Hyperthyroidism

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Meet the patient

A 28-year-old woman presents with three months of palpitations, a tremor she can now see in her coffee cup, and a stone of weight loss despite eating more than ever. Her mother takes levothyroxine. On the unit she is tachycardic with a bounding pulse and warm palms; you see lid lag as she looks down, and a diffuse, smooth goitre with an audible bruit; the registrar remarks her eyes look prominent.^[1][2]

Two exam questions are now live, and everything below exists to answer them: what is making her thyrotoxic? (the cause decides the treatment) and is she about to decompensate into storm? (the cause decides the urgency). The clinical skill in this topic is never the diagnosis — that is biochemical — it is identifying the cause and recognising the emergency.^[6]

Two words you must not blur — hyperthyroidism vs thyrotoxicosis

Hyperthyroidism is the gland actively over-synthesising hormone; thyrotoxicosis is the clinical state of excess circulating hormone from any source. The distinction is not pedantry — it decides whether a thionamide will work at all, because thionamides block new synthesis and do nothing for a gland that is merely leaking pre-formed hormone.^[2][4]

The syndrome sits on a spectrum: subclinical (suppressed TSH, normal free hormones), overt (suppressed TSH, raised free T4 and/or T3), and the decompensated extreme, thyroid storm — a medical emergency with mortality of 10 to 30 percent despite treatment.^[6]

The axis in one breath. The hypothalamus releases TRH, which drives pituitary thyrotrophs to secrete TSH; TSH binds the TSH receptor (TSH-R), a Gs-coupled receptor whose cAMP cascade drives iodide uptake (the sodium-iodide symporter, NIS), organification and coupling (thyroid peroxidase, TPO), and release of T4 (the prohormone) with a little T3. Peripheral D1 and D2 deiodinases convert T4 to active T3; D3 inactivates it to reverse T3. Circulating T4 and T3 feed back negatively on both TSH and TRH — which is exactly why a suppressed TSH is the single most sensitive marker of primary thyrotoxicosis, and why an inappropriately normal or raised TSH with raised free T4 is the red flag for a pituitary cause.^[1][4]

Why the TSH is the single best test

TSH is the single most sensitive first-line test, and a normal TSH — in the absence of pituitary disease — effectively excludes primary thyrotoxicosis. The steep pituitary feedback amplifies a tiny change in free hormone into a large log-scale swing in TSH, so TSH moves first and moves furthest.^[2]

Measure free T4 and free T3, never totals — total hormone is confounded by thyroxine-binding globulin shifts in pregnancy, oestrogen use, and nephrotic syndrome.^[3]

Reading the TFT pattern is the viva. Memorise the five rows:^[1]

^[1]

The bottom row is the one juniors miss: a TSH that is not suppressed when free T4 is high is never "normal" — it is the signature of a TSH-secreting pituitary adenoma or thyroid hormone resistance, and it changes the entire work-up (pituitary MRI, alpha-subunit, TRH test).^[4]

Graves, toxic nodule, or thyroiditis — the uptake scan decides

Sort every thyrotoxic patient into one of two buckets: the gland is over-making hormone (high uptake) or it is leaking it from outside the gland (low uptake). This single split drives both the differential and the treatment, because thionamides only work when synthesis is active.^[2][3]

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The discriminator line: high uptake means the gland is the problem and the factory is open; low uptake means the factory is shut and the hormone came from a leak or a bottle. Hold that image and the differential writes itself.^[3]

T3 toxicosis and subclinical disease fill in the severity axis. Always measure free T3 to catch T3 toxicosis, and confirm a suppressed TSH with normal free hormones on two samples two to three months apart before labelling subclinical disease — transient suppression occurs in non-thyroidal illness.^[2][3]

How common, and who gets it

^{[1] [2]}

Graves dominates in iodine-sufficient regions (about 2 percent of women, 0.5 percent of men), peaking in the third to fifth decades. Toxic multinodular goitre is a disease of older adults arising in a long-standing goitre, often in iodine-deficient regions; toxic adenoma (Plummer disease) typically presents between 30 and 50.^[1]

Risk factors to run on autopilot: female sex and a family history of autoimmune thyroid disease (Graves clusters with HLA-DR3, HLA-B8, and the CTLA-4 and PTPN22 polymorphisms); other autoimmunity (type 1 diabetes, Addison disease, vitiligo, pernicious anaemia, coeliac disease); pregnancy and the postpartum immune-reconstitution window; and — the one that pays off in marks every time — smoking, the strongest modifiable driver of Graves orbitopathy.^[1][5]

Iodine load is its own precipitant. Amiodarone is extraordinarily rich in iodine — a single 100 mg tablet contains an amount of iodine roughly 250 times the recommended daily requirement — and iodine-induced and drug-induced thyroid dysfunction are recognised causes of thyrotoxicosis: an iodine load (contrast, amiodarone, or iodine repletion in a deficient patient) can unmask hyperthyroidism in a gland with autonomous tissue (the Jod-Basedow phenomenon). Infection, surgery, trauma, severe emotional or physical stress, abrupt withdrawal of the antithyroid drug, and iodine exposure are the classic precipitants of thyroid storm in a previously compensated patient.^[4][8][9]

Why excess T3 causes every symptom — the one mechanism that explains the lot

Every thyrotoxic symptom is excess T3 turning up the dial on genes you can name. T3 acts through the nuclear thyroid hormone receptor (TR-alpha, TR-beta), a ligand-activated transcription factor that upregulates Na-K-ATPase, beta-adrenergic receptors, malic enzyme, SERCA, and alpha-myosin heavy chain. Learn the four downstream consequences and the whole clinical picture falls out of them.^[2][4]

• Na-K-ATPase upregulated drives a higher basal metabolic rate and thermogenesis — heat intolerance, sweating, and weight loss despite an increased appetite, with raised oxygen consumption in every tissue.^[4]
• Beta-adrenergic receptor density increased (plus direct T3 effects on the myocardium) sensitises the heart to catecholamines — tachycardia, high-output state, increased inotropy, fine tremor, anxiety, lid lag, hyperreflexia. This single fact is why a beta-blocker switches off the symptoms within hours.^[1][4]
• Bone turnover increased (resorption outstrips formation) — osteopenia and osteoporosis over years, and the reason subclinical disease still fractures bones.^[2]
• Gut motility and hepatic gluconeogenesis increased — diarrhoea, steatorrhoea, glucose intolerance, raised alkaline phosphatase and transaminases.^[1]

Enlarge

The Graves prototype. Graves is organ-specific autoimmunity: loss of self-tolerance to the TSH receptor produces thyrotropin-receptor antibodies (TRAb / TSI) that bind the receptor and mimic TSH, driving the Gs-cAMP cascade constitutively. The gland becomes diffusely enlarged and hypervascular (the bruit you heard at the bedside), overproduces T4 and T3, and — because the excess hormone suppresses pituitary TSH — is driven by the antibody, not by the axis. The feedback loop is broken.^[1]

Why the eye and the shin? TSH receptors and insulin-like growth factor-1 receptors (IGF-1R) sit on retro-orbital fibroblasts. TRAb activates them, the fibroblasts differentiate into adipocytes and secrete hydrophilic glycosaminoglycans (hyaluronic acid), which retain water and expand the orbital contents inside the rigid bony orbit — proptosis, oedema, inflammation, and in severe cases optic nerve compression. The same process in the pretibial dermis produces pretibial myxoedema. Smoking amplifies all of it.^[1][5]

The autonomous nodules. Toxic multinodular goitre and toxic adenoma are non-autoimmune: somatic gain-of-function mutations in the TSH-R signalling pathway or the Gs-alpha (GNAS) subunit switch on cAMP independent of TSH. Autonomous foci escape TSH control, overproduce hormone, suppress TSH, and the surrounding normal thyroid goes quiescent. A toxic adenoma reads on a scan as a single hot nodule with the rest of the gland suppressed.^[3]

Thyroiditis leaks, it does not make. In subacute, silent, and postpartum thyroiditis, inflammatory destruction of follicles releases pre-formed T4 and T3 from stored colloid — the leaked hormone suppresses TSH, which switches off NIS-mediated uptake, giving the low radioactive uptake that separates thyroiditis from Graves. The thyrotoxic phase is self-limiting (four to eight weeks, until the colloid store runs out), often followed by a transient hypothyroid phase and recovery. Thionamides are ineffective because no new synthesis is occurring.^[3][4]

Amiodarone does it two ways — and they need different drugs. Type 1 arises in patients with underlying thyroid pathology (an autonomous nodular goitre or Graves disease), where the iodine load drives excess hormone synthesis — treat with thionamides, adding potassium perchlorate in resistant cases. Type 2 is a destructive thyroiditis with hormone leak from a normal gland — treat with glucocorticoids. Mixed or indeterminate forms occur: a careful history and examination for pre-existing thyroid disease, an uptake test, and colour-flow Doppler help tell them apart, and combination therapy is used when the mechanism is unclear.^[10][11]

Factitious thyrotoxicosis is the one with the low thyroglobulin. Exogenous hormone suppresses TSH, drops radioactive uptake, and — unlike endogenous overproduction or thyroiditis, in both of which thyroglobulin is raised — leaves thyroglobulin low, because the gland is quiescent. Ask about weight-loss pills, supplements, and access to thyroid hormone.^[1]

Meeting the patient at the bedside — the named signs

Thyrotoxicosis is a hyperadrenergic, hypermetabolic state. Examine system by system and the pattern assembles itself.^[2][4]

General. Heat intolerance and sweating, unintentional weight loss despite an increased appetite (the single best clue — malignancy and most other weight-loss causes suppress appetite, thyrotoxicosis drives it up), fatigue, insomnia, nervousness, irritability, anxiety (often misattributed to a primary anxiety disorder), and proximal muscle weakness — difficulty climbing stairs or combing hair.^[1]

Cardiovascular — the exam favourite and the main source of morbidity. Palpitations, sinus tachycardia, supraventricular ectopics, and — especially in the elderly — atrial fibrillation (in 10 to 15 percent of thyrotoxic patients, and up to a third of older patients at presentation). A high-output state gives a hyperdynamic bounding pulse, widened pulse pressure, and a systolic flow murmur; longstanding disease drives high-output and later dilated cardiac failure. Exertional dyspnoea is common.^[1]

Neuromuscular. A fine tremor of the outstretched hands, brisk hyperactive reflexes with a snapping relaxation (the opposite of the delayed relaxation in hypothyroidism), proximal myopathy, and rarely thyrotoxic periodic paralysis — hypokalaemic flaccid paralysis in young Asian males provoked by carbohydrate or exertion, treated with a non-selective beta-blocker and cautious potassium.^[1]

Skin and soft tissues. Warm, moist, velvety skin, palmar erythema, onycholysis (Plummer nails — distal nail separation), diffuse alopecia, and — pathognomonic of Graves — pretibial myxoedema, a non-pitting plaque-like induration on the anterior shins or dorsa of feet.^[1]

Gastrointestinal and reproductive. Increased stool frequency or frank diarrhoea, nausea, rarely steatorrhoea; raised transaminases and alkaline phosphatase. Oligomenorrhoea or amenorrhoea, anovulatory infertility, reduced libido, and gynaecomastia in men from increased androgen-to-oestrogen aromatisation.^[1]

The bedside cluster that should trigger a TSH: warm moist palms, fine tremor, lid lag, hyperreflexia, and a tachycardia with a bounding pulse. Five seconds of observation and you have already raised the pre-test probability.^[1]

The Graves triad that earns the diagnosis

When the thyrotoxicosis is autoimmune, three extrathyroidal findings turn a biochemical diagnosis into a Graves diagnosis — and any one of them short-circuits the work-up.^[1]

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Thyroid storm — the five-part bundle

This is the decompensated extreme of thyrotoxicosis — the metabolic, thermoregulatory, and cardiovascular compensatory mechanisms are overwhelmed. Treatment must not wait for TFT confirmation; treat empirically on clinical grounds.^[6]

Recognise it. Hyperpyrexia (often 39 to 41 degrees C) out of proportion to other features, with profuse sweating; severe tachyarrhythmia (atrial fibrillation with rapid ventricular response or sinus tachycardia); heart failure, pulmonary oedema, and hypotension (late, pre-terminal); altered mental status from agitation through delirium, seizures, and coma; and gastrointestinal or hepatic features with jaundice (a grave sign).^[1]

It is almost always precipitated in a known or occult thyrotoxic patient — by infection (the commonest), surgery, trauma, parturition, iodine load (contrast, amiodarone), radioiodine therapy, withdrawal of the antithyroid drug, severe emotional stress, diabetic ketoacidosis, stroke, or myocardial infarction.^[1]

Score it at the bedside with the Burch-Wartofsky Point Scale (BWPS) — thermoregulation, CNS, gastrointestinal-hepatic, tachycardia, congestive heart failure, atrial fibrillation, and a precipitating event. A score of 45 or more is highly suggestive of storm; 25 to 44 is impending; under 25 is unlikely. Use it to justify empiric treatment, never to delay it.^[6]

The bundle — give simultaneously, in the correct pharmacological order.^[6]

1. Supportive care. ABCDE, oxygen, aggressive IV fluids (these patients are volume-depleted from vomiting, diarrhoea, and fever), cardiovascular and respiratory support, and active cooling for the hyperthermia — supportive care of the cardiovascular, respiratory, and thermoregulatory manifestations plays the lead role, alongside treatment of any intercurrent illness and coverage for possible adrenal insufficiency.^[6][8]
2. Beta-blockade. Beta blockers to counteract the adrenergic effects — the tachyarrhythmia, tremor, and agitation — with caution in heart failure or asthma.^[8]
3. Thionamide FIRST, then iodine AFTER. Antithyroid agents block new hormone synthesis; the inorganic iodine is given only after the thionamide, so that it cannot be used as substrate for new hormone synthesis. Reversing this order fuels new synthesis and worsens the storm.^[8] Propylthiouracil has long been favoured in storm (it also inhibits peripheral T4-to-T3 conversion), while its hepatotoxicity risk keeps it a short-course drug.^[18]
4. Glucocorticoid. Corticosteroids reduce peripheral T4-to-T3 conversion and cover possible coexisting adrenal insufficiency. Taper as the patient recovers.^[8]
5. Treat the precipitant. Cultures and empirical antibiotics for sepsis (the commonest precipitant); treat DKA, MI, or stroke; correct electrolytes.^[6]

The number rule for storm: thionamide first, then everything else. That single ordering rule — thionamide before iodine, never the reverse — is the line between controlling the storm and fuelling it.^[6][8]

Refractory storm is rare but real: plasma exchange (removes circulating T4, T3, and antibodies), cholestyramine (binds thyroid hormone in the gut, interrupting enterohepatic recirculation), and emergency thyroidectomy once plasma exchange has lowered hormone enough for safe anaesthesia.^[6]

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The atypical patients you will miss if you only look for the young woman

Apathetic hyperthyroidism (the elderly). The sympathetic features are muted — instead, lethargy, apathy, depression, weight loss, atrial fibrillation, heart failure, unexplained osteoporosis, or a proximal myopathy. It is mistaken for malignancy or depression until the TSH comes back suppressed. Lethargy plus AF plus weight loss in an older patient is apathetic hyperthyroidism until proven otherwise — have a low threshold to check a TSH in any older patient with AF, unexplained weight loss, or heart failure.^[2]

In pregnancy. The symptoms overlap with normal pregnancy (heat intolerance, palpitations, fatigue), so a persistent tachycardia, weight loss or failure to gain weight, and a goitre should prompt testing. hCG-mediated thyrotoxicosis (gestational transient thyrotoxicosis) in hyperemesis gravidarum or molar pregnancy mimics Graves but has negative TRAb and usually resolves with hydration and symptom control.^[7]

Thyrotoxic periodic paralysis. Predominantly in young Asian males — acute, episodic hypokalaemic flaccid paralysis, often provoked by a carbohydrate load or exertion. Treat with a non-selective beta-blocker (propranolol) and cautious potassium; do not over-correct, or you risk rebound hyperkalaemia as the paralysis resolves.^[1]

What else looks like this — the mimics

When the TFT is not yet back, three clinical mimics lead juniors astray — name them and name one discriminator each.^[1]

• Anxiety or panic disorder shares palpitations, tremor, and agitation, but the TSH is normal, weight loss is not accompanied by an increased appetite, and there is no goitre.^[1]
• Phaeochromocytoma shares palpitations, sweating, and anxiety, but runs episodic severe hypertension (thyrotoxicosis gives a wide pulse pressure, not a hypertensive crisis); check plasma metanephrines.^[1]
• Occult malignancy shares weight loss, but appetite is reduced rather than increased, and there is no goitre, no hyperreflexia, no lid lag.^[1]

When proptosis is the presenting feature, distinguish Graves orbitopathy (bilateral, lid retraction, restricted upgaze from inferior rectus involvement, TRAb positive) from orbital cellulitis (unilateral, fever, painful eye movement), idiopathic orbital inflammation / pseudotumour (painful, unilateral, steroid-responsive), orbital or ocular tumour (unilateral mass on imaging), and carotid-cavernous fistula (pulsatile proptosis, chemosis, bruit).^[5]

Confirming the cause — TRAb first, uptake scan when it is not Graves

Once the TFT confirms thyrotoxicosis, the next question is the cause, and two tests do almost all of the work.^[1][3]

• TSH receptor antibody (TRAb / TSI) — confirms Graves disease (sensitivity and specificity both over 95 percent in overt disease). A positive TRAb obviates the uptake scan in clear-cut Graves; it also predicts relapse after thionamide withdrawal and is essential in pregnancy to assess fetal and neonatal risk.^[1][3]
• Thyroid uptake scan (iodine-123/131 or Tc-99m pertechnetate) — when the cause is unclear or a nodule is present. Diffuse high uptake is Graves; patchy is toxic multinodular goitre; a single hot nodule is toxic adenoma; low or suppressed uptake is thyroiditis or factitious.^[3]
• Thyroid ultrasound for nodular disease — characterise nodules, identify a dominant nodule, and guide biopsy of any suspicious non-functioning nodule (a toxic nodule itself is rarely malignant, but coexisting cold nodules need the standard work-up).^[4]
• Thyroglobulin — low in factitious thyrotoxicosis (the gland is quiescent), high in endogenous overproduction and thyroiditis; rarely needed diagnostically, but decisive when factitious is suspected.^[4]

The big differential table — high vs low uptake, with the discriminator. Reproduce this in a viva and the cause is named.^[1]

^[1]

Characterising the goitre at the bedside

Inspect from the front (swelling, asymmetry, scars, distended veins — a Pemberton sign on raising the arms signals retrosternal goitre), palpate from behind the seated patient with both hands, roll the tissue with the thumbs, and ask the patient to swallow — a thyroid mass moves up with swallowing, which distinguishes it from other neck lumps. Auscultate over each lobe for a bruit, and palpate the cervical nodes.^[1]

^[1]

A goitre with a bruit is Graves until proven otherwise — the intense hypervascularity is unique to active Graves overproduction. A tender goitre with a raised ESR is subacute (de Quervain) thyroiditis.^[4]

Graves orbitopathy at the bedside uses the Clinical Activity Score (CAS) — one point each for spontaneous retrobulbar pain, pain on eye movement, eyelid erythema, eyelid oedema, conjunctival redness, chemosis, and caruncle swelling; a CAS of 3 or more indicates active disease amenable to immunosuppression. Always assess for sight-threatening features — reduced visual acuity, colour-vision loss or red desaturation, a relative afferent pupillary defect, or a visual field defect — any of which suggests dysthyroid optic neuropathy and mandates urgent treatment.^[5]

The block-and-replace vs titration fork

For overt high-uptake hyperthyroidism (Graves, toxic multinodular goitre, toxic adenoma), there are three definitive treatments: antithyroid drugs, radioactive iodine, and surgery. The choice turns on cause, goitre size, comorbidity, pregnancy status, the presence of Graves orbitopathy, and patient preference — individualise it.^[2][3]

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Beta-blockade — the symptom bridge, all causes

A beta-blocker is used for symptom control in any symptomatic thyrotoxic patient while definitive treatment is planned — and may be the only treatment needed for thyrotoxicosis caused not by excessive hormone production and release (thyroiditis, exogenous hormone), where it is continued until the stored hormone has been cleared.^[4][8]

Antithyroid drugs (thionamides) — carbimazole first, PTU for the exceptions

Mechanism. Thionamides inhibit thyroid peroxidase (TPO), blocking the organification and coupling of iodide to thyroglobulin and therefore new hormone synthesis. PTU additionally inhibits the D1 deiodinase, reducing peripheral T4-to-T3 conversion — which is exactly why it is preferred in thyroid storm.^[3][4]

Agents and regimens.^[3]

• Carbimazole (UK, India, Commonwealth) / methimazole (US) — the preferred antithyroid drug in most situations: better efficacy, fewer adverse effects, and once-daily dosing reflecting its longer half-life. Two regimens are used:^[17]
  • Titration regimen: a starting dose titrated down to a lower maintenance dose once the patient is euthyroid, continued for a course of 12 to 18 months — the standard approach worldwide.^[19]
  • Block-and-replace regimen: a full blocking dose of carbimazole plus levothyroxine replacement — less frequent monitoring, but avoided in pregnancy.
• Propylthiouracil (PTU) — reserved for the first trimester of pregnancy (methimazole carries the more severe teratogenic risk) and for thyroid storm. Avoid long-term use because of hepatotoxicity: PTU causes severe hepatic failure rarely but unpredictably, which is why carbimazole/methimazole is preferred elsewhere.^[15][17][18]

The fork, in one line: titration is standard — slightly more monitoring; block-and-replace trades monitoring burden for relapse risk and is off-limits in pregnancy. Both are acceptable first-line for Graves; choose by patient and local practice.^[3]

Role and duration. First-line for Graves in most regions. A 12 to 18 month course produces remission in 40 to 50 percent (higher if TRAb becomes negative). Relapse predictors — a large goitre, persistently positive TRAb, smoking, and severe biochemical disease at presentation — usually relapse within the first year. Thionamides are not for long-term use in toxic multinodular goitre or toxic adenoma: these are autonomous and do not remit, so use the drug only to render the patient euthyroid before definitive RAI or surgery.^[3]

Adverse effects — the examiner essentials.^[3]

• Agranulocytosis (0.2 to 0.5 percent), typically within the first 8 weeks. Counsel every patient on starting a thionamide: any sore throat, fever, or mouth ulcer — stop the drug and get an urgent full blood count. Treat with broad-spectrum antibiotics and G-CSF; do not rechallenge (cross-reactivity between carbimazole and PTU).^[3]
• Hepatotoxicity — cholestatic with carbimazole or methimazole, or fulminant hepatic necrosis with PTU (idiosyncratic) — the reason PTU is reserved for first trimester and storm.^[3]
• ANCA-positive vasculitis, especially with PTU — renal, skin, and respiratory involvement.^[3]
• Teratogenicity — carbimazole or methimazole in the first trimester is associated with aplasia cutis congenita, choanal atresia, tracheo-oesophageal fistula, and other anomalies (methimazole embryopathy). Use PTU in the first trimester, switch to carbimazole in the second.^[7]
• Milder effects: rash, pruritus, urticaria, arthralgia, transient mild leucopenia.^[3]

Radioactive iodine (I-131) — definitive, but not in pregnancy and not in active eye disease

Mechanism. Oral iodine-131 is taken up by NIS and concentrates in thyroid follicular cells, where its beta emission destroys thyroid tissue over weeks to months, reducing hormone output.^[3]

Indications. Definitive treatment for Graves (especially relapsed after thionamides, or where the patient prefers it), toxic multinodular goitre, and toxic adenoma; particularly suitable when surgery is high-risk.^[1]

Contraindications — name all three.^[3]

• Absolute: pregnancy (exclude with a pregnancy test beforehand), breastfeeding, and inability to comply with radiation safety precautions.^[3]
• Relative: active or moderate-to-severe Graves orbitopathy — radioiodine therapy can worsen eye disease. If RAI is chosen in a patient with mild eye disease, give prophylactic oral glucocorticoid; in active or moderate-to-severe orbitopathy, antithyroid drugs are the preferred option (surgery where definitive treatment is needed).^[5]
• Large goitres with retrosternal extension or compressive symptoms respond less well to RAI — surgery is preferred.^[3]

Pros and cons. Highly effective and definitive; outpatient; most patients become permanently hypothyroid (anticipated, and managed with levothyroxine — a planned, favourable outcome, since levothyroxine is far safer than recurrent hyperthyroidism); onset is slow (6 to 18 weeks to euthyroidism); transient worsening of thyrotoxicosis and rarely storm can occur. Continue thionamides (stop 3 to 7 days before RAI, resume 3 to 7 days after, then taper).^[3]

Surgery (thyroidectomy) — render euthyroid first, or the patient storms on the table

Indications. A large goitre with compressive symptoms (dysphagia, dyspnoea, Pemberton sign), retrosternal goitre, suspicion or coexistence of malignancy, refractory hyperthyroidism or relapse after thionamides with RAI declined or contraindicated, pregnancy with poor control or allergy to thionamides, active Graves orbitopathy needing rapid control (RAI avoided), and patient preference for definitive rapid cure.^[1]

Pre-operative preparation is non-negotiable. The patient must be biochemically euthyroid before surgery to avoid intra-operative or post-operative thyroid storm: carbimazole or methimazole (or PTU) to euthyroid, plus a beta-blocker, plus Lugol's iodine or SSKI for 7 to 14 days before surgery — the Wolff-Chaikoff effect reduces thyroid vascularity and hormone release and decreases operative blood loss. Stop the iodine on the day of surgery.^[3]

Extent. Total or near-total thyroidectomy is preferred in Graves (lower recurrence than subtotal; lifelong levothyroxine is anticipated). For a single toxic adenoma, a hemithyroidectomy (lobectomy) suffices.^[1]

Complications — the examiner favourites.^[1]

• Recurrent laryngeal nerve injury — hoarse voice (unilateral); airway compromise (bilateral — an emergency).^[1]
• Hypoparathyroidism — hypocalcaemia (perioral tingling, Chvostek or Trousseau signs, tetany, seizures); check corrected calcium and PTH post-operatively, give calcium and calcitriol; often transient but may be permanent.^[1]
• Haematoma — airway compromise; a surgical emergency (open the wound at the bedside if the airway is threatened).^[1]
• Thyroid storm if inadequately prepared, plus wound infection, seroma, and keloid.^[1]

Subclinical hyperthyroidism — the threshold question

Defined as suppressed TSH with normal free T4 and free T3. Confirm persistence with a repeat TFT at 2 to 3 months before treating (transient suppression occurs in non-thyroidal illness), then apply the thresholds:^[2][3]

• TSH persistently under 0.1 mIU/L — treat, especially if over 65 years (osteoporosis and AF risk), postmenopausal, with cardiac disease, or symptomatic.^[3]
• TSH 0.1 to 0.4 mIU/L — consider treatment in over-65s and those with cardiac or bone disease; otherwise observe and recheck in 6 months.^[3]

Thyroiditis (low-uptake) — symptom control only

Thionamides are ineffective because no active synthesis is occurring. Manage with a beta-blocker for symptoms in the thyrotoxic phase, NSAIDs (sometimes steroids) for pain in subacute thyroiditis, and levothyroxine if a symptomatic hypothyroid phase follows. The condition is self-limiting in most cases.^[1]

The named subtypes — what each one looks like and how it is treated

Graves disease is the commonest cause (60 to 80 percent): young women, a family history of autoimmunity, TRAb positive, and the classic triad of a diffuse vascular goitre with bruit, Graves orbitopathy, and pretibial myxoedema. Diagnose on a positive TRAb (or diffuse uptake on scan). Treat with thionamides for 12 to 18 months (40 to 50 percent remission), RAI, or surgery, individualised. Smoking cessation is critical for the orbitopathy, and anticipate transient worsening of eye disease with RAI — give prophylactic steroids in active eye disease or avoid RAI.^[1][5]

Toxic multinodular goitre affects older patients with a long-standing multinodular goitre, often in iodine-deficient regions. Gradual autonomous overproduction; no orbitopathy, no TRAb, no bruit. The uptake scan shows patchy hot spots. Thionamides do not produce remission — use them only to render euthyroid before RAI or surgery. RAI is often preferred in older patients with comorbidity; surgery for large compressive goitres.^[3]

Toxic adenoma (Plummer disease) is a single autonomous hyperfunctioning nodule (a somatic TSH-R or Gs-alpha activating mutation), typically 3 cm or larger to cause thyrotoxicosis. A single palpable nodule, no orbitopathy, no TRAb; the uptake scan shows a single hot nodule with suppression of the rest of the gland. Definitive treatment is RAI or hemithyroidectomy (thionamides only as pre-treatment). The prognosis is excellent — the suppressed normal tissue recovers after the nodule is ablated or removed.^[3]

Subacute (de Quervain, granulomatous) thyroiditis is a self-limited but painful disorder of the thyroid — a tender, firm goitre following a viral upper respiratory illness. The diagnosis is confirmed by a raised ESR, a raised thyroglobulin, and depressed radioactive iodine uptake; the thyrotoxic phase settles spontaneously, often through a transient hypothyroid phase before recovery.^[12][4] There is no definitive therapy, but effective symptomatic treatment lets the disease run its course: NSAIDs or salicylates in mild-to-moderate disease, corticosteroids if symptoms are severe, a beta-blocker for thyrotoxic symptoms, and levothyroxine if the hypothyroid phase is symptomatic.^[20]

Silent (painless, lymphocytic) and postpartum thyroiditis are painless and autoimmune-mediated, with a thyrotoxic then hypothyroid phase. Postpartum thyroiditis occurs within 6 months of delivery (anti-TPO positive; may recur in subsequent pregnancies; some patients progress to permanent hypothyroidism). Uptake is low. Symptom control only; consider levothyroxine in the hypothyroid phase, and arrange long-term monitoring (annual TSH) for evolving hypothyroidism.^[4]

Amiodarone-induced thyrotoxicosis. Screen for thyroid disease before starting amiodarone and monitor thyroid function periodically during therapy. Type 1 arises on pre-existing thyroid pathology (autonomous nodular goitre, Graves) with excess iodine-driven synthesis — treat with thionamides, with potassium perchlorate for resistant cases. Type 2 is a destructive thyroiditis in a normal gland — treat with glucocorticoids. Mixed forms need combination therapy; discontinue amiodarone where the cardiac condition allows, and individualise its continuation with the cardiologist.^[10][11]

Factitious (exogenous) thyrotoxicosis is surreptitious or accidental ingestion of thyroid hormone (weight loss, performance, meat contamination, supplements) — a suppressed TSH, low uptake, and a characteristically LOW thyroglobulin (the gland is quiescent). Treat by withdrawing the exogenous hormone; offer psychiatric support if intentional.^[1]

TSH-secreting pituitary adenoma and thyroid hormone resistance both show raised free T4 and T3 with an inappropriately normal or raised TSH — the TSH is not suppressed, which is the key discriminator from primary thyrotoxicosis. A TSHoma is a true pituitary adenoma with a raised alpha-subunit and a pituitary mass on MRI, treated with surgery plus or minus radiotherapy and a somatostatin analogue (octreotide). Thyroid hormone resistance (Refetoff syndrome) is a beta-receptor mutation; patients are usually euthyroid or hypothyroid clinically despite raised hormones, with a family history, and are managed conservatively — do not ablate the gland. Distinguish the two with the TRH stimulation test and the alpha-subunit to TSH molar ratio.^[4]

hCG-mediated hyperthyroidism. hCG is a weak agonist at the TSH receptor, so very high hCG (molar pregnancy, choriocarcinoma, hyperemesis gravidarum, multiple gestation) can drive thyrotoxicosis. TRAb is negative, and it resolves with molar evacuation or as hCG falls in the second trimester. Manage with a beta-blocker and hydration; antithyroid drugs are generally not needed.^[7]

Jod-Basedow phenomenon is iodine-induced hyperthyroidism when iodine is given to a patient with an autonomous gland (nodular goitre, latent Graves) — after iodine supplementation, contrast, or amiodarone. Uptake is high (the gland uses the iodine substrate). Treat with thionamides.^[1]

Graves orbitopathy — sight-threatening, and the most modifiable thing you do

Smoking cessation and restoration of euthyroidism are the key modifiable interventions — smoking and thyroid dysfunction are the modifiable risk factors for Graves orbitopathy, and both hypo- and hyperthyroidism can worsen the eye disease. Selenium (100 mcg twice daily for 6 months) improved eye involvement, quality of life, and progression in mild orbitopathy in a randomised trial conducted in an area of low selenium intake.^[16] Avoid RAI in active or moderate-to-severe disease — radioiodine is a risk factor for development and worsening of orbitopathy; if RAI is unavoidable in mild disease, give prophylactic oral glucocorticoid — and prefer antithyroid drugs (or surgery where definitive treatment is needed).^[5]

For active moderate-to-severe disease, the EUGOGO 2021 guideline recommends the combination of intravenous methylprednisolone (cumulative 4.5 g over 12 weekly infusions) plus mycophenolate as first-line; higher cumulative methylprednisolone doses (up to 8 g) as monotherapy are reserved for the most severe cases. Second-line options include teprotumumab, rituximab, tocilizumab, and orbital radiotherapy. Sight-threatening optic neuropathy needs urgent high-dose IV glucocorticoid, escalating to surgical decompression when the response is inadequate — this is an emergency, not a clinic referral.^[5]

Pregnancy, the fetus, and lactation — PTU first, switch at the second trimester

Hyperthyroidism in pregnancy is usually Graves (or gestational transient thyrotoxicosis from hCG). Poorly controlled disease risks pre-eclampsia, preterm labour, fetal loss, intrauterine growth restriction, maternal thyroid storm, and neonatal or fetal thyrotoxicosis from transplacental TRAb.^[7]

• Drug choice. Propylthiouracil (PTU) in the FIRST trimester — both PTU and methimazole/carbimazole carry congenital-anomaly risk, but a characteristic pattern of anomalies (aplasia cutis congenita, choanal atresia, and other facial, cardiac, and abdominal anomalies) is described for carbimazole/methimazole, and PTU is the selected drug for pre-pregnancy and early gestation — then switch to carbimazole in the SECOND and THIRD trimesters to limit PTU hepatotoxicity, which rarely results in liver transplantation or death.^[13][15][18]
• Targets. Maintain free T4 in the upper one-third of the trimester-specific reference range — the marker of successful therapy.^[13]
• Measure maternal TRAb (at diagnosis, and at 20 to 24 weeks if positive) — high TRAb predicts fetal or neonatal hyperthyroidism. Monitor the fetal heart rate (tachycardia over 160 bpm is a clue) and check the neonate's TFTs at birth.^[7]
• RAI is absolutely contraindicated in pregnancy and lactation. If surgery is needed, it is safest in the second trimester.^[3]
• Beta-blocker (propranolol) for short-term symptom control only — prolonged use is associated with fetal growth restriction.^[7]
• Gestational transient thyrotoxicosis (hyperemesis) is managed supportively with hydration, antiemetics, and a beta-blocker; antithyroid drugs are usually not needed, and it resolves as hCG falls.^[7]
• Lactation. Continuing breastfeeding is safe and should be encouraged in hyperthyroid mothers taking antithyroid drugs; because of PTU hepatotoxicity, experts recommend low-to-moderate-dose methimazole/carbimazole as first-line in lactation (PTU second-line), taken in divided doses immediately after each feed.^[14]

Neonatal or fetal hyperthyroidism is caused by transplacental passage of maternal TRAb (the mother may be euthyroid after prior RAI or surgery but still TRAb-positive). It presents with fetal tachycardia, goitre, and growth restriction, and in the neonate with irritability, tachycardia, poor weight gain, and craniosynostosis. Treat the fetus by treating the mother with antithyroid drugs; the neonate needs a short course of antithyroid drugs as the antibody clears over weeks.^[7]

How thyrotoxic patients come to harm — the preventable list

• Death from an unrecognised thyroid storm treated as sepsis or psychosis — the preventable death. Treat empirically, do not wait for the TFT.^[6]
• A patient on a thionamide who develops a sore throat and is given antibiotics without a full blood count — agranulocytosis missed, neutropenic sepsis.^[3]
• Iodine given before the thionamide in thyroid storm — fuelling new hormone synthesis and deepening the crisis.^[6]
• Aspirin given for the fever in thyroid storm — displacing T4 and T3 from thyroxine-binding globulin and worsening the thyrotoxicosis.^[6]
• Carbimazole continued into the first trimester of pregnancy — methimazole embryopathy (aplasia cutis, choanal atresia).^[7]
• Radioactive iodine given to a pregnant or breastfeeding woman — ablating the fetal or neonatal thyroid.^[3]
• RAI given to a patient with active Graves orbitopathy — worsening sight-threatening eye disease.^[5]
• A dysthyroid optic neuropathy referred to a routine eye clinic instead of treated with urgent IV steroid and decompression — sight lost.^[5]
• T3 toxicosis missed because only T4 was measured — the patient sent home thyrotoxic.^[3]
• An elderly patient with atrial fibrillation, weight loss, and heart failure labelled "depression" — apathetic hyperthyroidism missed.^[2]

Prognosis, disposition, and follow-up

With thionamides, a 12 to 18 month course produces remission in 40 to 50 percent; relapse usually occurs within the first year (predictors: a large goitre, persistent TRAb, smoking, severe disease). Relapse is managed with a second course, RAI, or surgery. After RAI or surgery, permanent hypothyroidism is anticipated and managed with lifelong levothyroxine — a planned, favourable outcome. After thyroidectomy, levothyroxine starts immediately; check calcium and PTH for hypoparathyroidism.^[3]

Thyroid storm carries a mortality of 10 to 30 percent despite treatment; predictors of poor outcome are advanced age, severe hyperpyrexia, multi-organ failure, delayed presentation, and underlying cardiac disease. Survivors need lifelong definitive management of the underlying cause.^[6]

Untreated and subclinical disease carries an increased risk of atrial fibrillation, heart failure, osteoporosis and fracture, and — in cohort studies — increased all-cause mortality, particularly in older patients with TSH persistently under 0.1 mIU/L.^[2]

Monitoring and follow-up. On thionamides, check TFTs every 4 to 6 weeks initially, then 3-monthly once stable, with a baseline FBC and LFT and repeat if symptomatic; counsel about agranulocytosis at every visit. After RAI, check TFTs at 4 to 6 weeks then periodically — most patients are hypothyroid by 6 months. After surgery, check calcium and PTH on day 1 and TFTs at 6 weeks, with lifelong levothyroxine. Arrange an annual TFT for life after any definitive treatment. Refer to endocrinology for thyroid storm, pregnancy with thyrotoxicosis, Graves orbitopathy, amiodarone-induced thyrotoxicosis, refractory or relapsed disease, suspected TSHoma or resistance, complex comorbidity, and surgical candidates.^[3]

Evidence, guidelines, and regional deltas — the names that score marks

ATA 2016 Hyperthyroidism Guideline (Ross and colleagues) is the landmark — 124 recommendations covering diagnosis and management of all causes of thyrotoxicosis. Key points: establish the aetiology before treatment (TRAb, uptake scan); methimazole is preferred over PTU except in first-trimester pregnancy and thyroid storm; RAI, surgery, and antithyroid drugs are all acceptable first-line for Graves — individualise; surgery is preferred for large compressive goitres and suspected malignancy; and prepare every patient for surgery by rendering euthyroid.^[3]

Lee and Pearce, JAMA 2023 confirms the global prevalence (overt 0.2 to 1.4 percent, subclinical 0.7 to 1.4 percent), Graves as the dominant cause, and the principle that treatment of subclinical disease should target those at highest risk (over 65, persistent TSH under 0.1 mIU/L, osteoporosis, cardiac disease).^[2]

EUGOGO 2021 (Bartalena and colleagues) establishes the combination of intravenous methylprednisolone (cumulative 4.5 g over 12 weekly infusions) and mycophenolate as first-line for active moderate-to-severe orbitopathy, with second-line teprotumumab, rituximab, tocilizumab, and orbital radiotherapy; sight-threatening disease needs urgent high-dose IV steroid, escalating to decompression when the response is inadequate. Smoking cessation and risk-factor control are central.^[5]

ATA 2017 Pregnancy and Postpartum Guideline (Alexander and colleagues) establishes trimester-specific free T4 targets, PTU in the first trimester then carbimazole, maternal TRAb testing to predict fetal or neonatal disease, and the absolute contraindication of RAI in pregnancy and lactation.^[7]

^[1]

Regional deltas. In India and the Commonwealth, carbimazole is the standard thionamide (methimazole is the US equivalent); RAI is available but underused on cost and radiation-safety grounds, and surgery remains common for large goitres, with iodine deficiency persisting regionally and driving toxic multinodular goitre and Jod-Basedow after supplementation. In the US, methimazole is first-line and RAI is widely available, though declining with orbitopathy awareness. In Europe, the EUGOGO and ETA emphasise orbitopathy management, thionamides are first-line, and surgery is preferred at high-volume centres when chosen.^[1]

Controversies to handle calmly. Block-and-replace versus titration (titration is standard; slightly lower relapse with block-and-replace in some studies but more adverse effects — both acceptable). Routine surgery in active Graves orbitopathy is increasingly preferred over RAI (which worsens eye disease) when definitive treatment is needed. Teprotumumab (an IGF-1R inhibitor) is a major advance for active moderate-to-severe orbitopathy, but cost and access limit its use globally. The subclinical threshold for treatment (TSH under 0.1 versus under 0.4) remains debated in younger asymptomatic patients.^[5]

The memory bank

^[1]

Etymology nugget for the viva: Wolff-Chaikoff — described by Wolff and Chaikoff in 1948; a high iodine load acutely downregulates thyroid organification. It is the mechanism behind pre-operative Lugol's iodine, the iodine step in thyroid storm (given after the thionamide), and the transient hypothyroidism of an iodine load. Jod-Basedow fuses the German Jod (iodine) with von Basedow — iodine-induced hyperthyroidism in an autonomous gland.^[1]

The mantra: suppressed TSH means thyrotoxicosis; the uptake scan sorts the cause; carbimazole first — unless there is a baby or a storm.^[1][3][6][7]

^[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the young woman from the top of the topic (answer)ShowHide

The 28-year-old with palpitations, weight loss despite an increased appetite, a tremor, lid lag, a diffuse smooth goitre with a bruit, and prominent eyes. Name the cause, the first test, and the first drug. Model: This is Graves disease — the bruit on a diffuse goitre plus proptosis points to it before any scan. The aetiology is established from the clinical presentation, thyroid function tests (suppressed TSH with raised free T4/free T3), and TRAb status. First-line drug treatment is an antithyroid drug — carbimazole/methimazole is the preferred thionamide in most situations — with a beta-blocker for symptom control while it takes effect. Counsel her on agranulocytosis — sore throat, fever, or mouth ulcer means stop the drug and check a full blood count.^[1][2][17]

Stem 2 — the elderly man with atrial fibrillation and weight loss (answer)ShowHide

A 76-year-old presents in atrial fibrillation with a stone of weight loss, apathy, and a small multinodular goitre. He is quietly written off as "depression with CCF." What is the diagnosis and the first investigation? Model: This is apathetic hyperthyroidism from a likely toxic multinodular goitre — lethargy, AF, and weight loss in an older patient is hyperthyroidism until proven otherwise. Check a TSH with free T4 and free T3 (expect a suppressed TSH with raised free hormones). Once confirmed, control the rate with a beta-blocker (cautiously, given the heart failure), render euthyroid with carbimazole, and plan definitive RAI (often preferred in older patients with comorbidity) or surgery for a compressive goitre. Anticoagulate the AF by stroke-risk score.^[2][3]

Stem 3 — the storm ordering trap (answer)ShowHide

A known thyrotoxic patient presents with fever at 40 degrees C, atrial fibrillation at 150, agitation, and vomiting after stopping her carbimazole. The registrar orders Lugol's iodine now and the thionamide in an hour. What is wrong with that order? Model: The order is reversed, and that error is dangerous. In thyroid storm the thionamide goes FIRST, blocking new hormone synthesis, and the inorganic iodine goes only AFTER it — giving iodine first hands the gland fresh substrate for hormone synthesis and worsens the storm. Add a beta-blocker for the adrenergic drive, a glucocorticoid (which also reduces peripheral T4-to-T3 conversion), cooling, fluids, supportive care, and treatment of the precipitant. Storm is diagnosed clinically — do not delay treatment waiting for the TFT.^[6][8]

References20ShowHide

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2. [2]Lee SY, Pearce EN. Hyperthyroidism: A Review JAMA, 2023.PMID 37847271
3. [3]Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis Thyroid, 2016.PMID 27521067
4. [4]De Leo S, Lee SY, Braverman LE. Hyperthyroidism Lancet, 2016.PMID 27038492
5. [5]Bartalena L, Kahaly GJ, Baldeschi L, et al. The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy Eur J Endocrinol, 2021.PMID 34297684
6. [6]Kruithoff ML, Gigliotti BJ. Thyroid Emergencies: A Narrative Review Endocr Pract, 2025.PMID 40553957
7. [7]Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum Thyroid, 2017.PMID 28056690
8. [8]Kopp PA, Giordani I, Feldt-Rasmussen U, et al. Approach to the patient with thyroid storm J Clin Endocrinol Metab, 2026.PMID 41655224
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10. [10]Padmanabhan H. Amiodarone and thyroid dysfunction South Med J, 2010.PMID 20689491
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15. [15]Romeo AN, Običan SG Teratogen update: Antithyroid medications Birth Defects Res, 2020.PMID 32738035
16. [16]Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves' orbitopathy N Engl J Med, 2011.PMID 21591944
17. [17]Abdi H, Amouzegar A, Azizi F. Antithyroid Drugs Iran J Pharm Res, 2019.PMID 32802086
18. [18]Akmal A, Kung J. Propylthiouracil, and methimazole, and carbimazole-related hepatotoxicity Expert Opin Drug Saf, 2014.PMID 25156887
19. [19]Kahaly GJ. Management of Graves Thyroidal and Extrathyroidal Disease: An Update J Clin Endocrinol Metab, 2020.PMID 32929476
20. [20]Volpé R The management of subacute (DeQuervain's) thyroiditis Thyroid, 1993.PMID 8257868