• Location: Anterior neck, straddling the trachea at the level of C5–T1 vertebrae
• Structure: Two lateral lobes connected by an isthmus (± pyramidal lobe — a remnant of the thyroglossal duct, present in ~50%)
• Weight: Normal adult thyroid weighs 15–25 g
• Blood supply: Superior thyroid artery (from external carotid) and inferior thyroid artery (from thyrocervical trunk); one of the most richly vascularised organs per gram of tissue — this is why in Graves' disease you can hear a bruit and feel a thrill over the gland (↑vascularity from TSHr stimulation)
• Venous drainage: Superior and middle thyroid veins → IJV; inferior thyroid veins → brachiocephalic veins
• Lymphatic drainage: Pre-tracheal, pre-laryngeal (Delphian), paratracheal, deep cervical nodes
• Innervation: Sympathetic fibres from superior and middle cervical ganglia (vasomotor, not secretomotor — thyroid function is regulated hormonally, not neurally)

• Recurrent laryngeal nerve (RLN): Runs in the tracheo-oesophageal groove posterior to the thyroid lobes — at risk during thyroidectomy → injury causes hoarseness (unilateral) or stridor/airway obstruction (bilateral)
• Parathyroid glands: 4 glands embedded in posterior aspect of thyroid — at risk during thyroidectomy → hypoparathyroidism → hypocalcaemia
• External branch of superior laryngeal nerve: Runs close to the superior thyroid artery — injury causes loss of voice projection (cricothyroid muscle denervation)

The Hypothalamic-Pituitary-Thyroid (HPT) Axis:

• TRH (thyrotropin-releasing hormone) from the hypothalamus stimulates TSH (thyroid-stimulating hormone / thyrotropin) release from the anterior pituitary
• TSH binds the TSH receptor (TSHr) on thyroid follicular cells — a G-protein coupled receptor (GPCR) that activates the Gsα–adenylyl cyclase–cAMP pathway
• TSH stimulation causes: (1) ↑iodine trapping (via sodium-iodide symporter, NIS), (2) ↑thyroglobulin synthesis, (3) ↑thyroid peroxidase (TPO) activity, (4) ↑T4/T3 synthesis and release, (5) thyroid cell growth (goitre)
• T4 (thyroxine) is the main secretory product — it is a prohormone converted to the active T3 (triiodothyronine) by deiodinases (mainly type 1 and 2) in peripheral tissues (liver, kidney, muscle)
• T3 enters the nucleus → binds thyroid hormone receptors → acts as a transcription factor → regulates gene expression affecting virtually every organ system
• Negative feedback: T3/T4 inhibit TRH and TSH release

Why this matters in Graves':

• In Graves' disease, TRAb mimics TSH at the TSHr → the gland thinks it is being told to make more hormone → constitutive activation → ↑T4/T3 release
• But unlike TSH, TRAb is not subject to negative feedback — the pituitary cannot "turn off" an autoantibody
• Result: TSH is suppressed (often undetectable) by high T4/T3 via intact negative feedback, but the gland keeps producing hormone because TRAb keeps stimulating it

Graves' disease is autoimmune in origin. The fundamental problem is a loss of immune self-tolerance to the TSH receptor ^[2].

Genetic susceptibility + Environmental trigger → Loss of self-tolerance → Production of TRAb → Disease

1. Loss of self-tolerance: In a genetically susceptible individual, some trigger (infection, stress, iodine) causes breakdown of peripheral tolerance to the TSHr antigen
2. B-cell activation: Autoreactive B-lymphocytes produce TRAb (IgG) that targets the TSH receptor
3. TSHr stimulation: TRAb binds the extracellular domain of TSHr → activates the Gsα–cAMP signalling cascade → mimics the effect of TSH (but without feedback regulation)
4. Thyroid gland effects:
   • ↑Iodine uptake (↑NIS expression) → explains diffuse ↑uptake on scintigraphy
   • ↑Thyroglobulin synthesis and ↑TPO activity
   • ↑T4 and T3 synthesis and secretion → thyrotoxicosis
   • ↑Thyroid cell proliferation and vascularity → diffuse goitre with bruit
5. Pituitary feedback: High circulating T4/T3 → negative feedback → suppressed TSH (often undetectable < 0.01 mIU/L)
6. Extra-thyroidal effects: TSHr is also expressed on:
   • Orbital fibroblasts → Graves' ophthalmopathy (see below)
   • Dermal fibroblasts (pretibial skin) → Pretibial myxoedema
   • Periosteal fibroblasts → Thyroid acropachy

Understanding why excess T3 causes specific symptoms is crucial:

Occurs in ~20–25% of Graves' disease patients ^[3][6].

Pathophysiology (an area of active research, but the current understanding):

1. Target cell = orbital fibroblast — the inciting antigen is thought to be TSHr expressed on orbital fibroblasts (and possibly IGF-1 receptor, which cross-talks with TSHr) ^[3]
2. TRAb binds TSHr on orbital fibroblasts → activates downstream signalling:
   • Stimulates orbital pre-adipocytes (a subpopulation of fibroblasts) to differentiate into adipocytes with ↑expression of TSHr ^[3]
   • Stimulates orbital adipocytes to ↑expression of PPARγ, adiponectin, and TSHr genes ^[3]
   • Stimulates glycosaminoglycan (GAG) production (especially hyaluronic acid) → GAGs are extremely hydrophilic → draw water into the orbital space
3. T-cell activation due to cytokine release → inflammatory infiltrate → orbital and EOM oedema ^[6]
4. Consequence: ↑interstitial fluid content + ↑inflammatory infiltrate in orbital cavity → swelling and eventually fibrosis of EOM → ↑retrobulbar pressure ^[3]
5. → Proptosis, exophthalmos ± optic nerve compression (if severe) ^[3]

Histology ^[3]:

• EOM: oedema, mononuclear infiltration, mucopolysaccharides, fibrosis
• Retrobulbar fat: lymphocyte infiltration, replacement by fibrous tissues (collagen + hyaluronic acid)
• Optic nerve: atrophy, replacement by fibrous and fatty connective tissue

Why the orbit specifically? Because orbital fibroblasts uniquely co-express TSHr and IGF-1R at levels sufficient for TRAb-mediated stimulation. The orbit is also a confined bony space — so even small increases in tissue volume cause significant pressure effects (the "compartment syndrome" analogy).

Risk factors for GO ^[3][6]:

• Gender: F > M in general but M usually more severe
• Smokers: 2.22× risk, tends to be more severe
• RAI treatment: ↑risk of development or worsening of GO
• Higher TRAb titres: correlates with clinical severity

Important: GO is NOT limited to patients with clinical hyperthyroidism — it can occur in hypothyroidism and euthyroid individuals (because it is an autoimmune orbital disease driven by TRAb, not by thyroid hormone levels per se) ^[6].

Occurs in < 10% of Graves' disease patients ^[2].

• Mechanism: TRAb binds TSHr on dermal fibroblasts in the pretibial area → stimulates GAG (hyaluronic acid) and collagen deposition → tissue swelling
• Appearance: raised pink-coloured or purplish plaques on the anterior aspect of the leg ^[2]
• Why pretibial? The pretibial skin has a high density of fibroblasts with TSHr expression; also, this area is subject to minor trauma which may upregulate local TSHr expression (Koebner-like phenomenon)
• Almost always occurs in the setting of (or after) Graves' ophthalmopathy — virtually never without GO

• The rarest extra-thyroidal manifestation (< 1%)
• Mechanism: TRAb-mediated stimulation of periosteal fibroblasts → new bone formation (periosteal reaction) in the phalanges and metacarpals
• Presents as: digital clubbing and soft tissue swelling of hands and feet ^[2]
• Almost always accompanied by ophthalmopathy and pretibial myxoedema

A sporadic form of hypokalaemic periodic paralysis occurring in association with hyperthyroidism ^[7].

Pathophysiology ^[7]:

• Hyperthyroidism → ↑Na⁺/K⁺/ATPase activity (T3 upregulates Na⁺/K⁺-ATPase gene transcription)
• + ↑insulin release (esp after carbohydrate load) → intracellular shift of K⁺
• Consequences: paralysis and hypokalaemia
• The K⁺ is NOT lost from the body — it is shifted into cells. This is why total body K⁺ is normal and aggressive K⁺ replacement risks rebound hyperkalaemia when the transcellular shift reverses

Clinical presentation ^[7]:

• Always preceded by thyrotoxic S/S (thyrotoxic state essential for pathogenesis)
• Attacks of motor paralysis: proximal > distal, LL > UL, seldom respiratory/bulbar muscles
• Signs: typically hypotonia with hypo/areflexia
• Course: weekly/monthly attacks lasting mins-days
• Precipitants:
  • Events a/w ↑adrenaline release: rest after strenuous activity, stress, SABA use
  • Events a/w ↑insulin release: namely ↑carbohydrate load
• Cardiac arrhythmia due to severe hypoK (mean serum [K] = 2.1 but can be < 1.5)

• Sensitivity 97%, specificity 99% with newer assays ^[6]
• If positive → Graves' disease (virtually diagnostic)
• If negative → proceed to imaging

• Look for nodules and ↑blood flow in Graves' disease ^[6]
• Diffuse ↑vascularity without nodules → supports Graves'
• Nodules identified → need scintigraphy to determine functional status

Not widely available; useful in specific scenarios ^[6]:

Scintigraphy patterns ^[2][6]:

It is important to know that a low TSH is not ALWAYS thyrotoxicosis ^[2][6]:

• Central hypothyroidism (pituitary/hypothalamic insufficiency) — ↓TSH + ↓fT4 (not ↑fT4)
• Systemic illness (sick euthyroidism) — transient TSH suppression during acute illness
• Pregnancy (first trimester) — hCG cross-reacts with TSHr → physiological TSH suppression
• Drugs: glucocorticoids, dopamine agonists — suppress TSH secretion centrally
• Recovery phase of non-thyroidal illness — TSH may transiently drop before normalising

What it is: Serum measurement of TSH, free T4, and free T3.

Why FREE (unbound) T4 and NOT total T4? ^[1]

Serum total T4 is a measurement of total T4 bound to plasma binding proteins including thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) ^[1]. These binding protein levels are affected by many conditions:

• ↑ in pregnancy (oestrogen ↑TBG synthesis) → ↑total T4 without true thyrotoxicosis ^[1]
• ↓ in hypoalbuminaemia (nephrotic syndrome, liver failure) → ↓total T4 without true hypothyroidism ^[1]

Free T4 reflects the biologically active, unbound fraction and is therefore a more accurate measure of thyroid status.

Specific patterns and pearls:

• ↓TSH ↑T3 ↑fT4: diagnostic of thyrotoxicosis (TSH usually undetectable) ^[2][5][6]
• ↓TSH nT3 nfT4: subclinical hyperthyroidism ^[2][5][6]
• ↑TSH ↑T3 ↑fT4: TSH-dependent hyperthyroidism (very rare, due to TSH-secreting pituitary adenomas) ^[2][5][6]

What it is: Serum measurement of antibodies directed against the TSH receptor. Also known as TBII (TSH-binding inhibitory immunoglobulins) in older nomenclature, or TSI (thyroid-stimulating immunoglobulins) when specifically measuring the stimulatory subset.

Performance: Sensitivity 97%, specificity 99% with newer assays ^[2][6]

Why it's useful — Three main clinical indications ^[2]:

Why it is NOT routinely ordered: NOT routinely done (quite expensive) ^[2]. In a classic presentation (young woman + diffuse goitre + bruit + ophthalmopathy), clinical diagnosis is sufficient. TRAb is reserved for atypical presentations, prognostication, or pregnancy.

Key distinction: Anti-TPO and anti-Tg tell you there is autoimmune thyroid disease but do NOT distinguish Graves' from Hashimoto's. Only TRAb is specific for Graves'.

What it is: High-frequency (7.5–10 MHz) B-mode ultrasound of the thyroid ± colour Doppler.

Routine for ALL goitre/nodules ^[8][2] — but technically not mandatory if the clinical picture is classic Graves' without palpable nodules.

USS Roles ^[2][6][8]:

1. Look for nodules — important because thyroid nodules co-existing with Graves' may be malignant
2. Assess ↑blood flow in Graves' disease — supportive of diagnosis
3. Guide FNAC if suspicious nodule identified
4. Assess retrosternal extension of large goitres

What it is: Imaging of radiotracer uptake by the thyroid gland using I-123 (radioactive iodine) or Tc-99m pertechnetate ^[9].

Principle: The thyroid is the only organ that actively traps and organifies iodine (via the sodium-iodide symporter, NIS). Radioactive iodine or pertechnetate (which is also trapped by NIS but not organified) allows visualisation of functional thyroid tissue. Areas that take up tracer avidly = "hot" (hyperfunctioning); areas that don't = "cold" (non-functioning or destroyed).

Not widely available; useful in specific scenarios ^[2][6]:

Scintigraphy findings and interpretations ^[2][6][9]:

Practical note on lecture slides: The lecture slides illustrate the four classic scintigraphy patterns for thyrotoxicosis ^[9]:

Graves' disease → diffuse ↑uptake Toxic adenoma → focal "hot" nodule with suppressed surrounding gland Cold nodule → focal ↓uptake (concern for malignancy) Toxic nodular goitre → heterogeneous ↑uptake

Radio-isotope scintigraphy (I-123 or Tc-99m) — for diagnosis of malignancy: low sensitivity and specificity; for functional assessment in thyrotoxic patients: high utility ^[9]

Once Graves' disease is diagnosed, a set of baseline investigations is needed before initiating treatment:

When ophthalmopathy is present or suspected, additional specific investigations are needed ^[3][10]:

Clinical Activity Score (CAS) — 7 Items ^[10]:

1. Spontaneous retrobulbar pain
2. Pain on eye movements
3. Eyelid erythema
4. Conjunctival injection
5. Chemosis
6. Swelling of caruncle
7. Eyelid oedema or fullness

CAS > 3 = active disease → active inflammation (usually lasts 6–18 months) → ↑likelihood to respond to immunomodulatory treatment ^[10]

Severity classification by EUGOGO (European Group on Graves' Orbitopathy) ^[10]:

These are NOT routine in Graves' disease but may be indicated in specific situations ^[8][9]:

Adapted from the lecture slides and senior notes ^[8][9]:

Biochemistry: undetectable TSH, T3 and T4 at upper end of reference range ^[5]

• Often found in older patients with multinodular goitre ^[5]
• The TSH is low but the thyroid hormones are still within reference range — the patient may be asymptomatic or have subtle symptoms
• ↓TSH still associated with risk of AF and osteoporosis → treated if > 65y or TSH < 0.1 mIU/L (↑risk of complications) ^[5]

Biochemistry: ↓/normal TSH, ↑T4, normal/↓ T3 ^[5]

• Reason: systemic illness → ↓peripheral T4 conversion to T3, altered binding protein level/affinity, ↓TSH secretion ^[5]
• TSH may ↑ to hypothyroidism level in convalescence (i.e. during recovery, TSH temporarily overshoots upward — don't diagnose hypothyroidism at this stage) ^[5]
• Should avoid unnecessary TFT testing in asymptomatic individuals — if you check TFT in a sick patient and get confusing results, it is often sick euthyroidism ^[5]
• The distinguishing feature from true thyrotoxicosis: T3 is usually low in sick euthyroidism (because peripheral conversion is impaired), while in thyrotoxicosis T3 is ↑

Thionamides ("thio" = sulphur, "amide" = nitrogen-containing group) — these drugs contain a thioureylene moiety that is essential for their action:

Why is onset slow? Onset of euthyroid takes 3–4 weeks since the thyroid gland has large storage of hormones — the gland contains a ~2-week supply of pre-formed T4/T3 in thyroglobulin. Hormone needs to be depleted before manifestation of drug effects ^[1]. ATDs block new synthesis but cannot destroy already-stored hormone.

Two approaches ^[2]:

Taken up and processed by thyroid gland in the same way as normal iodide — specificity to thyroid is due to preferential thyroid uptake via the Na⁺-I⁻ symporter (NIS) ^[1]. Becomes incorporated into thyroglobulin → emits β-radiation in thyroid gland → destruction of thyroid gland by necrosis of follicular cells ^[1]. The β-particles have a very short range (~1–2 mm) so damage is confined to the thyroid with minimal systemic radiation.

Indications for definitive treatment (RAI or surgery): ^[2]

• Relapsed after a course of ATD
• Intolerant/allergic to ATDs (e.g. agranulocytosis)
• Complications (e.g. TPP)
• Contemplating pregnancy (in next 1–2 years) — want stable euthyroidism before conception
• Patient preference

RAI is preferred over surgery when:

• Small to moderate goitre (< 80g)
• No suspicious nodules requiring histological evaluation
• No significant ophthalmopathy (moderate-to-severe GO is a relative contraindication)
• Patient wishes to avoid surgery

For Graves' disease specifically: ATDs are 1st line; RAI is 2nd line ^[8]

Contraindications to RAI: ^[1]

• Pregnancy and lactation — damage of thyroid gland of fetus (¹³¹I crosses the placenta and is concentrated by the fetal thyroid from ~12 weeks gestation); avoid breast-feeding since it is secreted in breastmilk ^[1]
• Children and adolescents — avoid potential teratogenicity in young age ^[1] (relative contraindication; used in some centres for adolescents but generally avoided < 10 years)
• Moderate-to-severe active Graves' ophthalmopathy — RAI treatment: ↑risk of development or worsening of GO ^[3][10]; moderate/severe GO is a contraindication to RAI treatment ^[3][10]
• Very large goitre (> 80g) — unlikely to achieve adequate destruction with a single dose
• Suspected or confirmed thyroid malignancy (may need surgery instead)
• Inability to comply with radiation safety precautions

Before ¹³¹I therapy:

• Discussion of treatment options and patient's consent
• Instruct patients on post-therapy precautions and follow-ups
• Avoid iodine-containing food, medicine (cough suppressant) or radiological contrast for ≥ 4 weeks before ^[1] — exogenous iodine saturates the NIS and competes with ¹³¹I uptake, reducing treatment efficacy
• Avoid anti-thyroid medications for ≥ 4 weeks before ^[1] — ATDs reduce iodine organification; if the gland cannot organify ¹³¹I, the radioiodine washes out before it can deliver its radiation dose
• Symptomatic control of hyperthyroidism by propranolol ^[1] (β-blocker is continued through the RAI period to control symptoms)
• Pregnancy test for patients with child-bearing potential ^[1]

After ¹³¹I therapy:

• Symptomatic control of hyperthyroidism by propranolol ^[1] (thyrotoxicosis may transiently worsen in the first 1–2 weeks as damaged follicles release stored hormone)
• Discharge home immediately and avoid close contact with others ^[1] (radiation precautions — typically 1–2 weeks of distance from pregnant women and small children)
• Safe contraception ≥ 6 months; avoid pregnancy and breast feeding ≥ 6 months ^[1]

Indications for thyroidectomy (3Cs + others): ^[2][8]

• (Cancer): Co-existing suspicious nodule or confirmed malignancy
• Compressive symptoms: Dysphagia, dysphonia, dyspnoea, retrosternal goitre
• Cannot be treated medically: Frequent relapses, ATD intolerance (e.g. agranulocytosis to both CBZ and PTU), require definitive Tx when RAI unsuitable or large goitre > 80g
• Cosmesis: Very large goitre
• Moderate/severe Graves' ophthalmopathy — RAI contraindicated; thyroidectomy is preferred definitive Tx because it ↓thyroid antigen load → usually associated with ↓TRAb titres ^[3][10]
• Pregnant women intolerant to anti-thyroid medications ^[1]
• Patient preference / refused ¹³¹I ^[1]

For Graves' disease: total thyroidectomy is recommended (cf. subtotal thyroidectomy) ^[8]:

Modern practice favours total thyroidectomy for Graves' because the whole point of surgery is to eliminate the disease — leaving a remnant behind risks recurrence and makes subsequent RAI more difficult if needed. The trade-off is accepting certain hypothyroidism (which is easy to manage with T4 replacement) ^[8].

This is extremely high yield — a thyrotoxic patient undergoing thyroid surgery is at risk of thyroid storm if not adequately prepared.

Pre-op preparation in thyrotoxic patients undergoing thyroid surgery: ^[8]

1. Maintain biochemically euthyroid at operation to prevent thyroid storm ^[8]
2. High dose carbimazole (30–40 mg/day) for 8–12 weeks, then low dose (15 mg/day) to maintain euthyroid ^[8]
3. Propranolol (40 mg TDS): block β-receptor + reduce T4→T3 conversion ^[8]
   • More rapid clinical response (days instead of weeks) ^[8]
   • T4 level still high post-op: continue propranolol until 7 days post-op ^[8]
4. Lugol's iodine: ↓iodine uptake + ↓vascularity of thyroid gland (↓intra-op bleeding) ^[8]
   • Can be given with carbimazole/β-blocker for 10 days before operation ^[8]
   • Mechanism: Wolff-Chaikoff effect — supraphysiological iodine doses transiently inhibit organification and also reduce thyroid blood flow by inhibiting TSH-mediated VEGF expression
5. Monitor Ca and vitamin D level and supplement accordingly (post-op hypoPTH/hungry bone syndrome) ^[8]
6. Vocal cord function by laryngoscopy ^[8] — pre-operative documentation of baseline vocal cord function is medicolegally essential; if there is pre-existing RLN palsy, the surgeon needs to know

• Longstanding untreated hyperthyroidism
• Acute infection, thyroid and non-thyroid surgery, trauma, childbirth in previously untreated/undertreated hyperthyroidism
• Withdrawal of antithyroid drugs
• Shortly after treatment procedures (subtotal thyroidectomy or RAI)
• Acute iodine load, e.g. amiodarone

• CVS: tachycardia > 140/min, AF, high output failure
• Hyperpyrexia: may reach > 40°C
• CNS disturbance: agitation, anxiety, delirium, psychosis, stupor, coma
• ↓TSH/↑fT4 (typically not more profound than uncomplicated hyperthyroidism) ^[6]
• ± Mild hyperglycaemia, hypercalcaemia and deranged LFT ^[6]

Diagnosis: Burch and Wartofsky scoring system (sensitive but not specific): ≥ 45 = highly suggestive; 25–44 = supports diagnosis; < 25 = unlikely ^[5]

The treatment of thyroid storm follows a logical sequence — block every step of thyroid hormone action:

Critical sequencing point: Iodine must be given ≥ 1 hour after first dose of thionamide → prevent the iodine from being used as substrate for new hormone synthesis ^[5][6]. If you give iodine FIRST, the thyroid has a massive substrate load and will synthesise even MORE hormone before the ATD can block TPO.

PTU is preferred in thyroid storm for its blocking effect on T4-to-T3 conversion (in addition to blocking synthesis) ^[5][6].

Lithium: LiCO₃ 250mg Q6H to [Li] 0.6–1.0 mmol/L if contraindicated to thionamide ^[5] (e.g. previous agranulocytosis). Lithium inhibits thyroglobulin proteolysis and thyroid hormone release.

Consider plasmapheresis and charcoal haemoperfusion in desperate cases ^[1][5]

Subsequent management ^[6]:

• Stop iodine and taper steroids once clinical improvement is evident
• Titrate thionamide (and switch to methimazole/carbimazole) to maintain euthyroidism
• Plan for definitive treatment to prevent recurrence

• Smoking cessation: smoking renders patients more refractory to anti-inflammatory therapy ^[3][10]
• Reversal of hyperthyroidism if present:
  • Choice: total thyroidectomy, thionamides ^[3][10]
  • Effect: ↓thyroid antigen load → usually associated with ↓TRAb titres ^[3][10]
  • Note that moderate/severe GO is a contraindication to RAI treatment ^[3][10]
• Local symptomatic control:
  • Exposure-related discomfort: eye shades, artificial tears, eye lubricants (e.g. 1% methylcellulose) ^[3][10]
  • Diplopia: eye patching, prisms ^[3][10]

Why the specific surgical sequence (decompression → EOM → eyelid)? Because each procedure changes the anatomy that the subsequent procedure needs to address. Orbital decompression changes the position of the globe (and thus EOM alignment); EOM surgery changes lid position. Doing them out of order means the results of earlier surgery will be undone.

Teprotumumab (anti-IGF-1 receptor monoclonal antibody) — approved by FDA 2020 for moderate-to-severe active GO. It targets the IGF-1R/TSHr signalling complex on orbital fibroblasts, directly reducing the pathological process. This represents a paradigm shift in GO management, with significant reduction in proptosis and diplopia in clinical trials.

The heart is one of the most T3-sensitive organs. T3 upregulates β1-adrenergic receptors, increases myocardial contractility and heart rate, and decreases systemic vascular resistance — creating a chronic hyperdynamic circulatory state.

Why does AF matter specifically? Beyond the haemodynamic consequences (loss of atrial kick → ↓cardiac output by ~25%), thyrotoxic AF carries a significant thromboembolic risk. These patients need anticoagulation assessment (CHA₂DS₂-VASc score) just like any other AF patient. The AF is often resistant to rate/rhythm control until the thyrotoxicosis is treated.

This is the most feared acute complication of Graves' disease. It has been covered in detail in the management section, but its key points as a complication are:

• Rare but life-threatening (10% mortality, medical emergency) ^[5][6]
• Setting: longstanding untreated hyperthyroidism + precipitant (acute infection, surgery, trauma, childbirth, withdrawal of ATDs, shortly after thyroidectomy or RAI, acute iodine load e.g. amiodarone) ^[5][6]
• Thyroid storm develops in patients with longstanding untreated hyperthyroidism which is precipitated by acute event such as surgery, trauma or infection ^[1]
• Pathophysiology: rapid ↑ in serum thyroid hormone levels leading to increased response to sympathetic inputs from catecholamines (adrenaline/noradrenaline) by permissive effect ^[1]
• Leads to cardiovascular symptoms including hyperpyrexia, tachycardia, hypertension and followed by heart failure with hypotension and arrhythmia ^[1]
• CNS disturbance: agitation, anxiety, delirium, psychosis, stupor, coma ^[5][6]

Covered in detail in the clinical features and management sections:

• Up to 2% among Asian patients with hyperthyroidism ^[7]
• Majority underlying cause is Graves' disease ^[7]
• Attacks of motor paralysis with hypokalaemia and risk of cardiac arrhythmia ^[7]
• Rebound hyperkalaemia (40–59%) during K⁺ replacement ^[7]

Usually mild and self-limiting, but in rare cases:

• Elephantiasic form: Massive GAG accumulation → severe disfiguring swelling of the lower legs
• Secondary skin breakdown and infection of involved areas
• Cosmetic distress and psychosocial impact

Important reassurance for patients ^[1]:

• NO effect on fertility
• NO effect on congenital malformations (provided 6-month conception avoidance)
• NO effect on increased cancer risk of offspring