Hyperthyroidism
Hyperthyroidism is a condition of excessive thyroid hormone production resulting in a hypermetabolic state characterized by weight loss, tachycardia, tremor, and heat intolerance.
Hyperthyroidism
Let's start by getting the terminology absolutely straight — this is a classic exam trap.
- Thyrotoxicosis = the clinical state of thyroid hormone excess in the body, regardless of the source. Think of it as the "syndrome" of too much T3/T4 floating around.
- Hyperthyroidism = thyrotoxicosis caused specifically by excess thyroid gland function (i.e., the gland itself is overproducing hormones).
Thyrotoxicosis ≠ Hyperthyroidism [1][2]. Hyperthyroidism is a subset of thyrotoxicosis. You can have thyrotoxicosis without hyperthyroidism — for example, in subacute thyroiditis where stored hormone leaks out from a damaged gland, or in exogenous levothyroxine overdose. The gland isn't hyperactive in these cases; it's passive release or external supply.
Why does this matter? Because the management differs fundamentally. You don't give antithyroid drugs (which block hormone synthesis) to someone whose thyroid is being destroyed and leaking hormone — there's nothing to block. You give supportive care (beta-blockers, steroids for inflammation) instead.
Exam Trap
A common mistake is using "hyperthyroidism" and "thyrotoxicosis" interchangeably. Always clarify: Is the gland overactive (hyperthyroidism), or is there hormone excess from another cause (thyrotoxicosis without hyperthyroidism)?
Etymology:
- "Hyper-" = excess; "thyroid" = shield-shaped (Greek thyreos = shield, referring to the shape of the thyroid cartilage); "-ism" = condition
- "Thyrotoxico-sis" = thyroid + toxic + condition → a state of being poisoned by thyroid hormone
2. Epidemiology and Risk Factors
- Prevalence: Overt hyperthyroidism affects ~1.2–1.6% of the population (higher in iodine-sufficient areas). Subclinical hyperthyroidism (suppressed TSH, normal free T4/T3) has a prevalence of ~0.5–2%.
- Sex: Strong female predominance — F:M ratio approximately 5–10:1 for Graves' disease.
- Age: Graves' disease peaks in 30–50 years (younger women). Toxic multinodular goitre (TMNG) peaks in >50 years (older patients, often in iodine-deficient regions historically).
- High iodine intake is associated with hyperthyroidism [2] — this is particularly relevant in Hong Kong and coastal East Asian populations, where dietary iodine from seafood and seaweed is abundant. The Jod-Basedow phenomenon describes iodine-induced hyperthyroidism, especially in patients with pre-existing autonomous nodules or subclinical multinodular goitre who are suddenly exposed to iodine excess (e.g., CT contrast, amiodarone).
| Risk Factor | Mechanism |
|---|---|
| Female sex | Autoimmune diseases in general are more prevalent in females (X-chromosome–linked immune regulatory genes, estrogen effects on immune modulation) |
| Family history of autoimmune thyroid disease | HLA associations (HLA-DR3 in Caucasians), CTLA-4, PTPN22 polymorphisms |
| Other autoimmune diseases | Type 1 DM, Addison's disease, pernicious anaemia, vitiligo — autoimmune polyglandular syndromes |
| Smoking | Specifically increases risk of Graves' ophthalmopathy (not just Graves' disease itself) — mechanism involves orbital fibroblast activation by cigarette smoke components |
| High iodine intake | Substrate excess for hormone synthesis; Jod-Basedow effect in autonomous nodules |
| Stress / psychological trauma | Proposed trigger for Graves' via neuroendocrine-immune interactions (increased cortisol → immune dysregulation → loss of self-tolerance) |
| Postpartum period | Immune rebound after pregnancy-related immunosuppression → postpartum thyroiditis |
| Medications | Amiodarone (37% iodine by weight), interferon-alpha, lithium (paradoxically can cause both hypo- and hyperthyroidism), immune checkpoint inhibitors (pembrolizumab, nivolumab) |
| Excess exogenous thyroid hormone | Iatrogenic (over-replacement of levothyroxine) or factitious |
| Iodine contrast media | Acute iodine load — risk in patients with pre-existing nodular goitre |
- Hong Kong is an iodine-sufficient region due to high seafood consumption.
- Graves' disease is the most common cause of hyperthyroidism in Hong Kong [1][3], as in most iodine-sufficient regions.
- Toxic multinodular goitre is relatively less common than in iodine-deficient regions but still seen, particularly in elderly patients.
- Amiodarone-induced thyrotoxicosis (AIT) is an important cause in cardiology patients (prevalent AF population in Hong Kong).
3. Anatomy and Function of the Thyroid Gland
- The thyroid gland is a butterfly-shaped endocrine gland located in the anterior neck, wrapping around the 2nd–4th tracheal rings [4].
- Consists of two lateral lobes connected by an isthmus. A pyramidal lobe (embryological remnant of the thyroglossal duct) is present in ~50% of people, projecting superiorly from the isthmus.
- Weight: ~15–25 g in adults.
- The thyroid gland moves with swallowing because it is enveloped by the pretracheal fascia, which attaches to the trachea and larynx. This is a key clinical sign that distinguishes thyroid swellings from other neck masses [4][5].
Clinical Pearl: Any anterior neck mass that moves with swallowing is likely thyroid in origin. A thyroglossal duct cyst moves with swallowing AND tongue protrusion (because it is connected to the foramen caecum at the tongue base via the thyroglossal duct remnant).
- Anterior: Strap muscles (sternohyoid, sternothyroid, omohyoid), sternocleidomastoid
- Posterior: Parathyroid glands (2 superior, 2 inferior — at risk during thyroid surgery), recurrent laryngeal nerve (runs in the tracheoesophageal groove) [4]
- Lateral: Carotid sheath (common carotid artery, internal jugular vein, vagus nerve)
- Medial: Trachea, oesophagus
- Superior thyroid artery (first branch of external carotid artery)
- Inferior thyroid artery (branch of thyrocervical trunk from subclavian artery)
- Sometimes a thyroidea ima artery (variable, from brachiocephalic trunk or aortic arch — important to know if performing tracheostomy)
- The thyroid is one of the most vascular organs per gram of tissue in the body — hence the risk of significant bleeding during surgery and the audible thyroid bruit in Graves' disease (due to massively increased blood flow).
- Superior and middle thyroid veins → internal jugular vein
- Inferior thyroid veins → brachiocephalic veins
- Pre-laryngeal (Delphian), pre-tracheal, and para-tracheal nodes → deep cervical chain
- Important for staging of thyroid carcinoma
- Recurrent laryngeal nerve (RLN): Motor to all intrinsic laryngeal muscles except cricothyroid. Injury → vocal cord paralysis (hoarseness). Bilateral RLN injury → airway compromise (bilateral abductor paralysis) [4].
- External branch of superior laryngeal nerve (EBSLN): Motor to cricothyroid muscle (tensor of vocal cords). Injury → difficulty with high-pitched voice, vocal fatigue. Often called "the nerve of Amelita Galli-Curci" (a famous opera singer who lost her high notes after thyroid surgery).
Functional unit: The thyroid follicle — a spherical structure lined by follicular epithelial cells (thyrocytes) surrounding a central lumen filled with colloid (thyroglobulin).
Thyroid Hormone Synthesis (Step by Step):
- Iodide trapping: The sodium-iodide symporter (NIS) on the basolateral membrane of thyrocytes actively transports I⁻ from blood into the cell (against concentration gradient, 20–40× concentrated). This is the target of radioactive iodine (RAI) therapy.
- Iodide transport to lumen: Pendrin (an anion exchanger) on the apical membrane transports I⁻ into the colloid.
- Oxidation and organification: Thyroid peroxidase (TPO) oxidises I⁻ to I⁰ and attaches it to tyrosine residues on thyroglobulin → forms monoiodotyrosine (MIT) and diiodotyrosine (DIT). This is the step blocked by thionamides (carbimazole/methimazole, propylthiouracil).
- Coupling: TPO couples MIT + DIT → T3 (triiodothyronine); DIT + DIT → T4 (thyroxine). T4 is the major product (~90%). T3 is 3–5× more biologically active.
- Storage: T3 and T4 remain bound to thyroglobulin in the colloid. The thyroid stores ~2–3 months' worth of hormone — which is why it takes time for antithyroid drugs to take effect and why thyrotoxicosis in destructive thyroiditis is self-limiting.
- Secretion: TSH stimulates endocytosis of colloid → lysosomal proteolysis of thyroglobulin → release of T3 and T4 into blood.
- Peripheral conversion: ~80% of circulating T3 is produced by peripheral deiodination of T4 (by type 1 and type 2 deiodinases in liver, kidney, muscle). Propylthiouracil (PTU) additionally blocks this peripheral conversion — advantage in thyroid storm.
Transport: >99% of T3 and T4 circulate protein-bound (to thyroxine-binding globulin [TBG], albumin, transthyretin). Only the free fraction is biologically active (free T4, free T3).
HPT Axis:
- Hypothalamus → TRH (thyrotropin-releasing hormone) → anterior pituitary → TSH (thyroid-stimulating hormone) → thyroid → T3/T4
- T3/T4 exert negative feedback on both the hypothalamus and anterior pituitary.
- In hyperthyroidism: TSH is suppressed (except in TSH-secreting pituitary adenoma = "secondary hyperthyroidism," where TSH is inappropriately normal or elevated).
Parafollicular C cells: Located between follicles. Produce calcitonin (lowers serum calcium). Relevant because medullary thyroid carcinoma arises from C cells.
Why is TSH the best screening test for thyroid dysfunction?
TSH has a log-linear relationship with free T4 — a small change in free T4 produces a large change in TSH. Therefore, TSH is the most sensitive marker for detecting even subtle thyroid dysfunction (subclinical hyper- or hypothyroidism). A suppressed TSH (< 0.1 mIU/L) with normal free T4 = subclinical hyperthyroidism.
4. Etiology
The causes of thyrotoxicosis can be classified based on whether the thyroid gland is overactive (true hyperthyroidism) or not [2]:
| Category | Causes | Key Features |
|---|---|---|
| Primary Hyperthyroidism (gland overactive) | Graves' disease | Most common overall. Autoimmune. Diffuse goitre. |
| Toxic multinodular goitre (TMNG) | Most common in elderly/iodine-deficient areas. Multiple autonomous nodules. | |
| Toxic adenoma (Plummer's disease) | Single autonomous hyperfunctioning nodule. | |
| Metastatic functioning thyroid carcinoma (rare) | Large tumour burden producing thyroid hormone. | |
| Activating mutation of TSH receptor | Congenital/sporadic. | |
| McCune-Albright syndrome (Gsα mutation) [2] | Polyostotic fibrous dysplasia, café-au-lait spots, precocious puberty, autonomous endocrine hyperfunction. | |
| Secondary Hyperthyroidism (TSH-driven) | TSH-secreting pituitary adenoma (TSHoma) | Very rare. TSH inappropriately normal/elevated with high T4/T3. |
| Chorionic gonadotropin (hCG)-secreting tumour | hCG structurally similar to TSH → cross-stimulates TSH receptor. Hydatidiform mole, choriocarcinoma. | |
| Gestational thyrotoxicosis | Physiological high hCG in first trimester → transient TSH receptor stimulation. Associated with hyperemesis gravidarum. | |
| Thyrotoxicosis WITHOUT Hyperthyroidism (gland not overactive) | Subacute (de Quervain's) thyroiditis | Post-viral. Painful, tender thyroid. Self-limiting. |
| Silent (painless) thyroiditis | Autoimmune variant. Painless. Can be postpartum. | |
| Destructive thyroiditis (amiodarone type 2, radiation) | Gland destruction → release of stored hormone into blood [2]. | |
| Levothyroxine (T4) overdose / factitious thyrotoxicosis | Exogenous hormone. Thyroglobulin LOW (vs. all other causes where thyroglobulin is normal/high). | |
| Struma ovarii | Ectopic thyroid tissue in ovarian dermoid/teratoma producing thyroid hormone. |
How to think about etiology
Ask yourself: Is the thyroid gland making too much hormone, or is hormone being released/supplied from somewhere else? This determines whether radioactive iodine uptake (RAIU) will be HIGH (gland overactive → takes up iodine avidly) or LOW (gland inactive/suppressed → doesn't take up iodine).
Focus on the Major Causes (HK-relevant)
Pathophysiology:
- An autoimmune condition where B lymphocytes produce thyroid-stimulating immunoglobulins (TSI) — also called TSH-receptor antibodies (TRAb).
- These IgG antibodies bind to and activate the TSH receptor on thyrocytes, mimicking TSH.
- Unlike TSH, TRAb are not subject to negative feedback → unregulated, continuous stimulation → excess T3/T4 production and thyroid hyperplasia/hypertrophy → diffuse goitre.
- Why is the goitre diffuse? Because TRAb circulates in the blood and stimulates all follicular cells uniformly, unlike nodular disease where only certain clones are autonomous.
Extra-thyroidal manifestations unique to Graves':
- Graves' ophthalmopathy (GO): TRAb cross-reacts with TSH receptors expressed on orbital fibroblasts and adipocytes → inflammatory infiltration (T cells, macrophages) → glycosaminoglycan (GAG) deposition and oedema → expansion of retro-orbital tissue → proptosis (exophthalmos). Smoking significantly worsens this.
- Graves' dermopathy (pretibial myxoedema): Same mechanism — TSH receptor expression on dermal fibroblasts → GAG/mucin deposition in skin → raised, non-pitting, "peau d'orange" plaques, typically over the pretibial area. Occurs in <5% of patients.
- Thyroid acropachy: Clubbing of fingers/toes. Rarest manifestation (<1%). Pathophysiology poorly understood.
- Typically occurs in patients with longstanding non-toxic multinodular goitre where some nodules acquire activating somatic mutations in the TSH receptor or Gsα protein → autonomous thyroid hormone production independent of TSH.
- More common in older patients and in areas with historical iodine deficiency.
- Transition to toxicity may be triggered by iodine exposure (Jod-Basedow effect): e.g., iodinated contrast dye, amiodarone.
- A single, autonomous, hyperfunctioning nodule with an activating somatic mutation in the TSH receptor gene.
- The nodule produces hormone independently → suppresses TSH → the rest of the thyroid gland atrophies (because it's not being stimulated).
- On radioactive iodine scan: "hot nodule" with suppressed uptake in surrounding thyroid tissue.
- Post-viral inflammatory destruction of thyroid follicles (often follows URTI).
- Pathophysiology: Viral infection → granulomatous inflammation → disruption of follicles → release of preformed T3/T4 into blood → transient thyrotoxicosis (typically 2–8 weeks).
- This is followed by a hypothyroid phase (stores depleted) → then recovery (euthyroid) in most patients.
- Clinically: Painful, tender thyroid gland, fever, raised ESR/CRP, low RAIU.
Amiodarone is 37% iodine by weight and has a very long half-life (~100 days). Two types:
- AIT Type 1: Iodine-induced hyperthyroidism (Jod-Basedow) in patients with pre-existing thyroid autonomy (e.g., nodular goitre). RAIU may be normal/increased. Treat with thionamides ± perchlorate.
- AIT Type 2: Destructive thyroiditis from direct cytotoxic effect of amiodarone on thyrocytes → release of stored hormone. RAIU is low. Treat with glucocorticoids.
- In practice, mixed forms are common.
Understanding the pathophysiology of thyroid hormone excess explains virtually every clinical feature. Here's the fundamental concept:
Thyroid hormones (T3 >> T4) enter cells and bind to nuclear thyroid hormone receptors (TR) → increase gene transcription → increase basal metabolic rate (BMR), protein synthesis, and catecholamine sensitivity.
Key cellular effects:
- ↑ Basal metabolic rate: T3 increases Na⁺/K⁺-ATPase activity in virtually all cells → increases oxygen consumption and heat production.
- ↑ Catecholamine sensitivity: T3 upregulates β-adrenergic receptors (particularly β1 in the heart) → amplifies the effect of circulating catecholamines (even though catecholamine levels themselves are not elevated). This is why beta-blockers are so effective.
- ↑ Bone turnover: T3 stimulates both osteoblasts and osteoclasts, but osteoclast activity predominates → net bone resorption → hypercalcaemia, osteoporosis.
- ↑ GI motility: Direct stimulation of GI smooth muscle → hyperdefecation/diarrhoea.
- ↑ Carbohydrate metabolism: Enhanced glycogenolysis, gluconeogenesis, intestinal glucose absorption → hyperglycaemia/glucose intolerance.
- ↑ Lipid metabolism: Enhanced lipolysis + increased LDL receptor expression → low total cholesterol and LDL (opposite to hypothyroidism).
- ↑ Protein catabolism: Muscle wasting (thyrotoxic myopathy), proximal weakness.
6. Classification
- True hyperthyroidism (thyroid overactive) — high RAIU
- Thyrotoxicosis without hyperthyroidism (passive release/exogenous) — low RAIU
- Subclinical hyperthyroidism: Suppressed TSH, normal free T4 and free T3. Patient may be asymptomatic or have subtle symptoms.
- Overt (clinical) hyperthyroidism: Suppressed TSH, elevated free T4 and/or free T3.
- Thyroid storm (thyrotoxic crisis): Life-threatening, extreme thyrotoxicosis with multi-organ decompensation (fever > 40°C, tachycardia, delirium, heart failure, seizures). Usually precipitated by infection, surgery, RAI therapy, iodine contrast, or non-compliance with antithyroid drugs.
- Graves' disease — autoimmune, diffuse
- Toxic multinodular goitre — multiple autonomous nodules
- Toxic adenoma — single autonomous nodule
- Thyroiditis — destructive (de Quervain's, silent, postpartum, drug-induced)
- Exogenous/factitious — levothyroxine overdose
- Rare causes — TSHoma, struma ovarii, hCG-mediated
7. Clinical Features
The clinical presentation of thyrotoxicosis reflects the systemic effects of thyroid hormone excess on virtually every organ system. [1][3]
| System | Symptom | Pathophysiological Basis |
|---|---|---|
| General/Metabolic | Heat intolerance, excessive sweating | ↑ BMR → ↑ heat production; ↑ peripheral vasodilation to dissipate heat → sweating |
| Weight loss despite increased appetite | ↑ BMR exceeds caloric intake → net catabolism. Rarely, some patients gain weight if appetite increase > metabolic rate ("fat Graves'") | |
| Fatigue, weakness | Protein catabolism → muscle wasting; hypermetabolic state = exhausting | |
| Cardiovascular | Palpitations | ↑ β1-adrenergic receptor expression in heart → ↑ heart rate and contractility; may feel forceful/rapid heartbeat |
| Dyspnoea on exertion | High-output cardiac state + respiratory muscle weakness | |
| Chest pain (rare) | Increased myocardial oxygen demand in the setting of increased cardiac output | |
| Neuropsychiatric | Anxiety, irritability, emotional lability | ↑ catecholamine sensitivity in CNS → sympathetic overactivation |
| Tremor (fine resting tremor) | ↑ β-adrenergic activity in skeletal muscle | |
| Insomnia | Sympathetic overactivation, hypermetabolic state | |
| Difficulty concentrating | CNS hyperexcitability | |
| Psychosis (rare, "thyrotoxic psychosis") | Severe, prolonged excess thyroid hormone effect on CNS | |
| GI | Increased stool frequency / diarrhoea | ↑ GI motility (direct T3 effect on smooth muscle + ↑ sympathetic tone) |
| Increased appetite (hyperphagia) | ↑ BMR → body's attempt to compensate for energy deficit | |
| Nausea, vomiting (in severe cases) | Thyroid storm or Graves'-associated | |
| Musculoskeletal | Proximal myopathy (difficulty climbing stairs, rising from chair) | Protein catabolism + accelerated muscle proteolysis → muscle wasting, particularly proximal muscles |
| Bone pain, fractures (rare) | ↑ Osteoclast activity → osteoporosis | |
| Reproductive | Oligomenorrhoea / amenorrhoea | ↑ Sex hormone-binding globulin (SHBG) → altered estrogen/progesterone dynamics; direct effect on GnRH pulsatility |
| Subfertility | Anovulation from hormonal disruption | |
| Gynaecomastia (males) | ↑ SHBG → ↑ bound testosterone → relative estrogen excess; also ↑ peripheral aromatisation | |
| Erectile dysfunction, ↓ libido | Hormonal imbalance | |
| Dermatological | Warm, moist skin | ↑ Peripheral vasodilation + sweating |
| Hair thinning / fine hair | ↑ Hair cycle turnover → telogen effluvium | |
| Pruritus | Increased skin blood flow, possible mast cell degranulation | |
| Onycholysis (Plummer's nails) | Separation of nail plate from nail bed — mechanism not fully understood; possibly related to increased nail matrix turnover | |
| Ophthalmological (General) | Lid retraction, lid lag, staring gaze | Not specific to Graves' — caused by ↑ sympathetic stimulation of Müller's muscle (superior tarsal muscle) in the upper eyelid → eyelid retracts. Present in ANY cause of thyrotoxicosis |
| Ophthalmological (Graves'-specific) | Proptosis (exophthalmos), diplopia, periorbital oedema, eye grittiness/tearing | TRAb-mediated inflammation of retro-orbital tissue → GAG deposition, fibroblast proliferation, fat expansion → increased retro-orbital volume → globe pushed forward. Only in Graves' disease |
| Neck | Neck swelling, dysphagia, dysphonia | Thyroid enlargement (goitre) compressing oesophagus/trachea/recurrent laryngeal nerve |
Key Distinction: Lid Retraction vs. Proptosis
Lid retraction and lid lag can occur in ANY thyrotoxic patient (sympathetic-mediated). Proptosis, periorbital oedema, chemosis, ophthalmoplegia = Graves' ophthalmopathy (autoimmune-mediated, specific to Graves'). Don't confuse the two!
General Examination:
| Sign | Pathophysiological Basis |
|---|---|
| Fine resting tremor (best elicited by placing a piece of paper on outstretched hands) | ↑ β-adrenergic activity |
| Warm, moist palms | ↑ Peripheral vasodilation + sweating from ↑ BMR |
| Tachycardia (resting HR > 90 bpm) | ↑ β1 receptor density and sensitivity in heart → chronotropic and inotropic effect |
| Atrial fibrillation (AF) | ↑ Atrial ectopic activity from catecholamine sensitisation → re-entrant circuits. Occurs in ~10–15% of thyrotoxic patients, more common in elderly and those with TMNG |
| Wide pulse pressure / bounding pulse | ↑ Cardiac output (↑ HR × ↑ stroke volume) + ↓ systemic vascular resistance (peripheral vasodilation) → high systolic BP, low diastolic BP |
| Weight loss | Hypermetabolism > caloric intake |
| Proximal muscle wasting and weakness | Protein catabolism. Test: ask patient to rise from squatting position without using hands |
| Hyperreflexia (brisk reflexes) | ↑ Nerve conduction velocity and neuromuscular excitability |
| Palmar erythema | ↑ Peripheral vasodilation |
| Spider naevi (rare) | Hyperdynamic circulation |
Thyroid Examination:
| Sign | Significance |
|---|---|
| Diffuse, smooth goitre | Graves' disease — uniform TRAb stimulation |
| Nodular goitre | TMNG (multiple nodules) or toxic adenoma (single nodule) |
| Thyroid bruit / thrill | Markedly increased blood flow through the thyroid — virtually pathognomonic of Graves' disease. Must be distinguished from a transmitted carotid bruit (check with bell of stethoscope directly over thyroid) |
| Tenderness | Suggests subacute (de Quervain's) thyroiditis |
| Moves with swallowing | Confirms thyroid origin of neck mass [4][5] |
| Retrosternal extension | Ask patient to raise arms above head → if obstruction of thoracic inlet → facial plethora, JVP elevation (Pemberton's sign) |
Eye Examination (Graves' Ophthalmopathy):
- Lid retraction (sclera visible above iris = "scleral show")
- Lid lag (upper eyelid lags behind the globe on slow downward gaze — Von Graefe's sign)
- Proptosis / exophthalmos (measured by Hertel exophthalmometer; > 18 mm or asymmetry > 2 mm)
- Chemosis (conjunctival oedema)
- Periorbital oedema
- Ophthalmoplegia (restrictive — most commonly inferior rectus affected → limitation of upgaze, then medial rectus → limitation of lateral gaze → diplopia)
- Exposure keratopathy (corneal drying due to incomplete lid closure from proptosis)
- In severe cases: optic neuropathy (compression of optic nerve at orbital apex → colour vision loss, reduced visual acuity — an emergency)
Graves' ophthalmopathy is classified using the NOSPECS system or CAS (Clinical Activity Score) — important for determining need for immunosuppressive therapy vs. surgery [3].
Skin Examination:
- Pretibial myxoedema (Graves' dermopathy): Raised, non-pitting, waxy, "peau d'orange" plaques on anterior shins. Despite the name "myxoedema," this is NOT hypothyroidism — it's a Graves'-specific autoimmune manifestation.
- Thyroid acropachy: Clubbing + periosteal new bone formation (looks like hypertrophic pulmonary osteoarthropathy). Very rare.
- Vitiligo, alopecia areata (associated autoimmune conditions)
Cardiovascular Examination:
- High-output heart failure: In severe, longstanding thyrotoxicosis → cardiac decompensation with biventricular failure, oedema, elevated JVP. Why? Chronic ↑ cardiac work → myocardial exhaustion + direct T3-mediated cardiomyocyte apoptosis.
- Systolic flow murmurs (ejection systolic murmur due to hyperdynamic circulation)
- Mitral regurgitation (papillary muscle dysfunction from thyrotoxic cardiomyopathy)
Neurological Examination:
- Hyperreflexia with shortened relaxation phase
- Fine tremor
- Proximal myopathy
- Rarely: thyrotoxic periodic paralysis — sudden episodes of severe hypokalemic muscle weakness, particularly in Asian males. Mechanism: T3 stimulates Na⁺/K⁺-ATPase → drives K⁺ intracellularly → acute hypokalaemia → muscle paralysis. Triggered by carbohydrate-rich meals, exercise, stress.
Thyrotoxic Periodic Paralysis
This is a high-yield topic for HK exams because it predominantly affects Asian males. It presents as acute flaccid paralysis (often legs > arms) with hypokalaemia. ECG may show U waves, prolonged QT. It mimics Guillain-Barré or hypokalaemic periodic paralysis. The key differentiator is checking thyroid function! Treatment: cautious K⁺ replacement (rebound hyperkalaemia risk), beta-blockers, and definitive treatment of hyperthyroidism.
Only Graves' disease causes:
- Ophthalmopathy (proptosis, ophthalmoplegia, periorbital oedema)
- Dermopathy (pretibial myxoedema)
- Acropachy (clubbing)
- Diffuse goitre with bruit
- Positive TRAb
These features are due to the autoimmune nature of Graves' — TRAb acting on TSH receptors expressed in extra-thyroidal tissues (orbit, skin, periosteum).
| Feature | Graves' | TMNG | Toxic Adenoma | Subacute Thyroiditis |
|---|---|---|---|---|
| Age | 30–50 | > 50 | 30–50 | Any (post-viral) |
| Goitre | Diffuse, smooth | Multinodular | Single nodule | Diffuse, tender |
| Thyroid bruit | Present | Absent | Absent | Absent |
| Eye signs | Ophthalmopathy | Lid lag only (sympathetic) | Lid lag only | Lid lag only |
| Pretibial myxoedema | Yes (rare) | No | No | No |
| Pain | No | No | No | Yes — painful, tender thyroid |
| ESR | Normal | Normal | Normal | Very elevated |
| RAIU | Diffusely increased | Patchy/increased | Hot nodule, cold rest | Low/absent |
| TRAb | Positive | Negative | Negative | Negative |
8. Special Populations
- hCG has structural homology with TSH → can stimulate TSH receptors → gestational thyrotoxicosis in first trimester (peaks when hCG peaks at ~10–12 weeks).
- Often associated with hyperemesis gravidarum.
- Usually self-limiting; resolves by second trimester as hCG declines.
- Must distinguish from Graves' disease in pregnancy (TRAb positive, goitre, eye signs → needs treatment).
- Treatment: PTU preferred in first trimester (methimazole associated with rare embryopathy — aplasia cutis, choanal atresia). Switch to methimazole/carbimazole in second trimester (PTU has risk of hepatotoxicity).
- Radioactive iodine is absolutely contraindicated in pregnancy.
- May present atypically — "apathetic thyrotoxicosis": weight loss, AF, heart failure, depression, apathy — WITHOUT classic sympathetic features (tremor, anxiety).
- AF is often the presenting feature.
- Higher risk of cardiovascular complications.
- TMNG is the more common cause in elderly.
- Suppressed TSH with normal free T4/T3.
- Associated with increased risk of: AF (especially in elderly), osteoporosis (especially postmenopausal women), cardiovascular mortality.
- Treatment considered when TSH persistently < 0.1 mIU/L, age > 65, or presence of AF/osteoporosis/cardiac risk factors.
High Yield Summary
Key Concepts for Exams:
-
Thyrotoxicosis ≠ hyperthyroidism — thyrotoxicosis is the syndrome of hormone excess; hyperthyroidism specifically means the gland is overactive.
-
Graves' disease is the most common cause of hyperthyroidism in iodine-sufficient regions (including HK). It is autoimmune, mediated by TRAb stimulating the TSH receptor.
-
The triad unique to Graves': ophthalmopathy, dermopathy (pretibial myxoedema), acropachy. These are TRAb-mediated, NOT from thyroid hormone excess per se.
-
RAIU scan is the key investigation to distinguish causes: HIGH uptake = hyperthyroidism (Graves'/TMNG/toxic adenoma); LOW uptake = thyrotoxicosis without hyperthyroidism (thyroiditis/exogenous).
-
Clinical features are driven by ↑ BMR and ↑ catecholamine sensitivity (β-adrenergic upregulation) — this explains why beta-blockers are the first-line symptomatic treatment.
-
Thyrotoxic periodic paralysis — think Asian males, acute hypokalaemic paralysis, check TFTs!
-
AF in the elderly — always check TFTs. Apathetic thyrotoxicosis may present without classic sympathetic features.
-
Thyroid moves with swallowing — key sign to identify a thyroid mass.
-
Lid retraction/lid lag = sympathetic (any thyrotoxicosis). Proptosis/ophthalmoplegia = Graves' only (autoimmune).
-
High iodine intake (HK-relevant) can precipitate hyperthyroidism in patients with autonomous nodules (Jod-Basedow phenomenon).
Active Recall - Hyperthyroidism: Definition, Epidemiology, Aetiology, Pathophysiology, Clinical Features
[1] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf [2] Senior notes: felixlai.md (Section II–III: Overview and Etiology) [3] Lecture slides: Management of differentiated thyroid carcinoma.pdf [4] Lecture slides: GC 218. I have a swelling in the neck Neck mass (Notes).pdf [5] Lecture slides: GC 218. I have a swelling in the neck Neck mass.pdf
Differential Diagnosis of Hyperthyroidism / Thyrotoxicosis
When a patient presents with clinical features suggesting thyrotoxicosis — weight loss, tremor, palpitations, heat intolerance — the real clinical challenge isn't just confirming thyrotoxicosis (that's a blood test). The challenge is determining the cause, because the management differs dramatically. You don't give carbimazole to someone with subacute thyroiditis, and you don't give steroids to someone with Graves'.
The differential diagnosis operates on two levels:
- Level 1: Is this truly thyrotoxicosis, or is it a mimic? (The "broad DDx" of a thyrotoxic-looking patient)
- Level 2: If it IS thyrotoxicosis, what is the underlying cause? (The "aetiological DDx" — distinguishing between causes of thyrotoxicosis)
Before you even get to the blood results, a patient with anxiety, tremor, tachycardia, weight loss, and sweating could have several other diagnoses. These are conditions that share sympathetic-overdrive features:
| Mimic | Key Distinguishing Features | Why It Mimics Thyrotoxicosis |
|---|---|---|
| Anxiety disorder / panic disorder | Normal TFTs. Episodic rather than constant. No goitre, no eye signs, no weight loss despite good appetite | Sympathetic activation → tachycardia, tremor, sweating, palpitations |
| Phaeochromocytoma | Paroxysmal headache, sweating, palpitations, hypertension (cf. Graves' has wide pulse pressure but not typically severe hypertension). 24h urinary catecholamines / plasma metanephrines elevated [6] | Catecholamine excess → direct sympathetic features. Unlike thyrotoxicosis, symptoms are typically episodic/paroxysmal |
| Cardiac arrhythmia (e.g., SVT, AF) | Palpitations dominant. No weight loss, no tremor, no heat intolerance. ECG diagnostic | AF can be caused by thyrotoxicosis — always check TFTs in new AF |
| Substance use (cocaine, amphetamines, excessive caffeine) | History is key. Dilated pupils, agitation. Normal TFTs | Sympathomimetic agents mimic catecholamine excess |
| Menopause | Hot flushes (episodic, not constant heat intolerance), irregular menses, age > 45. Normal TFTs. FSH elevated | Vasomotor instability from oestrogen withdrawal |
| Malignancy (occult) | Weight loss without increased appetite (anorexia present). Night sweats. Lymphadenopathy | Weight loss + sweating, but appetite is typically DECREASED (vs. thyrotoxicosis where appetite is INCREASED) |
| Diabetes mellitus (new onset) | Polyuria, polydipsia, weight loss. Elevated glucose. Normal TFTs | Weight loss + polyuria overlap with thyrotoxicosis. But DM has polydipsia and hyperglycaemia |
| Heart failure | Dyspnoea, tachycardia, oedema. But resting, not hypermetabolic. May coexist with thyrotoxicosis | High-output HF can be CAUSED by thyrotoxicosis — so check TFTs |
| Carcinoid syndrome | Episodic flushing, diarrhoea, wheezing. 24h urinary 5-HIAA elevated | Flushing + diarrhoea overlap. But carcinoid flushing is episodic and often triggered; thyrotoxic heat intolerance is constant |
Clinical Pearl
The single most important screening test to rule in/rule out thyrotoxicosis is serum TSH. If TSH is normal, the patient is almost certainly NOT thyrotoxic (exception: the very rare TSH-secreting pituitary adenoma where TSH is inappropriately normal/high). A normal TSH has a negative predictive value of > 99% for primary thyrotoxicosis.
Once thyrotoxicosis is biochemically confirmed (suppressed TSH, elevated fT4/fT3), the critical next step is determining the cause. This drives management.
The aetiological differential diagnosis is best approached by dividing causes into those with HIGH radioactive iodine uptake (RAIU) versus LOW RAIU [1][2][7]:
| RAIU | Category | Causes | Pathophysiology |
|---|---|---|---|
| HIGH (diffuse) | Gland uniformly overactive | Graves' disease | TRAb uniformly stimulates all TSH receptors → diffuse hyperfunction and iodine trapping |
| HIGH (patchy/multifocal) | Multiple autonomous zones | Toxic multinodular goitre (TMNG) [1][7] | Multiple nodules with activating mutations → patchy autonomous uptake |
| HIGH (focal, single) | Single autonomous nodule | Toxic adenoma (Plummer's disease) [1][7] | Single nodule with activating TSH-receptor mutation → focal "hot" uptake with suppressed surrounding tissue |
| LOW / absent | Gland damaged, leaking stored hormone | Subacute (de Quervain's) thyroiditis | Post-viral granulomatous inflammation → follicular destruction → passive release of preformed T3/T4. Gland NOT actively trapping iodine |
| LOW / absent | Gland damaged, leaking stored hormone | Silent (painless) thyroiditis | Autoimmune lymphocytic infiltration → follicular destruction → passive hormone release. Often postpartum |
| LOW / absent | Drug-induced destruction | Amiodarone-induced thyrotoxicosis type 2 | Direct cytotoxic effect on thyrocytes → hormone leakage |
| LOW / absent | Exogenous hormone | Factitious thyrotoxicosis / levothyroxine overdose [2] | Exogenous T4 suppresses TSH and native thyroid function → gland doesn't take up iodine. Thyroglobulin LOW (key distinguisher) |
| LOW / absent | Ectopic thyroid tissue | Struma ovarii | Ectopic thyroid tissue in ovarian teratoma producing T3/T4. Neck RAIU low but pelvic uptake present |
| Variable | TSH-driven | TSH-secreting pituitary adenoma [2] | TSH is inappropriately normal/elevated → drives thyroid to produce hormone. RAIU may be normal/high |
| Variable | hCG-driven | Gestational thyrotoxicosis / hCG-secreting tumour [2] | hCG cross-stimulates TSH receptor (structural homology with TSH — shared α-subunit, similar β-subunit) [8] |
Key Differentiating Features — Cause by Cause
This is the most common clinical distinction you'll need to make.
| Feature | Graves' Disease | Toxic MNG | Toxic Adenoma |
|---|---|---|---|
| Age | 30–50 years | > 50 years | 30–50 years |
| Goitre | Diffuse, smooth | Multinodular, irregular [1] | Single palpable nodule |
| Thyroid bruit | Present (increased vascularity) [9] | Absent | Absent |
| Eye signs | Graves' ophthalmopathy (proptosis, ophthalmoplegia, periorbital oedema) | Lid lag/retraction only (sympathetic) | Lid lag/retraction only |
| Pretibial myxoedema | May be present | Absent | Absent |
| TRAb | Positive (80–90%) [2] | Negative | Negative |
| Anti-TPO | 50–80% positive [2] | 10–20% | Usually negative |
| RAIU scan | Diffusely increased uptake [1] | Patchy uptake with hot and cold areas [1] | Single hot nodule with suppressed surrounding tissue [1] |
| Ultrasound | Diffuse enlargement, increased vascularity ("thyroid inferno") | Multiple nodules of varying echogenicity | Single well-defined nodule |
| Natural history | Relapsing-remitting; may remit spontaneously or with ATDs | Progressive; ATDs rarely induce remission | Grows slowly; may cause increasing toxicity over time |
On clinical examination, only 3 conclusions can be derived: thyroid nodule, multinodular goitre, or diffuse goitre [9]. This clinical distinction guides further investigation.
| Feature | Graves' | Subacute Thyroiditis |
|---|---|---|
| Onset | Gradual (weeks–months) | Acute (days), often follows URTI |
| Pain | Painless | Painful, exquisitely tender thyroid |
| ESR/CRP | Normal | Markedly elevated (ESR often > 50 mm/hr) |
| TRAb | Positive | Negative |
| RAIU | High (diffuse) | Low/absent (gland destroyed, not trapping iodine) |
| Phase | Sustained hyperthyroidism (unless treated) | Triphasic: thyrotoxic phase (2–8 wks) → hypothyroid phase (weeks–months) → recovery |
| Treatment | ATDs, RAI, or surgery | Supportive: NSAIDs/steroids for pain and inflammation, beta-blockers for symptoms. ATDs are USELESS (gland is not synthesising — it's leaking) |
Why are antithyroid drugs useless in thyroiditis?
Antithyroid drugs (carbimazole, PTU) work by inhibiting thyroid peroxidase (TPO), which blocks NEW hormone synthesis. In thyroiditis, the problem is RELEASE of PREFORMED hormone from damaged follicles — there's nothing to block. Giving carbimazole to a patient with subacute thyroiditis is a common student mistake. Beta-blockers for symptom control + NSAIDs/steroids for inflammation is all you need.
Both present with transient thyrotoxicosis followed by hypothyroidism, but:
| Feature | Silent Thyroiditis | Subacute Thyroiditis |
|---|---|---|
| Pain | Painless | Painful |
| ESR | Normal or mildly elevated | Very high |
| Aetiology | Autoimmune (lymphocytic infiltration); often postpartum | Post-viral (granulomatous) |
| Anti-TPO | Often positive | Usually negative |
| Recurrence | May recur, especially with subsequent pregnancies | Rarely recurs |
- Exogenous levothyroxine ingestion (intentional or accidental over-replacement).
- Key distinguishing feature: Thyroglobulin is LOW (because the native gland is suppressed and atrophic; exogenous T4 does not generate thyroglobulin). In ALL other causes of thyrotoxicosis, thyroglobulin is normal or elevated.
- RAIU is low (gland suppressed).
- No goitre (gland atrophies due to TSH suppression).
- Very rare (< 1% of pituitary adenomas, < 1% of thyrotoxicosis cases).
- Key distinguishing feature: TSH is inappropriately normal or elevated despite high fT4/fT3. In all other causes of primary thyrotoxicosis, TSH is suppressed.
- May have features of pituitary macroadenoma: headache, bitemporal hemianopia (compression of optic chiasm), hypopituitarism (compression of normal pituitary).
- Diagnosis: MRI pituitary, α-subunit elevated.
The TSH Paradox
In virtually all thyrotoxicosis, TSH is suppressed by negative feedback. If you find elevated fT4 with a NORMAL or HIGH TSH, think of only two things: (1) TSH-secreting pituitary adenoma (TSHoma) — autonomous TSH production, or (2) Thyroid hormone resistance syndrome — mutations in thyroid hormone receptor → tissues are resistant → hypothalamus/pituitary don't "see" the high T4 → keep making TSH. The key distinguisher: TSHoma patients are clinically THYROtoxic; resistance syndrome patients are clinically EUthyroid (tissues are resistant, so high T4 doesn't cause symptoms) [2][10].
| Feature | Gestational Thyrotoxicosis | Graves' in Pregnancy |
|---|---|---|
| Timing | First trimester (peaks with hCG at 10–12 weeks) | Any trimester |
| Goitre | Absent or minimal | Present (diffuse) |
| Eye signs | Absent | May be present |
| TRAb | Negative | Positive |
| hCG | Very high (often associated with hyperemesis gravidarum, multiple gestation, or molar pregnancy) | Normal for gestational age |
| Course | Self-limiting — resolves as hCG falls in 2nd trimester | Persists; needs treatment |
| Treatment | Supportive (rehydration, antiemetics). ATDs NOT needed in most cases | PTU in 1st trimester, carbimazole/methimazole in 2nd/3rd trimester |
- hCG and TSH share a common α-subunit and have considerable β-subunit homology; thus hCG has a weak thyroid-stimulating effect [8].
- Marked overproduction of hCG (e.g., from hydatidiform mole, choriocarcinoma, testicular germ cell tumour) can cause overt thyrotoxicosis [8][11].
- Distinguished from Graves' by: male sex or obstetric history, very high serum hCG, negative TRAb, pelvic/testicular mass.
Amiodarone is 37% iodine by weight and has an extremely long half-life (~100 days). It can cause both hypo- AND hyperthyroidism.
| Feature | AIT Type 1 | AIT Type 2 |
|---|---|---|
| Mechanism | Iodine-induced hyperthyroidism (Jod-Basedow) in pre-existing thyroid autonomy (nodular goitre, latent Graves') | Direct thyrotoxic effect of amiodarone on thyrocytes → destructive thyroiditis → hormone leakage |
| Underlying thyroid | Abnormal (pre-existing nodular disease) | Normal |
| Goitre | Often present (nodular) | Normal or small |
| RAIU | Normal or increased | Low |
| Colour-flow Doppler USG | Increased vascularity | Decreased/absent vascularity |
| Treatment | Thionamides (± perchlorate to block iodine uptake) | Glucocorticoids (prednisone) |
| Mixed forms | Common in practice — treat with both thionamides AND steroids |
Why is colour-flow Doppler useful? Because it reflects whether the gland is actively producing hormone (increased blood flow = type 1) or passively leaking it from destruction (absent blood flow = type 2). This is particularly helpful when RAIU is unreliable (amiodarone's iodine load can suppress uptake even in type 1).
When approaching a thyroid swelling, the goitre classification provides a useful framework for differential diagnosis:
| Goitre Type | Causes |
|---|---|
| Simple goitre (endemic or sporadic) — diffuse | Iodine deficiency, physiological (puberty, pregnancy), goitrogens |
| Simple goitre — nodular | Multinodular goitre (non-toxic) |
| Toxic goitre — diffuse (Graves') | Autoimmune (TRAb) |
| Toxic goitre — nodular (Plummer's / TMNG) | Autonomous nodule(s) with activating mutations |
| Toxic / functioning adenoma | Single autonomous nodule |
| Neoplastic goitre — benign | Follicular adenoma |
| Neoplastic goitre — malignant | Papillary, follicular, medullary, anaplastic carcinoma, lymphoma |
| Thyroiditis | Bacterial (acute suppurative), viral (subacute/de Quervain's), lymphocytic/Hashimoto/autoimmune (chronic) [1] |
Around 10–15% of thyroid nodules are malignant [7]. When evaluating a thyroid nodule, the differential includes:
| Category | Differential |
|---|---|
| Solitary nodule | Dominant nodule in MNG; cyst (true simple cyst, colloid nodule); neoplastic (adenoma, toxic adenoma, carcinoma) [7] |
| Multiple nodules | MNG (hyperplastic/adenomatous nodules with varying cystic degeneration); toxic MNG; multiple cysts; multiple adenomas [7] |
| Diffuse | Graves' disease; physiological (pregnancy, puberty); Hashimoto's thyroiditis; de Quervain's / subacute thyroiditis [7] |
The functional status of the nodule (hot vs. cold) is assessed by thyroid scintigraphy (I-123 or Tc-99m), which is indicated when TSH is suppressed [1][7]:
- Hot nodules (hyperfunctioning) → almost never malignant → do NOT require FNAC [2][7]
- Cold nodules (hypofunctioning) → 10–20% risk of malignancy → require FNAC (if sonographic criteria met) [2][7]
PET CT has NO diagnostic role in thyroid diseases — even malignant nodules can have low uptake [7].
Why do hot nodules rarely harbour malignancy?
Hot nodules are actively taking up iodine and producing thyroid hormone — they are well-differentiated, functional thyroid tissue. Malignant cells (especially papillary and anaplastic carcinoma) are typically poorly differentiated and lose the ability to trap iodine efficiently, making them appear "cold" on scan. Therefore, a cold nodule is the one that worries you. However, note that most cold nodules are still benign (only 10–20% are malignant).
| Investigation | Graves' | TMNG | Toxic Adenoma | Subacute Thyroiditis | Silent Thyroiditis | Factitious | TSHoma |
|---|---|---|---|---|---|---|---|
| TSH | ↓↓ | ↓↓ | ↓↓ | ↓↓ | ↓↓ | ↓↓ | Normal/↑ |
| fT4 | ↑ | ↑ | ↑ | ↑ | ↑ | ↑ | ↑ |
| TRAb | + | − | − | − | − | − | − |
| Anti-TPO | +/− | −/+ | − | − | + | − | − |
| ESR | Normal | Normal | Normal | ↑↑↑ | Normal | Normal | Normal |
| Thyroglobulin | ↑ | ↑ | ↑ | ↑ | ↑ | ↓↓ | ↑ |
| RAIU | ↑ diffuse | ↑ patchy | ↑ focal | ↓↓ | ↓↓ | ↓↓ | ↑ |
| USG | Diffuse, hypervascular | Multiple nodules | Single nodule | Diffuse, hypoechoic | Diffuse, hypoechoic | Normal/small | Normal |
High Yield Summary
Differential Diagnosis of Thyrotoxicosis — Key Exam Points:
-
First confirm thyrotoxicosis biochemically (suppressed TSH, elevated fT4 ± fT3). Then determine the CAUSE.
-
The pivotal investigation is RAIU scan — separates HIGH uptake (true hyperthyroidism: Graves'/TMNG/toxic adenoma) from LOW uptake (thyroiditis/exogenous/factitious).
-
Graves' is distinguished by: diffuse goitre + bruit, ophthalmopathy, positive TRAb, diffusely increased RAIU.
-
Subacute thyroiditis is distinguished by: PAIN + tenderness, raised ESR, low RAIU, self-limiting triphasic course. ATDs are useless.
-
Factitious thyrotoxicosis has LOW thyroglobulin (all others have normal/high).
-
TSHoma is the ONLY cause where TSH is inappropriately normal/high with elevated fT4.
-
Hot nodules (on scintigraphy) are almost never malignant and do NOT need FNAC. Cold nodules carry 10–20% malignancy risk and require FNAC.
-
hCG can cross-stimulate TSH receptors → gestational thyrotoxicosis (physiological) or paraneoplastic thyrotoxicosis (germ cell tumours).
-
Amiodarone-induced thyrotoxicosis: Type 1 = iodine-induced (thionamides), Type 2 = destructive (steroids). Colour-flow Doppler helps differentiate.
-
On clinical examination, only 3 conclusions: thyroid nodule, multinodular goitre, or diffuse goitre — this guides the DDx pathway.
Active Recall - Differential Diagnosis of Hyperthyroidism
References
[1] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf (p4, p13) [2] Senior notes: felixlai.md (Sections II–III: Overview and Etiology; Section V: Diagnosis; Section VI: Treatment) [6] Senior notes: maxim.md (Phaeochromocytoma section) [7] Senior notes: maxim.md (Approach to thyroid nodules — Differential diagnosis) [8] Senior notes: felixlai.md (Testicular cancer — hCG and thyroid-stimulating effect) [9] Senior notes: felixlai.md (Thyroid examination — bruit, clinical conclusions) [10] Senior notes: felixlai.md (Pituitary adenoma — Thyrotroph adenoma / TSHoma) [11] Senior notes: maxim.md (Testicular cancer — clinical features: gynaecomastia/hyperthyroidism from hCG)
Diagnostic Criteria and Algorithm
Unlike many conditions (e.g., diabetes with its HbA1c thresholds or rheumatoid arthritis with its classification criteria), hyperthyroidism doesn't have a formal "points-based" diagnostic criteria system. Instead, the diagnosis is biochemical, confirmed by a specific pattern on thyroid function tests (TFTs), combined with clinical context to determine the aetiology.
Biochemical Definitions
| Category | TSH | Free T4 | Free T3 | Clinical Significance |
|---|---|---|---|---|
| Overt primary hyperthyroidism | ↓↓ (suppressed, typically < 0.1 mIU/L) | ↑ | ↑ | Full-blown thyrotoxicosis. Both synthesis pathways (T4 and T3) are in overdrive |
| T3 thyrotoxicosis | ↓↓ | Normal | ↑ | 2–5% of hyperthyroid patients have ONLY elevated fT3 [2]. Easy to miss if you don't check fT3. Common in early Graves' or toxic adenoma (preferential T3 secretion) |
| Subclinical hyperthyroidism | ↓ (suppressed) | Normal | Normal | TSH suppressed but thyroid hormones haven't crossed upper limit yet. Still clinically significant — associated with AF, osteoporosis, cardiovascular mortality |
| Secondary hyperthyroidism | Normal or ↑ (inappropriately) | ↑ | ↑ | TSH is NOT suppressed despite high T4/T3 → TSH-secreting pituitary adenoma or thyroid hormone resistance syndrome [2] |
Why is TSH the single best screening test?
TSH has a log-linear relationship with free T4 — even a small rise in free T4 produces a large fall in TSH. This amplification means TSH becomes abnormal BEFORE free T4 leaves the reference range, making it the earliest and most sensitive marker. TSH is the MOST sensitive indicator of thyroid function due to its short half-life — it reflects real-time pituitary sensing of circulating thyroid hormone [2].
Exam Pitfall: TSH Limitations
TSH should NOT be used as an isolated test in these situations [2]:
- Suspected or known pituitary disease — TSH may be normal despite central hypothyroidism or inappropriately normal in TSHoma.
- ↑ TSH alone may not necessarily indicate hypothyroidism — recovery phase of sick euthyroid syndrome, adrenal insufficiency.
- ↓ TSH alone may not necessarily indicate hyperthyroidism — first trimester of pregnancy (hCG stimulates TSH receptor by molecular mimicry), high-dose glucocorticoids, dopamine infusion, non-thyroidal illness [2].
T3 and T4 are highly protein-bound (>99% bound to thyroxine-binding globulin [TBG], thyroxine-binding prealbumin [transthyretin], and albumin). Only the free fraction is biologically active [2].
Total T3 or T4 are elevated when TBG is increased [2]:
- Pregnancy
- Oral contraceptives / oestrogen therapy
- Hepatitis (increased hepatic TBG synthesis)
Total T3 or T4 are reduced when TBG is decreased [2]:
- Androgens
- Hypoalbuminaemia (nephrotic syndrome, liver disease)
- Glucocorticoids
Free T3 and fT4 are normal in euthyroid patients with these conditions — hence free hormones are preferable over total thyroid hormones [2].
In short: always request free T4 and free T3 — total values are misleading in any condition that alters binding protein levels.
Both fT3 and fT4 levels are required to determine subclinical or overt hyperthyroidism because 2–5% of patients have ONLY elevated fT3 ("T3 thyrotoxicosis") [2]. This occurs because:
- In early Graves' disease and toxic adenoma, the hyperactive gland preferentially secretes T3 (which is 3–5× more biologically active).
- Peripheral conversion of T4→T3 is also upregulated.
- If you only check fT4, you'll miss these cases.
Conversely, in hypothyroidism, fT3 is NOT needed because fT3 can be normal in 25% of hypothyroid patients due to compensatory upregulation of deiodinase enzymes (adaptive peripheral T4→T3 conversion) [2].
Master Diagnostic Algorithm
The diagnostic approach follows a systematic, stepwise algorithm. Let me walk through the logic:
Measure TSH and free T4 [2]. This is the starting point for every patient with suspected thyroid dysfunction.
Four possible patterns emerge:
| Pattern | TSH | fT4 | Next Step |
|---|---|---|---|
| A | ↓ | ↑ | Primary thyrotoxicosis confirmed → proceed to aetiological workup |
| B | ↓ | Normal | Measure fT3 → if ↑: T3 thyrotoxicosis; if normal: subclinical hyperthyroidism |
| C | Normal or ↑ | ↑ | TSH-secreting pituitary adenoma or thyroid hormone resistance syndrome [2] |
| D | Normal | Normal | No thyroid dysfunction → no further tests needed |
This is where clinical assessment and targeted investigations come in:
- Are there features of Graves' disease? (diffuse goitre, bruit, ophthalmopathy, dermopathy) → If yes, the diagnosis is likely Graves' disease. Confirm with TRAb.
- If no Graves' features → Is there a nodular goitre or solitary nodule? → Consider toxic MNG or toxic adenoma. Confirm with radionuclide scan (scintigraphy) [1][2].
- If radionuclide uptake is low → Destructive thyroiditis, iodine excess, or exogenous thyroid hormone [2].
- If none of the above → Rule out other causes including stimulation by chorionic gonadotropin [2].
- TRAb positive → Graves' disease (no further imaging needed for diagnosis)
- RAIU scan → Distinguishes Graves' (diffuse ↑) vs. TMNG (patchy ↑) vs. toxic adenoma (focal hot nodule) vs. thyroiditis (↓)
- ESR markedly elevated + tender thyroid → Subacute thyroiditis
- Low thyroglobulin + low RAIU → Factitious thyrotoxicosis
- Inappropriately normal/high TSH → MRI pituitary for TSHoma
Investigation Modalities — Detailed Guide
A. Biochemical Tests
This is the foundation of thyroid diagnosis.
| Test | What It Tells You | Key Interpretive Points |
|---|---|---|
| TSH | Most sensitive indicator of thyroid function [2] | Suppressed in primary thyrotoxicosis. Normal/elevated in TSHoma or resistance. Do NOT use TSH to monitor treatment response — it can remain suppressed for several months after starting ATDs. Use fT4/fT3 instead [2] |
| Free T4 | Degree of thyrotoxicosis | Elevated in overt disease. Normal in T3 thyrotoxicosis and subclinical disease |
| Free T3 | Catches T3 thyrotoxicosis | Needed because 2–5% have only elevated fT3 [2]. Also useful to gauge severity — disproportionately elevated fT3 relative to fT4 suggests Graves' (preferential T3 secretion) |
Monitoring Pitfall
Do NOT use TSH level to monitor response to treatment since it can remain suppressed for several months after starting antithyroid drugs [2]. The pituitary thyrotrophs have been suppressed for so long that they take time to "wake up." Instead, monitor fT4 and fT3 to assess response. TSH may take 6–8 weeks (or longer) to normalise.
- Baseline before starting thionamides (carbimazole/methimazole, PTU).
- Why? Because thionamides can cause agranulocytosis (absolute neutrophil count < 500/μL) — a rare (0.1–0.5%) but potentially fatal adverse effect. You need a baseline WBC/neutrophil count to compare against.
- Thyrotoxicosis itself can cause mild neutropenia and relative lymphocytosis.
- Baseline before starting thionamides.
- Why? Thionamides can cause hepatotoxicity — PTU more so (hepatocellular pattern, can cause fulminant liver failure); carbimazole/methimazole (cholestatic pattern, usually milder).
- Graves' disease itself may cause mildly deranged LFTs (hepatic congestion from high-output state, or direct T3 effect on hepatocytes).
Three key antibodies to know:
| Antibody | What It Detects | Clinical Utility |
|---|---|---|
| Thyrotropin receptor antibodies (TRAb / Anti-TSH receptor antibodies) | Autoantibodies that stimulate (TSI) or block the TSH receptor | Diagnostic of Graves' disease — positive in 80–90% of Graves' [2]. Also used in pregnancy to assess risk of neonatal thyrotoxicosis (TRAb crosses placenta) |
| Anti-thyroid peroxidase (Anti-TPO) antibodies | Autoantibodies against TPO enzyme | 50–80% positive in Graves'; 90–100% positive in Hashimoto's [2]. Present in 10–15% of normal population. Marker of autoimmune thyroid disease generally |
| Anti-thyroglobulin (Anti-TG) antibodies | Autoantibodies against thyroglobulin | 50–70% positive in Graves'; 80–90% positive in Hashimoto's [2]. Important because they can interfere with thyroglobulin assays (relevant for thyroid cancer follow-up) |
Interpretation summary table [2]:
| Anti-TSH (TRAb) | Anti-TPO | Anti-TG | |
|---|---|---|---|
| Normal population | 0% | 10–15% | 10–20% |
| Graves' disease | 80–90% | 50–80% | 50–70% |
| Hashimoto's thyroiditis | 10–20% | 90–100% | 80–90% |
| Multinodular goitre | 10–20% | 10–20% | 30–40% |
Clinical pearl: If you have classic clinical Graves' (diffuse goitre + bruit + ophthalmopathy) AND positive TRAb, you have your diagnosis and do NOT necessarily need a RAIU scan. TRAb is highly specific. However, if TRAb is negative and the diagnosis is unclear, RAIU scan becomes essential.
| Test | When to Order | Rationale |
|---|---|---|
| ESR / CRP | Painful thyroid | Markedly elevated in subacute (de Quervain's) thyroiditis. Normal in Graves'/TMNG |
| Thyroglobulin | Suspected factitious thyrotoxicosis | Low in exogenous T4 ingestion (gland suppressed). High/normal in all other causes |
| Serum calcium | All thyrotoxicosis, pre-operatively | Thyrotoxicosis increases bone turnover → mild hypercalcaemia in ~10%. Also baseline for post-surgical hypoparathyroidism risk |
| hCG | Pregnancy, suspected gestational thyrotoxicosis, young male with thyrotoxicosis | hCG cross-stimulates TSH receptor. Very high in molar pregnancy, choriocarcinoma, testicular GCT |
| Serum calcitonin | Suspected medullary thyroid carcinoma (MTC) | 95% of MTC produce calcitonin. NOT relevant for hyperthyroidism per se, but part of thyroid nodule workup |
B. Radiological / Imaging Investigations
USG is a routine investigation for all patients with a goitre or palpable thyroid nodule [1][7].
Characteristics of USG:
- Non-invasive, no radiation, convenient and cheap [1]
- Highly sensitive but relatively low specificity [1]
Roles of thyroid USG [7]:
- Assess thyroid gland size (goitre)
- Assess nodules: number, size, and suspicious features
- Assess cervical lymph nodes (especially deep nodes, e.g., level VI nodes)
- Assess retrosternal extension
- Guide FNAC
- Extend physical examination [1]
- NOT recommended as a screening test in the general population [1]
USG Findings in Hyperthyroidism by Cause:
| Cause | USG Findings |
|---|---|
| Graves' disease | Diffusely enlarged, hypoechoic gland ("thyroid inferno" on colour-flow Doppler = markedly increased vascularity). No discrete nodules |
| Toxic MNG | Multiple nodules of varying size, echogenicity, and cystic degeneration |
| Toxic adenoma | Single, well-defined nodule; may be hyper- or isoechoic; surrounding gland often atrophic |
| Subacute thyroiditis | Diffusely hypoechoic, heterogeneous; focal hypoechoic areas corresponding to inflammation. Reduced vascularity on Doppler |
Sonographic features suspicious of malignancy (relevant when evaluating nodules found incidentally in hyperthyroid patients) — mnemonic: "SHIT CME" [7]:
- S = Solid nodule
- H = Hypoechoic
- I = Irregular margin
- T = Taller than wide (AP > transverse)
- C = Chaotic central vascularity
- M = Microcalcifications
- E = Extrathyroidal extension
Most important features: solid AND hypoechoic [7]
Sonographic features of malignant lymph nodes [2]:
- Large > 2 cm
- Roundish (taller than wide)
- Heterogeneous hypoechoic
- Loss of central fatty hilum
- Presence of microcalcification
- Intranodal cystic or coagulative necrosis
USG Risk Stratification for FNAC (ATA 2015 Guidelines):
| Sonographic Pattern | USG Features | Risk of Malignancy | FNA Size Cut-off |
|---|---|---|---|
| High suspicion | Solid hypoechoic + ≥ 1 suspicious feature (microcalcifications, irregular margins, taller than wide, ETE, rim calcification with extrusive soft tissue) | > 70–90% | ≥ 1 cm [2][7] |
| Intermediate suspicion | Hypoechoic solid nodule WITHOUT suspicious features | 10–20% | ≥ 1 cm [2][7] |
| Low suspicion | Isoechoic / hyperechoic solid nodule, or partially cystic with eccentric solid areas, WITHOUT suspicious features | 5–10% | ≥ 1.5 cm [2][7] |
| Very low suspicion | Partially cystic nodule without suspicious features, spongiform | ≤ 3% | ≥ 2 cm or observe [7] |
| Benign | Purely cystic nodules | ≤ 1% | No biopsy [7] |
Isotopes used: I-123, Tc-99m pertechnetate, or I-131 [1]
NOT recommended for routine diagnostic use [2]. This is important — you don't order a scan on everyone.
- Patient with a thyroid nodule AND suppressed TSH — to determine if the nodule is hyperfunctioning ("hot")
- Differentiate between causes of thyrotoxicosis when clinical assessment and TRAb are inconclusive
- Patient with MNG — to determine functional status of each nodule (which are hot, which are cold)
- Differentiate toxic nodule (→ hemithyroidectomy) vs toxic MNG / Graves' (→ total thyroidectomy) [7]
NOT performed when TSH is normal or elevated — because in a euthyroid or hypothyroid patient, a nodule will never be hyperfunctioning, and USG ± FNAC is the appropriate pathway [2].
Interpretation:
| Scan Pattern | Uptake | Diagnosis | Next Step |
|---|---|---|---|
| Diffusely increased uptake | High, uniform | Graves' disease [1] | TRAb confirmation; treat medically or RAI/surgery |
| Patchy / multifocal increased uptake | Heterogeneous | Toxic multinodular goitre [1] | Cold nodules in the MNG → FNAC |
| Single hot nodule with suppressed surrounding tissue | Focal high uptake | Toxic adenoma [1] | Hot nodules do NOT require FNAC [2] — treat as toxic adenoma |
| Low / absent uptake | Globally reduced | Thyroiditis, exogenous T4, iodine excess | ESR, thyroglobulin, drug history |
| Single cold nodule | Reduced focal uptake | Possible malignancy | Cold nodules have 10–20% risk of cancer → require FNAC [2] |
Radio-isotope scintigraphy — diagnosis of malignancy: low sensitivity and specificity [1]. Its value is NOT in diagnosing cancer — it's in functional assessment of thyrotoxic patients.
Why do hot nodules NOT require FNAC?
Hot (hyperfunctioning) nodules are actively trapping iodine and producing thyroid hormone — this means they are well-differentiated, functional thyroid tissue. Cancer cells are typically poorly differentiated, lose iodine-trapping ability, and appear "cold." The risk of malignancy in a hot nodule is < 1%. Performing FNAC on a hot nodule wastes resources and can give misleading results (follicular cells from a functioning adenoma can look atypical).
Not routine. Selective indications [7]:
- Retrosternal goitre — USG cannot visualise below the thoracic inlet; CT delineates the retrosternal extent, relationship to great vessels, tracheal compression/deviation [7]
- Locally advanced thyroid cancer — CT with contrast for better delineation of important structures within the cervical fascial planes (carotid sheath, oesophagus, trachea, recurrent laryngeal nerve involvement) [7]
- Surgical planning for large goitres
Retrosternal goitre requires CT because: (1) Cannot be visualised by USG, (2) Surgical planning, (3) Retrosternal goitre may be malignant [7]
Caution: Iodinated CT contrast can exacerbate thyrotoxicosis (Jod-Basedow) or interfere with subsequent RAI therapy (saturates iodine stores). Must wait ≥ 4–6 weeks after iodinated contrast before RAI therapy or RAIU scan.
PET CT has NO diagnostic role in thyroid diseases — even malignant nodules can have low uptake [7].
- PET incidentalomas (incidentally found thyroid uptake on PET) do warrant workup (thyroid FDG uptake has ~30–50% malignancy rate), but PET is NOT ordered primarily to evaluate thyroid pathology.
- Assess tracheal deviation/compression from goitre
- Evaluate for retrosternal extension
- Baseline before RAI therapy or surgery
- Pre-operative vocal cord assessment — flexible nasopharyngoscopy to document baseline vocal cord function before thyroid surgery. If a patient already has vocal cord paralysis pre-operatively (from tumour invasion of RLN), the surgeon must know to preserve the contralateral nerve.
FNAC is a routine investigation for thyroid nodules meeting certain criteria [1].
Key principle: Core needle biopsy is NOT performed on the thyroid because it can lead to massive bleeding (thyroid is extremely vascular) and FNAC is very accurate in identifying thyroid cancer types [2].
FNAC is both diagnostic and therapeutic for thyroid cysts [7] — aspiration collapses the cyst.
Indications for FNAC [2]:
- Nodules meeting sonographic criteria for FNA (see USG risk stratification table above)
- Hypofunctioning ("cold") nodules on scintigraphy
- Dominant or atypical nodule in a multinodular goitre
- Nodules associated with abnormal lymph nodes
- Complex or recurrent cystic nodules
NOT indicated:
- Hot nodules on scintigraphy (almost never malignant)
- Purely cystic nodules (benign, ≤ 1% malignancy)
Limitation: Cannot distinguish follicular adenoma from follicular carcinoma — because the distinction requires demonstration of capsular/vascular invasion on histology, which FNAC (cytology only) cannot assess. This is why Bethesda Class IV ("follicular neoplasm") requires surgical excision (lobectomy) for definitive diagnosis [7].
Complications of FNAC: pain, bleeding, false negative [7]
The Bethesda System for Reporting Thyroid Cytopathology standardises FNAC results into 6 categories with corresponding malignancy risk and recommended management:
| Class | Diagnostic Category | Cancer Risk | Recommended Management |
|---|---|---|---|
| I | Non-diagnostic / Unsatisfactory | 1–4% | Repeat FNA (under USG guidance) |
| II | Benign | 0–3% | Clinical follow-up (repeat USG in 12–24 months) |
| III | Atypia of Undetermined Significance (AUS) OR Follicular Lesion of Undetermined Significance (FLUS) | 5–15% | Repeat FNA (consider molecular testing if available) |
| IV | Follicular Neoplasm / Suspicious for Follicular Neoplasm | 15–30% | Surgical lobectomy (need histology to distinguish adenoma from carcinoma) |
| V | Suspicious for Malignancy | 60–75% | Surgical lobectomy ± frozen section → total thyroidectomy |
| VI | Malignant | 97–99% | Total thyroidectomy (± neck dissection) |
Note: Bethesda Class III "atypia" is a morphological description rather than a premalignant lesion [7]. It represents indeterminate cytology that doesn't fit neatly into benign or suspicious categories.
Approach to multiple nodules [7]:
- Malignancy risk is much lower in multinodular goitres
- USG: assess each nodule separately
- FNAC decision depends on USG result:
- If no suspicious nodules → FNA the largest nodule
- If any suspicious nodules → FNA all suspicious nodules
Graves' ophthalmopathy is graded using the "NO SPECS" scoring system [2]:
| Grade | Category | Features |
|---|---|---|
| 0 | No signs and symptoms | — |
| 1 | Only signs, no symptoms | Lid retraction and lid lag (result of excess sympathetic activity — not specific to Graves') → staring appearance [2] |
| 2 | Soft tissue involvement | Periorbital oedema |
| 3 | Proptosis | Best detected by visualising sclera between lower border of iris and lower eyelid [2] |
| 4 | Extraocular muscle involvement | Diplopia/ophthalmoplegia — inferior rectus affected first, then goes anticlockwise (IR → MR → SR → LR) [2] |
| 5 | Corneal involvement | Corneal ulceration, scleral injection, chemosis, conjunctivitis |
| 6 | Sight loss | Compression of CN II → papilloedema, peripheral field defects, blindness [2] |
Investigations for ophthalmopathy: CT or MRI orbits (shows enlarged extraocular muscles, proptosis, increased retro-orbital fat), visual acuity and colour vision testing, formal perimetry, Hertel exophthalmometry.
High Yield Summary
Diagnosis of Hyperthyroidism — Key Exam Points:
-
TSH is the single most sensitive screening test. Suppressed TSH = suspect primary hyperthyroidism. Normal/high TSH with elevated fT4 = TSHoma or resistance.
-
Always measure BOTH fT4 AND fT3 — 2–5% have only elevated fT3 ("T3 thyrotoxicosis").
-
Measure FREE (not total) T4 — total T4 is misleading when binding proteins are altered (pregnancy, OCP, hypoalbuminaemia).
-
Do NOT use TSH to monitor treatment — it remains suppressed for months. Use fT4/fT3 instead.
-
TRAb is 80–90% sensitive for Graves' and is the key serological differentiator.
-
RAIU scan is NOT routine — indicated ONLY when TSH is suppressed AND you need to distinguish the cause (especially Graves' vs TMNG vs toxic adenoma vs thyroiditis).
-
Hot nodules do NOT require FNAC (< 1% malignancy). Cold nodules require FNAC (10–20% malignancy risk).
-
Routine investigations: TFT + USG thyroid ± FNAC. Selective: thyroid scan, CT, PET (PET has NO diagnostic role).
-
Bethesda system: 6 categories. Class IV (follicular neoplasm) requires lobectomy because FNAC cannot distinguish follicular adenoma from carcinoma (needs capsular/vascular invasion on histology).
-
Pre-ATD baseline: Always check CBC (agranulocytosis risk) and LFT (hepatotoxicity risk) before starting thionamides.
Active Recall - Diagnosis of Hyperthyroidism
[1] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf (p7, p8, p12, p13) [2] Senior notes: felixlai.md (Sections V–VII: Diagnosis, Treatment, Case Study; thyroid antibody table; Bethesda classification; radionuclide scan indications; TFT interpretation) [7] Senior notes: maxim.md (Approach to thyroid nodules: investigations, USG features, FNAC indications, thyroid scan, CT/PET roles, Bethesda classification, SHIT CME mnemonic)
Management of Hyperthyroidism
Before diving into specifics, let's understand the framework. Managing hyperthyroidism involves three layers:
- Immediate symptomatic relief — beta-blockers (works within hours to days)
- Definitive treatment of the underlying cause — antithyroid drugs (ATDs), radioactive iodine (RAI), or surgery (the "Big Three")
- Emergency management — thyroid storm (a medical emergency)
The choice among the Big Three depends on the aetiology, severity, patient factors (age, pregnancy, comorbidities), and patient preference. There is no single "best" treatment — it's a discussion.
Why beta-blockers? Thyroid hormones upregulate β-adrenergic receptors, amplifying the effect of circulating catecholamines. Beta-blockers directly counteract this — they don't affect thyroid hormone levels but dramatically improve symptoms.
| Drug | Dose | Key Points |
|---|---|---|
| Propranolol | 40 mg TDS [7] | The classic choice. Non-selective β-blocker. Additional benefit: blocks peripheral conversion of T4→T3 (unique among beta-blockers — inhibits type 1 deiodinase). Provides more rapid clinical response (days instead of weeks) compared to ATDs alone [7]. Continue propranolol until 7 days post-op because T4 levels remain high immediately after surgery [7] |
| Atenolol | 50–100 mg OD | Selective β1-blocker. Useful when propranolol is contraindicated (e.g., asthma — but even atenolol should be used cautiously in severe asthma) |
| Diltiazem | Variable | Consider if β-blockers are contraindicated (e.g., severe asthma, decompensated heart failure) [2]. Non-dihydropyridine calcium channel blocker that controls heart rate |
Why propranolol specifically?
All beta-blockers reduce heart rate and tremor. But propranolol has a unique pharmacological advantage: it inhibits the type 1 deiodinase enzyme that converts T4→T3 peripherally. Since T3 is 3–5× more active than T4, blocking this conversion provides additional clinical benefit beyond simple β-blockade. This is why propranolol is preferred over atenolol in thyrotoxicosis.
Layer 2: Definitive Treatment — The Big Three
Drugs: Carbimazole (prodrug, converted to methimazole in vivo) / Methimazole / Propylthiouracil (PTU)
Etymology: "Thio-" = sulphur (these drugs contain a thioureylene group); "-namide" = amide derivative
Mechanism of action [2]:
- Inhibit the action of thyroid peroxidase (TPO):
- Inhibit iodination (organification) of tyrosine residues on thyroglobulin
- Inhibit coupling of iodotyrosines (MIT+DIT→T3, DIT+DIT→T4)
- Net effect: block production of T3 and T4
- PTU additionally inhibits peripheral conversion of T4→T3 (via type 1 deiodinase inhibition) — this makes PTU the preferred drug in thyroid storm and first trimester of pregnancy
Why is onset slow? The thyroid gland stores 2–3 months' worth of preformed hormone. ATDs block new synthesis but don't affect the already-stored hormone. Onset of euthyroid takes 3–4 weeks since the thyroid gland has a large storage of hormones that need to be depleted before manifestation of drug effects [2].
Treatment protocol [2]:
- High dose initially (e.g., carbimazole 30–40 mg/day) to block synthesis quickly
- Reduction of dose when patient becomes euthyroid (e.g., carbimazole 5–15 mg/day maintenance)
- Therapy given for 12–18 months [2]
- Two strategies:
- Titration regimen ("dose-adjust"): Start high, reduce to lowest dose that maintains euthyroidism. Fewer side effects.
- Block-and-replace regimen: High-dose ATD (blocks all synthesis) + levothyroxine replacement simultaneously. Advantage: more stable TFTs. Disadvantage: higher drug dose → more side effects.
Indications [2]:
- Children
- Pregnancy (PTU in first trimester; carbimazole/methimazole in 2nd/3rd trimester)
- Mild disease
- First-line for Graves' disease [7]
- Patients who prefer non-invasive treatment
- Bridge to RAI or surgery
Adverse effects [2]:
| Adverse Effect | Frequency | Mechanism / Details |
|---|---|---|
| Skin rash / urticaria / pruritus | ~5% | Allergic reaction — triggers histamine release. Treated with antihistamine [2] |
| Fever | Uncommon | Hypersensitivity |
| Arthritis / arthralgia | Uncommon | Immune-mediated |
| Agranulocytosis | 0.1–0.5% | Occurs within the first 2–3 months of treatment [2]. Idiosyncratic, dose-related for methimazole. Potentially fatal — patients must be educated to stop the drug immediately and present for urgent FBC if they develop fever, sore throat, or mouth ulcers |
| Hepatotoxicity | Rare | PTU → hepatocellular necrosis (can be fulminant — why PTU is used only in 1st trimester, not long-term). Carbimazole/methimazole → cholestatic pattern (usually milder) |
Baseline CBC with differentials and LFT must be checked before starting thionamides [2] — to detect pre-existing cytopaenias or liver disease, and to have a comparison point if toxicity develops.
Carbimazole vs. PTU — When to Use Which?
| Scenario | Drug of Choice | Reason |
|---|---|---|
| Standard Graves' treatment | Carbimazole/methimazole | Once-daily dosing, better compliance, lower hepatotoxicity risk |
| 1st trimester of pregnancy | PTU | Methimazole is associated with rare embryopathy (aplasia cutis, choanal/oesophageal atresia). PTU crosses placenta less |
| 2nd/3rd trimester of pregnancy | Switch to carbimazole | PTU has higher risk of hepatotoxicity with prolonged use |
| Thyroid storm | PTU | Additional benefit of blocking peripheral T4→T3 conversion |
| Cross-reactivity allergy | ~30% cross-react between carbimazole and PTU. If severe allergy to one, the other may also cause reactions — consider RAI or surgery |
Relapse rate: High — approximately 70% relapse after 1 year of stopping ATDs [2]. This is because ATDs do not address the underlying autoimmune process (TRAb production continues). Favourable prognostic factors for sustained remission: small goitre, mild disease, declining TRAb levels during treatment, short duration of disease.
How it works: I-131 is taken up and processed by the thyroid gland in the same way as normal iodide — via the sodium-iodide symporter (NIS). Its specificity to the thyroid is due to preferential thyroid uptake via the Na-I cotransporter [2]. Once inside follicular cells, it becomes incorporated into thyroglobulin and emits β-radiation locally → destruction of thyroid gland through necrosis of follicular cells [2]. The β-particles have a short range (~2 mm), so damage is confined to the thyroid with minimal systemic radiation.
- Refractory to antithyroid medications
- Relapse after ATD course (most common scenario)
- 2nd-line for Graves' disease [7]
- Preferred for toxic MNG if no 4C indications [7]
- Ablation of residual tumour tissue after thyroidectomy (for thyroid cancer — different context)
- Refused surgery / poor surgical candidate
Contraindications [2]:
- Pregnancy and lactation — damage to fetal thyroid gland (fetal thyroid concentrates iodine from ~12 weeks gestation); secreted in breastmilk [2]
- Children and adolescents — avoid potential teratogenicity in young age [2]
- Active Graves' ophthalmopathy — RAI can worsen eye disease (proposed mechanism: release of thyroid antigens from destroyed gland → immune flare → orbital inflammation). If RAI is necessary in a patient with mild/inactive ophthalmopathy, steroid cover is given.
- Very large goitre (poor response; may need surgery instead)
- Suspected thyroid malignancy (need histological diagnosis first)
Important reassurances for patients [2]:
- NO effect on fertility
- NO effect on congenital malformations in future offspring
- NO increased cancer risk in offspring
Preparation and precautions for I-131 therapy [2]:
Before RAI:
- Discussion of treatment options and patient consent
- Instruct patients on post-therapy precautions and follow-ups
- Avoid iodine-containing food, medicine (cough suppressants with iodine), or radiological contrast for ≥ 4 weeks before RAI — excess stable iodine competes with I-131 for uptake, reducing efficacy
- Avoid antithyroid medications for ≥ 4 weeks before RAI — ATDs reduce iodine organification, which reduces I-131 retention in the gland
- Symptomatic control of hyperthyroidism by propranolol during the waiting period
- Pregnancy test for patients with child-bearing potential
After RAI:
- Symptomatic control of hyperthyroidism by propranolol (RAI takes 2–3 months to work)
- Discharge home immediately and avoid close contact with others (radiation precautions for ~1–2 weeks depending on dose)
- Safe contraception for ≥ 6 months
- Avoid pregnancy and breastfeeding for ≥ 6 months [2]
Adverse effects / Complications [2]:
- Hypothyroidism:
- Radiation thyroiditis (transient worsening of thyrotoxicosis 1–2 weeks post-RAI due to release of stored hormone from damaged follicles)
- Sialadenitis (salivary gland inflammation — salivary glands also have NIS)
- Theoretical concern about worsening Graves' ophthalmopathy (mitigated by steroid prophylaxis)
Onset of therapeutic effect: Months (2–3 months) [2]. This is why beta-blockers are essential during the interim.
Indications for thyroidectomy — commonly remembered as "4C" [7]:
| Indication | Explanation |
|---|---|
| CA thyroid (Cancer) | Malignancy confirmed or highly suspected on FNAC |
| Uncontrolled thyrotoxicosis (Cannot control) | Refractory to antithyroid medications, refused RAI [2], or need for rapid definitive control |
| Compression | Obstructive goitre — dysphagia, stridor, tracheal deviation, retrosternal extension [1][2] |
| Cosmetic concern | Large visible goitre causing distress to the patient [1] |
Additional indications [2]:
- Pregnant women intolerant to antithyroid medications
- Thyroid-eye signs (active Graves' ophthalmopathy) — surgery preferred over RAI because RAI can worsen ophthalmopathy [2]
- Multinodular goitre (regardless of thyroid status, if compression/cancer concern) [2]
Extent of resection [7]:
| Condition | Solitary Nodule | Multinodular |
|---|---|---|
| Euthyroid | Observe; Hemithyroidectomy if 4C | Observe; Total thyroidectomy if 4C |
| Hyperthyroid | Hemithyroidectomy | Total thyroidectomy |
Specifically for thyrotoxicosis [7]:
- Graves' disease: Total thyroidectomy recommended (preferred over subtotal) [7]
- Toxic MNG: Total thyroidectomy [7]
- Toxic adenoma: Hemithyroidectomy (if no evidence of nodules in contralateral lobe) [7]
Why total thyroidectomy for Graves' rather than subtotal? [7]:
| Feature | Total Thyroidectomy | Subtotal Thyroidectomy |
|---|---|---|
| Return to euthyroid | Immediate | Variable duration |
| Risk of recurrence | None | 5–20% (residual tissue still has TRAb stimulation) |
| Risk of thyroid failure | 100% (lifelong T4 replacement) | Lower but still significant |
| Risk of parathyroid injury | Higher | Lower |
| Risk of RLN injury | Higher | Lower |
The trade-off is clear: total thyroidectomy eliminates recurrence risk entirely but commits the patient to lifelong levothyroxine and carries higher surgical morbidity. In experienced hands, complication rates are low, making total thyroidectomy the preferred choice [7].
Surgical types — Terminology [7]:
- Total thyroidectomy: resection of both lobes + isthmus + pyramidal lobe
- Subtotal thyroidectomy: resection of > 1/2 of both lobes + isthmus (rarely indicated [1])
- Hemithyroidectomy: resection of one lobe + isthmus
- Lobectomy: resection of one lobe (isthmus preserved)
For benign thyroid nodules (non-toxic) [1]:
- Unilateral lobectomy (hemithyroidectomy): for uninodular goitre — safe, minimal morbidities, diagnosis and cure, future reoperation on contralateral lobe without difficulty. Around 10–20% chance of hypothyroidism [1]
- Total/near-total thyroidectomy: for symptomatic multinodular goitre — no recurrence/need for reoperation, additional surgical risk (hypoparathyroidism), needs long-term thyroxine replacement [1]
- Partial or bilateral subtotal thyroidectomy: rarely indicated [1]
Mechanism: Removal of the thyroid gland to lower thyroid hormone level [2]. Straightforward — physically remove the source.
Complications of thyroid surgery [2]:
| Complication | Mechanism | Prevention/Management |
|---|---|---|
| Hypoparathyroidism | Inadvertent removal or devascularisation of parathyroid glands (they're tiny, ~5 mm, on the posterior thyroid surface) → hypocalcaemia | Pre-op calcium/vitamin D supplementation. Post-op: monitor Ca²⁺. Treat with IV calcium gluconate if symptomatic (Chvostek's/Trousseau's sign) |
| Vocal cord paralysis | Injury to recurrent laryngeal nerve (RLN) → unilateral: hoarseness; bilateral: airway obstruction | Pre-op laryngoscopy to document baseline vocal cord function. Meticulous surgical technique. Intraoperative nerve monitoring |
| Thyroid storm | Manipulation of gland during surgery → massive hormone release into circulation | Patients should be brought to euthyroid before surgery [2] |
| Haemorrhage | Thyroid is highly vascular. Post-op haematoma can compress trachea → airway compromise | Hemorrhage — compression and oedematous effect compresses on trachea [2]. Emergency: open wound at bedside, evacuate haematoma |
| Hypothyroidism | Loss of functioning thyroid tissue | Planned: T4 replacement after total thyroidectomy. Monitor TSH at 6 weeks post-hemi |
| Wound infection | Any surgical wound | Standard aseptic technique |
| Hungry bone syndrome | Sudden removal of PTH/thyroid hormone effect → massive calcium influx into bones → severe hypocalcaemia | Pre-op calcium/vitamin D supplementation |
This is critically important and frequently tested. Operating on a thyrotoxic patient risks precipitating a thyroid storm.
Goal: Maintain biochemically euthyroid at operation to prevent thyroid storm [7]:
-
High-dose carbimazole (30–40 mg/day) for 8–12 weeks, then low dose (15 mg/day) to maintain euthyroid [7]
-
Propranolol (40 mg TDS): blocks beta receptors + reduces T4→T3 conversion [7]
-
Lugol's iodine: decreases iodine uptake + decreases vascularity of thyroid gland (decreases intra-operative bleeding) [7]
- Can be given with carbimazole/beta-blocker for 10 days before operation [7]
- Mechanism: The Wolff-Chaikoff effect — acute iodine excess transiently inhibits organification and hormone release. Additionally, excess iodine reduces thyroid blood flow.
-
Monitor Ca and vitamin D level and supplement accordingly (for post-op hypoPTH/hungry bone syndrome) [7]
-
Vocal cord function by laryngoscopy [7] — document baseline before surgery
Why Lugol's Iodine BEFORE Surgery?
Lugol's iodine (potassium iodide + iodine) serves a dual purpose pre-operatively: (1) it exploits the Wolff-Chaikoff effect — flooding the gland with iodine transiently inhibits hormone synthesis and release; (2) it reduces thyroid vascularity, making the gland less engorged and easier/safer to operate on with less bleeding. It is given for 10 days before surgery. It is NOT given alone (must be combined with ATDs) because the Wolff-Chaikoff effect is temporary and the gland can "escape" — resuming hormone production despite excess iodine.
Management by Aetiology — Summary
| Line | Treatment | Details |
|---|---|---|
| 1st line | Antithyroid drugs | Carbimazole 12–18 months. ~30% achieve sustained remission. ~70% relapse [2][7] |
| 2nd line | RAI | Preferred if no active ophthalmopathy and no 4C [7]. Steroid cover for mild/inactive eye disease |
| 2nd line | Surgery (total thyroidectomy) | Preferred if 4C present or active Graves' ophthalmopathy [7] |
| Line | Treatment | Details |
|---|---|---|
| ATDs | Ineffective long-term | Recur upon discontinuation [7]. Can be used for prolonged course if patient does not want RAI or surgery |
| Preferred | RAI | Preferred if no 4C [7] |
| Preferred | Surgery (total thyroidectomy) | Preferred if 4C [7] |
Why are ATDs ineffective for toxic MNG? Because TMNG is caused by autonomous somatic mutations in the TSH receptor — there is no autoimmune process to "burn out." Unlike Graves' (where TRAb may fluctuate and remission can occur), the autonomous nodules never stop producing. ATDs mask the problem but don't fix it. Stop the drug, and the thyrotoxicosis returns.
- Hemithyroidectomy — removes the single autonomous nodule, preserves the contralateral lobe [7]
- Alternative: RAI (if not surgical candidate)
- ATDs: temporary bridge only
- No ATDs (gland is not overproducing — it's leaking)
- Beta-blockers for symptomatic relief
- NSAIDs for mild pain; prednisolone for severe pain/inflammation
- Self-limiting: thyrotoxic phase → hypothyroid phase → recovery
Treat if:
- TSH persistently < 0.1 mIU/L
- Age > 65 (risk of AF, osteoporosis)
- Presence of symptoms, AF, osteoporosis, or cardiac risk factors
- Postmenopausal women (osteoporosis risk)
Otherwise: monitor with serial TFTs every 3–6 months.
| Feature | Surgery | Antithyroid Drugs | RAI (I-131) |
|---|---|---|---|
| Relapse rate | Low | High (70% after 1 year) | Low / Intermediate |
| Risk of hypothyroidism | Intermediate / High | Low | Intermediate / High (10–15% in first 2 years, 3%/year thereafter) |
| Other long-term complications | Significant morbidity (RLN, hypoPTH) | Rare | Rare |
| Ease of treatment and cost | Intermediate | Least favourable (long-term compliance) | Simple and easy |
| Onset of therapeutic effect | Immediate | Days / Weeks | Months (2–3 months) |
This is an emerging option for selected patients:
- Volume reduction rate (VRR): 50–80% [1]
- Patient selection: symptomatic / single / hyperfunctioning nodule; < 4 cm or < 20 mL / growth on sonogram; benign (FNAC ×2); motivated patients [1]
- Expectations: preserve function, minimally invasive, avoiding GA, day procedure, scarless, cosmetic outcome [1]
- Limitations: not cure, unsatisfactory shrinkage, regrowth, additional procedure, risk unique to ablation, expense [1]
- Modalities include: radiofrequency ablation (RFA), laser ablation, ethanol ablation (for cysts), high-intensity focused ultrasound (HIFU)
Thyroid storm (thyrotoxic crisis) is a life-threatening, decompensated thyrotoxicosis with multi-organ dysfunction.
Pathophysiology [2]:
- Develops in patients with longstanding untreated hyperthyroidism precipitated by an acute event such as surgery, trauma, or infection
- Rapid increase in serum thyroid hormone levels → increased response to sympathetic inputs from catecholamines (adrenaline/noradrenaline) by permissive effect
- Leads to cardiovascular symptoms including hyperpyrexia, tachycardia, hypertension, followed by heart failure with hypotension and arrhythmia [2]
Diagnosis: Clinical — use the Burch-Wartofsky Point Scale (BWPS) (scores > 45 highly suggestive of thyroid storm). Based on: temperature, CNS effects, GI-hepatic dysfunction, tachycardia, heart failure, AF, precipitant history.
General measures [2]:
- Correction of hyperthermia with paracetamol (NOT salicylate) and physical cooling [2]
- Why NOT salicylate (aspirin)? Salicylates displace T4 from TBG → increase free T4 → worsen thyrotoxicosis
- Correction of dehydration with IV fluid replacement
- Supportive therapy: O₂ supplementation, digoxin or diuretics for congestive heart failure and AF [2]
- Treat the precipitant (antibiotics for infection, etc.)
Medical treatment [2]:
Step 1 — Initial regimen (given simultaneously):
| Drug | Role | Mechanism |
|---|---|---|
| Propylthiouracil (PTU) | Block new hormone synthesis + block peripheral T4→T3 conversion | Inhibits TPO + inhibits type 1 deiodinase. PTU preferred over carbimazole in storm because of the dual action |
| Hydrocortisone (100 mg IV Q8H) | Block peripheral T4→T3 conversion; treat potential relative adrenal insufficiency; anti-inflammatory | Glucocorticoids inhibit type 1 deiodinase; accelerated cortisol metabolism in thyrotoxicosis can unmask adrenal insufficiency |
| Propranolol (IV or high-dose oral) | Block β-adrenergic effects; additionally blocks T4→T3 conversion | Directly counters tachycardia, tremor, agitation, and sympathetic storm |
Step 2 — Following regimen (after 1 hour):
| Drug | Role | Mechanism |
|---|---|---|
| Iodide — Lugol's solution, sodium iodide (NaI), or ipodate | Block thyroid hormone release | Acute iodine excess → Wolff-Chaikoff effect → inhibits hormone release AND organification |
Why wait 1 hour? You MUST give PTU first to block organification BEFORE giving iodide. If you give iodide first, the thyroid will use that iodine as substrate to make MORE hormone (Jod-Basedow effect), making the storm worse. PTU blocks the machinery first; then iodide is safe to give as it blocks release.
Alternative agents [2]:
- Diltiazem — if β-blockers are contraindicated (severe asthma, decompensated HF)
- Lithium carbonate (LiCO₃) — if antithyroid drugs are contraindicated (inhibits thyroid hormone release by a different mechanism)
- Plasmapheresis and charcoal haemoperfusion — in desperate cases [2] (physically removes circulating thyroid hormone from blood)
- Cholestyramine — binds thyroid hormone in gut, interrupts enterohepatic recirculation
Thyroid Storm Treatment Order Mnemonic
"P-P-H → then I": PTU + Propranolol + Hydrocortisone → then Iodide (1 hour later). The order matters! Never give iodide before PTU.
After any definitive treatment, patients require long-term follow-up:
- After ATDs: Monitor TFTs every 4–6 weeks during treatment (use fT4/fT3, NOT TSH initially). After discontinuation, monitor for relapse (TFTs every 3 months for the first year, then annually).
- After RAI: TFTs every 4–6 weeks. Most patients develop hypothyroidism — start levothyroxine when TSH rises. Lifelong monitoring because hypothyroidism can develop years later.
- After surgery:
- Monitor calcium post-operatively (risk of hypoPTH)
- Measure serum TSH 6 weeks after hemithyroidectomy to determine need for T4 replacement [7]
- After total thyroidectomy: start levothyroxine replacement immediately (unless RAI ablation needed)
Thyroid Nodule — Surgical Overview [7]
Overview of management by thyroid status and morphology [7]:
| Solitary | Multinodular | |
|---|---|---|
| Euthyroid | Observe; Hemithyroidectomy if 4C | Observe; Total thyroidectomy if 4C |
| Hyperthyroid | Hemithyroidectomy | Total thyroidectomy |
Indications for treatment of benign thyroid nodules [1]:
- Symptomatic (size of goitre/nodule)
- Increase in goitre size
- Trachea compression or deviation
- Retrosternal extension
- Suspected malignancy
- Cosmetic considerations / patient wish [1]
High Yield Summary
Management of Hyperthyroidism — Key Exam Points:
-
Beta-blockers (propranolol) are first-line for symptomatic relief — propranolol is preferred because it additionally blocks peripheral T4→T3 conversion.
-
Three definitive treatments: ATDs (thionamides), RAI (I-131), and surgery. Choice depends on aetiology, patient factors, and 4C indications.
-
Graves' disease: ATDs 1st line (12–18 months); RAI or surgery 2nd line. 70% relapse after ATDs. Surgery preferred if active ophthalmopathy or 4C.
-
Toxic MNG: ATDs ineffective long-term (recur on discontinuation). RAI preferred if no 4C; total thyroidectomy if 4C.
-
Toxic adenoma: Hemithyroidectomy.
-
Pre-op preparation is critical: Carbimazole 8–12 weeks → euthyroid; propranolol (continue until 7 days post-op); Lugol's iodine 10 days pre-op; monitor Ca/vitamin D; laryngoscopy.
-
Thyroid storm: PTU + propranolol + hydrocortisone → then iodide AFTER 1 hour. Never give iodide before PTU. Paracetamol (NOT salicylate) for fever.
-
4C indications for surgery: Cancer, Cannot control (uncontrolled thyrotoxicosis), Compression, Cosmetic.
-
RAI contraindications: Pregnancy, lactation, children/adolescents, active Graves' ophthalmopathy.
-
Post-RAI: Most patients develop hypothyroidism (10–15% in first 2 years, 3%/year after). Lifelong monitoring required.
Active Recall - Management of Hyperthyroidism
References
[1] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf (p14, p15, p18) [2] Senior notes: felixlai.md (Section VI: Treatment of hyperthyroidism; Section VII: Case study — RAI preparation; thyroid storm management) [3] Lecture slides: Management of differentiated thyroid carcinoma.pdf (p7, p8, p16, p17) [7] Senior notes: maxim.md (Thyrotoxicosis management, pre-op preparation, extent of resection, 4C indications, overview of management table)
Complications of hyperthyroidism fall into two broad categories: (A) complications of the disease itself (untreated or poorly controlled thyrotoxicosis), and (B) complications of treatment (antithyroid drugs, radioactive iodine, surgery). Both are equally important for exams and clinical practice.
A. Complications of Untreated / Poorly Controlled Hyperthyroidism
1. Cardiovascular Complications
The heart is the organ most vulnerable to thyroid hormone excess. This makes sense from first principles: T3 upregulates β1-adrenergic receptors on cardiomyocytes, increases heart rate, increases contractility, and decreases systemic vascular resistance. Over time, this sustained hyperdynamic state exhausts the myocardium.
- Occurs in 10–15% of thyrotoxic patients; much higher (~25–30%) in the elderly.
- Why? T3 increases atrial ectopic activity and shortens the atrial refractory period → promotes re-entrant circuits → AF. The atrial myocytes are particularly sensitive to thyroid hormone.
- Clinical significance: AF in thyrotoxicosis carries a thromboembolic stroke risk — anticoagulation should be considered (CHA₂DS₂-VASc scoring still applies).
- Key point: AF may be the presenting feature of hyperthyroidism, especially in the elderly ("apathetic thyrotoxicosis"). Always check TFTs in new-onset AF.
- AF often reverts to sinus rhythm spontaneously once euthyroidism is restored (within weeks to months). If it doesn't revert within 4–6 months of euthyroidism, consider cardioversion.
- Deterioration of CVS disease by thyrotoxicosis — increased workload of the heart and worsens ischaemic symptoms — angina, arrhythmias, cardiac failure [2].
- Mechanism: Chronic ↑ cardiac output (↑ HR × ↑ stroke volume) + ↓ SVR → initially compensated → eventually myocardial exhaustion + direct T3-mediated cardiomyocyte apoptosis + tachycardia-mediated cardiomyopathy → decompensated biventricular heart failure.
- Presents with dyspnoea, peripheral oedema, elevated JVP, hepatomegaly.
- Particularly dangerous in patients with pre-existing ischaemic heart disease — the increased myocardial oxygen demand can precipitate angina or myocardial infarction.
- A form of dilated cardiomyopathy caused by prolonged thyrotoxicosis.
- Potentially reversible if thyrotoxicosis is treated early.
- If not treated, progresses to irreversible fibrosis and permanent heart failure.
Thyroid storm develops in patients with longstanding untreated hyperthyroidism which is precipitated by an acute event such as surgery, trauma, or infection [2].
- Pathophysiology: Rapid increase in serum thyroid hormone levels → increased response to sympathetic inputs from catecholamines (adrenaline/noradrenaline) by permissive effect → cardiovascular symptoms including hyperpyrexia, tachycardia, hypertension, followed by heart failure with hypotension and arrhythmia [2].
- Mortality: 10–30% even with treatment. This is a true endocrine emergency.
- Common precipitants: Thyroid/non-thyroid surgery, infection, trauma, iodine contrast, RAI therapy, non-compliance with ATDs, DKA, labour/delivery.
- Clinical features: Fever > 40°C, severe tachycardia (often > 140 bpm), agitation/delirium/psychosis, seizures, nausea/vomiting/diarrhoea, jaundice (hepatic dysfunction), and eventually cardiovascular collapse.
The management of thyroid storm was covered in detail in the Management section: PTU + Propranolol + Hydrocortisone → then Iodide after 1 hour. Paracetamol (NOT salicylate) for hyperpyrexia [2].
- Mechanism: T3 stimulates both osteoblasts and osteoclasts, but the net effect is increased bone resorption (osteoclastic activity predominates). This leads to negative calcium balance, reduced bone mineral density, and osteoporosis.
- Particularly concerning in postmenopausal women and in subclinical hyperthyroidism (even mildly suppressed TSH increases fracture risk).
- Can present with mild hypercalcaemia (from bone resorption) and hypercalciuria.
- Prevention: Treat the underlying thyrotoxicosis; DEXA scan for patients at risk; calcium/vitamin D supplementation.
- Predominantly affects Asian males (very HK-relevant).
- Mechanism: T3 upregulates Na⁺/K⁺-ATPase → drives K⁺ intracellularly → acute hypokalaemia → muscle membrane hyperpolarisation → flaccid paralysis.
- Triggered by carbohydrate-rich meals (insulin surge further drives K⁺ into cells), exercise, stress, alcohol.
- Presents as sudden-onset bilateral lower limb weakness progressing to all four limbs. Reflexes reduced/absent. Respiratory muscles usually spared.
- ECG: U waves, prolonged QT, flattened T waves (hypokalaemia).
- Treatment: Cautious K⁺ replacement (risk of rebound hyperkalaemia as K⁺ shifts back out once thyrotoxicosis is treated); non-selective beta-blockers (propranolol — reduces Na⁺/K⁺-ATPase activity); definitive treatment of hyperthyroidism.
- Resolves completely once euthyroidism is achieved. Does not recur once thyrotoxicosis is controlled.
Graves' ophthalmopathy is graded by the NO SPECS scoring system [2]:
| Grade | Category | Features | Pathophysiological Basis |
|---|---|---|---|
| 0 | No signs and symptoms | — | — |
| 1 | Only signs, no symptoms | Lid retraction and lid lag | Result of excess sympathetic activity — not specific to Graves' [2]; sustained contraction of Müller's muscle |
| 2 | Soft tissue involvement | Periorbital oedema | T-cells and autoantibodies reactive to extraocular muscles and retro-orbital tissues → inflammation → deposition of collagen and glycosaminoglycan in muscles → swelling [2] |
| 3 | Proptosis | Exophthalmos | Expansion of retro-orbital fat and muscle → pushes globe forward. Best detected by visualising sclera between lower border of iris and lower eyelid [2] |
| 4 | Extraocular muscle involvement | Diplopia / Ophthalmoplegia | Fibrotic, swollen muscles become restrictive. Inferior rectus affected first, then goes anticlockwise (IR → MR → SR → LR) [2] |
| 5 | Corneal involvement | Corneal ulceration, scleral injection, chemosis, conjunctivitis | Incomplete lid closure from proptosis → exposure keratopathy → corneal drying and ulceration |
| 6 | Sight loss | Papilloedema, peripheral field defects, blindness | Compression of CN II at the orbital apex by swollen muscles [2] |
Risk factors for Graves' ophthalmopathy [2]:
- Smoking (single most important modifiable risk factor)
- High anti-TSH (TRAb) level [2]
- RAI therapy (can worsen eye disease — mitigate with steroid cover)
- Unstable thyroid status (both hyper- and hypothyroidism can worsen eyes)
Management of ophthalmopathy:
- Mild/inactive: Lubricating eye drops, sunglasses, head elevation at night, smoking cessation.
- Moderate-to-severe/active (high CAS score): IV methylprednisolone pulse therapy (first-line), orbital radiotherapy, or teprotumumab (anti-IGF-1R monoclonal antibody — newer agent, increasingly used).
- Sight-threatening (optic neuropathy): Emergency — urgent IV methylprednisolone; if no response → orbital decompression surgery.
- Rehabilitative (stable, inactive disease): Orbital decompression surgery (for proptosis), strabismus surgery (for diplopia), eyelid surgery (for retraction).
- Occurs in < 5% of Graves' patients. Almost always associated with ophthalmopathy.
- Raised, non-pitting, waxy "peau d'orange" plaques over pretibial area.
- Mechanism: TRAb stimulates fibroblasts expressing TSH receptors in the skin → glycosaminoglycan deposition.
- Usually mild and self-limiting. Treatment: topical corticosteroids under occlusive dressing.
- Rarest manifestation (< 1%).
- Clubbing of fingers and toes + periosteal new bone formation (resembles hypertrophic pulmonary osteoarthropathy).
- Almost always seen with ophthalmopathy AND dermopathy.
- No specific treatment; improves with control of thyrotoxicosis.
- Anxiety, emotional lability, insomnia, difficulty concentrating.
- In severe cases: thyrotoxic psychosis — paranoia, hallucinations, agitation.
- Reversible with treatment of underlying thyrotoxicosis.
- Women: Oligomenorrhoea, amenorrhoea, subfertility, increased miscarriage risk. In pregnancy: pre-eclampsia, preterm delivery, low birth weight, neonatal thyrotoxicosis (if TRAb crosses placenta).
- Men: Gynecomastia (↑ SHBG → relative estrogen excess), erectile dysfunction, reduced libido, oligospermia.
- Thyrotoxicosis can cause deranged LFTs: elevated ALP (from bone), mildly elevated transaminases (direct T3 effect on hepatocytes or hepatic congestion from high-output HF).
- In severe thyrotoxicosis / thyroid storm: hepatocellular injury, jaundice — an ominous prognostic sign.
B. Complications of Treatment
| Complication | Frequency | Mechanism / Details | Management |
|---|---|---|---|
| Skin rash / urticaria / pruritus | ~5% | Allergic reaction — triggers histamine release [2] | Treated by antihistamine [2]. If mild, may continue ATD with antihistamine cover. If severe, switch drug or consider alternative treatment |
| Fever | Uncommon | Drug hypersensitivity | Differentiate from agranulocytosis-related fever — check FBC urgently |
| Arthritis / arthralgia | Uncommon | Immune-mediated | Switch to alternative ATD or definitive treatment |
| Agranulocytosis | 0.1–0.5% | Occurs within the first 2–3 months of treatment [2]. Idiosyncratic (PTU) or dose-related (methimazole/carbimazole at high doses). Immune-mediated destruction of neutrophil precursors | STOP drug immediately. Urgent FBC. Broad-spectrum antibiotics if febrile. G-CSF may be used. Never rechallenge with the same drug. ~50% cross-react with the other thionamide — safest to switch to RAI or surgery |
| Hepatotoxicity | Rare | PTU: hepatocellular necrosis (can be fulminant liver failure — this is why PTU is reserved for 1st trimester only). Carbimazole/methimazole: cholestatic pattern (usually milder and reversible) | Stop drug. Supportive. LFT monitoring. Consider RAI or surgery |
| ANCA-positive vasculitis | Very rare | Mostly with PTU — anti-MPO antibodies | Stop PTU permanently |
Patient Education Point
Every patient started on thionamides MUST be educated: "If you develop a sore throat, fever, or mouth ulcers, STOP the medication immediately and go to A&E for an urgent blood test." Agranulocytosis can be fatal if not recognised early (severe sepsis in a neutropenic patient). This is a common exam question — "What would you counsel a patient starting carbimazole?"
| Complication | Frequency | Mechanism / Details |
|---|---|---|
| Hypothyroidism | Very common | Transient: 3.5–28%. Permanent: 10–15% in the first 2 years, then 3% per year [2]. Due to late effects of radiation and lymphocytic infiltration and destruction of thyroid tissue [2]. Requires lifelong T4 replacement [2] |
| Radiation thyroiditis | ~10% | Transient inflammation 1–2 weeks post-RAI → release of stored hormone → temporary worsening of thyrotoxicosis. Self-limiting. Manage with beta-blockers, NSAIDs |
| Worsening Graves' ophthalmopathy | Moderate risk | Release of thyroid antigens → immune flare → orbital inflammation. Mitigate with steroid prophylaxis (especially if eye disease is active/moderate) |
| Sialadenitis (salivary gland inflammation) | ~10–30% | Salivary glands also express NIS → take up I-131 → radiation damage → pain, swelling, dry mouth. Sour candy/lemon juice stimulates salivary flow to help clear isotope |
| Transient neck pain/swelling | Common | Local radiation effect on thyroid. Self-limiting |
| Theoretical concerns | Very rare | NO effect on fertility. NO effect on congenital malformations. NO increased cancer risk of offspring [2]. However, contraception required for ≥ 6 months post-RAI |
3. Complications of Thyroidectomy [2][7]
This is one of the highest-yield topics for surgical examinations. Complications are classified by timing:
| Complication | Mechanism | Clinical Features | Management |
|---|---|---|---|
| Intraoperative bleeding | Thyroid is one of the most vascular organs per gram of tissue. Branches of superior and inferior thyroid arteries at risk | Bleeding obscures surgical field | Meticulous haemostasis, bipolar diathermy, vessel ligation. Pre-op Lugol's iodine reduces vascularity |
| Recurrent laryngeal nerve (RLN) injury | RLN supplies all intrinsic muscles of the larynx except cricothyroid [2]. At risk during ligation of inferior thyroid artery or dissection near Berry's ligament | Ipsilateral RLN injury → unilateral vocal cord palsy → hoarseness and ineffective cough. Bilateral RLN injury → bilateral vocal cord palsy → stridor and dyspnoea (airway obstruction) [2]. 6 adductors > 2 abductors → cords tend to adduct → airway obstruction [7] | Pre-op laryngoscopy to document baseline. Intraoperative nerve monitoring. If bilateral injury: may need emergency intubation or tracheostomy. Management of unilateral injury: cord medialisation procedures — e.g., injection thyroplasty, open thyroplasty (Gore-Tex) [7] |
| Superior laryngeal nerve (external branch) injury | SLN supplies the cricothyroid muscle which lengthens (tenses) the vocal cord to produce high-pitched sound [2] | Vocal fatigue, changes in voice quality, loss of high pitch, poor volume, easy fatigue [2][7] | Careful identification of SLN during superior pole dissection. Close to the superior thyroid artery — ligate artery close to gland capsule |
| Oesophageal injury | Direct surgical trauma | Dysphagia, mediastinitis (if missed) | Intraoperative recognition and primary repair |
| Tracheal injury | Direct surgical trauma | Subcutaneous emphysema, pneumomediastinum | Primary repair, consider tracheostomy |
| Tracheomalacia | Floppy tracheal wall due to chronic compression by large goitre [7]. Tracheal cartilage rings become softened | Post-extubation stridor and respiratory distress as the trachea collapses without the external splinting effect of the goitre | Anticipate in large/longstanding goitres. May need prolonged intubation or tracheostomy |
| Thyroid storm | Manipulation of gland during surgery → massive hormone release | Hyperpyrexia, tachycardia, hypertension → cardiovascular collapse | Patients should be brought to euthyroid before surgery [2]. If storm occurs intraoperatively: aggressive medical treatment (PTU + propranolol + hydrocortisone + cooling) |
| Complication | Mechanism | Clinical Features | Management |
|---|---|---|---|
| Haematoma formation | Post-operative reactionary or secondary haemorrhage from thyroid bed vessels | Potentially fatal if compression on airways [2]. Neck swelling, increasing pain, respiratory distress, stridor. Haemorrhage — compression and oedematous effect compresses on trachea [2] | This is a surgical EMERGENCY. Open the wound at the bedside immediately — remove skin sutures/clips, evacuate haematoma to relieve tracheal compression. Then return to theatre for formal exploration and haemostasis. Removal of stitches and allow drainage of blood [2] |
| Wound infection | Bacterial contamination | Erythema, swelling, discharge, fever | Wound infection is NOT a recognised complication in most series (clean surgical field) [7]. If occurs: antibiotics, wound care |
Post-Thyroidectomy Neck Haematoma — The Bedside Emergency
A patient returning from thyroidectomy who develops neck swelling + respiratory distress requires immediate bedside wound opening — do NOT wait for the operating theatre. The expanding haematoma compresses the trachea and can cause fatal airway obstruction within minutes. The clinical sequence: increasing neck swelling → dyspnoea → stridor → respiratory arrest. Every surgical team on a thyroid ward must have stitch cutters at the bedside.
| Complication | Mechanism | Clinical Features | Management |
|---|---|---|---|
| Hypoparathyroidism → Hypocalcaemia | MOST common complication [2][7]. Inadvertent removal, devascularisation, or bruising of parathyroid glands → ↓ PTH → ↓ serum calcium. Only occurs in total thyroidectomy [7] (bilateral risk). Usually transient [7] — most recover within weeks to months as residual parathyroid tissue recovers | Perioral numbness, carpopedal spasm, Chvostek's sign (facial nerve tapping → facial muscle twitch), Trousseau's sign (BP cuff inflation → carpopedal spasm) [2][7]. Severe hypocalcaemia can lead to laryngospasm requiring emergency intubation / surgical airway [7] | Check serum corrected Ca²⁺ or PTH level post-operatively [2]. Acute symptomatic: IV 10–20 mL of 10% calcium gluconate over 10 mins (slow bolus) [2]. Maintenance: Calcium carbonate + Calcitriol (Vitamin D) [2][7] |
| Hungry bone syndrome | Severe and prolonged hypocalcaemia despite normal or even elevated PTH [2]. Occurs particularly after surgery for thyrotoxicosis (or hyperparathyroidism). Sudden removal of effect of high circulating levels of PTH/T3 → increased influx of calcium into bones [2]. The demineralised skeleton acts as a "calcium sponge." Associated with hypophosphataemia and hypomagnesaemia [2] | Severe, refractory hypocalcaemia not responsive to standard calcium replacement alone | Aggressive IV and oral calcium + calcitriol + magnesium replacement. May take days to weeks to stabilise |
| Hypothyroidism | Loss of functioning thyroid tissue | Fatigue, weight gain, cold intolerance, constipation. Around 10–20% chance of hypothyroidism after hemithyroidectomy [1]. 100% after total thyroidectomy | Levothyroxine replacement. Measure TSH at 6 weeks post-hemithyroidectomy to assess need |
| Recurrence (of goitre/thyrotoxicosis) | Residual thyroid tissue. Only if subtotal thyroidectomy or hemithyroidectomy was performed. Does not occur after total thyroidectomy | Return of thyrotoxic symptoms, palpable goitre | Re-operation (technically more difficult due to scarring) or RAI |
| Hypertrophic scar / keloid formation | Individual predisposition (more common in Asian skin) | Raised, thickened scar across the neck (Kocher's incision) | Silicone gel sheets, steroid injection, laser therapy |
Post-operative dyspnoea — Differential Diagnosis [7]:
This is a critical clinical scenario. A patient develops respiratory distress after thyroidectomy — think systematically:
| Cause | Mechanism | Key Features |
|---|---|---|
| Haematoma | Bleeding → tracheal compression + laryngeal oedema | Neck swelling, hypovolaemic shock signs. OPEN WOUND AT BEDSIDE |
| Bilateral RLN irritation/injury | Both vocal cords paralysed in adducted position → airway obstruction | Stridor. May need emergency intubation/tracheostomy |
| Laryngospasm from hypocalcaemia | Acute hypocalcaemia → neuromuscular hyperexcitability → laryngeal muscle spasm | Check calcium. IV calcium gluconate urgently. May need intubation |
| Tracheal injury / pneumothorax | Direct surgical trauma | Subcutaneous emphysema, respiratory distress |
| Tracheomalacia | Floppy tracheal wall due to chronic compression [7] | Post-extubation stridor. Trachea collapses without goitre "splinting" |
C. Complications of Specific Aetiologies
| Complication | Details |
|---|---|
| Graves' ophthalmopathy | Ranges from lid retraction to sight-threatening optic neuropathy (see NO SPECS above) |
| Graves' dermopathy | Pretibial myxoedema — cosmetic, rarely disabling |
| Thyroid acropachy | Clubbing + periosteal new bone — rarest, no specific treatment |
| Neonatal Graves' disease | TRAb (IgG) crosses placenta → stimulates fetal thyroid → neonatal thyrotoxicosis. More likely if maternal TRAb is high in 3rd trimester. Self-limiting (weeks) as maternal antibodies are cleared |
| Complication | Details |
|---|---|
| Retrosternal extension | Large goitres can extend behind the sternum → compress trachea, oesophagus, SVC (SVC obstruction → facial plethora, raised JVP with arms raised = Pemberton's sign) |
| Malignant transformation | Cold nodules within a MNG carry 10–20% malignancy risk. Important to perform FNAC on suspicious/dominant nodules |
| Jod-Basedow phenomenon | Iodine exposure (contrast, amiodarone) can trigger acute thyrotoxicosis in patients with autonomous nodules |
| Complication | Aetiology/Context | Pathophysiology | Reversible? |
|---|---|---|---|
| AF | Any thyrotoxicosis, especially elderly | ↑ Atrial ectopic activity + shortened refractory period | Often reverts with euthyroidism |
| Heart failure | Prolonged thyrotoxicosis | Chronic ↑ cardiac work → myocardial exhaustion + direct T3 toxicity | Early: reversible. Late: irreversible fibrosis |
| Osteoporosis | Prolonged thyrotoxicosis or subclinical disease | ↑ Osteoclastic bone resorption | Partially reversible with treatment |
| Thyroid storm | Precipitated event in untreated patient | Massive catecholamine sensitisation | Medical emergency; potentially fatal (10–30%) |
| Thyrotoxic periodic paralysis | Asian males with thyrotoxicosis | T3-driven intracellular K⁺ shift | Fully reversible once euthyroid |
| Ophthalmopathy | Graves' only | TRAb cross-reactivity in orbit | Variable; may progress independently of thyroid status |
| Agranulocytosis | Thionamide treatment | Immune-mediated neutrophil destruction | Reversible if caught early; potentially fatal if missed |
| Hypothyroidism post-RAI | RAI treatment | Radiation destruction of thyroid tissue | Irreversible — lifelong T4 replacement |
| Hypoparathyroidism | Thyroidectomy | Parathyroid removal/devascularisation | Usually transient; permanent in ~1–2% |
| RLN injury | Thyroidectomy | Surgical damage to nerve | Temporary neuropraxia recovers; transection may be permanent |
High Yield Summary
Complications of Hyperthyroidism — Key Exam Points:
-
AF is the most common cardiac complication (~10–15%). Always check TFTs in new AF. Often reverts with treatment.
-
Thyroid storm is a medical emergency with 10–30% mortality. Precipitated by surgery/infection/trauma in untreated patients. Treatment: PTU + propranolol + hydrocortisone → iodide after 1 hour. Paracetamol (NOT aspirin) for fever.
-
Thyrotoxic periodic paralysis — think young Asian male with acute hypokalaemic paralysis. Fully reversible once euthyroid.
-
Hypoparathyroidism is the MOST common complication of thyroidectomy — usually transient. Check calcium post-op. Treat with IV calcium gluconate acutely; oral calcium + calcitriol for maintenance.
-
Post-thyroidectomy neck haematoma is a life-threatening emergency — open the wound at the bedside immediately before theatre.
-
Post-op dyspnoea DDx: haematoma, bilateral RLN injury, laryngospasm (hypocalcaemia), tracheal injury, tracheomalacia.
-
RLN injury: unilateral → hoarseness; bilateral → airway obstruction (stridor). SLN injury → vocal fatigue, loss of high pitch.
-
Agranulocytosis from thionamides: occurs in first 2–3 months. Educate patients to stop drug and seek urgent FBC if sore throat/fever develops.
-
Graves' ophthalmopathy: NO SPECS grading. Sight loss (Grade 6) from optic nerve compression is an emergency requiring IV steroids ± orbital decompression.
-
Hungry bone syndrome: severe hypocalcaemia DESPITE normal/high PTH. Skeleton acts as "calcium sponge" after removal of chronic thyrotoxic/hyperparathyroid stimulation.
Active Recall - Complications of Hyperthyroidism
[1] Lecture slides: GC 177. A thyroid nodule benign thyroid nodules; thyroid cancer.pdf (p15, p17) [2] Senior notes: felixlai.md (Section IV: Clinical manifestation — Graves' ophthalmopathy NO SPECS; Section VI: Treatment complications; Section V: Thyroidectomy complications; Thyroid storm management; RAI side effects) [7] Senior notes: maxim.md (Thyroidectomy complications, post-op dyspnoea DDx, RLN injury management, parathyroid injury, pre-op preparation, extent of resection)
High Yield Summary
Key Concepts for Exams:
-
Thyrotoxicosis ≠ hyperthyroidism — thyrotoxicosis is the syndrome of hormone excess; hyperthyroidism specifically means the gland is overactive.
-
Graves' disease is the most common cause of hyperthyroidism in iodine-sufficient regions (including HK). It is autoimmune, mediated by TRAb stimulating the TSH receptor.
-
The triad unique to Graves': ophthalmopathy, dermopathy (pretibial myxoedema), acropachy. These are TRAb-mediated, NOT from thyroid hormone excess per se.
-
RAIU scan is the key investigation to distinguish causes: HIGH uptake = hyperthyroidism (Graves'/TMNG/toxic adenoma); LOW uptake = thyrotoxicosis without hyperthyroidism (thyroiditis/exogenous).
-
Clinical features are driven by ↑ BMR and ↑ catecholamine sensitivity (β-adrenergic upregulation) — this explains why beta-blockers are the first-line symptomatic treatment.
-
Thyrotoxic periodic paralysis — think Asian males, acute hypokalaemic paralysis, check TFTs!
-
AF in the elderly — always check TFTs. Apathetic thyrotoxicosis may present without classic sympathetic features.
-
Thyroid moves with swallowing — key sign to identify a thyroid mass.
-
Lid retraction/lid lag = sympathetic (any thyrotoxicosis). Proptosis/ophthalmoplegia = Graves' only (autoimmune).
-
High iodine intake (HK-relevant) can precipitate hyperthyroidism in patients with autonomous nodules (Jod-Basedow phenomenon).
High Yield Summary
Differential Diagnosis of Thyrotoxicosis — Key Exam Points:
-
First confirm thyrotoxicosis biochemically (suppressed TSH, elevated fT4 ± fT3). Then determine the CAUSE.
-
The pivotal investigation is RAIU scan — separates HIGH uptake (true hyperthyroidism: Graves'/TMNG/toxic adenoma) from LOW uptake (thyroiditis/exogenous/factitious).
-
Graves' is distinguished by: diffuse goitre + bruit, ophthalmopathy, positive TRAb, diffusely increased RAIU.
-
Subacute thyroiditis is distinguished by: PAIN + tenderness, raised ESR, low RAIU, self-limiting triphasic course. ATDs are useless.
-
Factitious thyrotoxicosis has LOW thyroglobulin (all others have normal/high).
-
TSHoma is the ONLY cause where TSH is inappropriately normal/high with elevated fT4.
-
Hot nodules (on scintigraphy) are almost never malignant and do NOT need FNAC. Cold nodules carry 10–20% malignancy risk and require FNAC.
-
hCG can cross-stimulate TSH receptors → gestational thyrotoxicosis (physiological) or paraneoplastic thyrotoxicosis (germ cell tumours).
-
Amiodarone-induced thyrotoxicosis: Type 1 = iodine-induced (thionamides), Type 2 = destructive (steroids). Colour-flow Doppler helps differentiate.
-
On clinical examination, only 3 conclusions: thyroid nodule, multinodular goitre, or diffuse goitre — this guides the DDx pathway.
High Yield Summary
Diagnosis of Hyperthyroidism — Key Exam Points:
-
TSH is the single most sensitive screening test. Suppressed TSH = suspect primary hyperthyroidism. Normal/high TSH with elevated fT4 = TSHoma or resistance.
-
Always measure BOTH fT4 AND fT3 — 2–5% have only elevated fT3 ("T3 thyrotoxicosis").
-
Measure FREE (not total) T4 — total T4 is misleading when binding proteins are altered (pregnancy, OCP, hypoalbuminaemia).
-
Do NOT use TSH to monitor treatment — it remains suppressed for months. Use fT4/fT3 instead.
-
TRAb is 80–90% sensitive for Graves' and is the key serological differentiator.
-
RAIU scan is NOT routine — indicated ONLY when TSH is suppressed AND you need to distinguish the cause (especially Graves' vs TMNG vs toxic adenoma vs thyroiditis).
-
Hot nodules do NOT require FNAC (< 1% malignancy). Cold nodules require FNAC (10–20% malignancy risk).
-
Routine investigations: TFT + USG thyroid ± FNAC. Selective: thyroid scan, CT, PET (PET has NO diagnostic role).
-
Bethesda system: 6 categories. Class IV (follicular neoplasm) requires lobectomy because FNAC cannot distinguish follicular adenoma from carcinoma (needs capsular/vascular invasion on histology).
-
Pre-ATD baseline: Always check CBC (agranulocytosis risk) and LFT (hepatotoxicity risk) before starting thionamides.
High Yield Summary
Management of Hyperthyroidism — Key Exam Points:
-
Beta-blockers (propranolol) are first-line for symptomatic relief — propranolol is preferred because it additionally blocks peripheral T4→T3 conversion.
-
Three definitive treatments: ATDs (thionamides), RAI (I-131), and surgery. Choice depends on aetiology, patient factors, and 4C indications.
-
Graves' disease: ATDs 1st line (12–18 months); RAI or surgery 2nd line. 70% relapse after ATDs. Surgery preferred if active ophthalmopathy or 4C.
-
Toxic MNG: ATDs ineffective long-term (recur on discontinuation). RAI preferred if no 4C; total thyroidectomy if 4C.
-
Toxic adenoma: Hemithyroidectomy.
-
Pre-op preparation is critical: Carbimazole 8–12 weeks → euthyroid; propranolol (continue until 7 days post-op); Lugol's iodine 10 days pre-op; monitor Ca/vitamin D; laryngoscopy.
-
Thyroid storm: PTU + propranolol + hydrocortisone → then iodide AFTER 1 hour. Never give iodide before PTU. Paracetamol (NOT salicylate) for fever.
-
4C indications for surgery: Cancer, Cannot control (uncontrolled thyrotoxicosis), Compression, Cosmetic.
-
RAI contraindications: Pregnancy, lactation, children/adolescents, active Graves' ophthalmopathy.
-
Post-RAI: Most patients develop hypothyroidism (10–15% in first 2 years, 3%/year after). Lifelong monitoring required.
High Yield Summary
Complications of Hyperthyroidism — Key Exam Points:
-
AF is the most common cardiac complication (~10–15%). Always check TFTs in new AF. Often reverts with treatment.
-
Thyroid storm is a medical emergency with 10–30% mortality. Precipitated by surgery/infection/trauma in untreated patients. Treatment: PTU + propranolol + hydrocortisone → iodide after 1 hour. Paracetamol (NOT aspirin) for fever.
-
Thyrotoxic periodic paralysis — think young Asian male with acute hypokalaemic paralysis. Fully reversible once euthyroid.
-
Hypoparathyroidism is the MOST common complication of thyroidectomy — usually transient. Check calcium post-op. Treat with IV calcium gluconate acutely; oral calcium + calcitriol for maintenance.
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Post-thyroidectomy neck haematoma is a life-threatening emergency — open the wound at the bedside immediately before theatre.
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Post-op dyspnoea DDx: haematoma, bilateral RLN injury, laryngospasm (hypocalcaemia), tracheal injury, tracheomalacia.
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RLN injury: unilateral → hoarseness; bilateral → airway obstruction (stridor). SLN injury → vocal fatigue, loss of high pitch.
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Agranulocytosis from thionamides: occurs in first 2–3 months. Educate patients to stop drug and seek urgent FBC if sore throat/fever develops.
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Graves' ophthalmopathy: NO SPECS grading. Sight loss (Grade 6) from optic nerve compression is an emergency requiring IV steroids ± orbital decompression.
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Hungry bone syndrome: severe hypocalcaemia DESPITE normal/high PTH. Skeleton acts as "calcium sponge" after removal of chronic thyrotoxic/hyperparathyroid stimulation.
Hyperparathyrodism
Hyperparathyroidism is a condition characterized by excessive secretion of parathyroid hormone, leading to hypercalcemia, bone resorption, and disturbances in calcium-phosphorus metabolism.
Hypothyroidism
Hypothyroidism is a condition of insufficient thyroid hormone production by the thyroid gland, resulting in decreased metabolic activity and clinical features such as fatigue, weight gain, cold intolerance, and bradycardia.