and positive TRAb
C) Low radioactive iodine uptake, elevated ESR/CRP, and hypovascular thyroid on Doppler
D) Positive TPO antibodies, thyroid bruit, and diffuse goitre
E) Low ESR/CRP, thyroid nodule on ultrasound, and increased uptake on scan
Case 4
• A 63-year-old man with ischemic cardiomyopathy and atrial fibrillation presents with unintentional weight loss,
increased sweating, and worsening palpitations over several weeks. He has been taking amiodarone 200 mg
daily for the past 18 months. On exam, he is tachycardic with a resting heart rate of 112 bpm. There is no eye
disease or goitre.
• Lab results:
• TSH: <0.01 mIU/L (normal 0.4–4.0)
• Free T4: 55 pmol/L (normal 10–22)
• Free T3: 10 pmol/L (normal 3.5–6.5)
• TPO antibodies: negative
• TRAb: negative
• ESR: 50 mm/hr
• CRP: 35 mg/L
• Thyroid uptake scan: very low uptake
• Color flow Doppler shows reduced vascularity of the thyroid, nil nodules
• Which combination of findings most strongly supports a diagnosis of Type 2 Amiodarone-Induced
Thyrotoxicosis?
• A) Low radioactive iodine uptake, negative thyroid autoantibodies, increased vascularity on Doppler
B) High radioactive iodine uptake, suppressed TSH, longstanding goitre, and positive TRAb
C) Low radioactive iodine uptake, elevated ESR/CRP, and hypovascular thyroid on Doppler
D) Positive TPO antibodies, thyroid bruit, and diffuse goitre
E) Low ESR/CRP, thyroid nodule on ultrasound, and increased uptake on scan
Case 5
• A 67-year-old man with a history of coronary artery disease and atrial fibrillation presents with new-onset
weight loss, sweating, and anxiety. He has been on amiodarone 200 mg daily for 2 years. Examination
reveals a mild resting tremor and a small, irregular goitre without tenderness or bruit. No orbitopathy.
• Investigations:
• TSH: <0.01 mIU/L
• Free T4: 50 pmol/L
• Free T3: 13 pmol/L
• ESR: 40 mm/hr
• CRP: 25 mg/L
• TRAb: negative
• Thyroid ultrasound: small, heterogeneous gland with several hypoechoic nodules
• Doppler: mildly increased vascularity
• Thyroid uptake scan: low uptake
Which of the following combinations of findings most strongly suggests a diagnosis of Mixed AIT
rather than pure Type 1 or Type 2?
• A) Low radioactive iodine uptake and elevated inflammatory markers
B) Thyroid nodules on ultrasound with low uptake on scan
C) TSH suppression with elevated free T4 and T3
D) Absence of TSH receptor antibodies
E) Longstanding use of amiodarone (>12 months)
Case 5
• A 67-year-old man with a history of coronary artery disease and atrial fibrillation presents with new-onset
weight loss, sweating, and anxiety. He has been on amiodarone 200 mg daily for 2 years. Examination
reveals a mild resting tremor and a small, irregular goitre without tenderness or bruit. No orbitopathy.
• Investigations:
• TSH: <0.01 mIU/L
• Free T4: 50 pmol/L
• Free T3: 13 pmol/L
• ESR: 40 mm/hr
• CRP: 25 mg/L
• TRAb: negative
• Thyroid ultrasound: small, heterogeneous gland with several hypoechoic nodules
• Doppler: mildly increased vascularity
• Thyroid uptake scan: low uptake
Which of the following combinations of findings most strongly suggests a diagnosis of Mixed AIT
rather than pure Type 1 or Type 2?
• A) Low radioactive iodine uptake and elevated inflammatory markers
B) Thyroid nodules on ultrasound with low uptake on scan
C) TSH suppression with elevated free T4 and T3
D) Absence of TSH receptor antibodies
E) Longstanding use of amiodarone (>12 months)
Case 5 continued
• He is diagnosed with Mixed AIT. His cardiac symptoms
are worsening, with increasing angina and poor rate
control.
• Which of the following is the most appropriate initial
management strategy for this patient?
A) High-dose carbimazole monotherapy
B) Prednisolone 40 mg daily with taper over 8 weeks
C) Combination of thionamide and glucocorticoid therapy
D) Immediate total thyroidectomy
E) Radioactive iodine ablation after ceasing amiodarone
Case 5 continued
• He is diagnosed with Mixed AIT. His cardiac symptoms
are worsening, with increasing angina and poor rate
control.
• Which of the following is the most appropriate initial
management strategy for this patient?
A) High-dose carbimazole monotherapy
B) Prednisolone 40 mg daily with taper over 8 weeks
C) Combination of thionamide and glucocorticoid therapy
D) Immediate total thyroidectomy
E) Radioactive iodine ablation after ceasing amiodarone